NB: cardiovascular resuscitation can be complex because of the severity of both the metabol ic derangement and concomitant cardiac disease. Give corticosteroids. NB: higher doses of hormones cannot be justi \201 ed by the current literature. Although m ore rapid correction may be tolerated by young patients, the risk of adverse cardiovas- cul ar events is signi \201 cant in the elderly, and mortality is increased. Warming Hypothermia is common and may be profound. A low tem- perature thermometer is requi red for accurate recordings. Patients require warm \202 uids, warm inspired gasses and ex ternal warming, e.g. warming blanket to achieve a tem- perature >34 C. Normothermia may no t be achieved until thyroid hormones are restored. NB: active warming will cause peripheral vascular dilata- tion and hypotension requiring increased \202 uid and vaso- pressor adm inistration. Additional measures \200 NG tube \200\224to prevent gastric dilation and aspiration (essential in patients with redu ced level of conscious- ness) Broad-spectrum antibiotics if infection is suspected Insert a bladder catheter \200 Pitfalls of myxoedema \200 \200 \200 \200 Electrolytes Sodium (Na+) Hyponatraemia is common, caused by a failure to excrete excess wa ter and may be severe (<120mmol/l). Correction should not exceed 12mmol/L/24h. \200 Adrenal insuf \201 ciency is a frequent association Hypoglycaemia must not be missed Warmi ng may precipitate hypotension High dose thyroid hormone replacement may be com- plicated b y serious cardiac events Patients do not absorb oral medications 0.9% Saline is adequate replacement; hypertonic saline is not indicated. Once \202 uid re suscitation is complete, water restriction is usually suf \201 cient to correct Na+ Prognosis Myxoedema coma is the rare extreme of a common condi- tion. Diagnosis is often di f \201 cult, and a high index of suspi- cion is required. However, with best care, mortali ty can be decreased from 60% \200\22325%. Glucose Hypoglycaemia can be severe, and requires early recogni- tion and treatment. \200 25g IV glucose followed by an infusion (20 \200\22350% glucose) via central venous access, titrated to maintain normogly- caemia. Further reading De Groot LJ, Dangerous dogmas in medicine: the nonthyroidal ill- ness syndrome. J Clin Endocrinol Metab 1999; 84: 151 \200\22364. Thyroid hormones Patients undoubtedly require thyroid hormone replace- ment to recover, but the optimum regimen remains con- troversial. Replacement is best achieved gradually; rapid replacement has been associated with sudden death from cardiac complications. In uncomplic ated hypothyroidism, the agent of choice is oral T4. In critically ill patients, oral T4 ma y be inadequately absorbed and the peripheral conver- sion of T4 to T3 is markedly decrease d. IV T4 is not available in the UK. T3 provides a more rapid correction of thyroid hormone function. Gradual replacement is recommended, and the following is a suggested regimen. \200 Jordan RM, Myxedema coma. Pathophysiology, therapy, and factors affecting prognosis. Med Clin North Am 1995; 79: 185 \200\22394. Kwaku MP, Burman KD, Myxedema coma, J Intensive Care Med 2007; 22: 224 \200\22332. Peeters RP, Wouters PJ, Kaptein E, et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003; 88: 32 02 \200\22311. Rodr guez I, Fluiters E, P rez-M ndez LF, et al. Factors associated with mortality of pa tients with myxoedema coma: propective study in 11 cases treated in a single institution. J Endocrinol 2004; 180: 347-350. Wartofsy L. Myxedema coma. Endocrinol Metab Clin North Am 2006; 35; 687 \200\22398. T3: initial IV dose 10 \200\22320mcg followed by 10mcg every 8 \200\22312h or a continuous IV infusion 20mcg/day, until the patient is established on an oral T4 regimen. 436 J LIGHTFOOT & H REECE-SMITH Hypoadrenal crisis Hypoadrenal crisis is a life-threatening condition that is dif- \201 cult to diagnose, bu t easy to treat. The critically ill popula- tion are at higher risk, and therefore a high i ndex of suspicion is appropriate. Others Irradiation of the adrenals. Iron deposits of haemochroma- tosis. Secondary/tertiary Acute failure of the pituitary or hypothalamus is rare. Causes include: neoplasms, hemorrhage, infarction, radia- tion damage and granulomatous in \201 ltration. Prolonged administration of glucocorticoids leads to HPA axis suppression. These patients a re therefore at risk of developing a crisis if there is inadequate replacement and/ or othe r causes of hypoadrenalism. Typically suppression occurs in regimes of >7.5mg prednisolone (or equivalent) daily for >2 weeks. Causes A crisis can be precipitated de novo by acute failure of the hypothalamus, pituitary or adrenal glands, or as a result of smaller change in function of any part of the hypotha lamo- pituitary \200\223adrenal (HPA) axis on a background of chronic insuf \201 ciency. T he causes are divided up on the basis of the organ they affect into: primary (adrenal), sec ondary (pitui- tary) and tertiary (hypothalamus). Primary (Addison \200\231s disease) Autoimmune adrenalitis 70 \200\22390% of cases are caus ed by autoimmune conditions. Polyglandular autoimmune syndrome I and II each include autoim mune adrenalitis (predominantly female). Autoimmune adrenalitis as an isolated autoimmune a dre- nal insuf \201 ciency is more common in males. Clinical approach Hypoadrenal crisis usually presents with shock. The shock is usually high output and dependent on vasopressors. It is often initially misdiagnosed as septic shock. The clinical approach should be tailored to identify likely causes and to gather clues of p receding adrenal insuf \201 - ciency as these will guide treatment after the initial crisi s has been dealed with. Infectious causes As described by Thomas Addison, most cases were caused by TB with bilater al adrenal in \201 ltration and destruction. Now this accounts for 7 \200\22320%. Active T B seeds to the adrenals via haematogenous spread. Disseminated fungal disease from histopla smosis or paracoccidioidomycosis is a signi \201 cant cause of adrenal failure in high ris k areas. Patients who have developed AIDS are at risk of developing necro- tizing adrenalit its secondary to CMV infection and in \201 ltra- tion by Mycobacterium avium-intracellular e, cryptococci or Kaposi \200\231s sarcoma. History \200\224key points Potential causes \200 \200 Severe stress: sepsis, burns, trauma, surgery Other autoimmune conditions, such as hypothyr oidism or gonadal failure Foreign travel/potential contact with infectious diseases Steroid use: length of treatment/cessation/reduction Anticoagulation Drugs which interfere with st eroid metabolism or syn- thesis (ketoconazole, etomidate, metayapone, phenytoin and suramin ) Inherited clotting disorders Previous history of cancer Pregnancy Sudden onset \202 ank or epigastric pain (suggestive of adrenal haemmorhage) \200 \200 \200 Metastatic cancer Metastatic in \202 itration of the adrenal glands is common, and 40 \200 \22360% of patients with disseminated lung or breast can- cer have adrenal deposits. Clinic al manifestations are rare as most of the adrenal cortex must be destroyed before symptoms occur. \200 \200 \200 Adrenal hemorrhage/infarction Risk factors: \200 Stress states, especially sepsis. Hemorrhage is classically associated with meningococcal s epticaemia (Waterhouse \200\223Friderichsen syndrome). Similar \201 ndings from Streptoco ccus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae and Staphy lococcus aureus have also been reported. Anticoagulation use, especially heparin. Thromobo- cytopaenic patients in their middle/old age are at high risk Hypercoaguable states, especi ally antiphospholipid syn- drome. Symptoms of preceding adrenal insuf \201 ciency should be identi \201 ed; these are very vague and include: \200 \200 \200 Weakness/tiredness Anorexia GI symptoms: nausea, vomiting, constipation, abdominal pain, di arrhea Salt craving Postural dizziness \200 Examination The patient will have signs of high output shock. These obviously depend on the clinical situation and the treat- ments already underway. In primary hypoadrenalism there will be hyperpigmenta- tion of the skin that has been exposed to light, friction or pressur e as a result of increased concentrations of adreno- corticotrophic hormone (ACTH). Drugs There are a small number of drugs which inhibit cortisol production. These include am inoglutethimide, eto- midate, ketoconazole, metyrapone and suramin. These agents are relati vely safe in patients with normal HPA axis function. In \201 ltrations Both granulomatous and amyloid in \201 ltrations can affect the adrenal . Investigations Hematology and biochemistry There is usually a slight neutropenia with relat ive eosi- nophilia. 437 CHAPTER 24.12 Hypoadrenal crisis Hyponatraemia and hyperkalaemia are often found. Pure Addison \200\231s disease usually has a normal CRP and procalci- tonin. Hypoglycaemia is often a feature, especially if the defe ct is primary and so there is a high serum concentration of ACTH. Initial treatment 1 Large bore IV access should be obtained and bloods taken for electrolytes, glucose, cortisol and ACTH. 2 0.9% Saline should be infused quickly; 2 or 3l may be required. The patient must be monit ored for signs of overload, preferably with CVP monitoring. Blood glu- cose should be monit ored and corrected with dextrose run alongside the saline as necessary. Endocrine Measure initial cortisol and ACTH levels. Primary adrenal failure \200\224inappro priately low serum corti- sol and very high serum concentrations of ACTH. In sec- ondary or tertiary failure both levels would be inappropriately low. Assays for ACTH can be unreliab le and results are slow to arrive, and therefore it is necessary to perform a stimulation t est. The short ACTH stimulation test can be run alongside emergency treatment for hypoadren al crisis as it is not affected by dexamethasone. It provides a quick easy test for identif ying most cases of adrenal insuf \201 ciency. A 250mcg IV bolus of ACTH (Synachthen) shoul d be given and blood taken for cortisol at 30 and 60min. Cortisol concentration peaks of <1 8mcg/dl at 30 or 60min indicate that there is adrenal insuf \201 ciency. This test has bee n shown in a large meta-analysis to have a 95% speci \201 city and 97.5% sensitivity for p rimary hypoad- renalism. However, the sensitivity for secondary adrenal insuf \201 ciency was only 57%. Therefore, a positive result establishes the diagnosis of hypoadrenalism and a negative result can rule out primary hypoadrenalism, but not sec- ondary or tertiary. Fur ther tests such as the insulin-induced hypoglycaemia or the metyrapone test will be require d to exclude secondary or tertiary hypoadrenal insuf \201 ciency. 3 IV glucocorticoid must be given. The usual choice is 10mg of dexamethasone as it does not interfere with the cortisol measurements. Hydrocortisone can be substi- tuted for dexameth asone after the \201 rst dose using the following regime: \200 \200 \200 \200 Day 1 hydrocortisone 100mg 6 \200\2238 hourly Day 2 hydrocortisone 100mg \200\223 8 hourly Day 3 hydrocortisone 100mg \200\223 12 hourly Day 4 maintenance regime. 4 ACTH (Synacthen) should be given at the same time for the short ACTH stimulation test, as detailed under investigations. 5 Further supportive measures and monitoring should be introduced as required. There is no need to give mineralocorticoids acutely as the saline infused replaces the sodi um and mineralocorticoids take several days to act. Subsequent treatment IV saline should be continued for 24 \200\22348h at a slower rate. On ce the saline infusion has \201 nished, it is necessary to start mineralocorticoid replac ement with \202 udrocortisone 0.1mg daily. The cause of the adrenal crisis should be foun d and treated if possible. This may involve more extensive hormonal investigations. ECG There may be changes of hyperkalaemia Radiology Plain chest \201 lm may show a small heart. Further cross-sec- tional imaging c an be undertaken in order to help reveal the cause of the event. Adrenal calci \201 cation can often be seen in tuberculous and fungal in \201 ltration, and enlarged adrenals are s een in adrenal hemorrhage. Further reading Addison T. On the constitutional and local effects of disease of the supra-renal capsules. London: Highley, 1855. Dorin R, Qualls C, Crapo L. Diagnosis of adrenal insuf \201 ciency. Ann Intern Med 2003; 139: 194 \200\223204. Falorni A,, Laureti S, De Bellis A, et al. Italian Addison network study: update of diagnos tic criteria for the classi \201 cation of primary adrenal insuf \201 ciency. J Clin Endo cinol Metab 2003; 89: 1598 \200\223604. Vedig A. Adrenocortical Insuf \201 ciency. In: Oh \200\231s intensive care manual. Management Treatment should be instigated in cases where clinical sus- picion of a crisis i s high, and should not be delayed in order to make a diagnosis. The aims of immediate treat ment are to correct: \200 \200 \200 London: Butterworth Heinemann, 2004: 575 \200\22382. Hypotension Electrolyte imbalance Cortisol de \201 ciency This page intentionally left blank 439 Chapter 25 Poisoning Chapter contents Management of acute poisoning 440 440 D WYNCOLL Management of acute poisoning Acute poisoning remains one of the most common medi- cal emergencies, 5 \200\22310% of hosp ital medical admissions. In the majority of cases, the drug ingestion is intentional, but t he in-hospital mortality remains low (<0.5%). There are speci \201 c antidotes available f or a small number of poisons and drugs; in most intoxications, basic supportive care is the main requirement and recovery follows. Internet-based information services such as Toxbase are useful: http:// www.spib.axl.co.uk. Gastric lavage Unless performed within 1h of drug ingestion, it is no longer recommended. T he amount of poison removed is insigni \201 cant, and lavage may only propel unabsorbed po i- son into the small intestine. Prior intubation is essential when laryngeal competence is absent or doubtful, espe- cially because, in the majority of overdoses, pulmonary aspirati on is more lethal than the ingested drug. Gastric lavage is contraindicated in ingestions o f corrosives, caus- tics and acids; oesophageal or gastric perforation may occur. General principles The general principles of the management of poisoned patients are diagno sis, clinical examination and resuscitation, investigations, drug manipulation, speci \201 c measures and continued supportive care. In the more acute situations, these actions ofte n have to be carried out simultaneously. Activated charcoal AC remains the \201 rst-line treatment for most acute poison- ings. Ow ing to its large surface area and porous structure, it is highly effective at adsorbing man y toxins, with few exceptions. Exceptions include elemental metals, pesti- cides, strong ac ids and alkalis, and cyanide. It should be given swiftly to all patients who present within 1h of inges- tion, although it is also acceptable to administer it after 1h if it follows an overdose of a substance that slows gas- tric emptying (e.g. opioids, tricyclic antidepre ssants (TCAs)). AC is given in 50g doses for adults and 1g/kg for children. It commonly cau ses vomiting; therefore, consider giving an antiemetic prior to administration. Repeated do ses (4 hourly intervals) of AC can increase the elimina- tion of some drugs, interrupting t heir enteroenteric and enterohepatic circulation. These include: \200 \200 \200 \200 \200 \200 \200 Airway and ventilation In unconscious patients, tracheal intubation and airway protection i s almost always necessary \200\224a test is when a patient tolerates insertion of an oropha ryngeal airway then intubate. Inadequate spontaneous ventilation, determined clinically or by blood gas analysis, obviously requires venti- latory support. Venous access should be es tablished, and basic observations, including blood pressure, pulse rate, peripheral perfusi on and urine output should be recorded. Clinical examination Full examination and look particularly for needle marks or evidence of previous self-harm. When no history is availa- ble, the diagnosis depends upon excluding o ther common causes of coma (such as ICH, intracranial infection or dia- betic comas). Speci \201 c attention should be paid to the tem- perature, pupil size, respiratory and heart r ate, as these may help to narrow the list of potential toxins. carbamazepine theophylline digoxin quinine phenobarbitone dapsone some sustained-release pr eparations. Investigations Initial investigations include: \200 Whole bowel irrigation Whole bowel irrigation involves administration of non- absorbable po lyethylene glycol solution to cause a liquid stool and reduce drug absorption by physically forcing con- tents rapidly through the GI tract. It may have a role in treating large inge stions of drugs that are not absorbed by AC, such as large ingestions of iron or lithium, d rug- \201 lled packets/condoms ( \200\230body packers \200\231), and ingestions of sus- ta ined-release or enteric-coated drugs. Urinalysis \200\224with a sample kept for later analysis if required (rapid reaction dipsti cks are available to screen for common drugs of abuse/recreational drugs; however, their re liability questionable). Basic biochemistry \200\224signi \201 cant renal insuf \201 cien cy may alter drug elimination. ABG analysis \200\224metabolic and/or respiratory acidosis a re most common. Metabolic alkaloses are unusual. Anion gap = ([Na+] + [K+]) \200\223 ([Cl \200\223] + [HCO3 \200\223]) \200\224it is normally 10 \200\22314. Ethanol, methanol, ethy lene glycol, met- formin, cyanide, isoniazid or salicylates are the most fre- quent causes of a high anion gap metabolic acidosis. Osmolal gap \200\224the difference between the labo ratory measured osmolality (Om) and the calculated osmolality (Oc). Oc = 2(Na+ + K+) + Urea + Glucose. The osmolal gap is normally <10. Causes of a raised osmolal gap are ethanol, me thanol and ethylene glycol. CXR \200\224inhalation of gastric contents is not uncommon. Dru g levels \200\224are rarely helpful except in paracetamol, salicylates, iron, digoxin and l ithium poisonings. Enhancing drug elimination In the overwhelming majority of patients who present after an ov erdose, gut decontamination techniques and sup- portive care are all that is required. In a limited number of acute poisonings it may be necessary to consider methods to enhance elim ination. Urinary alkalinization Urinary alkalinization may be useful for serious poisonings with: \200 \200 \200 \200 \200 Salicylates Phenobarbitone (with repeated dose AC) Chlorpropamide Methotrexate Gut decontamination Emesis Ipecacuanha-induced emesis is no longer recommended since it is often ineffective at removing signi \201 cant quantities of poison from the stomach, and i t limits the use of acti- vated charcoal (AC). IV sodium bicarbonate (>1.26%) is infused to maintain a neutral balance and attempt to achi eve a urine pH of 7.5. The term urine alkalinization emphasizes that urine pH manipulation is the prime objective of treatment. It should 441 CHAPTER 25.1 Management of acute poisoning Household chemicals: bleach Clinical features Bleach usually contains 5 \200\22310% sodium hypochlorite and causes moderate irritation of the mucous membranes and esophagus. Small ac cidental ingestions rarely cause more than nausea and vomiting; however, adults who deliber ately ingest large quantities can develop oesophageal ulceration, haematemesis or perforati on. be considered the treatment of choice for moderate to severe salicylate poisoning. Care mus t be taken to ensure the potassium does not fall rapidly. Extracorporeal techniques Extracorporeal techniques should be considered when there are cli nical features of severe toxicity and failure to respond to full supportive care, coupled w ith poisoning by a drug that can potentially be cleared. Impairment of the normal route of elimination of the compound may also in \202 uence the decision. Haemoperfusion is rarely performed in most ICUs, and intermittent haemodialysis is often con- \201 ned to renal un its. Consequently, the use of continuous haemo \201 ltration with or without dialysis, usi ng \201 ltration rates of >50 \200\223100ml/kg/h, is likely to be as equally effective. Treatment Severe poisoning in adults requires IV \202 uids and endoscopy to reveal the ex tent of the injury. Carbon monoxide Clinical features Neurological signs vary from mild confusion through to se i- zures and coma. A history of loss of consciousness may be the only indicator of signi \201 cant poisoning. ST segment changes may be present on the ECG. In the absence of res- p iratory depression or aspiration, PaO2 will be normal. It is essential that SaO2 is measure d directly by a co-oximeter, and not calculated. Cherry-pink skin is infrequently seen; cya nosis is far more common. Coma and/or carboxy-Hb levels >40% always indicate serious poison ing (smokers may have up to 10% carboxy-Hb without deleterious effects); however, delayed d eterioration can occur in their absence. Speci \201 c therapy of some common or dif \201 cult poisonings Amphetamines (including \200\230Ecstasy \200\231 MDMA) Clinical features Symptoms of mild overdose include sweating, dry mouth and anxiety. Although the majority of Ecstasy patients are dehydrated, a proportion have hyponatraemia from drink- ing excess water. More severe features include hypertonia, hyper-reflexia, hallucinations and hyper tension. Supraventric ular dysrhythmias may follow, with coma, con- vulsions and the risk of haemorrhagic stroke. A hyperther- mic syndrome may develop, leading to rhabdomyolysis, acute renal failure, DIC and MOF. Treatment High \202 ow oxygen (up to 100%) should be administered and continued until the carboxy-Hb level is <5% \200\224this can take up to 24h. Hyperbaric oxygen (HBO), although often used, remains controversial. Trials of HBO vs normobaric oxygen have not shown stati stical bene \201 t in reducing neu- rological sequelae at 1 month. Considering the frequen t logistical dif \201 culties in transferring unconscious patients to an HBO center, it ca nnot be recommended currently. Treatment AC should be considered up to 1h post-ingestion. Benzodiazepines are useful for a gitated or psychotic patients and have a central effect in reducing tachycardia, hypertensi on and hyperpyrexia. If benzodiazepines fail to control hypertension, A-blockers, labetalol or direct vasodilators should be started. Hypertonic saline should be considered in severe hyponatraemia. Hyperthermia should be treated with cold \202 uids, physical cooling meas - ures and, in the presence of convulsions, sedation, paralysis and ventilation. Dantrolene has been used in the treatment of Ecstasy-related hyperpyrexia, but it is better to direct treatment at the central mechanisms of thermoregulation. Methanol and ethylene glycol Clinical features Methanol and ethylene glycol are relatively non-toxic, but their ingestion is a medical emergency because of their metabolism (followin g a latent period of 12 \200\22318h) to formic and glycolic acid, respectively. These metab olites account for the metabolic acidosis, ocular toxicity, renal failure, coma, convulsion s and mortality that are occasionally seen. Mild features include dizziness, drowsiness and abdominal pain. The osmolal and the anion gap are increased. Cocaine Clinical features Features of severe intoxication include hyper-reflexia, drowsines s and convulsions. Severe hypertension may cause ICH, and coronary artery spasm may result in MI or ventricular arrhythmias; fatalities generally occur early. Hyperthermia associated with rhabdomyolysis, renal fail- ure and DIC may also occur. Treatment AC does not adsorb either toxin. The metabolic acidosis should be treated with so dium bicarbonate and the serum electrolytes measured. Ethanol prevents formation of the tox ic metabolites and historically has been the most com- mon treatment. Yet, ethanol dosing i s complex, requires repeated monitoring and has adverse effects. The recent introduction of fomepizole (4-methypyrazole), although expensive, has signi \201 cantly simpli \201 ed t he treatment of eth- ylene glycol and methanol poisoning, and is now strongly recommended a s \201 rst-line therapy. It has been shown to be safe and effective, with minimal adverse effects, and potentially prevents the need for haemodialysis in patients presenting with v isual disturbances or severe acidosis. If the ethylene glycol blood concentration is >20mg/ dl or if there is a good history of ethylene glycol/methanol inges- tion with an osmolal ga p >10, then patients should receive it. Folinic acid should also be given since it enhances the metabolism of formic acid. Treatment The toxic dose is variable and depends upon tolerance, presence of other drugs an d route of administration, but ingestion of >1g can be fatal. Blood pressure and ECG monito ring should be instituted early and AC administered within 1h of ingestion. Benzodiazepines are used for agi- tated or psychotic patients and have a central effect in reducing tachyc ardia, hypertension and hyperpyrexia. If benzodiazepines fail to control hypertension, B-bl ockers, labetalol or vasodilators such as nitrates should be started. B-blockers are contro versial and should be used with cau- tion because of the risk of unopposed A stimulation. H yperthermia should be treated in the standard manner (see Amphetamines above). 442 D WYNCOLL Organophosphorus poisoning Clinical features Treatment Multiple dose AC may be effective, but is not established. Vitamin K and glucose are used to correct hypoprothrom- binaemia and hypoglycaemia. Urinary alkalinization decrea ses the amount of non-ionized drug available to enter tissues, but is hazardous and should only be used for the most severe ingestions. Extracorporeal techniques are very effective i n removing salicylates and correcting acid \200\223 base disturbance, and should be conside red for severe cases. Organophosphorus compounds have numerous complex actions; however, their major effect is in hibition of cholineste- rase enzymes (especially acetylcholinesterase). This leads to accum ulation of acetylcholine at both nicotinic and mus- carinic receptors, and in the CNS. The onset, severity and duration of clinical features are dependent on the route of exposure an d the agent involved. Early muscarinic clinical features include vomiting, abdominal pain, diarrhea, miosis, diaphoresis, sweating, bronchoconstriction and hypersaliva- tion. Respira tory muscle weakness, drowsiness and coma occur later, but are the major cause of death in the severely poisoned. In general, clinical features are more helpful than red cell choline sterase measurements in determining toxic- ity, but measurements do con \201 rm the diagno sis. Sedatives: benzodiazepines Clinical features Overdose is common, but clinical features are not usually severe unless complicated by other CNS depressant drugs (such as alcohol), pre- existing disease or the extremes of age. Toxicity commonly produces drowsiness, dysarthria, ataxia and nystagmus; however, agitation and confusion can occur. Treatment If the compound has been ingested, gastric lavage can be attempted within 1h, fol lowed by AC. Convulsions should be controlled by benzodiazepines, and atropine (some- times in very large doses \200\224up to 30mg in 24h) reduces many of the unpleasant symptoms. Ch olinesterase reacti- vators such as pralidoxime are also helpful in symptomatic patients if given early, and duration of therapy is deter- mined by clinical response. Treatment AC can be given if patients present within 1h of ingestion, yet supportive treatm ent is usually all that is required. Flumazenil is a speci \201 c antagonist, but its brie f duration of action limits its use to diagnostic purposes. Moreover, \202 umazenil may c ause other symptoms in patients who have ingested a cocktail of drugs (e.g. precipitation o f \201 ts in patients co-ingesting TCAs), consequently administration risks increasing mo rbidity and mortality. Sedatives: opioids Clinical features Overdose is characterized by pi npoint pupils, drowsiness, shallow breathing and ultimately respiratory failure. Paracetamol Clinical features Nausea and vomiting may be the only features present in the \201 rst 24h. In normal adults, doses >10g may exceed the ability of hepatic glutathione t o conjugate the toxic metab- olite. Plasma concentrations >200mg/l at 4h or \211 50mg/l at 12h are usually associated with hepatic damage. Although severe hepatic injury has a 10% m ortality, the majority of patients recover within 1 \200\2232 weeks. Treatment AC may be effective for oral ingestions, otherwise treat- ment is supportive. Nal oxone 0.1 \200\2230.4mg IV can be given by bolus and if there is an inadequate response, re peat doses may be required. Intubation and mechanical ventilation are required if respirato ry failure is not rapidly reversed by naloxone. Treatment Measure drug levels, noting the time from ingestion, and administer AC as soon as possible even if >4h after over- dose. NAC should be given in all patients with signi \201 cant levels (see www.patient.co.uk/showdoc/40001390/). Treatment should begin at lower levels for those consid- ered to be high risk (such as those who regularly consume alcohol , or patients taking enzyme-inducing drugs such as phenytoin, carbamazepine, phenobarbitone or rifampicin, or patients with conditions causing glutathione depletion, such as HIV, eat ing disorders, malnutrition or cystic \201 brosis. Although an ingestion \200\223treatmen t interval of <10h gives the best results, NAC can be given >24h from ingestion with clinic al bene \201 t. Expert opinion should be sought early on from a regional center if liver f ailure is progressive since liver transplantation may become necessary. Tricyclic antidepressants Clinical features TCAs are the leading cause of death from overdo se in patients arriving at hospital alive, and account for 50% of all overdose-related adu lt ICU admissions. Features include anticholinergic effects such as warm dry skin, tachycar dia, blurred vision, dilated pupils and urinary retention. Severe features include respirat ory depression, reduced conscious level and cardiac arrhythmias, fits and hypotension. Arrh ythmias may be predicted by a QRS duration >100ms on the ECG; a QRS duration of >160ms incr eases risk of seizures. All forms of rhythm and conduction disturbance have been described, and are not necessarily predicted by the ECG. Toxicity is worsened by acidaemia, hypotensi on and hyperthermia. Salicylates (aspirin) Clinical features Moderate toxicity occurs with serum concentrations 500 \200\223 750mg/l (3600 \200\2235500 mol/l), and severe toxicity with con- centrations >750mg/l. Serum concentrations alone do not determine prognosis. The elimination half-life increases sig- ni \201 cantly with increasing concentrations. Small reductions in pH produ ce large increases in non-ionized salicylate, which then penetrates tissues. Tinnitus, deaf ness, diaphore- sis, pyrexia, hypoglycaemia, haematemesis, hyperventilation and hypokalaemi a may all occur. Coma, hyperpyrexia, pul- monary oedema and acidaemia are reported as more common in fatal cases, which present late. Treatment Continuous cardiac monitoring is essential, and multiple dose AC should be consid ered. Increasing arterial pH to \211 7.45 signi \201 cantly reduces the available free dr ug, and this may avoid TCA toxicity. Mild hyperventilation and 8.4% sodium bicarbonate in 5 0mmol aliquots achieves this strat- egy, and may improve outcome. Bicarbonate should prob- ably be given in all cases of QRS prolongation (even in the absence of metabolic acidosis), malignant arrhythmias, 443 CHAPTER 25.1 Management of acute poisoning hypotension or metabolic acidosis. If arrhythmias occur, avoid Class 1a agents; lidocaine m ay be best. Benzodiazepines are the drug of choice for sedation, treatment of seizures and prevention of the emergence of delirium. Barceloux DG, Bond GR, Krenzelok EP, et al. American Academy of Clinical Toxicology practic e guidelines on the methanol poison- ing. J Toxicol Clin Toxicol 2002; 40: 415 \200\22346. Buckley NA, Isbister GK, Stokes B, et al. Hyperbaric oxygen for carbon monoxide poisoning: a systematic review and critical analysis of the evidence. Toxicol Rev 2005; 24: 75 \200 \22392. Further reading American Academy of Clinical Toxicology; European Association of Poison Con trol Centers and Clinical Toxicologists. Position state- ment: gastric lavage. Clin Toxicol 1997; 35: 711 \200\2239. Chyka PA, Seger D, Krenzelok EP, et al. American Academy of Clinical Toxicology; European A ssociation of Poisons Centers and Clinical Toxicologists. Position paper: single-dose activ ated char- coal. Clin Toxicol 2005; 43: 61 \200\22387. American Academy of Clinical Toxicology; European Association of Poison Control Centers and Clinical Toxicologists. Position state- ment: whole bowel irrigation. Clin Toxicol 1997; 3 5: 753 \200\22362. Hall AP, Henry JA. Acute toxic effects of \200\230Ecstasy \200\231 (MDMA) and related comp ounds: overview of pathophysiology and clinical management. Br J Anaesth 2006; 96: 678 \200 \22385. American Academy of Clinical Toxicology; European Association of Poison Control Centers and Clinical Toxicologists. Position state- ment and practice guidelines on the use of multi-d ose activated charcoal in the treatment of acute poisoning. Clin Toxicol 1999; 37: 731 \200 \22351. Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alka- linisation. J Toxicol Clin Toxicol 2004; 42: 1 \200\22326. Seger DL. Flumazenil \200\224treatment or toxin. J Toxicol Clin Toxicol 2004; 42: 209 \200\22316. American Academy of Clinical Toxicology and European Association of Poisons Centers and Cli nical Toxicologists. Position paper: ipe- cac syrup. J Toxicol Clin Toxicol 2004; 42: 133 \200\22343. This page intentionally left blank 445 Chapter 26 Shock Chapter contents Shock: de \201 nition and diagnosis 446 Hypovolaemic shock 450 Cardiogenic shock 452 Anaph ylactic shock 456 Septic shock: pathogenesis 458 446 D DE BACKER Shock: de \201 nition and diagnosis Shock, or acute circulatory failure, defines a state in which the delivery of oxygen and nu trients to the tissue is insufficient to meet basal metabolic needs, leading to tissue hypo xia, and, if persistent, to MOF and death. Shock results from tissue hypoperfusion and micr ocirculatory dysfunction, and should thus not be restricted to hypoten- sion. Although freq uent, hypotension is not mandatory for the diagnosis of shock. In the absence of hypotensio n, increased lactate levels may indicate tissue hypoper- fusion and can be used to diagnose shock (at least at its initiation). Obstructive shock Hypovolemic shock Cardiogenic shock Distributive shock Fig. 26.1.1 The four categories of shock. Clinical \201 ndings Hypotension Hypotension is de \201 ned by an SBP <90mm Hg or a MAP <65mm Hg, or requirement for vasopressor agents to maintain blood pressure above these leve ls. Identifying the type of shock is thus important as it helps to indicate what should be the target of the primary interven- tion. There may be some overlap between these presenta- tio ns, as a patient with distributive shock may also present hypovolaemia and myocardial depre ssion. These four pres- entations of shock cover multiple causes. Distributive shock includ es septic shock, anaphylactic shock, pancreati- tis and ischaemia \200\223reperfusion injur y. All these causes of distributive shock are characterized by a marked activation of in \202 ammatory processes leading to the release of vasoac- tive substances. Signs of perfusion alteration to the organs Alteration in mental state: confusion, agitatio n, sometimes coma. Oliguria: urine output <0.5ml/kg/h. Requires at least 1h to be diagnosed , and sometimes longer when the bladder is not catheterized. Skin vasoconstriction (clammy skin): may be absent in dis- tributive shock states. How to diagnose the type of shock Differentiation between the four categories of shock can be made using several haemodynamic monitoring tools, including a pulmonary artery catheter, cardiac echocardi- ography and pulse contour analysis. Whatever the tech- nique used, clas sification of shock relies on the determination of cardiac output and evaluation of intrava s- cular pressures or volumes (Fig. 26.1.2). Measurement of cardiac output is essential to discriminate between the different types of shock: cardiac output and oxygen delivery are d ecreased (hypodynamic shock) in hypovolaemic, cardiogenic and obstructive shock, while it m ay be preserved and even increased in distributive shock (hyperdynamic shock). To identify further the different components of hypody- namic shock, the determination of intravascular pressures (CVP) is essential: it is decreased in hypovolaemia, but increased in cardiogeni c and obstructive shock. Of note, hypovolaemia can complicate any type of shock. Echocardio graphy is mandatory to differentiate obstruc- tive from cardiogenic shock (even though some indexes can be inferred from the pulmonary artery catheter or measurements of intravascula r volumes with transpulmo- nary thermodilution) and to determine the exact cause of cardiog enic shock (contractility, valve disease). Biological signs Metabolic acidosis is due to excess of hydrogen ions due to ATP hydrolysis occurring during anaerobic metabo- lism. Hyperlactataemia also occurs in response to hypox ia. In the absence of oxygen, pyruvate cannot enter the Krebs cycle and lactate is produced in large amounts. Normal values are close to 1mEq/l; values >2.0 suggest tis- sue hypoxia, values >4.0 are associated with a mortality rate >50%. Of note hyperlactataemia may also o ccur in the presence of oxygen (increased aerobic glycolysis in response to in \202 ammato ry processes) or may re \202 ect past rather than ongoing tissue hypoxia when liver lactat e clearance is decreased. In the early phases of shock, hyperlactataemia is highly suggesti ve of tissue hypoxia; at later stages, hyperlactataemia should be interpreted more cautious ly. Signs of organ dysfunction: decreased PaO2, increased cre- atinine levels, hyperbilirub inaemia. Increased tissue to arterial PCO2 gradient. Tissue PCO2 can be estimated in the st omach and in the sublingual area. An increased gradient (>10mm Hg) suggests tissue hypop- e rfusion. A gradient >20mm Hg may be associated with tissue hypoxia. Classi \201 cation of shock Weil and Subin have classi \201 ed shock into four categories : hypovolaemic, cardiogenic, obstructive and distributive. In this categorization of shock, the circulation is divided into its four essential components (Fig. 26.1.1): \200 \200 \200 \200 The four types of shock Hypovolaemic shock Hypovolaemic shock is characterized by a profoun d reduc- tion in blood volume. It is the most common source of shock, and can be due either to bleeding (trauma, digestive hemorrhage or other causes of blood losses) or to decreased plasma volume (dehydration most commonly due to diarrhea or vomiting). Children are very s ensitive to dehydration.