diabetic ketoacidosis. 4. Correct pH in speci \201 c circumstances only, e.g. NaHCO3 in renal failure. GENERAL ACID-BASE PRINCIPLES 501 See also: \210\222 \210\222 Blood gas analysis, p154; Electrolytes (Na+, K+, Cl ), p212; Lactate, p236; Crystalloids, p242; , HCO3 Sodium bicarbonate, p244; Metabolic acidosis, p50 2; Metabolic alkalosis, p504. 502 CHAPTER 29 Metabolic disorders Metabolic acidosis A subnormal arterial blood pH with a base de \201 cit >2mmol/L, reduced strong ion difference and/or an increase in weak acids. Outcome in criti- cally ill patien ts has been linked to severity, duration, and hyperlactataemia. Causes \200 Hyperlactataemia \200\224may be due to tissue hypoperfusion (e.g. circulatory shock) or nec rosis, cellular abnormalities (any cause of mitochondrial inhibition, e.g. sepsis, drug-rel ated inhibition of aerobic respiration), and accelerated anaerobic respiration. The latter may be due to tissue hypoxia or to excess adrenergic tone/catecholamine infusion (notably e pinephrine), increasing activity of muscle Na+ pumps. High lactate may be seen with increas ed muscle activity (e.g. post- seizure). Lung lactate release is seen in acute lung injury. Hyperchloraemia, e.g. excessive saline infusion. Ketoacidosis \200\224high levels of B-hyd roxybutyrate and acetoacetate related to uncontrolled diabetes mellitus, starvation, and al coholism. Renal failure \200\224accumulation of organic acids. Drugs \200\224in particular, aspirin (salicylic acid) overdose, acetazolamide (carbonic anhydrase inhibition), ammonium chloride, drugs inhibiting mitochondrial function (e.g. highly active antiretroviral thera py). Vasopressor agents may be implicated, possibly by inducing regional ischemia or, in th e case of epinephrine, accelerated glycolysis. Ingestion of poisons, e.g. paraldehyde, ethy lene glycol, methanol. Cation loss, e.g. severe diarrhea, small bowel \201 stulae, ileost omy. Glucose-6-phosphatase de \201 ciency. Thiamine de \201 ciency (affects glycolysis an d the Krebs \200\231 cycle). Prolonged seizures. Excessive muscular activity. \200 \200 \200 \200 \200 \200 \200 Clinical features \200 \200 \200 Dyspnoea. Haemodynamic instability. A rapidly increasing metabolic acidosis (over minutes t o hours) is not due to renal failure. Other causes, particularly severe tissue hypoperfusio n, sepsis, or tissue necrosis, should be suspected when there is associated systemic deteri oration. Management 1. The underlying cause should be identi \201 ed and treated where possible rat her than administering alkali or manipulating minute volume to nor- malise the arterial pH. 2. Urgent haemo(dia) \201 ltration may be necessary if oligoanuria persists. 3. Reversal o f the metabolic acidosis (other than simple buffering with bicarbonate) is generally an ind ication of successful therapy. An increas- ing base de \201 cit suggests that the therapeu tic maneuvers in operation are either inadequate or wrong. 4. Bicarbonate therapy may be appropriate when tissue hypoperfusion has been corrected/excl uded. This is particularly the case for ongoing loss of alkali (e.g. biliary \201 stula, diarrhea) or inability to acidify urine. 5. The bene \201 ts of buffers such as Carbicarb and THAM (tris-hydroxy- methyl-aminomethane) remain unproven. METABOLIC ACIDOSIS 503 Key paper Levy B, Gibot D, Franck P, et al. (2005) Relation between muscle Na+K+ ATPase act ivity and raised lactate concentrations in septic shock: a prospective study. Lancet 365: 8 71 \200\2235. See also: \210\222 \210\222 Blood gas analysis, p154; Electrolytes (Na+, K+, Cl ), p212; Lactate, p236; Crystalloids, p242; , HCO3 Sodium bicarbonate, p244; Acute renal failure \200\224diagnosis, p400; General acid-base principles, p500; Diabetic ketoacidosis, p510; S ystemic in \202 ammation/multi-organ failure \200\224causes, p556; Sepsis and septic shock \200\224treatment, p560. 504 CHAPTER 29 Metabolic disorders Metabolic alkalosis A supranormal arterial blood pH with a base excess >2mmol/L and an incr eased strong ion difference caused either by loss of (non-carbonic) acid or gain of base. A s the kidney is usually ef \201 cient at excreting large quantities of bicarbonate, persis tence of a metabolic alkalosis usually depends on either chronic renal failure or a diminis hed extracellular \202 uid volume with severe depletion of K+, resulting in an inability to reabsorb Cl \200\223 in excess of Na+. \200 The patient is usually asymptomatic althou gh, if spontaneously breathing, will hypoventilate. A metabolic alkalosis will cause a left shift of the oxyhaemoglobin curve, reducing oxygen availability to the tissues. If severe (pH >7.6), metabolic alkalosis may result in encephalopathy, seizures, decreased coronary b lood \202 ow, and cardiac contractility. Causes \200 \200 \200 \200 Diuretics. Large nasogastric aspirates, vomiting. Secondary hyperaldosteronism with potassi um depletion. Use of haemo \201 ltration replacement \202 uid containing excess buffer ( e.g. lactate). Renal compensation for chronic hypercapnia (increasing strong ion difference ). This can develop within 1 \200\2232 weeks. Though more apparent when the patient hyperve ntilates or is hyperventilated to normocapnia, an overcompensated metabolic alkalosis can o ccasionally be seen in the chronic state (i.e. a raised pH in an otherwise stable long-term hypercapnic patient). Excess administration of bicarbonate. Excess administration of citra te (large blood transfusion). Drugs, including laxative abuse, corticosteroids. Rarely, Cus hing \200\231s, Conn \200\231s, Bartter \200\231s syndrome. \200 \200 \200 Management 1. Replacement of \202 uid, sodium chloride (i.e. give 0.9% saline), and potas - sium losses are often suf \201 cient to restore acid-base balance. 2. With distal renal causes related to hyperaldosteronism, addition of spironolactone (or potassium canrenoate) can be considered. 3. Active treatment is rarely necessary. If so, give ammonium chloride 5g tds PO. Hydrochlo ric acid has been used on occasion for severe metabolic alkalosis (pH >7.7). It should be g iven via a central vein in a concentration of 1mmol HCl per mL water at a rate <1mmol/kg/h. 4. Compensation for a longstanding respiratory acidosis, followed by cor- rection of that acidosis, e.g. with mechanical ventilation, will lead to an uncompensated metabolic alkalos is. This usually corrects with time though acetazolamide (or rarely, mechanical \200\230hy poventilation \200\231, i.e. main- taining hypercapnia) can be considered. METABOLIC ALKALOSIS 505 See also: Haemo(dia) \201 ltration (1), p108; Haemo(dia) \201 ltration (2), p110; Blood g as analysis, p154; Electrolytes (Na+, K+, Cl \200\223, HCO3 Acute renal failure \200\224dia gnosis, p400; Vomiting/gastric stasis, p406; General acid-base principles, p500; Diabetic k etoacidosis, p510; Systemic in \202 ammation/multi-organ failure \200\224causes, p556; Sep sis and septic shock \200\224treatment, p560. \200\223), p212; Diuretics, p280; Sodium bicarbonate, p244; Blood transfusion, p248; 506 CHAPTER 29 Metabolic disorders Hypoglycaemia Causes \200 \200 \200 \200 \200 \200 Inadequate intake of carbohydrate. Excess insulin or sulphonylurea. Liver failure with depl etion of glycogen stores. Alcohol. Hypoadrenalism (including Addison \200\231s disease), hy popituitarism. Quinine, aspirin. Clincal features \200 Nausea, vomiting. \200 Increased sympathetic activity, e.g. sweat ing, tachycardia. \200 Altered behavior and conscious level. \200 Seizures, focal neuro logical signs. Management 1. Monitor carefully with regular bedside estimations. The frequency should be i ncreased in conditions known to precipitate hypoglycaemia, e.g. insulin infusion, liver fai lure, quinine treatment of malaria. 2. Administer 25mL 50% glucose solution if the blood gl ucose is: \200 \200 \211 3mmol/L or \211 4mmol/L and the patient is symptomatic or Within the normal range, b ut the patient is symptomatic (usually longstanding, poorly controlled diabetics). Repeat as necessary every few minutes until symptoms abate and the blood glucose level has normalized. 3. If the blood glucose is 3 \200\2234mmol/L and the patient is non-symptomatic, either red uce the rate of insulin infusion (if present) or increase calorie intake (enterally or pare nterally). In insulin-dependent diabetes mellitus, the insulin should continue with adequat e glucose intake. 4. A continuous parenteral infusion of 10%, 20%, or 50% glucose solution, varying from 10 \200\223100mL/h, may be required, depending on the degree of continuing hypoglycaemia and t he patient \200\231s \202 uid balance/urine out- put. 5% glucose solution only contains 2 0Cal/100mL and should not be used to prevent or treat hypoglycaemia. 5. In the rare instance of no venous access, hypoglycaemia may be tempo- rarily reversed by glucagon 1mg given either IM or SC. 6. Continuing hypoglycaemia in the face of adequate treatment and lack of symptoms should b e con \201 rmed with formal laboratory blood sugar estimation to exclude malfunctioning of the bedside testing equipment. HYPOGLYCAEMIA 507 See also: Enteral nutrition, p128; Parenteral nutrition, p130; Tight glycaemic control/inte nsive insulin therapy, p132; Acute liver failure, p430; Generalized seizures, p444; Hypoadr enal crisis, p516. 508 CHAPTER 29 Metabolic disorders Hyperglycaemia Causes \200 A common occurrence in critically ill patients due to a combination of impaired glucose tol erance, insulin resistance, high circulating levels of endogenous catecholamines and cortic osteroids, and regular administration of such drugs which antagonize the effect of insulin. Pancreatitis resulting in islet cell damage. Clinical features None in the short term, other than polyuria from the osmotic diuresis. Th e patient may complain of thirst or show signs of hypovolaemia if \202 uid balance is all owed to become too negative. Metabolic effects Relative lack of insulin prevents cellular glucose uptake and utilization resulting in: \200 \200 \200 \200 Increased lipolysis. Altered cellular metabolism. Increased oxidative damage. Increased ris k of infection (decreased neutrophil action). Prognostic signi \201 cance Strict maintenance of glycaemic control (approximately 4 \200 \2236.5mmol/L) with a regimen of insulin and glucose resulted in signi \201 cant outcome i mprove- ments in surgical and medical ICU population staying four days. Whether this is rel ated to prevention of hyperglycaemia and/or an effect related to additional administration of insulin still remains uncertain. However, sub- sequent multicentre studies have failed t o reproduce these \201 ndings. The increased risk of hypoglycaemia (and potential outcome detriment) has led some authorities to suggest an upper blood glucose level of 8mmol/L sho uld be tolerated. Management 1. Treatment should be given if blood glucose persists >7 \200\2238mmol/L. 2. Sh ort-acting insulin infusion (e.g. Actrapid ) should be used and ti- trated to maintain nor moglycaemia (4 \200\2237mmol/L). Usually 1 \200\2234U/h are required though may need to be much higher in diabetics who become critically ill. Regular bedside monitoring of blood sug ar should be per- formed; this should be undertaken hourly if unstable. 3. Oral hypoglycaemic agents should be generally avoided in the ICU patient because of thei r prolonged duration of action and unpredict- able absorption. HYPERGLYCAEMIA 509 Key papers Van den Berghe G, Wouters P, Weekers F, et al. (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345: 1359 \200\22367. Van den Berghe G, Wilmer A, Hermans G, et al. (2006) Intensive insulin therapy in the medic al ICU. N Engl J Med 354: 449 \200\22361. Brunkhorst FM, Engel C, Bloos F, et al. (2008) Intensive insulin therapy and pentastarch re suscita- tion in severe sepsis. N Engl J Med 358:125 \200\22339. See also: Enteral nutrition, p128; Parenteral nutrition, p130; Tight glycaemic control/inte nsive insulin therapy, p132; Diabetic ketoacidosis, p510; Hyperosmolar diabetic emergencies , p512. 510 CHAPTER 29 Metabolic disorders Diabetic ketoacidosis May occur de novo in a previously undiagnosed diabetic, or follow an acute insult (e.g. infection), or inadequate insulin in a known diabetic. Clinical features \200 \200 Excess fat metabolism to fatty acids with ketone production. An osmotic diuresis with large losses of \202 uid (up to 6 \200\22310L), sodium (400 \200\223800mmol), potassium (250 \200\223800mmol), and magnesium. Symptoms arise from hypovolaemia, metabolic acidosis, and electrolyte imbalance with polyur ia. Hyperventilation is a prominent feature. Coma needs not necessarily be present to be li fe-threatening. Plasma amylase commonly exceeds 1000U/L, but does not indicate pancreatitis . Monitoring Adequate invasive monitoring is essential, particularly if the patient has cir culatory instability or cardiac dysfunction. Urine output, blood gasses, and plasma electro lytes should also be monitored frequently. Fluid and electrolyte management 1. Fluid and el ectrolyte repletion should be tailored to individual needs. Traditional regimens (e.g. 3 \200\2234L within the \201 rst 3 \200\2234h) increase the risk of cerebral oedema, cardia c and/or renal failure. 2. Colloid \202 uid challenges should initally be given in states of hypotension and tiss ue hypoperfusion to restore the circulating blood volume. 3. Thereafter, replace \202 uid with 0.9% saline at a rate of 100 \200\223200mL/h until the salt and water debt has been replenished. 4. Hypotonic (0.45%) saline resuscitation may be appropriate in the non- shocked patient if the plasma sodium is rising rapidly (shift of water and potassium into cells and sodium ou t). 5. Use 5% glucose solution (100 \200\223200mL/h) after replacing the sodium debt. replaceme nt. Both acidosis and excessive K+ 6. Monitor K+ administration cause hyperkalaemia while \202 uid and insulin will produce hypokalaemia. Check levels frequently to maintain normok alemia. Infusion of 10 \200\22340mmol/h KCl will be needed. 7. Monitor magnesium replacement. 3 \200\2235mmol/h is usually suf \201 cient. Hyperglycae mia Correct at a rate of 2 \200\2234mmol/h by adjusting the insulin infusion (usually 1 \200\2235U/h). Monitor blood glucose hourly. Continue IV insulin until heavy ketonuria has disappeared and the base de \201 cit normalized. Other aspects of managing ketoacidosis 1. Seek and treat a precipitating cause, e.g. sepsis, myocardial infarction, stroke, gastroenteritis. 2. Only give antibiotics for proved or highly suspected infection. 3. Abdominal pain should not be dismissed as part of the syndrome. 4. If obtunded, a nasogastric tube should be ins erted as gastric emptying is often delayed and acute gastric dilatation is common. 5. Avoid bicarbonate, even for severe acidosis (pH <7.0). It causes an increased intracellu lar acidosis, depressed respiration due to a relative CSF alkalosis and sodium overload. 6. LMW heparin 5000U od SC is indicated in immobile patients. DIABETIC KETOACIDOSIS 511 See also: \210\222 \210\222 Electrolytes (Na+, K+, Cl ), p212; Bacteriology, p224; Urinal ysis, p232; Crystalloids, , HCO3 p242; Colloids, p246; Anticoagulants, p316; Antimicrobials , p326; Vomiting/gastric stasis, p406; Hyperkalaemia, p488; Hypokalaemia, p490; Hypomagnesa emia, p492; Metabolic acidosis, p502; Hyperglycaemia, p508; Infection \200\224diagnosis, p5 52. 512 CHAPTER 29 Metabolic disorders Hyperosmolar diabetic emergencies This is more common in elderly, non-insulin dependent dia betics though can present de novo in young adults. Precipitating factors are similar to ket oacidosis, e.g. sepsis, myocardial infarction. Clinical features \200 Fluid depletion is greater, blood glucose levels often higher, coma more common, and mortal ity much higher than diabetic ketoacidosis. Confusion, agitation, and drowsiness that may p ersist for 1 \200\2232 weeks. A metabolic acidosis may be present but is not usually profou nd; ketoacidosis is not a major feature. Hyperosmolality may predispose to thrombotic event s; this is the major cause of mortality. Hyperosmolality may not be severe. Focal neurologi cal signs and disseminated intravascular coagulation are occasionally recognized. \200 Management As for diabetic ketoacidosis, however: 1. Unless the patient shows signs of hypo volaemia and tissue hypoper- fusion, in which case colloid challenges should be given for p rompt resuscitation, \202 uid replacement should be more gradual as the risk of cerebral oedema is higher. This can be with either 0.9% saline or, if the plasma sodium is high, 0.4 5% saline at a rate of 100 \200\223200mL/h. 2. The plasma sodium rises with treatment, even with 0.45% saline, and can often increase i n the \201 rst few days to 160 \200\223170mmol/L before grad- ually declining thereafter. Aim to correct slowly. 3. Serum phosphate and Mg2+ levels fall rapidly with this condition; replacement may be nee ded as guided by frequently taken plasma levels. 4. Patients may be hypersensitive to insulin and require lower doses. 5. Unless otherwise c ontraindicated and in view of the high risk of throm- boembolism, these patients should be fully heparinised until full recovery (which may take \211 5 days). HYPEROSMOLAR DIABETIC EMERGENCIES 513 See also: Electrolytes (Na+, K+, Cl \200\223, HCO3 p242; Colloids, p246; Anticoagulants, p3 18; Antimicrobials, p326; Vomiting/gastric stasis, p406; Hypernatraemia, p484; Hyperkalaemi a, p488; Hypokalaemia, p490; Hypomagnesaemia, p492; Hypophosphataemia, p498; Metabolic acid osis, p502; Hyperglycaemia, p508; Diabetic ketoacidosis, p510; Infection \200\224diagnosis, p552. \200\223), p212; Bacteriology, p224; Urinalysis, p232; Crystalloids, 514 CHAPTER 29 Metabolic disorders Thyroid emergencies Thyrotoxic crisis Presents as an exacerbation of the clinical features of hyperthyroidism (e.g. pyrexia, hyperdynamic circulation, heart failure, confusion). Ther e is usually a precipitating factor such as infection, surgery, ketoacidosis, myocardial in farction, or childbirth. It may present with exhaustion in the elderly with few features of hyperthyroidism. The diagnosis is con \201 rmed by standard thyroid function tests. Management \200 Pyrexia should be controlled by surface cooling (avoid aspirin which displaces thyroxine fr om plasma proteins). Catecholamine effects should be reduced by B-blockade (e.g. propranolo l 1 \200\2235mg IV, then 20 \200\22380mg PO qds). These should be used with caution if ther e is acute heart failure. Blockade of thyroxine synthesis is achieved by potassium iodide 2 00 \200\223 600mg IV over 2h, then 2g/d PO and carbimazole 60 \200\223120mg/d PO. Blockade of peripheral T4 to T3 conversion is achieved by dexamethasone 2mg IV qds. Careful \202 u id and electrolyte management is essential. Myxoedema coma Presents as an exacerbation of the features of hypothyroidism (e.g. hypo- th ermia, coma, bradycardia, metabolic and respiratory acidosis, anemia). There may be a preci pitating factor (e.g. cold, infection, surgery, myocar- dial infarction, CVA, central nervo us system depressant drugs). Diagnosis is con \201 rmed by thyroid function tests. Management \200 Treatment of complications of severe hypothyroidism (e.g. hypo- tension, heart failure, hyp othermia, bradycardia, seizures) is more important than thyroid hormone replacement. Thyrox ine replacement should be with low doses (0.1 \200\2230.2mg PO or PR and reduced in ischaem ic heart disease). There are no de \201 nite advantages to using T3 replacement, high dose replacement regimens, or IV treatment. Corticosteroids (hydrocortisone 100mg qds IV) shoul d be given since coexisting hypoadrenalism is masked by myxoedema. Sick euthyroid /low T3 syndrome This is a frequent complication of critical illness with lo w T3 and T4 and high reverse T3 (rT3) levels. These correlate with the severity of disease and a poor outcome. There is both reduced TSH secretion and altered peripheral thyroid meta bolism. A trial of thyroxine administration in criti- cally ill patients produced a negativ e outcome although those suffering from the sick euthyroid syndrome were not identi \201 e d. Optimal treatment of this syndrome thus remains unknown. THYROID EMERGENCIES 515 See also: Hypotension, p380; Tachyarrhythmias, p384; Bradyarrhythmias, p386; Acute coronary syndrome (1), p388; Heart failure \200\224assessment, p392; Heart failure \200\224manageme nt, p394; Hypothermia, p600; Pyrexia \200\224causes, p602; Pyrexia \200\224management, p604 . 516 CHAPTER 29 Metabolic disorders Hypoadrenal crisis Clinical features Primary hypoadrenalism \200 Glucocorticoid de \201 ciency (e.g. weakness, vomiting, diarrhea, abdominal pain, hypoglyc aemia). Mineralocorticoid de \201 ciency (e.g. dehydration, hyponatraemia, weight loss, po stural hypotension, hyperkalaemia). Skin pigmentation due to ACTH excess. Secondary hypoadrenalism \200 May be due to critical illness, corticosteroid withdrawal after 2 weeks \200\231 treatment, hypopituitarism, or etomidate use. No skin pigmentation. Features of mineralocorticoid de \201 ciency may be absent. \200 Diagnosis Diagnosis is con \201 rmed by plasma cortisol, ACTH levels, and a negative Synac then (ACTH analog) test, although treatment should begin on clinical suspicion. Synacthen 250mcg IV should produce a >200nmol/L rise in plasma cortisol. In primary hypoadrenalism , levels remain below 600nmol/L. However, baseline levels may be normal or elevated in the relative adrenal de \201 ciency seen in sepsis and other critical illnesses. Dexamethasone may be used for corticosteroid replacement for 48h before a Synacthen test is performed si nce other corticosteroid treat- ments may be detected in the plasma cortisol assay. Management \200 Salt and water de \201 ciency should be corrected urgently. Initial \202 uid replacement should be with colloid if there is hypotension or evidence of poor tissue perfusion. Other wise, 4 \200\2235L/d 0.9% saline will be needed for several days. Fluid management should b e carefully monitored to ensure adequate replacement without \202 uid overload. Glucocort icoid replacement should be with hydrocortisone 50 \200\223100mg tds IV on day 1, then 20 \200\22350mg tds on days 2 \200\2233). Hydrocortisone may be changed to equivalent doses of dexamethasone when a Synacthen test is performed. The relative hypoadrenalism related to sepsis can be treated with hydrocortisone 50mg qds for seven days, and then a reducing dos e over the next 5 \200\2237 days. Studies have shown more rapid resolution of shock and an improved outcome in those showing a suboptimal response to synthetic ACTH. HYPOADRENAL CRISIS 517 See also: Electrolytes (Na+, K+, Cl \200\223, HCO3 Hyperkalaemia, p488; Hypoglycaemia, p506 . \200\223), p212; Corticosteroids, p328; Hyponatraemia, p486; This page intentionally left blank 519 Chapter 30 Poisoning Poisoning \200\224general principles 520 Salicylate poisoning 522 Paracetamol poisoning 524 Sedative poisoning 526 Tricyclic antidepressant poisoning 528 Amphetamines and Ecstasy 530 Cocaine poisoning 532 Inhaled poisons 534 Household chemicals 536 Methanol and ethylene gl ycol 538 Organophosphate poisoning 540 520 CHAPTER 30 Poisoning Poisoning \200\224general principles Consider poisoning in patients presenting with altered consciousness, respiratory or cardiovascular depression, vomiting, hypothermia, or sei- zu res. Diagnosis is often obvious though the obtunded or truly suicidal patient may prevent a n accurate history being taken. Clinical signs may be confused due to ingestion of multiple poisons or absent if effects are delayed. Poisons may also enter the body via routes other than ingestion, e.g. inhalation or transdermally. Salicylate and paracetamol are extremely common agents in self-poisoning and patients often present without alter- ation in conscio us level. Investigation All patients require urea and electrolyte, baseline liver function, coagu- la tion studies, blood glucose, and blood gas estimations. Urine samples and gastric aspirate should be saved for possible later toxicology analysis. Obtain salicylate and paracetamol l evels urgently due to the common lack of early signs and to direct speci \201 c early trea tment. Other drug levels may help in diagnosis but treatment is often supportive. Early sup port from the local Poisons Information Service should be solicited. Supportive treatment Treat cardiovascular and respiratory compromise and neurological distu r- bance as by standard intensive care methods. In the unconscious patient, opiates and ben zodiazepines may be reversed temporarily to allow assess- ment of underlying neurological s tatus though caution should be applied in epileptics. Gastric emptying Despite previous widespread use, there is little supporting evidence and i t carries signi \201 cant complication risks. Consider gastric emptying if the poison is n ot a corrosive or hydrocarbon, has been ingested <60min previously, and cannot be eliminate d by other means (e.g. iron). Forced emesis (ipecacuanaha 30mL in 200mL water) is no longer recommended as vomiting may be delayed for 30min and may be intractable. Aspiration is a s erious risk with either form of gastric emptying therapy; intubate the patient for airway p rotection if consciousness is at all impaired. Prevention of absorption Activated charcoal is probably more effective than gastric emptyin g to prevent drug absorption. A charcoal:poison weight ratio of 10:1 is recom- mended. Give activated charcoal (50 \200\223100g as a single dose) NG to adsorb poison remaining in the gut 9 a cathartic agent. Enhanced elimination Forced diuresis is no longer recommended. Fluid repletion with mild ur inary alkalinisation is useful for salicylates. Small molecules may be removed by haemodial ysis (e.g. ethylene glycol, methanol, oxalic acid, formic acid, salicylates, lithium). Acti vated charcoal given to prevent absorption may also adsorb poison returned to the small bow el via the enterohepatic circulation. This may be useful in carbamazepine, pheno- barbital, theophylline, quinine, and dapsone poisoning. Multiple doses of activated charcoal are pro bably ineffective. POISONING \200\224GENERAL PRINCIPLES 521 See also: Airway maintenance, p40; Endotracheal intubation, p42; Urea and creatinine, p210; Electrolytes (Na+, K+, Cl \200\223, HCO3 Paracetamol poisoning, p524; Sedative poisoning, p526; Tricyclic antidepressant poisoning, p528; Amphetamines and ecstasy, p530; Cocaine poi soning, p532; Inhaled poisons, p534; Household chemicals, p536; Methanol and ethylene glyco l, p538; Organophosphate poisoning, p540. \200\223), p212; Liver function tests, p218; Toxicology, p228; Salicylate poisoning, p522; 522 CHAPTER 30 Poisoning Salicylate poisoning Serious, life-threatening toxicity is likely after ingestion of >7.5g salicylate. Aspirin (acetyl salicylic acid) is the most common form ingested. Loss of consciousness is rare but metabolic derangements are complex (e.g. respiratory alka losis due to respiratory center stimulation, dehydra- tion due to salt and water loss, rena l bicarbonate excretion and hyper- thermia, hypokalaemia, metabolic acidosis due to interfe rence with carbohydrate, lipid and amino acid metabolism, hyperthermia due to uncoupling of oxidative phosphorylation and increased metabolic rate). There may also be pulmonary oedema due to capillary leak and bleeding due to reduced prothr ombin levels. Although gastric erosions are common with aspirin treatment, bleeding from th is source is rare in acute poisoning. Management Prevention of absorption Give activated charcoal (50 \200\223100g) NG to adsorb salicylate remaining in the gut. Salicylate levels Repeat blood levels as they may continue to rise as absorption continues. Levels taken after 12h may underestimate the degree of toxicity due to tissue binding. If salicylate levels are <3.1mmol/L after 1h of ingestion and there is no metabolic derangemen t, then observation, \202 uids, and repeat levels are all that is required. Urine alkalin isation is required if levels >3.6mmol/L or there is metabolic derangement but no renal fai lure. Levels >5.1mmol/L (or >3.6mmol/L with renal failure) require haemodialysis. Urine alkalinisation Alkalinisation rather than forced diuresis is more important for salic ylate excretion. Urinary pH must be >7.0 without arterial alkalosis (pH <7.5). Potassium lo ss occurs with a bicarbonate infusion due to the diuresis and as a toxic effect of the sali cylate. Monitor and correct potassium levels in a high dependency environment. Fluid replet ion is essential. Alkalinisation, if successful, should continue until salicylate levels fa ll <3.6mmol/L. Calcium levels may drop with prolonged alkalinisation. Haemodialysis Indications include salicylate levels >5.1mmol/L, renal failure, or marked me tabolic acidosis. SALICYLATE POISONING 523 See also: Blood gas analysis, p154; Electrolytes (Na+, K+, Cl \200\223, HCO3 phosphate, p21 4; Toxicology, p228; Poisoning \200\224general principles, p520. \200\223), p212; Calcium, magnesium and 524 CHAPTER 30 Poisoning Paracetamol poisoning Serious, life-threatening toxicity is likely after ingestion of >10 \200\22315g para- cetamol, particularly with co-ingestion of enzyme-inducing drugs (e.g. an ti- convulsants, anti-TB therapy) and/or alcohol. Paracetamol is rapidly absorbed and metabolized by conjugation in the liver. Hepatic necros is occurs due to toxicity of an alkylating metabolite normally removed by conjugation with glutathione; glutathione is rapidly depleted with overdose and may already be low in starva tion, alcoholics, and HIV disease, thus predisposing these groups to an increased risk of t oxicity. Toxicity is usually asymptomatic for 1 \200\2232 days although laboratory assessment of liver function may become abnormal after 18h. Hepatic failure develops after 2 \200\2237 days. Management If ingestion of >12g has occurred <1h previously, activated charcoal (50 \200 \223 100g) should be given NG to adsorb paracetamol remaining in the bowel. Take blood leve ls to con \201 rm ingestion, but should not be interpreted for toxicity unless taken four or more hours from ingestion. The mainstay of treatment is with N-acetylcysteine (NAC) to r estore hepatic glutathione levels by increasing intracellular cysteine levels. N-acetylcysteine Treatment is most effective if started within 8h of ingestion, but is curr ently advised for up to 36h of ingestion. Start NAC if paracetamol levels are in the toxic range (see \201 gure 30.1) or >12g paracetamol has likely been ingested. Continue NAC unt il paracetamol is not detected in the blood. It is given by continuous IV infusion (150mg/k g over 15min, 50mg/kg in 500mL 5% glucose over 4h, then 50mg/kg in 500mL 5% glucose 8-hourl y). Methionine Methionine is an alternative to NAC, but absorption is unreliable if there is vo miting or activated charcoal administration. Give 2.5g methionine PO 4-hourly for four dose s within 12h of ingestion. Complications The major complication is hepatic (9 renal) failure. A rise in prothrombin ti me, INR, and bilirubin are early warning signs of signi \201 cant hepatic damage and this should prompt early referral to a specialist center. Guidelines for referral to a Specialist Liver center \200 \200 \200 \200 \200 Arterial pH <7.3. INR >3 on day 2 or >4 thereafter. Oliguria and/or rising creatinine. Alte red conscious level. Hypoglycaemia. Guidelines for liver transplantation \200 Arterial pH <7.3. Or all the following: \200 \200 \200 High lactate levels (>3.5mmol/L at 4 and 12h) and low factor V levels are als o associated with a poor outcome if not transplanted. PT >100, INR >6.5. Creatinine >200 mol/L. Grade 3 \200\2234 encephalopathy. PARACETAMOL POISONING 525 1.4 1.2 1 ) l / l o m m Treatment with N-acetylcysteine required 0.8 ( l e v e l l o m a t e c a r a P 0.6 Treatment with N-acetylcysteine required for high risk patients 0.4 0.2 Treatment with N-acetylcysteine not required 0 4 6 8 10 12 14 16 18 20 22 24 Time since ingestion (h) Fig. 30.1. Graph for predicting treatment requirement. Treatment is required at lower levels if the patient is a known alcoholic, protein-depleted , HIV-positive, or is taking enzyme-inducing drugs, e.g. phenytoin. See also: Liver function tests, p218; Coagulation monitoring, p222; Toxicology, p228; Acute liver failure, p430; Poisoning \200\224general principles, p520. 526 CHAPTER 30 Poisoning Sedative poisoning Patients can present with alterated consciousness, respiratory failure, and sometimes, cardiovascular disturbance. Treatment is usually supportive. Consider the po ssibility of rhabdomyolysis after prolonged immobility. Benzodiazepine poisoning \200 Benzodiazepines are common agents used for self-poisoning, but severe features are uncommon , except at extremes of age. Flumazenil may be used as a speci \201 c antidote (0.2 \200 \2231.0mg IV given in 0.1mg increments), but is dangerous in benzodiazepine dependence and mixed poisoning with tricyclic antidepressants. Flumazenil is short-acting so benzodiazepin e reversal may be temporary. Rapid reversal of benzodiazepines may lead to anxiety attacks or seizures. Opioid poisoning \200 Treatment is supportive with attention particularly to respiratory depression and cardiovas cular disturbance. Naloxone may be used as an antidote (0.2 \200\2230.4mg IV) although rapi d reversal is not desired in opioid abusers. Naloxone is short-acting so reversal may be te mporary. Consider HIV or other viral infection, and endocarditis in IV drug abusers. In iat rogenic poisoning, naloxone will reverse the pain relief that opioids were given for. In th ese cases, respiratory depression is better reversed by the non-speci \201 c respiratory s timulant, doxapram (1.0 \200\223 1.5mg/kg over 30s IV followed by 1.5 \200\2234.0mg/min). \200 Barbiturates Treatment is supportive with particular attention to respiratory and car- diov ascular depression. Vasodilatation may be extreme requiring \202 uid support and, in some cases, inotropic support. Phenobarbital may be eliminated by forced alkaline diuresis. SEDATIVE POISONING 527 See also: Airway maintenance, p40; Respiratory stimulants, p256; Coma, p438; Poisoning \200 \224general principles, p520. 528 CHAPTER 30 Poisoning Tricyclic antidepressant poisoning Tricyclic antidepressants are prescribed to patients who are at greatest risk of a suicide attempt. They are rapidly absorbed from the gastrointes- tinal tract although gastric emptying is delayed. Clinical features \200 \200 Anticholinergic effects (dilated pupils, dry mouth, ileus, urine retention). Arrhythmias (o ften associated with prolonged QT interval and broad QRS complex). Hypotension related to a rrhythmias and/or cardiac depression through Na+ channel blockade. Hyper-re \202 exia with extensor plantars, visual hallucinations, coma, and seizures. Drug levels do not correlate with severity. Metabolic acidosis in severe poisoning. Metabolism is usually rapid and imp rovement is usually within 24h. \200 Management 1. There is no speci \201 c treatment for tricyclic antidepressant poisoning. 2 . Patients require ECG monitoring during the \201 rst 24h and until ECG changes have disappeared for 12h. 3. Activated charcoal (50g) via a nasogastric tube will adsorb tricyclics remaining in the bowel. 4. Cardiac arrhythmias are more common if there is an acidosis. Give bi- carbonate to achie ve an arterial pH of 7.5. If arrhythmias occur with no acidosis and fail to respond to trea tment with amiodarone or pheny- toin, bicarbonate (25 \200\22350mL 8.4% IV) may still be us eful. 5. Seizures are best managed with benzodiazepines and phenytoin. TRICYCLIC ANTIDEPRESSANT POISONING 529 See also: Airway maintenance, p40; Sodium bicarbonate, p244; Tachyarrhythmias, p384; Coma, p438; Generalized seizures, p444; Poisoning \200\224general principles, p520. 530 CHAPTER 30 Poisoning Amphetamines and Ecstasy Amphetamines, e.g. 3,4-methylenedioxymethamphetamine (MDMA, \200 \230Ecstasy \200\231) and 3,4-methylenedioxyethamphetamine ( \200\230Eve \200\231), are sti mulants taken pre- dominantly for recreational use or as appetite suppressants. They are ha llucinogenic at higher doses. MDMA cause rapid decreases in central nervous system 5-hydrox ytryptamine and 5-hydroxyindole-3-acetic acid levels and increases in dopamine release. Clinical features of overdose \200 Agitation, hyperactivity, hypertension, hallucinations, paranoia followed by exhaustion, co ma, convulsions, and hyperthermia. Idiosyncratic responses to Ecstasy and Eve are more comm on with numerous reports of mortality and major morbidity following ingestion of just 1 \200\2232 tablets. Ingestion in hot environments, e.g. nightclubs, and concurrent dehydrati on is more likely to be associated with idiosyncratic responses. Features include profound hyperthermia (>40*C), agitation, seizures, muscle rigidity, hypertension, tachycardia, swea ting, coma, disseminated intravascular coagulation, and rhabdomyolysis. These complications lead to hypovolaemia, electrolyte imbalance (particularly hyperkalaemia), and a metabolic acidosis. Some patients taking Ecstasy or Eve have been admitted with water intoxication an d acute hyponatraemia following ingestion of large amounts of water. Management 1. Supportive care, including airway protection, \202 uid resuscitation, elec- trolyte correction, and if needed, mechanical ventilation. 2. Early stages of amphetamine poisoning can be often controlled with tepid sponging, chlor promazine, B-blockade. Forced acid diuresis to increase urinary excretion is rarely needed. 3. Manage severe complications as they arise, e.g. rapid cooling for hyper- pyrexia, antico nvulsants for seizures, urine alkalinisation 9 fasciotomies for rhabdomyolysis, platelet, a nd fresh frozen plasma infusions for co- agulopathy. 4. Dantrolene is sometimes given to treat hyperpyrexia at a dose of 1mg/ kg IV, repeated to a cumulative maximum dose of 10mg/kg, particularly if the temperature is >40*C. However, n o outcome bene \201 t has been reported through its use and it can cause side effects. AMPHETAMINES AND ECSTASY 531 See also: Airway maintenance, p40; Hypertension, p382; Coma, p438; Delirium, p442; Generali zed seizures, p444; Hyperkalaemia, p488; Metabolic acidosis, p502; Poisoning \200\224genera l principles, p520; Hyperthermia, p600; Rhabdomyolysis, p612. 532 CHAPTER 30 Poisoning Cocaine poisoning Modes of action \200 Blocks reuptake of dopamine (causing euphoria, hyperactivity) and norepinephrine (causing v asoconstriction and hypertension). Arrhythmias may also result. Blocks Na+ channels, result ing in a local anesthetic action and myocardial depression. Platelet activation. Mitochondr ial dysfunction leading to myocardial depression. \200 Complications \200 Chest pain related to myocardial ischaemia or infarction, or to coronary artery spasm. Hear t failure. Seizures. Cerebrovascular accidents. Pneumothorax. Rhabdomyolysis. Premature lab or \200\224abruption. Agitated delirium, hyperthermia. \200 \200 \200 \200 \200 \200 Management 1. Local chest pain guidelines should be followed. ECG abnormalities of- ten res olve within 12h. Arrhythmias should be treated conventionally, but avoiding B-blockers (lea ving an unopposed A-action).