This report will examine two different types of hyperthermia in relation to the given case study. A 45-year-old female patient who has developed hyperthermia after receiving surgery; she is also on the prescription medications of citalopram and tramadol. To attempt to determine the type of hyperthermia suffered the causes, symptoms and treatments of the two types will be investigated. These are known as drug-induced hyperthermia and malignant hyperthermia. By examining these conditions we will attempt to find parallels with the given case study and hence conclude with a probable diagnosis.
Background of Hyperthermia
The normal range of human body temperature is between 36.1oC to 37.8oC.1
Above this temperature the body perspires to keep cool, for example during vigorous activity or in hot temperatures. The hypothalamus contains thermo-sensitive neurons, where it is in control of heat regulation and governs perspiration. The body sweats to decrease the core temperature, with surface temperature decreasing through evaporation. However when the body's heat production exceeds the heat loss hyperthermia can occur. With a body temperature of 40oC or above emergency treatment is needed, as it can be life threatening.2
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Hyperthermia is the common name given to different heat-related illnesses. These include heat cramps, heat oedema, heat syncope, heat exhaustion and heat stroke.
Heat cramps are painful muscle contractions in the arms, calves or abdomen, and can be due to insufficient fluid or electrolyte intake. Heat oedema is swelling in the ankles, feet or hands occurring from being too hot. Heat syncope is where the body temperature is or above 40°C, with symptoms of fainting and dizziness due to the heat. Heat exhaustion include symptoms of dizziness, nausea and vomiting, fainting, with a slightly increased temperature. The most severe heat illness is heat stroke as it can be life threatening. It is defined as a temperature of greater than 40oC that is caused by an environmental heat exposure with a lack of thermoregulation. Signs of a heat stroke are fainting, high body temperature but unable to perspire, confusion and possibly deliria or in a coma.3
Treatment for these different heat-related illnesses consist of keeping cool with ice packs, keeping hydrated with water and oral rehydration salts, stretching any cramped muscles and rest by sitting upright keeping the legs raised.
The main risk categories for this type of hyperthermia include being older, over- or under-weight, and drinking a lot of alcohol. Health risks include poor blood circulation and sweat glands that are not perspiring efficiently causing the body to stay warm when it should be cooling down. Any heart, lung or kidney disease, and illnesses that cause high blood pressure or general weakness can be a risk to develop hyperthermia. This is due to medications like diuretics, sedatives, tranquilisers, certain blood pressure drugs, or if they are on certain salt restricted diets that cause an increased risk in being unable to perspire.4 Lifestyle factors that may increase a person's risk of hyperthermia include hot living accommodation, overdressing if a person is unable to feel the heat, or going outdoors on especially hot days.
Drug Induced Hyperthermia
Hyperthermia can present itself in severe cases of 'serotonin syndrome.'5 This is an adverse drug reaction to serotonergic agents, like Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs.) They are mainly used as antidepressants prescribed for the treatment of depression, social anxiety, panic disorders, obsessive-compulsive disorders, and eating disorders. Serotonin syndrome is seen as an iatrogenic effect of modern medicines, with the incidence unclear due to the extent of under-diagnosis. Examples of the SSRI drug class include citalopram, fluoxetine, and sertraline, with SNRI examples including venlafaxine, duloxetine and tramadol.
Symptoms of serotonin syndrome usually present as cognitive, neuromuscular and autonomic changes. Restlessness or diarrhoea may be due to mild cases of serotonin syndrome, with severe cases causing symptoms of serious muscle rigidity and hyperthermia. Other symptoms can include confusion, hyperreflexia, agitation, delirium, tachycardia, muscular spasms, blood pressure fluctuations, nausea and diarrhoea. Symptoms usually develop within 2 hours of the increase in the synaptic level of serotonin. In these severe cases serotonin syndrome can be fatal.6
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Serotonin syndrome most likely occurs when serotonergic drugs have just been started in a patient, if the dose is increased, or after two drugs are taken together that both affect the body's serotonin levels, either causing too much serotonin to be released or too much serotonin remaining in the brain area.7 However it can also happen at any time during therapeutic use, an overdose, or through drug interactions.
Concurrent use of medications that interact with serotonergic drugs through the inhibition of the cytochrome P450 pathway can also contribute to serotonin syndrome. When serotonergic agents are taken together with triptan drugs like sumitriptan or rizatriptan used for migraines, illegal drugs like ecstasy and LSD, or the cough medicine dextromethorphan, for example Robitussin, serotonin syndrome can also follow.8
The most common adverse effects can be seen when tramadol is taken with citalopram, where seizures and serotonin syndrome can occur. The drugs can cause the patients seizure threshold to be lowered, 9 with the serotonin syndrome being responsible for the other effects, like hyperthermia.10
Citalopram, the selective serotonin reuptake inhibitor, is generally prescribed to help depression and anxiety disorders. The usual prescribed dose for depression is 20-40 mg, with a maximum dose of 60 mg each day. There are many side effects associated with citalopram including gastro-intestinal disturbances like nausea, vomiting, dyspepsia, and abdominal pain, anorexia with weight loss, hypersensitivity and abnormal dreams.11 There has also been suicidal behaviour linked with citalopram and other SSRIs in children and adolescents under 18 years old.12
Tramadol is widely used opioid analgesic related to venlafaxine, which, in addition to its opioid effects, also acts as a serotonin-norepinephrine reuptake inhibitor. It is a central acting analgesic, mainly used for treating moderate to moderately severe pain, however due to the action on the noradrenergic and serotonergic systems it has been seen to be effective for alleviating symptoms of depression, anxiety, and certain phobias.13 The dose for adults is 50-100 mg not more than every 4 hours, with a usual maximum of 400 mg each day. There are fewer typical opioid side effects with tramadol, including lesser risks of respiratory depression and constipation, but the most common side effects include fatigue, nausea and vomiting, and dry mouth.14
With higher doses of tramadol and citalopram there is an increased likelihood of serotonin syndrome occurring in the patient. This may occur with concomitant use of medications that inhibit the metabolism of tramadol or that increase the serotonin level in the central nervous system. This drug interaction was reported in different cases where an SSRI was given with tramadol. Citalopram 10 mg/day, fluoxetine 20-80 mg/day, paroxetine 10-20 mg/day and sertraline 100 mg/day was given with tramadol at a dose of 100-800 mg/day, where the combination resulted in the patients developing serotonin syndrome.15-21
If a patient is likely to have serotonin syndrome the serotonergic agents need to be discontinued immediately and hospital care should be given for a minimum of 24 hours. The condition will usually resolve in between 24 and 96 hours.22 To treat hyperthermia caused by serotonin syndrome a benzodiazepine such as diazepam or lorazepam should be given to decrease any agitation or seizure-movements. Cyproheptadine should also be given, which is a serotonin receptor antagonist to block any further serotonin production. Keeping the body cool is essential. This can be done using ice packs and intravenous fluids, which keep the patients internal temperature as low as possible. In severe cases the patient may need to be paralysed and placed on artificial ventilation to prevent any muscle damage.23 The pharmacist is a key link in the prevention and management of serotonin syndrome related to SSRIs and other medications.
A rare, but potentially life-threatening complication of anaesthesia is malignant hyperthermia.24 Malignant hyperthermia is an autosomal dominant inherited disease and usually develops during or after a general anaesthetic. This however does not occur with every exposure to the triggering agents, with patients that are susceptible able to undergo many routine anaesthetic uses before developing malignant hyperthermia if they have the inherited disease.25 It can be found in both sexes, directly affecting the next generation in line. There is a 50% chance of the first relatives, for example parents, brothers, sisters and children inheriting the disease. Abnormal proteins are produced inside susceptible individuals muscle cells. These proteins activate the release of excess calcium when the triggering anaesthetic is inhaled. This increase of calcium initiates sustained muscle contractions whilst significantly increasing the amount of energy the body uses. It is this that causes a corresponding increase in heat production. The overactive muscles cells ultimately run out of energy and die. Once the cells have died elevated levels of potassium and protein are released into the bloodstream, causing a cascade of very dangerous proceedings. This mainly includes muscle damage, cardiac arrest, brain damage, internal bleeding, and organ failure that may result in death. This can occur even when the proper treatment has been administered. Around 40 years ago the mortality rate was around 8-%, however it is now around 10%. 26
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Volatile anaesthetics most commonly trigger malignant hyperthermia. They are liquid at room temperature, and can easily be evaporated for inhalation administration. One example is halothane, a very potent anaesthetic that has a slow onset and offset, however due to the risk of hepatitis with repeated use it is now rarely administered. Another example is sevoflurane, an expensive volatile anaesthetic that has a rapid onset and offset. Succinylcholine, a neurotransmitter-blocking agent with a rapid onset with a short duration of action can also trigger malignant hyperthermia.27
Malignant hyperthermia symptoms generally progress within an hour after exposure to the trigger substances, but in rare cases may occur quite a few hours after. One of the main symptoms is muscle rigidity, which can destroy the muscle tissue eventually leading to renal failure from damaged kidneys. With destroyed muscle tissue, rhabdomyolysis can occur, which is the rapid breakdown of skeletal muscle. This is followed by hypermetabolism that is characterised through increased oxygen consumption and carbon dioxide production, tachycardia, acidosis and a rapid rise in body temperature that can be up to 2oC per hour.28
Dantrolene sodium is a powerful muscle relaxant and the only known drug that can treat malignant hyperthermia. It has also been seen to be effective in the management of neuroleptic malignant syndrome and chronic severe muscle spasticity. This drug should be given intravenously, and acts on the skeletal muscle cells preventing the release of calcium, therefore preventing the contractile process. Dantrolene is not easy to administer, as it must be administered through multiple vials in a quick-fire sequence to be effective. There is a new version of dantrolene that should enhance the reconstitution time to 20 seconds or less. The quicker this is done, the quicker it can be administered. Some adverse effects associated with dantrolene include pulmonary oedema, thrombophlebitis and tissue necrosis due to extravasation. It is also expensive with only a 3-year shelf life.29
The Association of Anaesthetists of Great Britain and Ireland have guidelines for the management of a malignant hyperthermia crisis, which states the diagnosis, treatment and management of the condition. Successful treatment of malignant hyperthermia is dependent on early diagnosis and aggressive treatment. To stop malignant hyperthermia rapidly all trigger drugs need to be removed, whilst using a high oxygen gas flow. If the symptoms occur during the surgery, anaethesia should be continued until the surgery is completed with non-triggering drugs, for example propofol. Dantrolene should be given intravenously initially at 2-3 mg per kg, and then at a dose of 1 mg per kg when required every 4-8 hours for 24-48 hours.
The next step is to cool the patient and try to decrease the internal body temperature until it reaches 38.5oC. Any less than this and the patient could become hypothermic. This can be done through placing ice packs on the groin, neck and underarms, giving cold intravenous infusions, as well as cold peritoneal and nasogastic rinsing. Vasoconstriction should be completely avoided. The patient's vitals should be constantly monitored, including their blood oxygen saturation level, core and peripheral temperature, ECG's, end-tidal carbon dioxide levels, blood pressure, central venous pressure and the arterial blood gases.
The after effects of malignant hyperthermia should then be treated. Cardiac arrhythmias should be treated with procainamide, magnesium and amiodarone. Calcium channel blockers, e.g. diltiazem, need to be avoided due to the interaction with dantrolene, as there is an increased risk of arrhythmias, hypotension, myocardial depression and hyperkalaemia. If hyperkalaemia occurs it should be treated with hyperventilation using glucose and insulin, sodium bicarbonate and in extreme cases, intravenous calcium chloride. Hyperventilation should also be given to treat hypoxaemia with 100% oxygen, with sodium bicarbonate given for acidosis. Rhabdomyolysis is to be treated with around 6-12 litres over 24 hours of intravenous fluid to treat shock and preserve kidney function. Ensuring a urine output of more that 3 ml per kg per hour, with a pH of more that 7.0 is important and can be done with large amounts of intravenous fluids including saline, the osmotic diuretic mannitol, or the loop diuretic furosemide as needed.30
Once the malignant hyperthermia crisis is under control, the patient should be observed in the Intensive Care Unit in the hospital for monitoring and management for at least 36 hours. Dantrolene should still be given as necessary, however recrudescence may occur in around 25% of patients. This is a reappearance of the malignant hyperthermia after it has calmed from the first attack. A different diagnosis may need to be considered, as there are many other unusual diseases that can look like malignant hyperthermia during anaethesia. This includes sepsis, myopathy, iatrogenic overheating, and phaeochromocytoma, which is a rare tumour that secretes catecholamines.31
The scenario sees a 45-year-old female who after just receiving surgery has developed hyperthermia, whilst on the prescription medications of citalopram and tramadol. Citalopram is an SSRI, and tramadol is an opioid analgesic that acts as an SNRI; together they may have caused the very serious condition of serotonin syndrome, and consequently made the patient hyperthermic. If this is the case, both citalopram and tramadol need to be stopped at once whilst being treated and constantly monitored.
However the hyperthermia was diagnosed after the surgery had taken place, therefore it seems most likely that anaesthesia caused malignant hyperthermia to develop in the patient. For the surgery the patient may have been given a general anaesthetic, which in turn could have triggered malignant hyperthermia. Early signs in a patient may include heart rhythm abnormalities and jaw muscle rigidity. Rigidity in the limbs, abdominal muscles and the chest muscles need to be monitored. High body temperature is one of the later signs of malignant hyperthermia, so information is needed to see if the patient has any other signs and symptoms. As this can be fatal it needs to be quickly diagnosed so the adverse effects can be treated to prevent any more damage to the patient. The treatment for malignant hyperthermia should be started immediately in this patient to maximise her chances for recovery. If the female patient is later diagnosed with serotonin syndrome, then the treatment of malignant hyperthermia will do no harm.
Not enough information has been provided to make an accurate diagnosis of the cause of hyperthermia. Information that is needed includes whether the patient was given anaesthesia during surgery, if there is any history of malignant hyperthermia in her family, or if the medications she was on had been recently started, increased or if she had accidently overdosed.
There are many reasons that can cause hyperthermia in the body, which we have examined in detail. However in the scenario given, where the female patient develops hyperthermia after surgery whilst on the prescription medications citalopram and tramadol there is not enough information available. Hyperthermia can either occur through serotonin syndrome or malignant hyperthermia, and can be classed as a heat-related illness. Hyperthermia may prove fatal if the treatment is delayed, especially if the diagnosis is made as malignant hyperthermia. For the patient to have the best possible outcome and prognosis, a fast diagnosis and prompt appropriate treatment is necessary.