The Australian Short Course on Intensive Care Medicine

The Australian
Short Course on
Intensive Care
Medicine
2005 Handbook
The Australian
Short Course on
Intensive Care Medicine
2005 Handbook
Editor
L.I.G. Worthley
Published in 2005 by
The Australasian Academy of Critical Care Medicine
“Ulimaroa”
630 St Kilda Rd, Melbourne,
Victoria 3004
ISSN 1327-4759
2005 The Australasian Academy of Critical Care Medicine
Requests to reproduce original material should be addressed to
the publisher.
Printed by Gillingham Printers Pty Ltd
153 Holbrooks Road
Underdale
South Australia 5032
CONTENTS
Page
Chapter 1. Red blood cell production and haemoglobin function
1
Chapter 2. Anaemias and polycythaemias
17
Chapter 3. Haemostasis, platelet function and coagulation
35
Trainee Presentations
65
Index
135
iii
iv
2005 SHORT COURSE PROGRAMME
April 12th
FMC
Travel to
FMC
Interactive
April 13th
RAH
April 14th
RAH
0900
April 11th
FMC
Travel to
FMC
Lecture
Lecture
OSCE
Presentations
Introduction
Vivas
1015
Introduction to the
critically ill patient
L W.
Interactive
L. W
Interactive
R.Y
Clinical cases
OSCE
Biochemistry
ECG’s
Vivas
Vivas
L.W.
Interactive
L.W
Interactive
Clinical Cases
Clinical cases
OSCE
Clinical
Vignettes
L.W.
Biochemistry
Vivas
Vivas
B.V
Lunch
Clinical Cases
Lecture
Interactive
OSCE
Hepatic Failure
Interpretation of
CXR and CT head
C.J
Lecture
Adrenocortical
function in the
critically ill
B.V
Interactive
Vivas
0815
1130
1245
1400
Review
1515
A.H.
Lecture
1630
Acute respiratory
failure syndrome
AB
Lecture
Presentations
1745
L.W
Travel To RAH
FMC = Flinders Medical Centre
Dinner at:
Biochemistry,
bacteriology
C.J.
Travel to RAH
R.Y.
OSCE
Vivas
Dinner
RAH = Royal Adelaide Hospital
19:00 hr, Wednesday 13th April 2005
Old Lion Hotel
161 Melbourne St, Adelaide
v
REGISTRANTS
Code Name
Institution
*† 1. Dr. B. Cheung
Intensive Care Unit, Ipswich Hospital, Queensland
*† 2. Dr. J. Lewis
Intensive Care Unit, Royal Perth Hospital, WA
*† 3. Dr. D. Moxon
Intensive Care Unit, Royal Perth Hospital, WA
*† 4. Dr. M. Ibrahim
Intensive Care Unit, The Austin Hospital, Victoria
*† 5. Dr. M. Reade
Intensive Care Unit, The Austin Hospital, Victoria
*† 6. Dr. T. Corcoran
Intensive Care Unit, Royal Perth Hospital, WA
*† 7. Dr. S. Simpson
Intensive Care Unit, Women’s and Children’s Hospital, SA
*† 8. Dr. T. Fraser
Intensive Care Unit, The Geelong Hospital, Victoria
*† 9. Dr. A. Holley
Intensive Care Unit, Royal Brisbane Hospital, Queensland
*†10. Dr. M. Heaney
Intensive Care Unit, Royal Perth Hospital, WA
*†11. Dr. R. Rai
Intensive Care Unit, Royal Adelaide Hospital, SA
*†12. Dr. M. Sanap
Intensive Care Unit, Flinders Medical Centre, SA
*†13. Dr. P. Rangappa
Intensive Care Unit, Queen Elizabeth Hospital, SA
*†14. Dr. W. M. G. Kwan
Intensive Care Unit, Queen Elizabeth Hospital, Hong Kong
*†15. Dr. H. Ramaswamykanive Intensive Care Unit, Concord Hospital, NSW
†16. Dr. H. Tewari
Intensive Care Unit, Queen Elizabeth Hospital, SA
*‡17. Dr. R. Ramadoss
Department of Critical Care Medicine, FMC, SA
*‡18. Dr. S. Verghese
Department of Critical Care Medicine, FMC, SA
*‡19. Dr. D. Gardiner
ICU, Princess Alexandria Hospital, Queensland
*‡20. Dr. G. Ding
Intensive Care Unit, The Canberra Hospital, ACT
* 21. Dr. J. Bellapart
Intensive Care Unit, Royal Brisbane Hospital, Queensland
* 22. Dr. V. Hamilton
Intensive Care Unit, Royal Adelaide Hospital, SA
* 23. Dr. S. Sane
Department of Critical Care Medicine, FMC, SA
* 24. Dr. M. Davey
Intensive Care Unit, The Canberra Hospital, ACT
* 25. Dr. S. Senthuran
Intensive Care Unit, Royal Brisbane Hospital, Queensland
* 26. Dr. D. Rigg
Intensive Care Unit, The Canberra Hospital, ACT
* 27. Dr. W-P. Chan
Intensive Care Unit, The John Hunter Hospital, NSW
* 28. Dr. A. MacCormick
Intensive Care Unit, Royal Melbourne Hospital, Victoria
* 29. Dr. L. Min
Intensive Care Unit, Flinders Medical Centre, SA
* 30. Dr. W. Newman
Intensive Care Unit, Mackay Base Hospital, Queensland
* 31. Dr. P. Dubey
Intensive Care Unit, Mater Hospital, Queensland
* 32. Dr. A. Enslin
Intensive Care Unit, Canberra Hospital, ACT
FACULTY
FMC
RAH
GUESTS
Dr. L. Worthley (L.W)
Dr. R. Young
(R.Y)
Dr. B. Venkatesh
(J.C)
Dr. A. Bersten (A.B)
Dr. M. White
(M.W)
Dr. P. Morley
(P.M)
Dr. A. Holt
(A.H)
Dr. N. Edwards
(N.E)
Dr. C. Joyce
(C.J)
Dr. M. Chapman
(M.C)
Dr. J. Morgan
(J.M)
ACH
Dr. P. Sharley
(P.S)
Dr. N. Matthews (N.M)
Dr. D. Evans
(D.E)
Dr. S. Keeley
(S.K)
Dr. A. Flabouris
(A.F)
Dr. A. Slater
(A.S)
Dr. T. Brownridge (D.C)
Dr. S. Peake
(S.P)
*† = registrants for both sessions
* = registrants for Interactive sessions at the FMC
† = active registrants for Exam oriented sessions at the RAH
‡ = observer registrants for Exam oriented sessions at the RAH
vi
PREFACE
A working knowledge of the basic sciences of anatomy, physiology and pharmacology is the
basis for the understanding and management of the critically ill patient. This year the Australian
Short Course on Intensive Care Medicine handbook has included a review of the basic sciences
of the haemopoietic system with chapters on red blood cell production, haemoglobin function,
anaemias and polycythaemias. I have also included a chapter on haemostasis, platelet function
and coagulation. As with the previous editions, the course registrants presentations (or those
that have been submitted on time) have also been included.
This handbook still remains the working document of the Australian Short Course on
Intensive Care Medicine and is designed to supplement the course. During the sessions, you
may find it useful to mark and note the text to facilitate your recall and review of the course at a
later date. Along with the previous editions I trust that you will also find this edition useful.
Dr. L.I.G. Worthley
Adelaide, April 2005
vii
viii
Chapter 1
RED BLOOD CELL PRODUCTION and
HAEMOGLOBIN FUNCTION
RED BLOOD CELL PRODUCTION
The red blood cell (RBC) is derived from a bone marrow pluripotent stem cell which has a
morphological characteristic of a lymphocyte and is capable of both self-renewal and
differentiation to form RBCs, granulocytes, monocytes or platelets. It is a committed erythroid
cell when it becomes a proerythroblast. Normally the transition from the proerythroblast to the
most mature normoblast involves three or four cell divisions over a 4 day period. During this
time, the nucleus becomes smaller and an increasing amount of haemoglobin is produced in the
cytoplasm. With the last division, the nucleus is removed from the normoblast forming the
reticulocyte, which stays in the bone marrow for 2.5 - 3.0 days. The reticulocyte is then
released into the circulation, where it circulates for 24 hr before it loses its mitochondria and
ribosomes and assumes the morphological appearance of a mature RBC.
Erythropoietin is a glycoprotein with a molecular weight of 30,000 – 36,000, the majority of
which is produced by the kidney in response to hypoxia (10 - 15% is produced in the liver).1 It
interacts with receptors on the surface of proerythroblasts, inducing them to differentiate into
pronormoblasts. The hormone also acts on later red cell precursors, stimulating haemoglobin
synthesis. Red cell mass is regulated by renal erythropoietin secretion which is in turn regulated
by tissue hypoxia.
The RBC is 7.5 µm in diameter and 2 µm thick and each contains about 29 pg of
haemoglobin. There is, on average, about 3 x 1013 RBCs and about 900 g of haemoglobin in the
circulating blood in an adult man, with about 7.5 g of haemoglobin destroyed and produced
daily (one unit of blood contains about 75 g of haemoglobin). The RBC survives in the
circulation for an average of 120 days.
HAEMOGLOBIN BIOSYNTHESIS
Haemoglobin is a protein with an anhydrous molecular weight of 64,458. It is a tetramer
composed of two pairs of four possible polypeptide chains designated alpha, beta, gamma and
delta, each of which are covalently linked to a haem group. Each chain harbours one haem
(consisting of protoporphyrin IX and Fe2+), and each haem molecule may bind reversibly to a
molecule of oxygen, with the affinity for oxygen increasing as each haem moiety takes up
oxygen. In the RBCs of normal adults, 97% of the haemoglobin is haemoglobin A (or HbA,
which consists of two alpha chains of 141 amino acid residues and two beta chains of 146
amino acid residues i.e. alpha2, beta2), the remaining 3% is mainly haemoglobin A2 (HbA2;
alpha2, delta2) . Fetal haemoglobin (HbF; alpha2, gamma2) usually accounts for less than 1% of
the haemoglobin in the normal adult RBC.
Disorders of haemoglobin biosynthesis
In disorders of haemoglobin biosynthesis, the production of haemoglobin may be affected
in one of three ways:
1
RBC Production and Haemoglobin Function
1.
2.
3.
Decreased production of a normal chain (i.e. thalassaemias): these disorders have a
recessive inheritance and therefore occur as homozygote (i.e. major) or heterozygote (i.e.
minor) forms:
a) Alpha thalassaemia is caused by depressed alpha-chain production.
b) Beta thalassaemia is caused by depressed beta-chain production, causing an increase
in HbF and HbA2 levels. This is the commonest form of thalassaemia. The
homozygous form presents as a severe anaemia early in life with hepatosplenomegaly, cardiomyopathy, leg ulcers, gall stones, transfusion haemosiderosis,
and expansion of bone marrow to give high cheek bones and enlargement of necks
of ribs on the chest X-ray. The heterozygous form may be asymptomatic (i.e.
thalassaemia minima) or present with mild anaemia (i.e. thalassaemia minor).
Treatment is often with regular blood transfusions or the judicious use of splenectomy and iron chelation therapy;2 although bone marrow transplantation3 and fetal
globin synthesis stimulation using azacitidine4 have been used with some success.
Production of an abnormal chain (e.g. sickle cell anaemia): this is caused by the
substitution of one of the amino acids in the polypeptide chains (e.g. HbS in sickle cell
anaemia). In sickle cell anaemia HbS precipitates at low oxygen tensions, causing the cells
to sickle and to lead to stasis in small vessels with subsequent microinfarction. Haemolytic
crises may be precipitated by infection, exertion or anoxia. The homozygous state is
associated with HbS levels of 76 - 100%. The heterozygous state is associated with HbS
levels of 22 - 45%, and is asymptomatic although under severe stress some sickling may
occur.
Persistence of the developmental chain (i.e., fetal haemoglobin)
HAEM BIOSYNTHESIS
Within the hepatic cell and precursor RBC mitochondria, glycine and succinyl CoA, in the
presence of aminolaevulinic acid (ALA) synthase, form alpha-amino-beta-keto-adipic acid.
This, in the presence of pyridoxal phosphate, is decarboxylated by the enzyme ALA-synthase
(which is under negative feedback by haem) to form delta-ALA. Increased demands for haem
are met by increased synthesis of hepatic ALA-synthase. This enzyme may be induced by a
large number of drugs that are substrates and inducers of cytochrome P450. During the process
of drug metabolism, consumption of haem by cytochrome P450 is greatly increased, which in
turn greatly reduces intracellular haem concentration and its effect on ALA synthase, increasing
haem synthesis.
In the cytosol, the delta-ALA is acted upon by ALA-dehydratase (a zinc-containing enzyme
which is inhibited by lead) to form porphobilinogen (PBG). This is acted on by PBGdeaminase to form hydroxymethylbilane which is the precursor of porphyrins. Porphyrins are
tetrapyrrole pigments that serve as intermediates in haem biosynthesis (Figure 1.1). Haem is
required for haemoglobin, myoglobin and some respiratory enzymes. The synthesis of haem in
red cell precursors is closely linked to haemoglobin synthesis.
Disorders of haem biosynthesis
The porphyrias
The porphyrias are a group of disorders characterised by an inherited or acquired enzymatic
block in the biosynthesis of the porphyrins (Table 1.1),5 leading to an overproduction of
porphyrins and/or their precursors. They are classified as either hepatic or erythropoietic,
depending upon whether the defect in porphyrin metabolism is in the liver (without affecting
haemoglobin formation) or the bone marrow. Protoporphyria has abnormalities in porphyrin
2
RBC Production and Haemoglobin Function
metabolism in both the liver and the bone marrow, therefore it is often classified as an
erythrohepatic porphyria. Congenital erythropoietic porphyria has an autosomal recessive
inheritance, the remainder are inherited by an autosomal dominance and have a variable clinical
expression. Porphyria cutanea tarda is an acquired disorder which is associated with alcoholic
cirrhosis, hepatic tumours or exposure to polychlorinated hydrocarbons.
Figure 1.1 The biosynthetic pathway of haem
ALA
ALA
PBG
Uro P'gen
Uro P'gen
Synthase dehydratase
deaminase
cosynthase
decarboxylase
Glycine
(IAP)
(EPP)
(PCT)
+
ALA
PBG → Hydroxy → Uro P'gen III → Copro P'gen III
Succinyl CoA
(EPP) methylbilane
↓
Coproporphyrinogen
Uroporphyrin I ← Uro P'gen I
oxidase (HCP)
↓
Coproporphyrin I ← Copro P'gen I
Protoporphyrinogen IX
Protoporphyrinogen (VP)
oxidase
Ferrochelatase
Haem ←
(EHP)
Protoporphyrin IX
ALA = delta aminolaevulinic acid, PBG = porphobilinogen. The enzyme defects of the porphyrias are bracketed (IAP =
Intermittent acute porphyria, EPP = erythropoietic porphyria, PCT = porphyria cutanea tarda, HCP = Hereditary
coproporphyria, VP = variegate porphyria, EHP = erythrohepatic protoporphyria)
Clinical features. These usually relate to either skin or neurological abnormalities. The
hepatic porphyrias are commonly characterised by the four 'P's' (i.e. abdominal pain, peripheral
neuritis, psychosis and purple or ‘port wine’ coloured urine).
1.
2.
Skin lesions: congenital erythropoietic porphyria, protoporphyria and porphyria cutanea
tarda predominantly have skin lesions with sensitivity of the skin to sunlight with
blistering and excessive fragility to mechanical trauma and scarring. If severe, dermal
features not unlike scleroderma appear. The skin lesions may also be associated with
hirsutism and hyperpigmentation, particularly of the face and hands. Congenital
erythropoietic porphyria is also associated with a haemolytic anaemia, splenomegaly and
erythrodontia.
Neurological lesions: intermittent acute porphyria (IAP), variegate porphyria (VP - which
also has the skin lesions) and the rare hereditary coproporphyria (HCP) have neurological
lesions which cause intermittent attacks of:
a) Nervous system dysfunction with lower motor neurone disorders (e.g. generalised
weakness, wrist and foot drop, flaccid quadriparesis, bulbar palsy, absence of deep
tendon reflexes), epilepsy, and mental disturbances of confusion, hysteria,
depression and psychosis. Neuritic pain in the limbs, back, buttocks and thighs, with
areas of paraesthesia and hyperaesthesia may also occur. The neuropathy is often
reversible.6
3
RBC Production and Haemoglobin Function
Table 1. 1 Characteristics of the Porphyrias
Erythropoietic
Hepatic
Erythro-Hepatic
Congenital
Intermittent Hereditary Variegate Porphyria
Proto
erythropoietic Acute
copro
Porphyria Cutanea
porphyria
porphyria
porphyria
porphyria
Tarda
Enzyme
defect
PBG
deaminase &
or Uro P'gen
cosynthase
Clinical
Skin
Neuro
Incidence
+++
70
cases
Onset (yr) 0-2
Biochem
Urine
PBG & ALA N
Uro P
+++
Copro P
++
Faeces
Copro P
+
RBC
Uro P
+++
Copro P
++
Proto P
(+)
PBG
C-P'gen
deaminase oxidase
P-P'gen
oxidase
U-P'gen
Ferro
decarboxylase chelatase
+++
1.5 per
100,000
15-30
+++
30
cases
++
+++
+++
-
+++
-
15-50
40-60
5-15
(+++)
++
N
(+++)
+
++
(+++)
+
++
N
+++
+
N
N
(+)
N
+++
++
(+)
(+)
N
N
N
N
N
N
N
N
N
N
N
N
+
+
+++
PBG = porphobilinogen, ALA = delta aminolaevulinic acid, Uro P = uroporphyrin, Copro P = coproporphyrin, Proto P
= protoporphyrin, N = normal, (+) = increased in some patients only, (+++) = increased only during acute attacks
b)
c)
Abdominal pain, constipation, colic and vomiting, which are caused by an autonomic
neuropathy. There is no abdominal rigidity and minimal abdominal tenderness,
although fever, tachycardia and leucocytosis may be found.
Hypertension, postural hypotension and angio-oedema.
Although specific enzyme deficiencies are required to produce IAP, HCP and VP,
approximately 90% of individuals with a deficiency of one of these enzymes remain
biochemically and clinically normal throughout life.7 Development of the disease state
depends on factors that increase the activity or concentration of ALA synthase, which
catalyses the rate limiting step in hepatic haem biosynthesis. Increased activity of ALA
synthase, in combination with the specific enzyme deficiency (porphobilinogen deaminase
in IAP, copro-porphyrinogen oxidase in HCP, or protoporphyrinogen oxidase in VP),
causes accumulation of the porphyrin precursor ALA and subsequent precursors to haem,
and hence induces the acute attack.
4
RBC Production and Haemoglobin Function
Investigations. During the acute attack, a rapid classification of the porphyria may be based
on the screening of urine for PBG, and faeces and RBCs for excess porphyrins.8 All hepatic
porphyrias (apart from porphyria cutanea tarda) are associated with a positive urinary PBG
screen. Faeces from patients with porphyria variagata and hereditary coproporphyria, produce a
pink luminescent colour under ultraviolet light. The only hepatic porphyria with a negative
faecal screen is the acute intermittent type. RBCs from patients with congenital erythropoietic
porphyria and protoporphyria produce a pink luminescent colour under ultraviolet light. All
relatives of the patient should be screened for the disease, as all porphyrias (apart from
congenital erythropoietic porphyria) are transmitted as a mendelian dominant.
Treatment. Skin lesions may be treated with skin lotions protecting against ultra violet, skin
coverings and avoidance of sunlight. Activated charcoal, to bind porphyrins within the
gastrointestinal tract, has been used successfully to reduce the photocutaneous sensitivity in a
patient with congenital erythropoietic porphyria.9 The use of beta carotene (30 mg/day)10 is still
experimental.
However, as many of the clinical features of acute porphyrias are caused by an acute over
production of porphyrins, treatment is often aimed at supression of porphyrin production (e.g.
supression of delta aminolaevulinic acid synthase). For example, treatment of the acute
gastrointestinal or neurological attack due to any of the acute hepatic porphyrias involves:
1. Supportive therapy, correcting fluid and electrolyte abnormalities and folic acid (the latter
has been used to activate porphobilinogen deaminase - the enzyme deficient in intermittent
acute porphyria - although, clinical benefit with its use has not yet been reported).11
2. Intravenous glucose at 20 g/hr (glucose depresses hepatic ALA-synthase induction
thereby decreasing ALA production. The effect is dose-related with increasing amounts of
glucose progressively depressing ALA-synthase induction).12
3. Intravenous haematin (to suppress ALA-synthase), 4 mg/kg infused over 10 min every 12
hr for 3 - 6 days.13 Because haematin is unstable and decays with time (with the decay products
exhibiting anticoagulant effects of prolongation of APTT, INR and thrombocytopenia),14 it
needs to be lyophilised, sealed under a vacuum and stored at 4ºC and, when reconstructed, used
immediately, as it has a half-life of only 4 hr.15 Rarely, when tolerance to haematin occurs,
coadministration of an inhibitor of haem oxygenase (e.g. tin protoporphyrin or zinc
mesoporphyrin) to inhibit haem catabolism, is required.16
4. Use only ‘safe’ drugs for pain relief and sedation or drugs that do not induce cytochrome
P450 and thereby induce ALA synthase (Table 1.2).14,17,18,19 Complete lists of potentially safe
and unsafe drugs are available at http://www.porphyria-europe.com and http://www.uct.ac.za/
depts/porphyria.
One report documented a patient with severe and incapacitating acute intermittent porphyria
being cured with an orthotopic liver transplant.20
Altered Haem
Methaemoglobinaemia21,22
Methaemoglobin arises when the haem moiety of the haemoglobin molecule is oxidised
from the ferrous to the ferric state. The altered haem is unable to bind oxygen and therefore is
inactive, becoming fully active only if the iron is reduced from ferric to ferrous. When one or
more of the iron molecules in the haemoglobin tetramer is in a ferric state, the other
nonaffected haem moieties have an increased affinity for oxygen (i.e. the curve is shifted to the
left).
5
RBC Production and Haemoglobin Function
Table 1.2 Drugs in acute hepatic porphyria
Drugs that may precipitate
Drugs that do not precipitate
or exacerbate an attack
or exacerbate an attack
Drugs used in Anaesthetic practice
Halothane
Bupivacaine
Enflurane
Succinylcholine
Methoxyflurane
Nitrous oxide
Barbiturates
Atropine
Hyoscine
Morphine
Ketamine
Pethidine
Lignocaine
Salicylates
Pancuronium
Tubocurarine
Propanidid
Phenoperidine
Propofol
Fentanyl
Cardiovascular agents
Spironolactone
Digoxin
Frusemide
Diazoxide
Aminophylline
Thiazides
Hydralazine
Propranolol
Minoxidil
Atenolol
Methyl-dopa
Adrenaline
Sedatives tranquillisers
Diazepam
Chlorpromazine
Nitrazepam
Oxazepam
Antidepressants
Amitriptyline
Anticonvulsants
Phenytoin
Magnesium sulphate
Carbamazepine
Clonazepam
Antidiabetic
Chlorpropamide
Insulin
Tolbutamide
Antibiotics
Erythromycin
Penicillins
Sulphonamides
Cephalosporins
Metronidazole
Aminoglycosides
Rifampicin
Chloramphenicol
Steroids
Oestrogens
Corticosteroids
Progesterones
Miscellaneous
Metoclopramide
Heparin
Cimetidine
Warfarin
Alcohol
Aspirin
6
RBC Production and Haemoglobin Function
Methaemoglobin formation is normally prevented by two protective mechanisms:
1. Reduced glutathione and ascorbic acid.
2. Enzymatic reduction: two enzymatic systems may be utilised, either
a. NADH methaemoglobin reductase which transfers an electron from NADH to haem,
using cytochrome b5 as an electron carrier, or
b. NADPH methaemoglobin reductase which transfers an electron from NADPH
(generated via the pentose phosphate shunt) to haem. In vivo, however, there is no
electron carrier for this system and it acts only if an electron carrier (e.g. methylene
blue) is present. This mechanism reduces methaemoglobin 10 times more rapidly
than the normal NADH methaemoglobin reductase mechanism.
Causes. Methaemoglobinaemia may be caused by an inherited abnormality or an acquired
disorder (Table 1.3).
Table 1. 3
Causes of methaemoglobinaemia
Acquired
Chemical compounds
sodium nitrite, amyl nitrite, ethyl nitrite, ammonium nitrite, silver nitrate,
bismuth subnitrate, potassium chlorate, aniline dyes, nitrobenzenes, aminobenzines,
nitrotoluenes, phenylenediamine, acetanilid, potassium permanganate
Therapeutic agents
sulphonamides, glyceryl trinitrate, phenacetin, benzocaine, lignocaine, prilocaine,
chloroquine, dapsone
Inherited
Methaemoglobin reductase deficiency
Cytochrome b5 deficiency
M Haemoglobins
Clinical features. In the absence of cardiovascular disease or severe anaemia, patients with
methaemoglobinaemia levels < 20% are usually asymptomatic. The symptoms of dyspnoea,
tachycardia, headaches and fatigueability, are commonly present at methaemoglobin levels of
30 - 40% (i.e. 45 - 55 g/L of blood). The lethal level of methaemoglobin is 70 - 80%, a state in
which the patient is practically black with cyanosis. Clinically, symptoms usually do not arise
unless the methaemoglobin level is greater than 10% (i.e., at 13 - 16 g of methaemoglobin/L of
blood).21 Cyanosis is the main feature of this condition, with the impairment in function of the
patient less than would be anticipated from the intensity of the cyanosis. Patients who have
congenital methaemoglobinaemia are often described as being more blue than sick. Clinical
cyanosis appears with 15 g of methaemoglobin/L of blood.
Investigations. The investigations include:
1. Methaemoglobin level: normal levels of methaemoglobin are usually 0.2 - 0.5% of the
total haemoglobin level, and methaemoglobinaemia is defined as being present when more than
1% of the total haemoglobin is methaemoglobin.21 Methaemoglobin is unique among the
haemoglobin derivatives because it changes colour with changing pH. In an acidic environment
(i.e. pH < 7.3) it is brown, in an alkaline environment (i.e. pH > 7.4) it is dark red.
7
RBC Production and Haemoglobin Function
Methaemoglobin levels in excess of 10% produces a brown discolouration when one drop of
blood is soaked into filter paper.
2. Blood gas analysis: This is performed to demonstrate a normal PaO2 in the presence of
cyanosis.
Treatment. If the patient is suffering no functional impairment, then nothing needs to be
done, because normal mechanisms will reduce and correct the methaemoglobinaemia within 24
- 48 hr, provided there is no continuing activity of a toxic compound. In severe cases,
intravenous methylene blue 1 - 2 mg/kg over 5 min will correct the cyanosis within 1 hr.
However the RBC pentose phosphate pathway needs to be effective. Accordingly, if a patient
has glucose 6-phosphate dehydrogenase (GPD) deficiency, methylene blue will be ineffective,
furthermore it may initiate a haemolytic episode in GPD deficient individuals, further
embarrassing their oxygen carrying capacity.23 Ascorbic acid in high doses and riboflavine (60
-120 mg daily) are effective but have delayed onset of action and are of limited value in an
emergency.24 Oxygen therapy does not reverse the defect.
If rebound methaemoglobinaemia develops following successful treatment with methylene
blue (usually from 1 - 20 hr) then the dose 1 - 2 mg/kg may be repeated,25 although the total
dose should not exceed 7 mg/kg due to adverse effects of nausea, vomiting and diarrhoea
(excess doses e.g. 15 mg/kg may even increase the methaemoglobinaemia).26
Sulphaemoglobinaemia27
Sulphaemoglobin is a green-pigmented molecule with a sulphur atom incorporated irreversibly into the porphyrin ring and a markedly reduced oxygen affinity. Because the remaining
unsulphurated haems have a decreased affinity for oxygen, the curve is shifted to the right. For
this reason dyspnoea is absent unless the level of sulphaemoglobin is extraordinarily high. As
the altered haems in sulphaemoglobin (like methaemoglobin) do not transport oxygen, the
effected individuals suffer the effects of an anaemia.
Cause. Hydrogen sulphide, sulphonamides, phenacetin and dapsone may produce
sulphaemoglobinaemia. Sulphaemoglobin may be mixed with methaemoglobin in
sulphonamide toxicity.
Clinical features. These patients may be profoundly cyanosed with minimal dyspnoea. This
is because cyanosis is detected at a blood sulphaemoglobin level of 5 g/L, and the rightward
shift of the dissociation curve causes the normal haemoglobin to be desaturated at high PaO2
levels.
Treatment. The abnormality remains with the RBC for its life span. Thus the main therapy
is to remove the cause. If severe sulphaemoglobinaemia exists, then an exchange transfusion
may be required.
HAEMOGLOBIN FUNCTION
When fully saturated, 1 g of haemoglobin A (15.51 µmol) combines with 1.39 mL of
oxygen at STPD (i.e. 62.06 µmol of oxygen). The iron in the haem molecule stays in a ferrous
state, so that the reaction is an oxygenation, not an oxidation.
Haemoglobin-oxygen affinity
By shifting the relationship of the 4 component polypeptide chains, HbA promotes either,
oxygen uptake by moving the two beta chains closer together, or oxygen delivery by moving
the beta chains further apart. This effect is caused by a competitive binding of oxygen and 2,3DPG with haemoglobin; 2,3-DPG binds specifically to deoxyhaemoglobin in the ratio of one
molecule of 2,3-DPG per haemoglobin tetramer molecule. It binds to the positively charged
8
RBC Production and Haemoglobin Function
residues of both beta chains that face the central cavity of the haemoglobin molecule, reducing
the haemoglobin affinity for oxygen. The wider gap between the beta chains in the deoxy state
allows entry of the 2,3-DPG to stabilise this state and reduce oxygen affinity of haemoglobin.
With oxygenation, the 2,3-DPG is displaced from the haemoglobin molecule. As each haem
moiety takes up oxygen, the affinity of haemoglobin for 2,3-DPG is reduced and the affinity of
the remaining binding sites for oxygen on the same haemoglobin molecule is progressively
increased, providing a sigmoid shape to the oxygen-haemoglobin dissociation curve. An
increase in RBC 2,3-DPG lowers the affinity of haemoglobin for oxygen directly as well as
indirectly by lowering the RBC pH (Bohr effect). In the absence of 2,3 DPG, the curve would
shift to the extreme left, i.e. the P50 of haemoglobin would decrease from its normal value of
26.6 to a value similar to that of myoglobin (i.e. 1 mmHg).28
Fetal haemoglobin (HbF) has two alpha chains and two gamma chains, and as gamma
chains have a lower affinity for 2,3-DPG than beta chains, fetal haemoglobin has a leftward
curve in comparison to adult haemoglobin (e.g. cord blood has a P50 of 20 mmHg, c.f. adult
blood which has a P50 of 26.6 mmHg).29 Factors affecting oxygen affinity of haemoglobin are
RBC intracellular, H+ ion activity (i.e. Bohr effect), carbon dioxide tension, Cl- ion
concentration, temperature and 2,3-DPG concentration.30,31,32 While all phosphates have an
effect on oxygen affinity, only 2,3-DPG and ATP are in sufficient concentrations to exert an
effect. The major effect is due to 2,3 DPG, because the molar concentration of ATP is onequarter that of 2,3-DPG and its effect on haemoglobin oxygen affinity is less than that of 2,3DPG.30,33 ,34 The 2,3-DPG also remains inside the RBC as it cannot permeate the normal RBC
membrane.
Increasing any of the above factors shifts the curve to the right and decreasing any of the
above factors shifts the curve to the left. Abnormal haemoglobins have also been described
which have either rightward or leftward curve shifts when compared to normal.35 Propranolol
also shifts the curve to the right by unknown mechanisms.36
The Bohr effect
The immediate decrease in oxygen affinity of haemoglobin when the pH of the blood falls
(i.e. shift of the curve to the right) is known as the Bohr effect. While the original Bohr
description referred to the immediate effect of carbon dioxide on the oxygen-haemoglobin
dissociation curve placement, it was soon realised that the H+ ion concentration was a more
important physiological factor (although when carbon dioxide is the acid variable, about 20%
of the Bohr effect is due to a carbon dioxide effect independent of pH).37 The Bohr effect is
related to the decrease in RBC intracellular pH. The normal RBC-plasma pH gradient is 0.2
(i.e. at a plasma pH of 7.4 the RBC pH is 7.2). The gradient may be reduced in citrate stored
blood, and increased in blood of critically ill patients.33
Increasing oxygenation of haemoglobin reduces its affinity for carbon dioxide (Haldane
effect), increasing the PCO2 and decreasing the pH (i.e. deoxygenated blood is a better buffer
than oxygenated blood).
2,3 Diphosphoglycerate
In the red blood cell, 2,3-DPG is produced from 1,3-diphosphoglycerate in the RapoportLuebering shuttle. This shuttle bypasses the ATP-producing phosphoglycerate kinase step of
the Embden Myerhof pathway, and so the pathways compete for 1,3-diphosphoglycerate,
producing either ATP or 2,3 DPG. Normally 20% of the 1,3-diphosphoglycerate is metabolised
through the Rapoport-Luebering shuttle, although with an increase in the ADP:ATP ratio, ATP
may be increased by increasing the amount of substrate metabolised through the
phosphoglycerate kinase step, at the expense of 2,3 DPG.29 A decrease in RBC pH reduces the
9
RBC Production and Haemoglobin Function
2,3 DPG levels by inhibiting phosphofructokinase (i.e. reducing glycolysis) and inhibiting 2,3DPG mutase and increasing 2,3-DPG phosphatase activity (i.e. decreasing synthesis and
increasing metabolism of 2,3-DPG, respectively), reducing the P50 and shifting the oxygenhaemoglobin dissociation curve to the left.38 This is opposite to the effect of an acute reduction
in pH (i.e. Bohr effect) which shifts the curve to the right. As P50 is measured under standard
conditions of pH and PCO2, the effect of a chronic acidosis is to reduce the P50.29 The Bohr
effect occurs immediately, whereas the pH effect on 2,3 DPG may take up to 12 - 24 hr, acting
in vivo to normalise the position of the oxygen-haemoglobin dissociation curve.
Intracellular pH has the strongest control over 2,3-DPG synthesis.39 The increase in 2,3DPG associated with elevation of normal subjects to high altitudes is due to hyperventilation
and respiratory alkalosis, as the 2,3 DPG levels do not alter in spite of hypoxia if the associated
pH changes are inhibited by acetazolamide.40
The 2,3-DPG levels are influenced by many factors, being reduced in chronic acidosis and
hypophosphataemia, and increased in chronic hypoxia, alkalosis, anaemia (detectable at Hb
100 g/L or less), and treatment with cortisol, aldosterone, androgens, triiodothyronine, and
inosine.
The P50
The P50 is the partial pressure of oxygen of a whole blood sample at which haemoglobin is
50% saturated, at a pH of 7.4, temperature 37º C and carbon monoxide level less than 2%. This
is sometimes refered to as the standard P50, with the in vivo P50 being defined as the partial
pressure of oxygen, at which haemoglobin is 50% saturated at the pH, PCO2, temperature and
carboxyhaemoglobin concentration of the blood in the subject. While the in vivo P50 may reflect
the oxygen-haemoglobin affinity better in vivo than the standard P50, the oxygen-haemoglobin
dissociation curve is constantly (and rapidly) changing in vivo (and from organ to organ39) in
response to PCO2, pH and temperature, so even this (particularly when it is calculated from a
peripheral blood sample) has limitations when used to assess organ oxygenation. The P50 (i.e
standard P50) is used largely to assess chronic changes in the oxygen-haemoglobin dissociation
curve.
The P50 is increased if the oxygen-haemoglobin dissociation curve is shifted to the right,
and is decreased if the curve is shifted to the left. The P50 can be estimated with an accuracy of
+ 1 mmHg between saturations of 20% to 90%, from a measurement of blood PO2 and SO2,
using a calculation that assumes that the shape of the oxygen-haemoglobin dissociation curve
remains constant.41 While the Siggaard-Andersen algorithm improved the accuracy of P50 when
calculated from arterial blood with saturations up to 97%,42 in critically ill patients the accuracy
has has been found to be suspect when arterial blood with saturations > 92% are used.43 When
severe abnormalities of acid-base balance or 2,3-DPG concentrations exist, the shape of the
oxygen-haemoglobin dissociation curve is changed significantly,44 and accurate P50 estimations
may require construction of the oxygen-haemoglobin dissociation curve. For a normal adult,
the P50 is 26.6 mmHg + 2 mmHg.
The oxygen-haemoglobin dissociation curve
The normal arterial oxygen tension of 90 - 100 mmHg at sea level corresponds to a
saturation of approximately 97%. If the PaO2 is decreased by 40% to 60 mmHg, the saturation
falls by 6% to 91%. A decrease of the PaO2 by a further 10 mmHg to 50 mmHg produces a
further 6% fall in saturation to 85%. With the mixed venous PO2 at 40 mmHg (SO2 75%), a
fall of a further 5 mmHg to 35 mmHg the saturation falls by 10% from 75% to 65%. The more
precise SO2 values at PO2 values ranging from 10 - 100 mmHg, of the normal oxygenhaemoglobin dissociation curve at pH 7.40 and a temperature of 37ºC, are listed in Table 1.4.45
10
RBC Production and Haemoglobin Function
Table 1.4 The PO2 and SO2 values of the normal oxygen-haemoglobin dissociation curve
at a pH of 7.4, PCO2 40 mmHg and temp 37ºC
PO2 (mmHg)
10
20
30
40
50
60
70
80
90
100
% Saturation
9.58
32.12
57.54
74.69
85.08
90.85
94.06
95.84
96.88
97.49
The oxygen-haemoglobin dissociation curve in disease
When oxygen delivery (DO2) is impaired, one of the compensatory mechanisms by which
oxygen consumption (VO2) is maintained is a decrease in haemoglobin’s oxygen affinity (i.e.
increase in P50)34,46,47, which is largely effected by an increase in RBC 2,3 DPG concentration.
While an increase in 2,3-DPG, and thus P50, is often reported in patients with chronic clinical
disorders of low cardiac output,46,48 cyanotic congenital heart disease,49 anaemia,50 chronic lung
disease,51 thyrotoxicosis33 and cirrhosis,52 both increases and decreases in P50 values have been
found in patients with acute illness. In acute myocardial infarction the P50 has been reported to
increase, to improve VO2, as DO2 decreases with a decrease in cardiac output.53 The increase
in P50 indicating a precarious oxygen transport-requirement balance in peripheral tissues of
these patients, which was reflected by a poor outcome, even with adequate DO2 and VO254
values. The P50 has also been used as a marker for evaluating adequacy of tissue oxygenation in
patients with cardiopulmonary disease,55 with the severity of tissue hypoxia being reflected by
the magnitude of the compensatory increase in P50. On the other hand, in other acute disorders,
particularly in association with massive transfusion,56,57 hypophosphataemia29,58,59,60 or shock,61
and in critically ill patients,62 low levels of 2,3 DPG and a reduction in P50 have been reported.
The rise in 2,3 DPG that occurs in vivo in transfused stored blood cells has a half-life of 4 8 hr,35 and 18 - 36 hr may elapse before the 2,3-DPG levels are fully restored. Studies in trauma
patients receiving massive transfusion of stored blood have shown that the P50 and 2,3-DPG
levels may take up to 4 days before they are restored to normal.56
In shock, a reduction in 2,3 DPG may be due to a decrease in RBC pH, which can occur in
the presence of a normal plasma pH, due an increase in the plasma-RBC pH gradient33 or an
increase in the RBC ADP:ATP ratio, both of which reduce RBC 2,3 DPG levels.62 In some
acutely ill patients in whom the P50 and 2,3 DPG values have been measured, low P50 values
occurred in the presence normal 2,3-DPG levels,58,63,64 indicating that the increase in
haemoglobin affinity for oxygen in critically ill patients is probably multifactorial.
Clinical effects of shifts in the oxygen-haemoglobin dissociation curve
Acute shift in the oxygen-haemoglobin dissociation curve. This is caused largely by the
Bohr effect, and change in temperature:
11
RBC Production and Haemoglobin Function
1. If the curve is shifted to the left, it is easier to load oxygen in the lung at a given partial
pressure. On the other hand, the blood would unload less oxygen at a given venous oxygen
partial pressure.
2. If the curve is shifted to the right, then there is a greater oxygen delivery at a given
venous oxygen partial pressure, but presumably it would be more difficult to load oxygen at the
lung, particularly when breathing hypoxic mixtures.
In vivo, carbon dioxide and heat are generated in the peripheral tissues, shifting the curve to the
right allowing more oxygen to be delivered at the same partial pressure. In the lung the reverse
occurs, i.e. unloading of the carbon dioxide and reducing the temperature shifts the curve to the
left facilitating oxygen uptake.65
Chronic shift in the oxygen-haemoglobin dissociation curve (i.e. change in P50)
1. Shift to the right (increase in P50): during exercise, subjects with increased P50 values
meet metabolic oxygen demands predominantly by increasing the oxygen extraction with only
modest increase in cardiac output; on the other hand, if the P50 values are decreased, then at the
same oxygen consumption the cardiac output may more than double to meet the oxygen
demand.66 Nevertheless, it would seem that oxygen affinity is not commonly a critical
parameter in the delivery of oxygen.65
2. Shift to the left (decrease in P50): a decrease in P50 appears not to be harmful to animals
breathing low oxygen mixtures. However, if they are exchanged-transfused first to the point of
anaemia with blood with low 2,3-DPG, then mortality is increased.33 While studies in
hypoxaemic hypoxia have shown that a decrease in P50 improves pulmonary uptake of oxygen
and tissue oxygenation when PaO2 is less than 30 - 35 mmHg67 (and therefore may be of value
to individuals living at high altitudes), this does not occur if hypoxaemia is due to venous
admixture caused by congenital heart disease, in which a rightward shift is still advantageous,
even with severe hypoxaemia, because increasing haemoglobin affinity for oxygen does not
increase the oxygen content of shunted blood.68
Haemoglobin binding of nitric oxide
Haemoglobin scavanges free circulating nitric oxide by binding with high affinity ferrous
sites on haem (with an affinity for nitric oxide 8000 times the affinity for oxygen). There is also
a binding site on the globin molecule (β93 cystine residue), where nitric oxide binds in the
form of S-nitrosothiol (which protects the nitric oxide from being scavanged by the high
affinity ferrous sites).69 As haemoglobin binds to oxygen in the lungs, its affinity for Snitrosothiol is increased. As haemoglobin releases oxygen in the periphery, its affinity for Snitrosothiol is reduced, and nitric oxide is released into the tissues. Thus haemoglobin acts as a
carrier of nitric oxide, releasing it in areas of hypoxia to cause vasodilation and improvement of
blood flow to hypoxic tissues.70
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46. Metcalfe J, Dhindsa DS, Edward MJ, Mourdjinis A. Decreased affinity of blood for
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47. Woodson RD, Torrance JD, Shappell SD, Lenfant C. The effect of cardiac disease on
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48. Woodson RD, Torrance JD, Lenfant C. Oxygen transport in low cardiac output hypoxia.
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49. Oski FA, Gottlieb AJ, Delivoria-Papadopoulos M, Miller W. Red cell 2,3
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51. Lenfant C, Ways P, Aucutt C. Effect of chronic hypoxic hypoxia on the 02-Hb
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52. Astrup P, Rorth M. Oxygen affinity of haemoglobin and red cell 2,3 DPG in hepatic
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54. Sumimoto T, Takayama Y, Iwasaka T, Sugiura T, Takeuchi M, Tarumi N, Takashima H,
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55. Valeri CCR, Fortier NL. Red cell 2,3-diphosphoglycerate and creatine levels in patients
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56. McConn R, Derrick JB. The respiratory function of blood; transfusion and blood storage
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57. Collins J. Problems associated with the massive transfusion of stored blood. Surgery
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58. Watkins GH, Rabeto A, Plzak LF, Sheldon GF. The left-shifted oxyhemoglobin curve in
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59. Lichtman MA, Miller DR, Cohen J, Waterhouse C. Reduced red cell glycolysis, 2,3
diphosphoglycerate and adenosine triphosphate concentration and increased hemoglobin
oxygen affinity caused by hypophosphatemia. Ann Intern Med 1971;74:562-566.
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Oski FA. Alterations of red cell glycolytic intermediates and O2 transport as a
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61. Chillar RK, Slawsky P, Desforges JF. Red cell 2,3 diphosphoglycerate and adenosine
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62. Myburgh JA, Webb RK, Worthley LIG. The P50 is reduced in critically ill patients. Intens
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63. McConn R. 2,3 DPG - What role in septic shock? In: Lillehie R, Stubbs S, ed. Shock in
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65. Hlastala MP. Physiological significance of the interaction of oxygen and carbon dioxide
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15
16
Chapter 2
ANAEMIAS and POLYCYTHAEMIAS
ANAEMIAS
Normal haemoglobin concentrations vary from 135 - 175 g/L in males and 120 - 160 g/L in
females. An anaemia is a reduction in the haemoglobin concentration below 120 g/L in females
and 135 g/L in males. In some circumstances, the blood haemoglobin values do not reflect
alterations in the red blood cell (RBC) mass. For example, in patients who have sustained an
acute reduction in plasma volume owing to extensive burns, pancreatitis, anaphylaxis or acute
histamine release reactions, the haemoglobin values may be high when the RBC mass is either
normal or low. By contrast, haemoglobin values may be low when the RBC mass is normal or
high in patients who have expanded blood volumes with excessive intravenous infusions or
during pregnancy.
Classification of anaemias
Anaemias may be caused by an increased loss or decreased production of haemoglobin
(Table 2.1) and are often classified as microcytic, macrocytic or normocytic (Table 2.2). The
use of hypochromia or normochromia to differentiate the anaemias has been lost with the
current automatic machines that have revealed the mean corpuscular haemoglobin
concentration (MCHC) is usually constant in all conditions (apart from hereditary spherocytosis
where the MCHC is usually greater than 36%).1
Table 2. 1
Causes of an anaemia
Increased loss or destruction
Blood loss
Haemolytic anaemias
Impaired formation
Deficiency of substances essential for erythropoiesis
iron, B12, folate, copper or vitamin C deficiency
Defective porphyrin synthesis
lead poisoning, sideroblastic anaemias
Defective or unbalanced globin synthesis
thalassaemias, haemoglobinopathies
Bone marrow failure
absolute (e.g. leukaemia, aplastic anaemia)
relative (i.e., chronic infection, renal failure, hepatic failure)
The common anaemias are blood loss or iron deficiency (microcytic), megaloblastic
(macrocytic), and secondary or haemolytic (normocytic).
17
Anaemias and Polycythaemias
Table 2.2
Classification of anaemias
Microcytic
Iron deficiency
Others (i.e., thalassaemia minor, sideroblastic anaemia)
Macrocytic
Nonmegaloblastic (alcoholism, chronic liver disease, myxoedema,
haemolysis (due to reticulocytosis), scurvy)
Megaloblastic (B12, folate deficiencies)
Normocytic
Secondary anaemias
chronic infections and chronic inflammation
chronic renal failure
rheumatoid arthritis, SLE, polyarteritis nodosa
malignancy
endocrine failure (Addison’s disease, hypogonadism,
panhypopituitarism)
Aplastic anaemia
Primary disorders of the bone marrow
leukaemias, myelofibrosis
MICROCYTIC ANAEMIA
Iron deficiency
The normal adult daily requirements for iron are 1 mg for males and 1.5 mg for females.
The diet normally contains about 10 - 15 mg of iron per day, so only 10 - 15% is absorbed.
Approximately 25 - 35 mg of iron is released daily by the reticuloendothelial system (RES)
from the breakdown of RBCs. Because ionic iron is poorly soluble, it is transported in the
circulation bound to transferrin, a transport protein with a molecular weight of 80,000 that can
bind two atoms of iron per molecule. Iron is stored attached to ferritin. Serum iron and
transferrin levels reflect transport iron, and serum ferritin reflects storage iron (Table 2.3).2
Table 2.3 Normal adult serum iron values
Males
Females
Serum ferritin
Serum iron
Serum transferrin
Transferrin saturation
20 - 250
8 - 35
25 - 50
10 - 50
10 - 150
8 - 27
25 - 50
10 - 35
µg/L
µmol/L
µmol/L
%
Approximately 2500 mg of iron exists as haemoglobin, 100 - 1000 mg exists as storage iron
(females low, males high), 300 mg exists as tissue iron containing enzymes (i.e. myoglobin,
cytochromes, etc.), and 4 mg exists in the plasma pool. A serum ferritin level of 1 µg/L is
equivalent to 10 mg of storage iron (i.e. tissue ferritin).
18
Anaemias and Polycythaemias
When iron deficiency develops, the iron stores fall first, followed by the serum iron level
and finally the haemoglobin level. While iron deficiency can deplete cytochromes, myoglobin
and iron-containing enzymes, there is no evidence that these effects are important clinically.
Causes. Iron deficiency is caused by increased requirements (commonest cause is due to
blood loss), inadequate intake, or both (Table 2.4).
Table 2. 4
Causes of iron deficiency
Increased requirements
physiological (pregnancy, puberty)
excess blood loss
peptic ulceration, diverticulitis, hiatus hernia
carcinoma (particularly gastrointestinal carcinoma)
hereditary haemorrhagic telangiectasia
parasitic infestations
Inadequate intake or poor GIT absorption
gastrectomy, achlorhydria, intestinal malabsorption
dietary
Clinical features.3 Chronic anaemia will often not be associated with symptoms unless it is
below 70 - 80 g/L. Symptoms include lassitude, weakness, pica (with a craving for ice),
dysphagia, anorexia, nausea, menorrhagia, angina and pulmonary oedema. The signs of the
anaemia include pallor, (the hand should be compared with the examiners hand; the crease
colour changes to white when the haemoglobin is less than 100 g/L), angular stomatitis,
atrophic tongue, tender mouth and tongue. Koilonychia is present in only 18% of patients with
iron deficiency anaemia and brittle nails with longitudinal ridging may be more common. A
bounding arterial pulse, with a large pulse pressure and prominent dicrotic notch (it may feel as
though there is a double pulse), a systolic ejection bruit (often heard loudest over the
pulmonary area) and a cervical venous hum may be present.
Investigations. These include:
1. Tests for occult blood loss: the commonest cause of an iron-deficient anaemia in men or
postmenopausal women is chronic occult blood loss and the site is commonly gastrointestinal
(e.g. peptic ulceration, carcinoma of the colon).4 On 3 successive days, 2 - 5 g of faeces are
collected and tested for blood using the faecal human haemoglobin test. Endoscopy,
radiological contrast and radiolabelled RBC studies may also be required.
2. Complete blood picture: chronic iron deficiency classically produces a microcytic
anaemia. An acute blood loss causes a normocytic anaemia.
3. Iron-binding proteins: serum ferritin, iron and transferrin measurements should be
performed on a specimen of blood from a patient who has fasted overnight. Low serum iron
with high transferrin levels characteristically indicates iron deficiency. A serum ferritin level of
less than 100 µg/L in anaemic patients should always be taken to indicate depleted iron stores.
Occasionally, serum ferritin levels may be normal or even elevated in the presence of reduced
tissue iron stores;5 therefore, if iron deficiency is suspected and the serum ferritin is normal, a
bone marrow aspirate will be required to determine the status of iron stores. High serum ferritin
levels can be caused by conditions other than iron overload, although low serum ferritin levels
are always indicative of low iron stores and obviates the need to perform a tissue estimate.
19
Anaemias and Polycythaemias
Treatment. If iron deficiency is due to a poor oral intake, then ferrous sulphate 300 mg (35
mg of elemental iron) one to two tablets 8-hourly for 4 - 10 weeks, may be prescribed. The total
iron requirement (i.e. 1 - 2 grams) may also be administered as an intravenous infusion of an
iron-dextran complex, after giving a test dose of 1 - 5 mg to asses whether any adverse allergic
reactions will occur. Transfusions (500 ml of blood contains about 250 mg of iron), and are
indicated only if surgery is contemplated or the patient is experiencing cardiovascular
symptoms of cardiac failure or ischaemia. In the presence of an adequate supply of folate and
B12, a reticulocytosis, thrombocytosis and leucocytosis usually begins after 4 days and peaks at
10 days. The reticulocyte count increases from 3 to 15% (increasing the MCV to 95 - 105 fl)
and the haemoglobin usually increases by 10 g/L per week. If iron deficiency is due to
excessive blood loss the disorder causing the excessive blood loss (e.g. peptic ulcer, colon
carcinoma, menorrhagia, etc.) should also be treated. Excessive blood loss due to epistaxis or
gastrointestinal blood loss caused by hereditary haemorrhagic telangectasia may respond to
fibrinolytic inhibitors (e.g. epsilon aminocaproic acid 2 g orally daily).6
Haemochromatosis
Cause. Haemochromatosis is an iron-storage disorder, in which an inappropriate increase in
gastrointestinal iron absorption results in excess iron deposition (iron stores of 20 - 25 g may
occur with haemochromatosis), and functional abnormalities of the liver, heart, pancreas and
pituitary. It may be inherited as an autosomal recessive (i.e. genetic haemochromatosis which is
associated with mutations in the histocompatability antigen HLA-H, as is porphyria cutanea
tarda7) or an acquired disorder (e.g. transfusion siderosis) . While an increase in iron stores may
also occur in alcoholic subjects with chronic liver disease, these individuals do not have
haemochromatosis. Haemochromatosis occurring in a heavy drinker may be distinguished from
alcoholic liver disease by studying relatives of the patient and by measuring the hepatic iron
content, which is within normal limits in patients with alcoholic liver disease.
Clinical features. The male:female ratio for homozygosity is 1:1 although the disease is
five times more frequent in males than females (probably due to the effect of increased
physiological iron loss during menstruation and pregnancy in females8) and often develops
during the ages of 40 - 60 years. The symptoms include lethargy and weakness (75%),
arthralgia (45%), loss of libido (30%), and abdominal pain (40%); the signs include
hepatomegaly (70%), skin pigmentation (80%), hypogonadism (30%), arthropathy (70%), and
signs of diabetes mellitus and hepatic and cardiac impairment. Hepatic and cardiac damage may
lead to cirrhosis and cardiomyopathy respectively. Hepatocellular carcinoma develops in 30%
of untreated cases.
Investigations. The investigations include serum iron studies (revealing an increase in
fasting serum transferrin saturation of > 60% for males and > 50% for females,9 and an increase
in serum ferritin levels), chest X-ray or abdominal X-Rays (showing an increase in hepatic
density) and an MRI,10 or liver biopsy, to measure the hepatic iron content and to confirm the
diagnosis.
Treatment. As the patient usually has 20 - 25 g of excess iron, weekly (even twice-weekly)
phlebotomy of 500 mL of blood is required for 2 - 3 years, keeping the haemoglobin at 100 110 g/L. This is followed by one phlebotomy every 1 - 3 months to maintain low normal serum
ferritin levels (i.e. 50 – 100 ug/L).11 Patients are advised not to take vitamin or mineral
preparations containing iron or vitamin C supplements and moderation with red meat and
alcohol. Desferrioxamine is not used because it removes only 10 - 20 mg of iron per day, at
best, compared with venesection of 500 ml of blood which removes 200 - 250 mg of iron. All
immediate relatives of the patient (i.e. brothers, sisters) should be screened.
20
Anaemias and Polycythaemias
MACROCYTIC ANAEMIA
Nonmegaloblastic
The commonest cause of macrocytosis in the absence of an anaemia and folate or B12
deficiency is chronic ethanol excess. An anaemia in an alcoholic may be due to folate
deficiency, iron deficiency (usually acute or chronic blood loss, as iron absorption is often
increased), hypersplenism, pyridoxal phosphate deficiency (i.e. sideroblastic anaemia), or
haemolysis (i.e., Zieve’s syndrome).12,13
Megaloblastic
The megaloblastic anaemias are caused by an impaired DNA synthesis due to folate or
vitamin B12 deficiency.
Vitamin B12
Vitamin B12 has a structure similar to the porphyrins with cobalt being in the position
occupied by iron in the haem molecule, the cyanide or hydroxyl ion filling the unsatisfied
valence of the cobalt ion for cyanocobalamin and hydroxocobalamin, respectively.
Both cyano- and hydroxocobalamin are present in the body in trace amounts only;
hydroxocobalamin binds more firmly to proteins and remains longer in the body than
cyanocobalamin. Twenty-four hours after parenteral administration, only 55% of 100 µg and
15% of 1000 µg of cyanocobalamin is retained whereas 90% of 100 µg and 30% of 1000 µg of
hydroxocobalamin is retained.14 Both cyano- and hydroxocobalamin are rapidly converted to
the two physiologically active forms of vitamin B12, i.e. methyl and 5-deoxyadenosylcobalamin
which cannot themselves be used for therapy because they are rapidly destroyed by light. The
minimum daily requirement of vitamin B12 is 2.5 µg.
Intestinal absorption of vitamin B12 is mediated by receptor sites in the ileum that require
cobalamin to be bound by the highly specific glycoprotein intrinsic factor (molecular weight
50,000), secreted by parietal cells of the gastric mucosa. As the cobalamin-intrinsic factor
complex crosses the ileal mucosa, the intrinsic factor is released and the vitamin is transferred
to a plasma transport protein, transcobalamin II. Other cobalamin-binding proteins, including
transcobalamin I, exist in the plasma and liver to provide an effective storage of cobalamin (a
unique situation for a water-soluble vitamin). Two milligrams are stored in the liver and 2 mg
are stored elsewhere in the body, thus supply for 3 - 6 years is available to the body if B12
absorption ceased abruptly.
Folic acid
Folic acid is the common name for pteroylmonoglutamic acid, and uncooked fruits and
vegetables constitute the primary source of the vitamin. It is absorbed from the duodenum and
jejunum and changed within the intestinal cell to 5-methyltetrahydrofolic acid which is carried
in the plasma. The minimum daily requirement is normally 50 µg, but requirements may
increase during pregnancy or disease, up to 300 - 500 µg/day. The total body stores normally
consists of 5 - 20 mg which provides the body with a 3 month supply of folate, although, in the
absence of folate supplementation in critically ill patients, a deficiency with thrombocytopenia,
hypersegmented neutrophils and macrocytosis, may develop within 3 to 4 days.15
Folate and B12 reactions
There are only two human enzymatic reactions that require cobalamin as a coenzyme:
1. Isomerisation of L-methylmalonyl-CoA to succinyl-CoA by methylmalonyl-CoA mutase,
utilising 5-deoxyadenosylcobalamin as the coenzyme.
21
Anaemias and Polycythaemias
2. Methylation of homocysteine to methionine by methionine synthetase utilising methyl
cobalamin as the coenzyme and 5-methyltetrahydrofolate as the methyl source. Methionine
synthetase is inhibited by nitrous oxide (which is 50% inactivated after 1 hour of nitrous oxide
exposure16), as nitrous oxide converts the cobalt in methyl cobalamin from the monovalent to
the divalent form (in a manner which is similar to the conversion of haemoglobin to
methaemoglobin), causing B12 to no longer act as a methyl carrier, decreasing the formation of
tetrahydrofolate (THF) and methionine (Figure 2.1).17,18 This effect is irreversible (or at best
slowly reversible over 4 days19) and does not effect the isomerisation of L-methylmalonyl-CoA
by methylmalonyl-CoA mutase.20,21
Figure 2.1
Folate and vitamin B12 reactions
Myelin (and other methylations)
↑
S-adenosyl homocysteine ← S-adenosyl-methionine

↑


↓
Methionine

Homocysteine
synthase
Methionine → Proteins
+

+
←THF ←
GIT→ 5-Methyl THF
B12
↑

↑


formate 

methylene 
serine

 DHF
THF

glycine 
reductase
reductase 
histidine 





← 5,10 methylene ←


Folinic → Tetrahydrofolate →

acid
→ dihydrofolate
↓
Deoxyuridine → Thymidilate → DNA
DHF = dihydrofolate; THF = tetrahydrofolate; GIT = gastrointestinal tract
The decrease in methionine reduces the formation of S-adenosyl-methionine which is a
direct methyl group donor for many methylation reactions (e.g. myelination). It also reduces
homocysteine, which is derived entirely from methionine, and an intracellular THF deficiency
also occurs.22 In the case of B12 deficiency (or inhibition) or methionine deficiency,
administering folate (to enhance protein and DNA metabolism) will reduce the methionine,
further reducing myelination and precipitating neurological disorders of subacute combined
degeneration of the spinal cord and peripheral neuropathy. In the experimental model the
development of subacute combined degeneration of the spinal cord due to B12 deficiency is
inhibited by methionine supplementation23. Subacute combined degeneration of the spinal cord
may also be precipitated by nitrous oxide in B12 deficient patients.24
S-adenosyl-methionine is a powerful inhibitor of methylene-THF reductase; therefore, when
B12 and methionine deficiency exists, THF (when it is converted to 5,10 methylene THF, with
formate, serine, glycine and histidine oxidations) is converted to, and 'trapped', as 5-methyl
22
Anaemias and Polycythaemias
THF. Both B12 and methionine can release the ‘trapping’, by increasing S-adenosyl methionine,
inhibiting the formation of 5-methyl TFH. 5,10 methylene THF provides the methyl group to
deoxyuridine to form thymidine which is a necessary precursor of DNA synthesis. The
dihydrofolate so formed is reduced by the enzyme, dihydrofolate reductase (trimethoprim,
pentamidine and pyrimethamine are selective inhibitors of this enzyme in bacteria;
methotrexate inhibits both the human and bacterial enzymes) to reform THF. Folate deficiency
reduces the amount of 5,10 methylene THF available for DNA synthesis (as does B12 and
methionine deficiency due to the ‘trap’), causing megaloblastosis (Table 2.1). Folinic acid is a
stable form of THF that can be administered orally or parenterally to provide reduced folate
without first being required to be acted on by dihydrofolate reductase.
In normal individuals, 50% nitrous oxide administered to patients for less than 5 - 6 hr does
not affect haemopoiesis. However, exposure for 6 hr produces mild, and exposure for 24 hr
severe, signs of megaloblastic depression (i.e. pancytopenia) of the bone marrow.25 In critically
ill patients megaloblastosis may be evident after 2 hr exposure, although it has been suggested
that exposures of nitrous oxide in excess of 45 min will be significant in compromised patients
and require the use of folinic acid therapy.26 Long-term neurological effects may occur with
prolonged administration of nitrous oxide.27 The marrow effects are reversed by folinic acid, 60
mg in 24 hr28 or 30 mg daily for 5 days;29 and, in the short-term methionine and B12 (in the
absence of B12 deficiency) are usually not required.
Causes, clinical features, investigations and treatment of megaloblastic anaemia
Causes
1. Pernicious anaemia: this anaemia is due to B12 malabsorption and deficiency, secondary
to atrophy of the gastric mucosa with absence of intrinsic factor.30 This may also occur after
gastrectomy.
2. Folate deficiency: deficient states often occur with inadequate dietary intake (e.g. in the
elderly, alcoholic or mentally disturbed), malabsorption (e.g. steatorrhoea) or excess demands
(e.g. pregnancy, chronic haemolytic anaemia).
Clinical features. Symptoms of B12 or folate deficient megaloblastic anaemia include
weakness, lassitude, sore atrophic tongue, angular stomatitis, and diarrhoea. Signs include
pallor, weakness, jaundice, and, in the case of B12 deficiency (not folate deficiency),
neurological disorders which may not remit with treatment and which may be provoked by
folic acid administration. Classically posterior column signs of joint position sense defects are
observed with a positive Romberg sign, and abnormal vibration and joint position sense.
Peripheral neuropathy may be found with signs of, numbness, paraesthesia, weakness and
ataxia. Dementia has also been described. Occasionally the neurological symptoms and signs
may occur in the absence of haematological defects and with serum B12 levels at low normal
levels (i.e 200 - 350 ng/L or 150 -250 pmol/L).31
Investigations. The investigations include:
1. Complete blood picture: this will reveal a macrocytic anaemia (MCV > 100 fl),
thrombocytopenia with hypersegmented polymorphs and, occasionally, agranulocytosis
2. Bone marrow: this will reveal a megaloblastosis.
3. Serum folate and B12 levels: an overnight fasting serum specimen for folate (normal 3.0 15 µg/L or 6.8 - 34 µmol/L) and B12 (normal 200 - 1000 ng/L or 150 -750 pmol/L), are taken.
In pernicious anaemia, B12 values are almost invariably below 100 ng/L, although a
physiologically adequate serum level is above 258 pmol/L as clinical evidence of B12
deficiency can exist below this value.32 While vegetarians often have low serum levels of B12, a
deficient state does not usually occur.
23
Anaemias and Polycythaemias
4. Intrinsic factor antibody: patients who have an antibody to intrinsic factor with low
serum concentrations of B12 have pernicious anaemia, and absorption tests (e.g. Shilling test)
are not needed to confirm the diagnosis33.
5. Plasma biochemical tests: the indirect bilirubin and LDH-1 are often elevated due to
marrow destruction of megaloblastic erythroid cells.
Treatment. Parenteral hydroxocobalamin 1000 µg monthly is used for vitamin B12 deficient
states34,35 and should be considered for all elderly patients if folate supplementation is given.36
Large doses of oral cobalamin (1000 µg daily) will also produce successful long term results in
patients with pernicious anaemia, due to a vitamin B12 transport system that is independent of
intrinsic factor and the terminal ileum.37 Rarely, patients may exhibit an allergy to
hydroxocobalamin (e.g. pruritis, utricaria, bronchospasm, angio-oedema) with no crossreaction to cyanocobalamin.38
If a folic acid deficiency exists then this is usually corrected by oral or intravenous folic
acid 5 - 15 mg/day. Folinic acid (30 - 60 mg daily) is administered when folate inhibitors have
caused the deficient state.
Following replacement therapy, the reticulocyte count usually increases up to a maximum
of 10-20% by the 10th day.
NORMOCYTIC ANAEMIA
The secondary anaemias
Anaemia associated with chronic infections or chronic inflammation
An anaemia (Hb 90 - 110 g/L) is often associated with an inflammatory (e.g. systemic lupus
erythematosus, polyarteritis, rheumatoid arthritis) or infective process that has been present for
longer than 1 month. If the haemoglobin is less than 80 g/L then it is likely that another process
is present (e.g. blood loss). The reticulocyte count is normal, the serum iron and transferrin
levels are reduced, the saturation is normal and the serum ferritin is raised. It appears that
hepatic transferrin synthesis is depressed, iron is less freely released from the RES, and some of
the suppression of RBC production is due to the decreased availability of iron. The RBC
survival time is also about 85% shorter than in normal subjects.39 It has been suggested that the
decrease in serum iron associated with chronic infection increases the body resistance to
infection because it reduces the iron available to support the growth of microorganisms.40
Anaemia associated with chronic renal failure
While uraemic toxins, hyperparathyroidism, hypersplenism, folate deficiency and iron
deficiency may play a role in causing the anaemia of end-stage renal disease, the anaemia is
largely due to a persistent mild haemolysis and decreased levels of erythropoietin.41,42,43 The
RBC morphology often reveals distorted and fragmented cells (e.g. schistocytes, burr,
tear-drop, and helmet cells). The haemoglobin concentration usually falls to 50 - 80 g/L, with a
linear relationship existing between the haematocrit and the creatinine clearance.
Recombinant erythropoietin has been used to correct the anaemia of chronic renal failure in
patients on long-term haemodialysis, which improves the patient's wellbeing and physical
capacity.44,45 The patient's maximum oxygen consumption is increased after two months, and a
30% reduction in the left ventricular mass occurs after 12 months of treatment.46 A dose of 25 50u (up to 200 u) is usually administered three times weekly, or 2 -12 mg every year.47
However, it appears that thrombosis is more likely (e.g. the AV shunts often clot48), particularly
if the haemoglobin response is too rapid, therefore it is recommended that the dose be tailored
so that the monthly haemoglobin rise is no greater than 20 g/L.49
24
Anaemias and Polycythaemias
Haemolytic anaemias
Haemolytic anaemias are caused by the premature destruction of RBCs due to disorders that
cause either intravascular or extravascular haemolysis (Table 2.5).
Table 2. 5
Causes of haemolytic anaemias
Intravascular haemolysis
Incompatible blood transfusion
Hypotonic intravenous fluids
Cardiac prosthesis, march haemoglobinuria
Arteriopathies
thrombotic thrombocytopenic purpura
haemolytic uraemic syndrome,
scleroderma, malignant hypertension
DIC
Envenomation
Extravascular haemolysis
Autoimmune haemolytic anaemia
(warm antibody, cold antibody)
Physical abnormalities of the RBC
RBC membrane disorders, enzyme defects
thalassaemias, haemoglobinopathies
Hypersplenism
Intravascular haemolysis
The causes of intravascular haemolysis include, incompatible blood transfusion, hypotonic
intravenous fluids, RBC trauma (march haemoglobinuria, cardiac prosthesis), paroxysmal
nocturnal haemoglobinuria (caused by an acquired genetic disorder which enhances RBCs
sensitivity to complement and characterised by chronic haemolytic anaemia, nocturnal
haemolysis and thrombosis50) and the arteriopathies.
1. Hypotonic intravenous fluids: normal RBCs do not begin to haemolyse unless they are
suspended in a solution with an osmolality of 160 mosmol/kg (e.g. 0.5% saline), and
complete haemolysis occurs when the RBCs are suspended in a solution with an
osmolality of 110 mosmol/kg (e.g. 0.35% saline). In clinical practice, solutions down to
an osmolality of 143 mosmol/kg (e.g. 0.45% saline solutions) can be infused through a
peripheral vein without causing haemolysis, and, due to rapid mixing, even sterile water
can be infused through a central venous catheter without causing intravascular
haemolysis.51
2. Arteriopathies
a. Thrombotic thrombocytopenic purpura (TTP) is a disease caused by an acquired
reduction in plasma von Willebrand factor – cleaving protease activity (due to an
IgG autoantibody),52,53 leading to the binding of unusually large multimers to
platelets and results in platelet microthrombi that characterise the disorder. It has
been described following the administration of chemotherapeutic agents (e.g.
cyclosporine, mitomycin),54 ticlopidine,55 clopidogrel,56 and has been associated with
HIV infection57, systemic lupus erythematosis, scleroderma and Sjögren’s
syndrome.58
25
Anaemias and Polycythaemias
b.
c.
It is characterised by intravascular fibrin deposition on the damaged surface of
small blood vessels, causing a thrombocytopenia (< 20,000), microangiopathic
haemolytic anaemia (haemoglobin < 55 g/L in 30%; RBCs are fragmented and
nucleated), elevated plasma LDH, renal failure and fluctuating neurological
manifestations. The coagulation tests are often normal (if they indicate a DIC then
the diagnosis is most likely doubtful). A positive antinuclear antibody is present in
20% of cases. The disease may span days to months; and, while arthralgias,
abdominal pain, purpura and fever are common, as the disease progresses the brain
and kidney become progressively involved and the clinical picture usually becomes
predominantly neurological, with confusion, disorientation, seizures, hemiparesis
and aphasias. TTP is a clinical diagnosis, because biopsy tissue (e.g. renal) may not
contain arterial thrombi.
The most consistently effective form of treatment is plasmapheresis (to remove
the IgG autoantibody) using 7 exchanges of FFP in 9 days (to replenish the plasma
von Willebrand factor – cleaving protease activity),59 and may be associated with
reversal of coma.60 Variable success has been reported with, corticosteroids,
antiplatelet agents (e.g. aspirin, dipyridamole), fresh frozen plasma, prostacyclin and
cytotoxic agents (e.g. vincristine 1 mg per 1-4 weeks for 2-5 doses,
cyclophosphamide or azathioprine).61
The haemolytic uraemic syndrome (HUS) characterised by a triad of
microangiopathic haemolytic anaemia, thrombocytopaenia and renal failure, is
thought to be a variant of TTP (although unlike TTP it does not have a reduction in
von Willebrand factor – cleaving protease activity and has less CNS involvement,
and more renal involvement). It exists in a diarrhoeal-associated epidemic form, and
may follow an Escherichia coli (particularly the Shiga toxin producing serotypes
O157:H7 and O103:H2),62 Shigella, Salmonella, Streptococcus pneumoniae,
Campylobacter, Yersinia, coxsackie, influenza or Epstein-Barr infection,63 as well as
nondiarrhoeal sporadic or rare familial forms. The diarrhoeal-form is more common
in children of 3 - 10 years and they often recover. The sporadic and non-infective
forms usually affects adults and generally carries a worse prognosis. An overactivity
of the alternative complement pathway has been reported in the familial form of
HUS,64 suggesting that an abnormality of factor H (with an increase in complement
activation by the alternative pathway) may be involved in the aetiology of all cases
of HUS.
Treatment of HUS is commonly plasmapheresis (e.g. 7 exchanges of FFP in 9
days). Antibiotics early during the course of the disease (e.g. beta-lactams,
fluroquinolones, tetracyclines) do not alter the course of the disease and may even
worsen it.65
A TTP-like syndrome may also occur with malignant hypertension, eclampsia,
transplantation, scleroderma and systemic lupus erythematosus; these are discussed
elsewhere.
Clinical features. The symptoms and signs of an intravascular haemolysis depends on the
rate of haemolysis. For example, intravenous haemolysis due to an incompatible blood
transfusion presents with shock, rigors, urticaria, and dyspnoea, followed by haemoglobinuria,
excessive bleeding and oliguria, whereas haemolysis due to in intravascular prosthesis may
present with features of an anaemia (e.g. tiredness, weakness, angina, cardiac failure).
26
Anaemias and Polycythaemias
Investigations. The investigations include:
1. Complete blood picture: the features of an intravascular haemolysis include an anaemia,
reticulocytosis and altered RBC morphology. The bone marrow can increase RBC production
by eight times before an anaemia occurs, which will present when the RBC life span is reduced
to less than 20 days. At this stage the reticulocyte count will be approximately 20 - 30%. The
RBC morphology reveals spherocytosis, polychromasia and (in the case of microangiopathic
haemolytic anaemia), fragmented cells.
2. Plasma haptoglobin, haemopexin, methaemalbumin and free haemoglobin levels, and
urinary haemoglobin and haemosiderin excretion: haptoglobin is an alpha-globulin
acute-phase reactant, with a normal half-life of 4 days. Half the circulating pool of haptoglobin
is renewed daily. It combines specifically and tightly with the globin moiety of free
haemoglobin, being able to bind 500 - 1500 mg of free haemoglobin per litre of plasma, which
is cleared rapidly from the circulation, with a half-life of 9 - 30 min. An intravascular
haemolysis, with a RBC half-life of 17 days or less, is associated with an undetectable plasma
level of haptoglobin.66
Haemopexin is a plasma beta-globulin which binds specifically to haem and becomes
depleted in patients with moderate to severe haemolysis. In addition, some of the free
haemoglobin may combine with albumin to form methaemalbumin when haptoglobin and
haemopexin are depleted. Once the protein binding capacity of the plasma is exceeded, free
haemoglobin is filtered at the glomerulus, which is reabsorbed by the proximal tubule and
stored as haemosiderin and ferritin. The presence of haemosiderin in the urine indicates that a
significant amount of haemoglobin has been filtered by the kidneys. When the absorptive
capacity of the proximal tubule is exceeded, haemoglobinuria occurs, producing a red colour in
alkaline urine (i.e. oxyhaemoglobin) and a black colour in an acidic urine (i.e.
methoxyhaemoglobin).
3. Plasma bilirubin and LDH levels: significant intravascular haemolysis is associated with
an elevated unconjugated bilirubin level (often no greater than twice normal unless hepatic
disease is also present), acholuria (i.e. the unconjugated bilirubin is bound to albumin and so is
not excreted in the urine), increased urobilinogen excretion (although faecal measurement is
difficult and urinary excretion is unreliable because it is dependent upon urinary pH) and an
elevation in the plasma LDH (isoenzymes 1 and 2).
4. RBC survival studies: the demonstration of a reduced RBC life span is the definitive test
of a haemolytic anaemia. This can be performed using chromium 51 labelled RBCs, measuring
the rate of disappearance of the labelled RBCs from the circulation and is usually coupled with
an estimation of organ uptake to assess the major sites of RBC destruction.
Extravascular haemolysis
In these disorders RBCs are taken up and destroyed by the RES of the liver and spleen.
Extravascular haemolysis is not associated with release of free haemoglobin into the
circulation.
Extravascular haemolysis may be caused by an autoimmune haemolytic anaemia (AIHA),
RBC enzyme defect or hypersplenism.
Autoimmune haemolytic anaemia.67
1.
Warm antibody: warm antibody AIHA is often due to an IgG, and occasionally an IgA,
RBC antibody which may be idiopathic or associated with lymphomas, SLE or drugs.68
The drug induced AIHA may be one of three types:
27
Anaemias and Polycythaemias
a.
2.
Alpha methyldopa may induce an IgG antibody to the RBC surface. Approximately
10% of patients taking 2 g of alpha-methyl-dopa have a positive Coombs' test.
Procainamide may induce a similar antibody.69
b. Penicillin may associate with the RBC surface and induce an IgG antibody against
the RBC-penicillin complex. This is usually found only in patients taking 15 - 20
million units of penicillin daily, and occurs 7 - 10 days after therapy begins.
Cephalosporins may also cause this type of haemolytic anaemia.
c. Quinidine forms a complex with plasma protein, to which an IgG or IgM antibody
forms. The quinidine-protein-AB complex then settles on RBCs or platelets causing
the 'innocent bystander' AIHA (or thrombocytopenia). Other drugs to cause this type
of AIHA include, quinine, sulphonamides, quinolones, isoniazid, and phenacetin.
Cold antibody: cold agglutinins are IgM RBC antibodies which may be associated with
acute diseases (i.e. mycoplasma, infectious mononucleosis) or chronic diseases (i.e.
lymphoma, idiopathic). The agglutination of RBCs by IgM cold agglutinins occur at low
temperatures (less than 32ºC); disagglutination occurs with rewarming. Most cold
agglutinins are inefficient in fixing complement to the cell surface and so agglutination
and haemolysis in vivo may be only mild.
Clinical features of AIHA. These are similar to the features of any chronic anaemia.
Investigation of AIHA. The Coombs' Test is used to detect sensitisation of RBC or
antibody in plasma.
1. Direct Coombs' test: this is performed to detect sensitisation of red blood cells (i.e. the
process of adherence of protein molecules to the surface of the RBC) by an antibody. The
RBCs under investigation are washed thoroughly, then mixed in equal amounts with the
Coombs' reagent. The Coombs' reagent is prepared by injecting rabbits repeatedly with either
whole human serum or with pure components, until an antiserum of sufficient anti IgG and anti
complement titre can be harvested. If whole serum has been used, certain components have to
be removed to make the test specific. The Coombs' test is generally accepted to work by
bridging the gap between incomplete antibodies, thus linking RBCs and therefore causing
agglutination. After an incompatible blood transfusion, the Coombs' test will be positive on the
post-transfusion specimen, showing sensitisation of RBCs
2. Indirect Coombs' test: this is performed to detect the presence of an antibody in the
serum (e.g. to detect rhesus antibody). In this case the RBCs containing the appropriate antigen,
are used as indicators only. Suitable RBCs are mixed with serum under investigation for 30 60 min then washed and then treated as for the direct Coombs' test.
Treatment of AIHA. The warm antibody autoimmune haemolytic anaemias are treated by
treating the precipitating factors (i.e. cease drugs, removal of thymoma or ovarian tumour).
Oral or intravenous corticosteroids improve the survival of the antibody-coated cells without
dramatically changing antibody levels or production. Prednisolone 1 - 2 mg/kg/day (60 - 120
mg/day) will produce an effective remission in 60% of patients, (40% of whom are able to be
controlled by low doses, i.e. < 20 mg/day, and 60% are controlled by intermediate doses, i.e. 20
- 40 mg/day). The remaining 40% are either controlled by unacceptably high steroid
administration or are steroid resistant. The variable response to splenectomy and its long term
complications such as overwhelming sepsis makes the introduction of immunosuppressive
agents of azathioprine and cyclophosphamide the next option. These have a slow onset and
have been reported to be successful in 60 - 70% of steroid resistant AIHA patients.
28
Anaemias and Polycythaemias
Plasmapheresis is considered to be relatively ineffective for AIHA. Splenectomy or
immunoglobulin may be considered for steroid and immunosuppression-resistant patients.
The cold antibody autoimmune haemolytic anaemias are treated by treating the underlying
disease (e.g. lymphoma, chronic lymphatic leukaemia), otherwise treatment is largely
supportive as it is usually unresponsive to glucocorticoids. For example, avoidance of cold,
folic acid and transfusions of packed, warmed (i.e. infused through a warming coil) and washed
RBC (to remove any extra source of complement).
Physical abnormalities of the RBC: RBC enzyme defects. The RBC, at maturity, retains
non-oxygen utilising metabolic pathways (i.e. the glycolytic pathway, hexose monophosphate
shunt and the Rapoport-Luebering shuttle). The glycolytic pathway generates ATP, 50% of
which is used to drive the cell-wall cation pump. Much of the remaining energy is used for
renewal of membrane phospholipids. The Hexose monophosphate shunt forms reduced
nicotinamide adenine dinucleotide, which in turn is used to maintain levels of reduced
glutathione needed to protect haemoglobin and the membrane from exogenous oxidants. The
protection is afforded by the continual availability of the thiol (-SH) groups of reduced
glutathione, which are used in preference to the -SH groups of haemoglobin and the cell
membrane. The normal RBC protects itself against oxidant stress by increasing the amount of
glucose metabolised by the hexose monophosphate shunt (which is normally only 10%) to
increase the regeneration of reduced glutathione. Also the oxidation of Fe2+ to Fe3+
(methaemoglobin) is reversed by this system.
Defects of the glycolytic pathway (i.e. pyruvate kinase deficiency) present with haemolytic
anaemias in early childhood. Defects in the hexose-monophosphate shunt (i.e. GPD deficiency)
inhibits the formation of reduced glutathione, resulting in oxidation of haemoglobin sulphydryl
groups and causing some of the haemoglobin to precipitate within the RBC and form Heintz
bodies. Patients with GPD deficiency may also present with an acute haemolytic crisis within 1
h of ingesting an oxidant (e.g. drug-induced haemolysis; Table 2.6), causing hypotension, a
rapid drop in haematocrit, a rise in plasma haemoglobin and a fall in haptoglobin. As the
disorder is self-limiting the treatment is largely supportive (i.e. discontinue the drug, correct
shock, anaemia and dehydration)
Table 2. 6 Drugs which may cause haemolysis in G6PD deficient individuals
Sulphonamides
Primaquine, chloroquine
Quinine, quinidine and chloramphenicol
Methylene blue, vitamin K, nalidixic acid, nitrofurantoin
Nitrates
Hypersplenism. This term is applied to any clinical situation in which the spleen removes
excessive quantities of circulating cellular elements. The criteria for its diagnosis include
splenomegaly (Table 2.7), splenic destruction of one or more of the circulating cellular
elements, normal or hyperplastic cellularity of the bone marrow, and evidence of increased
turnover of the depleted cell line with evidence of increased splenic uptake.
POLYCYTHAEMIA
Polycythaemia is diagnosed in the presence of a packed cell volume (PCV) of greater than
52% for males or greater than 47% for females (i.e. haemoglobin > 180 g/L for males and >
29
Anaemias and Polycythaemias
165 g/L for females), and may be primary (polycythaemia rubra vera) or secondary (e.g.
hypoxia).
Polycythaemia rubra vera
Cause. While polycythaemia rubra vera is characterised by overproduction of all myeloid
elements, the disease is usually dominated by an elevated haemoglobin concentration.
Clinical features. The symptoms include, headache, dizziness, vertigo, tinnitus, weakness,
pruritus (particularly with warm bath or shower, which is histamine mediated and may be
corrected with cimetidine),70 sweating and a predilection to thrombosis and haemorrhage.
The signs include ruddy cyanosis, injected conjunctiva, engorged retinal veins,
splenomegaly and hepatomegaly.
Table 2. 7 Causes of splenomegaly
Infections
infectious mononucleosis, septicaemia, endocarditis
tuberculosis, malaria, hydatid, AIDS, viral hepatitis, brucellosis
leishmaniasis, histoplasmosis, trypanosomiasis, typhoid, paratyphoid
Immunoregulation diseases
rheumatoid arthritis, SLE, AIHA, serum sickness
Portal hypertension
cirrhosis, congestive heart failure
hepatic, splenic or portal vein obstruction
RBC diseases
thalassaemia, sickle cell disease
Infiltrative diseases of the spleen
amyloidosis, lipid storage diseases
leukaemias, lymphomas, myelofibrosis, polycythaemia rubra vera
Miscellaneous
thyrotoxicosis, sarcoidosis
Investigations. An elevated RBC volume in males greater than 36 ml/kg and females
greater than 32 ml/kg, in the presence of a normal arterial blood saturation (or greater than
91%) and in the absence of carboxyhaemoglobin, is usually diagnostic (i.e. in the absence of a
secondary polycythaemia). Serum or urinary erythropoietin levels are reduced or absent, serum
uric acid is increased, the ESR is low and leucocyte alkaline phosphatase is often elevated. The
neutrophil and platelet counts and the serum vitamin B12 binding capacity (i.e. transcobalamin I
and II levels) are elevated in 75% of cases.
Treatment. Without treatment, survival is often reduced to 2 years. With treatment survival
may be extended to 10 - 12 years. Treatment consists of phlebotomy, which is best used
initially to reduce RBC mass, and for young patients with mild disease (to reduce the
haematocrit to below 45%), or myelosuppressive therapy, consisting of radiation, 32P, or
hydroxyurea, which is best used in the elderly who have extreme symptomatic thrombocytosis,
a rapidly enlarging spleen or symptoms of hypermetabolism.
30
Anaemias and Polycythaemias
Secondary polycythaemia
Causes. Causes of secondary polycythaemia include disorders that increase erythropoietin
secondary to hypoxia or ectopic production, and disorders that reduce plasma volume, i.e.
spurious polycythaemia. (Table 2.8)
Treatment. In patients who have COPD and polycythaemia, a reduction in PCV down to
50-55% reduces pulmonary vascular resistance and right ventricular stroke work (particularly
during exercise). Further reduction of PCV is of no benefit, thus a reduction in PCV in COPD
patients is only considered if it is greater than 55%.71 In patients with cyanotic congenital heart
disease, if PCV values are above 60%, a reduction in PCV by 10% is associated with increased
oxygen uptake and reduction in oxygen debt; these patients may also benefit from venesection
to no lower than 55%.
Table 2. 8
Causes of secondary polycythaemia
Hypoxaemia
chronic pulmonary diseases, sleep apnoea
chronic carboxyhaemoglobinaemia (i.e., smoking)
cyanotic cardiac diseases
haemoglobinopathy with an abnormal 'shift to the left'
Ectopic erythropoietin production
renal carcinoma, hepatoma, cerebellar haemangioma
Reduced plasma volume
diuretics
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22. Scott JM, Weir DG. The methyl folate trap. Lancet 1981;ii:337-340.
23. Scott JM, Dinn JJ, Wilson P, Weir DG. Pathogenesis of subacute combined degeneration:
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24. Flippo TS, Holder WD Jr. Neurologic degeneration associated with nitrous oxide
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haemopoiesis in patients receiving nitrous oxide. Lancet 1978;ii:339-345.
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Anesth Analg 1988;67:1018-1019.
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29. Nunn JF, Chanarin I, Tanner AG, Owen ERTC. Megaloblastic bone marrow changes after
repeated nitrous oxide anaesthesia. Br J Anaesth 1986;58:1469-1470.
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31. Lindenbaum J, Rosenberg IH, Wilson PWF, Stabler S, Allen RH. Prevalence of
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32. Spence D. Uses of error: knowledge gaps. Lancet 2001;358:1934.
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J 1974;2:550-553.
35. Linnell JC, Matthews DM. Cobalamin metabolism and its clinical aspects. Clin Sci
1984;66:113-121.
36. Allen LH, Casterline J. Vitamin B-12 deficiency in elderly individuals: diagnosis and
requirements. Am J Clin Nutr 1994;60:12-14.
37. Elia M. Oral or parenteral therapy for B12 deficiency. Lancet 1998;352:1721-1722.
38. Heyworth-Smith D, Hogan PG. Allergy to hydroxocobalamin, with tolerance to
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39. Wallerstein RO. Role of the laboratory in the diagnosis of anemia. JAMA 1976;236:490493.
40. Editorial. Iron and resistance to infection. Lancet 1974;ii:325-326.
41. Editorial. Anaemia of chronic renal failure. Lancet 1983;i:965-966.
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42. Eschbach JW, Adamson JW. Anemia of end-stage renal disease (ESRD). Kidney Int
1985;28:1-5.
43. Dodds A, Nicholls M. Haematological aspects of renal disease. Anaesth Intens Care
1983;11:361-368.
44. Winearls CG, Oliver DR, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human
erythropoietin derived from recombinant DNA on the anaemia of patients maintained by
chronic haemodialysis. Lancet 1986;ii:1175-1178.
45. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the
anaemia of end-stage renal disease with recombinant human erythropoietin: results of a
phase I and phase II clinical trial. N Engl J Med 1987;316:73-78.
46. MacDougall IC, Lewis NP, Saunders MJ, Cochlin DL, Davies ME, Hutton RD, Fox
KAA, Coles GA, Williams JD. Long-term cardiorespiratory effects of amelioration of
renal anaemia by erythropoietin. Lancet 1990;335:489-493.
47. Cotes PM. Erythropoietin: the developing story. Br Med J 1988;296:805-806.
48. Raine AEG. Hypertension, blood viscosity, and cardiovascular morbidity in renal failure:
implications of erythropoietin therapy. Lancet 1988;i:97-100.
49. Firkin F. Recombinant human erythropoietin enters the pharmacopeia. Aust NZ J Med
1989;19:279-280.
50. Schwartz RS. PIG-A - the target gene in paroxysmal nocturnal hemoglobinuria. N Engl J
Med 1994;330:283-284.
51. Worthley LIG. Hyperosmolar coma treated with intravenous sterile water - a study of
three cases. Arch Intern Med 1986;146:945-947.
52. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer
I, Aumann V, Mittler U, Solenthaler M, Lammle B. Von Willebrand factor - cleaving
protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
New Engl J Med 1998;339:1578-1584.
53. Tsai H-M, Lian EC-Y. Antibodies to von Willebrand factor-cleaving protease in acute
thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585-1594.
54. Moake JL. TTP - desperation, empiricism, progress. N Engl J Med 1991;325:426-428.
55. Kupfer Y, Tessler S. Ticlopidine and thrombotic thrombocytopenic purpura. N Engl J
Med 1997;337:1245.
56. Bennett CL, Connors JM, Carwile JM, Moake JL, Bell AJ, Tarantolo SR, McCarthy LJ,
Sarode R, Hatfield AJ, Feldman MD, Davidson CJ, Tsai H-M. Thrombotic
thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342:17731777.
57. Stewart GJ. Could it be HIV? 1. The challenge: clinical diagnosis of HIV. Med J Aust
1993;158:31-34.
58. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347:589-600.
59. Moake JL. Moschcowitz, multimers, and metalloprotease. N Engl J Med 1998;339:16291631.
60. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA,
and the Canadian Apheresis Study Group. Comparison of plasma exchange with plasma
infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med
1991;325:393-397.
61. Schmidt JL. Thrombotic thrombocytopenic purpura: successful treatment unlocks
etiologic secrets. Mayo Clin Proc 1989;64:956-961.
62. Rondeau E, Peraldi M-N. Escherichia coli and the hemolytic-uremic syndrome. N Engl J
Med 1996;335:660-662.
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Anaemias and Polycythaemias
63. Ferris TF. Preeclampsia and postpartum renal failure: examples of pregnancy induced
microangiopathy. Am J Med 1995;99:343-347.
64. Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P,
Goodship JA. Genetic studies into inherited and sporadic hemolytic uremic syndrome.
Kidney Int 1998;53:836-844.
65. Todd WTA. Prospects for the prevention of haemolytic-uraemic syndrome. Lancet
2001;357:1636-1638.
66. Hershko C. The fate of circulating haemoglobin. Br J Haematol 1975;29:199-204.
67. Gibson J. Autoimmune hemolytic anemia: current concepts. Aust NZ J Med 1988;18:625637.
68. Garratty G, Petz LD. Drug-induced immune hemolytic anemia. Am J Med 1975;58:398407.
69. Kleinman S, Nelson R, Smith L, Goldfinger D. Positive direct antiglobulin tests and
immune hemolytic anaemia in patients receiving procainamide. N Engl J Med
1984;311:809-812.
70. Easton P, Galbraith PR. Cimetidine treatment of pruritus in polycythaemia vera. N Engl J
Med 1978;299:1134.
71. Editorial. Polycythaemia due to hypoxaemia: advantage or disadvantage? Lancet
1989;i:20-22.
34
Chapter 3
HAEMOSTASIS, PLATELET FUNCTION
and COAGULATION
HAEMOSTASIS
There are four processes which maintain haemostasis and arrest bleeding after injury,
vascular smooth muscle constriction, platelet adhesion and aggregation (i.e. primary
haemostasis), fibrin generation by intrinsic and extrinsic coagulation pathways (i.e. secondary
haemostasis), and fibrinolysis and re-endothelialisation of the vascular surface. The
haemostatic function of the microvasculature and platelets are closely linked and vascular
disorders that cause bleeding often have similar clinical presentations to the thrombocytopenic
disorders and are often classified as non thrombocytopenic purpuras. The causes of non
thrombocytopenic purpuras are listed in Table 3.1.
Table 3.1 Nonthrombocytopenic purpuras
Age, idiopathic
Allergic or Henoch-Schönlein purpura
Septicaemia
Scurvy
Paraproteinaemias
Thrombocythaemia
Prolonged corticosteroid administration
Fat embolism
PLATELET FUNCTION
Platelets are non-nucleated cytoplasmic fragments with a diameter of 2 - 4 µm. They are
derived as cytoplasmic fragments from megakaryocytes and have a lifespan of 8 - 10 days.
While thrombopoietin is the dominant hormone controlling megakaryocyte development many
cytokines and other hormones are involved including IL-3, IL-6 and IL-11.1 Normally about
30% of platelets are sequestrated in the spleen, a percentage which is increased during
hypothermia (which may cause thrombocytopenia), and returned on rewarming.2
While the platelet factor nomenclature has largely been abandoned, platelet factor 3 (PF-3)
is still used to describe the platelet phospholipid procoagulant activity necessary for the
coagulation cascade, and platelet factor 4 is still used to describe the cationic alpha-granule
protein which has the capacity to neutralise heparin.
The endothelial cell products of nitric oxide and prostacyclin, maintain quiescent platelet
activity as they traverse intact vessels. With disruption of the endothelium, the platelet performs
its haemostatic function by the events; adhesion, activation, release and aggregation.
35
Haemostasis, Platelet function and Coagulation
Adhesion
Platelet adhesion is triggered by damage to the vascular endothelium and exposure of the
subendothelial matrix. Coverage of the exposed site by platelets depends on the recognition of
adhesive proteins by specific platelet-membrane glycoproteins, some of which are integrins
(e.g. glycoprotein Ia/IIa which binds to collagen, glycoprotein Ic/IIa which binds to fibronectin)
and others are not (e.g. glycoprotein Ib which binds to von Willebrand factor and Glycoprotein
IV which binds to thrombospondin as well as collagen, Figure 3.1). The platelet membrane
glycoprotein IIb/IIIa integrin, in addition to its function in platelet aggregation, also has a role
in platelet adhesion.3
Figure 3.1 Binding of von Willebrand factor (vWF) and fibrinogen to platelet membrane glycoproteins. Fibrinogen
binds to the glycoprotein IIb/IIIa-Ca2+ complex, in the presence of ADP. vWF can either bind to glycoprotein Ib, in the
absence of ADP or bind to the glycoprotein IIb/IIIa-Ca2+ complex, in the presence of ADP (Reproduced, and modified,
with permission, from Stein B, Fuster V, Israel DH, Cohen M, Badimon L, Badimon JJ, Chesebro JH. Platelet inhibitor
agents in cardiovascular disease: an update. J Am Coll Cardiol 1989;14:813-836).
Activation
A variety of platelet stimuli (e.g. collagen, thrombin, adrenaline, serotonin) bind to their
specific platelet surface receptors and function in concert to trigger a cascade of intracellular
reactions that lead to the release reaction. Shear stress can also directly activate platelets.
Release
There are two classes of secretory granules; dense granules and alpha granules. Following
platelet activation, the dense granules secrete ADP and calcium to reinforce platelet
aggregation and platelet-surface coagulation reactions.4 The alpha granules secrete a large array
of proteins including, platelet factor 4, fibronectin, thrombospondin, platelet-derived growth
factor, fibrinogen, plasminogen, factors V and VIII and vWF) to the exterior, and the
arachidonate products of prostaglandin G2 (PGG2), prostaglandin H2 (PGH2) and TxA2 (the
formation of which is blocked by aspirin), are also released causing platelet contraction.
Aggregation
Contact with collagen, and with thrombin formed from tissue injury, triggers platelet
liberation of ADP (ADP binding to its platelet receptor is inhibited by ticlopidine and
36
Haemostasis, Platelet function and Coagulation
clopidogrel) and serotonin, and formation of thromboxane A2 (TxA2) from platelet-membrane
phospholipids (blocked by aspirin), stimulating vasoconstriction, fibrin deposition and platelet
aggregation.
The aggregation of platelets is mediated by membrane glycoproteins IIb/IIIa and a
fibrinogen link (Figure 3.1).Glycoprotein IIb/IIIa antagonists inhibit platelet aggregation by
blocking fibrinogen binding to activated glycoprotein IIb/IIIa receptors. Platelet aggregation
does not occur in the absence of divalent cations or fibrinogen, which explains why a
prolonged bleeding time occurs in patients with hypofibrinogenaemia.
PLATELET DISORDERS
Thrombocytopenia
The circulating platelet count normally ranges from 150,000 to 400,000/µL.
Thrombocytopenia is usually defined as a platelet count less than 100,000/µL.
Causes. The causes of thrombocytopenia include those disorders listed in Table 3.2.
Clinical features. The main clinical feature is bleeding. Patients who have platelet counts:
- Below 100,000 /µL have an abnormal bleeding time and an abnormal Hess test
- Below 80,000 /µL have prolonged bleeding with trauma or surgery
- Below 40,000 /µL have spontaneous purpuric spots
- Below 20,000 /µL have spontaneous bleeding (e.g. haematemesis, epistaxis).
The characteristic feature of thrombocytopenic bleeding is that it occurs immediately after
injury. Spontaneous bleeding may present with purpura (i.e., capillary haemorrhages, the size
of a pinhead, into subcutaneous tissues on legs, conjunctival or buccal mucosa), ecchymoses,
mucosal bleeding (e.g. epistaxis, menorrhagia) and cerebrovascular haemorrhage. In women,
menorrhagia may be the first sign.
Table 3.2
Causes of thrombocytopenia
Reduced production
neoplasia, aplastic anaemia
drugs, severe sepsis, radiation, chemicals
folate or B12 deficiency
Reduced survival
antibody-induced
idiopathic thrombocytopenic purpura, SLE, CLL, haemolytic anaemias
drugs (quinidine, quinine, heparin, sulphonamides, penicillins, cephalosporins)
nonantibody induced
prosthetic cardiac valves, DIC, massive transfusion
thrombotic thrombocytopenic purpura
hypersplenism
Sequestration of platelets
hypothermia
Investigations. The investigations include:
1. Platelet count
2. Bone marrow: the megakaryocyte count is reduced if there is a decreased production of
platelets, and increased if there is a reduced platelet survival.
37
Haemostasis, Platelet function and Coagulation
3. Hess (or tourniquet) test: this is performed by inflating a tourniquet on the patient's arm,
midway between the systolic and diastolic pressures, for 5 min. The cuff is then deflated and
the number of petechiae in a circle of 3 cm diameter and 1 cm below the antecubital fossa are
counted. If there are more than 20 petechiae, the test is positive. If the count is less than 10, the
test is normal. Between 10 - 20 the test is borderline. The test is positive in thrombocytopenia
and in conditions that cause nonthrombocytopenic purpuras.
4. Bleeding time: this is performed by inflating a blood pressure cuff on the arm to be tested
to a pressure of 40 mmHg. An incision 9 mm long and 1 mm deep on the anterior surface of the
midforearm is made with a scalpel. The incision is touched at exactly 30 s intervals with a piece
of absorbent paper, and the time interval until blood no longer moistens the paper is recorded.
The normal bleeding time is 5 + 3 min (2 - 8 min). The bleeding time is prolonged with
thrombocytopenia, aspirin and other NSAIDs, a packed cell volume less than 30%,5 (as a low
packed cell volume reduces normal platelet margination6, thus bleeding times should be
standardised to a haematocrit of greater than 35%),7 uraemia (some of which may be due to a
reduced haematocrit), hypothyroidism, vWD, penicillins, cephalosporins and massive
transfusion.8 While the bleeding time is often described as the best single test for platelet
function, it has not been shown to be an accurate predictor of surgical bleeding.9
5. Other platelet function tests: platelet aggregation and secretion function tests are only
performed when a specific platelet disorder is suspected.
Treatment. The treatment may include:
1. Platelet concentrate: administered through a clean standard blood giving set, platelet
concentrate (i.e. platelets harvested from six donors) will raise the platelet count by about
30,000/µL, and should be used in postoperative patients or patients who are bleeding and have
a platelet count of less than 50 - 100,000/µL. Platelet concentrate should also be given to
patients who have platelet counts less than 5 - 20,000/µL who may not be bleeding, because
they are at risk of spontaneous haemorrhage.10,11 However, appropriateness of platelet
transfusion also depends on platelet function, timing and nature of an invasive procedure,
presence of an infection or coagulopathy, or the administration of chemotherapy. The half-life
of transfused platelets is usually 2 - 3 days. Platelet viability may be assessed by measuring the
platelet count 1 h after the platelet transfusion.12,13
2. DDAVP: desmopressin (DDAVP) is a vasopressin analogue which has a pronounced
antidiuretic action (i.e. a high affinity for V2 receptors), but virtually no pressor activity (i.e. no
affinity for V1 receptors). Intravenous desmopressin (0.3 µg/kg over 30 min or 300 µg
intranasally14), has been used to decrease the bleeding in patients with renal failure,15,16
cirrhosis,17,18 vWD.19 platelet defects (NSAID-induced and congenital platelet defects20,21) and
postoperative cardiac22,23 and orthopaedic surgery.24 It increases circulating plasma levels of
VIII/vWF complex by three- to five- fold (reaching a maximum at 60 - 120 min) and tissue
plasminogen activator, by releasing endothelial stores of these factors.25 It also increases
plasma levels of XII.26 It should be given with caution in patients with cerebral or coronary
atherosclerosis as there is an increased risk of coronary and cerebral artery thrombosis with its
use.
3. Fibrinolytic inhibitors: fibrinolytic inhibitors of epsilon-aminocaproic acid (15 mg/kg/hr)
or tranexamic acid (10 mg/kg 8-hourly) are sometimes given following DDAVP to inhibit the
activity of the associated increase in plasminogen activator. Also EACA may reduce bleeding
in patients with immune and nonimmune thrombocytopenia.27
4. Specific treatment: this involves the treatment of the underlying cause. For example, folic
acid and B12 repletion in deficient states, withdrawal of an offending toxin or drug (platelet
count usually returns to normal in 7-10 days), splenectomy in some instances of hypersplenism,
38
Haemostasis, Platelet function and Coagulation
and corticosteroids, immunosuppressants or plasmapheresis for autoimmune (i.e. antibody
induced) thrombocytopenias.
5. Recombinant human megakaryocyte growth and development factor: Pegylated
recombinant human megakaryocyte growth and development factor (0.03 - 1 µg/kg
subcutaneously for up to 10 days) has been used sucessfuly in the management of
thrombocytopenia in patients with advanced cancer.28
Platelet defects in disease
Renal failure
Haemostatic abnormalities occur in renal failure due to abnormal platelet adherence and
aggregation, and abnormal vasoconstriction; and nitric oxide (which inhibits collagen-induced
platelet aggregation29) may be partly responsible for the bleeding tendency.30 Treatment with
DDAVP (0.3 µg/kg or 20 µg/70 kg, in 50 mL of saline infused over 30 minutes) may give
temporary relief (i.e. 4 - 12 hr), whereas cryoprecipitate produces an effect which lasts for 24 36 h. Conjugated oestrogens (intravenous 'Premarin' 0.6 mg/kg daily for 5 days, i.e. 40 mg
daily for a standard man, or a total of 200 mg31) may also restore bleeding time in renal failure
patients for 3 - 14 days. Erythropoietin may be used to increase the PCV and thus reduce the
PCV effect on the bleeding time.
Hepatic failure
Haemostatic defects occur in hepatic failure due to a reduction in all coagulation factors
(apart from factor VIII), fibrinolysis and thrombocytopenia (which may be due to folate
deficiency, hypersplenism or marrow depression). Desmopressin (DDAVP, 0.3 µg/kg) has
been used to reduce the bleeding time in these patients.
Antiplatelet agents
Antiplatelet agents have been used to target the various steps of platelet function
Aspirin (acetyl-salicylic acid)
Action. For antiplatelet therapy, aspirin is the agent of choice. It inhibits platelet
aggregation mediated through activation of the arachidonic-thromboxane pathway (but not
platelet aggregation induced by ADP, collagen or low levels of thrombin). Aspirin irreversibly
acetylates and inactivates platelet and megakaryocyte cyclooxygenase (prostaglandin G/H
synthase), directly inhibiting conversion of arachidonic acid to prostaglandin G2 which reduces
prostaglandin H2 and ultimately TxA2 production (and its platelet effects of aggregation and
vasoconstriction)32. The antiplatelet effect is maximal in 20 minutes and it prolongs bleeding
time for the life of the platelet (i.e. 5 - 7 days)33. While long-term aspirin administration in
doses as low as 20 mg/day depress the platelet thromboxane formation by 90%, larger doses are
needed to prevent the thromboxane-induced platelet activation in vivo,34 with 100 mg almost
completely suppressing the biosynthesis of TxA2 in normal subjects and in patients with
atherosclerotic vascular disease. The effect of aspirin on endothelial cyclooxygenase is only
transient (i.e. lasts for only 2 - 4 hr35) because the endothelial cyclooxygenase is less sensitive
to aspirin and is able to be resynthesised (unlike platelet cyclooxygenase) between doses of
aspirin. Prostacyclin inhibition (and therefore inhibition of vasodilation) with aspirin therapy is
minimal36..
Indications. Aspirin is used to:37,38,39,40,41
- Prevent myocardial infarction and reduce mortality in patients with stable and unstable
angina and evolving myocardial infarction.
39
Haemostasis, Platelet function and Coagulation
-
Preserve coronary artery vein grafts (if administered 48 h postoperatively, although the
usual recommendation is 325 mg to start 6 hr after surgery42) and reduce morbidity and
mortality associated with coronary artery bypass grafting.43
Reduce abrupt closure (but not restenosis) following coronary artery angioplasty.
Prevent thromboembolic complications of cardiac valve disease.
Reduce the incidence and mortality of stroke in patients with TIAs, and in patients with
previous stroke.
Prevent occlusion in obliterative arterial disease of lower limbs.
Prevent colorectal cancer, particularly in patients with familial adenomatous polyposis, or to
prevent recurrence of gastrointestinal cancer in these patients after colectomy.44 However,
the reduction in colorectal cancer requires regular aspirin use for 10 (or more) years.45
It has also been used to:
- Reduce preeclampsia in nulliparous women who have a systolic blood pressure that is
persistently 120 mmHg or greater.46,47 However, in a large prospective, randomised, doubleblind, placebo-controlled trial, low-dose aspirin started between the 13th and 26th week of
gestation did not reduce the incidence of preeclampsia or improve perinatal outcomes in
pregnant women at high risk for preeclampsia.48
Dosage. Aspirin is usually administered in a dose ranging from 100 - 325 mg/day,49 (e.g. a
loading dose of 325 mg with a daily dose of 100 mg). To reduce the incidence of a stroke, a
dose of 30 - 75 mg/day is as effective as a daily dose of 325 mg.
Side-effects. These include peptic ulceration, gastrointestinal haemorrhage, asthma and
angio-oedema.
Sulphinpyrazone, indomethacin and other NSAIDs
The effect of these agents on platelet cyclooxygenase, unlike aspirin, is usually reversible
after 24 - 48 hr.
Dipyridamole
Dipyridamole is a phosphodiesterase inhibitor (predominantly phosphodiesterase V)50
which increases platelet cAMP, and is often combined with aspirin to gain an additive
antiplatelet effect. The antiplatelet effect has only been demonstrated when higher levels of
dipyridamole than that attained by conventional oral doses are achieved. In a comprehensive
review of all studies in which dipyridamole or dipyridamole plus aspirin were used, it was
concluded that there was little evidence to support its use as an antiplatelet agent.51
Dazoxiben
Theoretically drugs that inhibit thromboxane synthetase, such as dazoxiben, should be
superior to aspirin as antiplatelet agents. In addition to inhibiting TxA2 production they should
augment prostacyclin release by diverting platelet endoperoxide to serve as substrate for
prostacyclin synthesis in the vascular endothelium. However the prostaglandin endoperoxides
are proaggregatory in their own right and the thromboxane synthetase inhibitors have not been
found to prevent platelet aggregation as efficiently as aspirin.
Thienopyridines (Ticlopidine and Clopidogrel)
Action. Ticlopidine and its chemical analogue clopidogrel (which is six times as potent as
ticlopidine) are antagonists of ADP-induced platelet aggregation. They selectively and
irreversibly (i.e. noncompeditively) inhibit ADP binding to its platelet receptor thereby
40
Haemostasis, Platelet function and Coagulation
inhibiting ADP dependent activation of glycoprotein IIb/IIIa complex which is the major
receptor for fibrinogen on the platelet surface.52 They have no effect on phospholipase A
activity or thromboxane A2 and prostacyclin synthesis, and no direct effect on either cyclic
AMP-phosphodiesterase or adenylyl cyclase.53 Both ticlopidine and clopidogrel are inactive
when tested in vitro, thus the antiplatelet activity of both agents is produced by unidentified
metabolites, and their onset of action is delayed for hours or days, depending on the dose.54
Ticlopidine also reduces plasma fibrinogen, increases RBC deformity, inhibits platelet
adhesion, prolongs bleeding time, and blocks the release reaction of platelets. The antiplatelet
effect is associated with a twofold to fivefold prolongation of the bleeding time.
As clopidogel has a better adverse reaction profile when compared with ticlopidine it has
largely replaced ticlopidine in clinical practice.55
Indications. Clopidogrel and ticlopidine have a role in the primary and secondary
prevention of cerebrovascular infarctions and other thromboembolic complications in patients
who have suffered transient or reversible cerebral thromboembolic events.56,57 They reduce the
incidence of stroke, myocardial infarction and death in patients who have previously had a
stroke or TIAs.58 Clopidogrel also reduces the combined incidence of myocardial infarction,
stroke and vascular deaths in patients with atherosclerotic vascular disease, and in this regard
both of these agents are better than aspirin.59 Currently, they are administered for the
prevention of stroke, myocardial infarction, or vascular death in patients with atherosclerotic
vascular disease who are intolerant of aspirin.60
Dosage. An oral dose of 250 mg of ticlopidine twice daily is often administered. It has a
bioavailability of 80 - 90%. Its onset of activity is after 24 - 48 hr, with maximal activity
occurring after 3 - 5 days and activity still detectable 10 days after the last dose. The
elimination half-life for this agent is not known. An oral dose of clopidogrel 75 mg daily is
equivalent to an oral dose of ticlopoidine of 250 mg twice daily. Maximal inhibition of ADP
induced platelet aggregation occurs after 3 – 5 days after the initiation of the standard dose
(e.gt. 75 mg clopidogrel) but an oral loading dose of 300 – 600 mg of clopidogrel produces
detectable inhibition of ADP-induced aggregation after 2 hours, which is maximal at 4-6
hours.61
Side-effects. The side effects of ticlopidine include nausea, vomiting or diarrhoea in up to
10%, skin rash in 4% and reversible neutropenia in 2% of patients. The adverse effects of
neutropenia, thrombocytopenia or pancytopenia appear within the first three months of
treatment (requiring haemotological monitoring every two weeks for the first three months of
therapy) and are readily reversible (if neutrophil count < 1200) upon withdrawal of the drug.
Persistent diarrhoea necessitating discontinuation of the drug occurs in up to 5% of patients. It
also may cause cholestatic jaundice, an increase in serum cholesterol and thrombotic
thrombocytopenic purpura.62 Ticlopidine reduces phenytoin metabolism, and may lead to
phenytoin toxicity in previously stable patients.63
Clopidogel, at 75 mg/day, appears to have no toxic bone marrow effects (or a similar rate of
severe neutropenia to aspirin i.e. 0.05%) with a lower incidence of skin rash and diarrhoea
when compared with ticlopidine (although a higher incidence when compared with aspirin) and
a lower incidence of thrombotic thrombocytopaenic purpura (and usually within the first two
weeks of treatment64). It also has a lower incidence of severe gastrointestinal haemorrhage
when compared with aspirin (e.g. 0.49% cf. 0.71%).59
Glycoprotein IIb/IIIa receptor inhibitors
The final step leading to the formation of the platelet plug is platelet aggregation, which is
mediated by the binding of adhesive proteins to the glycoprotein IIb/IIIa receptor. Drugs that
inhibit glycoprotein IIb/IIIa receptors (e.g abciximab - developed from murine monoclonal
41
Haemostasis, Platelet function and Coagulation
antibody Fab fragments to the IIb/IIIa receptor, trigramin - from snake venom, and natural and
synthetic peptides or disintegrins such as integrelin, lamifiban and tirofiban) prevent the
binding of fibrinogen to these receptors and, unlike aspirin, inhibit platelet aggregation
irrespective of the pathway responsible for initiating aggregation.65 These drugs have been used
in clinical studies in patients with unstable angina to reduce myocardial infarction, and during
coronary angioplasty to reduce restenosis.
Abciximab produces a dose dependent irreversible blockade of the IIb/IIIa receptor, and an
effect of > 80% blockade occurs with 0.25 mg/kg as an intravenous bolus followed by an
intravenous infusion at 10 ug/min for 12 hours (this degree of receptor blockade is required to
prevent ischaemic complications in response to thrombotic provocations of balloon
angioplasty-induced damage to a stenotic atherosclerotic blood vessel, until the surface is no
longer highly reactive to platelets. A receptor blockade of 50% is not effective).66 While the
drug is cleared rapidly from the circulation, platelet-bound drug persists for several days.
Abciximab also binds to the vitronectin receptor (unlike the other peptide and nonpeptide
antagonists) an effect which may be important in its action in preventing thrombin generation
and restenosis following PTCA and coronary artery stenting.67
Bleeding is the major side effect (particularly from venous and arterial access sites) and can
only be overcome by platelet transfusions. Thrombocytopaenia (which may be profound i.e.
less than 10,000 /µL)68 and alveolar haemorrhage69,70 may also occur, requiring platelet
transfusion and discontinuation of all antiplatelet and anticoagulant therapy.71 Platelet counts
should be performed 2-4 hours after initiation of abciximab therapy and 24 hours later, to
monitor this rare complication.71 While human-antichimaeric antibodies develop in about 6% of
patients,72 in one study of approximately 500 patients, abciximab was readministered with a
similar efficacy and incidence of allergic reactions and thrombocytopaenia as with first-time
abciximab recipients.73
Tirofiban and lamifiban produce a rapidly reversible inhibition of the IIb/IIIa receptor. With
normal renal function tirofiban has a half life of 1.9 hours and lamifiban two hours.
Other agents
While, agents that block glycoprotein Ib/vWF interaction (e.g. monoclonal antibodies to vWF
or glycoprotein Ib) have been used experimentally, there is no experience with these agents in
humans.74 Prostacyclin has also been used to suppress platelet activity, although largely in
extracorporeal circuits where heparin cannot be used.75
Antiplatelet activity has also been reported with many other agents including, beta-lactam
antibiotics (e.g. penicillins, cephalosporins), calcium-channel blockers, EACA, heparin,
tricyclic antidepressants, phenothiazines, dextrans, ketanserin, radiographic contrast agents and
halothane,76,77 although they are not commonly used for their antiplatelet effect.
COAGULATION
Coagulation activation
Coagulation consists of a sequence of amplifying zymogen activations via an extrinsic or
intrinsic pathway, generating factor X activator to convert prothrombin to thrombin which
converts fibrinogen to fibrin (Figure 3.2).78
1. The intrinsic pathway: the exposure of blood to a negatively charged surface causes
factor XII to attach to the surface and form two activated factor XII molecules known as alphaXIIa and beta-XIIa. Alpha-XIIa remains bound to the surface and activates factor XI, and
factor XIa activates factor IX. Exposure to a negatively charged surface also causes high
molecular weight (HMW) kininogen to attach to the surface with prekallikrein. Beta-XIIa
42
Haemostasis, Platelet function and Coagulation
(which is not retained on the surface) activates prekallikrein (but not factor XI) to kallikrein.
Kallikrein splits bradykinin (a potent peripheral arteriolar vasodilator - due to endothelial
release of NO and prostacyclin79 - with a half-life of 20 s) from HMW kininogen, reciprocally
activates factor XII and activates plasminogen to plasmin.
It is suggested that perhaps the net effect of activation of Hageman factor to its fragments is
not to promote clotting by activating factor XI but, via the action of kallikrein and plasmin,
favour vessel patency by initiating vasodilation and fibrinolysis,80 particularly as patients who
have an autosomal recessive hereditary deficiency of one of the contact factors (i.e. factor XII,
prekallikrein or HMW kininogen), despite having a prolonged APTT, do not bleed abnormally
even after trauma.
Figure 3.2 A diagram of blood coagulation reactions. HMWK = high molecular weight kininogen, KAL = kallikrein,
PLAT. LIPID = platelet procoagulant phospholipid, PREK = prekallikrein, TF = tissue factor (Reproduced, with
permission, from Rapaport SI. Chapter 25 Haemostasis. In: West JB ed. Best and Taylor's Physiological Basis of
Medical Practice, 11th Ed. Baltimore: Williams and Wilkins, 1985:409-436).
2. The extrinsic pathway: factor VII is activated by tissue phospholipid.
3. Factor X activation: factor X is activated by either a complex (from the intrinsic
pathway) consisting of factor VIIIa (activated by thrombin), platelet phospholipid, Ca2+ and
factor IXa, or a complex (from the extrinsic pathway) consisting of tissue phospholipid, Ca2+
and factor VIIa.
43
Haemostasis, Platelet function and Coagulation
4. Thrombin formation: activated factor X then forms a complex with platelet phospholipid,
Ca2+ and factor Va (activated by thrombin) to form a prothrombin activator, which converts
prothrombin to thrombin.
5. Fibrin formation: thrombin is a proteolytic enzyme with a molecular weight of 30 000 36 000; it cleaves fibrinogen to form fibrin and activates factor XIII to convert fibrin to a stable
cross-linked fibrin polymer. Fibrin adsorbs large amounts of thrombin at the site of its
production and this property is given the term 'antithrombin I' although the thrombin so
adsorbed is not inactivated and may reappear during clot retraction or fibrinolysis.
While a single extrinsic or intrinsic pathway activation explains the in vitro coagulation
tests [i.e. the APTT and the International Normalised Ratio (INR) assesses the intrinsic and
extrinsic systems, respectively], there are many interactions between the intrinsic and extrinsic
systems, indicating that both pathways act during in vivo coagulation. In particular, factor VIIa
activates factor IX; factors IXa, Xa, XIIa and thrombin activate factor VII; factor Xa activates
VII; and thrombin activates platelet aggregation, factors I, XIII, VIII and V, Protein C (with the
endothelial thrombomodulin as a cofactor) and plasminogen81 (Figure 3.3).
Figure 3.3 The many actions of thrombin in blood coagulation. Prot C = Protein C, Prot Ca = activated Protein C
(Reproduced, with permission, from Rapaport SI. Chapter 25 Haemostasis. In: West JB ed. Best and Taylor's
Physiological Basis of Medical Practice, 11th Ed. Baltimore: Williams and Wilkins, 1985:409-436).
Coagulation factors
Fibrinogen (factor I)
Fibrinogen is an acute phase reactant that circulates in the plasma as a gamma-globulin at a
concentration of 2 - 4 g/L. It is made up of two pairs of three nonidentical polypeptide chains
(i.e. alpha, beta and gamma chains) which are held together by disulphide bonds. Thrombin
cleaves two pairs of arginine-glycine peptide bonds in fibrinogen, producing small peptides
known as fibrinopeptide A and B from both the alpha and beta chains, and converts fibrinogen
to fibrin monomer. Fibrin monomers are composed of a small central E domain connected to
two larger D domains (Figure 3.4), and they spontaneously polymerise (catalysed by factor
XIIIa) with covalent cross-linking of the adjacent D domains to form fibrin.
44
Haemostasis, Platelet function and Coagulation
Vitamin K factors (i.e. factors II, VII, IX, and X, and Proteins C, S and Z)
The metabolic role of vitamin K is to serve as a cofactor for an hepatic microsomal enzyme
that converts specific glutamyl residues in the protein precursors of factors II, VII, IX and X
(and Protein C, S and Z), to gamma-carboxyglutamyl residues.82 Vitamin K deficiency takes up
to 3 weeks to develop after ceasing intake. With 10 - 50 mg of intravenous vitamin K,
haemostatic levels of the vitamin K factors (i.e. > 30%) are achieved within 3 - 4 hr, although if
oral anticoagulation is once again required, if these doses of vitamin K are used, it may take
1 - 3 weeks before satisfactory anticoagulation is again achieved.
Figure 3.4 A diagrammatic representation of fibrin polymerisation and degradation. (Reproduced, with permission,
from Shafer KE, Santoro SA, Sobel BE, Jaffe AS. Monitoring activity of fibrinolytic agents. a therapeutic challenge.
Am J Med 1984;76:879-886).
45
Haemostasis, Platelet function and Coagulation
Proaccelerin (factor V)
Factor V is synthesised in the liver. Its properties are listed in Table 3.3.
Antihaemophiliac factor (factor VIII)
Factor VIII is a large complex protein that circulates in close association with vWF,83 both
of which arise from the endothelium. Adrenaline, vasopressin and its analogue DDAVP, all
increase the plasma concentration of factor VIII and have been used to aid haemostasis in
patients with haemophilia A. Factor VIII refers to the protein which is deficient or abnormal in
haemophilia A. Factor VIIIC refers to the biological activity of factor VIII as measured by
conventional blood coagulation assays. Factor VIII clotting antigen (VIIICAg) describes the
antigenic determinants of factor VIII as assayed by immunoradiometric assay.
von Willebrand factor (vWF)
vWF refers to the protein which is deficient or abnormal in von Willebrand's disease; vWF
antigen (vWFAg) describes the antigenic determinants of vWF. The factor forms by far the
largest portion of the factor VIII/vWF complex, occurring with factor VIII in a ratio of 50:1.84
The VIII/vWF complex circulates in multimeric forms. Its larger multimers are essential for
platelet adhesive activities (von Willebrand’s disease is usually associated with a prolonged
bleeding time, and a normal Hess test), as the lower molecular weight multimers have a
reduced capacity to induce platelet adhesion.85 Endothelial cells are the source of plasma vWF.
An acquired vWD can be caused under conditions of high fluid shear stress (e.g. AS, VSD or
patent ductus) causing the metalloprotease (ADAMTS 13 ) to cleave the large vWF multimers
and create inactive derivatives.86
The antibiotic ristocetin facilitates binding of the vWF to platelets and agglutinates platelets
in normal plasma but not platelets suspended in plasma from a patient with von Willebrand’s
disease.
Table 3.3
Factor
XII
XI
IX
VII
VIII
V
X
II
I
XIII
Properties of coagulation factors
Biological
Minimum
Synonym
molecular weight Half life
(Da)
(days)
Hageman factor
80,000
Prekallikrein Fletcher factor
88,000
HMW kinogen Fitzgerald factor 120,000
Plasma thromboplastin
160,000
antecedent (PTA)
Christmas factor
57,000
Proconvertin
50,000
Antihaemophilic factor (AHF) 100,000-2,000,000
Proaccelerin
330,000
Stuart factor
57,000
Prothrombin
70,000
Fibrinogen
340,000
Fibrin-stabilizing factor (FSF)
plasma (tetrameric)
320,000
platelet (diameric)
160,000
46
haemostatic
level (%)
2
0
0
2.5
0
1 (20 h)
0.2 ( 5 h)
0.5
1.5
1.5 (40 hr)
3 (70 hr)
4.5
40
20
30
10
30
30
1 g/L
7
7
5
20
Haemostasis, Platelet function and Coagulation
Factors XII and XI
Factor XII and factor XI are synthesised in the liver. Their properties are listed in table 3.3.
Factor XI circulates in the plasma as a complex with HMW kininogen.87 An elevated level of
factor XI is a risk factor for venous thrombosis due to a sustained generation of thrombin.88
Factor XIII
Plasma factor XIII is a tetramer with a molecular weight of 320,000 and is activated by
thrombin (in the presence of Ca2+) to catalyse the formation of covalent bonds between the
polymerising fibrin molecules. Factor XIIIa also participates in the cross-linking of fibrin
molecules to fibronectin and to an alpha 2-plasmin inhibitor as well as cross-linking fibronectin
to collagen. Platelets contain 30-50% of the total blood factor XIII in a diameric form (mol. wt
160,000), the function of which is not completely understood. Severe ulcerative colitis is
associated with factor XIII deficiency and intravenous factor XIII concentrate for 10 days has
been reported to reduce bloody diarrhoea and increase body weight in these patients.89
Coagulation inhibition
Antithrombin I refers to the capacity of fibrin to adsorb thrombin, antithrombin II has been
found to be the same as antithrombin III, antithrombin VI represents the inhibitory effects of
FDPs and antithrombin IV and V are of uncertain physiological significance.90
Antithrombin III
Antithrombin III (AT III) is an alpha-2-globulin with a half-life of 70 hr and a molecular
weight of 58,200. It is synthesised largely in the liver by hepatocytes, although a portion is also
synthesised by the endothelium.91,92 The normal plasma level is 150 mg/L. AT III is the
principal antagonist of the serine proteases (i.e. XIIa, XIa, Xa, IXa, VIIa, thrombin, plasmin
and kallikrein) and accounts for 85% of plasma inhibition of thrombin. An arginine reactive
centre of the AT III molecule is responsible for the AT III inhibition of the active serine centre
of the serine proteases. Heparin binds to lysine sites on AT III and produces a conformational
change at the arginine reactive centre, to potentiate the serine protease inhibition of AT III. The
potentiation is greatest for thrombin and factor Xa inactivation.93 The half-life and serum levels
are reduced with heparin infusions because the heparin-AT III complex has a higher rate of
removal from the circulation94 (i.e. the half-life is reduced from 70 to 50 hr). The AT III levels
return to normal 2 - 3 days after ceasing the heparin infusion.
Heparin cofactor II
Heparin cofactor II is a plasma antiprotease with a molecular weight of 65,600 which is
activated by heparin and (unlike AT III) dermatin sulphate. Heparin cofactor II also differs
from AT III in that it only inhibits thrombin.
Protein C anticoagulant pathway
Protein C is a vitamin K dependent glycoprotein with a molecular weight of 62,000, a half
life of 5 hr, which is activated to a serine protease by a thrombin-thrombomodulin complex on
the endothelial surface (Figure 3.5).95 Thrombomodulin is an endothelial cell membrane
glycoprotein (mol. wt. of 75,000) which contains thrombosis by binding and inactivating the
procoagulant effect of thrombin (converting it from a procoagulant enzyme into a potent
activator of protein C) generating activated Protein C (i.e. Protein Ca). In the presence of
phospholipid and Ca2+, Protein Ca inactivates thrombin, factors Va and VIIIa, inhibits the
conversion of prothrombin to thrombin by platelet-bound Va and Xa, and stimulates
fibrinolysis by neutralising a tissue plasminogen activator inhibitor.96 Protein S is a vitamin K47
Haemostasis, Platelet function and Coagulation
dependent plasma glycoprotein (mol. wt. 69,000) which acts as a cofactor for the protein Ca
inactivation of factors Va and VIIIa.97
Figure 3.5 A diagram depicting the conversion of Protein C to Protein Ca (which in turn inactivates factors VIIIa and
Va) by a thrombin-thrombomodulin complex on the endothelial cell surface (Reproduced, with permission from Clouse
LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986;314:1298-1304).
A familial thrombophilia characterised by an autosomal dominant inheritance, poor
anticoagulant response to activated protein C and an incidence 5-10 times that of thrombophilia
caused by deficiencies in ATIII, protein C or protein S, has recently been described.98,99 The
condition is diagnosed by the activated protein C resistance (APCR) test, where a standard
amount of activated protein C (APC) is added to the patient's plasma and the prolongation (i.e.
a normal response), or resistance to prolongation (i.e. an abnormal response), of the APTT is
assessed.100 The APCR test is usually expressed as a ratio (i.e. APTT with APC/APTT without
APC). The ratio is normally 1.9 to 4.0 and APC resistance is present if the ratio is greater than
4.0. The disorder is thought to be due to a selective defect in factor V (i.e. factor V Leiden,
which has a replacement of arginine with glutamine at position 506 thereby eliminating the
protein C cleavage site in factor V),101 which is resistant to inactivation by activated protein
C,102 as the defect is corrected by the addition of normal unactivated factor V.103
Other plasma coagulation inhibitors
An alpha-2-macroglobulin accounts for 15% of plasma inhibition of thrombin.104 Factor Xa
is inhibited by AT III, but in contrast to thrombin is less sensitive to alpha-2-macroglobulin
although is markedly inhibited by alpha-1-antitrypsin (although a deficiency in alpha-1antitrypsin is not associated with excessive thrombosis).
Tissue factor pathway inhibitor is a serine protease inhibitor (mol. wt. 34,000, the majority
of which is bound to endothelium), which is synthesised by endothelial cells and
48
Haemostasis, Platelet function and Coagulation
megakaryocytes.105 It is a factor Xa-dependent inhibitor. First it complexes with and inactivates
factor Xa, then factor VIIa is inactivated within the factor Xa/tissue factor complex.
Protein Z-dependent protease inhibitor. Protein Z forms a Ca2+- dependent complex with
activated factor X (Xa) at a phospholipid surface and serves as a cofactor to enhance (by more
than 1000 x) the inhibition of Xa by a protein-Z-dependent protease inhibitor (ZPI).106
Coagulation Blood Products
Fresh frozen plasma
Fresh frozen plasma (FFP) is the anticoagulated plasma prepared from the collection of one
unit of blood (i.e. approximately 250 ml or 8% of the plasma volume), that is frozen (and stored
below -30ºC) within 4 - 6 hr of collection. It is preferable to administer FFP within the
recipient's ABO blood group, and to use it within 2 - 6 hr of thawing. If it is used for:
1. factor VIII replacement, then as each unit contains 0.7 u/ml (i.e. 70% of factor VIII is
retained, or 175 u/250 ml), 6 units (i.e. 1.5 L) will be needed to increase factor VIII by 30%.
2. factor XII, XI, X, IX, VII, V and II replacement, then as each unit contains 1 u/mL (i.e.
100% of these factors are retained), 4 units (i.e. 1 litre) will be needed to increase these factors
by 30%.
3. factor I (fibrinogen) replacement, then as each unit contains 600 mg of fibrinogen, 5 u
(i.e. 1.25 L) will be needed to increase fibrinogen by 1 g/L (each unit raises the fibrinogen level
by 0.2 g/L).
Cryoprecipitate
Cryoprecipitate is prepared by thawing FFP at 4ºC and recovering the cold precipitate. This
contains 20% of the fibrinogen and 30% of factor VIII, factor XIII, vWF and fibronectin from
the original plasma to provide 10 - 15 mL with 80-100 u of factor VIII and 150 mg of
fibrinogen from each unit. The plasma of 5 u of blood are commonly pooled to give 50-80 mL
with 400 u of factor VIII and factor XIII and 0.6 g of fibrinogen. Cryoprecipitate may be used
up to 6 hr after thawing. ABO group compatibility is preferred but not essential.
Recombinant Factor VIIa (rFVIIa)
Recombinant factor VIIa (rFVIIa) has a half-life of about 2 h and been used empirically in
patients with traumatic bleeding (60µg/kg i.v),107 haemophilia A or B with inhibitors108 (100 µg
/kg 2-hourly until haemostasis is achieved)109, thrombocytopaenia110 and renal failure with
aspirin and low molecular weight heparin (bolus dose of 120 µg /kg).111 The advantage of
intravenous rFVII in the management of coagulopathic haemorrhage, is that it appears to
enhance haemostasis at the site of injury, without systemic activation of the coaculation
cascade112 and as such is being used more and more in the critically ill haemorrhagic patient.113
In patients with severe coagulopathy with intractable bleeding the dose is usually 100 µg/kg
(and rounded to the nearest 1.2 mg) as a single bolus (over 2-5 minutes) every 2-3 hours until
the bleeding is controlled.
Recombinant Factor VIII (rFVIII)
Recombinant Factor VIII is comparable to plasma-derived factor VIII (e.g. has a similar
half-life) and is effective in treating bleeding disorders.
Factor IX complex (Prothrombinex-HT, CSL)
Prothrombinex contains 600 u of factor X, 500 u of factor IX and 550 u of factor II in a vial
of freeze dried product, and thus will raise each of these factors by approximately 15% of the
49
Haemostasis, Platelet function and Coagulation
normal amount. If it is used in patients who have vitamin K deficiency (e.g. acute or chronic
liver disease or warfarin overdosage) then FFP should also be given to supply factor VII.
Coagulation tests
Apart from fibrinogen, all factors are measured in terms of activity, as a percentage of
control plasma. Bleeding tends to occur if the fibrinogen level is less than 1 g/L, or the activity
of a factor is less than 30% (Table 3.3). A reduction in plasma ionised Ca2+ commensurate with
life is not associated with excess bleeding.
Coagulation tests are usually indicated if there is a disease commonly associated with
bleeding problems (e.g. acute or chronic liver failure, massive transfusion, DIC), malnutrition
or malabsorption, a history of a bleeding disorder (e.g. easy bruising, prolonged bleeding with
tooth extraction, tonsillectomy or surgical procedure) or a need to monitor anticoagulant
therapy114.
Prothrombin time (PT)
Tissue thromboplastin is added to recalcified platelet-poor plasma and the time for a clot to
appear is compared with the time for a clot to appear with normal plasma. The result may be
expressed in seconds, as a percentage or as a ratio. This test reflects the function of the extrinsic
pathway and therefore the combined activity of factors VII, X, V, II and I, and is prolonged in
the presence of a deficiency (or antagonism) of any of these factors. The test is sensitive to
three of the four vitamin K-dependent clotting factors. At usual therapeutic doses, heparin has
no effect on the prothrombin time;115 also, factors I and V have to be very low before the
prothrombin time is affected. If the prothrombin time is prolonged and the APTT is normal an
isolated factor VII deficiency exists. To standardise the estimation of prothrombin activity and
correct for the differences in reagents and methods, a unit of measurement known as the
International Normalised Ratio (INR) has been recommended.116 To calculate the INR the
laboratory must first calibrate its own prothrombin method against a standard material which is
provided by the Community Bureau of Reference in Brussels, Belgium. The laboratory can
then translate its prothrombin ratios (patients prothrombin time : control's prothrombin time)
into an INR, the INR being that prothrombin ratio that would be obtained if the WHO reference
thromboplastin were used to test the sample.
Activated partial thromboplastin time (APTT)
A contact activating agent and phospholipids are added to recalcified platelet poor plasma
and the time is measured (in seconds) for a clot to form. The result is compared with the time
for normal control plasma to clot. This test reflects the combined activities of factors XII,
HMW kininogen, prekallikrein, XI, X, IX, VIII, V, II, I, and is prolonged in the presence of a
deficiency or antagonism (e.g. heparin, FDPs, warfarin or lupus anticoagulant) of these factors.
The test is independent of factor VII. False-positive results are often obtained if a sample of
blood is obtained from an intravascular catheter which is continually flushed with heparin or
through a preheparinised syringe needle.
Thrombin time
This test determines the time plasma takes to clot after adding a solution of thrombin. The
test is prolonged in the presence of hypofibrinogenaemia or thrombin inhibitors (e.g. heparin
and FDPs).
50
Haemostasis, Platelet function and Coagulation
Fibrinogen assay
Plasma fibrinogen levels are normally 2 - 4 g/L, and bleeding does not usually occur unless
levels are less than 1 g/L.
Fibrin degradation products (FDPs)
These are formed by plasmin degradation of fibrin and fibrinogen and are elevated in the
presence of intravascular fibrinolysis. They are measured in serum using a latex agglutination
test (normal < 10 µg/mL).
Cross-linked fibrin derivatives (XDPs or D-dimer)
These are formed exclusively by plasmin degradation of mature cross linked fibrin (not by
fibrinogen degredation) and are elevated in the presence of thrombolysis. They are measured in
the plasma by latex agglutination or by the more sensitive enzyme-linked immunosorbent assay
(normal < 200 ng/mL).
Euglobulin clot lysis time (ECL)
As the euglobulin fraction of plasma concentrates plasminogen activators and is relatively
free of inhibitors of fibrinolysis, the lysis time of the clot formed from this fraction measures
overall plasminogen activator activity. Normally, the lysis time is greater than 120 min, with
times less than this indicating significant plasminogen activator activity (e.g. effective
thrombolytic therapy).117
Thromboelastography (TEG)
Thromboelastography provides a global assessment of coagulation within 20-30 min,
measuring the interaction between platelets and the protein coagulation cascade from the initial
platelet-fibrin interaction, to platelet aggregation and clot strengthening with fibrin cross
linking, to fibrinolysis.118 Blood is placed in a heated (37ºC) cuvette which is oscillated. A pin
is suspended from a wire into the blood and the forces transmitted from the oscillating cuvette
to the pin (by fibrin strands) are amplified to give an TEG trace recorded on a paper moving at
2 mm/min (Figure 3.6). Abnormal TEG patterns occur with thrombocytopenia, coagulation
factor defects, and fibrinolytic abnormalities (Figure 3.7). While there is some correlation
between TEG abnormalities and the standard coagulation tests, in hepatic transplantation,
cardiac surgery and massive transfusion, the TEG more reliably predicts abnormalities that are
associated with perioperative bleeding. In hepatic transplantation, fresh frozen plasma (2 - 4 u)
are given if the 'r' time is greater than 15 min, platelets 1 u/10 kg are given if the MA is less
than 40 mm (even if the platelet count is normal) and cryoprecipitate 6-12 u is given for
persistent poor clot formation (alpha angle < 40º) with normal MA.119 Generally, coagulation
returns towards normal within 1 - 2 h after hepatic reperfusion.120
Coagulation disorders
Coagulation disorders are characterised by bleeding, which may be delayed 3 - 6 hr after
injury, with deep bruising and large surgical haematomas. Spontaneous retroperitoneal or
mesenteric haemorrhage, subdural haemorrhage and haemarthroses (ankles, knees, elbows) are
also common. There may also be a history of continuous bleeding (e.g. for up to 3 - 6 weeks)
after a dental extraction.
Causes
The coagulation defects that cause bleeding are listed in Table 3.4. Congenital deficiencies
of factors I, II, VII and X are extremely rare. Congenital deficiency of factor V (i.e. Owren's
51
Haemostasis, Platelet function and Coagulation
disease) is also rare and may be associated with duplex system and patent ductus arteriosus. An
acquired inhibitor of factor V may occur in patients with autoimmune disease121
Figure 3.6. A diagrammatic representation of the TEG variables. r = Reaction time (time from placement of blood into
the cuvette until tracing reaches an amplitude of 2 mm. Normal range is 6 - 8 minutes) and is prolonged with
coagulation factor deficiencies and anticoagulants. A small r value may occur with hypercoagulable states. K = clot
formation time (time taken for the amplitude to increase from 2 mm to 20 mm. Normal range is 3 - 6 minutes), this is
prolonged with coagulation defects. The alpha angle = angle formed by the slope of the TEG tracing from the r to the K
value (normal value 50 - 60º) and is reduced with coagulation defects. Maximum amplitude (MA) is the greatest
amplitude on the TEG trace and is a direct function of the strength of the clot (reduced with functional abnormalities of
coagulation and platelets. Normal range 50-60 mm). A60 = the amplitude of the tracing 60 minutes after MA is achieved
(normal range = MA - 5 mm). It is a measure of clot lysis and decreased with fibrinolysis. The clot lsis index = A60/MA
x 100 (normal value is > 85%) is a measure of loss of clot integrity as a result of lysis (Reproduced with permission
from Mallett SV, Cox DJA. Thromboelastography. Br J Anaesth 1992;69:307-313).
Figure 3.7 Characteristic thromboelastographic patterns. A = normal trace, B = haemophilia, C =
thrombocytopenia, D = fibrinolysis, E = hypercoagulability (Reproduced with permission from
Mallett SV, Cox DJA. Thromboelastography. Br J Anaesth 1992;69:307-313).
52
Haemostasis, Platelet function and Coagulation
Table 3.4
Causes of coagulation defects
Congenital
X-linked recessive causes (i.e. carried by X chromosome)
Haemophilia A (factor VIII)
Haemophilia B (factor IX)
Autosomal dominant causes
von Willebrand's disease
Factor XI deficiency
Dysfibrinogenaemias
Autosomal recessive causes
Deficiencies of factors I, II, V, VII, X
Acquired
Massive blood transfusion (factor dilution)
Disseminated intravascular coagulation (factor consumption)
Vitamin K
malabsorption and deficiency
(e.g. steatorrhoea, obstructive jaundice)
inhibition
(e.g. oral anticoagulants, salicylate intoxication)
Liver disease
Heparin
Haemophilia A
This is an x-linked disease that causes low or undetectable levels of factor VIII measured
either as VIIIC or VIIIAg (some haemophiliacs may have normal or elevated VIIIAg, whereas
others may have normal VIIIC with undetectable VIIIAg). Levels of vWF are normal or even
raised and consequently the bleeding time is normal. An acquired anti-factor-VIII antibody may
occur in 5-10% of haemophilia A patients (contrasting with haemophilia B patients who very
rarely develop anti-factor-IX antibodies) which may also occur spontaneously in autoimmune
disorders or in the post partum period.
The infusion of 1u of factor VIII per kilogram of body weight will increase the plasma level
of factor VIII by approximately 20 u/L. A minimal haemostatic level of 300u/l is usually
necessary to treat relatively mild bleeding episode, a level of 500/l is generally considered the
minimum for serious bleeding into joints or muscles, and in cases of major surgery or life
threatening bleeding, normal factor VIII levels are maintained. Treatment of a patient with
haemophilia A who has:
1. A minimal spontaneous bleeding, requires one dose of factor VIII of 10 u/kg (i.e. 2 bags
of cryoprecipitate or factor VIII concentrate from 10 units of blood).
2. A moderate bleed (e.g. a fully developed haemarthrosis), requires 20 - 25 u/kg of factor
VIII (i.e. four bags of cryoprecipitate), with a repeated dose, 12 and 24 hr later.
3. A severe bleed (e.g. a head injury or major trauma or surgery), requires 40 - 50 u/kg of
factor VIII (i.e. eight bags of cryoprecipitate) with a 12-hourly dose of 20 - 25 u/kg of factor
VIII (i.e. four bags of cryoprecipitate) for 7 - 10 days or until the bleeding is controlled.
4. An anti-factor-VIII antibody; the bleeding may be controlled by plasmapheresis and
infusing plasma-derived or recombinant factor VIII.122
53
Haemostasis, Platelet function and Coagulation
5. Treatment with rFVIIa (35 - 70 µg/kg) appears to be treatment of choice in patients with
acquired haemophilia or patients with anti-factor VIII antibody. The main disadvantages are a
short half life (requiring application 2 - 3 hourly) and as there is no laboratory tests currently
available to monitor the effectiveness of rFVIIa monitoring is largely clinical.
Apart from factor VIII replacement, DDAVP (0.3 µg/kg intravenously over 30 min),
followed by EACA (15 mg/kg/hr) or tranexamic acid (10 mg/kg 8-hourly), to inhibit the
associated increase in plasminogen activator release with DDAVP, has also been used to aid
haemostasis in patients with Haemophilia A and von Willebrand’s disease. Although, patients
who have severe deficiencies of factor VIII do not respond to DDAVP. Three patients with
haemophilia A who underwent hepatic transplantation, achieved haemostatic levels of factor
VIII within 6 - 18 hr of the procedure.
Recent advances in gene-replacement therapy indicates that a cure for coagulation factor
deficiencies (particularly factor VIII and IX deficiencies) will soon be available.123
von Willebrand's disease
von Willebrand's disease is inherited as an autosomal dominant with deficient or abnormal
vWF and reduced levels of factor VIII (e.g. 1 - 50% of normal factor VIII levels). It may also
be acquired with hypothyroidism, SLE, lymphoma or aortic stenosis.124,125,126 For surgical cover
(and with major trauma), one donor unit of cryoprecipitate per 10 kg per day is used (i.e. 1
bag/50 kg), with the first dose being given the day prior to surgery and continued for 7 - 10
days postoperatively.
Factor IX deficiency (Haemophilia B)
Haemophilia B is an x-linked disease (i.e. virtually all will be males) with low or
undetectable levels of factor IX. An acquired inhibitor may occur in patients with autoimmune
disease. One litre of FFP daily (i.e. 1000 u or 15 u/kg factor IX) is usually enough to stop
minor bleeding in patients who have factor IX deficiency. Patients with severe haemarthrosis
and during minor surgery (e.g. dental extractions), 20 - 25 u/kg of monocomponent factor IX
therapy is usually required. During major surgery, facilities to monitor factor IX levels should
be available. A preoperative dose of 40 to 65 u/kg should be infused to raise the factor IX level
to at least 400 u/L of plasma and further doses are given at 6 - 8 hr intervals to maintain the
concentration of factor XI greater than 250 u/L plasma. Treatment should be continued for 7 to
10 days. Treatment with rFVIIa is also the treatment of choice in patients with anti-factor VIII
antibody.
Factor XIII deficiency
Patients with a factor XIII deficiency have a moderate to severe bleeding disorder as well as
having an impairment of wound healing. Because an effective level of factor XIII is above
0.5% and as its half-life is 12 days, long-term prophylaxis may be obtained by infusing 1 donor
unit of cryoprecipitate per 10 kg (i.e., 1 bag/50 kg) every 2 - 3 weeks.
Disseminated intravascular coagulation127,128
Disseminated intravascular coagulation (DIC) is a syndrome characterised by an acute or
chronic intravascular coagulation and consumption of platelets and clotting factors with clinical
features of microvascular thrombosis and haemorrhage. It often complicates a variety of
disorders and therefore is considered to be an intermediary mechanism of disease In chronic
DIC, the factor levels may be normal and the only abnormality may be thrombocytopenia.
54
Haemostasis, Platelet function and Coagulation
Causes. The causes of DIC are listed in Table 3.5. Disorders causing intrinsic or extrinsic
activation of the coagulation system often do so through the thrombogenic effects of TNFalpha and circulating IL-6 and IL-8 (e.g. activation of coagulation factors and inhibition of
protein-C and protein-S pathway).129 In patients who develop DIC, the maintenance of the
coagulopathy occurs with, circulatory stasis (which prevents the circulating inhibitors from
reaching the coagulants) and RES blockade (inhibiting clearance of thromboplastins and
activated procoagulants from the thrombin generation), and is more likely to occur with
pregnancy, cirrhosis, or septicaemia.
Table 3.5
Causes of DIC
Endothelial cell injury (i.e. intrinsic pathway activation)
Heat stroke, hyperthermia, malignant hyperpyrexia
Viral, rickettsia or tubercle bacilli infections
Haemangioma, aneurysms
Shock, hypoxia, burns
Intravascular tissue thromboplastin release (i.e. extrinsic pathway activation)
Amniotic fluid embolism, death in utero.
Tumour cells, antigen-antibody complexes
Tissue from trauma and surgery
Intravascular haemolysis
Incompatible blood transfusion
Mixed intrinsic and extrinsic pathway activation
Bacterial sepsis
Neoplasia (adenocarcinoma, lymphoma, leukaemia)
Pre-eclampsia
Envenomation
While treatment with cytotoxic agents in leukaemic patients often induces rapid cell lysis
and DIC, treatment of promyelocytic leukaemia with all-trans retinoic acid has a different
effect as it induces a functional maturation of leukaemic promyelocytes and a progressive
reduction in the leukaemic chromosomal translocation.130 However, in up to 25% of patients
from 2 - 21 days after starting treatment, a ‘retinoic acid syndrome’ may develop, which is
characterised by fever, headache, nausea, vomiting, tachypnoea, haemoptysis, interstitial and
alveolar pulmonary infiltrates (i.e. ARDS, due to maturing myeloid cells invading lung
parynchyma and in severe cases pulmonary capillaritis131), pleural and pericardial effusions,
peripheral oedema, thromboembolism, cerebral haemorrhage, hypotension and renal
failure.132,133 Laboratory findings include, leukocytosis, disseminated intravascular coagulation,
hyperbilirubinaemia, hypertriglyceridaemia and elevated creatinine.
The treatment includes resuscitation (i.e. oxygen, mechanical ventilation) and intravenous
dexamethasone 10 mg 12-hourly for three days. While ceasing the all-trans retinoic acid
appears to be reasonable, anecdotal evidence from one report appeared to support its
continuation. One review concluded that discontinuation of the all-trans retinoic acid is
probably not effective.134
55
Haemostasis, Platelet function and Coagulation
Clinical features. The clinical features include symptoms and signs due to factor deficiency
and ischaemia. Factor deficiency will commonly cause mucosal haemorrhage (i.e.
gastrointestinal tract haemorrhage, haemoptysis) and wound haemorrhage. Vascular
microthrombi will commonly cause organ ischaemia and multiple organ failure (i.e. renal,
respiratory, hepatic, and cerebral failure).
Investigations. The investigations include:
1. Coagulation tests: these tests often reveal a coagulation deficiency (e.g.
thrombocytopenia, hypofibrinogenaemia, and prolonged INR, APTT and thrombin time).
2. Fibrinolysis testing: secondary fibrinolysis is often present which is reflected in a
shortened euglobulin lysis time.
3. Fibrin degradation products: the plasma fibrin and fibrinogen degradation products (i.e.
FDPs, XDPs) are elevated.
4. Complete blood picture: the fibrin mesh occluding the blood flow in the microcirculation
produces RBC deformation (e.g. helmet cells, schistocytes, spherocytes, RBC fragmentation),
intravascular haemolysis, an increase in reticulocyte count and an anaemia.
Treatment. Findings consistent with DIC may occur in many diseases, although the disorder
is often of no clinical significance. Severe and therefore clinically significant DIC may be
defined as that which is associated with hypofibrinogenaemia.
1. Identification and treatment of the underlying disorder: is the cornerstone of
management of DIC (i.e. correct circulatory failure, for example, shock and drain and remove
dead or septic tissue), once this is underway then if the patient is bleeding, coagulation factor
and platelet therapy may be administered. Once the precipitating cause has been removed the
clotting factors usually return to normal within 24 hr, although the thrombocytopenia may
persist for several days.
2. Coagulation factors: If the fibrinogen level is less than 1 g/L, 0.5 - 1 L of FFP (i.e. 0.6 1.2 g fibrinogen) and 1 - 2 packs of cryoprecipitate (i.e. 0.6 - 1.2 g of fibrinogen), are
administered and FFP or cryoprecipitate are administered thereafter to keep plasma fibrinogen
levels greater than 1 g/L. Intravenous vitamin K 10 - 20 mg and folic acid 15 mg are also given.
Coagulation factor replacement therapy and the progress of DIC are monitored by APTT, INR,
platelet count and FDP levels.
3. Platelets: If the patient is bleeding and the platelet count is below 80,000/µL, six packs
of platelets are infused, and are administered thereafter depending on clinical evidence of
bleeding and the platelet count.
4. Anticoagulants:
Heparin. Inhibition of thrombin generation with heparin at standard anticoagulant doses
has been used in patients where the thrombin generation is unable to be removed by treating the
underlying disorder, although, even in this group, heparin has not been associated with an
improvement in survival. Treatment of the DIC with heparin and factor replacement, without
management of the underlying disorder, has not been associated with improved survival, and
therefore is not recommended.
5. Coagulation inhibitors:
Antithrombin III. Antithrombin III infusions have been reported to be of use in patients
with severe DIC,135,136 although no significant reduction in mortality has been observed.137
While one study of ATIII infusions in critically ill patients without severe DIC but who had
acquired low levels of ATIII, appeared to be without benefit,138 another double blind placebo
controlled study of patients requiring respiratory and/or hemodynamic support because of
severe sepsis and/or post-surgery complications found that antithrombin III infusions to
56
Haemostasis, Platelet function and Coagulation
normalise plasma antithrombin activity had a net beneficial effect on 30-day survival.139
However, a recent multicentre, placebo controlled trial of 2300 patients with severe sepsis high
dose antithrombin III (6000 IU as a bolus followed by 6000 IU for 4 consecutive days) was not
associated with a reduction in 28-day all cause mortality.140
Protein C. Protein C infusions (100 IU/kg 8-hourly for 24 hr and thereafter according to
plasma protein C levels) have also been used to treat patients with sepsis-induced DIC141
(particularly when associated with meningococcal disease, as it has been associated with
beneficial effects,142,143,144 although currently there are no prospective randomised trials that
have shown that it improves outcome in meningococcal disease).145 However, in a recent trial
in patients with severe sepsis and one or more acute organ failures, an infusion of activated
protein C (drotrecogin alfa) 24 µg/kg/hr for 96 hours was associated with a reduction in the 28
day all cause mortality from 30.83% to 24.72% (i.e. 1 additional life saved for every 16 patients
treated), regardless of whether the patients had a low level of protein C or not (indicating that it
did not just correct a protein C deficiency). 146 However, it was associated with an increased
risk of bleeding and patients who had trauma or had undergone recent surgery, had a CVA
within the previous 3 months, platelet count of < 30,000, acute pancreatitis without an
established source of infection, chronic liver disease, dialysis dependent renal failure,
anticoagulated with heparin or warfarin or were < 18 years of age - were excluded.146
Thrombomodulin. While thrombomodulin infusions have been shown to have benificial
effect in the experimental model of DIC, currently no studies on thrombomodulin treatment in
humans with DIC have been reported.137
Inhibitors of tissue factor: Infusions of recombinant tissue factor pathway inhibitor (TFPI)
have been shown to have benificial effect in the experimental model of DIC, and in healthy
individuals with endotoxin-induced thrombin generation,147 although no clinical studies on
TFPI treatment in patients with DIC have been reported.137
6. Fibrinolytic inhibitors: Secondary fibrinolysis associated with DIC should not be
inhibited.
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64
TRAINEE PRESENTATIONS
Each registrant has prepared a five minute talk and summary on the topics listed below. The
summaries that were received in time for publication have been included (unedited).
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Discuss the advantages and disadvantages of the
various sedation regimens in the intensive care
patient.
Define and list the causes and management of
platypnoea and orthodeoxia.
What are the factors causing, and treatment of, an
acute subclavian vein thrombosis.
Discuss the difference in aetiology, diagnosis and
treatment of portopulmonary hypertension and
hepatopulmonary syndrome.
Discuss the management of a patient who has an
asystolic cardiac arrest.
Discuss the causes and management of acute
paralytic ileus.
Discuss the causes, clinical features and management
of a patient with D-lactic acidosis.
Discuss the clinical features and management of a
patient who has the ‘Retinoic acid syndrome’.
How would you manage a patient who has an acute
post-operative colonic pseudo-obstruction?
Discuss the management of a patient with AF,
hypotension and hypertrophic obstructive
cardiomyopathy.
Discuss all the methods used to improve the
likelihood of a successful canulation of a central
vein.
Discuss the clinical features and the management of
a patient with a TIA.
Discuss your management of a patient with chest
trauma who is mechanically ventilated and who
develops a broncho-pleural fistula.
A patient has been referred to you following a
nephrectomy for a hypernephroma performed 7 days
ago for management of pyrexia, oliguria and now
hyperkalemia. He has been confused during the past
three days with episodes of hypoglycaemia and the
numerous glucose infusions has caused him to
develop hyponatremia. how would you manage him?
Discuss how you would manage a patient who has
developed blindness with serum sodium of 122
mmols/L and measured osmolality of 290 mosm/kg 1
hour following a TURP.
65
Dr. M. Reade
page
67
Dr. M. Davey
70
Dr. S. Sane
72
Dr. S. Simpson
76
Dr. M. Ibrahim
80
Dr. G. Kwan
82
Dr. T. Fraser
84
Dr. D. Moxon
86
Dr. W. Newman
87
Dr. A. Holley
89
Dr. B. Cheung
92
Dr. H. Ramaswamykanive
95
Dr. M. Sanap
98
Dr. P. Dubey
102
Dr. S. Vergese
105
16. Discuss the ideal properties of a predictive scoring
system for severity of illness in the intensive care
unit.
17. Discuss your management of a mechanically
ventilated postoperative coronary artery bypass
patient who has just developed AF and who is
hypotensive.
18. Discuss the indications for and complications of
intravenous sodium bicarbonate
19. Discuss the antibiotic management of a patient with
MRSA aortic valve endocarditis with vancomycin
allergy
20. Do you use selective decontamination of the
gastrointestinal tract in your intensive care unit? If so
why? If not why not?
21. What are the indications for and complications of Nacetylcysteine
22. Discuss the indications and contraindications of
morphine in the treatment of acute pulmonary
oedema
23. Discuss the clinical presentation and management of
a patient who has an acute Budd-Chiari syndrome
24. Discuss the diagnosis and management of gout in a
critically ill patient with acute renal failure
25. Discuss the management of the Guillain Barre
syndrome
66
Dr. S. Senthuran
107
Dr. D. Gardiner
109
Dr. R. Ramadoss
111
Dr. A. MacCormick
115
Dr. G. Ding
117
Dr. L. Min
120
Dr. M. Heaney
122
Dr. J. Lewis
125
Dr. D. Corcoran
128
Dr. D. Rigg
131
DISCUSS THE ADVANTAGES AND DISADVANTAGES OF THE VARIOUS
SEDATION REGIMENS IN THE INTENSIVE CARE PATIENT
Dr. M. Reade. Intensive Care Unit, The Austin Hospital, Victoria
There are three related but distinct therapeutic goals in the management of cognitive
function and awareness in critically ill patients: analgesia; control of delirium; and sedation.
Many of the drugs employed to control one aspect of this triad will have effects (beneficial or
detrimental) on the other two. Sedation cannot therefore be considered in isolation, but a
discussion of analgesic and psychotropic pharmacology and regimens is beyond the scope of
this paper.
The need for sedation can be reduced by minimisation of sleep deprivation, reducing
delirium (by frequent reorientation and appropriate medications), use of appropriate analgesia,
optimisation of the temperature and use of a suitable ventilation strategy. Hypoxaemia,
hypercapnoea, hypoglyceamia and withdrawal from alcohol or benzodiazepines can also be
treated. The effectiveness of any sedation strategy must be adequately assessed. There are a
number of scoring systems to allow this, though few have been properly validated. The most
commonly used scores are the Ramsay,1 Riker2 and Motor Activity Assessment Scale
(MAAS),3 though others exist.4 The Ramsay score is used most frequently in clinical trials.5
There are few (if any) disadvantages in incorporating these simple measures into a sedation
regimen.
In patients who are receiving mechanical ventilation, daily interruption of sedative-drug
infusions decreases the duration of mechanical ventilation and the length of ICU stay.6 This
practice potentially exposes the patient to unpleasant awareness and to the risk of self harm by
removal of intravenous catheters etc. The need for nursing care is greater. Routine daily
interruption of sedatives is not universally practiced.
Allowing nurses to titrate the doses of sedatives and analgesics according to a protocol
reduced the duration of mechanical ventilation, the intensive care unit and hospital lengths of
stay and the need for tracheostomy among critically ill patients with acute respiratory failure.7
The only disadvantage of such a regimen is the extra training required of nursing staff.
The choice of medication used to primarily produce sedation is only a small part of the
overall sedation regimen. The ideal sedative agent would reduce anxiety, facilitate patient care,
produce anterograde amnesia and reduce psychomotor agitation. Pharmacologically, it would
be easy to titrate, haemodynamically stable, not produce tachyphylaxis and be cheap. Each drug
class has a number of theoretical advantages and disadvantages, as listed in Table 1.
Comparison of medications whose primary action is sedative.
The most commonly studied benzodiazepines in the ICU are midazolam, lorazepam and
diazepam. Intravenous midazolam and diazepam have an effect after 2 - 5 minutes, whereas
lorazepam takes 5 - 20 minutes. Midazolam has the shortest half life, but has an active hepatic
metabolite which accumulates in renal failure. Lorazepam has a longer elimination half life,
making it less titratable by infusion, though it has no active hepatic metabolites, possibly
making it more suitable in renal failure. Diazepam has a very long half life and an active
hepatic metabolite. In intravenous form its solvent causes phlebitis, restricting its use by many
to the enteral form. Midazolam and lorazepam have been compared in a number of trials:4
lorazepam infusions may be easier to manage (with fewer dose adjustments), and while there
was no difference in the time to recovery, there was less variability with lorazepam. For this
reason, the SCCM recommendation is that midazolam is indicated for short term use only, as it
produces unpredictable awakening after infusions of 48 - 72 hours. Lorazepam is preferred in
67
this situation, unless very rapid awakening is required, in which case propofol in indicated.4
Unfortunately, IV lorazepam is not available in Australia.
Table 1. Properties of the commonly used ICU sedative agents
Benzodiazepines
Propofol
Amnesia produced
Yes
As effective as midazolam
in one study but not another
Tolerance?
Yes
No
Opioid sparing?
Yes, mildly
No – thought to have no
analgesic effect
Withdrawal effect? Yes
No
Side effects
Paradoxical
Hypertriglyceridaemia.
agitation in low
Hypotension/bradycardia.
doses
Pancreatitis. Lactic acidosis.
Cardiac arrest. Possible
sepsis due to contamination.
Myoclonus.
Accumulation in
renal failure
Midazolam and
diazepam – yes;
lorazepam – no.
No
Titratable?
Midazolam – yes,
if short term.
Lorazepam – no
Diazepam - no
Highly
Haemodynamically
stable?
Yes
No – reduces cardiac
contractility; causes
vasodialtion
Cost
Inexpensive
Moderately expensive
Alpha agonists
No
Yes, markedly
No
Hypotension.
Hypertension.
Bradycardia.
Dry mouth.
Nausea.
Somnolence.
Corneal dryness.
No (though
kinetics of
metabolites are not
fully established)
Yes – though not
directly compared
to propofol. Likely
to have a larger
effective dose
range with fewer
side effects than
propofol.
Transient
hypertension then
hypotension;
reported to not be
clinically
significant.
Very expensive
Clonidine, an alpha-2 agonist, has been employed as a sedative, but its use is limited by
hypotension. With seven times less hypotensive effect, dexmedetomidine has only recently
become available, licensed in Australia for use in the first 24 postoperative hours. Two large (n
= 353 and 401) placebo controlled trials found patients given dexmedetomidine needed very
little ‘rescue’ sedative (either propofol or midazolam) and also required approximately half the
amount of morphine for analgesia.8 A trial in 295 postoperative patients compared the sedative
effects of dexmedetomidine with propofol. Dexmedetomidine alone was sufficient to achieve
satisfactory sedation in 89% of patients. Eighty eight percent of patients receiving propofol, but
only 50% of patients receiving dexmedetomidine, required morphine for analgesia. Ninety
eight percent of patients receiving dexmedetomidine were extubated without discontinuation of
the study drug, whereas this was true for only 6% of those receiving propofol, highlighting
68
dexmedetomidine’s ability to produce rousable sedation with little respiratory depression.8
Longer infusions have been used successfully in other case series and published trials.9,10
Which pharmacological sedative regimen produces optimal sedation, the shortest time to
extubation, and the shortest length of ICU stay has recently been systematically reviewed.5 The
majority of trials compared propofol with midazolam, finding propofol to be at least as
effective while allowing faster time to extubation, but with increased risk of hypotension and
increased cost. Dexmedetomidine was not included in this review.
There is no one pharmacological sedation regimen known to be superior in all
circumstances. Any discussion of sedation must include evaluation of analgesics and major
tranquilizers, which have both sedative effects, and by their primary action can also reduce the
requirement for sedation. Sedation requirement is also affected by the administration protocol
followed and the environment of the patient. Only when all of these factors are addressed can
the drugs be compared and the most effective selected.
References
1. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with
alphaxalone-alphadolone. BMJ 1974;2:656-659.
2. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale
for adult critically ill patients. Crit Care Med 1999;27:1325-1329.
3. Devlin JW, Boleski G, Mlynarek M, Nerenz DR, Peterson E, Jankowski M, et al. Motor
Activity Assessment Scale: a valid and reliable sedation scale for use with mechanically
ventilated patients in an adult surgical intensive care unit. Crit Care Med 1999;27:12711275.
4. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of
sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119-141.
5. Ostermann ME, Keenan SP, Seiferling RA, Sibbald WJ. Sedation in the intensive care
unit: a systematic review. JAMA 2000;283:1451-1459.
6. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in
critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342:14711477.
7. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol
on the duration of mechanical ventilation. Crit Care Med 1999;27:2609-2615.
8. MIMS Annual. St Leonards: MediMedia Australia Pty Limited, 2004.
9. Romero C, Bugedo G, Bruhn A, Mellado P, Hernandez G, Castillo L. Experiencia
preliminar del tratamiento con dexmedetomidina del estado confusional e hiperadrenergia
en la unidad de cuidados intensivos. Revista Espanola de Anestesiologia y Reanimacion
2002;49:403-6.
10. Perioperative sympatholysis. Beneficial effects of the alpha 2-adrenoceptor agonist
mivazerol on hemodynamic stability and myocardial ischemia. McSPI--Europe Research
Group. Anesthesiology 1997;86:346-63.
69
DEFINE AND LIST THE CAUSES AND MANAGEMENT OF PLATYPNOEA AND
ORTHODEOXIA
Dr. M. Davey. Intensive Care Unit, The Canberra Hospital, ACT
Definitions
Platypnoea: dyspnoea aggravated in the erect position and relieved in the supine position.
Orthodeoxia: is oxygen desaturation aggravated in the erect position and relieved in the supine
position.
The precise cause of the syndrome is unclear but patients develop right to left intracardiac
shunting, often in the presence of normal right sided cardiac pressures (Cheng 1999).
Causes
Common
• ASD or PFO (Rao 2001, Kubler 2000, Patel 2003) with position-dependent shunting,
often in combination with one of the conditions below.
Rare
• Other Cardiac
o Pericardial effusion
o Constrictive pericarditis
o Aortic aneurysm
• Pulmonary
o Multiple pulmonary emboli (Hussain 2004)
o Pulmonary emphysema
o Radiation-induced bronchial stenosis (Awan 1999)
o Hepatopulmonary syndrome (Gomez 2004)
o Amiodarone toxicity of the lungs
o Pulmonary A-V communications
• Autonomic
o Parkinson disease (Hussain 2004)
o Bilateral thoracic sympathectomy (van Heerdon 2004)
• Abdominal
o Hepatic cirrhosis
o Ileus
Management
• Closure of the ASD or PFO
• The case associated with Parkinson’s disease (Hussain 2004) was attributed to postural
hypotension, and improved with fludrocortisone.
• The case associated with radiation-induced bronchial stenosis (Awan 1999) was
relieved by bronchial dilation initially, and later by bronchial stenting.
• The case associated with bilateral thoracic sympathectomy (van Heerdon 2004) was
treated initially with noradrenaline and almitrine.
References
1. Awan AN. Ashraf R. Meyerson MB. Dunn TL. (1999) Radiation-induced bronchial
stenosis: a new cause of platypnea-orthodeoxia. Southern Medical Journal. 92:720-4.
2. Cheng TO. (1999) Platypnea-orthodeoxia syndrome: etiology, differential diagnosis, and
management. Catheterisation & Cardiovascular Interventions. 47:64-6.
70
3.
4.
5.
6.
7.
8.
Gomez FP. Martinez-Palli G. Barbera JA. Roca J. Navasa M. Rodriguez-Roisin R. (2004)
Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology.
40:660-6.
van Heerden PV. Cameron PD. Karanovic A. Goodman MA. (2003) Orthodeoxia—an
uncommon presentation following bilateral thoracic sympathectomy. Anaesthesia &
Intensive Care. 31:581-3.
Hussain SF. Mekan SF. (2004) Platypnea-orthodeoxia: report of two cases and review of
the literature. Southern Medical Journal. 97:657-62.
Kubler P. Gibbs H. Garrahy P. (2000) Platypnoea-orthodeoxia syndrome. Heart. 83:2213.
Patel AD. Abo-Auda WS. Nekkanti R. Ahmed S. Razmi RM. Pohost GM. Nanda NC.
(2003) Platypnea-orthodeoxia in a patient with ostium primum atrial septal defect with
normal right heart pressures. Echocardiography. 20:299-303.
Rao PS. Palacios IF. Bach RG. Bitar SR. Sideris EB. (2001) Platypnea-orthodeoxia:
management by transcatheter buttoned device implantation. Catheterization &
Cardiovascular Interventions. 54:77-82.
71
WHAT ARE THE FACTORS CAUSING, AND TREATMENT OF, AN ACUTE
SUBCLAVIAN VEIN THROMBOSIS
Dr. S. Sane. Department of Critical Care Medicine, Flinders Medical Centre, South Australia
Acute subclavian vein thrombosis is a component of a broader group of diseases grouped under
upper extremity deep vein thrombosis (UEDVT).
UEDVT occurs in two forms:
1. Effort induced thrombosis, also called as Paget-von Schrötter syndrome,1 or Primary
UEDVT which accounts for 25% cases of UEDVT& is the most common vascular problem
in athletes.2
2. Secondary UEDVT which accounts for 75 % cases of UEDVT.
Aetiology:
Primary UEDVT
Underlying chronic venous compressive abnormality caused by musculoskeletal structures in
costoclavicular space at the thoracic outlet or inlet.
Pathophysiology:
Virchow’s triad of stasis, hypercoaggulability & intimal damage, for thrombosis, plays an
important part.
Axillosubclavian vein is exposed to repeated trauma [with vigorous or unaccustomed arm
movements, 3,4 due to its relatively fixed position in the thoracic outlet/inlet which leads to
intimal hyperplasia causing venous stenosis.
Secondary UEDVT
CVC catheters
Permanent pacemakers
Hypercoagulable states
Mediastinal tumour/nodes
Mediastinal radiation & surgery
Trauma (e.g. fracture clavicle)
IV drug abuse
Contributory anatomic abnormalities:
1. Presence of cervical rib.
2. Posttraumatic deformity of surrounding bony structures.
3. Anomalous musculoskeletal bands.
Horrates et al found that 65% of catheter induced thromboses were left sided.5
Schillinger et al found in a study of hundred patients who underwent CVC for dialysis, 42% of
their subclavian veins & only 10 % jugular veins developed stenosis.6
Therefore the authors recommended right internal jugular vein for CVC canulation.
Management:
Relevant history (recent trauma, iv drug abuse or unaccustomed exercise etc)
72
Physical examination (signs of venous obstruction in the form of oedema, venous collaterals,
tenderness, warmth)
Acute management & prevention in future.
Investigations:
1. Colour flow duplex imaging:
sensitivity- 78 to100%
specificity- 90 to 100%
2. Venography: gives accurate diagnosis.
Position of arm: abduction , external rotation & extension especially to diagnose effort
induced vein thrombosis.
Patient should undergo bilateral venograms with provocative maneuvers even if signs &
symptoms of venous compression are unilateral.
Diagnosis made by visualising intraluminal defect & venous collaterals.
False positives - compression features with provocative measures can also occur in
asymptomatic patients.
3. X ray:
Can give suggestion of the diagnosis by evidence of fracture clavicle / 1st rib or presence of
a cervical rib.
4. CT scan:9
UEDVT is seen as hypoattenuating defect in contrast enhanced CT scan.
Cross section can detect soft tissue pathology such as tumour or lymphadenopathy
surrounding the vein in question.
Especially good diagnostic quality can be obtained with 3D images.
5. Magnetic Resonance venograms:9
It has shown good accuracy in diagnosing subclavian, brachiocephalic & SVC thrombosis,
an area that is poorly visualised by ultrasound.
6. Ultrasound:
Advantage- rapid, noninvasive & easily available.
Diagnosis made by absence of colour flow signals & augmentation or visualisation of
thrombus.
Morbidity & mortality:
Major complications of UEDVT can be:7
1. Pulmonary embolism2. The prevalence of PE in UEDVT is about 10-30% which is similar to lower limb DVT.
Catheter induced thrombosis has higher risk of causing pulmonary embolism.
3. Superior vena cava syndrome.
4. Sepsis especially with staphylococcus aureus secondary to septic thrombophlebitis.
5. Chronic disability.
6. Removal of a CV canula in a critically ill patient results in IV access problems.
Interventions:
Primary UEDVT “ Machleder algorithm” (10) which is as follows:
A. Thrombolysis“ Golden Week”- greatest benefits are obtained if thrombolysis is started within about seven
days of symptoms,8 even though a period of 10 to 14 days is considered reasonable.
73
Thrombolytic agents used are- urokinase, alteplase, reteplase.
Contraindications for thrombolysis areAbsolute:
1. active internal hemorrhage
2. recent GI hemorrhage
3. CNS tumour, aneurysms or AV malformations.
4. recent CVA.
Relative contraindications:
1. trauma
2. post partum (<10 days)
3. uncontrolled hypertension
4. hemorrhagic retinopathy
5. left sided cardiac thrombus
Current mechanical thrombectomy devices can facilitate clot removal & thus decrease
thrombolytic dose & infusion period.
B. Anticoagulation is recommended for 6 to 12 weeks after thrombolysis.
C. Surgical thoracic outlet decompression is indicated in case of significant persistent disability
or persistence of venous abnormality &can be achieved by trans axillary or trans thoracic
resection of first rib.
D. Follow up venography & angiography is done to detect residual venous stenosis after
decompression surgery. Use of vascular stents is relatively contraindicated in this position
due to low patency rates.
Secondary UEDVT
A. Traditional conservative measures include, removal of CV catheter, bed rest, limb elevation,
application of heat & anticoagulation.
Symptomatic relief is achieved because of development of collaterals & prevention of clot
propagation.
B. Surgical thrombectomy is sometimes required.
C. Catheter directed thrombolysis: most thrombosed veins reanalyse within 24 hours. If
underlying vein is normal after thrombolysis, short-term anticoagulation is needed, however
if it is abnormal anticoagulation for 10 to 12 weeks is warranted.
References
1. Hughes ESR: Venous obstruction in the upper extremity, Int Abst Surg, 949;88(2):89-127
2. Sotta RP: Vascular problems in the proximal upper extremity. Clin Sports Med
1990;9(2):379-388
3. Rutherford RB et al. Primary subclavian-axillary vein thrombosis:Cardiovascular Surg
1996; 4(4):420-423
4. Adams JT et al: PUEDVT Arch Surg 1965; 91:29-42
5. Horrates et al: Changing concepts of deep venous thrombosis of the upper extremity-report of a series and review of the literature. Surgery 1988 Sep; 104(3): 561-7
6. Schillinger et al: Post-catheterization venous stenosis in hemodialysis: comparative
angiographic study of 50 subclavian and 50 internal jugular accesses. Nephrology 1992;
13(3): 127-33
74
7.
Pradoni et al: Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and
complications. Arch Intern Med 1997 Jan 13; 157(1): 57-62
8. Adelman MA et al. A multidisciplinary approach to the treatment of Paget –Schrotter
syndrome, Ann Vasc Surg 1997;11(2):149-154
9. Rose SC: Systemic central veins of the thorax and neck. In: Noninvasive vascular imaging
with ultrasound, computed tomography, and magnetic resonance. 1997: 163-74
10. Craig et al: Deep vein thrombosis, upper extremity, May 2003, www.emedicine.com.
75
DISCUSS THE DIFFERENCE IN AETIOLOGY, DIAGNOSIS AND TREATMENT OF
PORTOPULMONARY HYPERTENSION AND HEPATOPULMONARY SYNDROME
Dr. S. Simpson. Intensive Care Unit, Women’s and Children’s Hospital, South Australia
Introduction
Cardiopulmonary abnormalities are common in patients with advanced liver disease,
resulting from malnutrition, immunosuppression, and the effects of severe portal hypertension
(eg. pneumonia, pleural effusion, atelectasis), or from the underlying disease (eg cystic fibrosis,
alpha-1-antitrypsin deficiency).1 There are also two distinct pulmonary syndromes
pathogenically linked to the presence of portal hypertension. Hepatopulmonary syndrome
(HPS) is characterised by pulmonary vasodilation, with anatomical shunt and an alveolar
diffusion defect. Conversely, portopulmonary hypertension (PPHTN) results in pulmonary
vasoconstriction with arterial remodelling.1-5 Each entity requires a unique management
approach, and has different prognostic relevance, especially in relation to liver transplantation.
Common features
Both HPS and PPHTN occur in the presence of portal hypertension, defined as portal
pressure >10mmHg. Although more commonly associated with parenchymal liver disease, nonhepatic causes of portal hypertension can lead to either syndrome.1-5 There is no correlation
between the severity of portal hypertension and the development of either HPS or PPHTN.
Both have a poor prognosis if untreated.
Hepatopulmonary syndrome (HPS)
The classic triad2
• Hepatic dysfunction
• Arterial hypoxaemia in air (PaO2 < 70mmHg, or Alveolar-arterial gradient >20mmHg)
• Intrapulmonary vascular dilatations (IPVD’s)
The incidence of HPS ranges between 4-47% of patients with chronic liver disease.1-3
Pathogenic theories centre upon the circulatory consequences of portal hypertension, with
altered bowel perfusion increasing the translocation of gut bacteria and endotoxin, stimulating
the release of vasoactive mediators, including TNFα, carbon monoxide, and nitric oxide (NO).
NO is found in higher concentrations in the breath of HPS patients.2 Animal models display
abnormal expression and activity of endothelin-type-B receptors, which further enhances the
effects of NO.2 HPS is defined by finding IPVD’s in precapillary arterioles, often with the
creation of direct arterial-venous vascular malformations, particularly in the lower lobes.1-3
These structures have been likened to telangiectasia, which are common in liver disease.
Nonspecific clinical findings include progressive dyspnoea (common), digital clubbing and
cutaneous spider naevi. HPS may present with paradoxical embolism, cerebral haemorrhage, or
brain abscess.1-3
The hallmark clinical finding in HPS, although not universal, is orthodeoxia (a fall in PaO2
> 3mmHg when transferred from supine to upright), associated with platypnoea (dyspnoea
which improves in recumbency).2 These findings relate to postural changes in pulmonary
perfusion.
Diagnostic investigations
Contrast enhanced 2-D echocardiography using agitated saline shows the appearance of
bubbles in the left atrium within 3-6 cardiac cycles of IV injection. Earlier appearance indicates
76
intracardiac R-L shunt, which is an important differential. A 99mTc microaggregated albumin
scan is more specific. Normal pulmonary capillaries (15µm diameter) traps labelled albumin
(>20µm diameter) in the lungs.1,2 Uptake in brain indicates transpulmonary passage, and the
ratio can be used to quantify severity. Pulmonary angiography is not routinely done in HPS,
unless the patient is poorly responsive to oxygen, indicating large shunt.2 Angiography may
identify localised arterio-venous malformations that are amenable to surgical excision or
embolisation.1
Management
Oxygen is the main therapy. Drugs including NO synthetase inhibitors, almitrine and
somatostatin, have not shown any benefit.1-3 Trials are underway with antibiotics to reduce
translocation of microorganisms, and methylene blue.1 Success has been reported with portal
pressure reduction using transjugular porto-systemic shunting (TIPS), but it is not yet
established as a standard therapy for HPS.1,2 In severe cases with refractory hypoxaemia the
definitive treatment is orthotopic liver transplantation (OLT).1-3
Prognosis
Once PaO2 is less than 50mmHg, one year survival is between 16-38%.3 Complete
resolution of HPS after liver transplantation is not universal, but has been documented in 6282% of survivors.2
Portopulmonary hypertension (PPHTN)
PPHTN is defined by elevated mean pulmonary arterial pressure (mPAP >25mmHg at rest)
in the setting of portal hypertension, and normal left ventricular end diastolic pressure.1,4,5
Mild-moderate symptoms correlate well with histo-pathological findings of pulmonary
vasoconstriction and endothelial and smooth muscle hypertrophy.5 Severe cases develop
progressive plexogenic arteriopathy with in situ thrombosis and fibrosis, leading to right heart
failure.4,5 These histological lesions are indistinguishable from those found in primary
pulmonary hypertension.
The incidence ranges from 0.7% in the presence of cirrhosis, to 16% of patients assessed for
liver transplantation.1,4 Factors involved in the development of pulmonary arteriopathy are yet
to be identified. Proposed mechanisms include imbalances in endothelin vs nitric oxide, and/or
thromboxane vs prostacyclin levels, due to altered liver function. Plasma endothelin-1 levels
are substantially higher in PPHTN patients than patients with cirrhosis and no PPHTN.4
Genetic mutations in tissue growth factor receptor families have also been implicated, but no
conclusive evidence exists. PPHTN is more common in the subset of auto-immune diseases
involving the liver.4
The commonest presenting symptom is progressive dyspnoea on exertion. Other nonspecific complaints include fatigue, palpitations, syncope, and chest pain.1,3,4,5 Signs of
pulmonary hypertension with right heart failure may be present, such as loud P2 associated
with a systolic murmur of tricuspid regurgitation, raised JVP, ascites, and peripheral oedema. It
is important to exclude other causes of pulmonary hypertension, such as left heart failure,
valvular heart disease, interstitial or obstructive lung disease, chronic thrombo-embolism, and
sleep-related breathing disorders.4,5
The investigation of choice is transthoracic echocardiography, measuring pulmonary and
intracardiac pressures.1,3,4,5 Once the diagnosis of PPHTN has been established the severity is
determined by the clinical symptoms, and values derived for cardiac index, pulmonary vascular
resistance (PVR), and right atrial pressure (RAP).1 (see table).Right heart catheterisation is
required for definitive diagnosis.5
77
Normal
Mild
Moderate
NYHA class
I/II
II/III
mPAP (mmHg)
15-24
25-34
35-44
Cardiac index (L/min/m2)
2.5-4.0
>2.5
>2.5
PVR (dynes/s/cm5)
<240
240-500
500-800
RAP (mmHg)
0-5
0-5
5-8
Prognosis
Favourable ??????
Specific treatment req’d
No
??????
Reversible after OLT
Yes
??????
Diagnostic criteria for determining mild, moderate, or severe PPHTN.1
Severe
III/IV
>45
<2.0
>800
>8
Poor
Yes
No
Management
Patients with mild disease are monitored using bi-annual 2-D echocardiography.4 More
severe cases warrant medical treatment, either with palliation, or as a bridging therapy to
transplantation.
Medications
Drugs used in primary pulmonary hypertension may not be suitable. B-blockers and nitrates
increase the risk of variceal bleeding.4 Anticoagulation is controversial.1 Sildenafil and
calcium-channel blockers have not been studied in PPHTN. Prostacyclin is recommended for
its antiproliferative effects which can reverse the remodelling of the pulmonary vasculature.4
Data obtained from open-label trials show improvement in symptomatic end-points (eg exercise
capacity), but there are no data showing survival benefits.1,4,5,6 Intravenous epoprostenol
administration has significant risks. New inhaled, subcutaneous, or oral equivalents may be safe
but have not been studied.6 Endothelin receptor-1 antagonists have theoretical benefits, but also
have known hepatotoxic side effects. Experience with bosentan is restricted to specialised
centres.1,4,6
Liver transplantation
Recent outcome studies indicate patients with mild-moderate PPHTN (mPAP < 40mmHg)
are at no additional risk from liver transplantation (OLT) than other patients with advanced
liver disease.4 Severe PPHTN is a contraindication for OLT because of high intraoperative
mortality (38-42%), and poor quality post-operative survival.1,3,4,5 World-wide experience with
heart-lung-liver transplant is limited.4
Prognosis
In severe PPHTN median survival is 6 months after diagnosis.1
References
1. Hoeper, MM, Krowka, MJ, Strassburg, CP. Portopulmonary hypertension and
hepatopulmonary syndrome. Lancet, 2004;363:1461-1468.
2. Yen, KT, Krowka, MJ, et al. Liver and lung: hepatopulmonary syndrome: recognising the
clinical features and selecting the right studies. J Crit Illness. 2002;17:309-315.
3. Naeije, R Hepatopulmonary syndrome and portopulmonary hypertension. Swiss Med
Wkly 2003:133:163-169.
4. Budhiraja, R, Hassoun, PM. Portopulmonary hypertension: A tale of two circulations.
Chest 2003;123:562-576.
5. Krowka, MJ. Portopulmonary hypertension: understanding pulmonary hypertension in the
setting of liver disease. Eur Respir J 1998;1:1153-1166.
78
6.
Benza, RL, Medical treatment options / advances in portopulmonary hypertension: how
the spectrum is expanding. Advances in Pulmonary Hypertension 2004;3:16-22.
79
DISCUSS THE MANAGEMENT OF A PATIENT WHO HAS AN ASYSTOLIC
CARDIAC ARREST
Dr. M. Ibrahim. Intensive Care Unit, The Austin Hospital, Victoria
A. Primary ABCD Survey
Initial Management
1. Diagnose (check responsiveness, absent carotid pulse, respiration)
2. Call for assistance (Emergency medical response)
3. Place patient on firm surface
4. Call for Defibrillator
5. Allocate responsibilties
6. Proceed to BLS
Basic Life Support (BLS)
1. Airway:
open airway (Head tilt, Jaw thrust, open mouth, clear airway)
2. Breathing: provide PPV (give 2 breaths)
100% 02 via Bag & mask or mouth to mask
3. Circulation: Give chest compressions (80-100/min)
4. Defibrillator: Attach Defibrillator paddles/ leads (To confmn asystole + if any doubt it
could be fine VF -7 shock as per ACLS
* Note: It is very important to identify and/or treat VF if any suspicion as prognosis is much
better than asystole
B. Secondary ABCD survey
Advanced Cardiac Life Support (Asvstole)
1. Airway:
Place airway device (Intubate)
2. Breathing: Confirm airway device by exam + confmnation device (!!)
Breathing: Secure airway device
Breathing: Confirm effective oxygenation and ventilation
3. Circulation: Confirm true asystole/ identify rhythm
Circulation: Obtain IV access
Circulation: Administer drugs:
1. Adrenaline Img IV push (Or 3mg via ETT)
Repeat every 3 minutes
OR
Consider Vasopressin 40U IV (single dose)
If no response use Adrenaline as above
2. Atropine Img IV (Or 3mg via ETT)
Repeat every 3 min (up to 0.04 mg/kg)
3. Recheck rhythm and treat accordingly
4. Differential Diagnosis:
Search and treat identifiable causes (5H/5T)
Hypoxia/Hyperinflation
Toxins/ Tablets (OD, illicit drugs)
Hypovolaemia
Tamponade, cardiac
Hydrogen ion (Acidosis)
Tension pneumothorax
Hyperkalaemia/Hypokalaemia Thrombosis, coronary
Hypothermia/Hyperthermia
Thrombosis, pulmonary
80
Indications for:
Potassium (K) → Hypokalaemia
Calcium (Ca) → Hypocalcaemia, Hyperkalaemia, Massive transfusion, Ca antagonist OD
Bicarbonate (HC03) → TCA overdose, Hyperkalaemia, Preexisting acidosis
Magnesium (Mg) → Polymorphic VT, Hypokalaemia, Hypomagnesaemia
C. When to stop
Depends on reversible factors, comorbidities (generally 20-25 mins acceptable)
D. Prognosis
Generally poor for asystole patients (1-2% walk out of hospital)
References
1. International Guidelines 2000 for CPR and ECC : a consensus on science. Circulation.
102( Suppl)
2. Wenzel V, et al. A comparison of Vasopressin and Epinehrine for out-of-hospital.
cardiopulmonary resuscitation NEJM 2004; 350(2): 105-113
3. Oh's Intensive Care Manual, 5th Edition
4. Irwin and Rippe's Intensive Care Medicine, 5th Edition.
81
DISCUSS THE CAUSES AND MANAGEMENT OF PARALYTIC ILEUS
Dr. G. Kwan. Intensive Care Unit, Queen Elizabeth Hospital, Hong Kong
Definition of ileus
A partial or complete non-mechanical blockage of the small and/or large intestine with
temporary arrest of intestinal peristalsis
It is common for a patient to acquire an ileus during a stay in ICU. The presence of ileus can
lead to significant morbidity and possibly mortality. A rapid and efficient search for the cause
of the ileus is critical to reduce this morbidity and to restore enteral nutrition promptly.
Intra-abdominal causes of Ileus
Infective disorders
Peritonitis
Diverticulitis
Cholecystitis
Appendicitis
Tubo-ovarian abscess
Inflammatory disorders
Pancreatitis
Perforated viscus
Toxic Megocolon
Intraperitoneal bleeding
Peritionitis
Ischaemic disorders
Local arterial insufficiency
Local venous insufficiency
Mesenteric arteritis
Strangulated disorders
Retroperitoneal disorders
Nephrolithiasis
Pyelonephritis
Hemorrhage
Extra-abdominal causes of Ileus
Drug induced
Anticholinergic medication
Opioids
Chemotherapy e.g. vinblastine, vincristine
Ganglionic blocking agents
Metabolic disturbances
Electrolytes disturbances e.g. hypokalaemia
Sepsis
Uremia
Diabetic ketoacidosis
Sickle cell anaemia with painful crisis
Hypothyroidism
82
Reflex inhibition
Myocardial infarction
Pneumonia
Pulmonary embolus
Burns
Fractures of the pelvis, ribs or spine
Management
• Review Patient medical and surgical history
• Review drug history
• Initial steps should entail establishing the presence of obstruction or ileus
• Evaluate and correct for electrolyte disturbances – measuring serum sodium, potassium,
chloride and bicarbonate levels)
• Searching for evidence of infection and inflammatory disorders – white cell count with
differential
• Other laboratory abnormalities including serum amylase, ALP, CPK, AST, ALT and LDH,
anion gap metabolic acidosis
• Abdominal radiographs (supine and upright views) to help localise the abnormality and to
exclude free intraperitoneal air, look for intestinal gas and fluid level and evidence of
mechanical obstruction
• Chest radiographs can indicate the presence of associated pulmonary disease as an extraabdominal cause of ileus
• CT should be considered to look for possible cause of ileus
• Initiation of nasogastric suction with low intermittent suctioning as bowel distension can
result in nausea, vomiting, and increased risk of aspiration
• Intravenous fluid for fluid supplement
• Avoid use of opioids and other antimotility agents
• Normalising glucose levels if hyperglycaemia is present
• The therapy for ileus should be directed toward the treatment of the underlying causes
• Gastric prokinetic agents can be considered if obstruction has been ruled out. Examples:
Nesostigmine, Cisapride, Erythromycin, metaclopramide
• Start Enteral feeding as presence of food in small bowel stimulates peristalsis
• Surgical decompression e.g. rectal tube or endoscopic decompression if grossly distended
large bowels with risk of perforation
References
1. Ileus and mechanical obstruction. In : Kumur D, Wingate D: An illustrated guide to
gastrointestinal motility. New York: Churchill Livingstone, 1993, pp 547-582.
2. Ileus and obstruction. In : Haubrich WS, Schaffner F, Berk JE: Bockus Gastroenterology.
Philadelphia: WB Saunders, 1995, pp 1235-1248.
3. Approach to the patient with ileus and obstruction. In : Yamada T, Aplers DH, Owyang C
et al: Gastroenterology. Philadelphia: JB Lippincott, 1995, pp 796-812.
4. Bauer AJ, Schwarz NT, Moore BA, Turler A, Kalff JC. Ileus in Critical illness:
mechanisms and management. Curr Opin Crit Care 1998;8:152-157.
5. Corke C. Gastric emptying in the critically ill patient. Critical Care and Resuscitation
1999;1:39-44.
83
DISCUSS THE CAUSES, CLINICAL FEATURES AND MANAGEMENT OF A
PATIENT WITH D-LACTIC ACIDOSIS
Dr. T. Fraser. Intensive Care Unit, The Geelong Hospital, Victoria
D-lactic acidosis is a rare disorder. It was first described by vets in cattle! L-lactate is
produced by mammalian cells. Under normal circumstances, the primary product of glycolysis,
pyruvate, is metabolised in the Kreb’s cycle to produce energy, carbon dioxide and water.
Under anaerobic conditions NAD+ is exhausted, pyruvate is transformed to lactate, and NAD+
regenerated.
L-lactate is also the primary product of cellular energy metabolism in some tissues (eg red
blood cells), which is returned to the liver to be converted back to glucose, in a process referred
to as the Cori cycle.
D-lactate is a stereoisomer of L-lactate, formed primarily by some gram positive anaerobic
bacteria. D-lactate is only formed by mammalian cells in trivial amounts.
Causes
Gut pathology
a) Short gut syndromes
- Due to incomplete carbohydrate absorbtion so that it is metabolised by colonic flora.
D-lactate is then absorbed
- Described in small bowel resection, jejunoileal bypass and gastric bypass surgery
b) Blind loops
c) Bacterial overgrowth
- Lactobacillus acidophilus
- Strep bovis and others
d) Intestinal ischaemia and other bowel catastrophes
- Increasingly recognised
- Levels rise within 5 minutes in rat models of intestinal infarction
- Levels appear to rise further with reperfusion
- Early evidence in human studies
Other
Has been linked with:
- Thiamine deficiency syndromes
- Treatment with medium chain triglycerides
- Impaired metabolism
Precipitants
- Antibiotic therapy
- Increased carbohydrate intake
- Lactobacillus therapy
Development of D-lactate is often delayed many years, and occurs in response to a
precipitant. This is likely to be due to progressive selection of resistant organisms and
increasing colonisation. Patients who develop D-lactic acidosis often have higher baseline Dlactic acid levels, reflecting this.
Clinical Features
Patient is unwell
Marked CNS symptoms
84
- Confusion
- Ataxia, dysarthria, visual disturbance
- Headache
Marked anion gap metabolic acidosis
- No apparent cause
- Serum lactate is normal (not measured with currently available assays)
Clinical features attributable to cause
Management
Confirm diagnosis
- D-lactate assays are available, but turn around time compromises utility
• D-lactate dehydrogenase test available from SIGMA
• Not difficult, just not widely available
- Anion gap metabolic acidosis
- Stool cultures
• Useful to identify resistant organisms
- Exclude other causes
Treatment
- Symptoms are usually short lived if stimulus removed
- Supportive
• Maintain oxygenation and perfusion along standard lines
- Identify and manage the cause
• Withdraw causative antibiotics (may be enough on its own)
• Carbohydrate restriction
• Antibiotics (oral vancomycin, metronidazole, ciprofloxacin or clindamycin have
been suggested)
• Surgical correction as indicated
Conclusions
Rare syndrome
Be aware in the clinical context
May be of interest in dead gut
Vets are smarter than doctors
References
1. Coronado BE, Opal SM, Yoburn DC: Antibiotic-induced d-lactic acidosis. Ann Intern
Med 122:839–842
2. Mordes J, Rossini A. Lactic Acidosis. In ed: Irwin RS, Rippe JM Intensive Care
Medicine. 5th Ed. Lippencott, Williams, Wilkins 2003. Chapter 107
3. Serum D(-)-lactate levels as an aid to diagnosing acute intestinal ischemia. Am J Surg.
1994 Jun;167(6):575-8
85
DISCUSS THE CLINICAL FEATURES AND MANAGEMENT OF A PATIENT WHO
HAS THE ‘RETINOIC ACID SYNDROME’
Dr. D. Moxon. Intensive Care Unit, Royal Perth Hospital, WA
DEFINITION
Complex of symptoms and signs reported among patients receiving All Trans Retinoic Acid
(ATRA)
For the treatment of Acute Pro-Myelocytic Leukaemia (APML)
This is molecular genetic subtype of AML
APML is curable in >70% of patients
SYMPTOMS AND SIGNS
Respiratory Distress
84%
Fever
81%
Pulmonary Infiltrates 52%
Pleural/Pericardial Effusions
Episodic Hypotension
Renal Dysfunction
36%
18%
11 %
EPIDEMIOLOGY
Approximately 20% of patients on ATRA will develop RAS
Median time to onset of symptoms is 7days from commencement of ATRA
PATHOLOGY
Lung biopsy shows interstitial infiltration with mature myeloid cells.
These cells release mediators and cause local capillary leak
TREATMENT
Close cooperation with haematologist
Supportive care (NIV, Pressors, RRT, Factors)
Cessation of ATRA
Prompt administration of steroids vs possibility of infective cause for fever and infiltrates
References
1. Up to date. RPA FRACP Course handout "Haematology 1".
86
HOW WOULD YOU MANAGE A PATIENT WHO HAS AN ACUTE POSTOPERATIVE COLONIC PSEUDO-OBSTRUCTION?
Dr W. Newman. Intensive Care Unit, Mackay Base Hospital, Queensland
Colonic pseudo-obstruction, or Ogilvie’s syndrome, occurs especially after trauma and
orthopaedic surgery, and as a complication of serious medical conditions, such as pneumonia.
More common in men past middle-age. Electrolyte imbalance is often a contributory factor.
It is clinically recognisable where nausea, vomiting, abdominal pain and bloating
complicate the post-operative state. The abdomen is distended, tympanitic, and bowel sounds
are usually present. Abdominal Xrays show dilated right hemi-colon, gas in the rectum, the
small bowel may also be dilated.
Peritoneal signs are a sign of ischaemia or impending perforation, with an attendant
mortality rate of 40%.1 Mechanical obstruction and toxic megacolon need to be excluded, as
the treatment differs.
With obstruction, X-rays may show lack of gas in the rectum, air-fluid levels in the small
bowel, but a water-soluble contrast enema is needed to exclude obstruction with certainty.
Toxic megacolon is characterised by fever, tachycardia, bloody diarrhoea and typical
endoscopic findings of pseudo-membranous colitis. (Clostridium difficile infection, especially
after broad spectrum antibiotics). Xrays may show “thumb-printing” due to submucosal
oedema.
The condition, originally reported by Ogilvie in 1948, was thought to be due to sympathetic
deprivation of the colon. However, interrupting parasympathetic fibers from S2 to S4 leaves the
distal colon atonic and a similar situation arises. Furthermore, administration of neostigmine
improves the condition due to stimulation of muscarinic receptors in the colon.
MANAGEMENT
- Treatment of the underlying disorder.
- Nil by mouth.
- Nasogastric tube drainage and intermittent suctioning.
- Lactulose should not be given, due to it supplying substrate for fermentation and further gas
formation.
- Discontinuation of anticholinergic drugs and opiates.
- Correction of electrolyte imbalances: potassium, magnesium, calcium and phosphate.
- Rectal tube placement and gravity drainage.
- Positioning. For example, the knee-chest prone position with elevation of the pelvis.2
- Daily abdominal X-ray. A caecal diameter greater than 12 cm is associated with an
increased risk of perforation.3
THE ABOVE SHOULD LEAD TO A RESPONSE in most patients within three days.4
If there is still no resolution after these measures, pharmacological agents can be used.
Erythromycin, which binds to motilin receptors in the proximal small bowel and colon, is an
option.5 This treatment has not been evaluated in a randomised study.
In a prospective, randomised, controlled, double-blinded trial; 2mg IV neostigmine caused
resumption of normal colon function in 91 % of patients.6
Neostigmine treatment
- Bronchospasm, bradycardia, signs of ischaemia, perforation, obstruction, pregnancy and
renal failure are contra-indications.
87
-
Atropine 1 mg, should be drawn up and ready for any severe side effects (Glycopyrrolate
can be considered as an alternative to atropine as it diminishes the central cholinergic
effects of neostigmine without reducing the increased colonic drive)7
ECG monitoring for 30 mins after injection.
Abdominal X-ray before and after the injection
With the patient supine, 2 mg of neostigmine are given IV over 3 mins. A response occurs
within minutes.
The patient should remain recumbent for 60 mins.
If no response occurs, a second dose may be tried. If the condition persists, colonoscopic
decompression is indicated. A sustained response is reported in 42% of patients. Advancement
of the colonoscope to the hepatic flexure is considered sufficient. Placement of a
decompression tube may be tried, but this is a difficult procedure and the mortality rate
associated is 1 %.8
Surgical treatment is needed if the above measures fail. Tube caecostomy is the procedure
of choice.
References
1. Saunders MD, Kimmey MB. Colonic Pseudo-Obstruction: The Dilated Colon in the lCU.
Seminars in Gastrointestinal Disease. 2003;14(1): 20-27
2. Eisen GM, Baron TH,Dominitz JA et al. Acute colonic pseudoobstruction.Gastrointestinal Endoscopy. 2002;56(6)
3. Vanek VW, Al-Salti M. Acute pseudo-obstruction of the colon (Ogilvie's syndrome).
Analysis of 400 cases. Dis Colon Rectum 1986;29:203-210
4. Sloyer AF, Panella VS, Demas BE, et al: Ogilvie's syndrome. Successful management
without colonoscopy. Dig Dis Sci 1988;33:1391-1396
5. Armstrong DN,Ballantyne GH, Modlin 1M. Erythromycin for reflex ileus in Ogilvie's
syndrome. Lancet 1991;337:378
6. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the Treatment of Acute Colonic
Pseudo-Obstruction. NEJM 1999;341(3):137-141
7. Child CS. Prevention of neostigmine-induced colonic activity: a comparison of atropine
and glycopyrronium. Anaesthesia 1984;38:1083-1085
8. Vantrappen G. Acute colonic pseudo-obstruction. Lancet 1993; 341:152-153.
88
DISCUSS THE MANAGEMENT OF A PATIENT WITH AF, HYPOTENSION AND
HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY
Dr. A. Holley. Intensive Care Unit, Royal Brisbane Hospital, Queensland
Issues in this patient:
Hypertrophic obstructive cardiomyopathy (HOCM)
Hypotension
Rapid atrial fibrillation
Potential for ischaemia, degeneration to VF/VT and cardiac arrest
Pathophysiology:
Hypertrophic cardiomyopathy (HCM) is a common disease, affecting approximately 1: 500.
It usually displays autosomal dominant inheritance.
Approximately 25% of patients with HCM exhibit a dynamic subaortic pressure gradient,
hypertrophic obstructive cardiomyopathy (HOCM) used to describe this group.
The characteristic feature of HOCM is myocardial hypertrophy that is out of proportion to
the haemodynamic load. Hypertrophy can affect any or all areas of the heart and is usually
asymmetrical. The predominant form involves disproportionate hypertrophy of the
interventricular septum, with a normal or mildly hypertrophied left ventricular free wall. The
ventricular cavities are usually small. Diastolic dysfunction ensues, with impaired left
ventricular relaxation and increased filling pressures. Outflow obstruction arises as a result of
the combined effects of septal hypertrophy and systolic anterior motion of the mitral valve
leaflets. As the ventricle contracts the subaortic flow velocity increases. The acceleration of
blood through the narrowed outflow region causes a pressure drop that draws the anterior
mitral valve leaflet towards the ventricular septum (‘Venturi effect’). The mitral valve
apparatus then contacts against the hypertrophied septum in mid-systole, obstructing the
passage of blood through the outflow region. The onset of atrial fibrillation in both obstructive
and non-obstructive HCM may result in:
•
•
•
•
Cardiac failure
Cardiogenic shock
Syncope
Systemic emboli.
Many patients with HCM, particularly those with diastolic dysfunction, are intolerant of rapid
atrial fibrillation, the following contribute to haemodynamic collapse:
• Rapid heart rate
• Loss of atrial systole
• Greater degree of outflow obstruction due to the reduction in ventricular filling.
The importance of atrial systole is increased in HCM, which is often associated with a
decrease in peak early filling and an increased atrial contribution to ventricular filling
Rapid AF with a rapid ventricular response can quickly evolve into ventricular tachycardia and
ventricular fibrillation
AF in HCM significantly increases the risk for stroke (21 versus 2.6 % in those in sinus
rhythm).
89
Approach to this patient.
1. Ensure an adequate airway
2. Provide high flow oxygen
3. Secure IV access
4. Confirm AF with 12 lead ECG
5. Take bloods for electrolytes (ensure no hypokalaemia, hypomagnesaemia,
hypophosphotaemia, hypocalcaemia), FBC (exclude anaemia) and Troponin.
6. Elevate legs to increase preload.
7. If the patient was already in ICU, the administration of inotropes may be responsible and
should be switched off (Inotropes increase the gradient across the aortic valve).
8. Increase preload with bolus of crystalloid fluid. 250 ml 0.9% NaCl titrated to effect.
9. Recommendations for treatment of AF in patients with HCM were published in 2001 by the
American College of Cardiology/American Heart Association/European Society of
Cardiology:
Therapeutic options for AF include:
• Rhythm control (DC cardioversion with antiarrhythmic drugs to prevent recurrence)
• Rate control with a beta blocker or calcium channel blocker.
•
Rhythm control is warranted in patients who deteriorate haemodynamically when in AF.
Depending on the extent of hypotension, associated symptomatology and ventricular rate
e.g. chest pain, profound dyspnoea, confusion/deteriorating consciousness the patient should be
electrically cardioverted.
A ß-blocker should be added as soon as possible, and in the context of hypotension, a
pressor agent should paradoxically be provided.
If the arrhythmia is prolonged or associated with more mild symptoms, therapeutic options
include suppression of the arrhythmia with:
1. Amiodarone (current agent of choice)
2. Sotalol
3. Disopyramide
Since AF in patients with HCM carries a significant risk of thromboembolism, all such
patients, even those with paroxysmal AF, should be anticoagulated. This includes patients
treated with rhythm control.
Patients may present with haemodynamic collapse secondary to acute severe LV outflow
tract obstruction which may be recurrent. This syndrome may occur spontaneously, or be
precipitated by events that increase obstruction.
These include:
• Withdrawal of a beta blocker or calcium blocker
• Decreased preload due to dehydration, diuretics, or an acute reduction in blood volume as
with hemorrhage
• Decreased afterload due to administration of a vasodilator
Considerations:
Severe obstruction usually resolves rapidly with the institution of the following :
• Increase preload by elevation of the legs and administering intravenous fluids.
• Intravenous phenylephrine to increase blood pressure, at a rate of 100 to 180 µg/min.
(When the blood pressure is stabilised, the rate may be reduced).
• Intravenous administration of a beta blocker (propranolol 1 mg, or esmolol).
• Temporary dual chamber pacing.
90
Strategies for possible subsequent management / prevention:
In obstructive HCM, dual-chamber pacing or myectomy surgery is indicated in patients
refractory to medical therapy
1). A dual-chamber pacemaker with a short atrioventricular delay reduces the magnitude of
left-ventricular outflow tract obstruction and alleviates symptoms in patients with
severely symptomatic obstructive hypertrophic cardiomyopathy. Mechanisms by which
pacing might improve the LV outflow obstruction are unclear, but possibly involve
changes in the ventricular contraction pattern. Selection of optimal atrioventricular delay
appears critical to achieving a beneficial haemodynamic result.
2). Myomectomy ( Morrow procedure) thins the ventricular septum and widens the outflow
tract, which results in abolition of the systolic anterior motion, with resultant relief of
the outflow obstruction and the concomitant mitral regurgitation. (mortality <1-2%),
although the risks are somewhat higher in older patients who also require coronary
artery bypass grafting. Candidates for surgery represent only a very small subset of the
overall HCM population (about 5%).
3). Catheter-based alcohol septal ablation.( mortality < 2-3%.
References
1. Maron BJ. Hypertrophic cardiomyopathy. Lancet 1997;350:127-133.
2. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287:13081320.
3. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy:
clinical spectrum and treatment. Circulation 1995;92:1680-1692.
4. Nishimura RA, Holmes DR. Hypertrophic Obstructive Cardiomyopathy. N Engl J Med
2004;350:1320-1328.
91
DISCUSS ALL THE METHODS USED TO IMPROVE THE LIKELIHOOD OF A
SUCCESSFUL CANULATION OF A CENTRAL VEIN
Dr. B. Cheung. Intensive Care Unit, Ipswich Hospital, Queensland
SITE SELECTION
indication, operator experience / institution practice
options include internal jugular vein, subclavian vein, femoral vein, external jugular vein,
antecubital vein/ Peripherally inserted central venous catheter (left/ right sides, different
approaches- e.g. anterior, central, posterior approach for IJV)
ANATOMICAL LANDMARKS
Use of external anatomical landmark guided techniques, cut down method infrequent
Reported failure rate 7 -20% depend on experience
183 consecutive patients require IJ cannulation (most for endomyocardial Bx), ultrasound to
determine position (Denys & Uretsky, 1991)
ƒ 92% lateral, anterior to carotid
ƒ 2.5% not visualised, ?thrombosed
ƒ 1% >1 cm lateral to carotid
ƒ 2% medial, overlying carotid
ƒ 3% small (< 0.5cm, unresponsive to Valsalva)
CAROTID ARTERY PALPATION
ƒ Carotid artery palpation can result in reduction in IJ vessel diameter (Armstrong et al
1994)
HEAD ROTATION
ƒ 20 degree/ maximum rotation
ƒ Boyd et al (1996) 140 patients increased successful catheterisation
ƒ Contralateral head rotation may increase vessel overlay of IJ vein upon the carotid artery
(Troianos C, et al 1996, Sulek et al 1996)
ƒ Underlie the muscle belly
ƒ ? Risk of kinking
POSTURE
ƒ Venous filling, reduce gas embolism
ƒ Patient may not tolerate Trendelenburg position (15/ 25 degree)
USE OF VALSALVA MANOEUVRE
ƒ Venous filling, PEEP
WHICH SIDE?
Left sided sites higher risk than right-sided (Balckshear & Gravenstein 1993, Sulek et al
2000)
KEY- combination of variables results in largest cross sectional area of central vein and least
potential risk
EVIDENCE- mixed results
SEEKER NEEDLE
Latto (1999) advocated seeker needle to increase success & safety
21G, 40 mm needle
92
Allow more accurate control of insertion depth
ULTRASOUND
ƒ 2 dimensional ultrasound guidelines better than auditory signal (external/ internal) & tactile
perception using external anatomical landmarks in identifying IJV
ƒ real time
ƒ Supported by literature review & meta-analysis (Randolph et al 1996, Calvert 2003)
ƒ limited evidence for subclavian & femoral veins
ƒ NICE guidelines
- for central venous catheterisation into IJV in children & adults using 2D ultrasound
guidance
- Elective & emergency situation
- Appropriate training
- Audio-guided doppler NOT recommended
ƒ Advantages
- Precise target vein location
- Detect anatomical variations & thrombosis
- Avoid arterial puncture & other complication
ƒ potential cost effectiveness- less procedure time & less complication
ƒ resource impact- high set up cost but low procedure cost
ƒ implementation & audit issues ?compliance/ medical legal
ƒ deskilling issue (NICE state operators maintain their ability to use landmark method & that
the method continue to be taught alongside the 2D ultrasound guided technique)
OTHERS
SMART Needle vascular access needle, 18-20 G with continuous wave Doppler at its tip to
differentiate artery from vein (Verghese et al 2000)
ECG guidance- may be useful to confirm position
Electromagnetic technology- may be useful to confirm position.
References
1. Denys B & Uretsky B (1991) Anatomical variation of internal jugular vein location:
Impact on central venous access CCM, 19: 1516-19.
2. Latto I (1999) Avoid internal jugular vein transfixation. Anaesthesia; 54: 400-1
3. Armstrong P, Sutherland R & Scott D (1994) The effect of position and different
manoeuvers on internal jugular vein diameter. Acta Anaesthesiologica Scandinavica; 38:
229-31
4. Troianos CA, Kuwik RJ, Pasqual JR, Lim AJ, Odasso DP (1996) Internal jugular vein and
carotid artery anastomotic relationship as determined by ultrasonography. Anesthesiology;
85: 43-8.
5. Bell D & McLeod SR (1999) Correspondence to ultrasound guided central vein
cannulation. Anaesthesia; 54: 809-22.
6. Boyd R, Saxe A & Phillips E (1996) Effect of patient position upon success in placing
central venous catheters. Am J Surg; 172(4): 380-2.
7. Sulek C, Gravenstein N, Blackshear R, Weiss L (1996) Head rotation during internal
jugular vein cannulation and the risk of carotid artery puncture. Anesthesia & Analgesia;
82(1): 125-8.
8. Balckshear R & Gravenstein N (1993) Left sided sites for central venous catheterisation
associated with higher risk than right-sided sites. Anesthesiogy; 79:A1073
93
9.
Sulek C, Blas M & Lobato E (2000) A randomised study of left versus right internal
jugular vein cannulation in adults. J Clin Anesth; 12(2): 142-5
10. Randolph A, Cook D, Gonzales C & Pribble C (1996) Ultrasound guidance for placement
of central venous catheters: a meta-analysis of the literature. CCM; 24(12): 2053-8.
11. Calvert N, McWilliams R, Davidson A, Paisley S, Beverley C & Thomas T (2003)
Ultrasonic locating devices for central venous cannulation: meta-analysis. BMJ;
2003(327): 361-7
12. Verghese S, McGill W, Patel R, Sell J, Midgley F & Ruttimann U (2000) Comparison of
three techniques for internal jugular vein cannulation in infants. Paedatric Anaesthesia,
10: 505-11.
SUMMARY
DISCUSS ALL THE METHODS USED TO IMPROVE LIKELIHOOD OF A
SUCCESSFUL CANNULATION FOR A CENTRAL VEIN
SITE SELECTION
- indication
- options
ANATOMICAL LANDMARKS
Reported failure rate 7 -20% depend on experience
CAROTID ARTERY PALPATION
HEAD ROTATION
POSTURE
USE OF VALSALVA MANOEUVRE
WHICH SIDE
SEEKER NEEDLE
- Latto (1999) advocated seeker needle to increase success & safety
ULTRASOUND
- 2 dimensional ultrasound guidelines better than auditory signal (external/ internal) & tactile
perception using external anatomical landmarks in identifying IJV
- real time
- Supported by literature review & meta-analysis (Randolph et al 1996, Calvert 2003)
- limited evidence for subclavian & femoral veins
- NICE guidelines:
ƒ for central venous catheterisation into IJV in children & adults using 2D ultrasound
guidance
ƒ Elective & emergency situation
ƒ Appropriate training
ƒ Audio-guided doppler NOT recommended
- other issues
OTHERS
94
DISCUSS THE CLINICAL FEATURES AND THE MANAGEMENT OF A PATIENT
WITH A TIA
Dr. H. Ramaswamykanive. Intensive Care Unit, Concord Hospital, New South Wales
Transient ischaemic attack:
Defined as transient neurologic deficits due to ischaemia in a particular angioanatomic
territory, lasting for minutes to hours followed by complete restoration of function. Such
attacks may anticipate oncoming thrombotic strokes.
Epidemiology:
Approximate incidence of TIA over the age of 65 years is 300,000 per year in USA.
Patients who have one or more TIAs have 10-fold increase in risk of subsequent stroke. The
combined risk for an adverse event (Stroke, CHF, AMI, Unstable angina, Ventricular
arrhythmia, Death, or Recurrent TIA) was 25.1% within 90 days of TIA, about ½ of which
occur in first 2 days and long term risk is about 4% per year after TIA.
Pathophysiology:
A critical level of blood flow is needed to maintain neuronal function and to prevent
ischaemic damage. Normal cerebral bloodflow lies between 40 to 60 mls /100 gm/min. Less
than 20 mls/100gm/min normal neuronal function fails and neurologic symptoms begin. At
less than 8 mL/100g/min irreversible damage ensues. There is demonstrable temporary
arrest in blood flow in the affected territory.
The vascular occlusion is either by thromboembolic process secondary to atherosclerosis or
cardioembolic source. TIAs also can occur in association with hypercoaguble states, arterial
dissection, arteritis and cocaine. TIAs occurred before the development of atherothrombotic
strokes in 25% - 50% of cases, 11% - 30% of cardioembolic strokes and in 11% - 14% of
lacunar infarcts.
The blood flow to the brain is classified into anterior and posterior circulation. TIAs from
anterior circulation may be embolic or thrombotic and from posterior circulation more
likely to be thrombotic.
Clinical features:
ƒ Carotid TIAs take the form of mono ocular blindness (amaurosis fugax), hemiparesis,
hemisensory syndromes, aphasia, dyscalculia and confusion.
ƒ Vertebrobasilar branch attacks consists of blindness, hemianopia, diplopia, vertigo,
dysarthria, dysphagia, facial weakness or numbness, hemiplegia or quadriplegia and sensory
syndromes in various combinations.
Differential diagnoses of TIA include
Migrainous accompaniments, Labrynthine vertigo, Cerebral seizures, Syncope, Transient
global amnesia, Transient monoocular blindness of undetermined origin, Paraesthesia in
women, Carpal tunnel syndrome, Cervical disc disease, Ulnar or median nerve compression
at elbow, Hypoglycemia, Hyperventilation, Somatic symptoms associated with depression,
Anxiety or hysteria, Transient symptoms of multiple sclerosis, Cervical traction.
Evaluation of TIA
This is based on symptomatology and pretest probability for each investigation. Current
recommendations include a full blood count, blood chemistry, coagulation profile, ESR,
ECG. Imaging studies include Noncontrast CT scan of brain, CT angiography; Duplex
Ultrasonography, MRI and MR angiography is useful in evaluating infarct location and
cerebral blood flow. Other investigations include Vasculitic screening, Cardiac ECHO and
Holter Monitoring.
95
Management of TIA.
The primary goal of TIA is the prevention of ischaemic stroke. Risk factor modification is
essential in the management of stroke.
Modifiable risk factors include hypertension, atrial fibrillation, diabetes,
hypercholesterolaemia, obesity, cigarette smoking, excessive alcohol use, physical
inactivity and stress.
Nonmodifiable risk factors are age, sex, race/ethnicity, family history and genetics.
By definition symptoms of TIA can persist up to 24 hours. But we know from the placebo
group of the NINDS study that it is unlikely, patients with a persistent neurologic deficit
longer than 90 minutes will resolve spontaneously and hence there is little justification for
treating TIA any differently from stroke. Sensitive MRI sequences (diffusion weighted
images) reveal evidence of brain infarction in 2/3rd of patients presenting with TIA and
stroke in general.
Anticoagulants, antiplatelet agents, antihypertensive agents and lipid lowering agents are
fundamental to TIA/ Stroke management.
1. Anticoagulation is recommended after imaging brain in patients with TIA or in patients
with atrial fibrillation, hypertension, poor left ventriclular function, rheumatic mitral
valve disease, prosthetic heart valves, prior history of stroke or TIA, a history of
systemic embolism, age greater than 75 years (the older you are, the more you need
warfarin), considered to be at higher risk for stroke.
2. Antiplatelet agents used are Aspirin, Ticlopidine, and Clopidogrel and Extended
release dipyridamole plus aspirin. Aspirin prevents only 1 in 6 strokes; ticlopidine not
used much because of poor side effect profile, clopidogrel best option in patients with
multiple risk factors.
Extended release dipyridamole plus aspirin provides 23% better risk reductions than
lower doses of aspirin.
3. Antihypertensive agents. Hypertension control is considered the crown jewel of stroke
prevention. Patients with TIA have pressure dependent flow problem and therefore
avoid acute lowering of blood pressure unless it hypertensive urgency. Studies have
shown lowering blood pressure results in dramatic reduction in stroke risk. ACE
inhibitors may have secondary stroke prevention effect above and beyond blood
pressure lowering effect.
4. Lipid lowering agents (HMG Co A reductase inhibitors) have antithrombotic,
antioxidant and anti atherosclerotic activity. Therefore approved for use in high normal,
normal and even in those with low lipid levels.
5. Surgical therapy is robust for men, patients with hemispheric symptoms without
diabetes and for persons with significant ulcerative atherosclerotic plaques as
demonstrated by angiography, provided the surgeon has <6% perioperative complication
rate. Studies have shown carotid endarterectomy decreases the risk of ipsilateral stroke
or death from 26% to 9% in high grade (70% - 99%) stenosis. Benefit is less in women,
patients with moderate grade (50%- 69%) stenosis and patients with retinal TIAs.
6. Angioplasty and stenting as alternative to carotid endarterectomy is being evaluated
and is considered as investigational.
References
1. Cerebrovascular Cases, John N Fink and Louis R Caplan. Med Clin North Amer
2003;87:755–770.
2. Atrial fibrillation/ Hypertension. Audio-Digest Internal Medicine 50(23) December 7,
2003.
96
3.
4.
5.
6.
7.
Secondary stoke prevention. Audio-Digest Internal Medicine 50(01) January 7, 2003.
Transient ischemic attack: an emergency medicine approach, Keith Thomas Borg and
Arthur Martin Pancioli. Emergency Medicine Clinics Of North America 20(2002) 597–
608.
Diagnosis and Treatment of Ischemic Stroke, Mark J Alberts, Am J Med.1999; 106: 211221.
Principles and practice of neurology, Companion Handbook, Raymond D Adams and
Maurice Victor. 5th edition 1994.
Neurological and Neurosurgical Intensive care, Allan H Ropper 3rd editon.1993.
97
DISCUSS YOUR MANAGEMENT OF A PATIENT WITH CHEST TRAUMA WHO IS
MECHANICALLY VENTILATED AND WHO DEVELOPS A BRONCHO-PLEURAL
FISTULA
Dr. M. Sanap. Intensive Care Unit, Flinders Medical Centre, South Australia
Introduction
Bronchopleural fistula ( BPF) is defined as a communication between the bronchial tree and
pleural space. Clinically seen as a persistent air leak 24 hours after pneumothorax.
Aetiology of BPF in chest trauma:
- direct trauma
- iatrogenic: puncture, laceration, barotraumas
- spontaneous alveolar rupture due to underlying lung pathology
- necrotising infection
- acute lung injury
Consequences:
- persistent pneumothorax
- inadequate ventilation
- VQ mismatching
- infection of pleural space
- inability to maintain PEEP
- inappropriate cycling of ventilator
Problems with a BPF:
- Failure of lung re-expansion
- Loss of delivered tidal volume
- Inability to apply PEEP
- Inappropriate cycling of ventilator
- Inability to maintain alveolar ventilation with resultant hypoxia and hypercapnia
- Problems of weaning
- Attributable mortality
Main factors which perpetuate BPF are:
- high airway pressures that increase leak during inspiration
- increased mean intrathoracic pressures throughout the respiratory cycle (PEEP, inspiratory
pause, high I:E) that increase leak throughout the breath
- high negative suction
All these factors tend to be present in patients with ARDS because they are necessary to
support gas exchange and lung inflation.
How to identify
- Failure to reinflate lung despite chest tube drainage ( even with large lumen ICD) or
continued air leak after evacuation of the PTX in the setting of chest trauma.
- A persistent BPF results in air leak which can be detected by the continuous bubbling of air
through the water seal of the suction system.
98
Management of BPF:
A. CONSERVATIVE:
1. Large size chest tube (multiple if necessary)
- Use drainage system with adequate capabilities
- Large chest drains allow sufficient gas flow.
2. Application of positive intrapleural pressure:
- Equivalent to PEEP via chest tube.
- Synchronised closure of chest tube during inspiration has been tried in an attempt to
decrease leak.
- Increased risk of tension pneumothorax and very close observation is essential.
3. Drainage system:
- Use drainage system with adequate capabilities
- Ensure drainage system is capable of dealing with flow rates.
4. Ventilation:
a. Conventional ventilation:
- Aim is to reduce flow through fistula to promote healing and to decrease wasted ventilation
while still maintaining adequate ventilation and oxygenation.
- Use lowest possible tidal volumes, ventilatory rates, PEEP and inspiratory time. Encourage
spontaneous breathing. IMV may have an advantage over assist control.
- Goal is to maintain adequate ventilation and oxygenation while reducing the fistula flow
and allow the repair to occur, lowest effective VT , fewest mechanical breaths per minute,
lowest level of PEEP – reduce airway pressure, shortest inspiratory time, use greatest
number of spontaneous breaths per minute, intermittent mandatory ventilation better than
control ventilation, permissive hypercapnia and accept a lower arterial oxygenation.
b. High frequency jet ventilation (HFJV) :- May be useful in severe BPF, particularly when there is a tracheal or bronchial fistula in the
presence of normal lung parenchyma
- However, better at controlling pO2 and pCO2 than conventional modes
- Remains controversial in terms of benefit
c .Independent Lung Ventilation:- Limited experience
- It can be used for unilateral BPF
- Patient intubated with double lumen tube
- Needs 2 ventilators (synchronous or asynchronous)
- Conventional ventilation of unaffected lung, affected lung either ventilated with lower
pressures and volumes or with CPAP alone
- Guided by volume of air leak, haemodynamic and gas exchange stability
- Short term solution, bridge to surgical intervention.
5. Fibreoptic bronchoscopy and direct application of sealant
(cyanoacrylate, fibrin agents, absorbable gelatin sponges e.g.
Gelfoam):
99
Bronchoscopy may be useful to identify sites of proximal leak and can be used to localise distal
leaks with the use of a balloon catheter passed down the suction channel and into more distal
airways. Reduction of air leak on inflation of balloon indicates that catheter is in the correct
area. An occluding material can then be injected. For distal fistulae a PA catheter has been
used. Experience with this technique is extremely limited. It cannot be used for proximal leaks.
B. INVASIVE:
- Mobilisation of intercostal or pectoralis muscle
- Thoracoplasty
- Bronchial stump stapling
- Pleural abrasion and decortication.
Prognosis
Mortality higher when: BPF develops late in the illness of a mechanically ventilated patient not
related to chest trauma volume of leak greater (leaks of 500 ml or more associated with 100%
mortality in one study) .
References
1. Rajan Jain, S.S. Baijal , R.V. Phadke Endobronchial Closure of a Bronchopleural
Cutaneous Fistula Using Angiography Catheter American Jornal of Roentogenology AJR
2000, 175: 1646 – 1648
2. Junaid H Khan, MD, et al Management Strategies for Complex Bronchopleural Fistula
Asian Cardiovasc Thorac Ann 2000;8:78-84
3. Carvalho P, Thompson WH, Riggs R, Carvalho C, Charan NBManagement of
bronchopleural fistula with a variable-resistance valve and a single ventilator. Chest. 1997
May;111(5):1452-4
4. Baumann MH, Sahn SA. Medical management and therapy of bronchopleural fistulas in
the mechanically ventilated patient.Chest. 1990 Mar;97(3):721-8. Review
5. Sjostrand UH, Smith RB, Hoff BH, Bunegin L, Wilson E.Conventional and highfrequency ventilation in dogs with bronchopleural fistula. Crit Care Med. 1985
Mar;13(3):191-3
6. Ost D, Corbridge T. Independent lung ventilation.Clin Chest Med. 1996 Sep;17(3):591601. Review
7. Gas flow through a bronchopleural fistula. Measuring the effects of high-frequency jet
ventilation and chest-tube suction.Chest. 1988 Jan;93 (1):210-3
8. M Litmanovitch, GM Joynt, PJ Cooper and P Kraus Persistent bronchopleural fistula in a
patient with adult respiratory distress syndrome. Treatment with pressure-controlled
ventilation Chest, Vol 104, 1901-1902
9. Ventilatory management of life-threatening bronchopleural fistulae. A summary. Crit Care
Med. 1981 Jan;9(1):54-8
10. Prolonged high-frequency jet ventilation in a patient with bronchopleural fistula. An
alternative mode of ventilation.Intensive Care Med. 1986;12(3):161-3
11. Unilateral high frequency jet ventilation. Reduction of leak in bronchopleural
fistula.Intensive Care Med. 1984;10(1):39-41
13. Management of bronchopleural fistula with a variable-resistance valve and a single
ventilator.Chest. 1997 May;111(5):1452-4.
14. EL York, DB Lewall, M Hirji, ET Gelfand and DL Modry Endoscopic diagnosis and
treatment of postoperative bronchopleural fistula Chest, Vol 97, 1390-1392,
100
15. AG Fleisher, KG Evans, B Nelems and RJ Finley Closure of bronchopleural fistulas using
Albumin-Glutaraldehyde tissue adhesiveAnn. Thorac. Surg., January 1, 2004; 77(1): 326 328.
16. K. Takaoka, S. Inoue, and S. Ohira Central Bronchopleural Fistulas Closed by
Bronchoscopic Injection of Absolute Ethanol* Chest, July 1, 2002; 122(1): 374 - 378.
17. P. H. Hollaus, F. Lax, B. B. El-Nashef, H. H. Hauck, P. Lucciarini Natural History of
Bronchopleural Fistula After Pneumonectomy: A Review of 96 Cases Ann. Thorac. Surg.,
May 1, 1997; 63(5): 1391 - 1396
18. Shah AM, Singhal P, Chhajed PN, Athavale A, Krishnan R, Shah AC Bronchoscopic
closure of bronchopleural fistula using gelfoam. J Assoc Physicians India. 2004
Jun;52:508-9
19. Dale K. Mueller, MD; Patrick E. Whitten, MD; William P. Tillis, MD; Linda M. Bond,
MA and James R. Munns, MD Delayed Closure of Persistent Postpneumonectomy
Bronchopleural Fistula* Chest. 2002;121:1703-1704.)
20. Transposition of modified latissimus dorsi musculocutaneous flap in the treatment of
persistent bronchopleural fistula after posterolateral incision. J Thorac Cardiovasc Surg.
2004 Feb;52(2):84-7.
21. Closure of bronchopleural fistula after pneumonectomy with a pedicled intercostal muscle
flap. Eur J Cardiothorac Surg. 1999 Aug;16(2):181-6.
101
A PATIENT HAS BEEN REFERRED TO YOU FOLLOWING A NEPHRECTOMY
FOR A HYPERNEPHROMA PERFORMED 7 DAYS AGO FOR MANAGEMENT OF
PYREXIA, OLIGURIA AND NOW HYPERKALEMIA. HE HAS BEEN CONFUSED
DURING THE PAST THREE DAYS WITH EPISODES OF HYPOGLYCAEMIA AND
THE NUMEROUS GLUCOSE INFUSIONS HAS CAUSED HIM TO DEVELOP
HYPONATREMIA. HOW WOULD YOU MANAGE HIM?
Dr. P. Dubey, Intensive Care Unit, The Mater Hospital, Queensland
Management in Ward:
Are there any emergencies to deal with?
1. How severe is the hyperkalemia?
2. How severe is the hyponatremia and does it need to be treated with hypertonic saline?
3. Is this an Adrenal crisis?
The combination of pyrexia, hyperkalemia, hyponatremia and hypoglycaemia is strongly
indicative of adrenal insufficiency.1 A combination of Hyponatremia and Hyperkalemia (Na: K
ration <25:1)) is very strongly suggestive of Addison’s disease.2
Best would be to do an arterial blood gas analysis, this would confirm the most current
levels of Na, K, Cl, Glucose, rule out hypoxia as a cause of confusion and confirm the
existence of metabolic acidosis - another indicator of Adrenal crisis.2 Blood tests as UEC,LFTs,
Ca++,Mg++, Glucose, Cortisol and ACTH with blood cultures can be sent and, already available
levels of Ser Na. K+ and Ca++ can be compared for rapidity of decline in these values from preoperative state.
Clinically assess intra-vascular volume status with HR, JVP and postural hypotension, if
possible. Volume replacement with Normal saline is most important as this would correct the
hyponatremia as well, and this should, at least, initially, cover for the electrolyte deficit from a
mineral corticoid deficiency. Intravenous 0.9% saline, 1-2 Litres over 2-4 hours is given
initially and thereafter on the basis of cardiovascular status.3 The volume deficit in acute
adrenal crisis is seldom greater than 10% of TBW6 and a 1000 mL can be given in the first
30mins.
A random cortisol sample can be drawn (if not already done-although not an absolute
necessasity) and the patient given Hydrocortisone 100 mg IV bolus or Dexamethasone 10 mg
can be given IV and a basal cortisol level requested followed by a short synacthen test (later in
ICU). While the volume resuscitation is ongoing and the patient haemodynamically stable, he
can be transferred to ICU but treatment should not be delayed pending transfer to ICU.
Hyponatremia usually responds to saline resuscitation and care should be taken in treating
hyponatremia with Hypertonic saline because of increased risk of Osmotic demyelination in a
catabolic patient.4
Hyperkalemia of Adrenal insufficiency is usually close to 5.5 mol/L unless a significant
degree of volume depletion is present.5 The hyperkalemia usually does not require specific
therapy but, in this particular case the diagnosis is as yet unconfirmed and, if the electrolyte
disorder is an urgency then, I would be inclined to treat is as an emergency, especially if, ECG
changes of hyperkalemia are also present. Much less K+ loss is needed to decrease plasma K+
from 7.0 to 6.0 than is required to decrease it from 6.0 to 5.0. Hence, creating a small K+ loss
can be very important if there is severe degree of hyperkalemia.5
102
50 mL of 50% dextrose can be given to correct for hypoglycaemia or 5% Dextrose be given
with Normal Saline. Further fluid loading can be managed with assessment of volume status
with serial CVP and arterial line for BP monitoring in ICU.
Management in the ICU:
The bolus dose is followed by Hydrocortisone 100mg IV 6-hourly. Once the synacthen test
is complete, the steroid can be switched over to Hydrocortisone as it has mineralocorticoid
activity as well.
Mineralocorticoid replacement is usually not required initially, as saline resuscitation is
enough to correct the electrolyte deficits and, Hydrocortisone 50mg has the activity of 0.1mg of
Fludrocortisone.7 hence a total of 400mg of hydrocortisone/day would have the equivalent
activity of nearly 1mg of Fludrocortisone.
Blood cultures should then be sent and Broad-spectrum antibiotic started as diagnosis of
sepsis would be difficult in presence of adrenal crisis and sepsis itself can lead to relative
adrenal insufficiency. These antibiotics can later be stopped if blood cultures are negative and
the steroids stopped if the synacthen test is normal and an alternative cause is found for this
presentation.
An Imaging of KUB is required to rule out obstruction of the remaining kidney, ureters. A
CXR to check position of CVL placement may show a pathologic process as Consolidation and
help identifying the source of sepsis.
In critically ill patients with septic shock , a cut off level of 18 - 25 µg/dL of basal random
cortisol can be used to identify patients who may benefit from low dose hydrocortisone
replacement(200-300mg/day).
A look into patient’s notes to check if adrenals were removed as well and chemotherapy, if
any, that patient had involved use of steroids or the patient had been on long-term steroids in
the year before surgery. If Etomidate was used perioperatively.
Paraneoplastic syndromes associated with hypernephroma…hypercalcemia is commonest
and hypoglycaemia has also been found but symptoms of Paraneoplastic syndrome usually
subside after nephrectomy and their recurrence is a sign of tumour recurrence or incomplete
removal.
When the results of synacthen test and ACTH levels are available and an Adrenal
insufficiency is confirmed, the IV steroids can be replaced with oral Steroids with or without
mineralocorticoid replacement (Secondary adrenal insufficiency).
If the patient fails to respond (confusion) to this treatment despite near normalisation of
electrolyte parameters then further imaging of Brain and an EEG may be required to rule out
metastatic disease to Brain or a non convulsive status epilepticus as a cause of neurological
deterioration and, the electrolyte abnormalities, a result of intial management (aggressive
treatment with 5% Dextrose) and inadequate intravascular repletion causing pre-renal failure,
metabolic acidosis and hyperkalemia. (Just in case this missed Occam’s razor !)
References
1. Oelkers W. Adrenal Insufficiency. NEJM 1996;vol 335,No 16: 1206-1212
2. Oh’s Intensive care manual, 5th Ed, p 577
3. Worthley LIG. Disorder of Adrenal function. In The Australian Short course in Intensive
care –2003 Handbook. Editor Worthley LIG, 2003
4. Gerlach H. Adrenal Insufficiency. In Textbook of Critical care. Edited by Fink et
al.Elsevier Saunders;2005 :1491-1503
5. Halperin M. Disorders of Plasma Potassium concentration. In Textbook of Critical care.
Edited by Fink et al.Elsevier Saunders;2005 :1097-1111
103
6.
7.
Vedig A. Adrenocortical Failure. In The Australian Short course in Intensive care – 1998
Handbook. Editor Worthley LIG, 1998
Adrenal insufficiencyWiebke Arlt; Bruno AllolioThe Lancet; May 31, 2003; 361, 9372;
Academic Research Library. Pg. 1881
104
DISCUSS HOW YOU WOULD MANAGE A PATIENT WHO HAS DEVELOPED
BLINDNESS WITH SERUM SODIUM OF 122 MMOLS/L AND MEASURED
OSMOLALITY OF 290 MOSM/KG 1 HOUR FOLLOWING A TURP
Dr. S. Vergese. Intensive Care Unit, Flinders Medical Centre, South Australia
Transurethral resection of the prostate or a bladder tumour is often associated with the use
of as much as 20 to 30 litres of nonconductive flushing solutions containing glycine, sorbitol or
manitol.
Variable quantities of this fluid enter the circulation via two routes: slowly via fluid that has
leaked into the retroperitoneal space through the perforated prostatic capsule; and rapidly via
direct entry into the large prostatic veins.
The TURP syndrome consists of hypoosmolar hyponatremia, cardiovascular disturbances
(e.g. hypertension, hypotension, bradycardia), an altered state of consciousness (e.g. agitation,
confusion, nausea, vomiting, myoclonic and grand mal seizures) and (when glycine solutions
are used) transient visual disturbances of blurred vision, blindness and fixed dilated pupils,
associated with transurethral resection of the prostate.1,2
It may occur within 15 minutes or be delayed for up to 24 hours, postoperatively, and is
caused by an excess absorption of the irrigating fluid which contains 1.5% glycine with an
osmolality of 200 mosmol/kg (although hyponatremia syndromes have also been described
when irrigating solutions containing 3% mannitol or 3% sorbitol have been used, both of which
have an osmolality of 165 mosm/kg).3 The addition of ethanol 1% to these solutions has
allowed fluid absorption to be monitored by expired ethanol tests.4 Symptomatology usually
occurs when > 1 litre of 1.5% glycine or > 2 - 3 litres of 3% mannitol or sorbitol are absorbed.5
The excess absorption of irrigating fluid causes an increase in total body water (which is
often associated with only a small decrease in plasma osmolality), hyponatremia (as glycine,
sorbitol or mannitol reduces the sodium component of ECF osmolality), and an increase in the
osmolar gap.6-8
When glycine is used, other features include hyperglycinaemia (up to 20 mmol/l - normal
plasma glycine levels range from 0.15 to 0.3 mmol/l), hyperserinemia (as serine is a major
metabolite of glycine), hyperammonaemia (following deamination of glycine and serine),
metabolic acidosis and hypocalcaemia (due to the toxic effects of the glycine metabolites,
glyoxylic acid and oxalate).9 Because glycine is an inhibitory neurotransmitter (by blocking
chloride channels).10 and as it passes freely into the intracellular compartment, when glycine
solutions are used, hyperglycinaemia may be more important in the pathophysiology of this
disorder than a reduction in body fluid osmolality and cerebral oedema,11 as cerebral oedema is
often minimal in this condition.12
Treatment is largely supportive with the management of any reduction in plasma osmolality
being based on the measured plasma osmolality and not plasma sodium levels. If the measured
osmolality is > 260 mosmol/kg and mild neurological abnormalities exist, if the patient is
haemodynamically stable with normal renal function, close observation and reassurance (e.g.
the visual disturbances are reversible and will last for less than 24 hours) are usually all that is
needed. If the patient is hypotensive and bradycardic with severe and unresolving neurological
abnormalities, haemodialysis may be warranted.13 Hypertonic saline is only used if the
measured osmolality is < 260 mosmol/kg and severe non-visual neurological abnormalities
exist.
105
References
1. Arieff AI, Ayus JC. Endometrial ablation complicated by fatal hyponatremic
encephalopathy. JAMA 1993;270:1230-1232.
2. Istre O, Bjoennes J, Naess R, Hornbaek K, Forman. Postoperative cerebral oedema after
transcervical endometrial resection and uterine irrigation with 1.5% glycine. Lancet
1994;344:1187-1189.
3. Gravenstein D. Transurethral resection of the prostate (TURP) syndrome: a review of the
pathophysiology and management. Anesth Analg 1997;84:438-446.
4. Hahn RG. Ethanol monitoring of irrigating fluid absorption (review). Eur J Anaesth
1996;13:102-115.
5. Hahn RG. Irrigating fluids in endoscopic surgery. Br J Urol 1997;79:669-680.
6. Wang JM, Creel DJ, Wong KC. Transurethral resection of the prostate, serum glycine
levels, and ocular evoked potentials. Anesthesiology 1989;70:36-41.
7. Hahn RG. Fluid and electrolyte dynamics during development of the TURP syndrome. Br
J Urol 1990;66:79-84.
8. Ghanem AN, Ward JP. Osmotic and metabolic sequelae of volumetric overload in relation
to the TURP syndrome. Br J Urol 1990;66:71-76.
9. L I G Worthley. Osmolar Disorders. Critical Care and Resuscitation 1999; 1: 45 -54.
10. Schneider SP, Fytte RE. Involvement of GABA and glycine in recurrent inhibition of
spinal motor neurons. J Neurophysiol 1992;66:397-406.
11. Jensen V. The TURP syndrome. Can J Anaesth 1991;38:90-97.
12. Silver SM, Kozlowski SA, Baer JE, Rogers SJ, Sterns RH. Glycine-induced hyponatremia
in the rat: a model of post-prostatectomy syndrome. Kidney Int 1995;47:262-268.
13. Agarwal R, Emmett M. The post-transurethral resection of prostate syndrome: therapeutic
proposals. Am J Kid Dis 1994;24:108-111.
106
DISCUSS THE IDEAL PROPERTIES OF A PREDICTIVE SCORING SYSTEM FOR
SEVERITY OF ILLNESS IN THE INTENSIVE CARE UNIT
Dr S. Senthuran. Intensive Care Unit, Royal Brisbane Hospital, Queensland
Accuracy
ƒ High discrimination: This refers to how well the model can tell apart those who will live
from those who will die. If the scoring system predicts 90% mortality, discrimination is
perfect if observed mortality is 90%.
ƒ Highly calibrated: The scoring system performs over a wide range of predicted mortalities –
i.e it is accurate at predicted mortalities of 90%, 50% and 20%.
Discrimination can be assessed using the receive operating characteristic (ROC) curve
which plots sensitivity on the Y axis against (1-specificity) on the X axis. The co-ordinates for
the curve are obtained by measuring the sensitivity & specificity at different decision thresholds
i.e what is considered acceptable uncertainty (e.g 90%, 95% or 99% certain of correct
prediction).
Almost ideal system
ROC curve
sensitivity
System no better
than chance
Area under the
curve is
proportional to
the discriminatory
power.
1- specificity (i.e false positive rate)
Reliability
There should be inter and intra observer agreement in data collection process and in how the
score is used. The greater the subjectivity the (e.g choosing a primary diagnosis) the poorer the
reliability of the system.
ƒ Intra observer reliability estimates the random error in any measured score and can be
measured by scoring on two occasions to see the fluctuations from session to session.
ƒ Inter observer reliability can be measured by the intraclass correlation coefficients for
continuous variables or the Kappa statistic for categorical data.
Content Validity
The model should be comprehensive: i.e should include quantifiable and difficult to
quantify (e.g elective vs emergency admission, co-morbidities etc) factors in giving a predictive
score for severity of illness. However as the number of variables in the model increase, the
reliability and ease of administration decrease, necessitating a balance between content validity
and reliability be struck.
107
Methodological rigour
Scoring system should be derived from a large cohort of patients from several intensive care
units to make it generally applicable and avoid bias. The variables used should be routinely
collected and independent of ICU interventions so that any treatment effect is avoided. Rules
for data collection must be rigorously adhered to especially with regard to missing data and
classification of medical diagnosis. The scoring system should be validated using a different
population than from which it was derived.
References
1. Ridley S. Severity of illness scoring systems and performance appraisal (Review).
Anaesthesia 1998;53:1185-94.
108
DISCUSS YOUR MANAGEMENT OF A MECHANICALLY VENTILATED
POSTOPERATIVE CORONARY ARTERY BYPASS PATIENT WHO HAS JUST
DEVELOPED AF AND WHO IS HYPOTENSIVE
Dr. D. Gardiner. Intensive Care Unit, Princess Alexandria Hospital, Queensland
Consequences of AF: haemodynamic instability, discomfort, ↑ bleeding requiring re-operation,
prolongs ICU and hospital stay (↑cost), ↑ stroke – 3x risk, risk generally commencing after
48hrs
1. Cardioversion
a. Electrical - essential for severe haemodynamic compromise
i. Direct Current Cardioversion - start 200J monophasic
• Only 13.5% will remain in sinus at 48hrs, potentially harmful
b. Chemical – indicated for less severe haemodynamic compromise
i. Amiodarone
• Drug of choice in setting of hypotension or left ventricular
depression
• 5mg/kg load followed by up to 15mg/kg over 24 hrs
• Probably no better at cardioversion than other agents
• Provides effective rate control even if fails to cardiovert
• Cardiovascularly stable (not always) with low pro-arrhythmic
risk
ii. Other options: Sotolol (oral Class III anti-arrhythmic with β-antagonist
activity) or Ibuletide (not available in Australia, new Class III agent -role
expanding)
2. Supportive
a. Mean arterial pressure and cardiac output - start or increase inotropes
b. Rate Control – indicated in haemodynamically stable patient as spontaneous
cardioversion frequent or as 2nd line to failed cardioversion
i. β-blockers
ii. Other options: Calcium Channel Blockers or Digoxin (less useful in the
post cardiac patient where high catecholamine stimulation)
3. Prevent Recurrence - Most research has been in primary prophylaxis only not recurrence
a. Reduce precipitants
i. Electrolyte disturbances: Hypokalaemia (aim 4.5mmol/L),
Hypomagnesaemia (prophylactic Mg has been shown to ↓ incidence AF)
ii. Sympathetic activity – analgesia, reassurance, catecholamine infusions
iii. Respiratory compromise or SIRS
b. Specific strategies
i. Restart or commence β-blocker
• Major role in prevention of AF post-cardiac surgery
• Pre or intra-operative initiation superior to post-operative
ii. Amiodarone (effectively prevents post-operative AF in many trials)
• Often used in addition to β-blockers
• Care if: resting HR <50 bpm, 2nd or 3rd degree AV block, CCF,
prolonged administration → organ toxicity
iii. Sotalol - 80mg oral bd, REDUCE trial suggested inferior to amiodarone
for prevention and some ↓ in stroke volume
109
iv. Atrial Pacing - pacing the atria just above the atria’s intrinsic rate
Consider anti-coagulation – if AF persists for >48 hrs
a. 90% of patients will not require a 6 week elective cardioversion
Options: Warfarin (target INR 2-3), can be started immediately post-CABG without major ↑
bleeding risk; Heparin may increase bleeding risk post-CABG – not recommended; Aspirin
(325mg/day) in low risk patients may be an acceptable alternative to warfarin.
4.
References
1. Cresswell L.L. & Damiano, R.J. Postoperative atrial fibrillation: An old problem crying
for new solutions. J Thorac Cardiovasc Surg 2001;121:638-41.
2. Falk, R.H. Medical Progress: Atrial Fibrillation N Engl J Med 2001;344:1067-78.
3. Knotzer, H. et al. Postbypass arrhythmias: pathophysiology, prevention, and therapy. Curr
Opin Crit Care 2004;10:330-5.
4. Maisel, W.H. Atrial Fibrillation after cardiac surgery. Ann Intern Med 2001;135: 106173.
5. Mooss, A.N. et al. Electrophysiology: Amiodarone versus sotalol for the treatment of
atrial fibrillation after open heart surgery: The Reduction in Postoperative Cardiovascular
Arrhythmic Events (REDUCE) trial. Am J Heart 2004;148:641-8.
6. White, C.M. et al. Intravenous Plus Oral Amiodarone, Atrial Septal Pacing, or Both
Strategies to Prevent Post-Cardiothoracic Surgery Atrial Fibrillation: The Atrial
Fibrillation Suppression Trial II (AFIST II). Circulation 2003;108(SII):200-6.
110
DISCUSS THE INDICATIONS FOR AND COMPLICATIONS OF INTRAVENOUS
SODIUM BICARBONATE
Dr. R. Ramadoss. Department of Critical Care Medicine, Flinders Medical Centre, SA
Blood gas analysis is one of the commonest investigation done in Emergency department
and Intensive Care Unit. Metabolic acidosis is a common problem in patients admitted in
Intensive Care Unit. Though it remains uncertain, whether or not there is true cause- effect
relationship between acidosis and adverse clinical outcomes. Acidosis is a powerful marker of
poor prognosis in critically ill patients.1 The condition responsible for severe acidemia
determines the patient’s status and prognosis.2
Intravenous Sodium Bicarbonate (Sodabicarb, NaHCO3) is the mainstay of alkali therapy.
[Carbicarb has sodabicarb; THAM has not been documented to be clinically more efficacious
than bicarbonate2].
PHYSIOLOGIC BACKGROUND
Severe academia (blood pH < 7.1) suppresses myocardial contractility, predisposes to
cardiac arrhythmias, causes venoconstriction and can decrease peripheral vascular resistance
and blood pressure, reduce hepatic blood flow and impair oxygen delivery3. It also promotes
respiratory muscle fatigue and insulin resistance. Acidemia progressively attenuates the effects
of catecholamines on the heart and vasculature.
With administration of sodabicarb and improving pH towards the physiological level, the
vicious cycle of detoriation can be arrested. While maintaining the metabolic milieu the
physician buys time thus allowing general and cause specific measures can be taken4 as well as
endogenous reparatory processes to take effect.
INDICATIONS FOR SODIUM BICARBONATE THERAPY:
Normal Anion Gap (AG) Metabolic Acidosis:
Normal AG metabolic acidosis are due to renal tubular acidosis or gastrointestinal
bicarbonate loss.5 It also occurs as a complication of aggressive volume resuscitation with
solution that do not contain bicarbonate (Dilutional acidosis).2
Bicarbonate therapy is usually administered if the plasma bicarbonate level is 18 mmol/ L or
less.
Increased Anion Gap (AG) Metabolic Acidosis:
Three common conditions which produces increased AG acidosis are Lactic acidosis,
Diabetic Ketoacidosis (DKA) and during CardioPulmonary Resuscitation (CPR).
In all these situations bicarb therapy is controversial. This is discussed later.
Poisonings:
1. Aspirin intoxication.
Sodium bicarbonate must be administered to raise blood pH to about 7.45 – 7.50. The
resultant alkalinisation of the urine promotes the excretion of salicylate.
2. Methanol and Ethylene Glycol intoxication.
They can produce severe high AG acidosis. Large amount of alkali are often required to
combat the severe acidemia 2.
3. Tricyclic antidepressants poisoning.
111
Sodium bicarbonate therapy increase the binding of the drug with protein and reduce the
amount of circulating free drug5.
Hyperkalemia:
Life threatening arrhythmia due to hyperkalemia is a strong indication of sodabicarb
therapy. Infact sodabicarb therapy in VF/VT, PEA or Asystole due to hyperkalemia is the only
class I indication as per ACLS protocol 7.
How much Sodium Bicarbonate?
The administration of sodabicarb carries some risk, it should be given judiciously in
amounts that will return blood pH to a safer level of about 7.20 2, and not to create overshoot
alkalosis. To achieve this goal, plasma bicarbonate must be increased to 8 to 10 mmol / L
How to Administer?
Except in hyperkalemia and extreme acidemia sodabicarb should be administered as
infusion (over few minutes to few hrs). Rapid administration can cause a fall in Blood pressure,
fall in PaO2 and transient rise in intracranial pressure 6, hence should be avoided.
COMPLICATIONS OF SODIUM BICARBONATE THERAPY:
Is low pH bad?
The experience with permissive hypercapnia for patients with ARDS or status asthmaticus
in which hypercapnia and acidemia are tolerated has changed the perspective of acidemia.
Is sodium bicarbonate therapy without problem?
The most obvious side effects of sodium bicarbonate therapy are hyperosmolality and
hypernatremia 2, 6 . It can lead to extra cellular fluid overload especially in patients with heart
failure or renal failure 2.
Bicarbonate therapy during CPR:
Laboratory and clinical data indicates 8 that
Contrary to popular belief, it does not the ability to defibrillate or improve survival 9 .
Can compromise coronary perfusion pressure.
May inactivate simultaneously administered catecholamines.
In the presence of reduced capacity to excrete CO2, sodabicarb increases the mixed venous
pCO2.
CO2 may paradoxically increase intra cellular acidosis.
Hence routine use of bicarb is not advisable during CPR (except in hyperkalemia), it may be
harmful (class III).
In Diabetic Keto Acidosis (DKA):
Bicarb therapy is controversial in DKA. It has several potentially deleterious effects
including worsening of hypokalemia, worsening of intra cellular acidosis and production of
paradoxical central nervous system acidosis 10 . Studies have demonstrated no difference in
outcome.Jeffery.B et al 10 concludes that bicarbonate should not be administered during DKA
for pH > 6.9; for pH < 6.9, the evidence is incomplete and does not suggest a beneficial effect.
Patients with a substantial component of hyperchloremic acidosis, due to urinary loss of
ketoacid anions (which cannot be used to regenerate bicarbonate) can benefit alkali therapy 2.
112
In Lactic Acidosis:
In animals and humans bicarbonate infusion can augment the production of lactic acid,
possibly due to a shift in the oxyhemoglobin, saturation relationship, enhanced anaerobic
glycolysis mediated by pH sensitive rate limiting enzyme phosphofructokinase and changes in
hepatic blood flow or lactate uptake.6
Even when bicarb administration elevates arterial pH (administration of sodabicarb of 1
mmol / kg for 1 to 2 mt showed to increase pH by 0.05 units) its effects on the CSF and
intracellular spaces may not be concordant. Intracellular pH has been shown to fall with
bicarbonate in RBCs, Muscle, Liver, Lymphocytes and Brain.
Serum ionised calcium concentration is reduced by sodabicarb infusion. Because left
ventricular contractility has been shown to vary directly with ionised calcium concentration,
hence reduction in ionised calcium may cause ventricular depression 6.
Most importantly does sodabicarb therapy correct haemodynamics, buy time for other
interventions or improve outcome? In prospective trials11,12 sodabicarb did not improve
haemodynamics or Catecholamine responsiveness. Bicarbonate was indistinguishable from
saline with regard to heart rate, Blood pressure, Central Venous Pressure, Pulmonary Aretery
Occlusion Pressure, Cardiac output, Oxygen delivery and Oxygen consumption.
Current evidences do not encourage the use of sodabicarb in lactic acidosis.
CONCLUSION:
The indications for sodabicarb therapy are limited to normal AG metabolic acidosis, certain
poisons and hyperkalemia.5
Refrences
1. J.A.Kellum. Metabolic acidosis in patients with sepsis. Epiphenomenon or part of the
pathophysiology. Critical Care and Resuscitation 2004; 6: 197-203.
2. Adrogue H.J et al. Management of Life-threatening Acid-Base Disorders; NEJM 1998;
338: 26-34.
3. Kraut JA et al. Use of base in the treatment of severe acidemic states; AJKD 2001; 38:
703-27.
4. Bulent ceuhaci et al. Sodium bicarbonate controversy in lactic acidosis. Chest 2000; 118:
882-884.
5. J.McNamara, L.I.G. Worthley. Acid-Base Balance: Part II. Critical Care and Resuscitation
2001; 3: 188-201.
6. S.M.Forsythe, G.A. Schmidt. Sodium bicarbonate for treatment of lactic acidosis. Chest
2000; 117: 260-267.
7. Guidelines for Cardiopulmonary resuscitation and emergency cardiovascular care.
Circulation 2000; 102(supp I): I 142 –157.
8. Guidelines for Cardiopulmonary resuscitation and emergency cardiovascular care.
Circulation 2000; 102(supp I): I 129 –135.
9. Dybvik.T et al. Buffer therapy during out of hospital cardiopulmonary resuscitation.
Resuscitation 1995; 29: 87-88.
10. J.B.Boord et al. Practical Management of Diabetes in critically ill patients. AJRCCM
2001; 164: 1763-1767.
11. Cooper D.J, Waleey KR et al. Bicarbonate does not improve haemodynamics in critically
ill patients who have lactic acidosis; a prospective, controlled clinical study. Ann.Inter
Med 1990; 112: 492-498.
113
12. Mathieu D, Nevierw r, et al. Effects of bicarbonate therapy on haemodynamics and tissue
oxygenation in patients with lactic acidosis. a prospective, controlled clinical study. Criti
Care Med 1991; 19: 1352-1356.
114
DISCUSS THE ANTIBIOTIC MANAGEMENT OF A PATIENT WITH MRSA
AORTIC VALVE ENDOCARDITIS WITH VANCOMYCIN ALLERGY
Dr. A. MacCormick. Intensive Care Unit, Royal Melbourne Hospital, Victoria
Management of antibiotic therapy in the setting of vancomycin allergy includes:
1) Assessment of the allergy and its clinical relevance. If the reaction is minor or can be safely
managed and sensitivity testing suggests that vancomycin is the best agent then treatment
with vancomycin could be considered. Reactions include “red man” syndrome which can be
managed by slow infusion and prophylactic antihistamines, “pain and spasm” syndrome
which can also be avoided by slow injection and ototoxicity which may be avoided by
keeping levels < 40µg/mL. Skin rashes and drug fever occur in 4-5% of patients and may be
of varying severity. Anaphylaxis and, rarely, an induced neutropaenia would necessitate
avoidance or cessation of vancomycin therapy.
2) Specific antibiotic alternatives:
The clinical evidence for success of alternative antibiotics is limited but is beginning to
accumulate – especially as vancomycin intermediate and vancomycin resistant strains of
staph aureus are becoming more prevalent. Antibiotic choice must be guided by
demonstration of in vitro sensitivity.
a) Teicoplanin is a glycopeptide antibiotic with the same spectrum of activity as
vancomycin but has a better side-effect profile and may be better tolerated. In clinical
studies it is as, or less effective than vancomycin.1 An initially recommended dose of 6
mg/kg/d has been said to be too low. Teicoplanin trough serum concentrations provide
the best predictor of treatment success. Trough serum levels > 25mg/L are associated
with a 90% success rate.2
b) Trimethoprim-sulphamethoxazole has been compared with vancomycin for the
treatment of Staph Aureus including cases of MRSA endocarditis. It was not as
successful as vancomycin overall and was least successful in those with right-sided
endocarditis and methicillin sensitive staph aureus. Thus it could be considered as an
agent for MRSA endocarditis.3
c) Oral ciprofloxacin and rifampicin has been given for right-sided endocarditis in iv
drug users and been found to be as effective as vancomycin.2
d) Quinupristin-dalfopristin is a combination of two naturally occurring compounds
isolated from Streptomyces pristinaspiralis. It inhibits protein synthesis by binding to the
50S ribosome. Its spectrum of activity is similar to vancomycin. 99.9% of staph aureus
were sensitive in one study. It is given iv every 8 hours in a dose of 7.5mg/kg.4
e) Linezolid is an oxazolidinone that belongs to a class of synthetic antimicrobial agents. It
interferes with protein synthesis by inhibiting the initiation complex at the 30S
ribosome. This is a unique action and no cross-resistance with other antimicrobials
currently occurs. It is active against most gram-positive organisms including MRSA. It
has 100% oral bioavailability. The recommended dose is 600mg BD. There are case
reports of successful treatment of MRSA endocarditis.5,6,7,8
f) Daptomycin is a naturally occurring antibiotic that is a fermentation by-product of
Streptomyces roseosporus. It binds to the cell membrane in a calcium dependant manner
causing depolarisation and cell death. It is active against Streptococci, multi-drug
resistant staph aureus and enterococcal species. It is administered once daily up to 6
115
mg/kg. It has been shown to be active against Glycopeptide Intermediate-Resistant
Staph Aureus in a simulated model of endocarditis.9 A case study has described
successful treatment of prosthetic aortic valve endocarditis.10
g) Other agents which have been shown to be effective in MRSA endocarditis
experimental models are Lysostaphin11 and Ampicillin-Sulbactam.12
Considering availability of agents in Australia the best regimen practically, (provided in
vitro susceptibility is proven) may be linezolid until the infection is clinically controlled
(4-6 weeks) followed by an alternative regimen (usually rifampicin with fusidic acid)
as described in a recent study of treatment of reduced vancomycin susceptibility staph
aureus in Australia and New Zealand.13
Refrences
1. Wood MJ, “The comparative efficacy and safety of teicoplanin and vancomycin” J
Antimicrob Chemother 1996 Feb; 37(2):209-222
2. Hoen B “Special issues in the management of infective endocarditis caused by Grampositive cocci” Infect Dis Clin N Am 16(2002):437-452
3. Markowitz et al “Trimethoprim-sulfamethoxazole compared with vancomycin for the
treatment of Staphylococcus aureus infection.” Ann Intern Med 1992 Sep 1; 117(5):390-8
4. Lundstrom and Sobel “Antibiotics for gram-positive infections: vancomycin, quinupristindalfopristin, linezolid, and daptomycin” Infect Dis Clin N Am 18 (2004) 651-668
5. Leung et al “Treatment of vancomycin-intermediate Staphylococcus aureus endocarditis
with linezolid” Scand J Infect Dis 2004; 36(6-7);483-5
6. Bassetti et al “Successful treatment of methicillin-resistant Staphylococcus aureus
endocarditis with linezolid” Int J Antimicrob Agents 2004 Jul; 24(1): 83-4
7. Pistella et al “Successful treatment of disseminated cerebritis complicating methicillinresistant Staphylococcus aureus endocarditis unresponsive to vancomycin therapy with
linezolid” Scan J Infect Dis 2004;36(3):222-5
8. Birmingham et al “Linezolid for the treatment of multi-drug resistant, gram-positive
infections: experience from a compassionate-use program” Clin Infect Dis 2003;36:15968
9. Akins and Rybak “Bactericidal activities of two daptomycin regimens against clinical
strains of glycopeptide intermediate-resistant staphylococcus aureus, vancomycin-resistant
enterococcus faecium and methicillin-resistant staphylococcus aureus isolates in an in
vitro pharmacodynamic model with simulated endocardial vegetations” Antmicr Agents
and Chem Feb 2001 45(2):454-459
10. Mohan et al “Methicillin-resistant Staphylococcus aureus prosthetic aortic valve
endocarditis with paravalvular abscess treated with daptomycin” Heart Lung 2005 JanFeb; 34(1):69-71
11. Patron et al “Lysostaphin treatment of experimental aortic valve endocarditis caused by a
staphylococcus aureus isolate with reduced susceptibility to vancomycin” Antmicr Agents
and Chem; July 1999 43(7):1754-1755
12. Backo et al “Treatment of Experimental Staphylococcal Endocarditis Due to a Strain with
Reduced Susceptibility In Vitro to Vancomycin: Efficacy of Ampicillin-Sulbactam”
Antmicr Agents and Chem; Oct 1999; 43(10):2565-2568
13. Howden et al “Treatment Outcomes for serious infections caused by Methicillin-Resistant
Staphylococcus Aureus with Reduced Vancomycin Susceptibility” Clin Inf Dis
2004;38:521-8.
116
DO YOU USE SELECTIVE DECONTAMINATION OF THE GASTROINTESTINAL
TRACT IN YOUR INTENSIVE CARE UNIT? IF SO WHY? IF NOT WHY NOT?
Dr. G. Ding. Intensive Care Unit, The Canberra Hospital, ACT
We do not use selective decontamination of the gastrointestinal tract in our ICU.
The aim of selective decontamination of the digestive tract (SDD) is to reduce the incidence
of nosocomial infections and ventilator associated pneumonia (VAP) in the critically ill ICU
population.
Hospital acquired pneumonia occurs in approximately 0.5 – 1% of all hospital admissions in
the US and affects approximately 27% of critically ill patients. Mortality ranges from 20 to
70%. Cost of treatment US$5,800 to $20,000 per case.
The nosocomial infections targeted by selective decontamination of the digestive tract are
VAP caused by micro aspiration of organisms from the oropharynx, catheter sepsis and
pancreatic colonisation (in cases of pancreatitis) from translocation of gut organisms to the
blood stream.
Decontamination is achieved by the application of topical paste to the aerodigestive tract,
nasogastric antimicrobials and administration of a parenteral antibiotic(s). Targeted organisms
are gram negative aerobic and fungal pathogens that may colonise the patient. Indigenous gut
flora (anaerobes) are not targeted in an attempt to retain their protective effect.
A suggested regimen includes:
Topical paste 6 hourly to oropharynx of 2% tobramycin, 2% polymyxin E, and 2%
amphotericin B.
Plus
10 mL of solution with 100mg polymyxin E, 80mg Tobramycin, 500mg amphotericin B 6
hourly via NGT.
Plus or minus
4 day parenteral treatment with cefotaxime.
The topical and enteral antibiotics are non absorbable and therefore systemic toxicity is
avoided.
The argument for SDD.
Reduction in VAP and other nosocomial infections.
A meta-analyses by D’amico et al,1 showed a reduction in respiratory infections from 36%
in control patients to 16% in patients treated with topical and systemic antibiotics and 28% in
control patients to 18% in patients only treated topically. Implying treating 5 patients with
topical and systemic prophylaxis or 9 patients with topical prophylaxis will prevent one
infection. The mortality was reduced in the group treated with systemic and topical prophylaxis
from 30% in controls to 24%. Mortality in the group treated only topically was 26%.
Treatment/prophylaxis of 23 patients would be required to prevent one death with topical and
systemic methods. No mortality benefit was seen in the topical group alone.
117
The meta-analyses by Nathens et al,2 only showed a reduction in mortality in surgical
patients treated with systemic and topical prophylaxis. Medical patients appeared to derive no
statistical benefit.
Luiten et al,3 in a prospective randomised trial of SDD in acute pancreatitis, demonstrated a
50% reduction in the incidence of infected pancreatic necrosis (38% vs 18%).
The benefits are therefore:
1 a reduction in mortality (possibly only in surgical/trauma patients)
2 reductions in infections
3 reductions in cost associated with nosocomial infections.
Argument against SDD
With regular use of antibiotics there is a selective pressure in the bacterial population
towards resistance to the antimicrobials in use.
Levy 4 formulated five underlying principles of antimicrobial resistance
First: given sufficient time and drug use, antibiotic resistance will emerge.
Second: antibiotic resistance is progressive, evolving from low levels through intermediate
to high levels.
Third: organisms that are resistant to one drug are likely to become resistant to other
antibiotics.
Fourth: once resistance appears, it is likely to decline slowly, if at all.
Fifth: the use of antibiotics by any one person affects others in the extended as well as the
immediate environment.
These principles apply to all antibiotic administration, including the use of SDD; therefore,
the clinical benefits of SDD must be balanced against the potential for the greater emergence of
antibiotic-resistant infections as a result of its use.
The use of antibiotics in SDD not only potentially increases the risk of resistance in
microbes that are targeted but also in others.
Hammond and Potgieter5 found a statistically significant increase in the occurrence rate of
infections caused by Acinetobacter species in the year after beginning a trial of SDD in their
ICUs compared to the year preceding the trial.
Sanchez-Garcia6 found level of carriage of MRSA, coagulase-negative staphylococci, and
enterococci was significantly higher in the SDD-treated patients
Verwaest7 found significantly more bacteremias due to Gram-positive bacteria were
observed among SDD-treated patients. Increased antimicrobial resistance was also detected
among the SDD-treated patients, including tobramycin-resistant Enterobacteriaceae, ofloxacinresistant nonfermenters, ofloxacin-resistant Enterobacteriaceae, and MRSA.
Cost of the intervention
Components include the cost of antibiotics.
Preparation of the paste from components? Topical preparations manufactured by drug
companies or hospital pharmacists.
Added nursing time placing the paste in the oropharynx and administering nasogastric and
parenteral antimicrobials.
Manipulation of the airway with risks of tube dislodgment and/or increased risk of micro
aspiration.
118
Conclusions
On the basis that the unit I work in has a majority of medical ICU patients and the future risk
of significant antimicrobial resistance, measures other than SDD are used to reduce the risk of
VAP and other nosocomial infections. Possible exceptions to this generality may occur in
specific cases such as severe pancreatitis
Refrences
1. D’Amico R, et al. Effectiveness of antibiotic prophylaxis in critically ill adult patients:
systemic review of randomized trials. BMJ 1998;316:1275.
2. Nathens A, et al. Selective Decontamination of the Digestive Tract in Surgical Patients. A
Systematic Review of the Evidence Arch Surg. 1999;134:170-176.
3. Luiten EJT, Hop WCJ, Lange JF, Bruining HA. Controlled clinical trial of selective
decontamination for the treatment of severe acute pancreatitis. Ann Surg. 1995;222:57-65.
4. Levy SB. Multidrug resistance: a sign of the times. N Engl J Med 1998;338,1376-1378.
5. Hammond JM, Potgieter PD. Long-term effects of selective decontamination on
antimicrobial resistance. Crit Care Med 1995;23,637-645.
6. Sanchez-Garcia, M, Cambronero Galache, JA, Lopez Diaz, J, et al Effectiveness and cost
of selective decontamination of the digestive tract in critically ill intubated patients: a
randomized, double-blind, placebo-controlled, multicenter trial. Am J Respir Crit Care
Med 1998;158,908-916.
7. Verwaest C, Verhaegen J, Ferdinande P, et al. Randomized, controlled trial of selective
digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary
intensive care unit. Crit Care Med 1997;25,63-71.
119
WHAT ARE THE INDICATIONS FOR AND COMPLICATIONS OF NACETYLCYSTEINE
Dr. L. Min. Department of Critical Care Medicine, Flinders Medical Centre, SA
Acetylcysteine (Parvolex), the acetylated variant of the amino acid L-cysteine, and is
deacetylated in the liver to cysteine, or oxidised to other metabolites such as N-acetylcystein, It
is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites
capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting
directly as free radical scavengers. It’s chemical formula is C5H9NO3S and a molecular weight
is 163.2.
Following intravenous administration, mean terminal half-life is 1.95 hours and 5.58 hours
for reduced and total acetylcysteine.
Indications
Acetaminophen Overdose. NAC provide a glutathione substitute, directly conjugate with
NAPQI, reduces acetaminophen-induced damage. Experimental evidence indicates the
combination of NAC and cimetidine might have an additive effect in the treatment of
acetaminophen overdose.
Contrast-introduced nephropathy. In patients with chronic renal insufficiency, usage of
acetylcysteine can prevent the rise in serum creatinine level post intravenous administrationof
contrast.
ARDS. As an antioxidant, used in the treatment of patients “at risk” for the development of
acute respiratory distress syndrome.
Sepsis. As free radical scavengers, may improve survival of sepsis patient
Prevent liver injury. Continuous infusion of N-acetylcysteine reduces liver warm ischaemia
reperfusion injury, and improved flow in the microcirculation and intracellular tissue
oxygenation. Can be used in liver resection and liver transplantation.
Preeclamptic prophylaxis. Preeclampsia is associated with an imbalance between oxidants
and antioxidants, resulting in reduced effects of the endothelium-derived, relaxing-factor nitric
oxide, NAC remove reactive oxygen species, resulting in an improvement of endothelial
function.
Type2 diabetes . Improves insulin sensitivity
Sjogren’s syndrome. Therapeutic effect on ocular symptoms, halitosis and daytime thirsty.
Respiratory. Oral NAC protect against inhalation of perfluoroisobutene. Oral NAC has been
advocated as a mucolytic agent for use in chronic bronchitis, improvements in expectoration
and decrease of cough severity. Research also indicates intravenous NAC can improve
contractility and attenuate low-frequency human diaphragm fatigue.
Myoclonus Epilepsy. Decreased in myoclonus and some normalisation of somatosensory
evoked potentials.
HIV. NAC supplementation might be a valuable component of an integrated protocol for
HIV-seropositive individuals, particularly those with low GSH levels and CD4+ cell counts of
more than 200X10(6)/l. It can inhance the antibody–dependent cellular cytotoxicity of
neutrophils.
It can protect hematopoietic progenitor cells from zidovudine (AZT) –induced toxicity. It may
help to prevent the early stage HIV-infected patients to progress to AIDS.
Influenza. NAC treatment decreased both the frequency and severity of influenza-like
episodes, and length of time confined to bed.
120
Cancer. Prevent cardiotoxity of doxorubicin and reduce haemorrhagic cystitis due
cyclophosphamide and ifosfamide.
Heart Disease. NAC seems to positively impact homocysteine and possibly lipoprotein (a)
levels, protect against ischemic and reperfusion damage, and enhance of the effectiveness of
nitroglycerine(NGT).
Heavy Metals. NAC is more effective than calcium EDTA or dimercaptosuccinic acid as an
agent to increase the urinary excretion of chromium and boron. NAC is protective against
mercury-induced damage to the liver and kidneys, promote the urinary elimination of methyl
mercury.
Other toxicology. Prevent hepatotoxicity due to CHCl3 or CCl4 or neuropsychiatric sequele
of CO poisoning
Cigarette Smoking. NAC inhibited cigarette–induced mucous cell hyperplasia and epithelial
hypertrophy. Oral administration of NAC also counteracted the cigarette-induced decline in the
proportion of alveolar lymphocytes and the decreased phagocytic capacity and ability to
produce leukotriene B4 of alveolar macrophages in smokers.
Kidney stones. Inhibit calcium stone formation
Controindication and precautions
Hypersensitivity or previous anaphylactic reaction to acetylcysteine or any component of
the preparation. Be caution to be used in asthma or where there is a history of bronchospasm,
May cause coughing and stidor.
NAC infusion in doses used to treat paracetamol intoxication causes small to moderate
derangements of the coagulation system, which affect both vitamin K dependent coagulant and
anticoagulant proteins.
Be caution to be used in patients with a past medical history of oesophageal varices and
peptic ulceration (acetylcystein induced vomiting may increase the risk of haemorrhage)
May cause a false positive reading for ketones on a urine test strip. Can chelate zinc and
copper, long term use should take extra zinc and copper. Urticaria, rash (erythematous and
maculopapular), cyanosis and injection site reaction. Tachycardia, chest pain, and extrasystoles.
Cough congestion, runny nose. Might increase the incidence of teratogenicity when
administered during pregnancy. In healthy individuals, doses as low as 1.2 g daily might act as
a pro-oxidant and might lower GSH and increase the amount of oxidised GSH.
Overdose
Severe anaphylactoid reactions, Respiratory depression. Haemolysis, DIC, Renal failure,
ARDS
GI haemorrhage, Death.
121
DISCUSS THE INDICATIONS AND CONTRAINDICATIONS OF MORPHINE IN
THE TREATMENT OF ACUTE PULMONARY OEDEMA
Dr. M. Heaney. Intensive Care Unit, Royal Perth Hospital, Western Australia
Acute cardiogenic pulmonary oedema is a common problem in the hospital setting with a
reported in hospital mortality of 15 - 20%. Patients present with acute onset shortness of breath
and are markedly distressed. Clinical findings include diaphoresis, clamminess, tachycardia,
crepitations throughout both lung fields, left ventricular S3 and occasionally bronchospasm.
Before the mid twentieth century treatment options for acute pulmonary oedema (APO)
were limited, consisting simply of digitalis, opium and venesection. While morphine has been
used for centuries to treat acute pulmonary oedema, it is only part of a therapeutic
armamentarium including oxygen, furosemide, nitrates and newer therapies such as nesiritide
and levosemindan. To understand the rationale for the use of morphine in acute pulmonary
oedema it is essential to first understand the pathophysiology of this condition.
Pathophysiology
Acute pulmonary oedema occurs in the setting of an acutely decompensated left ventricle
either as a result of an acute process- myocardial ischaemia/infarction or as a result of
exacerbation of a pre-existing cardiac condition such as valvular disease, hypertensive heart
disease, or cardiomyopathy. In patients with a chronic process neurohumeral mechanisms
including the sympathetic, RAAS, and AVP are activated in attempts to compensate for the
failing ventricle. Intense sympathetic activation leads to a compensatory tachycardia and
increased vascular tone- in the venous system this helps to maintain preload, however in the
arterial system this adaptive response results in increased after load which is deleterious to the
failing ventricle.
As the decompensating left ventricle fails, left ventricular end diastolic pressure increases
which in turn increases pulmonary venous and capillary hydrostatic pressures. When this
pressure is greater than 18mmHg (may be lower in patients with hypoalbuminaemia) a protein
sparse plasma ultrafiltrate is forced across the alveolo- capillary membrane resulting in
interstitial oedema (Kerley B lines and upper lobe diversion on CXR). Compensatory
mechanisms for lymphatic drainage of fluid are rapidly overwhelmed ultimately leading to
alveolar flooding (Bat wing appearance on CXR) The patient develops acute dyspnoea, coughs
and expectorates pink frothy fluid- and literally feels they are drowning. This sensation of
suffocation intensifies firght, increases heart rate and blood pressure, increases work of
breathing and further impairs ventricular function; if this vicious cycle is not broken, death
ensues rapidly.
The therapeutic goals in treatment of APO are:
1. reduction of cardiac workload by reduction of preload and after load
2. Relief of pain and agitation
3. Improve cardiac contractility
4. Control excess retention of salt and water
The ideal therapeutic agent shoud be titratable, rapidly acting and have minimal side effects
As will be outlined below morphine certainly fulfils some of these goals but its side effect
profile limits its usefulness.
Advantages
Morphine has been used in the treatment of APO for centuries and many authors
uncritically encourage its continuing use. Its potent anxiolytic and sedative effects are
122
extremely advantageous in relieving the agitation associated with APO. By reducing systemic
catecholamines and possibly vagotonic activity, morphine reduces heart rate, reduces blood
pressure, reduces contractility and thus reduces myocardial oxygen consumption.
Morphine also has potent effects on the vasculature via both central sympatholytic
mechanisms and peripheral histaminergic mechanisms. Arterial vasodilatation reduces after
load, which decreases myocardial workload. Pulmonary capillary pressure is reduced and
cardiac output increases. Morphine is a potent venodilator of peripheral and splanchnic
systems. This increased venous capacitance results in a reduced preload to the failing ventricle.
Recent research has suggested that the vasodilator effects of morphine are solely due to
histamine release with very little or no involvement of mu opiate receptors.
Morphine administered intravenously has peak clinical effects within minutes and clinical
duration of action of three to four hours. The dose (2 - 4mg every 5 - 10 min) can be titrated to
clinical effect- as ascertained by the patient’s degree of anxiety and level of consciousness.
Morphine administered cautiously does not cause respiratory failure or aggravate existing CO2
retention associated with APO. Morphine’s potent analgesic action is dually advantageous in
the patient with chest pain and APO. Relief of pain reduces deleterious sympathetic effects.
Disadvantages
Morphine also has significant disadvantages in this setting. Rapid administration of
morphine potentiates histamine release from the lungs resulting in pulmonary vasoconstriction
and bronchospasm, further increasing the work of breathing.
While administration of morphine results in advantageous preload reduction in volume
overloaded patients with chronic heart failure, not all patients with APO are overloaded- and
administration of morphine to these patients may result in severe hypotension. Morphine can
cause excessive preload reduction – with resultant decreased cardiac output and hypotension;
patients with less compliant hearts – particularly those with diastolic dysfunction, aortic
stenosis and acute myocardial infarction are most susceptible. Most patients with APO have a
compensatory tachycardia, but in those patients who do not, morphine’s vagotonic effects may
result in symptomatic bradycardia.
While the dose of morphine is titratable its clinical effects may be markedly prolonged in
this predominantly elderly population resulting in decreased levels of consciousness and even
obtundation. Several case series report excessive administration of morphine to elderly patients
with APO requiring reversal with naloxone. Although naloxone will reverse morphine’s effects
on conscious level it does not reverse morphine’s vasodilator effects and hypotension may be a
persistent problem.
Morphine is a potent respiratory depressant and while not contraindicated in patients with
marginally elevated CO2 levels, which are presumed due to alveolar flooding, its effects in the
patient subgroup with hypercarbia and respiratory acidosis- having more severe APO must be
monitored vigilantly. As elderly patients with APO often have impaired renal function- the
accumulation of morphine-6-gloucuronide with its prolonged half-life may cause further
respiratory depression. Administration of morphine to patients with severe pulmonary oedema
has been shown to result in increased need for intubation (OR 5.0) and increased requirement
for admission to the intensive care unit (OR 3.1), however this data was collected
retrospectively and may have been subject to observer bias.
Morphine also increases antral tone and decreases gastrointestinal motility resulting in
delayed gastric emptying, which may have implications in patients who require noninvasive
ventilation or intubation for worsening symptoms. Morphine’s emetogenic side effects are also
unwelcome in this setting of an agitated distressed patient who may require airway
intervention/tight fitting mask.
123
Conclusion
While the administration of morphine to patients with acute pulmonary oedema is a time
honoured practice, in this age of evidence based medicine available data does not suggest that
morphine reduces morbidity and mortality, in fact treatment with morphine may have
deleterious effects on patient outcome with need for increased intubation and admission to the
intensive care unit. A large prospective randomised trial is necessary to answer this question
definitively.
Refrences
1. Braunwald: Heart Disease: A Textbook of Cardiovascular Medicine 6th ed 2001
2. Jackson G, Gibbs CR, Davies MK, Lip GY.ABC of heart failure: Pathophysiology. BMJ
2000; 320: 167-170
3. Hakim TS, Grunstein MM, Michel RP. Opiate action on the pulmonary circulation. Pulm
Pharmacol 1992;5:159-165
4. Vasko JS, Henney RP, Oldham HN et al. Mechanisms of action of morphine in the
treatment of experimental pulmonary oedema. Am J Cardiol 1966; 18:876-883
5. Vismara LA, Leaman DM, Zelis R. The effects of morphine on venous tone in patients
with acute pulmonary oedema. Circulation 1976;54:335-7
6. Mattu A. Cardiogenic pulmonary oedema. Current opinion in Cardiovascular, Pulmonary
and Renal Investigational Drugs.2000; 2:9-16
7. Millane T, Jackson G, Gibbs CR, Lip GY. ABC of heart failure:Acute and chronic
management strategies.BMJ 2000; 320:559-62
8. Sacchetti A, Ramoska E, Moakes ME, McDermott P, Moyer V. Effect of ED management
on ICU use in acute pulmonary edema. Am. J. Emerg. Med. 1999; 17:571-4
9. Chambers JA, Baggoley CJ. Pulmonary oedema-prehospital treatment: Caution with
morphine dosage. Med J. Aust. 1992;157:326-8
10. Hoffman JR, Reynolds S. Comparison of nitroglycerin, morphine and furosemide in
treatment of presumed pre-hospital pulmonary oedema. Chest 1987;92:586-93.
124
DISCUSS THE CLINICAL PRESENTATION AND MANAGEMENT OF A PATIENT
WHO HAS AN ACUTE BUDD-CHIARI SYNDROME
Dr. J. Lewis. Intensive Care Unit, Royal Perth Hospital, Western Australia
Definition
Budd-Chiari Syndrome refers to hepatic venous drainage obstruction. It is usually
associated with thrombosis in the hepatic veins that frequently extends into the IVC.
Aetiology
Most cases are secondary to an underlying condition however 20% are idiopathic.
Underlying aetiologies are listed below:1,2,3,4
1. Myeloproliferative disorders ~50%
Polycythaemia rubra vera
Essential thrombocythaemia
Agnogenic myeloid metaplasia
2. Malignancy
Hepatocellular, adrenal, renal, pancreatic, gastric, lung, sarcoma of right atrium
3. Infections and benign lesions of the liver
Hepatic cysts, abscesses
4. Hypercoagulable states
OCP
Pregnancy
Factor V Leiden mutation
Prothrombin gene mutation
Anti-thrombin III deficieny
Protein C, S deficiency
Lupus anticoagulant
Paroxsmal nocturnal haemoglobinuria
5. Membranous webs
6. Others
Vasculitis…
Clinical Presentation
The clinical presentation maybe divided into history, examination and Investigation. Notes
on each of these aspects are below.4,5
History
Females > males (2:1)
Any age (especially 20-40yo)
Epigastric/ Right upper quadreant pain
Abdominal distension
Features of Liver dysfunction
Features of underlying aetiology
Maybe acute (20%), even fulminating, subacute (40%) or chronic (40%)
Maybe asymptomatic (5%)
Examination
Tender hepatomegaly
Ascites
Signs of liver failure (jaundice, oedema, coagulopathy, encephalopathy)
125
Signs of portal Hypertension take time to develop
Cirrhosis takes time to develop
Investigations
LFTs variable increases in transaminases, ALP, Bili
May see synthetic dysfunction (coagulopathy, hypoalbuminaemia)
Imaging US
MRI angiography
Venography
(contrast CT, sulfur colloid scintigraphy, arteriography)
Other liver biopsy
other tests to guide supportive care
Differential diagnosis
Veno-occlusive disease
Acute liver failure
Chronic liver failure
Portal hypertension
Right heart failure
Treatment
The treatment maybe divided into medical, radiological and surgical. These are considered
below.
Medical
Control of oedema/ascites
Fluid and salt restrict
Frusemide/spironolactone
Stockings
Paracentesis
Consider thrombolysis6, 7
Consider if <3-4 weeks
Systemic vs local administration
Only case series level of evidence
Seek and treat underlying condition
?anticoagulation
?aspirin /hydroxyurea if myeloproliferative disorder
Routine supportive care
Includes optimising nutrition and other supportive care for liver failure
Radiological
Angioplasty8
If focal stenosis that is accessible radiological (eg membranous web in IVC)
Stenting9
Helps patency post angioplasty
Avoid placement in sites that preclude liver transplantation (if possible future option)
TIPS10
If above options not viable
Surgical11
Portosystemic shunting
Various shunts (portocaval, splenorenal, mesocaval, portoatrial)
126
Usually requie anticoagulation
Thrombectomy usually not possible
Liver transplantation
If cirrhosis or advanced liver failure
May cure underlying condition (eg Protein C or S deficiency or AT III deficiency)
Refrences
1. Dilawari, JB, Bambery, P, Chawla, Y, et al. Hepatic outflow obstruction (Bubb Chiari
syndrome): Experience with 177 patients and a review of the literature. Medicine 1994;
73:21
2. Powell-Jackson, PR, Melia, W, Canalese J, et al. Budd-Chiari syndrome: Clinical patterns
and therapy. Q J Med 1982; 51:79
3. Maddrey, WC. Hepatic vein thrombosis (Budd-Chiari syndrome). Hepatology 1984;
4:445
4. Murad, SD, Valla, DC, De Groen, PC, et al. Determinants of survival and the effect of
portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology 2004; 39: 500
5. Hadengue, A, Poliquin, M, Vilgrain, V, et al. The changing scene of hepatic vein
thrombosis: Recognition of asymptomatic cases. Gastroenterology 1994; 106: 1042
6. Raju, G, Felver, M, Olin, J, et al. Thrombolysis for acute Budd-Chiari syndrome: Case
report and literature review. Am J Gastroenterol 1996; 91:1262
7. Sholar, PW, Bell, WR. Thrombolytic therapy for inferior vena cava thrombosis in
paroxysmal nocturnal haemoglobinuria. Ann Intern Med 1985; 103:539
8. Sparano, J, Chang, J, Trasi, S, et al. Treatment of the Budd-Chiari syndrome with
percutaneous transluminal angioplasty: Case report and review of the literature. Am J Med
1987; 82: 821
9. Witte, AM, Kool, LI, Veenendaal, R, et al. Hepatic vein stenting for Budd-Chiari
syndrome. Am J Gastroenterology 1997; 92: 498
10. Mancuso, A, Fung, K, Mela, M, Tibballs, J. TIPS for acute and chronic Budd-Chiari
syndrome: a single-centre experience. J Hepatol 2003; 38: 751
11. Orloff, MF, Daily, PO, OrloffSL, et al. A 27 year experience with surgical treatment of
budd-Chiari syndrome. Ann Surg 2000; 232: 340.
127
DISCUSS THE DIAGNOSIS AND MANAGEMENT OF GOUT IN A CRITICALLY
ILL PATIENT WITH ACUTE RENAL FAILURE
Dr. T. Corcoran. Intensive Care Unit, Royal Perth Hospital, Western Australia
The necessity to diagnose and treat gout may arise in one of three situations in the critically
ill. Patients with documented gout may develop an acute attack during admission to the
Intensive Care Unit; previously undiagnosed patients may develop gout during the course of
their stay in ICU and patients may rarely be admitted to ICU with a complication of gout. The
development of acute renal failure limits the treatment options in all three scenarios as most
therapies are relatively contraindicated. This discussion will focus on the diagnostic and
therapeutic issues in the previously undiagnosed patient developing gout in ICU.
Gout (monosodium urate crystal deposition disease) is a metabolic disorder characterised by
deposition of monosodium urate (MSU) crystals in tissues and the development of local
inflammatory response. When plasma becomes saturated with MSU, crystals become deposited
in tissues and joints provoking an intense neutrophil-mediated inflammatory response. Uric
acid is the end product of purine nucleotide degradation in humans, being converted from
xanthine to uric acid by the enzyme xanthine oxidase, the liver and intestine accounting for the
majority of production owing to high content of the enzyme in these tissues. MSU is 75%
excreted in the urine and 25% in the intestine. Alkalinisation of the urine promotes excretion
and it is easily dialysed. All patients with gout are hyperuricemic although not necessarily at the
time of presentation. The hyperuricemia may arise out of increased production or decreased
excretion and there are primary and secondary classifications in both categories. The majority
of patients who have idiopathic gout have decreased excretion of uric acid, although conditions
with increased cellular turnover (increased uric acid production- myeloproliferative conditions)
and certain drugs (decreased renal excretion – low dose aspirin and loop / thiazide diuretics)
produce secondary gout. Idiopathic gout is associated with Type 2 Diabetes Mellitus,
Hypertension, Truncal Obesity, Hypothyroidism, Hyperlipidaemia and Coronary Artery
Disease but whether these are just epiphenomena remains to be determined.1;2 Renal failure has
unpredictable effects upon uric acid levels and uremia may suppress the immune response to
MSU crystals and therefore modify the presentation of the disease.
Many of the factors associated with the precipitation of an acute attack are present at the
time of admission to intensive care for many patients- surgery, trauma, dehydration, use of
diueretics or aspirin, First attacks are almost invariably characterised by acute mono/pauciarticular arthritis,3 although patients with myeloproliferative disorders or those receiving
cyclosporine for solid organ transplantation may develop polyarticular attacks.4 The affected
joint is acutely inflamed, tender, with reduced range of movement and swelling and
inflammation of overlying tissues. It must be distinguished from disorders with similar
presentations such as septic arthritis, cellulitis and pseudogout, which may also co-exist. This
may at times be difficult and the distinction from septic arthritis is not always clear, as acute
gout may be associated with similar systemic manifestations such as pyrexia, neutrophil
leucocytosis, elevated ESR and C-reactive protein levels. There are eleven clinical diagnostic
criteria for gout but these are unhelpful in the critically ill patient.5 As mentioned serum uric
acid levels may be normal or low during an acute attack and the performance of 24-hour
urinary uric acid excretion is impractical and imprecise even in the non-emergent setting. The
most useful diagnostic examination is to aspirate a sample of fluid from an affected joint. This
should be sent for gram stain, microscopy, culture, cell count and examination for the presence
of crystals under polarised light. In a severe attack the synovial fluid may be very cloudy owing
to a high content of neutrophils (5,000 to 50,000 per µL) and the fluid may appear purulent if
128
there is a heavy MSU crystal load, again leading to confusion with a diagnosis of septic
arthritis. As large a sample of joint fluid possible should be collected (if necessary using
ultrasound guided sampling) and sent fresh to the laboratory for processing, - there it should be
examined under polarised light for the presence of intra- and extracellular needle-shaped MSU
crystals- they are yellow when aligned parallel to the axis of a red compensator, but they turn
blue when aligned across the direction of polarisation – this is negative birefringence. Calcium
pyrophosphate crystals which are found in pseudogout are of a different shape and show weak
or no positive birefringence.6;7 If the diagnosis remains unclear but a high suspicion of gout
exists then examination of synovial fluid from an uninvolved joint may yield positive results as
the crystals will be detectable here also.
Once the diagnosis has been reached and infection excluded the principle aim of treatment
is symptomatic and to aid resolution of inflammation. Correction of uric acid concentrations, an
important consideration in the non-critical illness setting are of less importance. In chronic gout
serum urate concentrations are lowered by increasing renal excretion (using probenecid or
sulphinpyrazone – uricosuric agents) or by decreasing production (using allopurinol- a xanthine
oxidase inhibitor). None of these treatments are pertinent to the care of the critically ill patient
with an acute attack. It should be remembered that gout is a self-limiting disease and a single
acute attack in a critically ill patient is relatively innocuous.
The most commonly used treatment for acute gout, colchicine is no longer popular. It works
by inhibiting microtubule polymerisation and thus disrupting chemotaxis and phagocytosis in
inflammatory cells, undesirable actions in the immunologically – threatened critically ill
patient. It has an extensive adverse reaction profile including nephro-, hepatoto- and marrow
toxicity. Nonsteroidal antiinflammatory drugs have become the drugs of first choice in the
treatment of acute attacks of gout. These agents, such as indomethacin, acting through
inhibition of prostaglandin synthesis via an action on the enzyme cyco-oxygenase, are effective
anti-inflammatory agents and also have analgesic properties. However, they do have side
effects which are particularly poorly tolerated in the critically ill; impaired platelet function,
gastric mucosal erosions, altered intrarenal haemodynamics producing renal impairment and
fluid retention. In particular because of their unpredictable effect in evolving or resolving acute
renal failure in the critically ill patient, this class of drugs is not employed and therefore are not
an option in this scenario. Recently, systemic or intra-articular steroids or corticotrophin have
been employed with some success for the treatment of acute attacks in patients with monoarticular gout. They appear to provide rapid relief and a potent anti-inflammatory effect, and
may be suitable for termination of an acute attack in a critically ill patient in whom other agents
sre unsuitable- particularly given the neutral effect of these agents in relation to renal function.
Relatively high doses need to be employed however (Methylprednisolone 100 - 150mg per day
for three days for example) and mandates the absolute exclusion of an infective process as the
use of glucocorticoids is associated with a) immunosuppression and b) masking of the signs of
developing infection both of which are undesirable in the critically ill patient. The use of intraarticular glucocorticoids is particularly attractive if trying to avoid systemic effects but the same
argument for ruling out infection applies.
There may be a case to be made for no treatment at all for the following reasonsa). Use of definitive agents (which reduce serum urate concentrations) is not possible in the
critically ill patient with acute renal failure.
b). Agents which provide symptomatic anti-inflammatory relief are either not suitable in this
class of patient or have a marginal risk-benefit ratio.
Given the benign nature of an acute attack of gout, and the significant array of potentially
hazardous side effects that treatment may entail, it may be that treatment is less important than
accurate diagnosis in the critically ill patient. Once we can be sure that an acutely inflamed
129
joint is neither cellulitic nor septic then perhaps appropriate analgesia while awaiting the attack
to recede may be a more prudent course to follow rather than risk incurring a costly drug
adverse reaction
Refrences
1. Rott KT, Agudelo CA. Gout. JAMA 2003; 289(21):2857-2860.
2. McGill NW. Gout and other crystal-associated arthropathies. Baillieres Best Pract Res
Clin Rheumatol 2000; 14(3):445-460.
3. Wortmann RL. Gout and hyperuricemia. Curr Opin Rheumatol 2002; 14(3):281-286.
4. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 2000;
11(5):974-979.
5. Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF. Preliminary criteria
for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977;
20(3):895-900.
6. Lumbreras B, Pascual E, Frasquet J, Gonzalez-Salinas J, Rodriguez E, Hernandez-Aguado
I. Analysis for crystals in synovial fluid: training of the analysts results in high
consistency. Ann Rheum Dis 2005; 64(4):612-615.
7. Pascual E, Batlle-Gualda E, Martinez A, Rosas J, Vela P. Synovial fluid analysis for
diagnosis of intercritical gout. Ann Intern Med 1999; 131(10):756-759.
130
DISCUSS THE MANAGEMENT OF THE GUILLAIN BARRE SYNDROME
Dr. D. Rigg. Intensive Care Unit, The Canberra Hospital, ACT
Guillain – Barre Syndrome (GBS) is an acute idiopathic inflammatory demyelinating
polyneuropathy characterised by generalised neuromuscular weakness and areflexia. The
following points should be noted:
ƒ Several forms are recognised with specific distinguishing features.
ƒ Diagnosis is based on history, clinical features and CSF and neurophysiological testing.
ƒ Mortality rate is 3- 5%, with 7-15% having permanent neurological sequelae
ƒ If patients advance past the acute phase of illness most recover function spontaneously
requiring only supportive treatment and clinical monitoring.
ƒ Patients can now be treated with specific, effective, disease-modifying therapies –
intravenous immunoglobulin (IVIg) OR plasma exchange (PE).
ƒ Approximately 20-30% will require invasive mechanical ventilation in ICU. Additionally,
autonomic dysfunction may necessitate ICU admission.
Factors during the acute phase associated with poor prognosis include:
ƒ age > 60
ƒ severe and rapidly progressive disease,
ƒ mean nerve conduction amplitudes on distal stimulation <20% normal.
ƒ Mechanical ventilation, for more than one month and pre-existing pulmonary disease are
also associated with poor outcome.
The key management issues at admission to hospital include:
ƒ Initial disposition – Ward or ICU bed?
ƒ In whom do we initiate specific therapy – when, what type (IVIg or PE), dose regimen,
duration?
Initial Disposition
This decision depends on rate of onset, nature and severity of disease and respiratory
function.
Ambulatory patients with mild disease may go to a general ward provided they have
frequent clinical review. Deterioration can occur rapidly and unpredictably. Assessment should
include peripheral motor function, bulbar function, respiratory system and cough. Bedside
spirometry looking at FVC, maximum inspiratory and expiratory pressures is useful in those at
risk for respiratory failure.
Non-ambulatory patients, those with rapid progression (<7 days), inability to raise head
against gravity, bilateral facial weakness, significant autonomic dysfunction or obvious
aspiration, atalectasis or respiratory failure require ICU admission.
Specific Immunomodulatory Therapy
The American Academy of Neurology (AAN) practice parameter on immunotherapy for
GBS published in 2003 assessed the evidence for use of immunotherapy for GBS including
plasma exchange (PE), immunoadsorption, intranenous immunoglobulin (IVIG), or steroids.
General conclusions were:
ƒ Treatment with PE or IVIg hastens recovery from GBS.
ƒ The effects of plasma exchange and IVIg are equivalent.
131
ƒ Combining the two treatments is not beneficial.
ƒ Steroid treatment given alone is not beneficial.
Specific Recommendations:
ƒ PE is recommended for nonambulant adult patients with GBS who seek treatment within 4
weeks of the onset of neuropathic symptoms. PE should also be considered for ambulant
patients examined within 2 weeks of the onset of neuropathic symptoms;
ƒ IVIg is recommended for nonambulant adult patients with GBS within 2 or possibly 4
weeks of the onset of neuropathic symptoms. The effects of PE and IVIg are equivalent;
ƒ Corticosteroids are not recommended for the management of GBS;
ƒ Sequential treatment with PE followed by IVIg, or immunoabsorption followed by IVIg is
not recommended for patients with GBS;
ƒ PE and IVIg are treatment options for children with severe GBS.
Recent Cochrane reviews have reached similar conclusions.
ICU MANAGEMENT OF GUILLAIN-BARRE SYNDROME
Upon admission to Intensive Care, specific management issues include:
1. When to intubate and ventilate. Choice of drugs for induction and optimal timing for
tracheostomy are important subsequent considerations.
2. Recognition and management of Autonomic Dysfunction.
3. Who gets immunomodulatory therapy (see above).
4. Monitoring, prevention and treatment of medical complications.
5. Nutritional support.
6. Supportive nursing care.
7. Analgesia, anxiolysis and psychological support for patient and family.
Multidisciplinary rehabilitation involving physio, occupational and speech therapists.
Monitoring and preventing of both short and long term complications is the cornerstone of
good multidisciplinary ICU management.
Mechanical Ventilation
Certain clinical and diagnostic features are associated with severity of disease and increased
risk of mechanical ventilation. Sharshar (2003) identified several features as independent
predictors for invasive mechanical ventilation. These include: 1) time from onset to hospital
admission of <7 days; 2) inability to lift elbows or head off bed; 3) inability to stand; 4)
ineffective cough; and 5) increased liver enzymes.
The 20/30/40 rule states that patients with FVC <20 mL per kg, maximal inspiratory
pressure <30 cm H2O or maximal expiratory pressure < 40 cm H2O generally progress to
mechanical ventilation (Lawn 2001). Ropper and Kehne suggest intubation if one of the
following criteria are met: ventilatory failure with reduced expiratory VC of 12 to 15 mL per
kg, oropharyngeal paresis with aspiration, falling VC over 4 to 6 hours, or clinical signs of
respiratory fatigue at a VC of 15 mL per kg.
In general, indications for intubation and mechanical ventilation include:
ƒ Impending or worsening hypercapnoeic respiratory failure
ƒ High risk of aspiration (bulbar involvement)
ƒ Ineffective cough (i.e. inability to clear secretions)
The presence of autonomic dysfunction may result in profound hypotension at induction
due to inability to increase cardiac output in response to vasodilatation.
132
Suxamethonium may precipitate arrhythmia and should be avoided in those with significant
autonomic dysfunction.
While early tracheostomy is desirable, delaying this up to 10-14 days may result in up to
30% of patients avoiding the procedure.
Autonomic Dysfunction
50% have autonomic dysfunction, although most are mild. Specifically:
ƒ Arrhythmias are common including bradycardia, complete heart block, VT and cardiac
arrest;
ƒ Blood pressure variation
ƒ Paralytic ileus and bladder dysfunction
ƒ Excessive sweating
BP may fluctuate with transient hypertensive episodes. Sympathetic overactivity may cause
sudden diaphoresis, general vasoconstriction, and sinus tachycardia. Sympathetic underactivity
may lead to postural hypotension and heightened sensitivity to dehydration and sedativehypnotic agents. Excessive parasympathetic activity may cause facial flushing with feelings of
generalized warmth and bradycardia.
Those in ICU require continuous ECG and BP monitoring. Occasionally transcutaneous
pacing and invasive haemodynamic monitoring is required. Short acting drugs (eg nitroprusside
/ esmolol / noradrenaline / metaraminol ) and the judicious use of volume loading is used for
BP control.
General Medical, Nursing and Allied Health Management
This revolves around the prevention of complications, similar to all long term ICU patients,
including:
ƒ Prophylaxis for thromboembolism - calf compressors, TED stockings, heparin - DVT/PE
are common causes of morbidity and mortality in GBS.
ƒ Monitoring and treatment of infective complications
ƒ Bowel, bladder, pressure and eye care
ƒ Nutritional support - enteral route is preferred. There may be gastric paresis, paralytic ileus
and diarroea. Swallowing should be carefully assessed by speech pathologist during
recovery phase.
ƒ Chest physiotherapy is routine.
ƒ Analgesia, anxiolysis and management of insomnia. They may have pain requiring opiate
analgesia. There is evidence that tricyclics, carbamazepine and gabapentin may reduce
opiate requirements.
ƒ Early introduction of musculoskeletal rehabilitation including joint and tendon mobilisation,
splinting and tilt table work.
ƒ Early education and good communication help facilitate good psychological health during
recovery and rehabilitation phases.
Refrences
1. Hughes RA et al. Practice parameter: immunotherapy for Guillain-Barre syndrome: report
of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 2003 Sep 23;61(6):736-40
2. Hughes RA, van der Meche FG: Corticosteroids for treating Guillain-Barré syndrome.
Cochrane Database Syst Rev (2):CD001446, 2000.
3. Hund EF, Borel CO, Cornblath DR, et al. Intensive management and treatment of
Guillain-Barré syndrome. Crit Care Med 1993;21:433–446.
133
4.
5.
6.
Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF. Anticipating
mechanical ventilation in Guillain-Barré syndrome. Arch Neurol 2001;58:893-8
Ropper AH, Kehne SM: Guillain-Barré syndrome: management of respiratory failure.
Neurology 35:1662, 1985
Sharshar T et al. Early predictors of mechanical ventilation in Guillain-Barre syndrome.
Crit Care Med 2003 Jan 31(1):278-83
134
INDEX
2,3-diphosphoglycerate, 8, 9
ADP/ATP ratio and, 11
shock and, 11
stored red blood cells and, 11
Abciximab, 42
Activated partial thromboplastin time, 50
Addison’s disease, 102
Anaemia, 17
causes, 17
chronic inflammation, 24
chronic renal failure, 24
classification, 17
folate deficiency, 23
haemolysis
causes, 25
haemolytic, 25
autoimmune, 27
clinical features, 28
investigations, 28
treatment, 28
iron deficiency, 18
macrocytic, 21
megaloblastic, 21
causes, 23
clinical features, 23
investigations, 23
treatment, 24
microcytic, 18
nonmegaloblastic, 21
normocytic, 24
pernicious, 23
secondary, 24
sickle cell, 2
Antithrombin III, 47
Arteriopathies, 25
Aspirin
action, 39
dosage, 40
indications, 39
side-effects, 40
Atrial fibrillation, 109
Broncho-pleural fistula
management, 98
Budd-Chiari Syndrome, 125
Cardiac arrest
asystolic, 80
Cardiomyopathy
hypertrophic, 89
Central venous cannulation, 92
Clopidogrel
action, 40
dosage, 41
indications, 41
side-effects, 41
Coagulation, 42
activation, 42
blood products, 49
disorders, 51
causes, 51
extrinsic pathway, 43
factors, 44
inhibition, 47
inhibitors, 48
intrinsic pathway, 42
tests, 50
Cold antibody, 28
Coronary artery bypass, 109
Cross-linked fibrin derivatives, 51
Cryoprecipitate, 49
Cyanocobalamin, 21
Dazoxiben
action, 40
Desmopressin, 38
Dipyridamole, 40
action, 40
Direct Coombs test, 28
Disseminated intravascular coagulation, 54
causes, 55
clinical features, 56
investigations, 56
treatment, 56
B12
deficiency, 22
Bleeding time, 38
Bohr effect, 9
Embden-Myerhof pathway, 9
Epsilon-aminocaproic acid, 38
Erythroid cell, 1
135
Erythropoietin
molecular weight, 1
physiology, 1
Euglobulin clot lysis time, 51
A, 1
A2, 1
binding of nitric oxide, 12
biosynthesis, 1
disorders of, 1
fetal, 9
function, 8
molecular weight, 1
normal values, 17
oxygen affinity, 8
Haemolysis
extravascular, 27
intravascular, 25
clinical features, 26
investigations, 27
Haemolytic crisis, 2
Haemolytic uraemic syndrome, 26
Haemopexin, 27
Haemophilia A, 53
Haemophilia B, 54
Haemostasis, 35
Haptoglobin, 27
Heparin
cofactor II, 47
Hepatopulmonary syndrome, 76
Hydroxocobalamin, 21
Hypersplenism, 29
Hypoadrenalism, 102
Hyponatraemia, 105
Factor IX
complex, 49
Factor V, 46
Factor VIIa
recombinant, 49
Factor VIII, 46, 47
recombinant, 49
replacement, 49
Factor X
activation, 43
Factor XI, 47
Factor XII, 47
Factor XIII
deficiency, 54
FDPs, 51
Fibrin
formation, 44
Fibrin degradation products, 51
Fibrinogen, 44
Fibrinogen assay, 51
Fibrinolytic inhibitors, 38
Folate
deficiency, 22
Folic acid
physiology, 21
Folic acid and B12 interactions, 21
Fresh frozen plasma, 49
Indirect Coombs, 28
Intestinal pseudo-obstruction
acute postoperative, 87
Intrinsic factor antibody, 24
Iron
deficiency
causes, 19
clinical features, 19
investigations, 19
treatment, 20
normal serum levels, 18
normal tissue levels, 18
Iron binding proteins, 19
Glycoprotein IIb/IIIa inhibitors, 41
Gout
treatment in acute renal failure, 128
Granulocyte, 1
Guillain-Barre syndrome
management of, 131
Haem
biosynthesis, 2
disorders of, 2
Haemochromatosis, 20
causes, 20
clinical features, 20
investigations, 20
treatment, 20
Haemoglobin
Koilonychia, 19
Lactic acidosis
D-lactate, 84
Lymphocyte, 1
136
Megakaryocytes, 35
Methaemoglobinaemia, 5
causes, 7
clinical features, 7
investigations, 7
treatment, 8
Methicillin resistant Staphylococcus
aureus, 115
Monocyte, 1
defect
drugs
aspirin, 39
hepatic failure, 39
renal failure, 39
function, 35
intravenous, 38
lifespan, 35
Platypnoea, 70
Polycythaemia, 29
causes, 29
rubra vera
causes, 30
clinical features, 30
investigations, 30
treatment, 30
secondary, 31
causes, 31
treatment, 31
Porphyria
congenital erythropoietic, 3
cutanea tarda, 3, 20
Porphyrias, 2
clinical features, 3
erythropoietic, 2
hepatic, 2
inducing drugs, 5
investigations, 5
neurological lesions, 3
safe drugs, 5
skin lesions, 3
treatment, 5
Porphyrin, 2
Portopulmonary hypertension, 76
Proerythroblast, 1
Pronormoblast, 1
Protein C
pathway, 47
Prothrombin time, 50
Protoporphyria, 2
Pulmonary oedema
acute, 122
treatment with morphine, 122
Purpura
nonthrombocytopenic, 35
N-acetylcysteine
complications of, 120
Normoblast, 1
Orthodeoxia, 70
Oxygen-haemoglobin dissociation curve,
10
acute myocardial infarction and, 11
anaemia and, 11
chronic change, 12
chronic lung disease and, 11
cirrhosis and, 11
clinical effects of, 11
congenital heart disease and, 11
critically ill patients and, 11
hypophosphataemia and, 11
in disease, 11
low cardiac output and, 11
massive transfusion and, 11
normal, 10
shift to the left, 12
shift to the right, 12
shock and, 11
thyrotoxicosis and, 11
P50, 10
alterations of, 10
definition, 10
normal value, 10
Paralytic ileus, 82
Platelet
activation, 36
adhesion, 36
aggregation, 36
disorders, 37
release, 36
Platelet factor 3, 35
Platelet factor 4, 35
Platelets, 1
Rapoport-Luebering shuttle, 9
Red blood cell
enzyme defects, 29
137
half-life, 1
morphology, 1
production, 1
Reticulocyte
circulation time, 1
life cycle, 1
Retinoic acid syndrome, 86
clinical features, 37
investigations, 37
nonimmune, 38
treatment, 38
THromboelastography, 51
Thrombophilia, 48
Thrombopoietin, 35
Thrombotic thrombocytopenic purpura, 25
TIA
clinical features and management, 95
Ticlopidine
action, 40
Tirofiban, 42
Transcobalamin I, 21
Transcobalamin II, 21
Transfusion siderosis, 20
TURP Syndrome, 105
Scoring system, 107
Sedation in ICU, 67
Selective decontamination of the
gastrointestinal tract, 117
Severity of illness
score, 107
Sodium bicarbonate
complications of, 111
Subacute combined degeneration, 22
Subclavian vein thrombosis, 72
Sulphaemoglobinaemia, 8
causes, 8
clinical features, 8
treatment, 8
Vancomycin allergy, 115
Vitamin
B12, 21
absorption, 21
intrinsic factor, 21
K factors, 45
von Willebrand factor, 36
von Willibrand factor, 46
von Willibrand’s disease, 54
Thalassaemia, 2
alpha, 2
beta, 2
Thrombin
formation, 44
Thrombin time, 50
Thrombocytopenia, 37
causes, 37
Warm antibody, 27
XDPs, 51
138
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