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Diagnosis and treatment of drug-induced hyperthermia Megan E. Musselman and Suprat Saely yperthermia is generally de- fined as the elevation of the Purpose. The etiology, pathophysiology, identification of the provoking agent core body temperature to above clinical presentation, and management based on the ’s history, H of drug-induced hyperthermia (DIH) syn- the clinical presentation, and the timing of 37 °C. In addition to exposure to ex- dromes are reviewed. symptom onset is essential to determine tremely hot or humid environments, Summary. DIH syndromes are a rare and the appropriate treatment and mitigate the causes of hyperthermia include often overlooked cause of body tempera- potentially life-threatening sequelae. For the use of some , taken ture elevation and can be fatal if not rec- all DIH syndromes, appropriate manage- alone or in combination. A long ognized promptly and managed appropri- ment includes the immediate discontinu- duration of drug-induced hyper- ately. There are five major DIH syndromes: ation of the suspected offending agent(s) thermia (DIH) correlates with per- (1) neuroleptic malignant syndrome, (2) and supportive care (external cooling, manent neurologic sequelae such as serotonin syndrome, (3) anticholinergic volume resuscitation as needed); in some poisoning, (4) sympathomimetic poison- cases, pharmacologic (e.g., a ben- cerebellar syndrome with long-term ing, and (5) malignant hyperthermia. The zodiazepine, bromocriptine, dantrolene) neurologic deficits, , dysarthric differential diagnosis of DIH syndromes may be appropriate, with the selection of speech, ocular dysmetria, and gener- can be challenging because symptoms a specific agent primarily determined by alized weakness.1 Therefore, hyper- are generally nonspecific, ranging from the medication history and suspected DIH thermia can be extremely harmful pressure changes and excessive syndrome. and potentially fatal if not recognized sweating to altered mental status, muscle Conclusion. DIH is a hypermetabolic early and treated properly. This ar- rigidity, convulsions, and metabolic state caused by medications and other acidosis. Evidence from the professional agents that alter neurotransmitter levels. ticle provides an overview of basic literature (per a MEDLINE search for ar- The treatment of DIH syndromes includes concepts of thermoregulation and ticles published through November 2011) supportive care and pharmacotherapy as five well-described DIH syndromes: indicates that few currently available appropriate. neuroleptic malignant syndrome treatment options can reduce the dura- Am J Health-Syst Pharm. 2013; 70:34- (NMS), serotonin syndrome, anti- tion of hyperthermia; therefore, prompt 42 cholinergic syndrome, sympatho- mimetic syndrome, and malignant hyperthermia syndrome. range, or “set point,” defined as a normal core body temperature of 37 Physiology of thermal regulation temperature range within which no °C (Figure 1).2,4 Temperature regulation. Core thermal regulatory responses oc- The exact mechanism that deter- body temperature is tightly regu- cur.2,3 This set point is not precisely mines the absolute threshold tem- lated by a negative feedback system defined but generally fluctuates by perature is not known, but it appears to maintain a precise interthreshold approximately 0.5–1.0 °C around the to be mediated by norepinephrine,

Megan E. Musselman, Pharm.D., BCPS, is Clinical — macy Services, Detroit Receiving , 4201 St. Antoine Boule- Emergency Medicine/Critical Care, University of Kansas Hospital, vard, Detroit, MI 48201 ([email protected]). Kansas City, MO; at the time of writing she was Emergency Medicine Peter Whittaker, Ph.D., is acknowledged for advice, suggestions, Specialty Pharmacy Resident, Detroit Receiving Hospital, Detroit, and critical review of the manuscript. MI. Suprat Saely, Pharm.D., BCPS, is Emergency Medicine Clini- The authors have declared no potential conflicts of interest. cal Pharmacist Specialist and Program Director, Postgraduate Year 2 Emergency Medicine Pharmacy Residency Program, Detroit Receiv- Copyright © 2013, American Society of Health-System Pharma- ing Hospital. cists, Inc. All rights reserved. 1079-2082/13/0101-0034$06.00. Address correspondence to Dr. Saely at the Department of Phar- DOI 10.2146/ajhp110543

34 Am J Health-Syst Pharm—Vol 70 Jan 1, 2013 clinical Reviews Drug-induced hyperthermia dopamine, serotonin, acetylcholine, and initiates the effector responses.3 Hyperthermia versus . Both prostaglandin, and neuropeptides.2 Efferent responses include active hyperthermia and fever result in The anterior hypothalamus inte- arteriovenous shunt vasoconstric- increased core body temperature; grates and processes afferent ther- tion, piloerection, and shivering in however, their underlying mecha- mal information. The preoptic area response to the cold threshold; ac- nisms and treatment are different. of the hypothalamus contains both tive vasodilation and sweating occur Fever, defined as a temperature of heat- and cold-sensitive neurons in response to the warm threshold.3 ≥38.3 °C, is a process in which the that exert increased activities by Despite the body’s complex ther- hypothalamus increases the core stimulating efferent mechanisms in moregulatory responses, behavioral body temperature set point, or core response to temperature changes. responses such as taking off or put- temperature threshold, in response The posterior hypothalamus inte- ting on additional layers of clothing to or noninfectious causes grates signals from peripheral and are usually the most effective way to such as adrenal insufficiency.5 An- preoptic areas of the hypothalamus control body temperature. tipyretics, the standard treatment

Figure 1. Thermoregulation consists of three phases: afferent thermal sensing, central regulation, and efferent responses.2 Thermal- sensitive receptors are located in the and viscera throughout the body, and their function is to sense changes in temperature. When the core body temperature falls below or rises above the set-point range, thermoregulatory defense responses are triggered,2 and the thermoreceptors send and relay afferent thermal information via the spinal cord to the hypothalamus (the central thermoregulatory control center).4

Exposure to warm Exposure to cold

Warm-sensitive Thermoreceptors Cold-sensitive receptors (visceral and skin) receptors

Afferent sensing

Anterior hypothalamus (preoptic nuclei)

Increased warm-sensitive neuron activities Increased cold-sensitive neuron activities n Increase in heat loss effector neurons n Increase in heat gain effector neurons n Decrease in heat gain effector neurons n Decrease in heat loss effector neurons

Posterior hypothalamus Central regulation

Heat-defense responses Cold-defense responses n Sweating n Vasoconstriction n Vasodilation n Shivering n Behavioral (e.g., take off a layer of clothing) n Nonshivering thermogenesis (newborns) n Behavioral (e.g., put on a layer of clothing)

Efferent responses

Am J Health-Syst Pharm—Vol 70 Jan 1, 2013 35 clinical Reviews Drug-induced hyperthermia for fever, reduce the elevated set books. Most of the published lit- heat production secondary to extra- point within the hypothalamus. In erature is in the form of case reports, pyramidal rigidity.23 contrast, in hyperthermia, the body case series, and review articles, as Symptoms and diagnosis. NMS develops a hypermetabolic state; the hyperthermia-associated syndromes symptoms vary widely, but major heat-loss mechanisms governed by are relatively rare. Articles included characteristic features must be pres- the hypothalamus fail, which results in this review highlighted informa- ent in order to make the diagnosis. in excessive heat production that tion pertaining to drug-induced According to the Diagnostic and Sta- exceeds the body’s dissipative abil- hyperthermia, as well as current tistical Manual of Mental Disorders, ity.6 The term hyperthermia is not areas of controversy. Four aspects 4th Edition, Text Revision criteria, consistently defined but is gener- of each DIH syndrome are reviewed the core features of severe muscle ally used in reference to temperature here: (1) causes and, in some cases, rigidity and elevated temperature elevation above 37 °C.7 Although incidence, (2) pathophysiology, (3) associated with the use of neuro- effective against fever, antipyretics symptoms and diagnosis, and (4) leptic medication should be present are ineffective at reducing elevated treatment options. for the diagnosis of NMS, as well as core body temperature because the two or more of the following symp- hypothalamus-governed tempera- NMS toms: diaphoresis, dysphagia, tremor, ture set point is not involved in the Causes and incidence. NMS is incontinence, changes in level of mechanism of hyperthermia.5 a rare but serious of consciousness, mutism, tachycardia, DIH syndromes. Hyperthermia the use of medications that act on elevated or labile blood pressure, leu- induced by medication use is uncom- dopamine receptors. The medica- kocytosis, and laboratory evidence of mon and therefore often overlooked tions most commonly implicated in muscle injury (an elevated creatine as a cause of elevated temperature. NMS are . Other kinase level).24 The clinical symptoms associated drugs that act as dopamine antago- More sensitive criteria proposed with all of the DIH syndromes are nists also have been associated with by Levenson21 require the presence similar; therefore, it is imperative to NMS but to a lesser degree than the of three major manifestations, or obtain a precise medication history ; these other drugs two major and four minor mani- to aid in differential diagnosis when include prochlorperazine,8-10 meto- festations, to establish the diagnosis a DIH syndrome is suspected. Other clopramide,11-13 droperidol,14,15 and of NMS. The major manifestations causes of hyperthermia such as thy- .16,17 are hyperthermia, rigidity, and an rotoxicosis, infection, and substance The of developing NMS ap- elevated creatine kinase level; the mi- use (including use) should pears to correlate with the , po- nor manifestations are tachycardia, be ruled out first. The general ap- tency, and rate and route of admin- abnormal blood pressure, tachypnea, proach to the treatment of the five istration of dopamine antagonists.18 altered consciousness, diaphoresis, DIH syndromes discussed below is Widely varying estimates of the in- and leukocytosis.21 similar: As soon as a DIH syndrome cidence of NMS have been reported, NMS may be accompanied by is suspected, the suspected precipi- with estimates in retrospective stud- abnormal laboratory findings such tating agent should be discontinued, ies ranging from 0.2% to 12.2%.19 as impaired function, electro- and supportive treatment should be In one prospective study involving lyte disturbances, renal impairment, initiated. 2695 presumed neuroleptic-treated metabolic acidosis, , , the estimated frequency of and low serum iron concentrations.25 Literature review NMS was 0.1–2.0%.20 NMS is associ- Of course, in addition to the signs Articles on DIH syndromes were ated with a high fatality rate, vari- and symptoms described above, a identified through a MEDLINE ously estimated at 15.0–18.8%.21,22 history of exposure to neuroleptic search (through November 2011) Pathophysiology. The underlying medication is essential to establish a using the following key words: anti- pathophysiology of NMS is poorly diagnosis of NMS. cholinergic syndrome, bromocriptine, understood but believed to involve NMS is considered a diagnosis of cyproheptadine, dantrolene, drug- dopamine depletion or blockade exclusion; therefore, it is important induced hyperthermia, malignant within the hypothalamus. This to consider a wide range of other hyperthermia, neuroleptic malignant dopamine-mediated effect results in disorders that can be mistaken for syndrome, serotonin syndrome, and the derangement of central thermo- NMS, including serotonin syndrome sympathomimetic syndrome. Addi- regulation.21 Hyperthermia is caused and malignant hyperthermia.21 Due tional articles were identified from by antidopaminergic drugs blocking to similarity in the clinical presen- the reference lists of search-identified the heat-loss pathways in the anterior tation of NMS and malignant hy- publications and text- hypothalamus along with increased perthermia, establishing the timing

36 Am J Health-Syst Pharm—Vol 70 Jan 1, 2013 clinical Reviews Drug-induced hyperthermia of the onset of symptoms is vital in used to treat NMS, but the support- tive serotonin-reuptake inhibitors differential diagnosis. The onset of ing data are limited. (SSRIs), serotonin–norepinephrine- symptoms in NMS occurs typically In severe cases of NMS, dan- reuptake inhibitors, monoamine more than 24 hours (and may take trolene, a ryanodine receptor type 1 oxidase inhibitors, tricyclic antide- up to 30 days) after the initiation or (RYR-1) antagonist, can be used to pressants (TCAs), , amphe- a change in the dosage of neuroleptic relax skeletal muscle without caus- tamines, dextromethorphan, linezo- medications26; in contrast, symptom ing total paralysis. Relaxation of lid, sumatriptan, lithium, fentanyl, onset in malignant hyperthermia skeletal muscle by dantrolene occurs meperidine, and 3,4-methylene- occurs within minutes to hours. As through a dose-dependent inhibi- dioxymethamphetamine (MDMA). NMS progresses, complications such tion of sarcoplasmic calcium release, The use of dietary supplements with as pneumonia, acute renal failure sec- primarily at skeletal-muscle RYR-1 serotonin activities, such as St. John’s ondary to rhabdomyolysis, , receptors, thereby directly inhibiting wort34 and tryptophan,35 has also sepsis, pulmonary embolism, pulmo- excitation–contraction coupling.30 been reported to be associated with nary edema, cardiac arrest, and even Dantrolene can be used as a mono- serotonin syndrome. The prevalence may occur.27 therapy or in conjunction with do- of serotonin syndrome is unknown, Treatment. As soon as NMS pamine . Dantrolene sodium but it is reported to occur in as many is suspected, dopamine-blocking is typically given initially as a bolus as 14% of cases of SSRI overdose.36 agents should be discontinued. Sup- (1.0–2.5 mg/kg) and continued until Pathophysiology. In serotonin portive measures such as volume signs of hypermetabolism subside or syndrome, serotonergic agents can resuscitation and external cooling until a cumulative dose of 10 mg/kg is enhance synaptic serotonin (5-HT) are the mainstays of treatment and administered.31,32 Dantrolene sodium concentrations, thereby inhibit- should be initiated immediately. is generally continued at a dosage of ing the or reuptake such as lorazepam 1 mg/kg every 4–6 hours for at least of 5-HT, potentiating 5-HT activ- and midazolam, administered at 24 hours to prevent the recurrence of ity, or increasing substrate supply.33 doses starting at 1–2 mg intra- symptoms.31 Excessive serotonin levels increase muscularly or intravenously every Common adverse effects of i.v. the stimulation of both central and four to six hours, are considered or intramuscular dantrolene ad- peripheral serotonergic receptors. appropriate supportive treatments ministration are muscle weakness Of importance, the stimulation of and can be used to attenuate sym- and phlebitis caused by the highly central nervous system serotonergic pathetic activity such as agitation or alkaline solution. The most seri- neurons (found in the midline raphe restlessness.25 ous adverse effect associated with nuclei) responsible for assisting in Bromocriptine and dantrolene dantrolene therapy is liver ; the thermoregulation process con- have also been recommended; how- therefore, its use should be avoided tributes to the ever, there are limited data to validate in patients with liver . When of serotonin syndrome.37 Specifical- their use in patients with NMS. The patients are able to take oral medi- ly, the agonism of the 5-HT1A- and use of bromocriptine, a centrally act- cations, dantrolene sodium may be 5-HT2A-receptor subtypes is most ing dopamine , can increase given orally at a dosage of 4–8 mg/ frequently implicated as the cause of dopamine activity in the hypothala- kg/day (divided into four doses) and serotonin syndrome.37 Other neu- mus, thereby reducing the rigidity continued for 1–3 days to prevent the rotransmitters, such as norepineph- and hyperthermia caused by dopa- recurrence of symptoms.31 Symp- rine, N-methyl-d-aspartate receptor mine blockade. When used in the toms typically resolve within 6–10 antagonists, and g-aminobutyric management of NMS, bromocrip- days after treatment is initiated. acid, have also been associated with tine is generally started at a dosage of serotonin syndrome.37-39 2.5 mg orally or via nasogastric tube Serotonin syndrome Symptoms and diagnosis. Sero- every eight hours, with the dosage Causes and incidence. Sero- tonin syndrome has been described increased up to a total daily dose of tonin syndrome is a potentially as a spectrum of toxicity character- 45 mg if necessary.25 However, bro- life-threatening iatrogenic disorder. ized by a classic triad of clinical mocriptine can worsen psychosis and It results from complications of features: autonomic hyperactiv- hypotension and may also precipitate therapeutic or inadvertent use of ity ( or hypotension, . Thus, it should be used (or drug interactions involving) tachycardia, hyperthermia), neu- carefully in patients at risk of aspira- one or more medications with romuscular abnormalities (clonus, tion.25 Other centrally acting dopa- serotonergic activities.33 Medica- muscular rigidity, and hyperreflexia, mine agonists such as levodopa28 and tions that have been implicated in usually more prominent in the lower amantadine29 have been successfully serotonin syndrome include selec- versus the upper extremities), and

Am J Health-Syst Pharm—Vol 70 Jan 1, 2013 37 clinical Reviews Drug-induced hyperthermia altered mental status (ranging from and NMS. In order to distinguish be- rotonin receptors.45 Cyproheptadine agitation and confusion to delirium, tween the two syndromes, the timing may cause excessive sedation, espe- seizures, and coma).36 In its most of symptom onset may be useful. In cially in high doses. Chlorpro­mazine severe form, serotonin syndrome serotonin syndrome, symptom onset hydrochloride, a phenothiazine with rapidly progresses to coma, sei- is rapid, usually within minutes to antagonistic activities at 5-HT2A re- zures, multiple- failure with hours after a change in neuroleptic ceptors, has been used successfully disseminated intravascular coagula- medication or self-poisoning.37 In as an alternative to cyproheptadine; tion (DIC), and cardiac arrest.40 contrast, NMS may take 24 hours to it is given intramuscularly at doses The clinical findings associated days to develop and up to two weeks of 50–100 mg, repeated as necessary with the diagnosis of serotonin tox- to resolve once the offending agent is every 6 hours.46 icity in a study of 2222 consecutive discontinued. It is important to rec- such as propranolol, cases of serotonergic drug overdose ognize the distinction between NMS bromocriptine, and dantrolene are were the following: autonomic de- and serotonin syndrome because not recommended in serotonin syn- rangements (including hypertension, the pharmacologic treatments differ. drome. Hypotension and shock may tachycardia, body temperature of For instance, bromocriptine is com- result from the use of propranolol, a

>38 °C, mydriasis, diaphoresis, and monly used as a treatment option for long-acting b-blocker with 5-HT1A- ), neuromuscular abnor- NMS, but its use can exacerbate the antagonist activities. The use of bro- malities (including hyperreflexia, in- symptoms of serotonin toxicity.37 mocriptine has been implicated in ducible and spontaneous clonus, my- Treatment. The mainstay of treat- the development and exacerbation of oclonus, ocular clonus, nystagmus, ment for serotonin syndrome is serotonin syndrome. Dantrolene was tremor, shivering, and peripheral discontinuation of the suspected reported to have no effect on survival hypertonicity), and mental status ab- offending serotonergic agent. Hy- in research involving animal models normalities (including agitation, perthermia in serotonin syndrome of serotonin syndrome and seems ataxia, delirium, and ).41 is secondary to muscle rigidity; thus, unlikely to be useful in patients.37 Serotonin syndrome is a clinical antipyretic therapy to reset the hypo- diagnosis based on signs and symp- thalamic temperature set point is not Anticholinergic syndrome toms and medication history. Serum useful.37 Supportive measures such as Causes and incidence. Anticho- concentrations of 5-HT have no cor- external cooling and linergic agents are a common cause relation with the clinical presentation; therapy are recommended to reduce of hyperthermia at both therapeu- however, urinary 5-HT concentra- muscle rigidity and hyperthermia. If tic and toxic doses. Medications tions can possibly be used as a bio- those symptoms are left untreated, with anticholinergic activities, such marker in serotonin syndrome.42 To they can lead to further complica- as antispasmodics, , assist with the diagnosis of serotonin tions such as rhabdomyolysis and TCAs, anti-Parkinsonian drugs, neu- syndrome, the use of formal mea- death. Many cases of serotonin syn- roleptics, atropine, and belladonna sures such as Sternbach’s43 criteria drome resolve within 24 hours of the alkaloids can cause anticholinergic and the Hunter Serotonin Toxicity discontinuation of the precipitating syndrome.44,47 Criteria41 has been proposed. Accord- drug(s) or the initiation of treat- The incidence of anticholinergic ing to Sternbach’s43 criteria, three of ment. However, symptom resolution syndrome is unknown. According to the following symptoms (combined can take longer, depending on the the 2009 annual report from the Na- with suspected serotonergic agent half-life of the offending agent.44 tional Poison Data System, that year exposure) are required for a diagno- In moderate-to-severe cases, there was a total of 99,366 exposures sis of serotonin syndrome: mental pharmacologic therapies such as to anticholinergic agents and anti- status changes, agitation, myoclonus, cyproheptadine, an histamines in the form of cough and hyperreflexia, diaphoresis, shivering, with 5-HT1A- and 5-HT2A-antagonist cold preparations; antihistamines tremor, diarrhea, incoordination, activities, can be considered. Cypro- alone or in combination with other and fever. Diagnostic criteria pro- heptadine hydrochloride has been agents were responsible for 61 fatali- posed by Dunkley and colleagues,41 administered at an initial dose of 12 ties.48 Children are more prone than which are based on the Hunter cri- mg orally, followed by 2-mg doses adults to develop anticholinergic- teria, include spontaneous, inducible every 2 hours until symptoms have related hyperthermia, because chil- ocular clonus; agitation; diaphoresis; ceased, followed by maintenance dren have a lower sweating rate, which tremor; hyperreflexia; hypertonicity; doses of 8 mg every 6 hours.37 A reduces their ability to dissipate heat.49 and body temperature of >38 °C. cumulative dose of 12–32 mg of cy- Pathophysiology. Hyperthermia There are many similarities in the proheptadine hydrochloride in a 24- is caused by the blockade of both symptoms of serotonin syndrome hour period binds 85–95% of the se- central and peripheral muscarinic

38 Am J Health-Syst Pharm—Vol 70 Jan 1, 2013 clinical Reviews Drug-induced hyperthermia acetylcholine receptors. Therefore, be used to accelerate the resolution thermia. The most common agents anticholinergic poisoning is often- of anticholinergic symptoms. The responsible for hyperthermia are times referred to as antimuscarinic tertiary structure of physostigmine , methamphetamine, poisoning syndrome.47 Central mus- allows it to cross the blood-brain MDMA (“ecstasy”), cocaine, and carinic blockade effects depend on barrier and act on both central monoamine oxidase inhibitors.44 Of the offending agent’s ability to per- and peripheral muscarinic and these, ecstasy has become a major meate the blood-brain barrier. For nicotinic receptors. The inhibition problem because of its recent in- example, atropine and scopolamine of acetylcholinesterases prevents the creased use as a recreational drug by possess a tertiary amine group that metabolism of acetylcholine, allow- young adults. allows these compounds to cross the ing acetylcholine to accumulate and Pathophysiology. The exact mech- blood-brain barrier and cause central antagonize anticholinergic effects anism by which sympathomimetic nervous system activity. Conversely, such as disorientation, agitation, agents induce hyperthermia is un- other agents, such as glycopyrro- combativeness, and anhydrosis.47,51 known but is believed to be related to late, contain a quaternary amine In adults, physostigmine salicylate is central and peripheral thermoregula- group that impairs the ability of the given at doses of 1–2 mg; in children, tion disturbances. These agents cause compound to cross the blood-brain a dose of 0.02 mg/kg (to a maximum hyperthermia by altering the levels barrier, and only peripheral adverse of 0.5 mg) is given intravenously of norepinephrine, dopamine, or effects are seen.47 Peripheral mus- over at least 5 minutes. The onset 5-HT in the central nervous system. carinic blockade by anticholinergic of action of physostigmine usually MDMA causes excessive dopamine agents interferes with cutaneous heat occurs within minutes, and its dura- and 5-HT release from the nerve loss by impairing sweat-gland func- tion of action is short (often less than endings, whereas cocaine stimulates tion. In such cases, hyperthermia one hour but not more than four the release and blocks the reuptake results from the combination of heat hours). If an adequate response is of endogenous catecholamines.50 production from increased muscle not achieved and muscarinic effects enhance the release activity and the inability to dissipate are not noted, the dose can be re- of norepinephrine, dopamine, and heat through sweating.6,44 peated after 10–15 minutes, with a 5-HT from presynaptic nerve termi- Symptoms and diagnosis. Symp- cumulative total dose of 4 mg being nals and inhibit their reuptake from toms produced by central muscarinic sufficient in most cases.51 However, the synapses.47 Peripheral effects of blockade include altered mental sta- because physostigmine can induce catecholamines include increased tus, confusion, mumbling or mute- bradycardia or seizures, it is rarely metabolism and impaired heat dis- ness, tremor, myoclonus, hallucina- used in managing anticholinergic sipation through vasoconstriction. tions, agitation, and restlessness.47 syndrome44 and is perhaps best Furthermore, sympathomimetics Peripheral symptoms of muscarinic reserved for cases in which all can cause psychomotor agitation, blockade include dry mouth and other treatment options have been motor excitability, and seizures axillae, mydriasis, blurred vision, exhausted. leading to increased muscle activity. sinus tachycardia, flushing, urinary In asthmatic patients, excessive These actions along with ambient retention, and decreased bowel cholinergic activity can precipitate temperature contribute to the rise of sounds.6,47 Severe cases of anticho- bronchospasms and bronchorrhea; core body temperature.6,47 linergic syndrome may progress to therefore, atropine should be avail- Symptoms and diagnosis. Com- coma, convulsions, and respiratory able to reverse potential excessive mon symptoms in sympathomimetic .47 The distinct peripheral cholinergic effects. syndrome are mental status changes signs and symptoms, in addition to In severe cases of anticholinergic such as agitation, confusion, panic, the absence of muscle rigidity, distin- syndrome involving uncontrolled and hallucinations.47 Ecstasy-related guish anticholinergic toxicity from hyperthermia, the use of paralytics hyperthermia can be also associ- the other DIH syndromes.50 (with sedation) may be necessary.6 ated with hyperkalemia, acidosis, Treatment. As with the other DIH As hyperthermia can persist for days, hypocalcemia or hypercalcemia, syndromes, the offending agent must the patient’s core body temperature hyponatremia, hypoglycemia, and be discontinued immediately. The should be monitored regularly until coagulopathy. Oftentimes, these ef- primary treatment options for anti- normal thermoregulation returns. fects lead to complications such as cholinergic poisoning are supportive rhabdomyolysis, , myocardial care with external cooling measures Sympathomimetic syndrome dysfunction, renal failure, DIC, and and benzodiazepine administra- Causes. Sympathomimetics are a even death.47,50 The syndrome may tion. In addition, physostigmine, an class of medications and agents that progress quickly to status epilepticus acetylcholinesterase inhibitor, can can cause life-threatening hyper- and coma, both of which can con-

Am J Health-Syst Pharm—Vol 70 Jan 1, 2013 39 clinical Reviews Drug-induced hyperthermia tribute to a poor neurologic outcome bination of potent inhaled anesthetic Hyperventilation with 100% oxy- if not treated promptly. Electrolytes, agents and succinylcholine is used, gen should begin immediately, and creatine phosphokinase, and urinaly- the incidence is higher (1 per 62,000 anesthesia should be maintained sis results should be monitored to patients).55 Malignant hyperthermia with opioids and hypnotic drugs.58 avoid these complications. is most common in the first three If muscle relaxation is required, only Treatment. Treatment of hy- decades of life, with half of all cases nondepolarizing neuromuscular perthermia caused by sympatho- occurring in patients younger than blocking agents should be used. Sup- mimetics predominately involves 15 years of age, and is more common portive therapy including external supportive care and rapid, aggressive in males than females.6,18 cooling measures (e.g., use of cooling external cooling. Benzodiazepines, in Pathophysiology. The manifesta- blankets, cool water mist, and fans) addition to offering anticonvulsant tions of malignant hyperthermia should be instituted immediately. properties, can be used to blunt in- syndrome are primarily due to a However, shivering can increase the creased sympathomimetic activity gene mutation affecting the RYR-1 metabolic rate and further contribute such as motor excitability. In cases channel, which facilitates calcium to the increased body temperature. where benzodiapines are insufficient release in skeletal muscle during Therefore, careful monitoring of core to control severe agitation, shivering, periods of excitation and contrac- body temperature for undesirable or seizures, consideration should be tion.56 The receptor also is a bind- effects of cooling (e.g., signs of end- given to the use of barbiturates, non- ing site for adenosine triphospate, organ damage, shivering) should be depolarizing paralytics, and mechani- magnesium, inhaled anesthetics, and performed, with the treatment strat- cal ventilation so that aggressive cool- dantrolene.33,54,57 Mutations of the egy modified as necessary.54 ing measures can be accomplished.47 RYR-1 gene cause an elevation of sar- The pharmacologic treatment Core body temperature should be coplasmic calcium within myocytes, of choice is dantrolene. Dantrolene closely monitored. Dantrolene has inducing muscle contraction, which binds to the RYR-1 receptor located been used in the treatment of ecstasy- causes accelerated cell metabolism, in the skeletal muscle, reducing the related hyperthermia; however, the excessive heat and lactate produc- release of calcium from the sar- safety and of its use have yet to tion, and rhabdomyolysis.54 coplasmic reticulum, which leads be established.52 In patients with co- Symptoms and diagnosis. Symp- to inhibition of the excitation– caine toxicity, drugs with b-blocking toms of malignant hyperthermia contraction coupling of skeletal activity, such as propranolol, should typically emerge within minutes to muscle and muscle relaxation.58 Dan- be avoided because they may cause hours after administration of the trolene sodium is generally adminis- coronary artery vasospasm via unop- offending agent.18 Early signs of ma- tered by rapid i.v. push initiated at a posed alpha stimulation.53 lignant hyperthermia include tachy- minimum dose of 1 mg/kg31; how- cardia, tachypnea, muscle rigidity, ever, a mean starting dose of 2.5 mg/ Malignant hyperthermia ventricular dysrhythmias, and hyper- kg was successfully used in one study syndrome carbia; muscle rigidity is usually first of patients who survived malignant Etiology. Malignant hyperther- noticed in the masseter muscles.54 hyperthermia.32 Dantrolene sodium mia is a rare autosomal dominant The late clinical findings associated should be continued until symptoms disorder of the skeletal muscle that with malignant hyperthermia are subside or the maximum cumulative results in an extreme form of hyper- muscle rigidity, hyperthermia, and dose of 10 mg/kg has been reached.31 metabolic crisis. Exposure to potent metabolic acidosis, all related to a Signs and symptoms of hyperme- inhalation agents (e.g., halothane, hypermetabolic response.54 These tabolism generally begin to resolve sevoflurane, desflurane), the depolar- findings—the “classic clinical triad” within 30 minutes after the effective izing neuromuscular blocking agent of malignant hyperthermia—can dose of dantrolene has been given. To succinylcholine, and, in rare cases, lead to end-organ damage, includ- prevent the recurrence of malignant stresses (e.g., vigorous exercise, heat) ing myoglobinuria, renal failure, hyperthermia, infusions of dan- can cause a hypermetabolic response hyperkalemia, liver failure, DIC, ar- trolene sodium (1 mg/kg every 4–6 in patients susceptible to malignant rhythmias, congestive heart failure, hours) can be continued for at least hyperthermia.54 A survey of anesthe- pulmonary edema, bowel ischemia, 24 hours, followed by administration sia departments in Denmark found neurologic injury, and death.6 of oral dantrolene sodium (4–8 mg/ that the overall incidence of fulmi- Treatment. The management of kg/day divided into four doses) daily nant malignant hyperthermia during malignant hyperthermia has been for one to three days.31,54 anesthetic procedures is low (1 per studied extensively and is well estab- In patients with known suscep- 250,000 patients), with a mortality lished. All suspected triggering agents tibility to malignant hyperthermia, rate of 10%; however, when a com- should be discontinued immediately. there are many potential alternative

40 Am J Health-Syst Pharm—Vol 70 Jan 1, 2013 clinical Reviews Drug-induced hyperthermia agents that can be used to provide patient. J Burn Care Res. 2006; 33. McAllen KJ, Schwartz DR. Adverse drug 27:237-41. reactions resulting in hyperthermia in the anesthesia or therapeutic paralysis, 14. Ratan DA, Smith AH. Neuroleptic malig- intensive care unit. Crit Care Med. 2010; such as nitrous oxide, , non- nant syndrome secondary to droperidol. 38:S244-52. depolarizing neuromuscular block- Biol . 1993; 34:421-2. 34. Dannawi M. Possible serotonin syndrome 54 15. So PC. Neuroleptic malignant syndrome after combination of buspirone and St ers, and benzodiazepines. induced by droperidol. Hong Kong Med J. John’s wort. J Psychopharmacol. 2002; 2001; 7:101-3. 16:401. Conclusion 16. Mendhekar DN, Andrade C. Neuroleptic 35. Price WA, Zimmer B, Kucas P. Serotonin malignant syndrome with promethazine. syndrome: a . 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