Overview of drug induced hyperthermic syndromes other than MH (Part A)

   In this month’s blog, I have asked Dr. Stanley Caroff, Professor of Psychiatry at the University of Pennsylvania, a long time member of MHAUS and prolific author on the subject of Neuroleptic Malignant Syndrome (NMS) to summarize several drug related reactions that resemble MH in some ways but are generally thought to be unrelated to the mechanisms that lead to MH. Dr. Caroff is also the director of our subsidiary, the Neuroleptic Malignant Information Service (NMSIS) whose goal is to provide education, information on NMS and similar syndromes to patients and providers. The web address is www.nmsis.org. 

            The several syndromes that Dr. Caroff addresses result either from a diminution of excess of substances in the brain responsible for the proper function of certain neuronal pathways in the brain. For example, the Neuroleptic Malignant Syndrome is related to a deficiency of dopamine, Serotonin Syndrome to excess serotonin, Baclofen withdrawal syndrome to a deficiency of gamma amino butyric acid .Drugs of abuse such as amphetamines and hallucinogens may act in part by altering concentrations of serotonin and other chemicals in the brain as well.

Very little is known about the manner in which such alteration in brain chemicals that mediate transfer of information among cells lead to the primary signs of these syndromes: high body temperature, muscle rigidity (with or without muscle breakdown) , cardiovascular changes, increased metabolism and derangements of acid base balance.

None of these disorders appear to be related to specific genetic changes and do not appear to be inherited. However, it is still a puzzle as to why some patients develop these potentially life threatening disorders and others not.

Also unclear in most cases, is how to treat the disorders other than symptomatically and withdrawal of the offending drug. In some cases that is easy, but in others very difficult because once the drug is in the body, it must be eliminated by metabolism and some of agents are long lasting.

Specific drug treatment is also based mostly on empiric observation. Sedative types of drugs such as the benzodiazepines (such as diazepam, midazolam) are helpful in many cases. In the NMS, bromocriptine, a drug that promotes dopamine release has been found to be of value. In other cases dantrolene has been shown to help manage the hyperthermia and other signs. Dantrolene is known to non-specifically lower body temperature in a variety of conditions, probably because the drug reduces muscle metabolism by blocking calcium related intracellular activation of muscle contraction. 

Not all of these drug induced hyperthermic syndromes are well known to clinicians.  First, because they are uncommon and second because the manifestations may be subtle.

Emergency medicine doctors and intensive care doctors and nurses are generally the ones who treat those patients with the most florid forms of the disorder, however, neurologists and psychiatrists are also well aware of the disorders. Pain doctors and rehab medicine doctors are probably most aware of the Baclofen withdrawal syndrome.

From time to time, the MHAUS hotline consultants are called on to provide advice in the management of one or more of these conditions. In addition, a separate panel of experts are available to assist in the management of NMS, serotonin syndrome and similar disorders. (Contact information is available on the NMSIS website-www.nmsis.org). 

These are complex disorders, so unfortunately the descriptions may be difficult to understand, but if there are any questions, I am sure that Dr. Caroff or I would be glad to answer them. 

Drug-Induced Hyperthermic Syndromes 

            The maintenance of normal body temperature, or thermoregulation, is essential to good health. Body temperature is one of the most tightly regulated vital functions. Thermoregulation is a complex physiologic process involving different levels of the nervous system as well as other body organs and systems.  As a result, there are many steps that can be affected by drug or toxins, which can seriously impair regulation of body temperature at rest or during exertion, and can impair the normal response to environmental heat and cold stress. While it is important for doctors and nurses to be familiar with all drugs that can interfere with body temperature regulation, there are some drugs that are known to increase heat production by increasing metabolic activity in muscles resulting in hyperthermic states that closely resemble malignant hyperthermia (MH).  All of these drug-induced syndromes have in common the characteristics of elevated temperature, skeletal muscle rigidity associated with muscle breakdown (rhabdomyolysis), abnormal heart rate and blood pressure, changes in mental status and level of consciousness, and laboratory findings indicating muscle hypermetabolism.  This clinical picture can be a medical emergency, with risk of serious medical complications and death. 

            This brief overview describes some of the syndromes of hyperthermia and hypermetabolism caused by drugs and toxins.  These disorders are important for clinicians, families and patients interested in MH for several reasons;

• when they occur, especially in surgical settings, these syndromes can be mistaken for MH;
• as far as is currently known, their occurrence does NOT imply a risk of MH during future exposure to anesthesia;
• there is also no clear evidence that  MH-susceptible patients  may be more likely to develop these drug reactions;
• we don’t know  whether these conditions just look like MH or whether people who develop them share some common genetic predisposition as there have been few genetic or other basic studies; 
• these syndromes should be recognized in their own right because different treatments have been proposed depending on the triggering drug;
• dantrolene has been proposed in some case reports as having a non-specific but positive effect on reducing temperatures in several of these conditions but this has not been proven.

 Neuroleptic Malignant Syndrome (NMS)

NMS occurs in about 0.02%(2/10,000) of patients who are treated with neuroleptic drugs that block the activity of the chemical dopamine in the brain.¹  These drugs are used to treat people with psychotic disorders. NMS may also result from treatment with other “hidden” neuroleptic drugs used in medicine, such as some drugs used to prevent nausea. The sedative drug haloperidol, which is still used frequently for sedation in the critical care setting, is associated with NMS in a significant number of patients.

Patients who develop dehydration, exhaustion, agitation, or catatonia have a higher risk of NMS after taking these drugs.  NMS is more likely to occur if patients had previous episodes or are given large doses of neuroleptic drugs by injection.  NMS may develop within hours, but usually takes days to develop. Most cases occur within 1-2 weeks after drugs are started.

The typical signs of NMS are high temperatures (hyperthermia), muscle rigidity with tremors, altered consciousness, and changes in vital signs.  Laboratory abnormalities, including muscle enzyme elevations (creatine kinase), acidosis and hypoxia, are common. There is no single laboratory test to confirm the diagnosis of NMS, but a thorough medical evaluation is essential to exclude other serious medical conditions. Several lines of evidence strongly implicate drug-induced blockade of dopamine receptors in the brain as the primary triggering mechanism in the occurrence of NMS. In-vitro muscle contracture tests in patients with NMS have been negative for MH-susceptibility, NMS patients and family members have had anesthesia without adverse effects, and there have been only a few inconsistent case reports of genetic predisposition. These findings suggest that NMS and MH are different disorders.

            Once triggering drugs are withheld, most NMS cases resolve within 1-2 weeks, although patients may have prolonged symptoms if long-acting drugs are administered.  A few patients develop a residual catatonic and parkinsonian state that can last much longer unless electroconvulsive therapy (ECT) is administered. NMS is still potentially fatal in some cases if not recognized early and treated effectively.

Treatment consists of early diagnosis, discontinuing neuroleptic drugs and supportive medical care. Valium-like compounds (benzodiazepines), dopamine agonists, dantrolene and even ECT have been advocated in clinical reports but rigorous studies comparing these agents have not been done and may not be possible because NMS is rare and often resolves after drug discontinuation.    For additional information about the diagnosis and management of NMS, the Neuroleptic Malignant Syndrome Information Service, a subsidiary of MHAUS, offers access to educational material and email access through its website (www.nmsis.org). 

Parkinsonism-Hyperthermia Syndrome (PHS)

People with Parkinson’s disease (PD) and related degenerative brain disorders are at risk for severe fluctuations of muscle tone.   Although muscle rigidity, slowed activity (bradykinesia), and other symptoms of the disease can be effectively controlled by drugs, like levodopa, that increase dopamine in the brain, patients often develop marked fluctuations in symptoms after several years of treatment. 

People with PD also may develop a Parkinsonism-Hyperthermia Syndrome (PHS) that is identical in appearance to NMS and MH if their anti-parkinsonian medications are stopped, or during “off” episodes when the drugs suddenly lose their effect.²  This typically happens when anti-parkinsonian medications, especially levodopa, are stopped due to side effects or at the time of hospital admission for an acute medical or surgical condition. For example, this syndrome has been reported after surgery in patients with PD who were told to stop taking their dopamine medications prior to surgery and were not restarted fast enough after surgery is completed.  Reports suggest PHS may occur in up to 2% to 3% of PD patients after drug cessation, and several deaths have been reported.  Symptoms develop from several hours to a few days after drug discontinuation. 

Apart from intensive medical and nursing care, restarting dopamine medications is vital. If there has been no alteration in dopamine medication prior to the episode, other causes should be sought (e.g., prescription of neuroleptic or cholinergic drugs, infection, and dehydration). Bromocriptine and dantrolene have been used in a few cases. However, prevention is most important and the message should be clear: complete and abrupt cessation of established anti-parkinsonian medication in a patient with PD should almost always be avoided.

As in NMS, the underlying cause of this syndrome is sudden reduction of dopamine activity in the brain; in NMS this happens because the patient takes neuroleptic drugs that block dopamine activity in the brain; in PHS this happens because there isn’t enough dopamine left in the brain of a person with PD after their dopamine replacement drugs are stopped.