Fever may reflect a wide variety of pathological processes including infection, inflammation, trauma, malignancy and connective tissue diseases (Table 74.1), necessitating a systematic and comprehensive diagnostic approach.³ It is often assumed that a patient presenting with a fever should be treated, regardless of the presence or absence of other symptoms. However, the evidence that anti-fever treatments lead to an improvement in morbidity or mortality, or even patient comfort, is lacking.⁴

Table 74.1 Causes of fever in the ICU

System	Infectious aetiology	Non-infectious aetiology
Cardiovascular	Endocarditis	Myocardial infarction
	Catheter-related infection	Deep-vein thrombosis
	Pacemaker infection	Pericarditis
Respiratory	Pneumonia	Atelectasis
	Empyema	Chemical pneumonitis
	Sinusitis	Pulmonary emboli
Alimentary	Abdominal abscess	Inflammatory bowel disease
	Biliary infection	Acalculous cholecystitis
	Peritonitis	Pancreatitis
	Diverticulitis	Ischaemic colitis
	Viral hepatitis	Non-viral hepatitis
	Antibiotic-related colitis	Gastrointestinal haemorrhage
Renal	Pyelonephritis
	Urinary tract infection
Central nervous	Meningitis	Cerebral haemorrhage/infarct
	Encephalitis	Seizures
Rheumatological	Septic arthritis	Connective tissue disease
	Osteomyelitis	Connective tissue disease
	Gout	Vasculitis

Endocrine		Adrenocortical insufficiency
		Alcohol and drug withdrawal
		Hyperthyroidism
Skin/soft tissue	Cellulitis	Burns
	Decubitus ulcer	Intramuscular injections
	Wound infections	Intramuscular injections
		Haematoma
Other	Parotitis	Drug fever
	Pharyngitis	Transfusion reaction
	Otitis media	Neoplasms

The development of fever in response to infection may be a protective adaptive response, and appears to be a phylogenetically preserved evolutionary response because of its survival value.⁵ In mammalian models, increasing body temperature results in enhanced resistance to infection. In humans, retrospective clinical trials have shown a positive correlation between maximum temperature on the day of bacteraemia and increased survival in patients with Gram-negative bacteraemia and spontaneous bacterial peritonitis.⁶ Also, septic patients with hypothermia have a poorer outcome than those who develop fever, although this causality is less clear. Both local and systemic hyperthermia has been used to facilitate cancer treatment. The protective effects of fever result from increased immune and cytokine functions.⁷^–¹⁰

Temperature elevation has been shown to enhance:

• antibody production

• neutrophil and macrophage mobility and function

• cytokine production

• T-lymphocyte activity

• reduction of serum iron, which is required for bacterial growth

In addition, elevated temperatures inhibit some pathogens, such as Streptococcus pneumoniae.¹¹

Moderate fever is a common occurrence in ICU patients, but approximately half of these are non-infectious in origin.¹²^–¹⁴ The presence of fever frequently results in the performance of diagnostic tests and exposes the patient to unnecessary invasive procedures and inappropriate use of antibiotics.¹⁵

Whilst very high fevers (> 40°C) are dangerous, it is less clear whether moderate elevation of body temperature is detrimental and, indeed, may be protective.⁴ Moreover, artificially lowering the temperature of a febrile patient may mask the signs of infection and make diagnosis and monitoring more difficult. Any decision to adopt anti-fever measures, physical or pharmacological, must take into consideration the variable response by this patient population. Antipyretics may be ineffective.The usual concern about external cooling measures inducing peripheral vasoconstriction, reducing heat loss and making the pyrexia worse by shivering and hypermetabolism, may not be observed in sedated ICU patients.¹⁶ The most likely cause for this response is the drugs used to maintain sedation.^17,¹⁸

Pyrexia is associated with a number of deleterious physiological effects. Cardiac output, oxygen consumption, carbon dioxide production and energy expenditure are all increased, particularly in the presence of shivering. Oxygen consumption is increased on average by 10%/°C.² These changes are poorly tolerated by patients with limited cardiorespiratory reserve, and this group of patients would probably derive benefit from cooling measures. Other patient groups that require special consideration include those with immunosuppression, prosthetic implants and acute brain injury. Recent trials of therapeutic moderate hypothermia and traumatic brain injury indicate that hypothermia is a complicated treatment that is likely to benefit only a subgroup of patients with traumatic brain injury.¹⁹^–²¹

HEAT STROKE

A diagnosis of heat stroke is suggested when hyperthermia is associated with neurological abnormalities after exposure to high ambient temperature and/or vigorous exercise. Rectal temperature is usually greater than 42°C. Two distinct forms are recognised, and the spectrum of injury includes milder forms of thermal injury often termed heat stress.

Exertional heat stroke is a consequence of prolonged, intense exercise in warm humid environments, often seen in athletes and military recruits. Classic heat stroke is commonly seen in sedentary, elderly patients with underlying illnesses during heat waves. Factors predisposing to heat stroke are listed in Table 74.2. About 80% of heat stroke deaths occur in people aged 50 years and older, because of the diminished ability of the older body to compensate for increased core temperatures. Heat stroke is estimated to be the cause of approximately 1700 deaths each year in the USA.²² The European heat wave of 2003 was responsible for > 14 000 excess deaths within 2 weeks in France alone, of which a third were attributed to heat stroke, hyperthermia or dehydration.^23,²⁴ A high mortality rate of > 62% was reported for this cohort, which is higher than that for leading killers in ICUs such as acute respiratory distress syndrome (ARDS) and septic shock.²⁵ Furthermore, there is a late mortality contributed by survivors who have sustained neurological injury. A study of former heat stroke patients suggests that susceptible individuals have a poorer physiological response to heat stress in terms of core temperature, heart rate and sweat response.

Table 74.2 Predisposing factors to heat stroke

Age	Elderly
Environmental	High ambient temperature and humidity
	Heat waves
	Poor ventilation
Behavioural	Lack of acclimatisation
	Salt and water deprivation
	Obesity
Underlying conditions	Infection/fever
	Diabetes
	Malnutrition
	Alcoholism
	Hyperthyroidism
	Impaired sweat production
	Healed burns
	Ectodermal dysplasia
	Impaired sweating
	Cardiovascular disease
	Fatigue
	Potassium deficiency
Drugs	Anticholinergics
	Antiparkinsonians
	Antihistamines
	Butyrophenones
	Phenothiazines
	Tricyclics
	Diuretics
	Sympathomimetics

There are two autonomic responses to heat stress: sweating and active precapillary vasodilatation. Sweating is extremely effective and can dissipate up to 10 times the basal metabolic rate, provided that environmental conditions such as ambient temperature, humidity and wind speed are optimal. The resemblance between heat illness and the effects of antimuscarinic drugs, which produce a central anticholinergic syndrome, is explained by the postganglionic, cholinergic sympathetic innervation of sweat glands. Vascular responses to heat stress include vasodilatation of peripheral vascular beds and vasoconstriction of splanchnic and renal beds. During severe heat stress, blood flow through the top millimetre of skin can be equal to the entire resting cardiac output.

PATHOGENESIS

The pathogenesis of multiple organ failure in heat stroke is complex. Although direct cellular damage from increased temperature constitutes the initiating insult,²⁶ the precise sequence of injury and responsible mediators are poorly understood. At the cellular level, thermal injury results in increased membrane permeability, which in turn stimulates membrane enzymes such as Na⁺K⁺-ATPase to maintain membrane integrity. This ATP-consuming enzyme activity is also responsible for nerve impulse conduction, which ismarkedly curtailed when ATP is depleted. This results in tissue oedema, reduced oxygen extraction and neuronal injury. High temperatures ameliorate ATP synthesis leading to fatigue.

Recent evidence suggests that the pathways for tissue injury in heat stroke share many features with that of sepsis, endotoxaemia and systemic inflammation. Increased levels of circulating endotoxin and cytokines have been identified in patients with heat stroke.^27,²⁸ The use of anti-endotoxin antibodies in primate models of heat stroke suggests that endotoxin at least in part mediates the tissue injury associated with hyperthermia. There was also a significant correlation between plasma IL-6 concentration and the severity of heat stroke. Since this cytokine is known to modulate the hypothalamic set-point, the ramifications of such a response in an already hyperthermic patient are obvious.

Activation of coagulation factors ²⁹ and release of endothelin and adhesion molecules^30,³¹ from activated or injured endothelium have also been demonstrated in heat stroke. These recent observations lead to the speculation that certain mediators that are implicated in the pathogenesis of acute organ injury are also elevated in heat stress, but become intense when heat stroke develops and are not normalised upon cooling.

CLINICAL PRESENTATION

Heat stroke induces multiple organ failure and the clinical presentation reflects this. The first clinical signs may be neurological, and include restlessness, delirium, pupillary abnormalities, seizures and coma. Brainstem reflexes may be lost in the presence of brainstem-evoked potentials. There may be focal pathology including cerebellar injury, which may remain permanent. Lumbar puncture may show increased protein, xanthochromia and lymphocytic pleocytosis.

The signs of distributive shock, with a hyperdynamic haemodynamic profile not dissimilar to that of sepsis, are present in a large number of patients. The marked hyperventilation results in respiratory alkalosis, and hypoxaemic respiratory failure may be due to cardiac failure or acute lung injury.

Dehydration follows excessive insensible losses although sweating is generally absent in the terminal stages of classic heat stroke, leaving a hot, dry skin. Hypovolaemia is a consequence of dehydration and fluid redistribution, and results in reduced organ perfusion. A severe metabolic (lactic) acidosis is present. The major biochemical abnormalities include hyperglycaemia, hypophosphataemia, and raised serum enzymes and acute phase proteins (Table 74.3). Haematological findings include leukocytosis, thrombocytopenia, and activation of coagulation and fibrinolysis.

Table 74.3 Biochemical differences between classic and exertional heat stroke

	Classic heat stroke	Exertional heat stoke
Arterial gases	Mixed respiratory alkalosis	Severe metabolic acidosis
Serum electrolytes	Na⁺, Mg²⁺, Ca²⁺ are usually normal	HyperkalaemiaHypocalcaemia
	Hypophosphataemia	Hyperphosphataemia
Blood glucose	Hyperglycaemia	Hypoglycaemia
Creatinine kinase	Moderately increased	Markedly increased
Hepatic enzymes	Markedly increased	Moderately increased
Acute phase proteins	Markedly increased	Moderately increased

Exertional heat stroke differs slightly in that additional findings include rhabdomyolysis and acute renal failure that is associated with hyperkalaemia, hyperphosphataemia and hypocalcaemia (Table 74.3).

MANAGEMENT

Heat stroke is a medical emergency. The principal therapeutic objectives are rapid cooling to below 40°C and support of vital organ systems. Heat is dissipated by:

• conduction (immersion in ice-cold water or packed ice)

• evaporation (repeated wetting of skin with tepid water and fanning the patient at room temperature and low humidity)

Evaporation is considerably more effective. Pharmacological treatment with antipyretic agents, or dantrolene,³² is ineffective. Prevention of vasoconstriction and shivering by overcooling is important because of the danger of subsequent rebound hyperthermia. Core and skin temperature monitoring is useful, but measurement of rectal temperature should be avoided because it lags considerably during cooling. Cooling can be stopped when core temperature reaches below 39°C. However, despite cooling, about 25% of patients experience failure of one or more organ systems.

Fluid and electrolyte imbalance, and acid–base disturbances must be corrected cautiously with appropriate fluids tailored to the individual and guided by measurements of filling pressure, serum electrolytes and haematocrit.

The mechanism of acute renal failure is multifactorial but rhabdomyolysis is the major component. Early institution of alkaline diuresis and mannitol may obviate the need for renal replacement therapy.

Oxygen therapy and controlled ventilation may be indicated, and anticonvulsants required. Prophylactic antibiotics and steroids are not recommended. Blood glucose must be controlled aggressively. Finally, any underlying illness should be sought and treated accordingly.

OUTCOME

The largest study reported of heat stroke patients in intensive care suggests an alarmingly high mortality of > 60%,²³ although this diminishes substantially with early recognition and aggressive treatment. The incidence of permanent neurological deficit remains at 7–15%. Variables associated independently with reduced hospital survival include:

• high core temperature

• high simplified acute physiology score (SAPS) II score

• having heat stroke at home

• prolonged prothrombin time

• vasoactive therapy within 24 hours

• admission to ICU lacking air conditioning

DRUG-INDUCED HYPERTHERMIAS

In contrast to fever, the thermoregulatory set-point during hyperthermia remains unchanged at normothermic levels; however, body temperature increases in an uncontrolled fashion and overrides the ability of effector mechanisms to dissipate heat. Although a raised body temperature is not necessarily due to increased heat production but rather due to an imbalance between heat production and loss, most hyperthermias result as a consequence of net heat gain. Hyperthermia can result in dangerously high core temperatures by two mechanisms:

• excessive exogenous heat exposure

• excessive endogenous heat production

The numerous causes of hyperthermia are listed in Table 74.4. This section will review the relatively common causes of drug-induced hyperthermias, including malignant hyperthermia, neuroleptic malignant syndrome, and the sympathomimetic and anticholinergic syndromes.

Table 74.4 Causes of hyperthermia

Disorders of excessive heat production	Exertional hyperthermia
	Heat stroke (exertional)
	Malignant hyperthermia
	Neuroleptic malignant syndrome
	Lethal catatonia
	Thyrotoxicosis
	Phaeochromocytoma
	Salicylate intoxication
	Sympathomimetic drug abuse
	Delirium tremens
	Seizures
	Tetanus
Disorders of diminished heat dissipation	Heat stroke (classic)
	Dehydration
	Autonomic dysfunction
	Anticholinergic poisoning
	Neuroleptic malignant syndrome
Disorders of hypothalamic function	Cerebrovascular accidents
	Encephalitis
	Trauma
	Granulomatous diseases
	Neuroleptic malignant syndrome

MALIGNANT HYPERTHERMIA

Malignant hyperthermia (MH) is a rare pharmacogenetic myopathy usually manifested when a susceptible individual is exposed to anaesthetic triggering agents. It is characterised by an intense hypermetabolic state and skeletal muscle rigidity upon exposure to volatile anaesthetics and depolarising muscle relaxants. In extreme cases, body temperature may exceed 42°C and the arterial pH reach 6.8, and can be rapidly fatal. The incidence of an MH reaction during general anaesthesia varies between 1/60 000 when succinylcholine is used, and 1/250 000 when only volatile agents are used. It is more frequent in children (1/15 000), with more than 50% of cases occurring before the age of 15 years.

PATHOGENESIS

Skeletal muscle is the principal tissue involved in an MH reaction. The primary defect is thought to be in the sarcolemma, and in particular the calcium release channel also termed the ryanodine receptor (RYR1). In MH, exposure of skeletal muscle to triggering agents depolarises the muscle hypersensitively to release massive amounts of calcium ions from the sarcoplasmic reticulum (SR), thus vastly increasing its cytoplasmic concentration. It is believed that the altered kinetics of the ryanodine receptor is due to exaggerated release of calcium by small increases in cytoplasmic calcium concentration (calcium-induced calcium release), as well as a decrease in inhibitory effects of high calcium concentrations. ATP-dependent membrane pumps (Ca²⁺-ATPase) attempt to return the calcium back to the SR, resulting in a sustained glycolytic and aerobic metabolism. Recovery of calcium by the SR is often incomplete, causing prolonged excitation–contraction coupling and leading to muscle rigidity. Muscle contractures impede blood flow and perturb nutrient supply and waste removal from this hypermetabolic reaction. Eventually, oxidative phosphorylation is uncoupled, metabolism becomes anaerobic, and a severe lactic and respiratory acidosis develops. As muscle constitutes about 40% of body mass and is a major source of body heat, increased activity results in hyperthermia.

Membrane phospholipase A₂ is also activated by calcium, leading to an increase in mitochondrial and sarcoplasmic permeability, with further loss of calcium regulation and release of intracellular contents (potassium [K⁺], calcium [Ca²⁺], creatinine kinase (CK) and myoglobin) into the circulation.

CLINICAL PRESENTATION

The earliest sign of an impending MH crisis is an unexplained rise in end-tidal CO₂ and heart rate, and not necessarily an increase in body temperature. This classic crisis of acute fulminant MH with its multiplicity of marked metabolic and muscle anomalies and sympathetic stimulation is unmistakable, but now rare. The pattern of presentation has altered since its first description in 1960, as anaesthetic techniques and succinylcholine use have changed.

The more gradual appearance of signs following exposure to triggering agents may be more difficult to diagnose as the signs may be subtle, non-specific and have variable intensity, incidence and temporal association (Table 74.5).³³ Apart from the classic crisis, other forms of MH – including smouldering, recurring, delayed and abortive – may also occur. Other conditions that may mimic MH include inadequate levels of anaesthesia or analgesia, sepsis, ischaemia or anaphylaxis. Early diagnosis is important as immediate treatment is associated with improved outcome. Masseter muscle spasm (MMS) has been associated with MH.³⁴ When MMS is the only presenting sign, the incidence of MH susceptibility is likely to be low. However, this incidence is increased if MMS is associated with other muscle or metabolic signs.

Table 74.5 Clinical features of malignant hyperthermia

Halothane is the most potent of the contemporary volatile anaesthetic agents at inducing sustained contractures in isolated muscle strips from MH patients, and has formed the basis of diagnostic testing for MH for 30 years. There may be a difference amongst the volatile anaesthetics in their relative potency to trigger an MH reaction. Succinylcholine will cause an increase in the calcium concentration in the cytosol of normal muscle, and it appears that this release of calcium is exaggerated in MH muscle. Non-depolarising muscle relaxants are generally accepted to be safe in MH. A list of safe and implicated drugs is shown in Table 74.6.

Table 74.6 Drug use in malignant hyperthermia

Contraindicated drugs	Safe drugs
Halothane	Nitrous oxide
Enflurane	Barbiturates
Isoflurane	Propofol
Desflurane	Etomidate
Sevoflurane	Ketamine
Succinylcholine	Opiates
Verapamil	Amide/ester local anaesthetics
Nifedipine	Noradrenaline (norepinephrine)
Diltiazem	Adrenaline (epinephrine)
	Dopamine
	Dobutamine

Several neuromuscular and musculoskeletal abnormalities such as scoliosis, strabismus, muscular dystrophy and central core disease have been associated with MH susceptibility but definitive evidence for this association is lacking. Patients with neuroleptic malignant syndrome are not considered at risk of developing MH under general anaesthesia.

MH susceptibility has been diagnosed for the last 30 years on the basis of abnormal in vitro contractures to separate exposures to halothane and caffeine performed on freshly biopsied muscle strips. Recently, a ryanodine contracture test has been shown to be more specific and may be of additional value.

NEUROLEPTIC MALIGNANT SYNDROME

The neuroleptic malignant syndrome (NMS) is a relatively rare but potentially fatal idiosyncratic reaction to neuroleptic drugs that is not dose related. Many features of this syndrome remain controversial as several other medical conditions generate similar symptoms, but characteristic findings include:

• encephalopathy

• muscle rigidity

• hyperthermia

• autonomic dysfunction

The incidence is estimated to vary between 0.07 and 2.2%. All ages are affected but males are disproportionately represented in some studies.

PATHOGENESIS

The pathophysiology of NMS remains unclear. Two mechanisms – a neuroleptic-induced perturbation of central thermo- and neuroregulatory mechanisms and an abnormal reaction of skeletal muscle – have been proposed.

Hypothalamic thermoregulation involves noradrenergic, serotonergic, cholinergic and central dopaminergic pathways. Neuroleptic blockade of dopamine receptors in the hypothalamus leads to disturbances in thermoregulation and heat dissipation. In addition, blockade of dopamine receptors in the basal ganglia is thought to cause muscle hypertonicity and contraction, leading to further heat production. Drugs linked to NMS appear to share the ability to antagonise dopamine receptors (primarily D₂ receptors) or to lower synaptic dopamine levels. Recent work suggests that glutaminergic excitatory amino acids may influence central dopamine activity and be more important in the development of NMS.

A common pathogenesis of NMS and MH has been suggested by virtue of similar clinical features (hyperthermia, rigidity, raised serum muscle enzymes), abnormal in vitro contracture tests and, interestingly, successful treatment with dantrolene in both. However, conflicting results have been reported regarding the prevalence of MH susceptibility among NMS patients. Neuroleptic agents induce muscle contracture in vitro; however, no difference was found in response to four neuroleptic drugs between muscle from NMS patients and normal individuals.³⁵

Although biochemical studies suggest the involvement of genetic factors in the pathogenesis of NMS, the molecular basis remains elusive. There does not appear to be an association between NMS and the mutations in the RYR1 gene associated with MH.

CLINICAL PRESENTATION

The presentation and course of NMS can be quite variable; it may take a relatively benign and self-limiting course, or it may be fulminant and fatal, although the latter is rare. NMS usually develops within 2–4 weeks of starting antipsychotic therapy but the majority of the cases develop within the first week. The main symptoms that indicate a high probability of NMS include:

• hyperthermia

• muscle rigidity

• elevated serum creatinine kinase

• autonomic instability

A predictable progression of symptoms may be identified in many patients with NMS where mental status changes and rigidity precede hyperthermia and autonomic dysfunction:³⁶

• temperature elevation can be mild or severe, but is rarely greater than 42 °C as seen in heat stroke

• muscle rigidity is characterised by a ‘lead pipe’ increase in tone that may result in decreased chest wall compliance and hypoventilation

• extrapyramidal symptoms may also be present

• autonomic instability is demonstrated by labile hypertension (hypotension is rare), tachycardia and sweating

• altered consciousness is typically of the form of delirium and agitation that may progress to stupor and coma

Other clinical features of lesser frequency include dysarthria, dysphagia, chorea, mutism and seizures. Elevated serum creatinine kinase is now considered to be a major feature of NMS. Other non-specific laboratory abnormalities include leukocytosis, mildly elevated hepatic enzymes, and secondary electrolyte disturbances including hypocalcaemia, hypomagnesaemia and hypophosphataemia. Urine analysis often reveals proteinuria and myoglobinuria from rhabdomyolysis. The electroencephalograph (EEG) may show diffuse slowing. CT scans of the brain as well as examination of cerebrospinal fluid is usually normal in NMS.

All classes of neuroleptic medications have been implicated in NMS including butyrophenones, phenothiazines, thioxanthenes and benzamides, as well as newer drugs such as clozapine and risperidone. Haloperidol and fluphenazine are the most frequently reported agents. Other agents that block dopamine receptors or inhibit dopamine release have been associated with NMS including metoclopramide, reserpine and α-methylparatyrosine. Discontinuation of anti-parkinsonian drugs (leading to a relative decrease in dopamine levels) has also been associated with NMS.

Risk factors include organic brain disease, functional psychoses, dehydration and rapid loading of antipsychotics.

Complications include:

• acute renal failure from rhabdomyolysis

• respiratory failure from hypoventilation and aspiration pneumonia

• cardiovascular collapse

• irreversible neurological injury may result from extreme temperatures

The differential diagnosis of NMS includes all disorders that can present with a combination of hyperthermia, rigidity and encephalopathy. These include CNS infections, cerebral masses, tetanus, heat stress, MH, catatonia and drug toxicities (lithium, atropine and monoamine oxidase inhibitors).

Neuroleptic-induced heat stroke is differentiated from NMS by its faster onset, absence of extrapyramidal signs and sweating (anticholinergic properties of neuroleptics), and a history of physical exertion and exposure to a hostile environment. Like NMS, lethal catatonia can present with hyperthermia, akinesia and muscle rigidity. The importance of distinguishing the catatonias from NMS lies in the differential treatment. Benzodiazepines are usually required for the former.

SEROTONERGIC SYNDROME

Drugs that enhance serotonergic neurotransmission or lead to a relative increase in synaptic levels of serotonin can result in a toxic state that resembles features of NMS. These drugs include selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), either alone or in combination. Serotonin syndrome may complicate the administration of drugs frequently used in anaesthetic practice, including pethidine and tramadol, in combination with the above drugs. This syndrome is a toxic effect that appears to be due to hyperstimulation of 5-HT_1A receptors in the brain and spinal cord. This is differentiated from NMS, which is an idiosyncratic response to antipsychotics and not serotonergic drugs.

Clinical features of the serotonergic syndrome include encephalopathy, hyperreflexia, nausea and vomiting, and autonomic instability. Sweating and mild increases in temperature are evident in 50% of cases. Rhabdomyolysis, hyperkalaemia, renal failure, DIC and seizures are all rare but reported findings. The serotonergic syndrome is usually self-limited, and resolves uneventfully once the offending drug has been withdrawn. However, rarely severe forms require more aggressive supportive therapy analogous to the treatment of NMS. Specific treatments including the use of serotonin antagonists have been proposed; however, these cannot be recommended at present due to lack of well-designed studies.

MANAGEMENT

Management of mild forms of NMS may only require early recognition, withdrawal of all neuroleptic, dopamine-depleting or dopamine-antagonist medication, and general supportive therapy. Cessation of all psychotropic drugs should be considered. Rarely, severe cases require aggressive treatment of fluid/electrolyte and acid–base balance as well as cardiorespiratory function. Because acute renal failure is the most frequent complication of NMS, therapy must be directed at renal protection from myoglobin injury. The hyperthermic patient should be cooled as described previously in this chapter. Haemodialysis may be required for renal failure, but is not useful for clearing neuroleptic drugs as these are protein-bound and therefore too large to dialyse.

The benefit of adding specific pharmacotherapies in addition to supportive measures is unclear, but potential use cannot be excluded. Treatments with bromocriptine (a dopamine agonist) and dantrolene have led to a faster resolution of symptoms than with supportive therapy alone.³⁷ However, the place of dantrolene in the treatment of NMS is less well defined. Bromocriptine seems to be well tolerated by psychotic patients despite being a strong central dopamine agonist. The drug is effective within 24 h, with a reduction in rigidity followed by resolution of temperature and normalisation of blood pressure. Similarly, amantadine, as well as a combination of levodopa-carbidopa, has also been reported to be effective. Anticholinergic drugs have little effect on muscle rigidity or hyperthermia. Non-specific adjuncts, such as the use of benzodiazepines, have been reported to be useful in agitated patients. Electroconvulsive therapy (ECT) may be of value in selected patients, e.g. those with refractory NMS, those who remain catatonic or those with ECT-responsive psychotic symptoms.

OUTCOME

A mortality of 22% prior to 1980 has been halved since 1984. This reduction has occurred largely due to early diagnosis, supportive therapy and advances in critical care medicine, rather than a consequence of therapy with either dantrolene or dopamine agonists. Renal failure increases the mortality rate to approximately 50%; however, prognosis remains good in survivors.

SYMPATHOMIMETIC AND ANTICHOLINERGIC SYNDROMES

SYMPATHOMIMETIC POISONING

Mild to severe hyperthermia may be associated with all centrally acting sympathomimetics. These drugs produce their clinical effects by increasing synaptic concentrations of noradrenaline (norepinephrine), dopamine and serotonin.

Cocaine predominantly blocks the presynaptic uptake of noradrenaline, although neurotransmission of dopamine and serotonin is also affected. Amphetamines and related drugs augment the release of noradrenaline, dopamine and serotonin from presynaptic nerve terminals and inhibit their uptake from the synapse. Some amphetamine metabolites also inhibit monoamine oxidase.

Central thermoregulatory disturbances from sympathomimetics may arise from complex interactions of these neurotransmitters in the brainstem and hypothalamus. The syndrome of hyperthermia associated with sympathomimetic poisoning bears similarity to that of heat stroke, MH, NMS and serotonin syndrome. This may reflect the final common pathway associated with the consequences of severe hyperthermia. Sympathomimetics such as MDMA (‘ecstasy’) have been shown to induce marked hyperthermia through central mechanisms involving 5-HT₂ receptors, with subsequent rhabdomyolysis, DIC and multiorgan failure.³⁸ Hyperkinetic muscle action, motor excitability and seizures may contribute to the rise in core temperature. Furthermore, elevated levels of both cocaine and amphetamine result in peripheral vasoconstriction, thus impairing heat dissipation. Mortality appears to be related to the extent and duration of hyperthermia.

Therapy involves rapid cooling measures as outlined previously, together with support of failing organ systems. Benzodiazepines may relieve myotonic and hyperkinetic thermogenesis. However, patients who remain agitated and non-compliant should be paralysed and ventilated to permit institution of aggressive cooling measures. In moderately severe hyperthermia, dantrolene therapy has been described to improve outcome by enabling rapid muscle relaxation and control of temperature. However, the basis of its utility in this setting has not been established.

HYPOTHERMIA

Hypothermia is defined as a core body temperature below 35 °C. In the UK, hypothermia accounts for 1% of winter admissions, particularly amongst the elderly population. The leading causes of hypothermia in the USA are exposure due to alcoholism, drug addiction, mental illness, or accidents involving immersion in cold water. The mortality rate from accidental hypothermia varies according to its severity, but averages 21% when core temperature is decreased to 28–32°C.³⁹ However, a core temperature of 32 °C or less in trauma victims is associated with a mortality rate near 100%, and any hypothermia is considered a poor prognostic sign.^40,⁴¹

Hypothermia is traditionally classified as:

• mild (temperature 32–35°C)

• moderate (temperature 28–32°C)

• severe (temperature below 28°C)

Significant hypothermia in terms of severity and duration results in multiple systemic derangements that ultimately lead to impaired tissue oxygenation. The major defence against cold stress is behavioural adaptation. However, autonomic thermoregulatory responses orchestrated by the hypothalamus are also activated to prevent heat loss and generate heat production. These include:

• peripheral vasoconstriction

• shivering

• increase in metabolism.

The four physical mechanisms of heat loss from the body surfaces are conduction, convection, radiation and evaporation.

Hypothermia may be induced deliberately for therapeutic purposes, e.g. cardiovascular surgery or neuroprotection, or it may be accidental. Primary accidental hypothermia occurs when an otherwise healthy individual experiences overwhelming cold stress, e.g. cold-water immersion. Secondary accidental hypothermia occurs despite mild environmental conditions and is due to illness or injury-induced perturbations in thermoregulation and heat production, e.g. drug intoxication or trauma.

The causes and predisposing conditions of hypothermia are listed in Table 74.7; however, the most frequent causes appear to be exposure, hypoglycaemia and the use of depressant drugs including alcohol. An impaired thermoregulatory system together with a reduced functional reserve makes the elderly more susceptible.

Table 74.7 Causes and predisposing conditions of hypothermia

Age	Extremes of age
Environmental	Exposure to cold
	Immersion
	Poor living conditions
Drugs	Anaesthetic agents
	Phenothiazines
	Barbiturates
	Alcohol
Central nervous system disorders	Cerebrovascular accidents
	Trauma
	Spinal cord transections
	Brain tumours
	Wernicke’s encephalopathy
	Alzheimer’s and Parkinson’s disease
	Mental illness
Endocrine dysfunction	Hypoglycaemia
	Diabetic ketoacidosis
	Hyperosmolar coma
	Panhypopituitarism
	Hypoadrenalism
	Hypothyroidism
Trauma	Major trauma
Debility	Severe cardiac, renal, hepatic impairment
Debility	Malnutrition, sepsis
Skin disorders	Burns
Skin disorders	Exfoliative dermatitis

Administration of anaesthesia impairs the ability to maintain thermal homeostasis, decreases heat production and causes heat loss due to vasodilatation and exposure. General anaesthesia also alters the threshold for thermoregulatory vasoconstriction and shivering in the non-paralysed patient.⁴²

PATHOGENESIS AND CLINICAL PRESENTATION

Hypothermia depresses all organ functions resulting in decreased cardiac function, shock, respiratory failure, confusion, muscle rigidity, renal failure and death. The cardiovascular response in hypothermia initially comprises an increase in heart rate, cardiac output and blood pressure in response to shivering and increased metabolic demand. Peripheral vasoconstriction is due to activation of the sympathetic nervous system as well as local cutaneous reflexes, resulting in shunting of peripheral blood to the central pool. With worsening hypothermia:

• progressive cardiovascular depression leads to a reduction in tissue perfusion

• cardiac output is halved at 28°C as a result of decreased heart rate and contractility

• conduction and pacemaker activity are reduced, and there is prolongation of PR, QRS and QT intervals as well as non-specific ST-T wave changes. The characteristic J or Osborn wave may be seen when core temperature is below 33°C

• atrial fibrillation and heart block are also common below this temperature. Ventricular fibrillation and asystole can occur below 28°C and 20°C respectively. Fibrillation may occur earlier if the myocardium is diseased or stimulated, either mechanically or pharmacologically

An initial increase in respiratory rate during hypothermia is followed by progressive depression of rate, vital capacity and minute volume. The cough reflex is abolished, exposing the patient to an increased risk of aspiration pneumonia. Bronchial secretions, atelectasis and pulmonary oedema may develop. Apnoea may occur below 24°C. The oxyhaemoglobin dissociation curve is shifted to the left, resulting in reduced oxygen delivery to the tissues, but this is partially balanced by a right shift due to the underlying acidosis.

Shivering occurs in the early phase of hypothermia and is characterised by intense heat and energy production from the metabolism of stored fuels. Non-shivering thermogenesis is probably only of importance in children. Metabolic processes slow by approximately 6%/°C, and the metabolic rate is reduced by half at 28°C.⁴³ A mixed respiratory and metabolic acidosis results from hypoventilation and reduced tissue perfusion, leading to lactate accumulation from anaerobic metabolism. Hepatic function is depressed, affecting most enzymatic and detoxifying processes. There is a high risk of developing pancreatitis.

There is generalised cerebral depression as the metabolism of the brain declines with a fall in core temperature. This adaptation is neuroprotective and may improve the chances of survival even after prolonged hypothermic arrest. Cerebral blood flow falls as a consequence of reduced cardiac output and increased blood viscosity at a rate of 7%/°C drop in temperature.⁴⁴ Confusion can cause illogical behaviour (e.g. aggression) and paradoxical undressing. Coma, pupillary dilatation, absence of tendon reflexes and rigidity are present below 28°C. Cerebral electrical activity ceases below 20°C.

Hypothermia causes an initial increase in catecholamine and cortisol release as a result of the stress response. There is a delayed increase in serum thyroxine levels. Below 30°C, pituitary and pancreatic functions, as well as catecholamine secretion, are blunted. Blood sugar concentration is increased as a result of increased glycogenolysis and insulin resistance.

Haemoconcentration develops as a consequence of hypovolaemia as well as fluid shifts between compartments. Hypothermia increases blood viscosity by 2%/°C. Splenic sequestration results in leukopenia and thrombocytopenia. Low temperature also interferes with the intrinsic coagulation cascade. In severe hypothermia, platelet dysfunction and DIC are common.

MANAGEMENT

Once the diagnosis of hypothermia has been made, further heat loss must be prevented and rewarming started with close monitoring to avoid complications. Individual management should be modified according to aetiology and severity of hypothermia, as well as the functional reserve of the patient. Severe hypothermia, especially in the immersion victim, can mimic death, with apnoea, cardiac standstill, coma, unreactive pupils, and a silent electrocardiogram and electroencephalogram. Successful resuscitation of such patients has been reported and death should not be assumed until resuscitation has failed in an adequately warmed patient (at least 35°C).⁴⁵

General measures begin with removal of the patient from the cold environment as rapidly as possible. Rough handling must be avoided during transport as this may precipitate fatal arrhythmias in severe hypothermia. Also, transport in the upright position must be avoided because cerebral blood flow may be compromised due to orthostatic hypotension.

Recommendation for basic and advanced life support for hypothermic patients is according to the principles of Advanced Cardiorespiratory Life Support (ACLS). Aggressive rewarming should be continued during resuscitation until the core temperature is at least 35°C. A resuscitation protocol based on core temperature and cardiac monitoring may be used.⁴⁶ If core temperature is unknown or known to be above 28°C, cardiopulmonary resuscitation (CPR) should be instituted for apparent cardiac arrest. If the patient is known to be severely hypothermic (< 28°C) but maintains sinus rhythm, chest compression may precipitate ventricular fibrillation (VF) and may be best withheld.

Vascular cannulation may be difficult in the presence of intense vasoconstriction and a central catheter is inevitably required, taking precautions to avoid myocardial stimulation.

For the same reasons, a pulmonary artery catheter should be deferred until normothermia has been re-established. Hypotension should be treated with aggressive warm fluid therapy. Lactated Ringers should be avoided because the liver may not be able to metabolise lactate to bicarbonate.

Atrial arrhythmias, bradycardia or atrioventricular block generally do not require treatment with antiarrhythmic agents unless decompensated, and resolve on rewarming.

Electrical defibrillation may not be effective at body temperature below 30°C. Indeed, VF may resolve spontaneously upon rewarming.

Sodium bicarbonate should be avoided because of paradoxical intracellular acidosis, and severe alkalosis on rewarming may induce refractory VF and left shift of the oxyhaemoglobin dissociation curve, thereby reducing tissue oxygen uptake. Progressive cardiac depression during rewarming (‘recovery shock’, ‘afterdrop’) may be due to further cooling of blood as it redistributes from the core to the relatively colder periphery.⁴⁷

The increased metabolic demand during rewarming requires oxygen therapy. Patients in coma or respiratory failure should be intubated and ventilated with warm gases. Drug administration during hypothermia may reach toxic levels after rewarming because of functionally prolonged half-lives, and therefore should be used sparingly. Insulin treatment should be delayed until the temperature is above 30°C. It should be administered in small doses because degradation is slow and accumulation may occur with rebound hypoglycaemia as the patient is warmed.

REWARMING

Various methods of rewarming have been employed depending upon the severity of the hypothermia (Table 74.8). Careful monitoring and supportive therapy are mandatory during rewarming.

Table 74.8 Rewarming methods

Passive	Warm environment > 30°C (rate 0.5–1.0 °C/hour)
Passive	Insulating cover (warm blanket)
Active, external	Conduction methods
	Warmed pads, blanket
	Convective methods (rate at 2–3°C/hour)
	Hot air blower (e.g. Bair Hugger)
	Radiant methods
Active, core	Humidified warm inspired gases (rate 0.5–1.5°C/hour)
	Warmed intravenous fluids
	Body cavity lavage (rate 2–3°C/hour)
	Gastric irrigation
	Pleural irrigation
	Peritoneal dialysis
	Extracorporeal methods
	Haemodialysis, continuous arteriovenous or venovenous rewarming (rate 5°C/hour)
	Cardiopulmonary bypass (rate up to 10°C/ hour)