The Australian Short Course on Intensive Care

Medicine

2003 Handbook

The Australian Short Course on

Intensive Care Medicine

2003 Handbook

Editor L.I.G. Worthley

Published in 2003 by The Australasian Academy of Critical Care Medicine Department of Critical Care Medicine Flinders Medical Centre, Bedford Park South Australia 5042 ISSN 1327-4759 2003 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

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CONTENTS

Page

Chapter 1. Neuroendocrine and adrenal regulation in the critically ill 1 Chapter 2. Disorders of adrenal function 9 Chapter 3. Normal thyroid function and effects of critical illness 17 Chapter 4. Thyroid disorders 21 Chapter 5. Diabetes mellitus 31 Trainee Presentations 55 Index 113

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2003 SHORT COURSE PROGRAMME March 31st April 1st April 2nd April 3rd FMC FMC RAH RAH 0815 Travel to Travel to FMC FMC 0900

Lecture

Introduction to the critically ill patient

L W.

Lecture Pulmonary artery

catheters. A sceptic’s view

C.J

Lecture

Introduction

R.Y

OSCE

Vivas

1015

Interactive

Clinical Vignettes

L.W.

Interactive

Presentations

L. W

Clinical cases

Vivas

Clinical Cases

OSCE

Vivas

1130

Interactive

Biochemistry, bacteriology

C.J.

Lecture

Hepatic Failure

A.H.

Clinical cases

Vivas

Clinical Cases

OSCE

Vivas

1245

Lunch

1400

Lecture

Trauma management

J.C

Interactive

Path Forms

L.W

OSCE

Vivas

Review

R.Y.

1515

Interactive

Biochemistry

L.W.

Lecture

Acute Respiratory Failure Syndrome

AB

OSCE

Vivas

1630

Lecture

Presentations

L.W

Interactive

ECG's

L.W

1745

Travel To RAH

Travel to RAH Dinner

FMC = Flinders Medical Centre RAH = Royal Adelaide Hospital Dinner at: 19:00 hr, Wednesday 2nd April 2003 ‘House of Chow’ 82 Hutt St, Adelaide

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REGISTRANTS

Code Name Institution *† 1 Dr. J. Brieva Intensive Care Unit, John Hunter Hospital, NSW *† 2. Dr. T. Wigmore Intensive Care Unit, Westmead Hospital, NSW *† 3. Dr. J. Cohen Intensive Care Unit, Royal Brisbane Hospital, Queensland *† 4. Dr. D. Morgan Intensive Care Unit, Royal Perth Hospital, WA *† 5. Dr. C. Bradford Intensive Care Unit, Royal North Shore Hospital, NSW *† 6. Dr. C. Cody Intensive Care Unit, The Alfred Hospital, Victoria *† 7. Dr. D. Charlesworth Intensive Care Unit, Royal Melbourne Hospital, Victoria *† 8. Dr. M. Saxena Intensive Care Unit, St George Hospital, NSW *† 9. Dr. P. Goldrick Intensive Care Unit, Townsville Hospital, Queensland *†10. Dr. O. Sheffer Intensive Care Unit, Royal Melbourne Hospital, Victoria *†11. Dr. S. Sturland Intensive Care Unit, Royal Brisbane Hospital, Queensland *†12. Dr. H. Koelzow Intensive Care Unit, Royal Prince Alfred Hospital, NSW *†13. Dr. P. Nelson Intensive Care Unit, Royal Perth Hospital, WA * 14. Dr. P. Liston Intensive Care Unit, The Liverpool Hospital, NSW * 15. Dr. R. O’Connor Intensive Care Unit, Port Macquarie Base Hospital, NSW * 16. Dr. C. Allen Intensive Care Unit, Royal Perth Hospital, WA * 17. Dr. A. Dennis Intensive Care Unit, St Vincent’s Hospital, Victoria * 18. Dr. S. Morphett Intensive Care Unit, Royal Hobart Hospital, Tasmania * 19. Dr. B. Welch Intensive Care Unit, Mackay Base Hospital, Queensland * 20. Dr. M. McNamara Intensive Care Unit, Royal Adelaide Hospital, SA * 21. Dr. B. O’Brien Intensive Care Unit, The Alfred Hospital, Victoria * 22. Dr. C. Graves Intensive Care Unit, Royal Brisbane Hospital, Queensland * 23. Dr. S. Hockley Intensive Care Unit, Royal Adelaide Hospital, SA * 24. Dr. U. Kadam Intensive Care Unit, Royal Adelaide Hospital, SA * 25. Dr. S. Wilson Intensive Care Unit, Royal Melbourne Hospital, Victoria †26. Dr. L. Trent Intensive Care Unit, Royal Perth Hospital, WA †27. Dr. G. Ghelani Intensive Care Unit, Queen Elizabeth Hospital, SA †28. Dr. K. Deshpande Department of Critical Care Medicine, Flinders Medical Centre, SA

FACULTY FMC RAH GUESTS Dr. L. Worthley (L.W) Dr. R. Young (R.Y) Dr. J. Cooper (J.C) Dr. A. Bersten (A.B) Dr. M. Finnis (M.F) Dr. P. Morley (P.M) Dr. A. Holt (A.H) Dr. P. Thomas (P.T) Dr. C. Joyce (C.J) Dr. M. Chapman (M.C) ACH Dr. P. Sharley (P.S) Dr. N. Matthews (N.M) Dr. B. Griggs (W.G) Dr. S. Keeley (S.K) Dr. P. White (P.W) Dr. A. Slater (A.S) Dr. N. Edwards (N.E) Dr. T. Brownridge (D.C) Dr. S. Peake (S.P) * = registrants for Interactive sessions at the FMC † = registrants for Exam oriented sessions at the RAH

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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 endocrine system with chapters on neuroendocrine, renal and thyroid function. I have also included chapters on disorders of adrenal and thyroid function as well as a chapter on diabetes mellitus. 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, March 2003

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1

Chapter 1

NEUROENDOCRINE AND ADRENAL REGULATION IN THE CRITICALLY ILL NEUROENDOCRINE REGULATION The anterior pituitary produces growth hormone (GH, somatotropin), prolactin (PRL), luteinising hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH). The posterior pituitary stores vasopressin (ADH) and oxytocin, which are produced by neurones of the hypothalamus. A feedback relationship exists between the anterior pituitary and the gonads, thyroid and adrenal glands. When the gonads are removed LH and FSH rise; ACTH increases when the adrenal glands are removed and TSH increases when the thyroid is removed. When the pituitary gland is removed, secondary hypogonadism, hypoadrenalism and hypothyroidism occur; whereas antidiuretic hormone and oxytocin secretion may not be affected, providing their hypothalamic neuronal site of origin remains intact. The pituitary is under the control of the hypothalamus, which produces thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), luteinising hormone releasing hormone (LHRH), growth hormone releasing hormone (GHRH), growth hormone-release inhibiting hormone (i.e. somatostatin), prolactin release inhibiting factor (PIF) and prolactin releasing factor (PRF). These mediators enter the pituitary portal vascular system and are carried through the pituitary stalk to the anterior lobe of the pituitary. Somatostatin inhibits TRH-stimulated TSH release and TRH stimulates prolactin release. The major prolactin release inhibiting factor is dopamine, thus dopaminergic blocking agents such as phenothiazines increase prolactin levels whereas dopaminergic agents (e.g. bromocriptine, dopamine) decrease prolactin levels. ENDOCRINE CHANGES IN THE CRITICALLY ILL In response to acute ‘stress’ (e.g. trauma, sepsis, pyrogens, burns, surgery, hypotension, pain, hypoglycaemia, severe exercise and emotional trauma) the sympathetic system and the adrenal medulla release catecholamines, and the renin-angiotensin-aldosterone system increases plasma renin activity (PRA), angiotensin II (AII) and aldosterone levels.1,2 A subset of critically ill patients have been described who have inapropriately low aldosterone levels despite elevated PRA, plasma AII and ACTH levels, and normal potassium and atrial natriuretic peptide levels.3,4 This effect may be caused by tumor necrosis factor or adrenal ischaemia5 inhibition of aldosteronogenesis, or a shift in steroidogenesis from mineralocorticoid to glucocorticoid due to prolonged ACTH stimulation. Generally, the hypathalamo-pituitary response to acute ‘stress’ involves only the release of prolactin, vasopressin, growth hormone, ACTH (which in turn stimulates cortisol, aldosterone and small amounts of sex steroid, biosynthesis and release) and ACTH related peptides, although plasma levels may range widely due to the pulsatile nature of their secretion.6 During ‘stress’, the plasma gonadal steroid and thyroid hormone levels decrease,7 whereas the production and plasma levels of TSH, FSH, LH and oxytocin may increase, decrease or remain unaffected.

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Plasma PTH levels have also been reported to increase in response to severe stress (e.g. cardiac arrest).8 The hormone liberation provoked by ‘stress’ is outlined in Table 1.1.

Table 1.1 Hormonal liberation due to stress Sympathetic nerves Noradrenaline Adrenal medulla Adrenaline, and noradrenaline Renin-angiotensin Angiotensin II Pituitary Neurohypophysis Vasopressin Adenohypophysis Adrenocorticotropic hormone Beta-lipotropin Prolactin Growth hormone

Growth hormone (somatotropin) Growth hormone is secreted in a pulsatile fashion (greatest at night) from the anterior pituitary under the control of the hypothalamic hormones, growth hormone releasing hormone (GHRH) and growth hormone-release inhibiting hormone (i.e. somatostatin).9 It has a plasma half life of 6 - 20 minutes and the daily output in an adult is estimated to be 0.2 - 1.0 mg. The effects of growth hormone are mediated directly through a cell membrane receptor (causing sodium retention, insulin resistance, lipolysis, protein synthesis, epiphyseal growth) and indirectly through stimulation of hepatic secretion of insulin-like growth factor-I (IGF-I; somatomedin-C). While growth hormone has been used for many diseases associated with waisting (e.g. AIDS, COPD, burns, postoperatively, congestive cardiomyopathy, liver transplantation, renal failure), no consistent benefit has been demonstrated with its use.9 Recently, two large prospective randomised, placebo-controlled trials in critically ill patients, revealed that growth hormone was associated with an increased mortality, 10 (although it was given in large doses at a stage when many of the patients may have been GH sensitive rather than GH resistant).11 High doses of GH is harmful and is not recommended for the treatment of acute catabolism in critically ill patients. Insulin like growth factor The insulin-like growth factor family consists of insulin (synthesised in the beta cells of the pancreas), IGF-I and IGF-II (which are synthesised primarily in the liver). IGF-I has insulin like activity (approximately 6% that of insulin on a molar basis, although it circulates at a 1000 fold higher concentration than insulin, with less than 1% circulating free),12 antilipolytic activity, increases protein synthesis and epiphyseal growth and supresses hypothalamic GHRH secretion and pituitary GH secretion. Greater than 99% of the IGF’s are bound to a family of 6 high affinity binding proteins (which allow them to have a prolonged circulating half-life while preventing them binding to the IGF receptors with subsequent activation). They suppress

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circulating insulin and glucagon levels, inhibit hepatic glucose output, increase glucose uptake, and decrease circulating free fatty acids and amino acids. IGF-II is essential for embryonic development (as is IGF-I) although in adult life its physiological role is unknown. Recently, the IGF’s have been shown to be potent antiapoptotic agents.13 Insulin, IGF-I and IGF-II bind to two membrane associated receptors that are tyrosine kinases (i.e the insulin receptor and the IGF-I receptor) with insulin stimulating the insulin receptor predominantly and IGF-I stimulating the IGF-I receptor predominantly.14 The predominant regulator of IGF-I is growth hormone, although insulin also stimulates hepatic secretion of IGF-I (and IGF-I in turn supresses insulin secretion).15 However, in critically ill patients plasma GH levels are normal or elevated and plasma IGF-I levels are usually very low.16,17 THE ADRENAL CORTEX Normal adrenocortical function The zona faciculata and zona reticularis (i.e. the middle and inner adrenal cortical zones) secrete glucocorticoids and small amounts of androgens and oestrogens. The zona glomerulosa (i.e. the outer adrenal cortical zone) secretes aldosterone. Corticotropin releasing hormone Corticotropin releasing hormone (CRH) is synthesised in the hypothalamus and carried to the anterior pituitary in portal blood to stimulate the anterior pituitary to secrete ACTH, which in turn causes the adrenal cortex to secrete cortisol. Corticotropin releasing hormone is the major (but not the only) regulator of ACTH release. Vasopressin, oxytocin, angiotensin II and beta-adrenergic agents also stimulate ACTH release. Somatostatin, beta-endorphin and enkephalin decrease ACTH release. Cortisol has a negative feedback on the hypothalamus and pituitary, inhibiting hypothalamic CRH release induced by stress, and pituitary ACTH release induced by CRH. Corticotropin-releasing hormone is released in response to a normal hypothalamic circadian regulation and various forms of ‘stress’. Adrenocorticotropic hormone (ACTH) or corticotropin Adrenocorticotropic hormone and the ACTH related peptides are formed from the pituitary precursor molecule pro-opiomelanocortin, which forms gamma melanocyte stimulating hormone, ACTH and beta-lipotropin. Beta-lipotropin forms alpha-, beta- and gamma-endorphins.18 ACTH is the only physiologic agent known that stimulates cortisol biosynthesis and release. It also stimulates aldosterone (and small amounts of sex steroid) biosynthesis and release, although normal modulation of aldosterone secretion is by angiotensin II. ACTH has a half-life of 10 - 15 min. Both ACTH and cortisol are secreted cyclically throughout a 24 hr period. A decrease in circulating glucocorticoids is not a potent stimulus to ACTH secretion as the rate of ACTH secretion is determined largely by two opposing forces of neural and other influences. The magnitude of circulating glucocorticoids, however, inhibits ACTH secretion. Cortisol The normal daily output of cortisol is 40 - 80 µmol/day (i.e. 15 - 30 mg/day), producing a maximum plasma cortisol level of 110 - 520 ηmol/L (4 - 19 µg/dL) at 8 - 9 am, and a minimal cortisol level of < 140 ηmol/L (< 5 µg/dL) after midnight. The aldosterone output in a normal individual on a sodium intake of 100 - 150 mmol/day is 200 - 500 ηmol/day (i.e., 70 - 180 µ

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g/day). In a normal subjects with severe sodium restriction or patients with severe heart failure the aldosterone secretion may increase to 1100 - 1400 ηmol/day (400 - 500 µg/day).19 Cortisol promotes muscle protein catabolism and stimulates gluconeogenesis to produce glucose from the amino acids provided by the protein catabolism, it also promotes the lipolytic effect of catecholamines. Cortisol enhances vascular smooth muscle and myocardium responsiveness to noradrenaline or adrenaline and renal water excretion, all of which are impaired in the absence of glucocorticoids. The half-life of cortisol is 60 - 90 min. Cortisol exists in plasma in a bound form bound to both an alpha-globulin called transcortin or corticosteroid-binding globulin (CBG) and albumin, and also exists in a free form. The free hormone is the active form. At normal levels of total plasma cortisol (e.g. 375 ηmol/L or 13.5 µg/dL) less than 5% exists as free cortisol in the plasma. Cortisol binding by CBG in normal subjects can bind approximately 700 ηmol/L (i.e., 25 µg/dL). At levels greater than this the increase in plasma cortisol is largely in the unbound fraction. When CBG levels rise (e.g. pregnancy) the total cortisol level rises, a reciprocal change occurs with depressed transcortin levels (e.g. with cirrhosis, burns and nephrotic syndrome). In pharmacological doses, glucocorticoids have anti-inflammatory and immunosuppressive effects causing a reduction in the peripheral lymphocyte, eosinophil and monocyte count, and an increase in neutrophil count.20 The relative potencies of the commonly used glucocorticoids are listed in Table 1.2. Table 1.2 Characteristics of the commonly used glucocorticoids Agent Dose Mineralocort- Glucocort- duration of Plasma half (mg) icoid potency icoid potency action (hr) life (min) Cortisone 25 1 0.8 8 90 Hydrocortisone 20 1 1 8 90 Prednisolone 5 0.8 4 24 200 Methylprednisolone 4 0.5 5 24 200 Dexamethasone 0.75 0 25 36 300 Hydrocortisone is the synthetic equivalent of cortisol and is assigned the glucocorticoid and mineralocorticoid equivalent of 1 (one). Prednisone and prednisolone are equivalent, as are triamcinolone and methylprednisolone, and betamethasone and dexamethasone.21 Adrenocortical response to ‘stress’ The hypothalamus responds to the stress of surgery, trauma, hypoglycaemia and sepsis by increasing ACTH secretion. Plasma cortisol levels in critically ill patients are usually elevated above 555 ηmol/L (i.e., 20 µg/dL) with a loss in the diurnal rhythm. However, the range is wide.22 The maximum stress-induced output of cortisol is thought to be up to 555 µmol/day (i.e., 200 mg/day), with corresponding plasma levels of approximately 1650 ηmol/L (i.e., 60 µg/dL).23 Reports of occult hypoadrenalism with cardiovascular decompensation in acutely ill patients,24 adrenal hyporesponsiveness in some patients with severe inflammation25 or septic shock,26 and agents such as etomidate which suppress cortisol synthesis, being associated with increased mortality,27,28 indicate that cortisol secretion is important in the critically ill patient.29,30 However, the cortisol concentration appropriate for an acute illness is unknown, and there is no correlation between severity of illness and cortisol levels,31 indicating that the

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relationship between cortisol secretion and mortality, is far from clear. This uncertainty is even greater in patients who are already taking corticosteroid medication. With bilateral adrenal haemorrhage the serum cortisol levels are usually less than 50 ηmol/L, and the diagnosis of hypoadrenalism is not in doubt. In critically ill patients (particularly those in whom the baseline cortisol level is less than 350 ηmol/L), glucocorticoid replacement (e.g., 50 - 300 mg of hydrocortisone/day as a continuous infusion29) should be used if a short synacthen test does not double the baseline level25 or elicit a rise in serum cortisol of at least 250 ηmol/L.31,32,33 In critically ill patients, a plasma cortisol level of more than 700 ηmol/L (i.e., 25 µg/dL) probably rules out adrenal insufficiency.34 One study found 25% of critically ill patients with an eosinophilia (>3%) had an abnormal low-dose short synacthen test and may be a useful sign in critically ill patients who have adrenal insufficiency.35 In a recent multicentre, placebo controlled, randomised, double blind study of mechanically ventilated, critically ill patients with septic shock unresponsive to intravenous fluids and catecholamine infusions, 7 days of intravenous hydrocortisone (50 mg 6-hourly) and nasogastric tube instillation of 9-α-fludrocortisone (50 µg in 10 - 40 mL water) significantly reduced the 28 day mortality (NNT 7 patients to save one additional life) in patients with relative adrenal insufficiency (i.e. those who had a cortisol rise of < 9µg/dL or 250 µmol/L at 30 or 60 minute following 0.25 mg of synacthen intravenously). In this study approximately 2/3 of patients were found to have relative renal insufficiency, and there was a slight increase in mortality in patients who were adrenal ‘responsive’ who received cortisol and 9-α-fludrocortisone compared with the placebo group.36

REFERENCES 1. LeQuesne LP, Cochrane JPS, Fieldman NR. Fluid and electrolyte disturbances after

trauma: the role of adrenocortical and pituitary hormones. Br Med Bull 1985;41:212-217. 2. Hawker F. Endocrine changes in the critically ill. Br J Hosp Med 1988;39:278-288. 3. Findling JW, Waters VO, Raff H. The dissociation of renin and aldosterone during critical

illness. J Clin Endocrinol Metab 1987;64:592-595. 4. Zipster RD, Davenport Mw, Martin Kl, Tuck Ml, Warner NE, Swinney RR, Davis CL,

Horton R. Hyperreninemic hypoaldosteronism in the critically ill: a new entity. J Clin Endocrinol Metab 1981;53:867-873.

5. Raff H, Findling JW, Diaz SJ, Majmudar MH, Waters VO. Aldosterone control in critically ill patients: ACTH, metoclopramide, and atrial natriuretic peptide. Crit Care Med 1990;18:915-920.

6. Voerman HJ, Strack van Schijndel RJM, Groeneveld J, de Boer H, Nauta JP, Thijs LG. Pulsatile hormone secretion during severe sepsis: accuracy of different blood sampling regimens. Metabolism 1992;41:934-940.

7. Editorial. Neurohumoral responses to thermal injury. Lancet 1990;336:1221-1222. 8. Haspel K, Williams M, Andrei A, Nussbaum S, Napolitano L, Stanford G, Conn A,

Chernow B. Parathyroid hormone: identification of a new stress hormone in humans. Crit Care Med 1990;18(suppl):S195.

9. Vance ML, Mauras N. Growth hormone therapy in adults and children. N Engl J Med 1999;341:1206-1216.

10. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785-792.

11. Bengtsson BÅ. Rethink about growth-hormone therapy for critically ill patients. Lancet 1999;354:1403-1404.

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12. Guler HP, Zapf J, Froesch ER Short-term metabolic effects of recombinant human

insulin-like growth factor I in healthy adults. .N Engl J Med 1987;317:137-140. 13. Bach LA. The insulin-like growth factor system: basic and clinical aspects. Aust NZ J

Med 1999;29:355-361. 14. Roith DL. Insulin-like growth factors. N Engl J Med 1997;336:633-640. 15. Bondy CA, Underwood LE, Clemmons DR, Guler H-P, Bach MA, Skarulis M. Clinical

uses of insulin-like growth factor I. Ann Intern Med 1994;120:593-601. 16. Ross RJM, Rodriguez-Arnao J, Bentham J, Coakley JH. The role of insulin, growth

hormone and IGF-I as anabolic agents in the critically ill. Intens Care Med 1993;19:S54-S57.

17. Gibson FAM, Hinds CJ. Growth hormone and insulin-like growth factors in critical illness. Intens Care Med 1997;23:369-378.

18. Buckingham JC. Hypothalamo-pituitary responses to trauma. Br Med Bull 1985;41:203-211.

19. Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2001;345:1689-1697. 20. Fauci AS, Dale DC, Balow JE. Glucocorticoid therapy: mechanisms of action and clinical

considerations. Ann Intern Med 1976;84:304-315. 21. Melby JC. Clinical pharmacology of systemic corticosteroids. Ann Rev Pharmacol

Toxicol 1977;17:511-527. 22. Sainsberg JRC, Stoddard JC, Watson MJ. Plasma cortisol levels: a comparison between

sick patients and volunteers given intravenous cortisol. Anaesthesia 1981;36:16-20. 23. Ziment I. Steroids. Clin Chest Med 1986;7:341-346. 24. Hubay CA, Weckesser EC, Levy PR. Occult adrenal insufficiency in surgical patients.

Ann Surg 1975;181:325-332. 25. Mackenzie JS, Burrows L, Burchard KW. Transient hypoadrenalism during surgical

critical illness. Arch Surg 1998;133:199-204. 26 . Soni A, Pepper GM, Wyrwinski PM, Ramirez NE, Simon R, Pina T, Gruenspan H, Vaca

CE. Adrenal insufficiency occuring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 1995;98:266-271.

27. Fellows IW, Bastow MD, Allison SP. Adrenocortical suppression in multiply injured patients: a complication of etomidate treatment. Br Med J 1983;287:1835-1837.

28. Ledingham IMcA, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983;i:1270.

29. Lamberts SWJ, Bruining HA, De Jong FH. Corticosteriod therapy in severe illness N Engl J Med 1997;337:1285-1292.

30. Masterson GR, Mostafa SM. Adrenocortical function in critical illness. Br J Anaesth 1998;81:308-310.

31. Drucker D, Shandling M. Variable adrenocortical function in acute medical illness. Crit Care Med 1985;13:477-479.

32. McKee JI, Finlay WE. Cortisol replacement in severely stressed patients. Lancet 1986;i:484.

33. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582-583.

34. Vermes I, Beishuizen A, Hampsink RM, Haanen C. Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab 1995;80:1238-1242.

35. Beishuizen A, Vermes I, Hylkema BS, Haanen C. Relative eosinophilia and functional adrenal insufficiency in critically ill patients. Lancet 1999;353:1675-1676.

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36. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G,

Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.

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9

Chapter 2

DISORDERS OF ADRENAL FUNCTION ADRENOCORTICAL DEFICIENCY Aetiology Primary adrenocortical insufficiency (Addison’s disease) Primary adrenocorticoid insufficiency is caused by a primary autoimmune disease in 70% of cases, 50% of whom have antiadrenal antibodies and some of whom have other autoimmune diseases (e.g. pernicious anaemia, type I diabetes mellitus, thyroiditis and myasthenia gravis). Other causes include sudden withdrawal of corticosteroids, granulomatous diseases (e.g. tuberculosis, cryptococcus, histoplasmosis), cytomegalovirus (particularly in AIDS patients), bilateral adrenal haemorrhage [e.g. retroperitoneal haemorrhage following trauma, ruptured aortic aneurysm, anticoagulants or disseminated intravascular coagulation in patients who have fulminant meningococcal (i.e. Waterhouse-Friderichsen syndrome), pneumococcal or Haemophilus septicaemia], bilateral adrenal thrombosis and infarction (e.g. antiphospholipid syndrome1,2,3), tumour metastases, sarcoidosis, fluconazole4 and ketoconazole (although the testosterone secretion is usually reduced more than cortisol secretion, and plasma cortisol levels are often normalised by a compensatory rise in ACTH secretion),5 and etomidate.6,7 Rifampicin induces the cytochrome P450 enzymes, and accelerates the metabolism of cortisol, which may precipitate an adrenal crisis early in the course of antituberculous chemotherapy.8 The adrenal disease must involve destruction to greater than 90% of the gland before signs and symptoms of hypoadrenalism appear. Secondary adrenocortical insufficiency 1. Long-term corticosteroid therapy Suppression of secretion of ACTH and atrophy of the adrenal cortex become progressively greater as the doses of glucocorticoids exceed physiological levels (e.g. a daily dose greater than 37.5 mg of hydrocortisone, 7.5 mg of prednisolone, or 2 mg of dexamethasone) and the longer the treatment is continued,9 although some patients may show adrenal suppression after only 5 days of corticosteroid therapy.10 The suppression is less if the steroid is given as a single dose in the morning (matching the circadian pattern) than when the dose is divided throughout the day, and almost normal adrenal responsiveness to ACTH may be maintained when up to 80 mg of prednisolone is given on alternate days.11,12 When a patient has been on glucocorticoids for prolonged periods, inhibition of hypothalamic-pituitary-adrenocorticoid function may persist for 12 months after treatment is withdrawn,13 which may lead to an adrenal crisis if the patient is subjected to ‘stress’ during this period.14 2. Pituitary dysfunction Post partum necrosis (i.e. Sheehan’s syndrome) or pituitary apoplexy may cause secondary adrenocortical insufficiency.

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Sheehan’s syndrome is caused by a sudden hypotensive post partum episode, causing a susceptible hypertrophied pituitary gland to develop ischaemic infarction. This disorder usually presents with pituitary insufficiency over a prolonged period and often requires hormonal replacement therapy. Pituitary apoplexy is an acute haemorrhagic infarction of a pituitary adenoma, which may present with sudden onset of a severe headache, visual loss, cranial nerve palsy, nausea, vomiting and depression of consciousness.15 The onset may be over minutes, causing death, or over 24 - 48 hr. Treatment may require neurosurgical decompression and hormonal replacement therapy.15

Clinical features The clinical features of hypoadrenalism caused by gradual adrenal destruction are usually insidious in onset. The symptoms include, salt craving, asthenia, malaise, weakness, fatigue, alteration in personality, depression, confusion, delirium, psychosis, anorexia, nausea, vomiting, diarrhoea, abdominal pain (which may be severe), arthralgias, fever (or pyrexia of unknown origin16) and weight loss. The signs include, postural and supine hypotension, vitiligo and flexural contractures. There is also an increased sensitivity to central nervous system depressant drugs including opioids. The patient who presents with an adrenal crisis may appear to be in ‘septic’ shock (with high cardiac output and decreased systemic vascular resistance, or low cardiac output with normal systemic vascular resistance) or hypovolaemic shock (with decreased preload, myocardial contractility and increased systemic vascular resistance),29 although the features of eosinophilia and hypoglycaemia are uncharacteristic of a ‘septic’ or ‘hypovolaemic’ event. The cardiovascular effects are probably secondary to a reduction in intravascular volume (due to vomiting and chronic salt waisting) and reduction in myocardial contractility and peripheral resistance due to a reduction in adrenoreceptor sensitivity to catecholamines.30 In primary adrenal insufficiency the ACTH levels rise causing hyperpigmentation due to the melanocyte-stimulating properties of ACTH. The areas of pigmentation occur at the elbows, belt-line, scars and hand creases. Longitudinal pigmentation of nails and bluish black patches of pigment on the buccal mucosa may also occur.17 Patients with primary ACTH deficiency are not hyperpigmented or hyperkalaemic because the melanocyte stimulating effect of excess ACTH is absent and aldosterone production and stimulation occurs via angiotensin II. Investigations These include: 1. Plasma biochemical tests. Hyponatraemia, hyperkalaemia (with a Na+:K+ ratio of < 25:1), hypoglycaemia, hypercalcaemia and renal tubular acidosis (type IV) are characteristic findings of primary adrenocortical insufficiency. 2. Complete blood picture. Eosinophilia, lymphocytosis and a normocytic anaemia (which may be masked by the decrease in plasma volume) may be present. 3. ECG. While hyperkalaemia may be severe (e.g. > 7 mmol/L) and associated with ECG changes, cardiac arrest from hyperkalaemia due to Addison’s disease has not been reported, probably due to the slow rise in plasma potassium and presence of hypercalcaemia. 4. Urine electrolytes. With primary adrenocortical insufficiency the urine sodium loss is greater than 40 mmol/L and potassium loss is usually less than 20 mmol/L. 5. Chest X-ray. Characteristically, the chest X-ray reveals a small heart. 6. Short synacthen test. This requires plasma cortisol levels to be measured before (i.e. baseline level), and at 30 and 60 min after 0.25 mg of synacthen is given intravenously or intramuscularly.8,18 The plasma cortisol level should increase to two or three times the basal

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level and be more than 500 ηmol/L with stimulation, if the adrenal cortex is responsive. In the critically ill patient the cortisol rise should be at least 250 ηmol/L. Typically the basal plasma cortisol levels are more than 200 ηmol/L rising to 500 ηmol/L after administering the synacthen. In Addison’s disease the baseline cortisol levels are often < 100 ηmol/L (if ACTH levels are also measured then they are usually > 200 ηg/L), and with stimulation the plasma cortisol does not rise.8 If secondary (i.e., pituitary) adrenocorticoid insufficiency is suspected (e.g. ACTH level < 10 ng/L), then 1 mg of synacthen is administered intramuscularly daily for three days, and 48 hr after the last dose a short synacthen test is performed.8 If hydrocortisone has been administered, the short synacthen test may be performed 24 hr after the last dose. In the critically ill patient impaired adrenocortical function may be determined better by the low-dose short synacthen test, where a plasma cortisol level < 500 nmol/L, 30 minutes after 1µg of synacthen indicates impaired adrenal reserve.19 A modification of this test, known as the low-dose corticotropin test (baseline plasma cortisol levels are taken before 1 µg synacthen is administered i.v., then plasma cortisol is taken 30 minutes later, with a normal response being defined as a stimulated plasma cortisol level > 550 nmol/L),20 has been used to detect partial adrenal insufficiency.21,22,23 7. Thyroid function studies. While treatment of myxoedema should include hydrocortisone to guard against the development of an adrenal crisis,24 patients with Addison’s disease may have an elevated TSH with low or normal thyroxine levels which are completely reversible with hydrocortisone therapy alone.25 8. Acute phase reactants. C-reactive protein and the non specific serum marker procalcitonin have been used to differentiate septic shock from Addisonian shock (i.e. both are elevated in the former and are within normal limits in the latter).26 9. CT scan. CT scanning of the adrenal glands may reveal adrenal haemorrhage or carcinomatous infiltration. Treatment The management of the patient depends on whether the patient has a non-‘crisis’ hypoadrenalism or an adrenal ‘crisis’. 1. Non-‘crisis’ hypoadrenalism. The treatment of an acute episode of hypoadrenalism in the absence of hypotension is oral cortisone varying from 12.5 to 50 mg daily, with the average dose usually being 37.5 mg daily (e.g. 25 mg in the morning and 12.5 mg in the evening, with meals, although 12.5 mg with all three meals, may reduce the mid-afternoon trough, and improve the sense of well-being).27 Fludrocortisone 0.05 - 0.1 mg is often administered as well. During an intercurrent illness the cortisone dose is increased to 75 - 150 mg daily. The patient is monitored and assessed clinically (e.g. sense of well-being, arthropathy, temperature) and by the plasma potassium, blood pressure and clinical signs of oedema. 2. Adrenal ‘crisis’. An acute adrenal insufficiency or adrenal ‘crisis’ is a life-threatening episode following an acute ‘stress’ event (e.g. trauma, infection, burns, surgery), in a patient who has insufficient glucocorticoid and mineralocorticoid reserve. The ‘crisis’ follows the acute event by presenting with vomiting, hypotension, pyrexia (even rigors), hyperkalaemia, hypoglycaemia and shock resistant to fluid and sympathomimetic amines. Treatment involves resuscitation with intravenous 0.9% saline, 1 - 2 L over 2 - 4 hr (which may require right heart catheter and arterial monitoring), thereafter the fluid regimen is governed by cardiovascular status. Hydrocortisone 100 mg is usually administered intravenously as a loading dose, followed by 300 mg/day (e.g. 50 mg intravenously 4-hourly). The hydrocortisone may be reduced to 50 - 100 mg over the next 1 - 3 days. If hypoglycaemia

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exists then 50 mL of 50% dextrose solution is infused over 3 min. The hyperkalaemia usually does not require specific therapy. Because the concentration of cortisol in the blood during maximum stress is less than 2750 ηmol/L (i.e., 100 µg/dL) and the daily production of cortisol is 200 mg and as cortisol distributes in the ECF, has a half-life of 90 min and a clearance rate of 200 L/day, theoretically a loading dose of 10 mg followed by an infusion of 8 - 10 mg/hr (i.e. 200 mg in 24 hr) is all that is required for hormone replacement during acute stress. 3. Steroid replacement in patients undergoing major surgery. In patients who have been on long term corticosteroid therapy, large and complex regimens are usually recommended for intraoperative and postoperative steroid replacement. However, with excess replacement there is an increased susceptibility to infection, impaired wound healing and decrease in glucose tolerance.28 The normal adrenocortical response due to major surgery is a cortisol secretion of 75 - 150 mg/24 hr.29 For major surgery the hydrocortisone required to prevent adrenal insufficiency is 25 mg as an intravenous bolus, at the induction of anaesthesia, followed by 100 mg as an intravenous infusion during the next 24 hr, which is then followed by the patients normal maintenance dose.29,30,31 4. Withdrawal of corticosteroid treatment. If the patient has been treated with a morning dose of prednisolone for 7 - 10 days, withdrawal of treatment may be rapid. If corticosteroids have been used for many years as an anti-inflammatory agent, then the disease activity may be monitored by using C-reactive protein or ESR as the prednisolone is withdrawn by 2.5 mg every 1 - 3 weeks. Once the dose of prednisolone is 10 mg or less, the dose reduction may be by increments of 1 mg amounts. The function of the adrenal cortex may also be assessed by the short synacthen test.32 CUSHING’S SYNDROME Cushing’s syndrome is caused by pituitary ACTH overproduction in 70% (i.e. Cushing’s disease which usually caused by a pituitary microadenoma), ectopic ACTH overproduction in 15% (often associated with a small cell carcinoma of the lung), adrenal tumours in 15% and ectopic CRH overproduction in < 1% of cases.33,34 Excessive exogenous glucocorticoid administration can also cause Cushingoid features. Pseudo-Cushing’s syndrome (i.e. patients who have clinical features similar to glucocorticoid excess) may occur in chronic alcoholism, COPD, obesity and chronic depression. Clinical features Glucocorticoid excess is characterised by muscle weakness (i.e. proximal myopathy), central distribution of adipose tissue (e.g. ‘moon’ facies, ‘buffalo’ hump, and ‘lemon on toothpicks’ obesity), hypertension, purple striae, hirsutism, oedema, glucose intolerance, amenorrhoea, osteoporosis, fatigue, bruising, cataracts and psychiatric problems.17 Glucocorticoid excess from ectopic ACTH production due to a rapidly growing tumour (e.g. small cell carcinoma of the lung) usually presents with rapid onset of hypertension, pigmentation, hypokalaemia, weight loss and muscle weakness. Whereas ectopic ACTH production from a slowly growing tumour (e.g. thymic, pancreatic, or ovary carcinoma, medullary carcinoma of the thyroid or bronchial adenoma) usually presents with a classical Cushing’s syndrome.33 Investigations These include: 1. Urinary ‘free’ cortisol. A 24 hr urinary ‘free’ cortisol measures the amount of cortisol that is unbound (and hence active and filtered by the kidney) over a 24 hr period. This test reflects hypercortisolism, although it may also be positive in patients with ‘stress’ and

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depression, and may be falsely negative in up to 15% of patients with hypercortisolism35 and in patients with renal failure.36 It is a useful screening test and a level greater than 275 ηmol/day (i.e., 100 µg/day) is an indication for a dexamethasone suppression test. 2. Dexamethasone suppression test. This test is performed by measuring the plasma cortisol at 08.00 hr after the oral administration of 1 mg of dexamethasone at 24.00 hr the night before. Normally the plasma cortisol will be suppressed below 100 ηmol/L (i.e. 3.6 µg/dL). Borderline values are between 100 and 150 ηmol/L (i.e. 3.6-5.4 µg/dL) and abnormal values are greater than 150 ηmol/L (5.4 µg/dL). While, depression, alcohol abuse, stress, oral contraceptives or anticonvulsants, and 20 - 35% of obese patients, may register a nonsuppressed result (i.e. the test has a low specificity), the test has a 95% sensitivity.37 A high-dose dexamethasone suppression test may be performed (i.e. 2 mg 6-hourly for 2 days) to maximally suppress the hypothalamic-pituitary-adrenocorticoid function. In the critically ill patient, suppressability of the adrenal cortex is unachievable,38 and thus the dexamethasone suppression test cannot be used to diagnose hypercortisolism in these patients. The diagnosis of Cushing’s syndrome in a critically ill patient has to await for the acute illness to be corrected. Dexamethasone will supress cortisol production in the rare ectopic ACTH syndrome.33 3. ACTH. After confirming Cushing’s syndrome, the next step is to detect whether corticotropin is detectable in plasma (e.g. adrenal adenoma or carcinoma supresses ACTH secretion whereas ACTH is readily detectable in Cushing’s disease and the ectopic ACTH syndrome). 4. CRH test. Plasma ACTH increases by 50% in most patients with Cushing’s disease (c/f a lower response with patients with the ectopic ACTH syndrome). 5. CT scan. CT scanning of the adrenal glands may confirm adrenal hyperplasia or an adenoma.36 6. MRI scan. High resolution MRI scanning may be required to detect a pituitary ACTH secreting microadenoma. 7. Bilateral inferior petrosal sinus ACTH levels. This is a highly specialised (and sensitive test) to determine whether or not the source of ACTH is the pituitary, and is useful when imaging is negative. A central to peripheral plasma ACTH gradient is found in Cushing’s disease (both before and after CRH) but not in the ectopic ACTH syndrome.39 Treatment Microadenomas are resected by trans-sphenoidal microsurgery. Adrenal adenomas and adrenal hyperplasia may be corrected by surgical excision.

REFERENCES 1 Dorling A, Knowles GK. Antiphospholipid syndrome and acute adrenal insufficiency. R

Soc Med 1991;84:560. 2 Yap AS. Lupus anticoagulant. Ann Intern Med 1989;111:262-263. 3 Asherson RA, Hughes GRV. Recurrent deep vein thrombosis and Addison's disease in

primary' antiphospholipid syndrome. J Rheumatol 1989;16:378-380. 4 Gradon JD, Sepkowitz DV. Fluconazole-associated acute adrenal insufficiency. Postgrad

Med 1991;67:1084-1085. 5. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med

1987;317:812-818. 6. Fellows IW, Bastow MD, Allison SP. Adrenocortical suppression in multiply injured

patients: a complication of etomidate treatment. Br Med J 1983;287:1835-1837. 7. Ledingham IMcA, Watt I. Influence of sedation on mortality in critically ill multiple

trauma patients. Lancet 1983;i:1270.

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8. Clayton RN. Diagnosis of adrenal insufficiency. Br Med J 1989;298:271-272. 9. Livanou T, Ferriman D, James V. Recovery of hypothalamo-pituitary-adrenal function

after corticosteroid therapy. Lancet 1967;ii:856-859. 10. Spiegel RJ, Vigersky RA, Oliff AI, Echelberger CK, Bruton J, Poplack DG. Adrenal

suppression after short-term corticosteroid therapy. Lancet 1979;i:630-633. 11 Fauci AS. Alternate-day corticosteroid therapy. Am J Med 1978;64:729-731. 12. Harter JG, Reddy WS, Thorn GW. Studies on an intermittent corticosteroid dosage

regimen. N Engl J Med 1963;269:591-595. 13. Axelrod L. Glucocorticoid therapy. Medicine 1976;55:39-65. 14. Salassa RM, Bennett WA, Keating FR Jr, Sprague RG. Postoperative adrenal cortical

insufficiency occurrence in patients previously treated with cortisone. JAMA 1953;152:1509-1515.

15. Vance ML. Hypopituitarism. N Engl J Med 1994;330:1651-1662. 16. Page RCL, Alford F. Adrenocorticosteroid deficiency: an unusual cause of fever of

unknown origin. Postgrad Med 1993;69:395-396. 17. Kannan CR. Diseases of the adrenal cortex. Dis Mon 1988;34:601-674. 18. Oelkers W. Adrenal insufficiency. N Engl J Med 1996;335:1206-1212. 19. Thaler LM, Blevins LS Jr. The low dose (1-microg) adrenocorticotropin stimulation test

in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998;83:2726-2729.

20. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773-778.

21. Broide J, Soferman R, Kivity S, Golander A, Dickstein G, Spirer Z, Weisman Y. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995;80:1243-1246.

22. Tordjman K, Jaffe A, Grazas N, Apter C, Stern N. The role of the low dose (1 microgram) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995;80:1301-1305.

23. Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet 2000;355:542-545.

24. Fonseca V, Brown R, Hochhauser D, Ginsburg J, Havard CWH. Acute adrenal crisis precipitated by thyroxine. Br Med J 1986;292:1185-1186.

25. Davis J, Sheppard M. Acute adrenal crisis precipitated by thyroxine. Br Med J 1986;292;1595.

26. Hatherill M, Jones G, Lim E, Tibby SM, Murdoch IA. Procalcitonin aids the diagnosis of adrenocortical failure. Lancet 1997;350:1749.

27. Groves RW, Toms GC, Houghton BJ, Monson JP. Corticosteroid replacement therapy: twice or thrice daily?. J Roy Soc Med 1988;81:514-516.

28. Dujovne CA, Azarnoff DL. Clinical complications of corticosteroid therapy. A selected review. Med Clin N Am 1973;57:1331-1342.

29. Symreng T, Karlberg BE, Kagedal B, Schildt B. Physiological cortisol substitution of long-term steroid-treated patients undergoing major surgery. Br J Anaesth 1981;53:949-954.

30. Kehlet H. A rational approach to dosage and preparation of parenteral glucocorticoid substitution therapy during surgical procedures. Acta Anaesthiol Scand 1975;19:26-29.

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31. Kehlet H, Binder C. Adrenocortical function and clinical course during and after surgery

in unsupplemented glucocorticoid-treated patients. Br J Anaesth 1973;45:1043-1049. 32. Editorial. Corticosteroids and hypothalamic-pituitary-adrenocortical function. Br Med J

1980;1:813-814. 33 . Orth DN. Cushing’s syndrome. N Engl J Med 1995;332:791-803. 34. McHardy KC. Suspected Cushing's syndrome. Br Med J 1984;289:1519-1521. 35. Newell-Price J, Grossman A. Diagnosis and management of Cushing’s syndrome. Lancet

1999;353:2087-2088. 36. Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med

1990;112:434-444. 37. Invitti C, Giraldi FP, de Martin M, Cavagnini F. Diagnosis and management of Cushing's

syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis.J Clin Endocrinol Metab 1999;84:440-448.

38. Perrot D, Bonneton A, Dechaud H, Motin J, Pugeat M. Hypercortisolism in septic shock is not suppressible by dexamethasone infusion. Crit Care Med 1993;21:396-401.

39. Boscaro M, Barzon L, Fallo F, Sonino N. Cushing’s syndrome. Lancet 2001;357:783-791.

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17

Chapter 3

NORMAL THYROID FUNCTION AND EFFECTS OF CRITICAL ILLNESS NORMAL THYROID FUNCTION The thyroid hormones 3,5,3-triiodo-L-thyronine (T3) and L-thyroxine (T4) increase oxygen consumption (by stimulating Na/K-ATPase and activating mitochondrial metabolic pathways), regulate lipid and carbohydrate metabolism, and are necessary for normal growth and maturation of tissues.1,2 Thyroid function is controlled by thyroid-stimulating hormone (TSH) which in turn is controlled by thyrotropin releasing hormone (TRH). Thyrotropin releasing hormone The major function of TRH is to release TSH from the adenohypophysis. However, TRH is also found in the neurohypophysis, brain, brainstem, medulla, spinal cord, pancreas, gastrointestinal tract, adrenal and placenta, and can act as a partial opioid antagonist and inhibit pancreatic secretion. It has also been used to improve motor function in spinocerebellar degeneration and motor neurone disease, and to reduce mortality in experimental shock and limit the neurological deficit in spinal trauma.3,4 Thyroid stimulating hormone TSH is released from the adenohypophysis in response to TRH and the negative feedback effects of T3 and T4. Somatostatin (and octreotide), glucocorticoids and dopamine also inhibit TSH release. By binding to specific thyroid follicular cell surface receptors and activating adenylate cyclase, TSH stimulates synthesis and release of T3 and T4. Thyroid hormones The principle thyroid hormones are T3 and T4, which are synthesised in the colloid of the thyroid gland and bound to thyroglobulin until they are excreted into the circulation as free T3 (FT3) and free T4 (FT4). The normal daily thyroid secretion consists of approximately 100 ηmol (78 µg) of T4 [35 ηmol (27 µg) of which is converted to T3 and 45 ηmol (35 µg) of which is converted to rT3], 5 ηmol (4 µg) of T3 and 2.5 ηmol (2 µg) of rT3. As T3 has approximately 3 times the potency of T4, and as 87% of the circulating T3 is formed from peripheral tissue conversion of T4, virtually all of the action of T4 is due to the T3 it gives rise to,5 indicating that T4 functions largely as a circulating thyroid hormone store. Approximately 45% of T4 is converted to reverse T3 (rT3) which has little if any metabolic potency. With systemic illness, malnutrition and with propylthiouracil, propranolol, glucocorticoids and amiodarone therapy, the peripheral conversion of T4 to T3 is decreased and plasma rT3 is increased (both of which are caused by an inhibition of the peripheral 5-monodeiodination). The biological half lives of T4 and T3 are 7 days and 24 hr, respectively. Thyroid hormones circulate either free or bound to thyroxine-binding globulin (TBG), thyroxine binding prealbumin and albumin. Approximately 99.98% of the circulating T4 is bound (70% to TBG, 20% to thyroxine binding prealbumin and 10% to albumin) and 99.8% of

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the circulating T3 is bound (50% to TBG, 50% to albumin, and minimal amounts to thyroxine-binding prealbumin). Only 0.02% of the circulating T4 is free and 0.2% of T3 is free. The free thyroid hormone is the active form. Measurement of total plasma T4 or T3 may be altered due to alteration of the amount of bound thyroid hormone without altering the FT3 or FT4 levels. THYROID FUNCTION TESTS Plasma TSH Using two specific monoclonal antibodies, the ultrasensitive TSH assay has improved the sensitivity of the TSH assay to the extent that both hypo- and hyperthyroid states may be discriminated from the euthyroid state. However, an undetectable TSH concentration is compatible with and not diagnostic of hyperthyroidism because it may occur in hypopituitarism, euthyroid patients in the first trimester of pregnancy, early phase of treatment of hyperthyroidism (the TSH may remain suppressed for up to 6 months despite low circulating thyroxine levels) and in patients being treated with dopamine, dobutamine or corticosteroids.6,7 Plasma values may be taken during any time of the day. The normal, upper borderline, lower borderline, and levels diagnostic of primary thyrotoxicosis and hypothyroidism, are listed in Table 3.1. In pituitary (i.e. secondary) hypothyroidism, the circulating TSH levels are low relative to the circulating FT4 levels. The TSH levels are suppressed by adequate T4 replacement in patients with primary hypothyroidism, but 8 weeks should be allowed after changing the dosage of T4 to allow adequate equilibration of thyroxine with tissues before measuring TSH levels. TRH stimulation test This test is usually performed to confirm the presence of thyrotoxicosis. Following the intravenous infusion of TRH, the TSH increases and reaches a peak within 20 - 45 min then rapidly declines. In hyperthyroidism (or pituitary hypothyroidism) the response is blunted. While the response may be augmented in primary hypothyroidism the response is not consistent.8 Total T4 The total T4 measurement includes the protein bound as well as the FT4 fraction, and is subject to false interpretation of thyroid status when there are abnormalities of thyroid binding proteins. For example, an increase in TBG occurs during pregnancy, oral contraceptive treatment, hepatitis and biliary cirrhosis, and a decrease in TBG occurs with androgen treatment, corticosteroid treatment, chronic liver disease and severe systemic illness, all of which may alter the total T4 levels in the absence of thyroid disease. Free thyroxine The FT4 assay is a radioimmunoassay that uses a T4 tracer to measure the plasma non-protein bound T4. The free hormone concentrations correlate better with the metabolic state, and should always be used to assess thyroid status. It is often performed as a second-line test, to investigate an abnormal plasma TSH level. The normal, upper borderline, lower borderline, and levels diagnostic of thyrotoxicosis and hypothyroidism are listed in Table 3.1. In early primary hypothyroidism, the TSH is a more sensitive test than the plasma FT4, which may be within the normal range. Patients who are on adequate thyroxine replacement therapy have plasma T4 levels which are slightly higher than normal (i.e. 16 - 32 ρmol/L).

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Table 3.1 Free thyroid hormone plasma levels Primary Lower Normal Upper Primary hypothyroid borderline borderline hyperthyroid TSH (mU/L) > 4.5 0.2 - 0.4 0.5 - 3.5 3.6 - 4.5 < 0.2 Free T4 (pmol/L) < 8 8 - 12 13 - 23 24 - 26 > 26 Free T3 (pmol/L) 4 - 8 8.1 - 10 > 10 Free triiodothyronine The FT3 assay is a radioimmunoassay that uses a T3 analogue tracer to measure the plasma non-protein bound T3 fraction. While elevated levels confirm thyrotoxicosis, the FT3 estimation is not a useful test to detect hypothyroidism because low levels only occur late in the disease. Other tests For thyroid masses, ultrasonography is usually performed first to detect whether the enlargement is cystic, solid or multinodular. If it is solid, a radionuclide scan is performed. If a solitary ‘cold’ lesion is found, the mass is biopsied. The radionuclide scan will also detect ‘hot’ nodules and metastatic deposits. If the lesion is multinodular, serum autoantibodies (e.g. antithyroglobulin, antithyroid microsomal antibodies and thyroid-stimulating antibodies) are measured. A CT is performed if a thoracic inlet syndrome due to thoracic extension of the thyroid is suspected. THYROID FUNCTION IN NONTHYROIDAL ILLNESS Euthyroid sick syndrome In patients who have a severe nonthyroidal illness, the TSH level decreases (the degree of which is related to the severity of the illness9) and returns to normal within 24 - 48 hr. There is a decrease in FT3 and increase in rT3 which is caused by an inhibition of peripheral 5-monodeiodination (due to an increased cortisol level10 and starvation11) which reduces the peripheral conversion of T4 to T3 and decreases the clearance of plasma rT3. The FT4 levels are low or normal and the plasma half-life of T4 is reduced from 7 days to 1 - 5 days.28 The euthyroid state is maintained in the presence of a reduction in FT3 levels due to an increase in synthesis of tissues T3 receptors.12 Protein binding for T4 and T3 is also reduced in acute nonthyroidal illness, contributing to the reduction in total T4 and T3 levels. During the recovery phase of the illness, there is often a transient elevation in the TSH level until the FT4 and FT3 levels are returned to normal.13,14 Generally, abnormal thyroid function studies in an acutely ill patient (or during starvation) without clinical signs of thyroid disease should not be treated (as there are no studies that have shown a reduction in mortality with thyroid hormone treatment),15 but should be reviewed after the acute illness has resolved.28 While plasma rT3 is usually elevated in ‘euthyroid sick syndrome’ and unmeasurable in hypothyroid sick patients the plasma rT3 level has not been found to differentiate reliably between the two disorders.16 Euthyroid hyperthyroxinaemia This condition is characterised by high levels of total T4 and FT4, and high, normal or low levels of FT3, in the absence of clinical signs of hyperthyroidism. It is associated with increased T4 binding and peripheral thyroid-hormone resistance and is caused by drugs that inhibit T3 formation (e.g. amiodarone, propranolol, cholecystographic contrast agents), heparin, L-

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thyroxine therapy, acute psychiatric illness or stress, hyperemesis gravidarum, lead poisoning and hyponatraemia.17,18,19,20

REFERENCES 1. Sterling K. Thyroid hormone action at the cell level (First of two parts). N Engl J Med

1979;300:117-123. 2. Sterling K. Thyroid hormone action at the cell level (Second of two parts). N Engl J Med

1979;300:173-177. 3. Editorial. Extrathyroidal actions of TRH. Lancet 1984;ii:560-561. 4. Griffiths EC. Clinical applications of thyrotropin-releasing hormone. Clin Sci

1987;73:449-457. 5. Cavalieri RR, Rapoport B. Impaired peripheral conversion of thyroxine to

triiodothyronine. Ann Rev Med 1977;28:57-65. 6. Editorial. Sensitivity thyrotropin measurements: utility and futility. Lancet 1989;i:1176. 7. Dayan CM. Interpretation of thyroid function tests. Lancet 2001;357:619-624. 8. Bethune JE. Interpretation of thyroid function tests. Dis Mon 1989;35:541-596. 9. Rothwell PM, Udwadia ZF, Lawler PG. Thyrotropin concentration predicts outcome in

critical illness. Anaesthesia 1993;48:373-376. 10. Zaloga GP, Chernow B, Smallridge RC, Zajtchuk R, Hall-Boyer K, Hargraves R, Lake

CR, Burman KD. A longitudinal evaluation of thyroid function in critically ill surgical patients. Ann Surg 1985;201:456-464.

11. Tibaldi JM, Surks MI. Effects of nonthyroidal illness on thyroid function. Med Clin N Amer 1985;69:899-911.

12. Williams GR, Franklyn JA, Neuberger JM, Sheppard MC. Thyroid hormone receptor expression in the "sick euthyroid" syndrome. Lancet 1989;ii:1477-1481.

13. Hamblin FS, Dyer SA, Mohr VS, Le Grand BA, Lim c-F, Tuxen DV, Topliss DJ, Stockigt JR. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinaemia of critical illness. J Clin Endocrinol Metab 1986;62:717-722.

14. Bacci V, Schussler GC, Kaplan TB. The relationship between serum triiodothyronine and thyrotropin during systemic illness. J Clin Endocrinol Metab 1982;54:1229-1235.

15. McIver B, Gorman CA. Euthyroid sick syndrome: an overview. Thyroid 1997;7:125-132. 16. Burmeister LA. Reverse T3 does not reliably differentiate hypothyroid sick syndrome

from euthyroid sick syndrome. Thyroid 1995;5:435-441. 17. Stockigt JR, Barlow JW. The diagnostic challenge of euthyroid hyperthyroxinaemia. Aust

NZ J Med 1985;15:277-284. 18. Cogan E, Abramow M. Transient hyperthyroxinaemia in symptomatic hyponatremic

patients. Arch Intern Med 1986;146:545-547. 19. Tiwari I, Timms P, Rothe P. Lead poisoning and euthyroid hyperthyroxinaemia. Lancet

1985;i:1508-1509. 20. Jackson JA, Verdonk CA, Spiekerman AM. Euthyroid hyperthyroxinaemia and

inappropriate secretion of thyrotropin. Recognition and diagnosis. Arch Intern Med 1987;147:1311-1313.

21

Chapter 4

THYROID DISORDERS SIMPLE (NONTOXIC) GOITRE This is any enlargement of the thyroid gland, due to hypertrophy and hyperplasia, which is not the result of a neoplastic or inflammatory process and is not initially associated with myxoedema or thyrotoxicosis. The thyroid hypertrophy may be caused by excessive thyroid stimulation due iodine deficiency, ingestion of a goitrogen or a defect in the hormone biosynthetic pathway, although often the cause is unknown. Clinical features The thyroid-hormone profile is usually normal and the clinical manifestations, commonly due to the mechanical effects of the enlarged gland, include compression and displacement of the trachea or oesophagus, superior mediastinal obstruction, superior vena cava syndrome (may be associated with a positive Pemberton’s sign, i.e. raising hands above the head causes, facial suffusion, giddiness and syncope).1 Hoarseness due to recurrent laryngeal nerve damage is rare and suggests carcinoma. Investigations These include: 1. Thyroid function studies. These are performed to identify patients who may have toxic multinodular goitre. 2. CT scan. This is performed to identify the extent of thyroid enlargement (and whether there is intrathoracic extension, tracheal compression). 3. Fine needle aspiration. If a solitary nodule exists, then a fine needle aspiration is the test of choice.2 Treatment Thyroid hyperplasia is treated by reducing thyroid stimulation (i.e. reducing TSH secretion). If iodine deficiency or a specific goitrogen can be identified these abnormalities are corrected. Often no cause can be found and L-thyroxine 100 µg daily is administered, with the dose increasing over 4 - 8 weeks to a maximum of 150 - 200 µg/day. The gland should regress within 3 - 6 months of complete suppression of TSH (i.e. TSH level < 0.1 mU/L by an ultrasensitive assay). However, before thyroxine is administered, an ultrasensitive TSH level should be performed. If the TSH is less than 0.1 mU/L and a TRH stimulation test indicates functional autonomy of the thyroid gland, thyroxine administration will be of no benefit and the disorder is likely to be a toxic multinodular goitre. Treatment for the latter requires avoidance of iodine and either surgery (e.g. subtotal or total thyroidectomy) or high dose 131I. HYPOTHYROIDISM Myxoedema is a term applied to chronic hypothyroidism associated with a thickening of skin about the eyes, dorsum of hands and supraclavicular fossa, caused by an increased amount of hydrophilic polysaccharides, hyaluronic acid and chondroitin sulphate in the ground

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substance of the dermis. Approximately 95% of hypothyroid patients have a primary hypothyroid disorder, the remaining 5% are secondary to pituitary or hypothalamic hypofunction. Aetiology Primary hypothyroidism may be caused by a congenital abnormality, autoimmune thyroiditis, postablative defect (e.g. surgical removal, radioiodine ablation) or goitrous defect (e.g. hereditary, iodine deficiency, lithium, amiodarone). Clinical features The clinical features include bradycardia, atrial fibrillation, hypotension, (cardiogenic shock responsive to triiodothyronine has even been reported),3 hypothermia (sometimes missed unless a ‘low reading’ thermometer is used), fatigue, lethargy, constipation, intolerance to cold (with erythema ab igne of legs), stiffness and cramping of muscles, rhinorrhoea, deafness, slowing of motor activity, increase in weight, carpal tunnel syndrome, menorrhagia, dry and icteric skin (the latter is due to hypercarotinaemia, n.b. sclera are not icteric), thickening about the eyes and dorsum of the hands (i.e. myxoedema), hyperkeratosis over elbows and knees, and hair which is dry and brittle. In the elderly patient, the features may be incorrectly attributed to depression or Alzheimer’s disease. The facial features become thickened the expression is dull and lifeless, the lateral third of the eyebrows may be absent, there may be thinning of the scalp hair (also thininning of the axillary and pubital hair), periorbital puffiness, a large tongue, pale cool skin, and the voice becomes deep and hoarse. Cerebellar ataxia, obstructive sleep apnoea and hypoventilation may also occur. The heart may be enlarged due to both dilation and pericardial effusion, the abdomen may protrude due to an adynamic ileus and, rarely, psychiatric symptoms (e.g. myxoedema madness) develop. The relaxation phase of deep tendon reflexes are characteristically prolonged (i.e. ‘hung up’) although this may also occur with hypothermia and myotonia. Investigations These include: 1. Plasma biochemistry. Hypercholesterolaemia, hyponatraemia, hypermagnesaemia, hypoglycaemia and increased CPK, LDH and AAT may be found. 2. Complete blood picture. A normocytic anaemia may occur. Approximately 12% of patients have pernicious anaemia. 3. ECG. Bradycardia, atrial fibrillation, low voltage QRS complexes, prolonged QTc, with generalised flattening or inversion of T waves may be found. In the event of severe hypothermia, J (Osborne) waves may also be present. 4. Arterial blood gases. Hypercapnia and hypoxia may be found in patients who have alveolar hypoventilation. 5. Thyroid function tests. The TSH is characteristically elevated (unless pituitary hypothyroidism exists) to levels above 20 mU/L and the FT4 and FT3 levels are low. Elevation of the TSH to levels of 5-10 mU/L with normal circulating levels of FT4 may represent a diminished thyroid reserve or ‘subclinical’ hypothyroidism.'4 These patients are often followed up with 6 to 12-monthly thyroid function tests, with commencement of T4 replacement therapy if the TSH doubles from its previous level.8 Treatment

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Management of the hypothyroid patient depends upon whether the patient has non life-threatening hypothyroidism, hypothyroidism with angina or myxoedema coma. Non life threatening hypothyroidism. Oral thyroxine 25 µg is administered daily and increased by 25 µg increments at 3 week intervals. The daily dose is administered as a single dose and usually increased until the symptoms resolve, the TSH and FT3 return to normal limits, and the FT4 is at the upper limit of normal (i.e. 16 - 32 ρmol/L), which usually occurs at a daily dose of 1.8 µg/kg of thyroxine (i.e. 100 - 200 µg/day).5,6 If the TSH is elevated, the dose is often insufficient. If the FT3 is elevated the dose may be excessive. Patients who are on adequate thyroxine replacement therapy often have plasma FT4 levels which are slightly higher than normal (i.e. 16 - 32 ρmol/L) and TSH values lower than normal (i.e. 0.05 - 0.2 mU/L). However, suppression of TSH for prolonged periods should be avoided because of potential adverse effects on morbidity (bone density, atrial fibrillation, dementia) and mortality.8 Currently, it is recommended that the thyroxin dose be adjusted to maintain a normal plasma thyrotropin concentration.7 Indications for reducing the dose are new atrial fibrillation, accelerated loss of bone density, amenorrhea, tiredness, diarrhoea, palpitations or borderline high T3 concentrations.8 If the patient is unable to take oral thyroxine, then intravenous T3 is administered, as a loading dose of 10 µg followed by an infusion of 20 µg/day. The total daily dose of T3 ranges from 30 - 50 µg/day. The patients thyroid status is assessed by measuring the TSH and FT3, or TSH only in acutely ill patients. Hypothyroidism with angina. Hypothyroid patients with angina should be treated with thyroxine because angina improves in the majority of patients rather than worsens.9,10 In the event of worsening angina during treatment, heparin should be administered and coronary artery angiography and angioplasty or coronary artery bypass surgery may be required before the hypothyroid state can be corrected.11 Myxoedema coma. If myxoedema is poorly controlled or remains undiagnosed, the patient may progress to become somnolent or unconscious, particularly if hypnotics or opioids are administered, or in the event of trauma, cerebral vascular accident, surgical operation, hypothermia, infection or hyponatraemia.1 Treatment requires: 1. Resuscitation. If the patient is hypotensive, intravenous therapy and inotropic agents may be required, monitored with right heart and arterial pressure measurements. Infection requires appropriate antibiotics, and respiratory failure may require endotracheal intubation and careful mechanical ventilation because excessive ventilation will produce severe alkalosis and exacerbate the hypotension. Hypoglycaemia is treated with intravenous dextrose (50 mL of 50% dextrose) and monitored with 2- to 4-hourly blood glucose measurements. Hypothermia is managed by passive warming techniques. If the core temperature is less than 30°C active warming may be undertaken until the core temperature is 33 - 35°C. 2. Thyroid hormone replacement. Because thyroxine has a long biological half-life (i.e. 7 days c.f. 24 hr for T3), requires peripheral conversion to T3 (which is inhibited by systemic illness - see ‘euthyroid sick syndrome’) and excessive dosages may precipitate myocardial ischaemia or infarction12,13, even in the presence of normal coronary arteries;14 T3 is used for urgent thyroid hormone replacement. Experimentally, T3 has been shown to reduce postischaemic dysfunction,15 and while high doses of T3 (e.g. 0.8 µg/kg i.v.) used in the postoperative cardiothoracic bypass patient have not improved surviival it does not increase the risk of ischaemic myocardial damage.16,17

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Urgent thyroid hormone replacement is achieved by administering 10 µg of T3 as a bolus, (which has an onset time of 0.5 - 3 hr) followed by an infusion of 20 µg/day and increasing to 30 - 40 µg /day (using a 5% albumin as the T3 carrier) and monitored with FT3, TSH levels, ECG and haemodynamic measurements. The additional administration of 100 mg of T4 is also recommended by some to saturate the large number of unsaturated binding sites.18 3. Hydrocortisone: this is administered as an intravenous infusion (e.g. 200 mg/day), because an acute adrenal crisis may be precipitated by thyroxine treatment in hypothyroid patients.19 THYROTOXICOSIS Aetiology Hyperthyroidism may be caused by, Grave’s disease, toxic multinodular goitre, toxic uninodular goitre (i.e. adenoma), thyroiditis, excess thyroxine administration (i.e. factitious), drug induced (e.g. amiodarone, iodine, radiocontrast agents, lithium), pituitary TSH adenoma, ectopic TSH production (e.g. chorioncarcinoma, testicular carcinoma) or thyroid carcinoma.20 Graves disease. This has three major manifestations: hyperthyroidism with diffuse goitre, dermopathy and opthalmopathy. Any one of these may appear separately. It is caused by excess thyroid stimulation due to a circulating IgG immunoglobulin that attaches to the TSH receptor on the thyroid cell membrane. The disease is associated with other autoimmune diseases (e.g. pernicious anaemia, insulin-dependent diabetes, Addison’s disease and myasthenia). The hyperthyroidism of Grave’s disease is characterised by phases of exacerbation and remission, with the disease often leading to progressive thyroid failure and hypothyroidism.21 Toxic multinodular goitre. This is often seen in the elderly patient who has a long history of goitre and is the result of an autonomous thyroid nodule. The onset of thyrotoxicosis is often subtle, and may present with resistant atrial fibrillation and myopathy (i.e. as an ‘apathetic’ thyrotoxicosis). Clinical features The symptoms include agitation, emotional lability, insomnia, increased appetite, weight loss, loose stools, vomiting, excessive sweating, heat intolerance, hairloss, pruritus, undue fatigue, proximal myopathy (e.g. difficulty in rising from a chair, climbing stairs or keeping a leg extended), dyspnoea, palpations, gynaecomastia and amenorrhoea. The signs include palmar erythema, warm moist skin, soft finger pulps (acropachy) clubbing, onycholysis (separation of nail from its bed, particularly the distal portion of the ring finger), pretibial myxoedema (i.e. raised violaceous induration of skin overlying the pretibial area and dorsum of feet in patients with Grave's disease; it may rarely appear on the dorsum of hands and face as peau d’orange), tachycardia, atrial fibrillation, wide pulse pressure, high output cardiac failure, fine tremor, hyperreflexia, proximal myopathy (with a ‘duck waddle’ walk), periodic paralysis, myasthenia, diffuse goitre, and thyroid bruit. In Grave’s disease there are also characteristic ocular signs of: - Sympathetic overstimulation (e.g. widened palpebral fissure, stare, lid lag, failure to wrinkle

brow with upward gaze, tremor of lightly closed lids) - Opthalmoplegia (e.g. inability to gaze upward and outward, failure to converge, proptosis) - Congestive occulopathy (e.g. chemosis, conjunctivitis, periorbital swelling, corneal

ulceration) - Other manifestations (e.g. optic neuritis, optic atrophy, enlarged lacrimal glands).

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Apathetic thyrotoxicosis is a rare clinical presentation of thyrotoxicosis; it usually occurs in an elderly patient and cardiac failure, rapid and resistant atrial fibrillation and severe myopathy dominate the clinical picture. Subclinical hyperthyroidism (e.g. normal plasma thyroid hormone levels and low thyrotropin levels) is associated with an increased incidence of atrial fibrillation22 and increased all cause mortality.23 Investigations These include: 1. Plasma biochemistry. Hypokalaemia, hypercalcaemia, hypomagnesaemia, increased alkaline phosphatase, hyperglycaemia, renal tubular acidosis (type I), and hyperbilirubinaemia often occur.24,25 2. Complete blood picture. A mild leucocytosis may be present. 3. Thyroid function studies. The plasma TSH is unrecordable and unresponsive to TRH stimulation, and the FT3 and FT4 levels are elevated. Rarely, the FT3 is elevated in isolation, in patients who have a T3 thyrotoxicosis variant. Subclinical hyperthyroidism has been defined as a thyrotropin concentration less than 0.1 mU/L (as measured by second generation or third generation sTSH assays) with plasma thyroid hormone levels within the normal range in the absence of pituitary-hypothalamic dysfunction, an acute non-thyroidal illness or treatment with dopamine, dobutamine or high doses of glucocorticoids.7 Treatment of non life-threatening thyrotoxicosis Management may vary depending on whether the thyrotoxicosis is non life-threatening or life threatening (i.e. thyrotoxic crisis; see later).26 Therapy consists of measures to reduce T3 and T4 synthesis and release, reduce peripheral conversion of T4 to T3, and inhibit the peripheral effects of T3 and T4. Antithyroid drugs. The antithyroid drugs of carbimazole, methimazole and propylthiouracil are commonly used. Carbimazole is metabolised to methimazole and so these two agents are considered to be interchangeable (methimazole dose is approximately 2/3 that of carbimazole). The antithyroid drugs are ineffective against thyrotoxicosis associated with thyroiditis or toxic adenoma and should not be used in these disorders. As propylthiouracil also blocks peripheral conversion of T4 to T3 and is highly protein bound, it is often preferred to carbimazole in thyrotoxic crisis or during pregnancy or lactation.27 1. Propylthiouracil may be used in partially suppressing doses of 300 - 600 mg a day (100 - 200 mg 8-hourly, as the half-life is 6 hr), reducing by half after 2 - 6 weeks and keeping the FT4 at midnormal levels and the TSH levels suppressed. Another regimen uses propylthiouracil at 200 - 300 mg 4 to 6-hourly to completely suppress the thyroid gland, which requires additional T4 replacement therapy (e.g. 100 µg/day) as well. As the latter regimen completely suppresses TSH, it will also reduce the size of a goitre. Treatment is continued for 6 - 24 months, thereafter reducing the dose and reviewing the patient for biochemical and clinical signs of a return in thyrotoxicosis. 2. Carbimazole has a half-life of 6 - 8 hr (i.e. can be given as a single daily dose), is 10 times as potent and is probably less toxic than propylthiouracil, although it has no effect on the peripheral conversion of T4 to T3.27 The standard dose is 10 - 40 mg daily, or 40 - 60 mg daily with T4 supplementation.

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In approximately 5% of patients who are treated with antithyroid drugs, side-effects occur and usually within the first 2 months of treatment. Leucopenia occurs in 0.5% of patients and is the most serious side effect. As it occurs suddenly, routine monitoring of the neutrophil count is of little value. A neutrophil count is performed before therapy and the patient is asked to stop therapy and to report if a fever, mouth ulcers, pharyngitis or stomatitis occur. If the neutrophil count decreases to 1500/mm3 or less, the drug should be discontinued. The agranulocytosis is self limiting and usually only lasts 5 - 15 days, which may resolve more rapidly with glucocorticoid treatment28 or granulocyte-colony stimulating factor therapy.29 Other side-effects include, aplastic anaemia, thrombocytopenia, hepatitis, cholestatic jaundice, nausea, vomiting, headache, skin rashes, urticaria, vasculitis, pruritus, arthralgia, myalgia and fever. Beta adrenergic receptor blockers. Propranolol reduces the peripheral effects of thyroid hormones as well as reducing the peripheral conversion of T4 to T3. The adrenergic-excess like features (probably caused by an increase in tissue adrenergic receptor density as circulating catecholamine levels are usually low30) of tachycardia, fever, tremor and agitation often respond rapidly. Beta-adrenergic receptor blockers should not be used in the presence of cardiac failure.31 Ablative therapy. Partial thyroidectomy or radioactive iodine are used if the disease recurs following drug therapy, if drug toxicity has occurred, or if a large goitre, toxic multinodular goitre or adenoma, exist.28 Preoperative preparation for partial thyroidectomy is usually undertaken with propranolol (e.g. 40 - 200 mg orally for 1 - 2 weeks, which is continued for 2 - 8 weeks postoperatively); this allows surgery to be performed safely in patients who have moderate hyperthyroidism.32 Thyrotoxic crisis and its treatment Thyrotoxic crisis is often precipitated in a poorly controlled or previously undiagnosed thyrotoxic patient, by infection, trauma, surgery, labour or pre-eclampsia, or it may be caused by a massive overdose of thyroxine. Overdoses of up to 10 mg of thyroxine are usually well tolerated.33,34 However, with massive overdoses (e.g., 70 - 1200 mg over 2 - 12 days), signs of thyrotoxicosis develop within 3 days and thyrotoxic crisis and coma usually develop after 7 - 10 days.35 Clinical features. Thyrotoxic crisis is characterised by hyperpyrexia, irritability, delirium, coma, muscle weakness, rhabdomyolysis, sinus tachycardia, atrial or ventricular tachyarrhythmias, hypotension, vomiting, abdominal pain and diarrhoea. Rarely, (particularly in elderly patients) it may present as an apathetic crisis with severe myopathy, tachycardia, hypotension and coma. The differential diagnosis are delirium tremens, opiate withdrawal, phaeochromocytoma, panic attack, mania and amphetamine overdosage. Treatment. This includes: 1. Resuscitation. Supportive care with fluids, dextrose and B group vitamins. Ideally oxygen

consumption studies and close haemodynamic monitoring should be performed. Digoxin, beta-blockers, verapamil, and amiodarone (which also inhibits peripheral conversion of T4 to T3;36 its metabolism also yields 3 mg (24 µmol) of free iodine per 100 mg37) have all been used to control atrial arrhythmias.

2. Antithyroid drugs a. Propylthiouracil 1000 mg orally (or via the nasogastric tube) as a loading dose followed

by 100 mg 2-hourly, is the treatment of choice because it also inhibits peripheral conversion of T4 to T3.27

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b. Carbimazole 60 - 100 mg as a loading dose, followed by 100 - 120 mg/day may be administered if propylthiouracil is contraindicated.

3. Iodine. Large doses of iodine immediately inhibit the uptake of iodine and release of thyroid hormone from a hyperfunctioning gland (Wolff-Chaikoff effect). However, the effect is transient (i.e. lasts 1 - 4 weeks), and iodine should be administered at least 1 hr after antithyroid drugs have been given. Sodium ipodate (1 g/day orally), a radiocontrast agent, also inhibits peripheral conversion of T4 to T3, and is often used; otherwise 500 - 1000 mg of sodium iodide is infused intravenously every 8 hr. Lithium (500 - 1000 mg) has been used as an alternative to iodine in patients sensitive to iodine; however, a steady state is achieved only after 5 - 6 days and it only weekly inhibits thyroid hormone release and synthesis.38 Frequent lithium levels are required to ensure nontoxic levels (i.e. < 1.5 mmol/L).

4. Beta blockers. Propranolol 40 - 200 mg orally usually alleviates the adrenergic-excess like effects. For rapid effect, 1 - 2 mg of propranolol may be administered intravenously over 5 min up to a total of 20 mg, or until the desired effect is achieved. The fever, tachycardia, diaphoresis, agitation, tremor and myopathic features usually respond rapidly.39 While selective beta-1 blockers do not inhibit peripheral conversion of T4 to T3 as effectively as propranolol, these agents may be used in patients with reactive airways (e.g. asthma, COPD).40 If heart failure exists then beta blockers may cause a marked deterioration in cardiac function leading to severe cardiac failure or cardiogenic shock.41 Cardiac failure and atrial fibrillation in these circumstances should be treated with digoxin31 (which may require a higher than normal dose42).

5. Dexamethasone. 4 mg 6-hourly, dexamethasone reduces the conversion of T4 to T3 and therefore is administered to severely thyrotoxic patients.

6. Other therapy a. Oral activated charcoal is used in patients with severe thyroxine overdosage. b. Plasmapheresis will increase T4 clearance in severe thyroxine overdosage (i.e 70 - 1200

mg over 2- 12 days)35 and has also been used in thyrotoxic crisis.43,44 In one report of a patient who ingested 6 mg of thyroxine, plasmapheresis was of no significant pharmacokinetic or clinical benefit.45

c. Dantrolene has also been used successfully in a patient in whom the thyrotoxic crisis mimicked malignant hyperpyrexia.46

REFERENCES 1. Smallridge RC. Metabolic and anatomic thyroid emergencies: a review. Crit Care Med

1994;20:276-291. 2. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993;328:553-

559. 3. MacKerrow SD, Osborn LA, Levy H, Eaton P, Economou P. Myxoedema-associated

cardiogenic shock treated with intravenous triiodothyronine. Ann Intern Med 1992;117:1014-1015.

4. Stockigt JR. Thyroid disease. Med J Aust 1993;158:770-774. 5. Toft AD. Thyroxine replacement treatment: clinical judgement or biochemical control? Br

Med J 1985;291:233-234. 6. Rippere V. Thyroxine replacement treatment: clinical judgement or biochemical control?.

Br Med J 1985;291:970. 7. Fatourechi V. Adverse effects of subclinical hyperthyroidism. Lancet 2001;358:856-857. 8. Toft AD. Subclinical hyperthyroidism. N Engl J Med 2001;345:512-516. 9. Sawin CT. Hypothyroidism. Med Clin N Am 1985;69:989-1004.

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10. Toft AD. Thyroxine therapy. N Engl J Med 1994;331:174-180. 11. Drucker DJ, Burrow GN. Cardiovascular surgery in the hypothyroid patient. Arch Intern

Med 1985;145:1585-1587. 12. McCulloch W, Price P, Hinds CJ, Wass JAH. Effects of low dose oral triiodothyronine in

myxoedema coma. Intens Care Med 1985;11:259-262. 13. Keating FR, Parkin TW, Selby JB, Dickinson LS. Treatment of heart disease associated

with myxoedema. Prog Cardiovasc Dis 1961;3:364-381. 14. Bergeron GA, Goldsmith R, Schiller NB. Myocardial infarction, severe reversible

ischemia, and shock following excess thyroid administration in a woman with normal coronary arteries. Arch Intern Med 1988;148:1450-1453.

15. Hsu RB, Huang TS, Chen YS, Chu SH. Effect of triiodothyronine administration in experimental myocardial injury. J Endocrinol Invest 1995;18:702-709.

16. Klemperer JD, Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, Isom OW, Krieger K. Thyroid hormone treatment after coronary-artery bypass surgery.N Engl J Med 1995;333:1522-1527.

17. Bennett-Guerrero E, Jimenez JL, White WD, D'Amico EB, Baldwin BI, Schwinn DA. Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo- controlled trial. Duke T3 study group. JAMA 1996;275:687-692.

18. Mathes DD. Treatment of myxoedema coma for emergency surgery. Anesth Analg 1998;86:450-451.

19. Fonseca V, Brown R, Hochhauser D, Ginsburg J, Havard CWH. Acute adrenal crisis precipitated by thyroxine. Br Med J 1986;292:1185-1186.

20. Lazarus JH. Hyperthyroidism. Lancet 1997;349:339-343. 21. Weetman AP. Graves’ disease. N Engl J Med 2000;343:1236-1248. 22. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW,

Benjamin EJ, D'Agostino RB. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249-1252.

23. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358:861-865.

24. Stockigt JR, Topliss DJ. Diagnosis and management of hyperthyroidism. Med J Aust 1986;145:278-282.

25. Kaplan MM. Clinical and laboratory assessment of thyroid abnormalities. Med Clin N Amer 1985;69:863-880.

26. Franklyn JA. The management of hyperthyroidism. N Engl J Med 1994;330:17311738. 27. Cooper DS. Which anti-thyroid drug? Am J Med 1986;80:1165-1168. 28. Cooper DS, Ridgeway EC. Clinical management of patients with hyperthyroidism. Med

Clin N Am 1985;69:953-971. 29. Mani S, Barry M, Concato J. Granulocyte-colony stimulating factor therapy in drug-

induced agranulocytosis. Arch Intern Med 1993;153:2500-2501. 30 . Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid and the heart. Circulation

1993;87:1435-1441. 31 . Stockigt JR. Hyperthyroidism and the heart: clinical dilemmas. Med J Aust 1995;162:398. 32. Utiger RD. Beta-adrenergic-antagonist therapy for hyperthyroid Grave's disease. N Engl J

Med 1984;310:1597-1598. 33. Nystrom E, Lindstedt G, Lundberg PA. Minor signs and symptoms of toxicity in a young

woman in spite of a massive thyroxin ingestion. Acta Med Scand 1980;207:135-136.

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34. Ratnaike S, Campbell DG, Melick RA. Thyroxine overdosage. Aust NZ J Med

1986;16:514. 35. Binimelis J, Bassas L, Marruecos L, Rodriguez J, Domingo MLP, Madoz P, Armengol S,

Mangues MA, de Leiva A. Massive thyroxine intoxication: evaluation of plasma extraction. Intens Care Med 1987;13:33-38.

36. Sheldon J. Effects of amiodarone in thyrotoxicosis. Br Med J 1983;286:267-268. 37. Gammage MD, Franklyn JA. Amiodarone and the thyroid. Quart J Med 1987;62:83-86. 38. Braverman LE, Vagenakis AG. The thyroid. Clin Endocrinol Metab 1979;8:621-639. 39. Editorial. Beta blockers in thyrotoxicosis. Lancet 1980;i:184-186. 40. Perrild H, Hansen MJ, Skovsted L, Christensen LK. Different effects of propranolol,

alprenolol, sotalol, atenolol and metoprolol on serum T3 and rT3 in hyperthyroisdism. Clin Endocrinol 1983;18:139-142.

41 . Ko GTC, Chow C-C, Sanderson JE, Yeung VTF, Cockram CS. Should β-blocking agents be used in thyrotoxic heart disease? Med J Aust 1995;162:426-427.

42 . Shenfield GM. Influence of thyroid dysfunction on drug pharmacokinetics. Clin Pharmacokinet 1981;6:275-297.

43. Ashkar FS, Katims RB, Smoak WM, Gilson AJ. Thyrotoxic storm treatment with blood exchange and plasmapheresis. JAMA 1970;214:1275-1279.

44. Tajiri J, Katsuya H, Kiyokawa T, Urata K, Okamoto K, Shimada T. Successful treatment of thyrotoxic crisis with plasma exchange. Crit Care Med 1984;12:536-537.

45. Henderson A, Hickman P, Ward G, Pond SM. Lack of efficacy of plasmapheresis in a patient overdosed with thyroxine. Anaesth Intens Care 1994;22:463-464.

46. Christensen PA, Nissen LR. Treatment of thyroid storm in a child with dantrolene. Br J Anaesth 1987;59:523.

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31

Chapter 5

DIABETES MELLITUS Diabetes mellitus is a chronic disorder caused by an insulin deficiency or insulin resistance, which is characterised by an elevated plasma glucose concentration and long-term complications involving the eyes, kidneys, nerves and blood vessels. Insulin is synthesised in the beta cells of the islets of Langerhans as a polypeptide precursor known as preproinsulin, which is converted to an 86 amino acid polypeptide called proinsulin. Proinsulin has only 5 - 10% of the activity of insulin in enhancing peripheral glucose uptake, although it may be more active than insulin in suppressing hepatic production of glucose.1 Proinsulin forms an equal amount of insulin and C peptide which are stored in membrane bound granules. Elevated glucose levels increase intracellular ATP which closes the pancreatic beta-cell ATP-sensitive K channels, prolonging depolarisation and allowing Ca2+ to enter the cell which in turn causes the granules fuse with the cell wall and release equal amounts of insulin and C peptide to the exterior by exocytosis. Insulin is secreted into the portal system in the basal state at a rate of 0.5 to 1 U/hr increasing to 5 - 10 U during a meal. The insulin secretion is markedly reduced with exercise. Insulin binds to its plasma membrane receptor and sets in motion the translocation of intracellular vesicles containing the transmembrane glucose transporter (GLUT-4) to the cell surface to fuse with the plasma membrane, increasing the number of GLUT-4 molecules in the membrane and thus the rate of glucose transport into the cell. Exercise also increases translocation of GLUT-4 containing vesicles to the cell membrane.2 Translocation of the GLUT-4 vesicles is inhibited in patients with type II diabetes and by TNF-α. The total daily secretion of insulin is approximately 40 U/day (50% of which is removed by the liver).1 In normal man, fasting insulin levels range from 1 - 10 mU/L and peak at about 50 mU/L following a meal. CLASSIFICATION Type I diabetes (insulin-dependent diabetes mellitus or IDDM) This condition is caused by an immunologically mediated destruction of the insulin-secreting islet cells (i.e. an insulitis), which results in an absolute insulin deficiency, a dependence on insulin therapy and a proneness to ketosis.3 It usually begins before the age of 40 and characteristically at around 14 years of age (i.e. at puberty). The plasma insulin and C peptide levels are low or unmeasurable and glucagon levels are elevated. Once the diagnosis is made, the patient usually requires insulin, although occasionally, following the resolution of an intercurrent illness, the patient may have a period of up to 1 year of normoglycaemia before insulin is required. During this early or prediabetic phase of the illness, agents which provide an immune tolerance to the enzyme glutamic acid decarboxylase (GAD), in experimental studies, have arrested the autoimmune damage and prevented diabetes. Others have reported a reduction in the frequency of diabetes when BCG or complete Freund’s adjuvant are administered to

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patients late (i.e. 11 weeks) in the prediabetic phase (perhaps by channelling the immune response away from beta cell destruction).4 Type II diabetes (non insulin dependent diabetes mellitus or NIDDM) This condition is associated with two defects, 1) insulin resistance and, 2) a relative insulin deficiency. Hyperglycaemia does not develop until a defect in the insulin secretion occurs.5 The glucose abnormalities are often mild and there is no proneness to ketosis. Most patients are obese and the diagnosis is often made in an asymptomatic individual on routine blood examination. The insulin levels are normal to high (but relative to the blood glucose level they are low) and there is an exaggerated glucagon response to ingested nutrients. If significant weight loss is able to be achieved, most patients are able to be managed by diet alone. Failing this, sulphonylureas are used although insulin may also be required.6 Other specific types (e.g. endocrinopathies, diseases of the exocrine pancreas) Diabetes may be caused by pancreatitis, haemochromatosis, hormonal disturbances (e.g. acromegaly, phaeochromocytoma, Cushing’s syndrome, endogenous glucocorticoid administration) drugs or stress. Gestational diabetes Gestational diabetes is a disorder of carbohydrate metabolism which has its onset during pregnancy and is due to the distinctive hormonal environment and metabolic demands of pregnancy. The disorder remits after parturition, although it is a risk factor for the development of type II diabetes in later years. CLINICAL FEATURES The clinical features are those which are associated with hyperglycaemia (e.g. glycosuria, polyuria, polydipsia, nocturia, polyphagia, weight loss, deterioration in consciousness), ketosis (e.g. Kussmaul breathing, sweet breath) and degenerative disorders (e.g. neuropathy, retinopathy, nephropathy). The degenerative disorders, which often present as late complications,7 are listed in Table 5.1. INVESTIGATIONS These include: 1. Fasting or random blood glucose concentration > 7 mmol/L. The blood glucose levels vary depending on whether they are measured in venous plasma, capillary plasma, venous whole blood or capillary whole blood (e.g. whole-blood glucose levels may be of to 13% lower than plasma glucose levels).8 Ideally blood glucose levels should be measured on a venous plasma sample. This is all that is required to diagnose diabetes in routine clinical practice.9,10 2. Oral glucose tolerance test. This is now no longer needed to diagnose diabetes in routine clinical practice. Before the test is performed the patient the patient must be in good health for at least 2 weeks prior to the test as an abnormal glucose tolerance test may be associated with many conditions (e.g. Table 5.2).11 Also the patient should ingest at least 150 g of carbohydrate for the previous 3 days (i.e. at least an extra three slices of bread per day if in doubt). For 8 hr before the test the patient should undergo an absolute fast (apart from water), with no alcohol, no smoking and no undue exercise.12 During the test the patient should lie in a semirecumbent position and not smoke. Venous blood samples are taken in the morning after the 8 hr fast, and again at 1 and 2 hr after 75 g of glucose (dextrose monohydrate not anhydrous dextrose12) in 300 mL of water, ingested over 5 min (i.e. 300 mL of a 25% dextrose solution), or, in children, 1.75 g of glucose per kilogram (up to 75 g).

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Table 5.1 Late complications of diabetes mellitus Atherosclerosis Ischaemic heart disease, myocardial infarction (painless) Hypertension Cerebrovascular accidents Gangrene of limb, foot ulcers Retinopathy Capillary microaneurysms, venous dilation Haemorrhages, waxy exudates New vessel formation, vitreous haemorrhages Fibrotic bands, retinal destruction, blindness Other ocular manifestations Cataracts Horner’s syndrome Diplopia with sudden III, IV or VI cranial nerve palsies Argyl Robertson pupil Osmotic accommodation changes Arcus senilis, xantholesma Nephropathy, Chronic renal failure Nephrotic syndrome Papillary necrosis Preponderance for urinary tract infection Peripheral and autonomic neuropathy Gastric stasis, diarrhoea Postural hypotension Foot ulcers Diminished sweating Bladder retention Neuropathic joints Impotence Skin lesions Necrobiosis lipoidica (destruction of collagen) Lipodystrophy Moniliasis of nails Xantholesma

Guidelines for the diagnosis of abnormal glucose tolerance13,14 1. If symptoms of diabetes are present,

a. a fasting venous plasma glucose level of 7 mmol/L or greater is diagnostic of diabetes mellitus

b. a plasma glucose level taken at least two hours after last eating of 11.1 mmol/L or greater is diagnostic of diabetes mellitus.

c. if a random venous plasma glucose value lies in the uncertain range (i.e., 5.5 - 11.0 mmol/L, further investigations may be necessary.

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2. If symptoms of diabetes are absent, a. at least two test results with values in the diabetic range are desirable, from a fasting or a

random sample, or from the oral glucose tolerance test. 3. Diagnostic values of the oral glucose tolerance test, these are shown in Table 5.3.

Table 5.2. Causes of an abnormal glucose tolerance test Prolonged inactivity Stress within the previous 12 weeks (e.g. myocardial infarct, stroke, trauma or surgery) Stress within the previous 2 weeks (e.g. fever, ‘flu’, gastroenteritis) Starvation, recent weight loss, recent weight gain of more than 2 kg Hypokalaemia Hepatocellular disease Endocrinopathies hyperthyroidism, Cushing’s syndrome, acromegaly, phaeochromocytoma Pyridoxine deficiency Drugs oestrogens, ovulation suppressants, corticosteroids, cyclosporine thiazides, frusemide, ethacrinic acid, phenothiazines, tricyclics phenytoin, diazoxide, minoxidil, salicylates, nicotinic acid, salbutamol.

Table 5.3 Diagnostic values of the 75 g oral glucose tolerance test Glucose concentration (mmol/L) Venous Capillary Venous Capillary plasma plasma whole blood whole blood Diabetes mellitus Fasting value > 7.0 > 7.0 > 6.1 > 6.1 2 hr after glucose load > 11.1 > 12.2 > 10.0 > 11.1 Impaired glucose tolerance Fasting value < 7.0 < 7.0 < 6.1 < 6.1 2 hr after glucose load 7.8 - 11.0 8.9 - 12.1 6.7 - 9.9 7.8 - 11.0

While glucose intolerance is not the fundamental defect in diabetes mellitus, there is no suitable alternative to the oral glucose tolerance test as a screening test when glucose levels lie in an uncertain range; although HbA1c levels of > 7.0% may be useful in identifying patients with glucose intolerance who require treatment.15 It is believed that the degree of hyper-glycaemia is relevant to the development of microangiopathy, as shown in the eye and kidney, and a 2 hr blood glucose greater than 11 mmol/L has been identified as the point above which the relative risk of retinopathy rises. Selection of the value of 11 mmol/L has also taken into account the observation that below a 2 hr concentration of 11 mmol/L, spontaneous remissions to normal glucose tolerance may occur in some people.8

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In one study of patients with type I diabetes between the ages of 13 and 39 years, where insulin was used to keep the preprandal blood sugar levels between 3.9 and 6.7 mmol/L and the postprandal level lower than 10 mmol/L, the onset of diabetic retinopathy, nephropathy and neuropathy was effectively delayed and the progression of microangiopathy was slowed, although there was a two-to-threefold increase in the incidence of severe hypoglycaemia.16 TREATMENT The main aim in the management of patients with diabetes mellitus is to minimise the impact of complications. In the short-term this means preventing the effects of insulin resistance, hypoinsulinaemia or hyperinsulinaemia (i.e. maintenance of normoglycaemia), and in the long term preventing the development and progression of vascular complications. In type II diabetes if the glycemic goals are not met with a 3-month trial of diet and exercise, pharmacologic agents (e.g. sulfonylureas, metformin, acarbose, troglitazone, insulin) should be initiated.17 However, in one large study comparing conventional treatment (e.g. diet, exercise, weight reduction and tolerating blood glucose levels < 15 mmol/L) with an ‘intensive’ normoglycaemic strategy (e.g. using sulphonylureas supplemented with insulin to maintain pre meal blood glucose between 4 - 7 mmol/L), while the ‘intensive’ normoglycaemic strategy affected diabetes-related events beneficially (i.e. improved microvascular outcomes), it did not change diabetes-related or all cause mortality (i.e. did not change macrovascular outcomes).18 However, in the group of obese type 2 diabetic patients treated with metformin, a lower diabetes mortality and all cause mortality was recorded compared to the conventionally treated group (although sulfonylurea-treated patients given metformin early had an increased diabetes and all cause mortality).19 Lifestyle Weight reduction, cease smoking, reduction in alcohol and regular exercise should be encouraged to improve glucose tolerance as well as to reduce the patients atherogenic risk.20 Diet An estimate is made of the total daily energy intake, based on ideal body weight, which ranges from 42 kcal/kg body weight (i.e. 175 kJ/kg) in an 18-year-old man to 30 kcal/kg body weight (140 kJ/kg) in a 75-year-old woman. The protein requirement is 0.9 g/kg, and the recommended carbohydrate content is 55 - 60% of total energy intake (although up to 85% has been prescribed). The remainder of the energy intake (i.e. 30-35%) usually consists of polyunsaturated fat. Refined sugars usually provoke postprandal hyperglycaemia and are not recommended. As the average serve of most foods (e.g. one slice of bread) provides approximately 15 g of carbohydrate, the measure of an average serve of carbohydrate is 15 g. This is known as an ‘exchange’, which has replaced the 10 g carbohydrate ‘portion’. The partitioning of calories for each meal for type I diabetic patients depends upon lifestyles, and a typical pattern is 20% for breakfast, 35% for lunch, 30% for dinner and 15% for evening meal. Insulin There are three types of insulin preparations which are categorised according to their absorption characteristics: short-, intermediate- and long-acting (slow onset). Information concerning the duration of action and peak activity time of insulins (Table 5.4)21 should only be regarded as approximate, as there are large variations between and within individuals.1 In a recent study of subcutaneously injected regular insulin, the blood glucose began to decrease in 1 - 2 hr (range 0.5 - 2 hr), reached its nadir in 5.7 hr (range 4 - 8 hr) and had a total duration of

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16.2 hr (range 9 - 24 hr),22 values which are considerably longer than standard teachings. Furthermore, the larger the dose, the longer the peak effect and duration of insulin, and exercise and different subcutaneous sites cause variation in insulin absorption rates (e.g. the abdominal wall causes regular insulin to decrease 86% faster than from the leg and 30% faster than from the arm, and exercise reduces the insulin absorption time).23 Insulin lispro is a human insulin analogue (where the natural sequence of proline at position B28 and lysine at position B29 is reversed - which hinders the ability of insulin monomers to form dimers) which is absorbed subcutaneously more rapidly than regular insulin (causing an earlier plasma peak level, e.g 40 minutes, compared to regular insulin e.g. 100 minutes) with a duration of action of about 3 hours compared with 5 hours for regular insulin.24 Table 5.4 Characteristics of currently available insulins Trade name Peak activity Duration Source Short-acting (hr) (hr) Insulin lispro 0.5 - 2 3 - 5 Human Insulin soluble Insulin-2 2 - 5 6 - 8 Bovine Insulin neutral Actrapid 2 - 5 6 - 8 Human Intermediate-acting Insulin isophane Isotard MC 6 - 12 12 - 24 Bovine Protaphane HM 6 - 12 12 - 24 Human Insulin zinc Lente MC 6 - 14 12 - 24 Bovine suspension Monotard HM 6 - 14 12 - 24 Human Slow-onset Insulin zinc Ultralente MC 10 - 24 24 - 36 Bovine suspension Ultratard HM 10 - 24 24 - 36 Human Insulin protamine Protamine zinc MC 10 - 20 20 - 36 Bovine Zinc HOE 901 10 - 24 20 - 36 Human Conventional treatment involves 1 - 2 subcutaneous injections a day of intermediate-acting insulin, with or without addition of a short-acting insulin. Long-acting insulin may be used for baseline insulin requirements with the addition of a short-acting preparation before each meal. Daily production of insulin in a standard non-diabetic adult is approximately 40 U/day, although only 50% enters the systemic circulation, as 50% of the insulin released into the portal system is removed by the liver. Therapy may begin with 20 U/day (25 - 30 U/day for obese patients) as a subcutaneous injection. Changes in insulin therapy should be by 5 - 10 U, after 3 - 5 days, and modified by blood sugar levels. If the blood sugar level is poorly controlled, then two-thirds of the injection may be administered before breakfast and one-third before supper (usually required if the total insulin dose is greater than 50 U/day). Other techniques to enhance blood glucose control involve multiple injections or continuous subcutaneous insulin infusions. Insulin should be reduced if exercise is anticipated. Insulin resistance is defined as a state in which normal amounts of insulin (0.5 U/kg/day) produces a subnormal biological response. However, for most type I diabetes patients the total daily dose of insulin is 0.5 - 1 U/kg25 and most clinicians usually do not consider patients

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resistant to insulin until the dose exceeds 2 U/kg/day, although this clearly exceeds the amount required for physiological replacement.26 Oral agents Sulphonylureas The sulphonylureas act primarily by increasing the beta-cell sensitivity to glucose (by closing the ATP-sensitive K channels,27 decreasing the islet cell-membrane permeability to potassium,28 prolonging depolarisation and allowing more Ca2+ to enter the cell20), so that more insulin is released at every level of blood glucose. They do not increase the synthesis of insulin and therefore are of no value in type I diabetes.29 Oral agents should be given to a type II diabetes patient when diet has failed. Alcohol may potentiate oral hypoglycaemics, whereas thiazide diuretics, and oral contraceptives have a hyperglycaemic effect (although the latter rarely disturb diabetic control).30 Long-acting sulphonylureas should only be used for patients under the age of 65 who have normal renal function. Treatment should be started with the minimum dose (Table 5.5).28,31 The average fall in fasting blood glucose is 25% (i.e. 3 mmol/L),20 ranging from 20% - 30% (i.e. 2.2 - 4.4 mmol/L).32 Secondary failure, defined as the recurrence of symptomatic hyperglycaemia (with fasting blood glucose concentrations of approximately 13.9 mmol/L), occurs in approximately 10% of patients per year, requiring additional therapy to improve glycaemic control. The side-effects include rashes, pruritus, weight gain, hyponatraemia, adverse reaction to alcohol (disulfiram reaction), nausea, vomiting, cholestasis, haemolytic anaemia, bone marrow aplasia and hypoglycaemia.28 Table 5.5 Oral hypoglycaemic agents Agent Daily dose Duration of Metabolism/excretion Dose frequency (mg) action (hr) (per day) Acetohexamide 250 - 1500 12 - 18 Hepatic 2 Chlorpropamide 100 - 500 24 - 72 Renal 1 Glibenclamide 2.5 - 15 12 - 24 Hepatic 1 - 2 Glipizide 2.5 - 40 16 - 24 Hepatic 1 - 2 Gliquidone 15 - 180 12 - 24 Hepatic 1 - 2 Tolazamide 100 - 1000 16 - 24 Hepatic 1 - 2 Tolbutamide 500 - 2000 6 - 10 Hepatic 2 - 3 Metformin 500 - 3000 2 - 4 Renal 1 - 3 Biguanides Metformin (dimethylbiguanide) acts as an hypoglycaemic agent by decreasing the hepatic glucose output, which is accounted for largely by the inhibition of hepatic gluconeogenesis.33,34 It also improves glycaemic control by increasing the efficiency of skeletal muscle glucose uptake (particularly at high doses), increasing the insulin-mediated glucose disposal and (by decreasing the patient’s appetite) reducing caloric intake.20,35 It is not effective in the absence of insulin. Metformin is usually reserved for the obese diabetic with poor dietary compliance, because, unlike insulin and the sulphonylureas, it is not likely to cause weight gain and results in a 10% - 20% reduction in plasma triglyceride levels. It is contraindicated in renal insufficiency (as it is excreted entirely by the kidneys), pregnancy, liver disease, alcoholism, and cardiopulmonary insufficiency (as tissue anoxia and cellular metabolism may promote the

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production of lactic acid). The fasting blood glucose levels fall on average by 2-3 mmol/L.20 The initial dose of metformin is 500 mg daily, which may be increased up to 1 g 8-hourly (Table 5.5). The side-effects include decreased appetite, nausea, diarrhoea, decreased plasma vitamin B12, lactic acidosis and rarely hypoglycaemia (i.e. hypoglycaemia is less likely than with sulphonylureas).28 Metformin can be used alone or in conjunction with sulphonylureas, as it is well tolerated and improves glycemic control and lipid concentrations in patients with type II diabetes who are unresponsive to diet or sulphonylurea therapy (e.g. after a 6 month trial of monotherapy).36 If treatment targets are not achieved, insulin should be added or substituted.20 Adjunctive drugs α-glucosidase inhibitors Acarbose (a complex oligosaccharide with a m.w. of 645.6 and a low systemic bioavailability) and miglitol reversibly inhibit intestinal α-glucosidases, impairing polysaccharide (but not monosaccharide) digestion and therefore carbohydrate absorption. While they reduce the postprandal blood glucose levels by up to 3 mmol/L, the fasting blood glucose levels and haemoglobin A1c may only fall slightly37 and the carbohydrate malabsorption often causes gastrointestinal problems of flatulence, diarrhoea and bloating.20 Thiazolidinediones The thiazolidinediones increase insulin sensitivity on glucose and lipid metabolism (they have no effect in the absence of insulin) in the adipose tissue and skeletal muscle.38,39,40 They also reduce hepatic glucose output and very-low density lipoprotein (VLDL) levels and increase high density lipoprotein (HDL) levels.41 The mechanism is distinct from metformin. These agents are believed to bind to and activate the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ), which then binds to a specific region of DNA and regulates the transcription of many genes involved in glucose and fatty acid metabolism.42 Troglitazone was the first agent of this class and was effective,43 but was withdrawn because of the side effect of severe and unpredictable hepatic failure. Rosiglitazone (2 mg twice daily) and piogitazone (15 - 45 mg daily) are newer thiazolidinediones that have not been associated with hepatotoxicity and have been approved for use as monotherapy or in combination with sulfonylureas, metformin or insulin in patients with type 2 diabetes with inadequate glycaemic control.44 While rosiglitazone and piogitazone have not been associated with hepatotoxicity, it is recommended that liver function tests be performed at baseline and 2-monthly for the first year of therapy and periodically thereafter. If the ALT increases more than three times normal during treatment then the drug should be discontinued. Serotonergic drugs The serotoninergic drug D-fenfluramine reduces food intake and may be useful in the obese diabetic with poor dietary compliance. It also enhances glucose uptake into muscle and fat. Fasting blood glucose can fall by 2 - 3 mmol/L.20 Recombinant human IGF-I A moderate dose of (40 µg/kg/day) recombinant human IGF-I (rhIGF-I) when given as an adjunct to insulin therapy has been reported to reduce HbA1c levels.45 The proposed additional benefits of this treatment are to reduce retinopathy and nephropathy by reducing the circulating GH levels.46 Islet transplantation Islets (separated from the donor pancreas by gentle mechanical dissociation and purified) have been transplanted sucessfully in animals and in humans (maintaining tight glycaemic

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control for nine to 12 months after the procedure47) and may in future be used in the management of diabetic patients.48,49 Choice of agent There is little to choose between the oral hypoglycaemic agents, other than if the patient has significant renal failure, tolbutamide or tolazamide should be used. Chlorpropamide has the advantage of being able to be prescribed as a single daily dosage. Oral hypoglycaemic agents rarely cause hypoglycaemia; however, if they do, the patient should be admitted to hospital, because the hypoglycaemic episode is usually severe and prolonged. If hypoglycaemic agents do not control the blood glucose, insulin therapy should be considered. Biochemical monitoring Ideal control of blood glucose concentration, delays or prevents many of the long term complications of diabetes.50 For the type I diabetic patient, blood sugar levels are regularly measured to adjust the dose of insulin. Lipid studies should also be performed to assess the metabolic control of diabetic patients. Glycosylated (glycated or glyco) haemoglobin (Hb A1c). Glycohaemoglobin is a compound which is formed by a non-enzymatic (and irreversible) interaction between glucose and the amino groups of valine and lysine residues of haemoglobin. The level of HbA1c increases during episodes of hyperglycaemia and for patients in whom blood sugar control may be less than ideal, a measurement of HbA1c indicates the degree of long term blood glucose control (i.e. the average ambient glycaemia over the preceding 4 - 5 weeks). The risk of microalbuminuria in patients with type I diabetes increases markedly when HbA1c levels are 8.1% (which corresponds to an average daily blood glucose of 11.1 mmol/L)51 or greater, indicating that efforts to reduce diabetic nephropathy should focus on reducing the HbA1c levels below this threshold.52 For retinopathy the HbA1c threshold is slightly higher (8.5% - 9%).51 However, while non diabetic patients have HbA1c levels of up to 6%, if diabetic patients have levels < 6%, they have a high incidence of hypoglycaemic attacks.53,54,55 Advanced glycosylated end products-modified haemoglobin (Hb-AGE). As blood glucose concentrations increase, glucose attaches non-enzymatically to the amino groups of many proteins to form glycosylated products (e.g. HbA1c). Some glycosylated products are degraded but those formed on collagen, DNA, or other long-lived macromolecules undergo further change to form advanced end-products (AGEs), which probably have a central role in the pathogenesis of diabetic complications.56 Measurement of Hb-AGE may provide a longer term measure of diabetic control as well as an index of the risk of diabetic complications.57 Biochemical indices of metabolic control in patients with diabetes mellitus are listed in table 5. 6,28 although these numerical targets may not be as important in the elderly as they are in the young. Table 5.6 Biochemical indices of metabolic control in diabetes mellitus Good Acceptable Fair Poor Fasting blood glucose (mmol/L) 4.4 - 6.6 6.7 - 7.7 7.8 - 10 > 10.0 Postprandal blood glucose (mmol/L) 4.4 - 7.8 7.8 - 10.0 10.0 - 12.0 > 13.0 Haemoglobin A1c (%) 6.0 - 7.0 7.0 - 8.0 7.0 - 9.0 > 9.0 Total plasma cholesterol (mmol/L) < 5.2 5.2 - 5.8 5.8 - 6.3 > 6.3 Plasma HDL cholesterol (mmol/L) > 1.1 0.9 - 1.1 0.9 - 0.8 < 0.8 Plasma triglyceride (mmol/L) <1.7 1.7 - 2.2 2.2 - 2.7 > 2.7

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DIABETIC KETOACIDOSIS Diabetic ketoacidosis is defined as a condition characterised by an absolute insulin deficiency (i.e. plasma insulin < 6 µU/mL) or relative insulin lack (plasma insulin level between 6 - 50 µU/mL when plasma glucose is > 14 mmol/L), in which ketone acids accumulate in blood to levels greater than 7 mmol/L, causing an acidaemia (pH < 7.25), or a decrease in serum bicarbonate to less than 10 mmol/L or both. When a relative insulin lack is present, an excess of counter-regulatory hormones of glucocorticoids, glucagon, adrenaline, noradrenaline, and growth hormone is also required to cause the ketoacidosis. Aetiology Ketoacidosis The anticatabolic effects of insulin (e.g. inhibition of lipolysis, ketogenesis, gluconeogenesis, glycogenolysis, and proteolysis) are sensitive to low levels of insulin (i.e. 4 - 10 µU/mL), whereas the anabolic actions of insulin (i.e. lipogenesis, glycogenesis and protein synthesis) predominate with high insulin levels (i.e. 10 - 50 µU/mL)58. Ketogenesis may be caused by an absolute insulin lack in the fasting state (e.g. the newly diagnosed type I diabetic patient, or the type I diabetic patient who has stoped his or her insulin therapy), or a relative insulin lack in the stressed state (e.g. the type I or type II diabetes patient who has a fixed insulin intake and an excess catabolic hormone secretion due to, an acute illness, such as infection, myocardial infarction, stroke, post operative or trauma, or hormonal excess, such as Cushing’s disease, steroid therapy, phaeochromocytoma, sympathomimetic therapy). In both cases the excess FFA mobilisation and stimulation of ketogenesis causes ketoacidosis. Hyperglycaemia The normal glucose production by the liver in the fasting individual is approximately 50 mmol/hr/70 kg which rapidly increases to 100 mmol/hr/70 kg when insulin is withdrawn (although hepatic glucose production returns to normal when ketoacidosis develops59). The total ECF glucose is 85 mmol/70 kg, which increases to 255 mmol/70 kg within 2 hr of insulin lack, increasing the ECF glucose from 5 mmol/L to 15 mmol/L.27 Normal peripheral metabolism of glucose is 150 - 300 mmol/hr/70 kg60, thus the hyperglycaemia of an absolute insulin lack is largely due to a reduction in peripheral glucose utilisation. In the patient who has a relative insulin lack, with hormonal excess or stress, stimulation of gluconeogenesis adds to the impairment of peripheral utilisation of glucose to cause hyperglycaemia. Clinical features The clinical features of diabetic ketoacidosis, and their causes are listed in Table 5.7.31 The hypotension is due to fluid loss (i.e. reduced preload) as severe ketoacidosis does not affect myocardial contractility.61 The abdominal pain associated with diabetic ketoacidosis is caused by a reversible autonomic neuropathy. It is generalised and usually occurs in the younger patient, abating after 4 - 6 h of treatment. Other causes of abdominal pain include pancreatitis, appendicitis or any acute abdominal disorder. The ketoacidotic patient is normally mildly hypothermic;62 if a pyrexia exists, sepsis should be suspected. Investigations These include: 1. Plasma biochemistry. Hyperglycaemia (usually between 30 - 40 mmol/L, although rarely it may vary from less than 11.1 mmol/L to greater than 55.6 mmol/L),63 hyponatraemia (i.e. plasma sodium < 135 mmol/L - due to hyperglycaemia induced ICF to ECF fluid shift, although severe hyponatraemia may be artifactual due to hyperlipidaemia), elevated anion gap,

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hyperkalaemia, hyperlipidaemia (triglyceride concentration usually > 4.5 mmol/L) and hyperphosphataemia are the characteristic findings in a patient who has diabetic ketoacidosis. Table 5.7 Clinical features of diabetic ketoacidosis and their cause Clinical features Cause Thirst, polyuria, blurred vision Osmotic diuresis leg cramps Nausea vomiting, abdominal pain Ileus, gastric stasis Hypotension, tachycardia, dehydration Fluid loss Kussmaul’s breathing Acidosis Ketones on breath Acetone Drowsiness, coma Hyperosmolality Hypothermia Reduced metabolic rate Warm dry skin Peripheral vasodilation 2. Blood gases. The characteristic findings are an acidaemia, low bicarbonate and hypocapnia (i.e. a compensated metabolic acidosis). 3. Complete blood picture. An elevated haemoglobin (due to haemoconcentration) and an elevated neutrophil count in the absence of infection often occur. 4. Plasma ketones. The plasma ketoacids (i.e. beta-hydroxybutyrate and acetoacetate, which usually exist in a ratio of 3:1, but may increase up to 9:1 with reduced redox states) normally are less than 1 mmol/L. During starvation they rise to 2 - 4 mmol/L and in ketoacidosis they are in excess of 5 mmol/L, rising up to 15 mmol/L, and almost totally account for the anion gap. As the major ketoacid is beta-hydroxybutyrate, this is often measured to assess the degree of ketoacidosis. Normally in sepsis and stress, the ketone levels are low. Alcoholic ketoacidosis is the other common cause of ketoacidosis (starvation ketosis is not associated with an acidaemia), which usually follows 24 hr after a drinking binge, due to an excessive mobilisation of FFA. It never occurs in the absence of starvation and frequently is associated with vomiting and abdominal pain (75% have pancreatitis). In this disorder, on admission to hospital the blood glucose level is within normal limits in 75%, low in 15%, mildly elevated in 5% of cases; the level is almost never elevated above 17 mmol/L. The ketoacidosis is rapidly reversed with intravenous dextrose and thiamine.64 5. Plasma lactate. This is elevated in the presence of shock or with alcoholic ketoacidosis. 6. Blood, urine and sputum culture. These are performed if the type I diabetic patient developed ketoacidosis during normal insulin administration. Treatment The fluid deficit in an adult is usually 3 - 8 L, sodium deficit 200 - 700 mmol, potassium deficit 20 - 700 mmol, phosphate deficit 50 - 80 mmol, calcium deficit 30 - 80 mmol and magnesium deficit 25 - 50 mmol.31,27 Central venous pressure measurements and right heart catheterisation and arterial pressure measurements may be required in the hypotensive elderly patient. Treatment requires, fluid resuscitation, insulin, potassium and general measures as outlined in Table 5.8.

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Table 5.8 Treatment guidelines for adult diabetic ketoacidosis Fluid - 0.9% Saline; 1st litre over 30 min, 2nd litre over 1-2 hr (if blood pressure, or pulse have not improved, further saline requires close haemodynamic monitoring). - 0.45% Saline is administered, 1 L/4 - 6 hr until the blood glucose is less than 15 mmol/L, thereafter - 5% dextrose is administered, 1 L/6 to 8-hourly. Insulin - Loading dose of 20 U i.v., then 4 U/hr as an infusion using the sliding insulin scale outlined in Table 5.12. (If blood sugar not decreasing by > 2 mmol/L/hr the insulin rate is increased to 8 U/hr) Potassium - If plasma K is; > 5 mmol/L, no potassium 4-5 mmol/L, administer potassium at 20 mmol/hr < 4 mmol/L, administer potassium at 40 mmol/hr Other electrolytes - Magnesium and phosphate deficits are corrected depending on the plasma levels. The calcium loss does not need to be replaced acutely. General measures - Continuous nasogastric aspiration if the patient is not conscious (to reduce the risk of aspiration) - Urinary catheterisation in a patient who is not conscious - Antibiotics, only in the presence of infection - Low-dose heparin for the elderly Insulin The insulin infusion will normally decrease the blood glucose at a rate of 3 - 4 mmol/L/hr. Insulin resistance occurs if shock or sepsis exists, thus effective resuscitation is required before the maximum effect of insulin can be expected.31 Insulin has a half-life of 4 - 5 min, although its biological half-life is 40 min.31 In a normal individual, fasting insulin levels range from 1 - 10 µU/mL, and insulin concentrations rarely exceed 50 µU/mL. With each 1 U/hr of insulin infused, the plasma level rises by 20 µU/mL. Thus a bolus of 20 U given initially followed by 4 - 6 U hourly will produce insulin levels of 60 - 100 µU/mL.31 Glass and plastic surfaces of infusion equipment bind approximately 20% - 30% of insulin.65 This is not a major problem and while some clinicians infuse insulin with a protein carrier (e.g. 1 mL of 25% albumin), the overall adsorption is only decreased by up to 10%,66 therefore 50 U of soluble insulin is normally added to 0.9% saline up to 50 mL, and, using a plastic syringe pump, this solution is infused until an effect is achieved. Potassium The reduction in potassium is due to an insulin effect and correction of the acidosis, both of which cause a shift of potassium from the ECF to the ICF. While hyperkalaemia may be present on admission, the patient is commonly depleted of potassium, and usually between 100 - 200 mmol of potassium is required in the first 24 hr.31 Potassium chloride (and

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phosphate) are administered according to 2 hr monitored serum potassium levels, and usually at a rate of no greater than 40 mmol of potassium per hour. Sodium bicarbonate Due to the detrimental effects of sodium bicarbonate, it is not administered routinely, unless severe hyperkalaemia exists or unless a prolonged ketoacidosis has caused an excess renal loss of ketone salts (i.e. sodium or potassium beta-hydroxybutyrate and acetoacetate), producing a normal anion gap hyperchloraemic acidosis. Other electrolytes Phosphate and magnesium depletion may also occur in diabetic ketoacidosis. Intravenous phosphate is administered up to a rate of 4 mmol/hr, and intravenous magnesium up to a rate of 2 mmol/hr, with 6 to 8-hourly plasma levels guiding therapy. Monitoring The plasma glucose and potassium are monitored hourly if the plasma potassium is less than 3 or more than 6 mmol/L, otherwise they are measured 2-hourly for the first 6 hr and thereafter depending on the plasma levels. The acidosis is monitored by blood gases and anion gap levels. Complications The mortality associated with ketoacidosis is about 5% and often related to complications of, infection (i.e. pneumonia, pyelonephritis or septicaemia), ARDS, vascular thrombosis (gastrointestinal or cerebral) or myocardial infarction, rather than the ketoacidosis per se. Cerebral oedema associated with ketoacidosis, is often fatal and occurs usually in children rather than adults, and at a time when the biochemical defect is controlled. Its aetiology is largely unknown, although excessive hypotonic fluid, and bicarbonate administration have been incriminated.27,67 In hyperosmolar states cerebral tissue has the capacity to accumulate osmotically active particles within the intracellular compartment and thereby, over a period of time, limit the osmotic effect and the volume change imposed.68,69 The nature and mechanisms by which these intracellular ‘idiogenic osmoles’ (which include myo-inositol, N-acetylaspartate, choline and taurine70,71) accumulate and dissipate are not yet fully understood,72 although they appear to increase in concentration in a response to physiological conditions of hypertonicity (i.e. hyperglycaemia and hypernatraemia) rather than nonphysiological conditions of hypertonicity (i.e. glycerol or mannitol).73 They also accumulate more rapidly than they are dissipated. The formation of ‘idiogenic’ osmoles with prolonged hypertonicity, may provoke rebound cerebral oedema if the blood glucose is rapidly lowered below 14 mmol/L.72 Treatment of cerebral oedema is largely preventative, by preventing excessive fluid administration and infusing dextrose solutions when the plasma glucose is 15 mmol/L or less. Otherwise cerebral oedema is treated by standard measures (e.g. mannitol, frusemide).28 NONKETOTIC HYPERGLYCAEMIC COMA Cause This condition occurs characteristically in the elderly type II diabetic patient, and is usually precipitated by an intercurrent illness (e.g. pneumonia, meningitis, urinary tract infection, septicaemia). It has also been reported in nondiabetic patients with pancreatitis, burns, heat stroke, cerebrovascular accidents, myocardial infarction, septicaemia, thyrotoxicosis, acromegaly, corticosteroid therapy, l-asparaginase therapy, and with excess dextrose

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administration during intravenous nutrition or peritoneal or haemodialysis. As the hyperosmolality is the predominant feature, and as ketones may be present and coma absent, some prefer to label the disorder the diabetic hyperosmolar syndrome.74 Clinical features The clinical features include those caused by hyperglycaemia (e.g. polyuria, polydipsia, hypotension) and those caused by hypertonicity (e.g. coma). Patients with hyperosmolality are generally not comatose if the serum osmolality is less than 350 mosmol/kg,75 although attempting to correlate coma with osmolality is difficult, particularly when the permeant solute of urea may have a greater or lesser effect in determining its value, but has no effect on ICF fluid shift. If the effect of urea is removed and one calculates the ‘tonicity’, then patients with ‘tonicity’ values of greater than 320 mosmol/kg are often obtunded or comatose.76 Apart from coma a wide variety of other neurological abnormalities may also be present. For example focal seizures (generalised seizures may be due to cortical-vein thrombosis), epilepsia partialis continua, myoclonus, opsoclonia, coarse flapping tremor (i.e. asterixis), the posturing of paroxysmal kinetogenic choreoathetosis and “fencing (stance) seizures”. Facial motor abnormalities have also been described including aphasia, facial muscle twitching and jerking.77 Transient and sustained hemiplegia has also been described, although the latter may indicate cerebral artery thrombosis. Investigations These include: 1. Plasma ketones. The patient has ketone levels no greater than the starvation range (i.e. 2 - 4 mmol/L) because the small amounts of circulating endogenous insulin, while not reducing the blood glucose levels, are sufficient to inhibit ketogenesis. 2. Plasma glucose. Patients who have symptoms have plasma glucose levels of 40 - 70 mmol/L (i.e. twice that seen with ketoacidosis). 3. Plasma osmolality. This is usually 350 mosmol/kg or greater.78,79 4. Plasma biochemistry. The initial biochemical findings in patients with diabetic ketoacidosis compared with nonketotic hyperosmolar coma, are listed in Table 5.9.8,80 Treatment The sodium deficit is usually 400 mmol and the water deficit varies from 4 - 18 L,17 therefore fluid with a sodium content of approximately 60 mmol/L would seem to be ideal.29 Some of the water deficit may be predicted by correcting the serum sodium for normal glucose levels (for every 3 mmol/L elevation of glucose the serum sodium falls 1 mmol/L) and assessing the fluid required to correct the corrected sodium level back to normal.81 The aim is to decrease the osmolality by no greater than 2 mosmol/kg/hr and the serum glucose to no less than 10 - 15 mmol/L in 48 hr. Once this is achieved, 5% dextrose solutions are administered to maintain the serum glucose between 10 - 15 mmol/L for 24 hr, in an attempt to reduce the incidence of cerebral oedema (see above).72 An outline of fluid and electrolyte replacement, insulin therapy and general measures is shown in Table 5.10.29,36 Central venous pressure measurements and right heart catheterisation and arterial pressure measurements will be required in the hypotensive elderly patient. Blood glucose, potassium, sodium and osmolality are measured 2 hr. If the potassium is less than 3 or more than 5 mmol/L, then it is measured hourly.

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Table 5.9 Initial laboratory findings in diabetic ketoacidosis and nonketotic hyperosmolar coma Diabetic Nonketotic ketoacidosis hyperosmolar coma Glucose (mmol/L) < 40 > 50 Osmolality (mosmol/kg) < 330 > 330 pH < 7.2 > 7.2 HCO3

- (mmol/L) < 10 > 15 Na+ (mmol/L) < 135 > 135 Table 5.10 Treatment guidelines for hyperosmolar nonketotic coma Fluid - 0.9% saline 1 L over 30 min if still hypotensive and CVP (or wedge pressure is low) then 0.9% saline 1 L over 30 min - 0.45% saline is administered, 1 L/4 hr until the blood glucose is less than 15 mmol/L, thereafter; - 5% dextrose is administered 1 L/8 hr. Insulin - 4 U/hr as an intravenous infusion until the blood sugar level is 15 mmol/L, then cease Potassium - If plasma K is; > 5 mmol/L, no potassium 4-5 mmol/L, administer potassium at 20 mmol/hr < 4 mmol/L, administer potassium at 40 mmol/hr Other electrolytes - Magnesium and phosphate replacement are administered depending on the plasma levels. General measures Continuous nasogastric aspiration if the patient is not conscious (to reduce the risk of aspiration) Urinary catheterisation in a patient who is not conscious Antibiotics, only in the presence of infection Anticoagulation or low dose heparin DIABETES MELLITUS IN THE SURGICAL PATIENT82,83,84,85,86 The risk of operation in diabetics is related mainly to cardiovascular complications (myocardial infarct, cardiac failure, stroke), infections and reduced rates of wound healing,15 rather than metabolic decompensation (i.e. hyperglycaemia and ketoacidosis), which are rare causes of morbidity and mortality. Myocardial infarct, stroke and cardiac failure are responsible for 50% of deaths in diabetics in the postoperative period. Diabetic patients also often have renal insufficiency and require

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careful monitoring of fluids in the post operative period. The reasons to attempt to keep the blood sugar level between 7 - 10 mmol/L include suppression of ketoacidosis, hyperkalaemia and fluid loss, decreased protein glycosylation (which impairs wound healing, and which occurs when the plasma glucose level is greater than 11.1 mmol/L), and decreased hyperglycaemic interference of leucocyte chemotaxis, opsonisation and phagocytosis.87,88 Insulin-dependent diabetes mellitus Elective surgery Ideally these patients are operated on in the morning. On the day of operation, an intravenous infusion of 5% dextrose is administered preoperatively and half their usual dose of insulin is given subcutaneously. The patient’s blood sugar should be monitored 2-hourly, unless it is greater than 20 mmol/L or less than 7 mmol/L, when it should be monitored hourly. Postoperatively, the remainder of the usual insulin dose is administered. If the patient is eating by the next day, the regular dose of insulin is administered. If the patient is not eating, the intravenous 5% dextrose should be continued. As the patient in the postoperative period will not be exercising and will have an increase in circulating catecholamines, cortisol and growth hormone due to the stress of surgery, and will receive a 5% dextrose infusion, the patient’s standard insulin dose is unlikely to be adequate and should be supplemented with regular dose of subcutaneous insulin adjusted from 4-hourly blood sugar levels (see Table 5.11 for an example).

Table 5.11 Subcutaneous insulin sliding scale. Blood glucose Subcutaneous insulin (mmol/L) (Actrapid U) < 4.0 0 4.1 - 6 2 6.1 - 8 4 8.1 - 10 8 10.1 - 12 12 12.1 - 14 16 > 14.0 Notify doctor

Emergency surgery If the patient is undergoing an emergency operation, an insulin infusion is used (Table 5.12) and adjusted on 2-hourly blood sugar levels. If emergency surgery is required in a ketoacidotic patient, then the fluid, electrolyte and insulin regimen required, is continued throughout the surgery. Close cardiovascular haemodynamic monitoring, using a right heart catheter, is necessary. Intraoperative and postoperative insulin is administered as an infusion, with the infusion rates being adjusted from the 2-hourly blood sugar levels (see Table 5.12 for an example). Usually, 0.5 mL of Actrapid (100 U/mL) is diluted in 49.5 mL of 0.9% saline to give 1 U/mL, and infused using a syringe pump which is accurate down to a flow rate of 0.5 mL/hr.

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Table 5.12 Intravenous insulin sliding scale Blood glucose Insulin infusion (mmol/L) (Actrapid U/hr) < 4.0 0 4.1 - 6 0.5 6.1 - 8 1 8.1 - 10 2 10.1 - 12 3 12.1 - 14 4 14.1 - 16 5 > 16.0 Notify doctor

Non insulin dependent diabetes mellitus For both elective and emergency surgery, the oral hypoglycaemic agent is ceased on the day of surgery. During surgery and during the postoperative period, intravenous 5% dextrose is infused (50 g/8 hr) and subcutaneous insulin is administered using a sliding scale, with 4-hourly blood sugar levels to maintain the blood glucose level between 7 - 10 mmol/L.87,88 If the initial blood sugar is greater than 20 mmol/L, the patient is managed by an intravenous infusion of insulin which is varied according to a 2-hourly blood sugar level (Table 5.11). When the patient is able to eat the oral hypoglycaemic agent is readministered, although metformin is usually reintroduced 1-2 days later. HYPERGLYCAEMIA DUE TO STRESS OR CRITICAL ILLNESS Hyperglycaemia associated with insulin resistance is common in critically ill patients in the absence of a previous history of diabetes. Often the management of patients is to observe the blood glucose levels only (if less than 12.0 mmol/L) and treat the underlying condition in the belief that the patient will become normoglycaemic without a detremental effect caused by the episode of hyperglycaemia. However, in one study of mecanically ventilated critically ill patients admitted to a surgical intensive care unit (more than 60% of whom were post cardiopulmonary bypass patients) who received 200 - 300 g if glucose intravenously for the first day and 20 - 30 non nitrogen calories/kg per day (20 - 40 % as lipid) and 0.13 - 0.26 g N2 per kg per day either parenterally, enterally or mixed thereafter (until discharge from the intensive care unit); an insulin infusion (up to 50 U/hr) to maintain the blood glucose between 4.4 - 6.1 mmol/L was associated with a reduction in morbidity (renal failure, infection, polyneuropathy, anaemia) and mortality (particularly in patients who remained in the ICU for > 5 days) when compared with an insulin infusion to maintain the blood glucose between 10 - 11.1 mmol/L if the blood glucose was > 12 mmol/L.89 HYPOGLYCAEMIA In health the plasma glucose level is regulated within narrow limits, with insulin countering postprandial hyperglycaemia and glucagon acting to counter hypoglycaemia. With severe hypoglycaemia, adrenaline, growth hormone and cortisol also act with glucagon to correct low plasma glucose levels.90 Causes The causes of hypoglycaemia are listed in Table 5.1311,90,91,92,93

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Table 5.13 Causes of hypoglycaemia Factitious (due to elevated leucocyte count) Starvation, prolonged exercise Insulinoma (85% benign, 15% malignant) Hepatic disease Cirrhosis, acute hepatic failure Endocrine disease Addison’s Anterior pituitary insufficiency (with reduction in GH, ACTH) Hypothyroidism, phaeochromocytoma Medication induced Insulin, sulphonylureas, biguanides, Pentamidine, octreotide, salicylates, alcohol Quinidine, disopyramide, haloperidol Monoamine oxidase inhibitors, ACE inhibitors Sudden reduction in parenteral nutrition Carcinomas Primary hepatic carcinoma Adrenal carcinoma, carcinoid Renal failure Shock, septicaemia Metabolic disorders Carnitine deficiency, Reye’s syndrome Glycogen storage disease, hereditary fructose intolerance

Clinical features The clinical features of hypoglycaemia relate to the effects of: 1. Adrenergic stimulation. Tachycardia, palpitations, diaphoresis, anxiety, tremor, hunger, nausea, irritability, and pallor, often occur when the plasma glucose levels fall below 2.2 mmol/L (40 mg/dL). Symptoms may be absent in diabetic patients who have severe autonomic neuropathy, or in those patients treated with a non-selective beta-blocker, due to a beta-2-adrenergic receptor blocking effect.94 The differential diagnosis of hypoglycaemia induced sympathetic stimulation include phaeochromocytoma, panic attacks and hyperventilation. 2. Neuroglycopenia. Headache, blurred vision, paraesthesia, weakness, tiredness, confusion, dizziness, amnesia, incoordination, behavioural change, transient aphasia, hemiplegia, seizures, and coma, commonly occur with plasma glucose levels less than 2 mmol/L (36 mg/dL) and may cause cerebral oedema and permanent cerebral damage if prolonged. If seizures are prolonged and cerebral oedema develops, hyperthermia may be present, otherwise the patient is usually hypothermic. Investigations These include: 1. Plasma glucose. Most laboratories have their lower reference range limit for plasma glucose at 3.8 mmol/L (70 mg/dL). While a normal female may rarely have a fasting plasma glucose level down to 2.5 mmol/L (45 mg/dL) without any deleterious effect, a plasma glucose

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level below 2.8 mmol/L (50 mg/dL) is significant and is sufficient to make the diagnosis of hypoglycaemia.92 2. Plasma insulin:glucose ratio. Because hypoglycaemia normally suppresses insulin secretion, the value of the ratio - plasma (insulin (µU/mL) x 5.5) : plasma (glucose (mmol/L) - 1.8), should be less than 50, except in patients who have an insulinoma or an overdosage of insulin or sulphonylureas. 3. Plasma C peptide, and proinsulin. Fasting proinsulin and C peptide levels are elevated in patients who have an insulinoma or an overdosage of sulphonylureas. An increased ratio of proinsulin to insulin is also suggestive of an insulinoma. As plasma C peptide levels normally vary in parallel with the plasma insulin concentrations, C peptide levels are low with excess exogenous insulin administration. Serum levels of the sulphonylureas are elevated if hypoglycaemia is caused by these agents. 4. Prolonged 72 hr fast: this is normally begun after the evening meal, thereafter the patient may only have water or other calorie-free caffeine-free drinks. Plasma is obtained 6-hourly for glucose, insulin and C-peptide levels for the first 24 hr then 4-hourly thereafter. The patient is monitored carefully for symptoms, with plasma being taken during symptoms, for, glucose, insulin and C peptide levels. 5. β-Hydroxybutyric acid. The plasma β-Hydroxybutyric acid level is > 2.7 mmol/L in normal patients and < 2.7 mmol/L in patients who have excess insulin (e.g. insulinoma, insulin or sulfonylurea induced) at the end of a 72 hr fast. 6. The 6 hr glucose tolerance test. This is a 6 hr extension of the glucose tolerance test, taking fasting and 30 min specimens of plasma glucose and insulin. Treatment The standard treatment for hypoglycaemia is oral glucose or if the patient is unconscious, 50 mL of 50% dextrose administered intravenously as a bolus (i.e. 25 g or 139 mmol, which will elevate the extracellular glucose acutely by 8 mmol/L/70 kg). Intravenous glucose is then infused at 4 - 5 mmol/hr (i.e. 40 mL of 20% dextrose/hr), and blood glucose levels are measured 2 to 4-hourly. Glucagon 0.5 mg intramuscularly or intravenously may also be useful (the standard dose of 1 mg is often excessive and will produce nausea and vomiting 2 - 4 hr later in a significant number of patients95). If an insulinoma is responsible for the hypoglycaemia, it should be surgically removed. As octreotide is a potent inhibitor of insulinoma insulin secretion, it is used in cases of metastatic insulinomas.96 Octreotide (100 µg s.c. 6 - 12-hourly) has also been used successfully in cases of sulphonylurea overdose induced hypoglycaemia.97,98

REFERENCES 1. Zinman B. The physiological replacement of insulin. An elusive goal. N Engl J Med

1989;321:363-370. 2. Shepherd PR, Kahn BB. Glucose transporters and insulin action. Implications for insulin

resistance and diabetes mellitus. N Engl J Med 1999;341:248-257. 3. Eisenbarth GS. Type I diabetes mellitus: a chronic autoimmune disease. N Engl J Med

1986;314:1360-1368. 4. Williams G. IDDM: long honeymoon, sweet ending. Lancet 1994;343:684-685. 5. Editorial. Type II diabetes or NIDDM: looking for a better name. Lancet 1989;i:589-591. 6. Unger RH, Orci L. Glucagon and the A cell (first of two parts). N Engl J Med

1981;304:1518-1524. 7. Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med 1993;328:1676-

1685.

Diabetes Mellitus

50

8. Editorial. Impaired glucose tolerance and diabetes-WHO criteria. Br Med J

1980;281:1512-1513. 9. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes

Care 1997;20:1183-1197. 10. Zimmet P, Alberti G, de Courten MP. New classification and criteria for diabetes: moving

the goalpoasts closer. Med J Aust 1998;168:593-594. 11. Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of

glucose tolerance. Ann Intern Med 1993;118:529-539. 12. Wiener K. Diagnosis of diabetes mellitus: pitfalls in the glucose tolerance test. Br Med J

1987;295:1363. 13. World Health Organization. Diabetes mellitus: report of a WHO study group. Geneva:

WHO, 1985. (WHO Technical Report Series no. 727.) 14. Colman PG, Thomas DW, Zimmet PZ, Welborn TA, Garcia-Webb P, More MP. New

classification and criteria for diagnosis of diabetes mellitus. Position statement from the Australian Diabetes Society, New Zealand Society for the Study of Diabetes, Royal College of Pathologists of Australasia and Australasian Association of Clinical Biochemists. Med J Aust 1999;170:375-378.

15. Peters AL, Davidson MB, Schriger DL, Hasselblad V, for the Meta-analysis Research Group on the Diagnosis of Diabetes Using Glycated Hemoglobin Levels. A clinical approach for the diagnosis of diabetes mellitus. An analysis using glycosylated hemoglobin levels. JAMA 1996;276:1246-1252.

16. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.

17. Edelman SV. Type II diabetes mellitus. Adv Intern Med 1998;43:449-500. 18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with

sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.

19. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabeted (UKPDS 34). Lancet 1998;352:854-865.

20. Williams G. Management of non-insulin-dependent diabetes mellitus. Lancet 1994;343:95-100.

21. MacPherson JN, Feely J. Diabetes I: Insulins. Br Med J 1983;286:1502-1504. 22. Roy B, Chou MC, Field JB. Time-action characteristics of regular and NPH insulin in

insulin-treated diabetics. J Clin Endocrinol Metab 1980;50:475-479. 23. Koivisto VA, Felig P. Alterations in insulin absorption and in blood glucose control

associated with varying insulin injection sites in diabetic patients. Ann Intern Med 1980;92:59-61.

24. Holleman F, Hoekstra JBL. Insulin lispro. N Engl J Med 1997;337:176-183. 25. Ryan EA. Pancreas transplants: for whom? Lancet 1998;351:1072-1073. 26. Kahn CR. Insulin resistance: a common feature of diabetes mellitus. N Engl J Med

1986;315:252-254. 27. Challinor-Rogers JL, McPerson GA. Potassium channel openers and other regulators of

KATP channels. Clin Exper Pharmacol Physiol 1994;21:583-597. 28. Sturgess NC, Ashford MLJ, Cook DL, Hales CN. The sulphonylurea receptor may be an

ATP-sensitive potassium channel. Lancet 1985;ii:474-475. 29. Gerich JE. Oral hypoglycaemic agents. N Engl J Med 1989;321:1231-1245.

Diabetes Mellitus

51

30. Watkins PJ. ABC of diabetes. Treatment. Br Med J 1982;284:1853-1855. 31. Ferner RE, Alberti KGMM. Sulphonylureas in the treatment of non-insulin-dependent

diabetes. Quart J Med 1989;73:987-995. 32. United Kingdom Prospective Diabetes Study Group. United Kingdom prospective

diabetes study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. Br Med J 1995;310:83-88.

33. Abbasi AA, Kasmikha R, Sotingeanu DG. Metformin-induced lacticacidemia in patients with type 2 diabetes mellitus. Endocr Pract. 2000;6:442-446.

34 . Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:550-554.

35 Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-579. .36 . DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group. Efficacy of

metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:541-549.

37. Coniff RF, Shapiro JA, Seaton TB. Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med 1994;154:2442-2448.

38. Dagogo-Jack S, Santiago JV. Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions. Arch Intern Med. 1997;157:1802-1817.

39. Spencer CM, Markham A. Troglitazone. Drugs 1997; 54:89-101. 40. Scheen AJ, Lefebvre PJ. Oral antidiabetic agents. A guide to selection. Drugs

1998;55:225-236. 41. Schoonjans K, Auwerx J. Thiazolidinediones: an update. Lancet 2000;355:1008-1010. 42. Olefsky JM. Treatment of insulin resistance with peroxisome proliferator-activated

receptor gamma agonists. J Clin Invest 2000;106:467-472. 43. Imura H. A novel antidiabetic drug, troglitazone - reason for hope and concern. N Engl J

Med 1998;338:908-909. 44. O’Moore-Sullivan TM, Prins JB. Thiazolidinediones and type 2 diabetes: new drugs for

an old disease. Med J Aust 2002;176:381-386. 45. Acerini CL, Patton CM, Savage MO, Kernell A, Westphal O, Dunger DB. Randomised

placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus. Lancet 1997;350:1199-1204.

46. Møller N, Ørskov H. Does IGF-I therapy in insulin-dependent diabetes mellitus limit complications. Lancet 1997;350:1188-1189.

47. Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, oth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-238.

48. Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, Murphy M, Moloney MK, Schmehl M, Harris M, Mendez R, Mendez R, Sandford PA. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 1994;343:950-951.

49. Robertson RP. Successful islet transplantation for patients with diabetes - fact or fancy?. N Engl J Med 2000;343:289-290.

50. Tchobroutsky G. Relationship of diabetic control to development of microvascular complications. Diabetologica 1978;15:143-147.

51 . Viberti G. A glycemic threshold for diabetic complications? N Engl J Med 1995;332:1293-1294.

Diabetes Mellitus

52

52 . Krolewski AS, Laffel LMB, Krolewski M, Quinn M, Warram JH. Glycosylated

hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med 1995;332:1251-1255.

53. Koenig RJ, Cerami A. Hemoglobin AIc and diabetes melitus. Ann Rev Med 1980;31:29-34.

54. McFarland KF. Glycosylated hemoglobin. What is its value? Arch Intern Med 1981;141:712.

55. Goldstein DE. Is glycosylated hemoglobin clinically useful? N Engl J Med 1984;310:384-385.

56. Taylor M, Kerr D. Diabetes control and complications: a coming of AGE. Lancet 1996;347:485.

57. Wolffenbuttel BHR, Giordano D, Founds HW, Bucala R. Long-term assessment of glucose control by haemoglobin-AGE measurement. Lancet 1996;347:513-515.

58. Alberti KGMM, Natrass M. Severe diabetic ketoacidosis. Med Clin N Am 1978;62:799-814.

59. Foster DW, McGarry JD. The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983;309:159-169.

60. Wolfe RR, O'Donnell TF, Stone MD, Richmand DA, Burke JF. Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition. Metabolism 1980;29:892-900.

61. Maury E, Vassal T, Offenstadt G. Cardiac contractility during severe ketoacidosis. N Engl J Med 2000;341:1938.

62. Gale EA, Tattersall RB. Hypothermia: a complication of diabetic ketoacidosis. Br Med J 1978;2:1387-1389.

63 . Lebovitz HE. Diabetic ketoacidosis. Lancet 1995;345:767-772. 64. Wrenn KD, Slovis CM, Minion GE, Rutkowski R. The syndrome of alcoholic

ketoacidosis. Am J Med 1991;91:119-128. 65. Peterson L, Caldwell J, Hoffman J. Insulin adsorbance to polyvinylchloride surfaces with

implications for constant infusion therapy. Diabetes 1976;25:72-74. 66. Weber SS, Wood WA, Jackson EA. Availability of insulin from parenteral nutrition

solutions. Am J Hosp Pharm 1977;34:353-357. 67. Winegrad AI, Kern EFO, Simmons DA. Cerebral oedema in diabetic ketoacidosis. N Engl

J Med 1985;312:1184-1185. 68. Finberg L, Luttrell CN, Redd H. Pathogenesis of lesions in the nervous system in

hypernatraemic states: experimental studies of gross anatomic changes and alterations of chemical composition of the tissues. Pediatrics 1959;23:46-53.

69. McDowell ME, Wolf AV, Steer A. Osmotic volumes of distribution: idiogenic changes in osmotic pressure associated with administration of hypertonic solutions. Am J Physiol 1955;180:545-558.

70. Lien Y-HH, Shapiro JI, Chan L. Effects of hypernatraemia on organic brain osmoles. J Clin Invest 1990;85:1427-1435.

71. Gullans SR, Verbalis JG. Control of brain volume during hyperosmolar and hypo-osmolar conditions. Annu Rev Med 1993;44:289-301.

72. Arieff AI, Kleeman CR, Keushkerian A, Bagdoyan H. Studies on mechanisms of cerebral edema in diabetic comas. Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. J Clin Invest 1973;52:571-583.

Diabetes Mellitus

53

73. Arieff AI, Guisado R, Lazarowitz VC. CH 11 Pathophysiology of hyperosmolar states. In:

Andreoli TE, Grantham JJ, Rector SC Jr, ed. Disturbances in body fluids. Bethesda: American Physiological Society, 1977:227-250.

74 . Cruz-Caudillo JC, Sabatini S. Diabetic hyperosmolar syndrome. Nephron 1995;69:201-210.

75. Arieff AI, Carroll HJ. Cerebral edema and depression of sensorium in nonketotic hyperosmolar coma. Diabetes 1974;23:525-531.

76. Daugirdas JT, Kronfol NO, Tzamaloukas AH, Ing TS. Hyperosmolar coma: cellular dehydration and the serum sodium concentration. Ann Intern Med 1989;110:855-857.

77. Morres CA, Dire DJ. Movement disorders as a manifestation of nonketotic hyperglycemia. J Emerg Med. 1989;7:359-364.

78. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine 1972;51:73-94.

79. Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Am J Med 1984;77:899-904.

80. Small M, MacCuish AC. The hyperglycaemic, hyperosmolar non-ketotic syndrome: some aspects of management. Scottish Med J 1987;32:35-37.

81. To LB, Phillips PJ. Hyperosmolar non-ketotic diabetic coma - less sodium in therapy?. Anaesth Intens Care 1980;8:349-352.

82. Penn I. Diabetes mellitus and the surgeon. Curr Probl Surg 1987;September:540-603. 83. Palumbo PJ. Blood glucose control during surgery. Anesthesiology 1981;55:94-95. 84. Schade DS. Surgery and diabetes. Med Clin N Am 1988;72:1531-1543. 85. Alberti KGMM, Thomas DJB. The management of diabetes during surgery. Br J Anaesth

1979;51:693-710. 86. Rossini AA, Hare JW. How to control the blood glucose level in the surgical diabetic

patient. Arch Surg 1976;111:945-949. 87. Alberti KGMM. Diabetes and surgery. Anesthesiology 1991;74:209-211. 88. Hirsch IB, McGill JB, Cryer PE, White PF. Perioperative management of surgical patients

with diabetes mellitus. Anesthesiology 1991;74:346-359. 89. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M,

Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367.

90 . Service FJ. Hypoglycemic disorders. N Engl J Med 1995;332:1144-1152. 91. Gale E. Causes of hypoglycaemia. Br J Hosp Med 1985;33:159-162. 92. Field JB. Hypoglycemia. Definition, clinical presentations, classification, and laboratory

tests. Endocrin Metab Clinis N Amer 1989;18:27-43. 93. Seltzer HS. Drug induced hypoglycemia. A review of 1418 cases. Endocrin Metab Clinis

N Amer 1989;18:163-183. 94. Lager I, Blohme G, Smith U. Effect of cardioselective and non-selective beta-blockade on

the hypoglycaemic response in insulin-dependent diabetics. Lancet 1979;i:458-462. 95. Alberti KGMM. Diabetic emergencies. Br Med Bull 1989;45:242-263. 96. Vinik AI. Moattari AR. Treatment of endocrine tumors of the pancreas. Endocrinol Metab

Clin North Am 1989;18:483-518. 97. Krentz AJ, Boyle PJ, Justice KM, Wright AD, Schade DS. Successful treatment of severe

refractory sulfonylurea-induced hypoglycemia with octreotide. Diabetes Care 1993;16:184-186.

Diabetes Mellitus

54

98. McLaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for sulfonylurea-

induced hypoglycemia. Ann Emerg Med 2000;36:133-138.

55

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). page 1. Discuss the complications of intravenous

hydrocortisone when used in the management of a patient with septic shock

Dr. T. Wigmore 57

2. Discuss the clinical features and management of a patient with pancreatic abscess.

Dr. C. Graves 59

3. Discuss the indications and complications of intravenous amiodarone.

Dr. D. Morgan 61

4. Compare and contrast the effects of inhaled no and nebulised prostacyclin in a patient with ARDS

Dr. J. Cohen 66

5. Discuss the indications for, mechanism of action and complications of intravenous mannitol.

Dr. P. Goldrick 69

6. Discuss the management of a patient who develops severe thrombocytopenia and acute mesenteric artery thrombosis five days following iv unfractionated heparin for an acute PE.

Dr. P. Liston 71

7. discuss the indications and composition of lactate free dialysis.

Dr. D. Ghelani 74

8. Discuss the current indications and contraindications of intravenous lignocaine.

Dr. G. Brieva 76

9. Discuss the management of a one day post abdominal aortic aneurysm patient who has had an acute anterior myocardial infarct.

Dr. E. Trent 78

10. Discuss the management of a severely hypoxic patient who has been paralysed with suxamethonium whom you are unable to intubate or ventilate.

Dr. R. O’Connor 81

11. Discuss the management of a patient with severe verapamil overdosage.

Dr. P. Nelson 84

12. Discuss the clinical features and management of a patient with a sagittal sinus thrombosis.

Dr. B. Welch 86

13. Discuss the management of a patient with an acute central venous line candida septicaemia and endophthalmitis who develops oliguria and a progessive rise in plasma creatinine.

Dr. H. Koelzow 89

14. Discuss the clinical features and management of a patient with diastolic heart failure.

Dr. B. O’Brien 92

15. Discuss the indications and complications of intravenous octreotide

Dr. S. Morphett 94

16. Discuss the aetiology and management of a patient with hepatopulmonary syndrome and portopulmonary hypertension.

Dr. C. Allen 97

17. Discuss the causes and treatment of torsades de pointes.

Dr. M. McNamara 100

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18. Discuss the indications for and mechanism of action of intravenous activated protein C in a septic patient.

Dr. S. Sturland 104

19. Discuss the management of a patient with methyl alcohol poisoning.

Dr. A. Dennis 108

20. Discuss the indications for inhaled antibiotic therapy and what antibiotics have been used.

Dr. M. Saxena 111

21. Discuss the indications for and complications of intravenous calcium chloride during a cardiac arrest.

Dr. O. Sheffer

22. Describe the method used and the indications for the positions of insertion of an intercostal drain.

Dr. U. Kadam

23. Discuss all the methods used to improve the liklihood of a successful cannulation of a central vein.

Dr. S. Wilson

24. Discuss the indications and complications of intravenous calcium chloride.

Dr. S. Hockley

25. Define and list the causes and management of a ventilator associated pneumonia.

Dr. K. Deshpande

26. Discuss the clinical presentation and management of a patient who has an acute Budd-Chiari syndrome.

Dr. C. Bradford

27. Discuss the causes, clinical features diagnosis and management of a patient with an acute viral encephalitis.

Dr. C. Cody

28. Discuss the clinical features and management of a patient who has an acute acalculus cholecystitis.

Dr. D. Charlesworth

57

DISCUSS THE COMPLICATIONS OF INTRAVENOUS STEROIDS WHEN USED IN THE MANAGEMENT OF A PATIENT WITH SEPTIC SHOCK

Dr. T. Wigmore, Intensive Care Unit, Westmead Hospital, NSW The use of steroids in septic shock was originally contemplated due to their well known anti-inflammatory properties. They have been shown to inhibit inducible NO synthesis, prevent leucocyte aggregation and adhesion induced by exotoxin. In addition they decrease platelet activating factor, tumour necrosis factor and interleukin-1 release and prevent prostaglandin generation through induction of phospholipase A2 inhibitor. In consideration of the complications of steroids in septic shock it is important to distinguish between the early practice of giving large doses of steroids and that more recently adopted of giving “physiological doses” . Initial trials were conducted with ‘industrial’ doses of corticosteroids. An early report by Schumer1 suggested that treatment with either dexamethasone or methylprednisolone dramatically improved survival in patients with septic shock. As a result the administration of 2g of methylprednisolone became the defacto standard of care for proven or suspected septic shock during the late 1970s and early 1980s. In 1984 however Sprung et al2 showed that although a transient survival benefit was afforded to patients randomised to receive either dexamethasone or methylprednisolone, the improvement was not durable and the hospital mortality rates were similar for both groups A subsequent multi-centre RCT by Bone et al3 showed an increased mortality in the steroid group. Two meta-analyses4,5 of corticosteroid treatment were published in Critical Care Medicine in 1995, both showing increased mortality in the steroids group. Below is a list of the side effects found. 1. Significant increased mortality in patients with overwhelming infection RR 1.13 2. Trend towards increased mortality in the subgroup with septic shock RR 1.07 3. Trend towards increased mortality overall RR 1.10 4. Increased gastrointestinal bleeding RR 1.17 5. 3 studies reported increased hyperglycaemia in the steroid group (although hyperglycaemia

was not defined)1,6,7 6. One study reported increased blood urea in the steroid group8 7. Two double blind studies3,7 reported a trend towards increased cause-specific mortality in

patients receiving corticosteroids (RR 1.7, No overall increase was found in the meta-analyses).

More recent studies have concentrated on the use of physiological doses of corticosteroids

(200mg per day of hydrocortisone with some recommending the addition of 50 µg of fludrocortisone), particularly in functionally hypoadrenal patients (as classified in the recent Annane et al paper10). Annane et al,11 found an improvement in 28-day survival in patients with relative adrenal insufficiency who were treated with corticosteroids according to the above regimen. (although the statistics performed to show this are hugely complex and a more simple analysis would not appear to be so conclusive.) Interestingly Bollaert et al,9 also showed a trend towards improved survival in patients treated this time with 300 mg of hydrocortisone irrespective of response to a corticotropin test. In neither paper was there an excess of adverse events, suggesting that the earlier observed side effects with the use of steroids were related to dosage.

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References 1. Schumer W: Steroids in the treatment of clinical septic shock. Ann Surg 184:333-340 2. Sprung CL, Caralis PV, Marcial EH: The effects of high-dose corticosteroids in patients

with septic shock: a prospective, controlled study. NEJM 311:1137-1145 3. Bone RC, Fisher CJ Jr, Clemmer TP et al: A controlled clinical trial of high dose methyl

prednisolone in the treatment of severe sepsis and septic shock. NEJM 317:653-661 4. Cronin L, Cook DJ et al: Corticosteroid treatment for sepsis. CCM 1995;23(8):1430-1436 5. Lefering R, Neugebauer: Steroid controversy in sepsis and septic shock. CCM

1995;23(7):1294-1303 6. Luce JN, Montgomery AM, Marks JD et al: Ineffectiveness of high dose

methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988; 138: 62-68

7. The Veterans Administration Systemic Sepsis Cooperative Study Group: Effect of high dose glucocorticosteroid therapy on mortality in patients with clinical signs of systemic sepsis. NEJM 1987; 317:659-665

8. Slotman G, Fisher C, Bone R: Detrimental effects of high dose methylprednisolone on serum concentration of hepatic and renal function indicators in severe sepsis and septic shock. CCM 1993; 21:191-195

9. Bollaert P-E, Charpentier C, Debouverie M, et al: Reversal of late septic shock with supraphysiologic doses of hydrocortisone. CCM 26:645, 1998

10. Annane D, Sebille V, Troche G, et al: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283:1038, 2000

11. Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862, 2002

59

DISCUSS THE CLINICAL FEATURES AND MANAGEMENT OF A PATIENT WITH PANCREATIC ABSCESS

Dr. C. Graves. Division of Critical Care, Royal Brisbane Hospital, Queensland The Atlanta classification defines pancreatic abscess as “a circumscribed collection of pus, containing little or no pancreatic necrosis, which arises as a consequence of acute pancreatitis or pancreatic trauma”. Incidence reported at 1-5% following acute pancreatitis and is often associated with gastrointestinal fistulas, pseudoaneurysms and not uncommonly with multi-organ dysfunction. Microbiology may be mono-microbial (~50%) or poly-microbial (~50%). Culturing E. coli (35-50%), Klebsiella spp. (13-25%), Enterococcus spp. (7-28%), Staphylococcus spp. (14-36%) and occasionally Streptococcus spp., Bacteroides spp. and Candida spp. (all <9%). Infection is the result of translocation of bacteria across damaged bowel and secondary haematogenous spread. Mortality has previously been reported as high (20-60%) due to lack of standard nomenclature and subsequent inclusion of infected pancreatic necrosis. Currently, treated pancreatic abscess has a mortality of 2-14% % due to multi-organ failure, septic shock or haemorrhage. Treated infected pancreatic necrosis has a mortality of 20-40%. Infected pseudocysts have the least mortality. Presentation is heralded > 4 weeks after the onset of acute pancreatitis by persistent or worsening pain and localised tenderness (80-100%), fever esp. if > 39.5C (50-100%), nausea, vomiting and an abdominal mass (22-85%). There may be an associated left sided pleural effusion or an enlarging spleen secondary to splenic vein thrombosis. Diagnosis is dependent on clinical vigilance and suspicion and confirmed by rapid-infusion contrast CT scanning. Management involves: 1. Supportive care and early recognition of complications. 2. Broad spectrum antibiotics. 3. Drainage

a) Endoscopic stenting is an emerging treatment modality with ~9% in-hospital patient mortality which is comparable to surgical drainage and involves an average of two ERCP procedures.

b) Percutaneous radiological drainage has an increasing role in selected patients (i.e. single abscess, no loculations and an adequate window for drainage). Advantages include being minimally invasive and it may provide definitive treatment. If not resolved by 7-10 days a repeat CT scan is indicated and surgery or a second catheter considered. Complications include pancreatic (cutaneous or gastrointestinal) fistulas, empyema or bleeding. Requires Surgical and Radiological liaison.

c) Surgical management is the mainstay for patients with multi-organ dysfunction or those unsuitable for percutaneous drainage or for complications of drainage. Complications include fistulas and post-operative bleeding.

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4. Nutrition is by enteral (jejunal) feeding or TPN and avoidance of recommencing oral intake too early. References 1. Baril,N et al. Does Infected Peripancreatic Fluid Collection or Abscess Mandate

Operation?. Ann. Surg. 2000; 231(3):361-367. 2. Srikanth, G. et al. Pancreatic Abscess: 10 Years Experience. ANZ. J. Surg. 2002; 72:881-

886. 3. Venu RP et al. Endoscopic transpapillary drainage of pancreatic abscess: technique and

results. Gastrointest Endosc 2000; 51:391-5.

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DISCUSS THE INDICATIONS AND COMPLICATIONS OF INTRAVENOUS AMIODARONE

Dr. D. Morgan. Intensive Care Unit, Royal Perth Hospital, Newcastle, WA Description • Amiodarone has been described as a class III (drugs that slow the flow of potassium into

heart cells and prolongs the duration of the action potential) antiarrhythmic drug but in reality its effects extend across multiple mechanisms of action including effects on sodium, potassium, and calcium channels; as well as α and β adrenergic blocking properties.

• When given intravenously, amiodarone has little class III effect; the major action is on the AV node, causing a delay in intranodal conduction and prolongation of refractoriness

Indications (Supraventricular arrhythmias) • AF

o Incidence General population

• Overall 1-2% • < 60 years old 0.4% • > 60 years old 2-5%

AMI 10-15% • ↑ Mortality risk due to decreased LV function

CCF 40% Critically Ill 15% 3-5% Non cardiothoracic major surgery Usually reflects a combination of

• Cardio-respiratory disease • Adrenergic stress

o Conversion1,2 Spontaneous

• 60-65% at 24hours Amiodarone

• 72-82% at 24 hours Compared with other anti-arrhythmic drugs

• Of equal efficacy o Post CABG Prophylaxis3,4

Incidence • CABG 30% • Post valvular surgery 50%

Prophylactic amiodarone use • Reduces the rate of post CABG AF by ~ 50%

Possible role in poor risk patients • Large left atrium • Advanced age • Low ejection fraction

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o High Dose Amiodarone5 3 gram per day (125 mg/hr) Conversion at 24 hours

• Placebo 64% • Amiodarone 92% (p=0.0017)

Crossover • 85% of those not converting to placebo converted with high

dose amiodarone • All patients not responding to amiodarone where still in AF at

one month • WPW

o Safe choice in antidromic conduction • Unstable SVT7

o In patients with severely impaired heart function IV amiodarone is preferable to other antiarrhythmic agents for atrial tachyarrhythmias

• Paediatric SVT6 o Amiodarone is safe and effective

Indications (Ventricular Arrhythmias) • Stable VT7

o Listed on the 2000 ILCOR guidelines as a first line option for the “Stable Ventricular Tachycardia Algorithm”

o Class IIb (possibly helpful) • Unstable VT7,8,9

o Patients with CCF and depressed myocardial function should be treated cautiously with antiarrhythmic therapy

o In patients with severely impaired heart function IV amiodarone is preferable to other antiarrhythmic agents for ventricular tachyarrhythmias

o Amiodarone has the least additional impairment on LV function and has shown to be effective in treating haemodynamically unstable VT and VF

o The negatively inotropic and vasodilatory effects of amiodarone are dose and rate dependent

• Cardiac Arrest7 o ILCOR Guidelines for pulseless VT or VF

300 mg IV push 150 mg second dose IV push Maximum dose 2,200 mg over 24 hours Class IIb evidence (possibly helpful)

o ARREST Trial10 o (Amiodarone in out-of-hospital Resuscitation of REfractory Sustained ventricular

Tachyarrhythmias trial) Adults with non-traumatic out-of-hospital cardiac arrest were eligible for

inclusion if VF or pulseless VT was present were then randomly assigned to receive either amiodarone I.V. 300 mg or placebo (diluent).

Total patients 504 • Amiodarone 246 • Placebo 258

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The majority of patients in both groups were male, ≥65 years, and presented with ventricular fibrillation as the initial cardiac arrest rhythm.

Survival to hospital admission • Amiodarone 44% • Placebo 34% (P = 0.03)

But survival to hospital discharge was similar • Amiodarone 13.4% • Placebo 13.2%

Hypotension (the need for vasopressor infusions) and bradycardia (the need for chronotropic therapy) were significantly more common in the amiodarone group (59% vs. 48% and 41% vs. 25%, respectively).

There are some limitations to the wider applicability of this study. It took place in Seattle and King County, Washington, where response times are extraordinarily short (dispatch to arrival of first responder was 4.3 min).

Many would argue that an intervention that has been shown to improve survival to hospital admission, but not to hospital discharge neurologically intact, should not be adopted without data on long-term outcome

o ALIVE Trial11 o (Amiodarone vs. Lignocaine in Prehospital Refractory Ventricular Fibrillation

Evaluation) Enrolled patients between November 1995 and June 2000 Amiodarone vs. lignocaine

• Amiodarone 5mg/kg and 2.5 mg/kg • Lignocaine 1.5 mg/kg and 1.5 mg/kg

Total patients enrolled 347 (no difference in baseline characteristics) • Amiodarone 180 patients • Lignocaine 167 patients

Average time to drug therapy 25 minutes Endpoints

• Primary o Survival to admission to hospital

Amiodarone 22.7% Lignocaine 11.0% (p = 0.009)

o Survival rates much higher if patients received treatment in under 25 minutes

o Lower survival rates to hospital when compared with ARREST trial (44% vs. 23%)

• Secondary o Hospital discharge

Amiodarone 5% Lignocaine 3% (P=0.34)

In comparison with the Seattle study, the mean interval to first defibrillation was 2.5 minutes longer and the interval to study drug administration was 4 minutes longer.

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COMPLICATIONS • Adverse Effects12

o The most common adverse effect seen with intravenous amiodarone during controlled and open-label clinical trials were

Hypotension 16% • If hypotension does occur, slow the infusion rate. In addition,

standard supportive therapy may be required, including the use of vasopressor drugs, positive inotropic agents, and volume expansion

Bradycardia 4.9% Liver function test abnormalities 3.4% Cardiac arrest 2.9% VT 2.4%

• Like all antiarrhythmic drugs, amiodarone I.V. may exacerbate or precipitate arrhythmias.

• Proarrhythmia, primarily torsades de pointes, has been associated with amiodarone I.V. prolongation of the QTc interval to 500 ms or greater.

• Although QTc prolongation occurred frequently in patients receiving amiodarone I.V., the frequency of torsades de pointes or new-onset VF was <2%.

• Patients should be monitored for QTc prolongation during infusion with amiodarone I.V.

Congestive heart failure 2.1% Cardiogenic shock 1.3% AV block 0.5%

• Drug Interactions o Caution should be used when using amiodarone with drugs that have either

antiarrhythmic, vasodilatory or myocardial depressant properties o Conversely, drugs producing a significant effect on amiodarone pharmacokinetics

include phenytoin, cimetidine, and cholestyramine. • Contraindications

o Intravenous amiodarone is contraindicated in patients with Known hypersensitivity Cardiogenic shock Marked sinus bradycardia Second- or third-degree AV block unless a functioning pacemaker is

available References 1. Chevalier P, Durand-Dubief A, Burri H, Cucherat M, Kirkorian G, Touboul P.

Amiodarone versus placebo and class IC drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2003 Jan 15; 41(2):255-62

2. Hilleman DE, Spinler SA. Conversion of recent-onset atrial fibrillation with intravenous amiodarone: a meta-analysis of randomised controlled trials. Pharmacotherapy 2002 Jan;22(1):66-74.

3. Daoud EG, Strickberger SA, Man KC, et al Preoperative Amiodarone As Prophylaxis Against Atrial Fibrillation After Heart Surgery N Engl J Med 337: 1785-1791, 1997

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4. Crystal E, Connolly SJ, Sleik K, Ginger TJ, Yusuf S Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation 2002 Jul 2;106(1):75-80

5. Cotter G, Blatt A et al. Conversion of recent onset paroxysmal atrial fibrillation to normal sinus rhythm: the effect of no treatment and high-dose amiodarone: a randomised, placebo controlled study. Eur Heart J 1999; 20:1833-42

6. Soult JA. Munoz M. Lopez JD. Romero A. Santos J. Tovaruela A. Pediatric Efficacy and safety of intravenous amiodarone for short-term treatment of paroxysmal supraventricular tachycardia in children Cardiology. 16(1):16-9, 1995.

7. Advanced cardiovascular life Support. ILCOR Guidelines. Circulation 2000; 102 (supplement I)

8. Kowey PR, Levine JH, Herre JM, et al. Randomized, doubleblind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. Circulation. 1995;92:3255–3263.

9. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. Circulation. 1995; 92:3264–3272.

10. Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE, Hallstrom AP, Murray WA, Olsufka M, Walsh T. ARREST Trial: Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999 Sep 16; 341(12): 871-8

11. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A. ALIVE Trial: Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med 2002 Mar 21;346(12): 884-90.

12. Cordarone® I.V. Prescribing Information,Wyeth-Ayerst Laboratories.

66

COMPARE AND CONTRAST THE EFFECTS OF INHALED NO AND NEBULISED PROSTACYCLIN IN A PATIENT WITH ARDS

Dr. J. Cohen. Intensive Care Unit, Royal Brisbane Hospital, Queensland Nitric Oxide Nitric Oxide (NO) is a colourless, almost odourless gas that is slightly soluble in water. Environmental NO arises from combustion processes (fossil fuel combustion and tobacco smoke) and lightning. Atmospheric concentrations of NO usually range between 10 and 500 parts per billion (ppb) but can exceed 1.5 parts per million (ppm) in areas of heavy traffic. Endogenous NO arises from the action of the enzyme Nitric Oxide Synthase (NOS) on L-arginine, producing L-citrulline and NO. Three NOS isoforms have been identified, and classified according to the tissue in which they were first observed, and their regulation of activity. Constitutive neuronal NOS was initially described in neuronal tissue; Inducible NOS (iNOS) is expressed in a variety of inflammatory cells; and constitutive endothelial NOS was initially described in vascular endothelial cells. NO for medical administration is supplied in pressurised cylinders and requires specialised apparatus to ensure accurate delivery and monitoring . Mechanism of action NO activates soluble guanylate cyclase, which catalyses the conversion of guanosine 5 triphosphate to cyclic 3’:5’ GMP (cGMP). cGMP activates a variety of intracellular protein kinases to relax smooth muscle, inhbit leukocyte adhesion, platelet adhesion, and cellular proliferation. The action of cGMP is limited by phosphodiesterases which convert cGMP to GMP. Effects in Lung Injury Selective vasodilation of ventilated areas, resulting in improved ventilaton/perfusion matching. May lead to improved right ventricular performance, with improvements of RV ejection fraction and reduced RV end diastolic and systolic volumes. Decrease in pulmonary artery pressures and pulmonary vascular resistance. Rapid uptake and inactivation by hemoglobin prevents systemic effects. Decrease in pulmonary capillary pressure and pulmonary transvascular albumin flux, caused partly by effect on pulmonary venous resistance. May promote resolution of pulmonary oedema. Improvement in arterial oxygenation demonstrated in a number of human and animal studies, with reduction in shunt fraction and improved FiO2/PO2 ratios. Bronchodilator activity, although appears to be mild in studies of human volunteers. Interaction with pulmonary surfactant in animal models suggest it may reduce surfactant production and reduce its efficacy. Human trials suggest that about 50% of patients with ARDS will respond to inhaled NO therapy , but no outcome benefit in terms of mortality or reduced ventilatory time has been demonstrated. Metabolism Half life of NO in vivo is only a few seconds as it is rapidly inactivated by binding to haemoglobin, with subsequent release of NO3. Approximatly 90% of NO is absorbed during a steady state inhalation. Almost 70% of the inhaled gas appears within 48hrs as NO3 in the

67

urine. The remaining 30% is recovered as NO2 in the oral cavity through secretion from the salivary glands. NO2 is also partly converted to nitrogen gas in the stomach and some NO2 in the intestine is reduced to ammonia, reabsorbed, and converted to urea. Toxicity Reaction with haemoglobin results in the production of methaemoglobin (Fe 3+ haemoglobin). Most of the methaemoglobin created is reduced back by NADH cytochrome b5/cytochrome b5 methaemoglobin reductase within erythrocytes. NO reacts with oxygen to produce NO2. High levels of NO2 in animal models (> 10ppm) induced pulmonary oedema, alveolar haemorrhage, changes in surfactant surface tension, intrapulmonary accumulation of fibrin, neutrophils, and macrophages, and death. NO stimulates cGMP formation within platelets and can inhibit platelet function and augment the bleeding time. Sudden discontinuation of NO therapy may lead to severe rebound hypoxia and right ventricular failure. Prostacyclin Prostacyclin (PGI2) is a member of the prostaglandin family of lipid mediators derived from arichadonic acid and is synthesized predominantly by endothelial cells, including the pulmonary vascular endothelium. Supplied as a powder which must be dissolved in the glycine buffer provided by the manufacturer before use. After reconstitution it is stable for up to 12 hours at room temperature, and 48 hours if refrigerated. The solution must be protected from light to prevent photodegredation.Administration is via a standard nebuliser over 20 – 30 minutes at flow rates of 8l/min. Mechanism In contrast to NO, PGI2 activates adenylate cyclase to produce adenosine-3,5-cyclic monophosphate. The result is similar in producing smooth muscle relaxation. PGI2 is also the most potent known inhibitor of platelet aggregation, and has been shown to stimulate the release of NO from endothelial cells. Effects in Lung Injury Production of selective pulmonary vasodilation in a similar manner to NO. Has been shown to decrease pulmonary artery pressures, with significant increases in Pa02/FiO2 ratios. Efficay compared to INO appears similar, with one study showing both agents producing a 7% decrease in measured shunt and comparable improvements in PaO2. However PGI2 produced a greater decrease in PVR than NO. Further studies have suggested that NO may produce a greater oxygenation benefit than PGI2, and that PGI2 may generally only be effective in patients with ARDS caused by extrapulmonary disease. Percentage of responders appears similar to NO, with about 50% of patients showing an oxygenation benefit. No data on outcomes is available. Metabolism PGI2 is spontaneously hydrolysed at neutral plasma pH to its inactive metabolite, 6-keto-prostaglandin-f1. In vitro half life is approximately 6 minutes. Inhaled PGI2 is not metabolised within the lung to any significant extent. Systemic absorbtion can be determined by measurement of serum 6-kpf levels.

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Toxicity and side effects No known toxic metabolites.Rebound pheneomenen may be potential hazard, but there are no case reports. Produces platelet inactivation, but a study in post operative cardiac patients failed to show any clinically significant bleeding problems. REVIEW Nitric Oxide Prostacyclin Similar response rates (50%) Selective pulmonary vasodilator • Envoiromental Gas Arichadonic acid derivative • Requires specialised No specialised eqipment delivery apparatus needed. • Acivates guanylate cyclase Activates adenylate cyclase • Platelet inhibitor Profound platelet inhibitor • Mild bronchodilator Conflicting reports on effect on bronchial tone • Reduction in transvascular albumin flux • May produce greater May produce greater improvement in PaO2 decrease in PVR May be ineffective in intrinsic ARDS • Produces methaemaglobinaemia • Has toxic metabolites • Rebound phenomena Rebound phenomena not demonstrated documented Cheaper More readily available • No outcome benefit Data on outcome benefit demonstrated lacking References 1. Lowson, SM. Inhaled Alternatives to Nitric Oxide. Anesthesiology 2002, 96 6. 2. Steudel W, Hurford WE, Zapol WM, Fischer DM .Inhaled Nitric Oxide. Basic biology

and clinical applications.. Anesthesiology 1999, 91, 4. 3. Walmrath D et al Direct Comparison of Inhaled Nitric Oxide and Aerosolized

Prostacyclin in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med;1996;153 991-996.

4. Haraldsson A et al. Inhaled prostacyclin and platelet function after cardiac surgery and cardiopulmonary bypass. Int Care Med 2000;26; 188-94.

69

DISCUSS THE INDICATIONS FOR, MECHANISM OF ACTION AND COMPLICATIONS OF INTRAVENOUS MANNITOL

Dr. P. Goldrick. Intensive Care Unit, Townsville Hospital, Queensland Mannitol is a low MW alcohol (MW182). It presents as a 10% solution (549mosmol/l) or a 20%solution (1098mosmol/l).1 Administered IV it is not metabolised. It is freely filtered in the kidneys, with little re-absorption. The elimination T1/2 is 70min.2 PROPOSED INDICATIONS AND MECHANISMS OF ACTION 1. Effects on intracranial pressure (ICP) & cerebral blood flow (CBF)3 1. Immediate Effect: (15-30 mins) increase in cerebral blood flow (CBF) 20 to a increase in

circulating volume, improved viscosity, and a reduction in ICP mediated by vasoconstriction of pial arteries.4

2. Delayed effect. Reduction in brain mass 20 osmotic shrinkage and reduced CSF formation (onset 30-60min and lasts up to 6hrs)

3. Scavenging free hydroxyl radicals Indications (i) Management of raised ICP in traumatic brain injury (TBI) A bolus dose of IV mannitol (0.25-1.0 g/kg) may be effective in management of raised ICP in

the context of TBI with evidence transtentorial herniation. Need maintain euvolemia & serum osmolarity less than 320mosmoles [Level 2 Evidence].

(ii) Reduction infarct size & improvement outcome in stroke (No conclusive evidence).5 (iii) Improving neurosurgical field access with reduction in brain mass (iv) Management of raised ICP in acute hepatic encephalopathy.2

(v) Reduction in cerebral oedema associated with DKA 2. Renal Effects6

Increased renal blood flow and GFR (via ⇓ renal vasc resistance-direct & Indirect effects via changes in circulating volume & blood viscosity)

Diuretic/natriuretic-osmotic (30%filtered H2O, 15% filtered Na) Dissipation of medullary hypotonicity Scavenging free radicals

Post op cadaveric renal transplant oliguria – probable some benefit in graft protection.6 Contrast nephropathy,7 oliguric renal failure, peri-operative renal protection (major vasc. surgery) and myoglobinuric nephropathy diuretic effect established BUT no level 1 or 2 data for outcome.8 3. Reduction of raised Intra-ocular pressure (IOP) 4. Ciguatera poisoning. A dinoflagellate toxin that accumulates at the top of the food chain from algae near dead corals and causes acute Na channel block axonopathy characterised by GI, CVS, neurologic symptoms. Mannitol has been accepted as the treatment of choice in CP, on the basis of reversal of Na channel block & reduced neuronal oedema. Not borne out by only prospective controlled trial.9

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3. Complications of IV Mannitol Therapy 1. Circulatory overload and acute pulmonary oedema 2. Uremic renal failure 20 dehydration 3. ⇑ renal oxygen demand 4. Osmotic nephrosis: reversible vacuolisation of renal tubules with high dose mannitol 5. Electrolyte abnormalities, K (⇓), Mg (⇓), Na (⇓or⇑) 6. Agglutination with red cell transfusion 7. Rebound ⇑ ICP 8. Accumulation in cerebral tissues after breakdown of BBB with theoretical risk of reverse osmotic effect 9. Irritant to tissues/veins 10. Crystallises at low temperatures References 1. MIMS Annual 2001 2. Sasada M, Smith S. Drugs in Anaesthesia and Intensive care. Oxford University Press,

1997 3. Brain Trauma Foundation. The American Association of Neurological Surgeons. The

Joint Section on Neurotrauma and Critical care. Management & Prognosis of Severe Traumatic Brain Injury. Use Of Mannitol Journal of Neurotrauma 17 (6-7): 521-5, 2000 June-July

4. Schrot RJ, Muizelaar JP. Mannitol in Acute Traumatic Brain Injury. Lancet. 359 (9318): 1633-4, May 11 2002

5. Bereczki D, et al. Cochrane Report. A systematic review of mannitol for acute ischaemic stroke and cerebral parenchymal haemorrhage. Stroke 31(11): 2719-22, 2000 November

6. Better SB, Rubinstein I, Mannitol Therapy Revisited. Kidney International 52(4) pp 886-894 October 1997

7. Solomon R, Werner C, Mann D, et al. Effects of Saline, Mannitol, and Furosemide on Acute Decreases in Renal Function Induced by Radiocontrast Agents. New England Journal of Medicine 331(21):1416-1420 November 24, 1994

8. Dishart MK, Kellum JA. An evaluation of pharmacological strategies for the prevention and treatment of acute renal failure. Drugs 59(1) 79-91, January 2000

9. Schnorf H, Taurarii M, et al Ciguatera fish poisoning. A double blind randomised trial of mannitol therapy. Neurology 58 pp873-880, March 2002

71

DISCUSS THE MANAGEMENT OF A PATIENT WHO DEVELOPS SEVERE THROMBOCYTOPENIA AND ACUTE MESENTERIC ARTERY THROMBOSIS

FIVE DAYS FOLLOWING IV UNFRACTIONATED HEPARIN FOR AN ACUTE PE

Dr. P. Liston. Intensive Care Unit, Liverpool Hospital, NSW The following issues are identifiable 1. Acute PE, and its cardiorespiratory complications. 2. Heparin-induced thrombocytopenia (HITS) such that they have a thrombotic tendency and the need for alternative anticoagulation for the treatment of PE. 3. Acute mesentenc artery thrombosis with ischaemic gut and possible hypovolaemia, sepsis and septic shock. 4. The patient needs urgent surgery which will be complicated by thrombocytopenia and the medical condition. HITS and its treatment Thrombocytopenia is a well recognised complication of heparin therapy. HITS is an immune mediated disorder that classically occurs 4-10 days after commencement of therapy. IgG & IgM antibodies are provoked by the complex of heparin & platelet factor 4 on the platelet surface. This complex binds to the platelet surface and leads to further activation of the platelet with further release of PF4 creating a positive feedback loop. This leads to removal of platelets from the circulation & thrombosis. (Another form of thrombocytopenia can also occur with an earlier, transient lesser drop in platelet count, which is of no clinical consequence). The drop in platelet count is rarely below 20,000 & mostly about 60,000 so spontaneous bleeding is unusual. Surgical bleeds occurs in counts < 50,000. Treatment 1. Stop heparin

avoid LMWH as it may cross react with heparin induced antibodies. Don’t recommence UFH until antibodies are cleared & then for only short period. Don’t give warfarin until thrombocytopenia has resolved

2. Obtain diagnosis Thrombocytopenia in setting of heparin > 4 days Serotonin release assay ( the gold standard ) Heparin induced platelet antibody assays (HIPAA)

3 Commence alternative anticoagulation (as patients at risk for thrombosis, but in this case defer in the presence of the need for urgent surgery)

Danaparoid: a heparinoid that inhibits factor Xa BUT difficult to monitor, long Tl/2, can’t reverse it. 2500U bolus then infusion (400U decreasing to 200 U/hr )

4. Prevention judicious use of UFH or substitution where appropriate limit use of < 5 days and starting warfarin early

5. Other TEDs & calf compressors

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Ischaemic / infarcted gut & sepsis diagnosis & treatment Unfortunately the signs & symptoms of dead gut appear late in the course of the illness therefore delays in diagnosis & treatment are often inevitable.

acute abdo pain, bloody diarrhoea, fever, tachycardia, hypotension, abdo tenderness, decreased bowels, abdo distension. Peritonism often occurs later when the ischaemia becomes transmural.

AXR is often normal early on, later it may reveal distension, later perforation lschaemic gut can lead to

respiratory failure from abdo pain & distension cardiovascular instability renal dysfunction from dehydration & sepsis haematological disorders anaemia from haemolysis, thrombocytopenia, coagulopathy infection

Treatment should be directed at treating the ischaemic gut urgently resuscitation and correction of the above organ-system failures antibiotics urgent surgical consult &: preparation for surgery

- Decision to operate is based on clinical suspicion as there is no specific test for detecting ischaemia (except angiography)

- Place of Angiography - if the diagnosis is recognised early angiography may be useful to both confirm diagnosis &

treat the occlusion (esp in the setting of HITS) - if peritonitis is present then angio will only delay definitive treatment - Also false positive/false negative results can confuse the issue. - But advantages are that it is widely available, narrrowing can be treated angiographically

(treat spasm with papaverine, and clot can be treated with selective injection of thrombolytic) - complications include reaction to contrast, renal impairment, bleeding Definitive Surgery Failure of angiography should lead to surgery examination of the bowel, assessment of viability vascular reconstruction depends on surgical skill presence of viable bowel non viable bowel should be resected stoma formation leave abdo open second look after 24 hows Thrombocytopenia and bleeding in surgery

platelets should be given depending on the platelet count and on the amount of bleeding recommencement of alternative anticoagulation regimes 24 hrs after surgery (danaparoid)

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References 1. Coutre S. Heparin-induced thrombocytopenia. www.uptodate.com 2002. 2. Evans J. List the clinical features and management of a patient with HIT. ASCICM 1997

Handbook 3. Marston A, Ischaemic bowel OTCC 315-317.

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DISCUSS THE INDICATIONS AND COMPOSITION OF LACTATE FREE DIALYSIS Dr. D. Ghelani, Intensive Care Unit, Queen Elizabeth Hospital, SA Renal replacement therapies in ARF have three major aims; detoxification, fluid elimination and compensation of acidosis. In CRRT, the physical properties of haemofiltration, haemodialysis or haemodiafiltration are therefore used. Three different forms of substitution fluids have been used for haemofiltration. However, acetate -buffered substitution fluids should not be used as they provide lower haemodynamic stability & poor control of acidosis. In present day technique, lactate -buffered or bicarbonate-buffered (lactate free) substitution fluids are used. Up to 1000 mmols/day of bicarbonate is removed by CVVHDF and this needs to be replaced to ensure acid-base balance. Commercially available solutions are lactate buffered, which is converted to bicarbonate on equimolar basis under physiological conditions. The lactate buffer has advantage of greater stability over a physiological bicarbonate buffer. Lactate buffered solutions may lead to daily lactate load of 800-1300 mmol which needs to be converted to bicarbonate by liver. Composition of dialysate fluids: Lactate Buffered Bicarbonate Buffered Solution Solution* Sodium (mmol/L) 142 142 Chloride (mmol/L ) 103 109 Calcium (mmol/L) 2.0 1.66 Potassium (mmol/L ) 0 0 Magnesium (mmol/L) 0.75 0.66 Glucose (mmol/L) 5.6 10 Lactate (mmol/L) 44.5 3 Bicarbonate (mmol/L) 0 33 * Initial solution has sodium concentration of 109 mmol/L, with no bicarbonate ions. Hundred (100) mL of NaHCO3 (8.4%) is added immediately before use to form a buffered normotonic solution. The ready mixed solution is prepared in bags made of special plastic sheeting to prevent evaporation of CO2. To avoid precipitation of calcium & magnesium carbonate, the concentration of these electrolytes is reduced. Phosphate is not included in the solutions. Indications of Lactate free Dialysis: To date only few studies have compared different buffers used in substitution fluids. From these data, following conclusions can be drawn: 1. Control of uraemia within 48 hours with both buffered patients in acutely ill ARF patients is

same. 2. There was no difference in haemodynamic and other parameters (drop in MAP, need for

positive inotropic agents) between the groups with different buffers. 3. Sufficient control of acidosis was achieved with either bicarbonate or lactate-buffered

solutions. In critically ill patients, the physiological capacity of lactate metabolism allows either lactate or bicarbonate buffered solutions without any adverse events. However, hyperlactataemia may result in patients with severely impaired lactate metabolism or high existing lactate levels. Lactate accumulation can be associated with alteration in

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NADH:NAD ratio, increased protein catabolism, increased urea generation & myocardial depression. Therefore, only bicarbonate buffered (Lactate free) solutions are indicated for: 1. Concomitant Liver failure 2. After Liver transplantation 3. Lactic acidosis References

1. Kierdorf H P. Leue C, Arns S. Lactate- or bicarbonate-buffered solutions in continuous extra corporeal renal replacement therapies. Kidney Int 1999;56:Suppl 72:S32-36

76

DISCUSS THE CURRENT INDICATIONS AND CONTRAINDICATIONS OF INTRAVENOUS LIGNOCAINE

Dr. G. Brieva, Intensive Care Unit, John Hunter Hospital, Newcastle, NSW Lignocaine is a group lb anti-arrhythmic and a local anaesthetic agent of the amide type. By blocking the Na/K influx to the cells, it decreases the refractory period on the AV node and Purkinje fibers, reduces the action potential duration and decreases the automaticity and the membrane responses both in the Purkinje fibers and in the neural conduction pathways. On the ECG these effects will reduce the Q-Tc, evidence of shortened repolarization.1 Intravenous doses are based on weight and depending of the indication, usually between 1 and 2 mg/kg as a bolus, however doses up to 4 mg/Kg have been used in status epilepticus. Following initial bolus, maintenance is indicated and plasma levels must be obtained. Current Indications. 2,3,4 √ Serious venfricular arrhythmias (VT/VF) √ Digitalis-induced ventricular tachyarrhythmias √ Routine prophylactic use of lidocaine for the treatment of acute myocardial infarction

(AMI) is NOT recommended, with the possible exception being situations in which a defibrillator is unavailable.5

Not approved reported uses Aortocoronary bypass surgery: prior to clamp release reduces the rate of reperfusion VF.6 Asthma: attenuate reflex bronchoconstriction following inhalational histamine challenge in patients with bronchial hyperreactivity.7 Cough suppression: during cataract surgery.8 Adjunctive therapy for decompression illness.9 Diabetic Neuropathy: effective in reducing painful symptoms.10 Chronic intractable hiccups.11 Infusion-related pain: reduces the incidence of pain associated with propofol.12 Reduces the intracranial pressure increment during endotracheal suctioning.13 Liver function assessment: Principal lidocaine metabolite (MEGX) predicts morbidity and

mortality related to liver disease.14 Peripheral angiography- related pain.15 Postoperative pain control.16 Refractory pruritus.17 Pulmonary artery catheterisation: decreases the risk of mechanically-induced arrhythmias.18 Seizures: reported effective in the treatment of refractory status epilepticus.19 Tinnitus Aurium: can improve or abolish tinnitus.20

Contraindications Hypersensitivity to lignocaine or amide type of local anaesthetics

Precautions Adams-Stokes syndrome Advanced Heart failure Severe degree of SA, AV or intraventricular block Hepatic disease Hypovolaemia Renal disease Shock Sinus bradycardia Wolff-Parkinson-White syndrome

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References 1. Goodman and Gillman Pharmacology 847-849. 2. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of

patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1996;28:1328-1428.

3. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).Circulation 1996a;94:2341-2350.

4. American Heart Association in collaboration with the International Liaison Committee on Resuscitation: Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: an International Consensus on Science. Circulation 2000;102:11-1384

5. Sadawowski ZP, et al. Multicenter randomised trial and a systemic overview of lignocaine in acute myocardial infarction. Am Heart J 1999;137:792-798.

6. Baraka A, et al. Lignocaine for prevention of reperfusion ventricular fibrillation after release of aortic cross-clamping. J Cardiothorac Vasc Anaesth 2000;14:531-533.

7. Groeben H, et al. Both intravenous and inhaled lignocaine attenuate reflex bronchoconstriction but at different plasma concentrations. Am J Respir Crit Care Med 1999;159:530-535.

8. Stewart RH, et al. Lignocaine: an antitussive for ophthalmic surgery. Opthalmic Surg 1988;19:130-131.

9. Cogar WB. Intravenous lidocaine as adjunctive therapy for decompressive illness. Ann Emerg Med 1997;29:284-286.

10. Kastrup J, et al. Treatment of chronic painful diabetic neuropathy with intravenous lidocaine infusion. Br Med J 1986;292:173.

11. Cohen SP, et al. Intravenous lidocaine in the treatment of hiccup. South Med J 2001;94:1124-1125.

12. Ho CM, et al. The optimal effective concentration of lidocaine to reduce pain injection of propofol. J Clin Anesth 1999;4:296-300.

13. Donegan MF, Bedford RF. Intravenously administered lidocaine prevents intracranial hypertension during endotracheal suctioning. Anesthesiology 1980;52:516-518.

14. Orlando R, et al. A reassessment of the optimal sampling time for the MEGX liver function test. Clin Drug Invest 1996;12:181-187.

15. Cranston PE. Lidocaine analgesia in peripheral angiography: a confirmation of effectiveness. South Med J 1982;75:1229-1231.

16. Cassuto J, et al. Inhibition of postoperative pain by continuous low-dose intravenous infusion of lidocaine. Anesth Analg 1985;64:971-974.

17. Fishman SM, et al. Intravenous lidocaine for treatment-resistant pruritis. Am J Med 1997;102:584-585.

18. Sprung CL, et al. Prophylactic use of lidocaine to prevent advanced ventricular arrhythmias during pulmonary artery catheterisation. Am J Med 1983;75:906-910.

19. Anderson Walker L, Slovis CM. Lidocaine in the treatment of status epilepticus. Acad Emerg Med 1997;4:918-922.

20. Israel JM, et al. Lidocaine in the treatment of tinnitus aurium: a double blind study. Arch Otolaryngol 1982;108:471-473.

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DISCUSS THE MANAGEMENT OF A ONE DAY POST ABDOMINAL AORTIC ANEURYSM PATIENT WHO HAS HAD AN ACUTE ANTERIOR MYOCARDIAL

INFARCT

Dr E. Trent. Intensive Care Unit, Royal Perth Hospital, WA Risk /benefit situation. • Risk of bleeding from surgical site if treated conventionally for MI • Risk of death from MI if not treated The aggressiveness of treatment will depend on the clinical severity of the myocardial infarction and surgery related factors. Confirm diagnosis: History, examination, ECG, cardiac enzymes, ECHO (RWMA). ⇒Acute Reperfusion is ultimate goal - restore flow. GENERAL PRINCIPLES OF MANAGEMENT IN THE POST-SURGICAL SETTING Optimise the myocardial supply and demand • Increase Myocardial Oxygen supply: Increase O2 delivery (flow x O2 content)

1. Increase diastolic BP if low, CPP= DBP-LVEDP 2. Transfusion if Hb < 100. (80g/l some) 3. Decrease heart rate - analgesia, beta-blockers 4. Reperfusion is ultimate goal - restore flow 5. Maintain adequate oxygenation

• Decrease myocardial demand 1. Good analgesia 2. Decrease Heart rate, contractility 3. Decrease afterload 4. Treat fever

Initial MI therapy: Aim to relieve ischaemic pain, assess haemodynamic state and correct abnormalities present 1. Oxygen, analgesia- morphine, monitoring in appropriate environment, i.e. continuous ECG,

SPO2, U/O, NIBP +/- arterial pressure, PAC depending on circumstances and pre-existing monitoring

2. Aspirin as soon as possible after the symptoms (2) or Clopidogrel if aspirin not tolerated 3. Intravenous nitroglycerine if ischaemic pain present + for control hypertension and

symptoms of heart failure. No convincing evidence for prophylactic nitrates or continued therapy for 4-6 weeks

4. Beta-blocker: metoprolol or atenolol if no contraindications according to haemodynamic state. (Multiple studies support) Many high-risk vasculopathic patients would have been started on peri operative beta blockage.

Reperfusion therapies Liase with the surgical team about how aggressively you can anticoagulate. Aggressiveness of treatment approach depends to some extent on nature of the operation, other peri operative surgical complications and on the stability of the patient. In an unstable patient with cardiogenic shock you would accept a higher bleeding risk for the benefit of reperfusion. Aspirin/clopidogrel ⇒ heparin ⇒ GIIbIIIa inhibitors?

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1. Primary percutaneous coronary intervention (PCI): therapy of choice with better outcome than thrombolysis (ACC/AHA) in STEMI - consult cardiologists in this peri operative scenario

Issues in this AAA repair patient one-day post op: • Availability in hospital • Access (if through the groin with graft in abdominal aorta), alternative through arm

arteries. • Anticoagulants for PCI: GIIbIIIa , heparin and risk of bleeding at AAA graft site and

epidural space if epidural insitu. Interventional cardiologists in my hospital (RPH) have performed PCI with stenting in this situation with aspirin, clopidogrel, minimal heparin (2500u) and without GIIbIIIa inhibitors and would use femoral access past the new aortic graft.

2. PCI not available or surgical intervention indicated on angiogram; consider CABG consult cardiothoracic surgeons.

3. Thrombolysis is contraindicated one- day post operatively. Anticoagulation issues 1. Heparin infusion: Suggestive but no definitive evidence of benefit post PCI. ACC/AHA

currently recommends as class one evidence. Limits re-thrombosis on an ulcerated plaque. Use for 48hours only unless other reasons to continue like high risk of VT.

2. IV, SC Heparin or LMWH in patients not receiving reperfusion therapy 3. Epidural analgesia sited for post op analgesia may need consideration- epidural haematoma

risk versus benefit of good analgesia. Consult anaesthetists - Removal first then anticoagulate may be the best option.

Early risk stratification High-risk features are older age, previous MI, low BP, tachycardia, heart failure, and anterior MI - so this patient is high risk Patients with none of these features are considered low risk Further medical therapy Depends on the response to the initial regimen ⇒ relief of pain and reduction in ST elevation AND the current haemodynamic profile 1. ACE inhibitors should be given to all patients without a contraindication after first 24 hours.

Caution is necessary with hypotension. HOPE trial - all Caucasian patients might benefit from chronic therapy.3 ATII receptor blockers should not be considered a first line alternative to an ACE unless not tolerated

2. IV/Oral beta-blocker should be continued or begun if no contraindications.4 3. Statin therapy may benefit all patients not just those with LDL cholesterol > 3.2mmol/L.

Benefit within 24-96 hours so begin immediately. Probably via antiinflammatory and lipid lowering effects.5

4. DVT prophylaxis 5. No calcium channel blocker has been shown to reduce mortality in acute MI- restrict to

certain settings 6. Anticoagulation if chronic AF or left ventricular thrombus Complications 1. Cardiogenic shock: supportive care, dobutamine, vasopressors, IABP- Consider abdominal

stent and risk with IABP: Aortic surgical graft - probably OK if balloon above upper

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anastomosis. Endovascular stent may be different because of the spikes into the arterial wall.

2. Arrhythmias: Don’t use antiarrhythmics prophylactically. May be needed to revert or prevent recurrence of SVT and VT. AV nodal and IV Conduction abnormalities may be seen in ST elevation anterior MI’s. Symptomatic bradycardia’s may need temporary pacing

3. Post MI ischaemia in the setting where you have elected not to do PCI -Reconsider revascularisation options.

4. Surgical Bleeding - stop heparin, transfuse, support Discharge planning 1. Depends on the surgical management and complications and the STEMI management 2. Risk stratification - evaluation of LV function (reduced EF is one of the major predictors of

future cardiac events) 2D echo, exercise test if no PCI or CABG performed - timing differs between centres and in different circumstances

3. Lifestyle changes; dietary modification, exercise, smoking cessation, weight loss in obese patients, reducing emotional stress, multifactorial cardiac rehabilitation, treatment of hypertension and diabetes (tight sugar control DIGAMI study.6

References 1. ACC/AHA guidelines for the management of patients with AMI, Circulation 1999;

119:228S 2. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of

death, myocardial infarction, and stroke in high-risk patients. BMJ 2002 Jan 12; 324(7329): 71-86.

3. Effects of an angiotensin-converting-enzyme Inhibitor, ramipril, on cardiovascular events in high risk patients NEJM 2000; 342:145

4. Effect of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: CAPRICORN. Lancet 2001; 357:1385

5. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high risk individuals: a randomised RPCT.Lancet 2002; 360:7

6. Digami study. BMJ 1997 May 24, 314 (7093) General references 7. Up-To-Date 2003 11.1 8. Management of AMI in patients presenting with ST segment elevation. European Heart

Journal 2003 24: 28-66 (From the European society of Cardiology Taskforce - latest published STEMI Guidelines)

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DISCUSS THE MANAGEMENT OF A SEVERELY HYPOXIC PATIENT WHO HAS BEEN PARALYSED WITH SUXAMETHONIUM WHOM YOU ARE UNABLE TO

INTUBATE OR VENTILATE Dr. R. O,Connor, Intensive Care Unit, Port Macquarie Hospital, Port Macquarie, NSW This is a life threatening emergency. Call for assistance immediately. While rare in the operating theatre setting (incidences quoted in the literature range from 1:1,000 in the audit by Parmet et al,1 to 0.2-1:10,000) inability to intubate may occur in 0.5-1% of patients requiring invasive airway management in the Emergency Department or Intensive Care Unit. This is due to a variety of patient and ergonomic factors. Up to 15-20% of these will be difficult to ventilate by bag and mask. There are four management options:- • Cricothyrotomy, either surgical or needle; • Tracheostomy; or • Insertion of a laryngeal mask airway to enable ventilation and subsequent endotracheal

intubation. • Insertion of a Combitube to enable ventilation. Cricothyrotomy The two key problems associated with this procedure are obtaining access and maintaining it. The anatomy may be difficult to identify due to body habitus or pathological factors (e.g. haematoma, abscess, tumour, oedema, neck scarring). Access may be limited by distended veins. The surgical approach is simple in concept - incise the skin and cricothyroid membrane, dilate the entry wound with the scalpel handle or a set of artery forceps and insert a tracheostomy or endotracheal tube. Experienced operators can place an airway in less than 30 seconds. Haemorrhage and misplacing the tube are potential significant complications. Needle puncture can be performed even more rapidly, but has several disadvantages. Large bore IV cannulae are prone to kink. Needle movement can be difficult to prevent, leading to bleeding or even posterior tracheal wall perforation. To maintain adequate oxygenation through such narrow tubes, high pressure (jet) ventilation is required. A jury-rigged jet ventilation system can be assembled from an IV ‘pump’ giving set. The pump chamber is cut and one end placed over the common gas outlet of the anaesthetic machine. Breaths are delivered by hitting the oxygen flush button. Catheter migration can then cause pneumothorax or massive subcutaneous emphysema. If there is no route for exhalation (e.g. complete upper airway obstruction) gas trapping can lead to haemodynamic compromise. More complex needle-based approaches rely on percutaneous dilation using the Seldinger technique. A variety of cricothyrotomy kits are available in which a single dilator is passed before the airway tube over the guidewire. Care must be taken to ensure that the end of the guidewire remains intratracheal. In any case, cricothyrotomy is a temporising step until a definitive airway can be established. This is usually a tracheostomy.

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Tracheostomy There have been case reports of the successful use of percutaneous dilational tracheostomy to securing the airway in an emergency situation, e.g Dob et al.2 This appears to be a very useful technique, provided the operators are sufficiently skilled. Most of the time though, tracheostomies are going to be performed by surgeons under somewhat more controlled conditions. The potential for morbidity remains high, both in the short (bleeding, pneumothorax, air embolism) and long term (granulomata, tube malposition, obstruction, disconnection). It has been estimated that emergency surgical airways have an overall 30% complication rate.3 The Laryngeal Mask Airway The ordinary LMA and the intubating laryngeal mask (Fastrach) have been reported to provide good conditions for ventilating and enabling endotracheal intubation in a wide variety of difficult situations. The main advantage of these devices are that they are relatively easy to place. If cricoid pressure has been applied, briefly releasing it at the time of insertion may increase the likelihood of successful placement. Endotracheal tubes can then be inserted either blindly, or assisted with a bougie, tube changer or fibreoptic bronchoscope. The size 4 LMA will take up to a size 6 microlaryngoscopy tube. The size 5 LMA can be used with a 7 or 7.5 ETT. The LMA is less likely to be useful in the clinical situation described above, for the following reasons:- • In patients with periglottic or subglottic pathology causing their airway problems, the LMA is

unlikely to effect an improvement in the ability to ventilate. • The risk of aspiration is greatly increased if inspiratory pressures greater than 20cm water

(oesophageal opening pressure) are required using the LMA. Therefore, it is less likely to be useful in patients with poor lung compliance.

The Combitube This is a double lumen, double cuffed tube which can be blindly inserted into the oesophagus. It is designed to prevent or limit aspiration and facilitate ventilation by the arragement of side holes proximal to the tracheoesophageal cuff) which can be positioned either in the esophagus or in the trachea, serving to seal these structures. It has been used as an aid to endotracheal intubation. Problems with this device include the potential for soft tissue injury and even oesophageal perforation. Most of the literature discussing the Combitube comes from Europe and the U.S. The product doesn’t seem to be uniformly available in Australasia. It therefore has all the disadvantages of the LMA with the addition of lack of familiarity. Conclusions In the scenario initially outlined, placing a laryngeal mask airway and seeing if ventilation is possible is a valid first move in some cases. Most medical staff involved in acute care settings are familiar with the use of the LMA. Unfortunately, far fewer are proficient in establishing surgical airways which seems to be the most appropriate initial manoeuvre in this clinical context. This may change with more systematic and extensive training in airway management.

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SUMMARY Discuss the management of a severely hypoxic patient who has been paralysed with suxamethonium whom you are unable to intubate or ventilate. • ‘Can’t intubate can’t ventilate’ (CICV) scenario relatively rare but significantly higher

incidence in ICU or Emergency Department population (0.5-1%) compared to the operating theatre (1:1,000 - 0.2:10,000) for a wide variety of reasons.

• Calling an arrest or getting assistance by other means is a good opening gambit. • Cricothyrotomy best next move in the setting of CICV + severe hypoxia. • The operator should use the technique they are most familiar with in this crisis situation. • Both surgical and needle crics are not without potential morbidity. • Attempting to place an LMA or Combitube to restore ventilation and therefore buy time

another option, but unlikely to succeed with periglottic or diffuse pulmonary pathology. Tracheostomy is the definitive airway option, but ideally awaits a more controlled situation than that given above References 1. Parmet, J.L. et al. The Laryngeal Mask Airway Reliably Provides Rescue Ventilation in

Cases of Unanticipated Difficult Tracheal Intubation Along with Difficult Mask Ventilation. Anesth. Analg 1998; 87:661-5

2. Dob, D.P. et al. Failed intubation and emergency percutaneous tracheostomy. Anaesthesia 53(1), January 1998. pp72-74

3. Gillespie M.B. Eisle D.W. Outcomes of emergency surgical airway procedures in a hospital wide setting. Laryngoscope 1999; 109:1766-1769.

General References 4. Oh, T.E. and Young K.K. Airway Management. 5. Chapter 23, Intensive Care Manual, 4th ed..Oh, T.E. ed. Butterworth-Heinemann 1997. 6. O’Connor M.F. and Ovapassian A. Management of the Airway and Tracheal Intubation.

Chapter 9, Critical Care Medicine: Perioperative Management. 2d ed. Murray M.J., Coursin D.B., Pearl R.G. and Prough D.S. eds. Lippincott Williams and Wilkins 2002.

7. Campo S. The Laryngeal Mask Airway: Its Role in the Difficult Airway: Int Anesthesiol Clin, Volume 38(3).Summer 2000.29-45

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DISCUSS THE MANAGEMENT OF A PATIENT WITH SEVERE VERAPAMIL OVERDOSAGE

Dr. P. Nelson, Intensive Care Unit, Royal Perth Hospital, WA

Diagnosis 1. History 2. Clinical features: Cardiovascular Hypotension Bradyarrhythmias (blockade of AV nodal conduction) Asystole Central nervous system Lethargy, slurred speech, confusion, drowsiness, coma Respiratory arrest Seizures Gastrointestinal Nausea, vomiting Ileus, obstruction Bowel ischaemia, infarction Metabolic Hyperglycaemia (decreased insulin release) Lactic acidosis Management 1. General management Airway, breathing, circulation Gastric lavage (if <1 hour post ingestion) Activated charcoal Consider whole-bowel irrigation and repeat doses of activated charcoal* (*if sustained-release preparation) IV calcium chloride if critical ICU admission; ECG monitoring Exclude other poisons (e.g. paracetamol, aspirin) 2. Arrhythmias Asymptomatic: Supportive measures Symptomatic: Atropine, isoprenaline, pacing 3. Hypotension Arrhythmias as above 10ml 10% calcium chloride or 30ml 10% calcium gluconate over 5 minutes (Repeat doses as necessary every 15-20 minutes up to 4 times) Glucagon, 2-5mg IV over 5 min, repeat doses or infusion Dopamine, dobutamine, noradrenaline 4. Central nervous system Seizures: Phenytoin, benzodiazepine, or phenobarbitone 5. Other Insulin-dextrose (hyperinsulinaemic euglycaemia): not yet proven

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References 1. Pearigen PD. Calcium channel blocker poisoning. In: Haddad LM, Shannon MW,

Winchester JF (eds). Clinical management of poisoning and drug overdose. 3rd ed. WB Saunders Co. Philadelphia 1998

2. Kenny, J. Treating overdose with calcium channel blockers. BMJ 1994; 308:992-993

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DISCUSS THE CLINICAL FEATURES AND MANAGEMENT OF A PATIENT WITH A SAGITTAL SINUS THROMBOSIS

Dr. B. Welch, Intensive Care Unit, Mackay Base Hospital, Queensland Thrombosis of the venous sinuses is an uncommon cause of cerebral infarction relative to arterial disease but is an important consideration because of its potential morbidity. When occlusion of venous sinus occurs, resulting venous congestion can lead to infarction. Venous infarcts are frequently haemorrhagic and commonly occur within the white matter or at the grey-white matter junction.1,2 CLINICAL FEATURES Uniform age distribution in men with sagittal sinus thrombosis (SST), although 61% of women with SST aged between 20-35 years. This may be related to pregnancy and use of oral contraceptives. Symptoms: • Headache, may be thunderclap headache3 • Nausea and vomiting • Confusion • Focal or generalised seizures Signs: • Weakness of lower extremities with bilateral Babinski signs or unilateral hemiparesis or

paraplegia. • There may be a rapid development of stupor and coma. • When SST occurs as a complication of bacterial meningitis, nuchal rigidity with Kernig's

and Brudzinski’s signs may be present. AETIOLOGY OR POSSIBLE ASSOCIATED FACTORS Hypercoagulability • Pregnancy, puerperium, oral contraceptives4 • Antiphospholipid syndrome5 • Protein S and C deficiencies6,7 • Anti thrombin III deficiency • Lupus anticoagulant auto immune diseases • Haematological conditions, thrombotic thrombocytopaenic purpura, polycythaemia vera,

etc • Nephrotic syndrome, dehydration • Inflammatory bowel syndrome • Drugs: Tamoxifen, steroids Stasis of local bloodstream • Complication of septic meningitis, HIV8

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Abnormality of vessel wall • Trauma (even minor head trauma)9 • Neurosurgical procedures (dural tap) 25% of cases unknown aetiology. SPECIAL INVESTIGATIONS CT scan • Infarction that does not respond to an arterial distribution. In absence of haemorrhagic

component may delay demonstration of infarct 48-72 hours. • Empty delta sign 10,11 on contrast as enhancement of the collateral veins in SSS walls

surrounding a non-enhanced thrombus in the sinus - frequently absent. MRI • Infarct not typical of expected arterial occlusion. • MR venography • Single-slice phase-contrast angiography Carotid Arteriography Lumbar Puncture • Helpful in meningitis, but otherwise not performed, risk of herniation with large lesion. MANAGEMENT a. Fluids - N Saline b. Elevate head 30°-40° c. Treat seizures- Phenytoin, Diazepam, Lorazepam d. Anticoagulation

• Heparin infusion ) or ) Even in patients with small haemorrhagic infarct

• LMWH12 ) • Thrombolytic therapy - micro-catheter technique

=> Followed by Warfarin, depending on aetiology if permanent risk factor- lifelong

anticoagulation e. Surgical thrombectomy- Only in severe neurological13 deterioration combined with local

infusion of TPA f. Appropriate antibiotics for meningitis cases. PROGNOSIS • Mortality in recent studies varies between 6 and 20%, including residual focal neurological

deficits. • + 30-80% patients have14 a full recovery, but is improved with new diagnostic techniques. Frequency of long-standing epilepsy is low, suggesting longterm anticonvulsant not necessary. References 1. Partanen J. Roine RO, Halaveara J. Thrombosis of the Superior Sagittal Sinus. Circulation

1998;97:1308.

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2. Isselbacher, Braunwald et se. Principles of Internal Medicine. Harrison’s; chapter 372. 3. De Bruiin SFTM, Stam J. Kappelie LJ. Thunderclap headache as first symptom of

cerebral venous sinus thrombosis. Lancet 1996;348:1623-25. 4. Martinelli I, Taioli E, Palli D, Mannucci PM. Risk of cerebral vein thrombosis and oral

contraceptives. Lancet 1998;352:326. 5. Yuen SF, Lau KF, Steinberg AW, Grattan-Smith PJ, Hodson EM. Intracranial venous

thrombosis and pulmonary embolism with antiphospholipid syndrome in systemic lupus erythematosus. J. Paediatr Child Health 2001;37:405-408.

6. Sigert CEH, Smelt AHM, de Bruin T\NA. Activated Protein C resistance and Factor V Leiden mutation are risk factors for cerebral sinus thrombosis. Stroke 1997;28:129192.

7. Dulli DA, Luzzio CC, Williams EC, Schutta HS. Cerebral venous thrombosis and Activated Protein C resistance. Stroke 1996;27:11731-33.

8. Karim MS, Athar MK, Ghobrial MW. Superior Sagittal Sinus Thrombosis & HIV. Annals of Internal Medicine 2002;137:E375.

9. Meltzer H. LoSasso B. Sobo E. Depressed occiptial skull fracture with associated sagittal sinus occlusion. J. Trauma 2000;49:981.

10. Fink JN, McAuley DL. Cerebral venous sinus thrombosis: a diagnostic challenge. Intern. Med. J 2001;31 :384-90.

11. Yoshida S. Shidoh M. The empty delta sign. Neurology 2003;60:146. 12. De Bruijn SFTM, Stam J. Randomized, Placebo-controlled trial of anticoagulant treatment

with low-molecular-weight Heparin for cerebral sinus thrombosis. Stroke 1999;30:484-88.

13. Ekseth K, Bostrom S. Vegfors M. Reversibility of sever Sagittal Sinus Thrombosis with open surgical thrombectomy combined with local infusion of tissue plasminogen activator: Technical case report. Neurosurgery 1998;43:960-64.

14. Preter M, Tzourio C, Ameri A, Bousser MG. Long-term prognosis in cerebral venous thrombosis: Follow-up of 77 patients. Stroke 1996;27:243-46.

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DISCUSS THE MANAGEMENT OF A PATIENT WITH AN ACUTE CENTRAL VENOUS LINE CANDIDA SEPTICAEMIA AND ENDOPHTHALMITIS WHO

DEVELOPS OLIGURIA AND A PROGESSIVE RISE IN PLASMA CREATININE Dr. H. Koelzow, Intensive Care Unit, Royal Prince Alfred Hospital, NSW The management of this patient involves the treatment of the candida septicaemia and resuscitation to prevent / treat acute renal failure. As part of the treatment of the infection, the catheter should be removed, because it serves as a persistent nidus of infection and this is especially important for candida infected catheters. Most studies show that outcome is improved if the catheter is promptly removed.1 Major complications of catheter related infections include septic shock, suppurative thrombophlebitis, metastatic infection and endocarditis. In this patient ocular involvement has already occurred. Small white retinal exudates appear in about 10 % of patients with candidaemia. Retinal detachment, vitreous abscess and extension to the anterior chamber may occur over the following weeks. Antifungal treatment for patients with central venous catheter candidaemia is either fluconazole (400 mg/day) or amphotericin B (0.5 mg/kg daily).2 The preferred treatment for endophthalmitis is intravenous amphotericin B with or without flucytosine and should be continued for 2 weeks after the patient becomes afebrile. Vitrectomy may be necessary for a vitreous abscess and the injection of amphotericin B into the vitreous humor can also be helpful. Regular fundoscopy should be performed to ensure that retinal lesions resolve completely. The commonest and most serious unwanted effect of amphotericin B is renal toxicity, with some degree of reduction in renal function occurring in more than 80 % of patients. There are three liposome-encapsulated forms of amphotericin available with a significantly lower degree of nephrotoxicity and unchanged antimycotic action: Liposomal amphotericin B, Amphotericin B lipid complex and Amphotericin B colloidal dispersion. As this patient already demonstrates signs of renal impairment one of these formulation should be chosen for the antifungal treatment. The incidence of nosocomial bloodstream infections caused by Candida species has risen 5 to 10 fold in the past 20 years and candidemia currently accounts for 10 to 15 % of hospital acquired infections of the bloodstream.3 A recent cohort analysis found a very high mortality of 60 % and a high likelihood of associated multiple organ failure. These patients were also more likely to have underlying renal failure at baseline.4 This has already occurred in this patient who suffers from oliguria and progressive rise plasma creatinine. Aggressive resuscitation needs to be implemented as soon as possible in order to prevent acute renal failure and other organ dysfunction. The first step is restoration of intravascular volume which should be done with monitoring of intraarterial and central venous pressure. Mean arterial blood pressure should be maintained above 70 mmHg (higher in the presence of premorbid hypertension) to guarantee adequate renal perfusion. If this is unable to be achieved with fluid resuscitation alone, LV preload and CO should be assessed with a pulmonary artery catheter or PICCO and optimized using the appropriate inotropes and / or vasopressors. Unfortunately therapy with dopamine, frusemide. mannitol, calcium channel blockers, growth factor etc have not been shown to be beneficial in preventing or treating renal failure. Frusemide might convert oliguric into polyuric renal failure if used after adequate fluid resuscitation, but has no effect on mortality or duration of renal failure. If despite these measures renal failure progresses renal replacement therapy should be commenced early. The management of this patient involves the treatment of the candida septicaemia and resuscitation to prevent / treat acute renal failure.

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As part of the treatment of the infection, the catheter should be removed, because it serves as a persistent nidus of infection and this is especially important for candida infected catheters. Most studies show that outcome is improved if the catheter is promptly removed.1 Major complications of catheter related infections include septic shock, suppurative thrombophlebitis, metastatic infection and endocarditis. In this patient ocular involvement has already occurred. Small white retinal exudates appear in about 10 % of patients with candidaemia. Retinal detachment, vitreous abscess and extension to the anterior chamber may occur over the following weeks. Antifungal treatment for patients with central venous catheter candidaemia is either fluconazole (400 mg/day) or amphotericin B (0.5 mg/kg daily).2 The preferred treatment for endophthalmitis is intravenous amphotericin B with or without flucytosine and should be continued for 2 weeks after the patient becomes afebrile. Vitrectomy may be necessary for a vitreous abscess and the injection of amphotericin B into the vitreous humor can also be helpful. Regular fundoscopy should be performed to ensure that retinal lesions resolve completely. The commonest and most serious unwanted effect of amphotericin B is renal toxicity, with some degree of reduction in renal function occurring in more than 80 % of patients. There are three liposome-encapsulated forms of amphotericin available with a significantly lower degree of nephrotoxicity and unchanged antimycotic action: Liposomal amphotericin B, Amphotericin B lipid complex and Amphotericin B colloidal dispersion. As this patient already demonstrates signs of renal impairment one of these formulation should be chosen for the antifungal treatment. The incidence of nosocomial bloodstream infections caused by Candida species has risen 5 to 10 fold in the past 20 years and candidemia currently accounts for 10 to 15 % of hospital acquired infections of the bloodstream.3 A recent cohort analysis found a very high mortality of 60 % and a high likelihood of associated multiple organ failure. These patients were also more likely to have underlying renal failure at baseline.4 This has already occurred in this patient who suffers from oliguria and progressive rise plasma creatinine. Aggressive resuscitation needs to be implemented as soon as possible in order to prevent acute renal failure and other organ dysfunction. The first step is restoration of intravascular volume which should be done with monitoring of intraarterial and central venous pressure. Mean arterial blood pressure should be maintained above 70 mmHg (higher in the presence of premorbid hypertension) to guarantee adequate renal perfusion. If this is unable to be achieved with fluid resuscitation alone, LV preload and CO should be assessed with a pulmonary artery catheter or PICCO and optimized using the appropriate inotropes and / or vasopressors. Unfortunately therapy with dopamine, frusemide. mannitol, calcium channel blockers, growth factor etc have not been shown to be beneficial in preventing or treating renal failure. Frusemide might convert oliguric into polyuric renal failure if used after adequate fluid resuscitation, but has no effect on mortality or duration of renal failure. If despite these measures renal failure progresses renal replacement therapy should be commenced early. References 1. Rex JH, Bennett JE, Sugar AM, et al: Intravascular catheter exchange and duration of

candidemia. Clin Infect Dis 1995;21:994-998 2. Rex JH, Bennett, JE, Sugar, AM er al: A randomised trial comparing fluconazole with

amphotericin B for the treatment of canididemia in patients without neutropenia. NEJM; 331:1325-1330

3. Meunier, F: Management of Candidemia. NEJM 1994;331:1371-1372

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4. Hadley S. Winnie WL, Ruthazer R. et al: Candidemia as a cause of septic shock and multiple organ failure in nonimmunocompromised patients. Crit Care Med 2002;30:1808-1814

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DISCUSS THE CLINICAL FEATURES AND MANAGEMENT OF A PATIENT WITH DIASTOLIC HEART FAILURE

Dr. B. O’Brien, Intensive Care Unit, The Alfred Hospital, Victoria Diastolic cardiac failure means clinical heart failure in the presence of a normal ejection fraction (EF). This is postulated to result from slow or incomplete relaxation of the heart in diastole, impairing the organ’s filling. It probably contributes to the symptoms of over 50 % of elderly patients with heart failure. The existence of diastolic failure as a specific entity remains controversial, however. The symptoms of dyspnea on exertion, productive cough, reduced exercise tolerance, orthopnea/nocturnal dyspnea and fatigue are typical of heart failure. Physical findings of dependent edema, crepitations on ausculatation, a raised jugular venous pulse and tachypnea are expected. Those who recognise diastolic failure (DF) as a clinical entity cite the results of studies on a subgroup of heart failure patients with a normal EF – this is DF by definition. Epidemiologically, such studies suggest that DF is more commonly encountered in the elderly, diabetics, those with hypertension and in females than is systolic failure (SF).1 Those affected have less severe limitations to their exercise tolerance, and a better quality of life than those with SF, though both are worse than in age-matched controls. DF and SF do not differ in regard to findings on clinical examination, or measurement of central venous or pulmonary capillary wedge pressures (CVP and PCWP), and measures of neuroendocrine activation are also similar (eg plasma levels of norepinephrine and natriuretic peptides).2 Thus the diagnosis is problematic, especially since many patients with heart failure are managed through primary care, and are identified and treated according to clinical findings. In terms of routine monitoring of venous and pulmonary pressures, both forms of heart failure involve increased left ventricular end diastolic pressure (LVEDP), and thus of CVP and PCWP also. Echocardiographic findings of increased left ventricular mass/volume ratio, normality of EF, low end-systolic (LVESV) and end-diastolic volumes (LVEDV) and slow diastolic filling are typical of DF in contrast to SF.2 Many derived variables are suggested to distinguish DF and SF, but the usual criterion for inclusion in studies has been clinical heart failure with an EF above 50 %.1,2 On exercise testing such patients were found to have a significantly higher pulse pressure than healthy controls or those with SF.2 The optimum treatment of the DF patient is not established.3 It is suggested that the routine use of diuretics may be harmful and that they should be used with greater caution in DF than in SF lest preload be dangerously reduced. The heart with SF is relatively preload insensitive, tolerating diuresis well. Drugs that improve ventricular relaxation – positive lusitropes – are suggested to be appropriate agents for DF. Studies are underway to evaluate Perindopril and Candesartan, and it is believed that the renin-angiotensin-aldosterone axis will be a major target of therapy. Calcium channel antagonists and phosphodiesterase inhibitors may also prove to be useful, while exercise and magnesium supplementation are advocated without compelling evidence. There are no well-conducted trials in the literature on the effects of drugs on patients with pure DF. The best recommendations at present are that hypertension and ischemia be controlled, sinus rhythm maintained and circulating volume optimized, by avoiding salt intake, using diuretics or fluids 3. Interestingly, though caution regarding diuretic use is emphasized by many authors, in the most cited study on DF all patients were treated with furosemide 1. The critical care management of DF has not been investigated. The titration of standard therapy of diuretics, inotropes and vasodilators against measured variables – cardiac output, blood pressure, respiratory rate and oxygenation, etc – appears reasonable. This is common critical care practice.

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Many experts are sceptical about the concept of DF. Some point out that this distinction between subtypes of heart failure is simplistic, as “a heart that cannot fill cannot empty, and vice versa”,4 while the architecture of failing hearts varies widely. One study on those diagnosed with DF suggested that they had been mostly misdiagnosed, and had other illnesses which explained their symptoms.5 Others have suggested that transient systolic dysfunction or mitral regurgitation explains the phenomenon, though this seems unlikely 1. Finally there is a view that the changes of DF are part of the normal ageing process, and that they don’t constitute a genuine disease entity.6 Overall, it seems likely that diastolic dysfunction contributes to the illness of many people with cardiac failure, though presumably SF and DF may overlap in many individuals. The best treatment has not been established, and until a distinction in therapy for these subtypes of heart failure can be made, the usefulness of separating DF from SF will probably remain contentious. Though patients with DF and SF are not easily distinguished, there is as yet little evidence that the distinction is critically important. Ongoing trials may provide an evidence base to resolve this issue. References 1. The pathogenesis of acute pulmonary edema associated with hypertension. Gandhi SK et

al. N Eng J Med 2001;344:17- 22. 2. Pathophysiological characterization of isolated diastolic heart failure in Comparison to

Systolic Heart Failure. Kitzman DW et al. JAMA 2002; 288:2144 – 2150. 3. Diastolic heart failure – no time to relax. Vasan RS and Benjamin EJ. N Eng J Med

2001;344:56-9. 4. Physiology of the heart (Third Edition). Katz AM. Lipincott-Milliams, 2001. 5. Do patients with suspected heart failure and preserved left ventricular systolic function

suffer from “diastolic heart failure” or from misdiagnosis ? A prospective study. BMJ 2000; 321 :215 – 218.

6. Diastolic heart failure in older people – myth or lost tribe ? Baxter AJ and Gray CS. Clin Med 2002 Nov – Dec;2 (6):539-543.

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DISCUSS THE INDICATIONS AND COMPLICATIONS OF INTRAVENOUS OCTREOTIDE

Dr. S. Morphett, Intensive Care Unit, Royal Hobart Hospital, Tasmania Introduction Octreotide is a peptide and cyclic analogue of the hormone somatostatin. Somatostatin is actually a multigene family of peptides with two important bioactive products – somatostatin-14 and somatostatin-28. (14 and 28 amino acids respectively).1 Somatostatin has widespread and diverse effects that are mediated through specific membrane receptors, of which there are five subtypes.2 All five subtypes mediate their effect via modulation of adenylate cyclase activity, reducing intracellular cAMP, an effect which is G-protein linked. The spectrum of activity of somatostatin includes: CNS modulation of neurotransmission Inhibition of release of growth hormone and thyrotropin GIT Inhibition of glandular secretion Inhibition of release of vasoactive intestinal polypeptide and gastrin Inhibition of exocrine and endocrine functions of the pancreas (including inhibition of

insulin and glucagon production). Decrease in neurotransmission and smooth muscle contractility.

Other Inhibition of function of activated immune cells Antimitotic activity

Octreotide was developed as a longer acting analogue of somatostatin with particularly potent inhibition of growth hormone release. Indications The indications for the use of octreotide intravenously are essentially in the management of acute upper gastrointestinal haemorrhage. There are two areas to be considered – Oesophageal variceal and non-variceal bleeding. Acute oesophageal variceal haemorrhage: In this setting, octreotide decreases portal and intravariceal pressures by blocking the release of vasodilator substances such as glucagon. The dose used in relevant trials involves an initial bolus dose, usually 50 mcg, followed by an infusion of 25 – 50 mcg/hr for 2 – 5 days. Octreotide has been shown to be effective in the initial control of variceal bleeding and in the prevention of re-bleeding, when compared to placebo. It appears to be more effective than vasopressin and have fewer complications, in a recent meta-analysis.3 A different meta-analysis confirmed the effect on initial bleeding (compared to placebo) but questioned the size of the effect and found no effect on number of patients re-bleeding.4 Neither meta-analysis found a decrease in overall mortality with the use of octreotide/somatostatin, compared to placebo. The beneficial effect of octreotide appears to be about equivalent to that of sclerotherapy. Where possible, emergency endoscopic treatment remains the definitive therapy (banding is superior to sclerotherapy). The combination of octreotide with endoscopic treatment is better than either approach alone. (In stopping bleeding and reducing re-bleeding) This was confirmed in a recent meta-analysis5 and has been reccomended in a recent review.6 There is a trend towards decreased mortality with the combined approach.

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Octreotide for acute non-variceal upper gastrointestinal bleeding: Octreotide can be useful in this situation. It has been studied in a well-conducted meta-analysis.7 It included 1829 patients from 14 trials (12 using somatostatin and 2 using octreotide) The relative risk for continued or repeat bleeding if somatostatin/octreotide was used was 0.53 (95% CI 0.43-0.63). In subgroup analysis, the effect was most pronounced on stopping initial bleeding, rather than preventing re-bleeding and was also more pronounced if the bleeding was from peptic ulcer disease. There was a trend towards a decrease in need for surgery with somatostatin/octreotide but no difference in transfusion requirements. Mortality was not an endpoint. Of note is that octreotide was used in only 2 of the studies, which had conflicting results. Complications Octreotide is generally well tolerated with less side-effects than other vasoactive infusions used in the above settings, such as vasopressin.3 Problems are as might be expected from the drug’s spectrum of activity. • Hypo/hyper-glycaemia – suppresses glucagon more than insulin, therefore might expect

hypoglycaemia, but clinically may see either. Insulin requirements in diabetic pateints may fluctuate widely.

• Gastroinitestinal side effects – include anorexia, nausea, vomiting, abdominal bloating and pain and may cause steatorrhoea.

• Cholelithiasis – very unlikely to be a problem with short term use. • Rarely – acute pancreatitis, bradycardia, hypersensitivity. • Drug interactions – decreases absorption of cyclosporin, potentially precipitating transplant

rejection. Summary An intravenous infusion of octreotide is effective in stopping acute oesophageal variceal haemorrhage, both in combination with endoscopic therapy, or alone if this is not available. It does not alter mortality. It is also useful in stopping bleeding in non-variceal upper gastrointestinal haemorrhage and is used in our unit if the pateint has continued or re-bleeding on proton pump inhibitors. Octreotide is generally safe and well tolerated. Other indications: Octreotide may be used subcutaneously for therapy in acromegaly, high output fistulae or “short gut” syndromes, VIPomas, preparation for pancreatic surgery, AIDS associated diarrhoea, carcinoid and a variety of other endocrine tumors. References 1. Kurat J. A. and Murad F. Adenohypophyseal hormones and related substances in

Goodman & Gilman The pharmacological basis of therapeutics 8th ed McGraw-Hill;1992: 1355-6

2. Lamberts S. W. J. et al Octreotide NEJM 1996; 334(4): 246-53 3. Corley D. A. et al Octreotide for acute oesophageal variceal bleeding: a meta-analysis.

Gastroenterology 2001; 120: 946-54 4. Gotzsche P. C. Somatostatin analogues for acute bleeding oesophageal varices Cochrane

Database Syst Rev. 2000; (2):CD000193

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5. Banares R. et al Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology 2002; 35(3): 609-15.

6. Pratt D. S. and Epstein S. K. Recent advances in critical care gastroenterology. Am J Respir Crit Care Med 2000; 161: 1417-20

7. Imperiale T. F. and Birgisson S. Somatostain or Octreotide compared with H2 antagonists and placebo in the management of acute non-variceal upper gastrointestinal hemorrhage: a meta-analysis. Ann Intern Med 1997; 127: 1062-71.

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DISCUSS THE AETIOLOGY AND MANAGEMENT OF A PATIENT WITH HEPATOPULMONARY SYNDROME AND PORTOPULMONARY HYPERTENSION Dr. C. Allen, Intensive Care Unit, Royal Perth Hospital, WA High flow hyperdynamic circulation – imbalance between vasoconstrictors and vasodilators, and other mediators synthesised or metabolised by the liver Pulmonary Consequences: 1. Hepatopulmonary Syndrome 2. Portopulmonary Hypertension Hepatopulmonary Syndrome: 1. Liver disease 2. arterial hypoxaemia 3. intrapulmonary vascular dilatations Liver Disease: portal hypertension (almost always); cirrhotic (10-20% develop HPS), non-cirrhotic (relatively rare) Arterial Hypoxaemia: definitions vary, room air paO2 <70 mmHg, p(A–a)O2 > 20 mmHg

– co-morbidities must be considered (important in 20–30% of HPS cases) eg. Smoking-related lung diseases . . . – response to 100% may be useful

Intrapulmonary vascular dilatations: contrast ECHO or 99mTcMAA~>6% Aetiology: Almost any liver disease, cirrhotic or non-cirrhotic causing portal hypertension may give rise to HPS Pathophysiology:

1. Pre-capillary/capillary dilations (ventilation with excess perfusion) and 2. Anatomic shunting important (perfusion with no ventilation) Relative importance of these factors varies

Cause of these abnormalities uncertain, possibilities include 1. failure of liver to clear circulating pulmonary vasodilators 2. production of a circulating vasodilator

Increasing evidence that nitric oxide may play a central role in pathogenic vasodilatation • benefit from methylene blue on pulmonary pressures and oxygenation • variety of animal experimental work implicating NO

Treatments: No medical therapies demonstrated to be of sustained benefit – some evidence that methylene blue has short-lived benefit after single dose infusions – case reports of improvement with: long-term high-dose aspirin, almitrine bismesylate, indomethacin, garlic – supplemental oxygen, suggested 24 hours/day, 1–3 L/min – coil embolotherapy if discrete arteriovenous communications identified – TIPSS (case reports mixed, controversial) Liver Transplatation (OLT) – HPS once considered to be a relative contra-indication – now a recognised indication in many transplant centres – HPS resolves in 62–82% of cases of successful OLT, resolution of hypoxaemia may take up to 15 months – outcome likely to be poor if room air paO2 <50 mmHg AND Shunt fraction > 20%

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– mortality is higher (20–30% @ 1 year) than in transplanted patients without HPS (~10 % @ 1 year) – inhaled NO may improve hypoxaemia immediately post OLT (atelectasis, fluid overload, pneumonia) Portopulmonary Hypertension (PPH)

1. pulmonary arterial hypertension (mean PAP > 25 mmHg), usually RV systolic pressure > 50 mmHg

2. Portal Hypertension 3. PCWP < 15 mmHg, Pulmonary vascular Resistance (PVR) > 120 dyne•s•cm–5

• may occur in up to 20 % with advanced liver disease and portal hypertension Aetiology: Complex interaction of: hyperdynamic high flow circulation, excess central volume, non-embolic pulmonary vasoconstriction/obliteration Portopulmonary hypertension strictly only refers to the last process (rare @ ~ 4%) Pathology: Medial & intimal hypertrophy (reversible?), endothelial proliferation, thrombotic/fibrotic change (irreversible?) Indistinguishable from Primary Pulmonary Hypertension histopathological changes Treatments: Epoprostenol (PGI2) – Potent pulmonary and systemic vasodilator, synthesised by pulmonary endothelium – Improves pulmonary haemodynamics short and long term – Disadvantages: continuous central vein infusion, splenomegaly, thrombocytopenia, cost, side-effects Liver Transplantation – PPH is a relative contraindication to OLT if mean PAP > 35 mmHg or PVR > 250 dyne•s•cm–5 – PGI2 often needed before and after OLT (duration unclear) – recurrence/progression of PPH may occur despite OLT Pulmonary Vasodilators – bosentan (non-specific endothelin receptor antagonist) – oral mononitrates – PGI2 analogues – inhaled NO References 1. Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evaluation of outcomes

and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology. Jan 2003;37(1): 192-7.

2. Kamath PS. Portopulmonary hypertension and hepatopulmonary syndrome. Journal of Gastroenterology and Hepatology. Dec 2002;17 Suppl 3:S253-S255.

3. Vettukattil JJ. Pathogenesis of pulmonary arteriovenous malformations: role of hepatopulmonary interactions. Heart. Dec 2002;88(6):561-3.

4. Schenk P, Fuhrmann V, Madl C. Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences. Gut. Dec 2002;51(6):853-9.

5. Krowka MJ. Hepatopulmonary Syndrome and Portopulmonary Hypertension. Current Treatment Options in Cardiovascular Medicine. Jun 2002;4(3):267-273.

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6. Groneberg DA. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med. Sep 4, 2001;135(5):380-1.

7. Krowka MJ. Caveats concerning hepatopulmonary syndrome. Journal of Hepatology. May 2001;34(5):756-8.

8. Martinez GP, Barbera JA, Visa J, Rimola A, Pare JC, Roca J, Navasa M. Hepatopulmonary syndrome in candidates for liver transplantation. Journal of Hepatology. May 2001;34(5):651-7.

9. Schenk P, Madl C, Rezaie-Majd S, Lehr S, Muller C. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med. Nov 7, 2000;133(9):701-6.

10. Fallon MB. Methylene blue and cirrhosis: pathophysiologic insights, therapeutic dilemmas. Ann Intern Med. Nov 7, 2000;133(9):738-40.

11. Krowka MJ. Hepatopulmonary syndromes. Gut. Jan 2000;46(1):1-4. 12. Jones FD, Kuo PC, Johnson LB, Njoku MJ, Dixon-Ferguson MK, Plotkin JS. The

coexistence of portopulmonary hypertension and hepatopulmonary syndrome. Anesthesiology. Feb 1999;90(2):626-9.

13. Battaglia SE, Pretto JJ, Irving LB, Jones RM, Angus PW. Resolution of gas exchange abnormalities and intrapulmonary shunting following liver transplantation. Hepatology. May 1997;25(5):1228-32.

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DISCUSS THE CAUSES AND TREATMENT OF TORSADES DE POINTES Dr. M. McNamara, Intensive Care Unit, Royal Adelaide Hospital, SA DEFINITION Polymorphic QRS complexes that change in amplitude and cycle length, appearing as oscillations around the baseline. Associated with long QT by definition. ELECTROCARDIOGRAPHIC RECOGNITION Ventricular tachycardia - rates of 200 to 250/min QRS complexes of changing amplitude appear to twist around the isoelectric line Long QT on ECG documented previously QTc >0.46 men >0.47 women. The U wave also can become prominent. Torsades de pointes often reverts spontaneously to the basal rhythm, but may terminate with a period of ventricular standstill, a new attack of torsades de pointes, or ventricular fibrillation. Ventricular tachycardia that is similar morphologically to torsades de pointes but occurs in patients without Q-T prolongation, whether spontaneous or electrically induced, should be classified as polymorphic ventricular tachycardia, not as torsades de pointes. Can be treated as VT - without restrictions on QT prolonging antiarrhythmics. CAUSES Congenital long Qt Jervell and Lange-Nielsen syndrome sensorineural deafness autosomal recessive Romano-Ward syndrome normal hearing autosomal dominant Sporadic form normal hearing nonfamilial Acquired long Qt Drugs (see table below) Electrolyte abnormalities (hypokalaemia, hypomagnesaemia) Severe bradycardia (especially complete heart block) Cerebrovascular disease (SAH, ischaemic stroke) Cardiac pathology [heart failure, ischaemia, myocarditis, MVP] Idiopathic

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Some drugs associated with QTc prolongation Antibiotics Anaesthetics Anti psychotics Azithromycin halothane risperidone Clarithromycin fluphenazine erythromycin Antiarrhythmics haloperidol roxithromycin disopyramide clozapine metronidazole procainamide thioridiazine (with alcohol) quinidine ziprasidone moxifloxan amiodarone pimozide sotalol droperidol Antifungals fluconazole Antidepressants Antihistamines (in cirrhosis) amitriptyline terfenadine ketoconazole clomipramine astemizole imipramine Antivirals dothiepin Other Nelfinavir doxepin probucol cisapride Antimalarials chloroquine mefloquine Risk Factors for Drug Induced Torsades de Pointes Risk factors for the development of drug-induced Torsades de Pointes have been identified (Roden, 1998): • Female gender • Hypokalemia, hypomagnesemia • Bradycardia • Diuretic use • Recent conversion from atrial fibrillation • Congestive heart failure or cardiac hypertrophy • Rapid intravenous infusion, high doses or longterm usage of drugs prolonging QT • Baseline ECG showing QT prolongation, T wave lability • ECG during drug therapy showing marked QT prolongation, T wave lability, T wave

morphologic changes TREATMENT • As with any arrhythmia an immediate decision must be made on urgency of treatment. • Rapid assessment, attention to ABCs and DC cardioversion remain the treatments of choice

for the unstable patient. • DC cardioversion may be successful initially but is rarely effective unless other treatments

are instituted as well. • In all patients with torsades de pointes, administration of class IA, possibly some class IC,

and class III antiarrhythmic agents (amiodarone and sotalol) can increase the abnormal Q-T interval and worsen the arrhythmia.

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Treatment of acquired long QT Torsades Patients with the acquired form of long QT commonly develop torsades de pointes during periods of bradycardia or after a long pause in the R-R interval • Determine and correct or remove cause of long QT Intravenous magnesium is the initial

treatment of choice for torsades de pointes due to an acquired cause 1g -2g boluses • Potassium infusion 0.5meq/kg over 90 mins used effectively for quinidine induced QT

prolongation • Temporary ventricular pacing at a rate of 90-110 bpm is effective in >90% patients with

drug induced torsades. • Isoprenaline infusion, given cautiously because it can exacerbate the arrhythmia, can be

used until pacing is instituted. • Lignocaine, mexiletine and phenytoin have been used successfully • Potassium channel openers may be useful. Treatment of Congental Long QT associated Torsades. Patients with Congenital Long QT commonly develop ventricular tachyarrhythmias during periods of adrenergic stimulation such as fright or exertion. Torsades de pointes due to the congenital long Q-T interval syndrome is treated with • beta blockade, • surgical sympathetic interruption • pacing • implantable defibrillators • ECGs taken on close relatives can help secure the diagnosis of long Q-T syndrome in

borderline cases. Often a combination of the above is required. References 1. Harrisons Principles of internal medicine 14th edition McGraw Hill 2. Irwin and Rippes Intensive Care Medicine 4th Ed Lippincott Raven 3. Braunwald: Heart Disease 5th Edition WB Saunders 4. Roden DM. Taking the "idio" out of "idiosyncratic": predicting torsades de pointes

[editorial]. Pacing Clin Electrophysiol. 1998;21 :1029-1034.

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SUMMARY DISCUSS THE CAUSES AND TREATMENT OF TORSADES DE POINTES DEFINITION Polymorphic VT Preceded by long QT often in excess of 0.6s CAUSES Congenital Long Qt Jervell and Lange-Nielsen AR - Sensorineural deafness Romano Ward AD - Normal Hearing Sporadic Form Non familial with normal hearing Acquired Long Qt Drugs Electrolyte abnormality (hypokalaemia, hypomagneseemia) Severe bradycardia (especially complete heart block) Cerebrovascular disease (SAH, ischaemic stroke) Cardiac pathology [heart failure, ischaemia, myocarditis, MVP] Idiopathic TREATMENT Is Rhythm Stable or Unstable (Hypotensive, obtunded or not)? Unstable - DC Cardioversion + ABC Stable - Depends on cause of underlying prolonged QT Congenital long QT Beta Blockers QT interval shortening drugs - phenytoin Cervicothoracic sympathectomy Permanent pacemaker/AICD Acquired lone QT Treat underlying cause - remove precipitating factors Correct electrolyte abnormalities Remove drugs causing long QT Intravenous magnesium 1g -2g boluses Isoprenaline infusion whilst awaiting pacing wire Atrial or ventricular overdrive pacing Ventricular pacing at 90-110 beats per minute Effective in >90% patients References 1. Harrisons Principles of internal medicine r14th edition McGraw Hill 2. Irwin and Rippes Intensive Care Medicine 4th Ed Lippincott Raven 3. Braunwald: Heart Disease 5th Edition WB Saunders

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DISCUSS THE INDICATIONS FOR AND MECHANISM OF ACTION OF INTRAVENOUS ACTIVATED PROTEIN C IN A SEPTIC PATIENT

Dr. S. Sturland, Intensive Care Unit, The Royal Brisbane Hospital, Queensland The systemic inflammatory response and procoagulant state that arises during sepsis is associated with an extensive endovascular injury. This can result in a distributive shock state with regional microthrombosis and organ ischaemia leading to overt organ dysfunction (i.e. severe sepsis).1 As part of the body’s natural defence, the vitamin K-dependant serine protease – protein C – binds to thrombomodulin and becomes activated. Activated protein C has anti thrombotic, anti inflammatory and profibrinolytic effects designed to counter the microvascular injury. Indeed a deficiency in protein C is associated with increased morbidity and mortality and is seen in the majority of patients with severe sepsis.2,3 In cases of severe sepsis it is postulated that the activation of protein C may be impaired by generalised endothelial dysfunction and down regulation of thrombomodulin by inflammatory cytokines. As a result administration of activated protein C may be more effective. MECHANISM OF ACTION Drotrecogin alfa (activated) or recombinant human activated protein C (APC) acts in a similar manner to the endogenous vitamin K-dependant serine protease, acting as an antithrombotic, anti-inflammatory and profibrinolytic agent; Antithrombotic action APC acts by proteolytic inhibition of the coagulation factors Va and VIIIa.5 This has the effect of reducing thrombin formation and hence reducing the formation of fibrin from fibrinogen. It also reduces the ability of thrombin to stimulate multiple inflammatory pathways.6 Profibrinolytic action Plasminogen-activator inhibitor 1 (PAI-1) is released from platelets and the endothelium when they are stimulated by thrombin acting to suppress fibrinolysis. APC acts to directly inactivate this compound. APC also prevents the activation of “thrombin-activatable fibrinolysis inhibitor –TAFI” which also acts as a powerful endogenous anti-fibrinolytic.7 As a result of the above two mechanisms APC acts to preserve or restore microcirculatory blood flow, preventing ischaemia-reperfusion injury and subsequent organ dysfunction. Anti-inflammatory action Aside from reducing the inflammatory effects initiated by thrombin as above, it intervenes with leukocyte action specifically;APC reduces the production inflammatory cytokines (ie.tumour necrosis factor, interleukin –1 and interleukin-6) by monocytes. It binds selectins and as a result prevents the rolling migration of monocytes/neutrophils along the injured endothelium. It also reduces activation of nfKB (a nuclear transcription factor) in target cells, essentially preventing DNA from unwinding from its histone proteins, reducing the cellular output of inflammatory cytokines, adhesion molecules and enzymes. Indeed Japanese research has qualitatively measured the inhibition of cellular nitric oxide synthase by APC in septic animal models.8 It is suggested that no one factor is responsible for the clinical effect of APC and that a synergy of all of its complex mechanisms is the reason why it has shown benefit where so many other narrowly targeted therapies have failed.

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INDICATIONS FOR THE USE OF APC Worldwide use of APC follows the publication of the PROWESS trial (Protein C Worldwide Evaluation in Severe Sepsis). In this trial investigators used three specific entry criteria as described below; 1. Presence of a known/suspected infection i.e..-

- presence of white cells in a normally sterile body fluid - perforated viscus - radiographic evidence of pneumonia associated with purulent sputum - syndrome associated with a high risk of infection (i.e.. ascending cholangitis or

meningococcemia ) 2. Presence of at least three SIRS criteria i.e.-

- Core temperature >38 C or <36 C - Elevated heart rate (>90 beats/min) - Respiratory rate >20 breaths/min or PaCO2 <32 mmHg or mechanical ventilation for

acute respiratory process - WBC >12000 or <4000 or >10% immature neutrophils

3. Dysfunction of one or more organ systems i.e.-

Cardiovascular: systolic BP of < 90 mmHg or mean BP < 70 mmHg for > 1 hr despite adequate fluid resuscitation or the use of vasopressors to maintain this.

Renal: urine output of <0.5 ml/kg body weight despite adequate fluid resuscitation

Respiratory: Pa:Fi O2 ratio of <250 in the presence of other dysfunctional organ systems or <200 if alone

Hematologic: platelet count of <80000 or a 50 % decrease in the preceding 3 days Metabolic: pH <7.30 or base deficit >5.0 mmol/L with plasma lactate level >1.5 times

upper limit Patients were deemed eligible if they met the criteria within a 24 hour period, and after enrolment treatment had to begin within 24 hours. There was therefore a maximum of 48 hr between diagnosis and treatment. Although baseline APACHE II scores were recorded and subsequently to classify sub group analysis, there was no criteria based on entry APACHE II score. The US FDA has subsequently also used the APACHE II score AS AN EXAMPLE only of people who may benefit from APC therapy and not as guidelines. AUSTRALIAN CLINICAL GUIDELINES An Australian Clinical Advisory Board has been formed in conjunction with Eli Lilly in order to provide guidelines for the responsible use of APC. Its members are Prof M Fisher, Prof I Clarke, Dr R Barnett, Dr G Dobb, A Prof A Bell, A Prof J Lipman, A Prof R Bellomo, Dr P Thomas, A Prof D Bihari, A Prof D Tuxen The Board recommends the use of APC “in patients with severe sepsis who are at a higher risk of death as defined by their response to antibiotics and resuscitation over 4 hours, and who have persistent multi-organ failure or an APACHE II of >25”.9 Added to this are the absolute and relative contra-indications published by Eli Lilly-

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ABSOLUTE CONTRA-INDICATIONS - Active internal bleeding - Recent (within three months) haemorrhagic stroke - Recent (within three months) intra-cranial or intra-spinal surgery, or severe head trauma

requiring hospitalisation - Trauma patients with increased risk of life-threatening bleeding - Patients with an epidural catheter - Patients with intracranial neoplasm or mass lesion RELATIVE CONTRA-INDICATIONS - Concurrent heparin therapy >15 U/kg/hr - Platelet count of <30000 (even post transfusion) - Recent (within 6 weeks) GI bleed - Recent administration (within 3 days) of thrombolysis - Recent administration (within 7 days) of aspirin >650 mg or other platelet inhibitors - Recent (within 7 days) of oral anticoagulants or GPIIbIIIa inhibitors - Recent (within 3 months) ischaemic stroke - Patients with intracranial arteriovenous malformation - Known bleeding diathesis except for coagulopathy of sepsis - Chronic severe hepatic disease - Any other condition in which the physician thinks bleeding likely - Conditions increasing the risk of bleeding ( i.e.. Within 12 hours of major surgery) - HIV infection with CD4 count of < 50/mm - Chronic renal failure with dialysis - Acute pancreatitis with no established source of infection In summary, the clinical use of APC will become dependant on the recommendations of The Australian Clinical Advisory Board in conjunction with clinical judgment and observation. As experience with this drug grows, so will our ability to tailor its use appropriately. References 1. Bone RC, et al. Definitions for sepsis and organ failure and guidelines for the use of

innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians. Society of Critical Care Medicine. Chest 1992; 101:1664-55.

2. Fourrier F, et al. Septic shock, multi-organ failure and disseminated intravascular coagulation: compared patterns of antithrombin three, protein C and protein S deficiencies. Chest 1992; 101: 816-23

3. Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. NEJM 2001 Mar 8; 344 (10):699-709.

4. Boehme SN, et al. Release of thrombomodulin from endothelial cells by concerted action of TNF and neutrophils; in vivo and in vitro studies. Immunology 1996; 87 (1):134-40.

5. Vervolet MG, et al. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Heamostas 1998; 24 (1): 3-44.

6. Levi M, et al. Disseminated intravascular coagulation. NEJM 1999; 341: 586-92.

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7. Neshelm, et al. thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Throm Haemost 1997;78:386-91.

8. Harada, et al. Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting induction of nitric oxide synthase. Shock 1999;12:A167.

9. Eli Lilly Australian Clinical Advisory Board Guidelines for the use of Xigris 2002.

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DISCUSS THE MANAGEMENT OF A PATIENT WITH METHYL ALCOHOL POISONING

Dr. A. Dennis, Intensive Care Unit, St Vincent’s Hospital, Victoria Methyl alcohol poisoning requires high degree of suspicion as it may not be recognized, or presentation may be delayed especially when it occurs in combination with ethanol intoxication. Poisoning may also occur in a paediatric setting with accidental ingestion. Ingestion results in metabolic acidosis, blindness and death. Complications are due to • the chemical itself • it’s metabolites • concurrent administration of other chemicals • and their metabolites BACKGROUND Pharmacology It is a common industrial solvent, antifreeze and is used in paints and paint removers. Synonyms: methyl alcohol, carbinol, colonial spirit, columbian spirit, methylol, methyl hydrate, wood alcohol, wood naphtha, wood spirit, methyl hydroxide, pyroxylic spirit, RCRA waste number U154, meths Molecular formula: CH3OH Pharmacokinetics Absorption - rapidly absorbed from stomach, small intestine and colon. Distribution – throughout total body water including transfer via placenta to fetus. Metabolism – metabolism occurs predominately in the liver (97%) via the same enzymes that metabolize ethanol. These are alcohol dehydrogenase and aldehyde dehydrogenase which degrade methyl alcohol to toxic intermediates – formaldehyde and formic acid. Step 1 Methyl alcohol → Formaldehyde (alcohol dehydrogenase – rate limiting step) Step 2 Formaldehyde → Formic acid (aldehyde dehydrogenase - rapid) Step 3 Formic acid → formate (pH dependent) → CO2 + H2O (folate-dependent –slow) The rate of oxidation of methyl alcohol is independent of its concentration in the blood however the rate is only 1/7th that of ethanol and complete oxidation occurs over days. Excretion – renal Pharmacodynamics Toxicity Dose 15mls for blindness 70-100mls death Mechanism of toxicity Early manifestations are due to methyl alcohol and late manifestations are due to formic acid. 1. Formic acid causing • An increased anion gap metabolic acidosis (severity ∞ acidosis) in combination with lactic

acidosis (reduced tissue perfusion) and ketosis

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• inflammation followed by atrophy of retinal ganglion cells leading to blurred vision, diplopia, blindness

• pancreatic necrosis 2. Respiratory acidosis secondary to intoxication – death is most often due to respiratory failure Principles of treatment • treat acidosis • inhibition of further methyl alcohol metabolism thereby reducing the concentrations of

formic acid and formaldehyde. This is achieved with ethanol which acts as a preferential substrate for alcohol dehydrogenase thereby effectively inhibiting the metabolism of methyl alcohol.

• Haemodialysis should be considered if patient has persistent acidosis or methyl alcohol blood concentration > 500mg/L

MANAGEMENT 1. Immediate Resuscitation A B C IV access, IV fluids, Observation of vomitus,urine,faeces, Investigations - screening and specific FBE, U+E/Cr, LFTs, ABGs, INR/APTT, glucose, ECG, CXR Blood ethanol and methyl alcohol levels 2. Short term a. History/examination/review of investigations – assist in establishing a diagnosis and an

estimate of chemical(s) and dosage taken. Metabolic acidosis and elevated serum osmolality in association with visual disturbances is highly suggestive of the diagnosis of methyl alcohol poisoning. Respiratory acidosis and abdominal pain, in addition to non-specific symptoms/signs (headache, vertigo, vomiting, mild CNS depression) are also common features. Visual disturbances, persistent metabolic acidosis and blood methyl alcohol level > 200-300mg/L require specific intensive treatment with ethanol and levels > 500mg/L usually require additional treatment with haemodialysis.

b. Prevention of further drug absorption – due to rapid absorption from GIT, prevention of absorption is usually not possible.

c. Removal of absorbed drug Renal elimination – alkalinization of urine enhances formic acid excretion

Extracorporeal – haemodialysis for persistent acidosis and/or methyl alcohol level >500mg/L.

d. Administration of antidote/competitive substrate → ethanol

Ethanol CH3CH2OH Indicated for patients with visual disturbances or a methyl alcohol level exceeding 200-300mg/L. Acts as a competitive substrate for the metabolic enzymes due to its 100 fold increased affinity for alcohol dehydrogenase compared with that of methyl alcohol.

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Adult dosage: Loading dose IV 10mls/kg 10% ethanol (in 5%dextrose) Oral 1ml/kg 95% ethanol Infusion IV 1.5ml/kg/hr 10% ethanol (3.0ml/kg/hr 10% ethanol during haemodialysis) Aim for blood alcohol concentration of 1- 1.5g/L (20-30mmol/L)

SE – drunkenness, ataxia, nausea, sedation, hiccups, hypoglycaemia

Continue ethanol administration until all clinical signs have resolved and methyl alcohol levels < 200mg/L. Other agents 4-methylpyrazole – inhibitor if alcohol dehydrogenase. Not registered in Australia. It has increased half life compared with ethanol, is simpler to use with a single 20mg/kg dose however is expensive. Folate supplementation – assists in metabolism of formic acid to CO2 & H2O

50mg IV Q4H e. Level of care/Level of monitoring – if significant ingestion then ICU management is the appropriate level of care. 3. Long term Prevention References 1. The pathogenesis of acute pulmonary edema associated with hypertension. Gandhi SK et

al. N Eng J Med 2001;344:17- 22. 2. Pathophysiological characterization of isolated diastolic heart failure in Comparison to

Systolic Heart Failure. Kitzman DW et al. JAMA 2002; 288:2144 – 2150. 3. Diastolic heart failure – no time to relax. Vasan RS and Benjamin EJ. N Eng J Med

2001;344:56-9. 4. Physiology of the heart (Third Edition). Katz AM. Lipincott-Milliams, 2001. 5. Do patients with suspected heart failure and preserved left ventricular systolic function

suffer from “diastolic heart failure” or from misdiagnosis ? A prospective study. BMJ 2000; 321 :215 – 218.

6. Diastolic heart failure in older people – myth or lost tribe ? Baxter AJ and Gray CS. Clin Med 2002 Nov – Dec;2 (6):539-543.

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DISCUSS THE INDICATIONS FOR INHALED ANTIBIOTIC THERAPY AND WHAT ANTIBIOTICS HAVE BEEN USED

Dr. M. Saxena, Intensive Care Unit, St George Hospital, NSW Inhaled bronchodilators and steroids have transformed the management of asthma since their introduction. The concept of inhaled antibiotics is an attractive one, both in terms of the prophylaxis and the treatment of lung infections, but, at present, there are many technical and efficacy issues which need further attention before their use can be recommended. There is some objective evidence emerging for their usage in the outpatient setting, but as yet data is lacking to support their use in intensive care units. Current indications for nebulized antibiotic therapy include: Over time patients with cystic fibrosis inevitably become colonized with Pseudomonas Aeruginosa and this is associated with a gradual decline in FEV1 and an increased mortality. A recent randomized controlled clinical trial of 320 patients with cystic fibrosis and chronic colonization with Pseudomonas Aeruginosa demonstrated a significant benefit with nebulized Tobramycin as compared to placebo. Patients were randomized to receive nebulized tobramycin or saline for 28 days on treatment and then followed with 28 days off treatment. This cycling was repeated 3 times giving a total duration of therapy of 6 months. The benefits included an absolute improvement in FEV1 of 11 % in the treatment group (<1% with placebo) and a significant reduction of hospital days and parenteral antibiotic usage. A subsequent open label study of the above groups provided further support for the use of nebulized tobramycin. Importantly there was no associated ototoxicity or nephrotoxicity. Two studies support the use of inhaled antibiotic for chronically colonized non cystic fibrosis bronchiectasis. A small randomized and controlled study of 1 year of treatment with nebulized ceftazidine and tobramycin vs placebo demonstrated a reduction in both the frequency and duration of hospital admissions. 1/7 patients were hospitalized in the treatment group, whereas all 8 of the placebo group required hospitalization during the study. In a further study of 74 patients randomized to receive tobramycin or placebo, the treatment group had reduced sputum density, a third had pseudomonas eradicated ( vs none in the placebo arm) and 62% had an “improved medical condition” (vs 38% in placebo) In these oupatient groups the benefit of eradication and hence blunting the associated decline in respiratory function needs to be balanced against the pathogenicity of resistant bacteria that may emerge with treatment. Hence longer term data would be useful.. There is not currently enough evidence to support the usage of nebulized antibiotic therapy in the prophylaxis or treatment of ventilator associated pneumonia, although this would appear an interesting area for future research. In the past “oropharyngeal atomiztion” with non absorbable polymixins have attempted to eradicate the gram negative flora that come to colonize the oropharynx in intubated patients and, hence prevent ventilator associated pneumonia. Although early studies showed promise, this was not borne out subsequently. More recently an uncontrolled study of nebulized gentamycin vs nebulized amikacin (9 courses for 14 to 21 days) demonstrated a decrease in sputum volume, eradication of gram negatives in most cases and decresed levels of inflammatory cells in sputum. A further trial of nebulized tobramycin vs placebo on top of standard parenteral therapy (iv beta lactam and tobramycin) for ventilator associated pneumonia showed no difference between the groups. Other uses of inhaled antibiotic include the role of nebulized pentamidine for Pneumocystis Carinii infection complicating HIV and also tribavarin in children with respiratory syncitial virus infection.

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References 1. Prober CG et al American Academy of Paediatrics. Technical report: Precautions

regarding the use of aerosolized antibiotics. Paediatrics 2000:106(6) 1-6 2. Smaldone GC, Palmer LB. Aerosolised antibiotics: current and future. Respir Care 2000;

45(6) 667-675 3. Cole PJ The role of nebulized antibiotics in treating serious respiratory infections. Journal

of chemotherapy 2001; 13(4) 354-362

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INDEX Acarbose, 38 ACTH, 10

formation of, 3 half life, 4 inhibition, 3 prednisolone suppression, 9 release of, 3 'stress' response, 5

Activated protein C treatment in sepsis, 105

Addison's disease, 9 Adrenal cortex, 3 Adrenal crisis, 10

cardiovascular effects, 10 Adrenocortical insufficiency

primary. See Addison's disease secondary, 9

Adrenocorticotropic hormone. See ACTH Aldosterone, 4

daily output, 4 Amiodarone

indications and complications, 61 Anterior pituitary, 1 Antibiotics

inhaled, 112 Antidiabetic drugs, 37 Antiphospholipid syndrome, 9 Antithyroid drugs, 25 Biguanides, 38

side effects, 38 Candida septicaemia, 90 Carbimazole, 26 Corticosteroid-binding globulin. See

Transcortin Corticotropin. See ACTH Corticotropin releasing hormone, 3 Corticotropin-releasing hormone, 1 Cortisol, 3, 4

daily output, 4 half life, 4

C-peptide, 31 Critical illness

Hyperglycaemia, 48 Critically ill

cortisol, 5 cortisol levels in, 5 endocrine changes, 1 growth hormone in the, 3

Cushing’s syndrome, 12 ACTH, 13 clinical features, 13 CRH test, 13 investigations, 13

Cushing's syndrome causes, 12 treatment, 14

Dexamethasone, 5 Dexamethasone suppression test, 13 Diabetes mellitus, 31

biochemical monitoring, 39 classification, 31 clinical features, 32 complications of, 33 diet, 35 elective surgery in, 47 insulin

treatment, 36 investigations, 32 lifestyle, 35 surgical patient, 46 treatment, 35 type I, 31 type II, 32

Diabetic ketoacidosis, 40 aetiology, 40 blood gases, 42 cerebral oedema, 44 clinical features, 41 complications, 44 hyperosmolality, 44 insulin infusion, 43 investigations, 41 magnesium, 43 monitoring, 44 phosphate, 43 plasma biochemistry, 41 plasma ketones, 42 plasma lactate, 42 potassium, 43

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sodium bicarbonate, 43 treatment, 42

Dialysis lactate free, 75

Difficult intubation, 82 Euthyroid hyperthyroxinaemia, 20 Euthyroid sick syndrome, 19 Fenfluramine, 39 Fludrocortisone, 5 Follicle-stimulating hormone, 1 Gestational diabetes, 32 Glucocorticoid

drug potencies, 4 Glucocorticoid withdrawal, 12 Gluconeogenesis, 4 Glucose intolerance

causes of, 32 Glucose tolerance test, 32

abnormal result, 34 causes of an abnormal result, 34

Glycosylated haemoglobin. See HbAIc advanced end products. See Hb-AGE

Goitre clinical features, 21 investigations, 21 simple, 21 toxic multinodular, 24 treatment, 21

Grave's disease, 24 Growth hormone, 1. See Somatostatin

treatment with, 2 Growth hormone releasing hormone, 1 Growth hormone-release inhibiting

hormone. See somatostatin HbA1c, 35 Hb-AGE, 40 HbAIc, 39 Heart failure

diastolic, 93 Heparin induced thrombocytopaenia, 72 Hepatopulmonary syndrome, 98 Hydrocortisone, 5 Hyperglycaemia, 41 Hyperthyroidism

subclinical, 25

Hypoadrenalism basal cortisol level, 11 biochemical tests, 10 clinical features, 10 C-reactive protein, 11 drugs and, 9 ECG, 10 in 'stress', 5 investigations, 10 steroid replacement during surgery, 12 thyroid function studies, 11 treatment, 11 treatment of a non-crisis, 11 treatment of crisis, 12

Hypoglycaemia, 48 causes, 48 clinical features, 49 insulin - glucose ratio, 50 investigations, 49 treatment, 50

Hypothalamus, 1 Hypothyroid sick patients, 20 Hypothyroidism, 21

aetiology, 22 angina, 23 clinical features, 22 ECG, 22 investigations, 22 plasma biochemistry, 22 thyroid function tests, 22 treatment, 23 treatment of non-life threatening, 23

IGF-I, 3

recombinant, 39 IGF-I receptor, 3 IGF-II, 3 Insulin, 3

current preparations, 36 daily production, 37 deficiency, 31 receptor, 31 resistance, 31 synthesis, 31

Insulin receptor, 3 Insulin-like growth factor, 3 Islet transplantation, 39 Ketoacidosis

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alcoholic, 42 Ketogenesis, 40 Lignocaine

indications and complications, 77 Luteinising hormone, 1 Luteinising hormone releasing hormone, 1 Mannitol

indications and complications, 70 Metformin, 38 Methyl alcohol poisoning, 109 Microangiopathy, 35 Myocardial infarction

postoperative, 79 Myxoedema, 22 Myxoedema coma, 23

corticosteroids, 24 thyroid hormone replacement, 23 treatment, 23

Neuroendocrine regulation, 1 Nitric oxide in ARDS, 66 Non-ketotic hyperglycaemic clinical

features, 44 Non-ketotic hyperglycaemic coma

cause, 44 Non-ketotic hyperglycaemic

investigations, 45 Non-ketotic hyperglycaemic treatment, 45 Octreotide

indications and complications, 95 Oxytocin, 1 Pancreatic abscess, 59 Pembertons sign, 21 Piogitazone, 39 Pituitary apoplexy. See Sheehan's

syndrome Pituitary dysfunction, 10 Portopulmonary hypertension, 98 Posterior pituitary, 1 Prednisolone, 5 Preproinsulin, 31 Proinsulin, 31 Prolactin, 1 Prolactin release inhibiting factor, 1 Prolactin releasing factor, 1

Propranalol, 26 Propylthyrouracil, 26 Prostacyclin in ARDS, 66 Random blood glucose, 32 Retinopathy, 35 Reverse T3. See rT3 Rosiglitazone, 39 Sagittal sinus thrombosis, 87 Septic shock

complications of steroids, 57 Sheehan's syndrome, 10 Short synacthen test, 11

low dose, 11 Somatostatin

half life, 2 Somatotropin, 1 Sulphonylureas, 37

side effects, 37 Superior vena cava syndrome, 21 T3

free, 19 T4

free, 18 total, 18

Thiazolidinediones, 38 Thyroid

function tests, 18 hormone plasma levels, 19 hormones, 17

biological half lives, 18 daily secretion, 17

normal function, 17 radionuclide scan, 19 serum antibodies, 19 ultrasound, 19

Thyroid stimulating hormone, 1, 17. See TSH

Thyrotoxic crisis aetiology, 26 clinical features, 26 treatment, 27

Thyrotoxicosis, 24 ablative therapy, 26 aetiology, 24 apathetic, 25 clinical features, 24

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investigations, 25 thyroid function studies, 25 treatment

non-life threatening, 25 use of propranalol, 26

Thyrotropin releasing hormone, 17 stimulation test, 18

Thyrotropin-releasing hormone, 1 Thyroxin

free, 18 Thyroxine. See T4 Thyroxine binding globulin, 18

Torsade de pointes, 101 Transcortin, 4 Triiodothyronine. See T3 TSH, 1, 11, 17

plasma levels, 18 Vasopressin, 1 Verapamil overdosage, 85 Waterhouse Friderichsen syndrome, 9