Drug Induced Hyperthermia

This session considers the three main forms of drug related hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome.

Pathophysiology

Body temperature depends upon a balance of heat production and heat loss. Hyperthermia occurs when heat production exceeds heat loss. Obligatory thermogenesis describes the metabolic processes that are required for normal basal function. The body can adjust body temperature rapidly, this process is under hypothalamic control of the sympathetic nervous system. The pre optic nucleus of the anterior hypothalamus will respond to core body temperature and can induce either vasodilatation to aid cooling or vasoconstriction to conserve heat . Humans can also sweat, a reflex mediated via the autonomic nervous system. Muscle activity will increase heat production and this can either be exercise or shivering which is coordinated by the hypothalamus.

Drugs that alter levels of neurotransmitters such as noradrenaline, dopamine or serotonin influence hypothalamic regulation of temperature and alter body temperature.

Non-shivering thermogenesis occurs by uncoupling oxidative phosphorylation through the activity of mitochondrial proteins known as uncoupling proteins. Uncoupling proteins have been detected in skeletal muscle; expression of uncoupling can increase three fold in rodent skeletal muscle when exposed to low temperatures for 24 hours. Noradrenaline and beta3- adrenergic receptors increase the activity of uncoupling protein mediated thermogenesis.

Laboratory investigations to be considered include:

• FBC (leucocystosis is common in NMS)
• U&E
• Lactate
• CK (elevated in NMS and for detection of rhabdomyolysis as a complication)
• Clotting
• Toxicology screen
• CT head and lumbar puncture to be considered if central nervous system aetiologies are suspected.

Malignant hyperthermia is a rare syndrome with a prevalence of 1:15000 in children to 1:50000 in adults. It is a life threatening complication of anaesthesia.

Pathophysiology

There is a genetic defect at one of the receptors controlling the release of calcium from the sarcoplasmic reticulum. Uncontrolled release of calcium in skeletal muscle and uncoupling of oxidative phosphorylation are responsible for the clinical manifestations of malignant hyperthermia. Following exposure to a trigger, excessive jaw rigidity, excessive carbon dioxide production, hyperthermia and tachycardia develop. As ATP is used up, lactate production increases with a resulting metabolic acidosis. Muscle breakdown leads to potentially fatal hyperkalemia.

Triggering agents include inhalational anaesthesia and the depolarising agent suxamethonium. Previous exposure to known triggering agents does not rule out the disease. Excessive exercise in warm conditions can also trigger a reaction in those who are susceptible.

During a reaction there are significant increases in noradrenaline and increased survival has been demonstrated with alpha-blockade in animal models. Elevated levels of serotonin appear during malignant hyperthermia and serotonergic drug have exaggerated responses in susceptible swine but serotonin antagonists have not been shown to be effective.

Treatment of malignant hyperthermia

Dantrolene remains the mainstay of treatment. Dantrolene inhibits calcium release by direct action on the calcium release channels. This leads to complete skeletal muscle relaxation. Treatment with Dantrolene may be required for up to 72 hours in order to prevent recurrence.

Supportive treatment with active cooling and controlled hyperventilation are important.

Patient who have thought to have had a episode of malignant hyperthermia need to be referred to an malignant hyperthermia centre for investigation and genetic counselling.

Learning Bite

Dantrolene is the best treatment for Malignant Hyperthermia Grade C recommendation Level 4 Evidence.

Neuroleptic malignant syndrome is a rare idiosyncratic reaction occurring in patients that are taking neuroleptic drugs or after sudden withdrawal of dopamine agonists.

Pathophysiology

Neuroleptic malignant syndrome is thought to be due to decreased dopamine activity within the central nervous system either due to blockade or decreased availability. Within the nigrostriatum and hypothalamus dopamine blockade leads to muscular rigidity and altered thermoregulation

Neuroleptic syndrome can occur at any time; even after years of therapy but is more likely to develop within 10 days. Drug levels are often found to be therapeutic in neuroleptic malignant syndrome. Butryphenones and phenothiazines are most commonly implicated though at least 25 agents have been identified as triggers. Some patients will develop neuroleptic malignant syndrome with any dopamine agonist, some will develop neuroleptic malignant syndrome with specific dopamine agonists whilst others can be treated with the same drug without any ill effect.

Clinical features

Neuroleptic malignant syndrome typically presents with a clinical syndrome of hyperthermia, altered mental status, skeletal muscle rigidity and autonomic dysfunction. A temperature of 38 C or above is a key diagnostic feature. Autonomic dysfunction manifests as tachycardia, hypotension or hypertension and diaphoresis. Mental status changes often precede muscle rigidity.

It is often difficult to differentiate between neuroleptic malignant syndrome and serotonin syndrome in patients presenting with muscular rigidity, hyperthermia and autonomic instability. Patients with serotonin syndrome present within 24 hours of starting the medication, whilst those with neuroleptic malignant syndrome present at anytime with peak symptoms not occurring for days.

Management

The first step in the management of neuroleptic malignant syndrome is removal of the offending drug. In mild cases drug withdrawal and supportive care are often enough. In severe cases, Bromocriptine, a dopamine agonist and Dantrolene may be helpful. Bromocriptine is given orally and may cause hypotension, dyskinesia and erythematous tender extremities,

Learning Bite

Neuroleptic Malignant Syndrome should be considered when a patient taking psychiatric drugs presents with hyperthermia, muscle rigidity and altered mental status. Grade D recommendation Level 5 Evidence.

Serotonin syndrome is a predictable consequence of excess serotonergic agonism of central nervous system receptors and peripheral serotonergic receptors.It is not an idiopathic drug reaction. Most cases occur with a therapeutic concentration, not overdoses.

Pathophysiology

Serotonin is produced by the decarboxylation and hydroxylation of L-tryptophan. Its quantity and actions are tightly regulated by a combination of reuptake mechanisms, feedback loops and metabolizing enzymes. There are seven 5-hydroxytryptamine receptor families, several of which have multiple members.

Serotonergic neurons in the central nervous system are found primarily in the midline raphe nuclei located in the brain stem from the midbrain to the medulla. The rostral end of this system assists in the regulation of wakefulness, affective behaviour, food intake, thermoregulation, migraine, emesis and sexual behaviour. The neurons of the raphe in the lower pons and medulla participate in the regulation of nociception and motor tone. In the periphery, the serotonin system assists in the regulation of vascular tone and gastrointestinal motility. The commonest drugs that precipitate serotonin syndrome are Venlafaxine, Fluoxetine, Citalopram, Pethdine and Tramadol. Ondansatron blocks serontonin post synaptic receptors and can not induce this syndrome.

Clinical features

In moderate intoxication a core temperature of 40 C is not uncommon. Physical examination includes mydriasis, hyperactive bowel sounds, diaphoresis with normal skin colour. Clonus (inducible, spontaneous and ocular) is the most important finding in establishing the diagnosis. Hyperthermia and hypertonicity occur in life threatening cases.

Signs of excess serotonin range from tremor and diarrhoea in mild cases to delirium, neuromuscular rigidity and hyperthermia in life-threatening cases. Serotonin syndrome can result can result form therapeutic drug use, self-poisoning or inadvertent interactions between drugs. The increase in dose of a causative agent or the addition of a drug with pro-serotonergic effects may provoke a dramatic clinical deterioration.

Management

Management of the serotonin syndrome involves removal of precipitating drugs, provision of supportive care, control of agitation, the administration of 5HT antagonists, control of autonomic instability and the control of hyperthermia. Many cases will resolve within 24 hours after the initiation of therapy and the discontinuation of serotonergic drugs but symptoms may persist in patients taking drugs with long elimination half-lives, active metabolites or a protracted duration of action. The mainstay of treatment remains supportive care which includes intravenous fluids and correction of vital signs. An abrupt deterioration warrants an immediate and aggressive response.

The uses of benzodiazepines for agitation are essential in the management of the syndrome regardless of severity and are useful in blunting the hyperadrenergic component. Physical restraint should not be used and may increase mortality by enforcing isometric muscle contraction leading to lactic acidosis and hyperthermia.

Cyprohepatdine is recommended for severe cases, treatment may require 12 to 32 mg during a 24 hour period. This dose will bind 85 to 95% of serotonin receptors. Olanzipine sub-lingually has been used successfully in the treatment but its efficacy has not been determined. Chlorpromazine has been used as an intramuscular injection.

Severe hyperthermia requires intubation and ventilation with non-depolarising muscle relaxants; suxamethonium can precipitate arrhythmias secondary to hyperkalemia associated with rhabdomyolysis. Benzodiazepines may be sufficient in moderate cases.. Dantrolene has no effect on survival in animal models and in one case report was used with bromocriptine , a dopamine agonist, resulted in an abrupt increase in temperature and subsequent death of a patient.

Learning Bite

Serotonin syndrome is best treated with fluids and benzodiazepines. Dantrolene is unhelpful. Grade D recommendation Level 5 Evidence.

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