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Neuroleptic Malignant Syndrome: When Drug Therapy Can Kill

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Author:    Earl Bishop (RN, BSN, BA)

Purpose/Goals

The purpose of this course is to provide a basic understanding of a somewhat rare, but devastating drug reaction that can be lethal if not recognized early and treated correctly.

Objectives

Upon successful completion of this course, the learner will be able to:

  1. Identify three risk factors for developing NMS
  2. Identify three groups of drugs that can cause NMS and name at least one drug from each group
  3. Identify the signs and symptoms of Neuroleptic Malignant Syndrome(NMS)
  4. Outline the treatment of NMS
  5. Discuss the recommended cooling measures for hyperthermia

Case Study

John felt really encouraged as he left the mental health clinic after his regular appointment. The doctor had started him on a new medication that was sure to help him feel better. Let us see now what did the doc say that drug was called? John looked at the prescription in his hand but of course it was written in Klingon and he could not read what it said. He would just have to ask the pharmacist what it was.

As he left the pharmacy, with his Haldol bottle in his hand, John was anxious to get home and get the new medicine started. He took his medication exactly as it was prescribed. He was always careful to do that.

John came home from work early the next day as he just did not feel good. He had worked really hard in the hot warehouse unloading several extra trucks and was so busy he had not kept up his fluid intake. As he reached the house he noticed that his muscles seemed especially stiff and he felt really hot. He was sweating profusely and just could not seem to concentrate. It was very difficult to swallow and he could not keep his hands from shaking. John’s wife kissed his forehead and said John you are burning up. They took his temperature and it was 104.6 F. By this time John was confused and disoriented. His wife called an ambulance and John was taken to the local emergency room where he was promptly admitted to ICU with a diagnosis of Neuroleptic Malignant Syndrome (NMS)..

Causes and Predisposing Factors

NMS is an idiosyncratic reaction to certain medications. It is thought to result from central nervous system dopamine receptor blockade, or withdrawal of exogenous dopaminergic agonists (Mechem, 2004). The blockade of dopaminergic receptors in the corpus striatum results in spasticity of skeletal muscle which generates excessive body heat, impairs hypothalamic thermoregulation, and leads to autonomic dysfunction that impairs heat dissipation. As such, hyperthermia is universal and body temperatures above 105ºF (41ºC) may be reached.

NMS is known to occur with antipsychotic/neuroleptic drugs; haloperidol being the most common cause. It has been linked to atypical antipsychotic medications, dopamine antagonists, and selective serotonin reuptake inhibitors. Zoloft, Paxil, and Prozac may be implicated as well but sufficient research has not specifically linked them to NMS (Mechem, 2004). Neuroleptics are highly effective and safe medications that have achieved widespread use in medicine and psychiatry. However, they have been associated with NMS in about 0.2 percent of patients (Caroff, 2001).

Drugs Associated with NMS (NMIS.Org, 2005)

Antipsychotic/Neuroleptic Drugs

Generic Name

Brand Name

  • Haloperidol
  • Chlorpromazine
  • Pimoside
  • Loxapine Succinate
  • Mesoridazine Besylate
  • Molindone Hydrochloride
  • Perphenazine
  • Thioridazine Hydrochloride
  • Thiothixene
  • Trifluoperazine Hydrochloride
  • Haldol
  • Thorazine
  • Pimozide Orap
  • Loxitane
  • Serentil
  • Moban
  • Trilafon
  • Mellaril
  • Navane
  • Stelazine

 

Atypical Antipsychotics

Generic Name

Brand Name

  • Aripiprazole
  • Clozapine
  • Olanzapine
  • Questiapine Fumarate
  • Risperidone
  • Ziprasidone Hydrochloride
  • Ablilify
  • Clozaril
  • ZyprexaS
  • Eroquel
  • Risperdal
  • Geodon
  • Zoloft, Paxil, and Prozac may be implicated

 

Dopamine Antagonists

Generic Name

Brand Name

  • Droperidol
  • Metoclopramide, USPP
  • Prochlorperazine
  • Promethazine HCL
  • Inapsine
  • Reglan
  • Compazine
  • Phenergan
  • Venlafaxine
  • Effexor

 

The dosages and serum concentration of these medications are usually within the therapeutic range when NMS occurs, and the syndrome typically occurs within several days of starting the medication (Mechem, 2004). NMS can develop in patients with Parkinson’s disease following withdrawal of levodopa therapy. The probability of developing NMS is directly related to the antidopaminergic potency of the neuroleptic agent (Mechem, 2004).

NMS has been reported in both sexes and all age groups. Although elevated environmental heat and humidity have been proposed as contributing factors in a few cases, NMS generally occurs independently of ambient conditions. NMS is not specific to any neuropsychiatric diagnosis. It has been reported in patients treated with neuroleptics for diverse psychiatric illnesses, as well as in medical patients who receive neuroleptics as antiemetics or sedatives. However, several authors proposed a greater risk for NMS in patients with certain psychiatric disorders, pre-existing catatonia, and other disorders affecting deep brain structures. Evidence also suggests that exhaustion, agitation, and dehydration may predispose patients (Caroff, 2001).

Even though NMS occurs within the normal dosage ranges of the causative drugs, several studies have suggested that patients who develop NMS are more likely to have received higher doses, more rapid titration, and more parenteral injections of neuroleptics compared to controls. “Although evidence suggests that these clinical and pharmacologic variables may correlate with the risk of NMS, the disorder is too infrequent and idiosyncratic for these findings to be used as reliable predictive risk factors” (Caroff, 2001, p 801). Some patients may have genetic abnormalities in central dopamine systems that increase their susceptibility to NMS. Low serum iron concentrations also seem to increase the risk of developing NMS (Caroff, 2003).

Diagnosis

Returning to John, our hypothetical patient, we can get a good picture of the classical presenting signs and symptoms of NMS. There are many different disease processes that must be eliminated before a final diagnosis of NMS can be reached.

First of all his very high temperature necessitates consideration of all of the hyperthermic syndromes, listed below. Therefore a thorough history is essential in obtaining an accurate diagnosis. In John’s case the recent initiation of haldol therapy is of extreme importance, and is really the key to the diagnosis when coupled with the extremely high fever. The following are a list of differential diagnoses of hyperthermia (UpToDate.com, 2005).

  • Environmental exposuree
  • Sepsis
  • Hypothalamic stroke
  • Encephalitis
  • Brain abscess
  • Meningitis
  • Tetanus
  • Typhoid fever
  • Thyroid storm
  • Pheochromocytoma
  • Catatoniaa
  • Malignant hyperthermia
  • Status epilepticus
  • Cerebral hemorrhage
  • NMS
  • Alcohol or sedative/hypnotic withdrawal
  • Salicylate or lithium toxicity
  • Sympathomimetic toxicity
  • Anticholinergic toxicity
  • Dystonic reactions
  • Serotin syndrome

Other typical early signs of the syndrome include autonomic changes like diaphoresis, liable blood pressure, tachycardia, excessive salivation, incontinence, and neurological changes such as muscle rigidity (often described as “lead pipe”) tremors, and mental status changes ranging from confusion to catatonia.

Although there is no specific lab test that is diagnostic for NMS the following studies should be completed and may be helpful: CBC, Bun/Creatinine, electrolytes, liver enzymes, serum iron, Pt/Ptt, CPK, Ca, P, and urine myoglobin. The risk of both rhabdomyolysis and disseminated intravascular coagulation (DIC) developing is very real; so, liver and renal function must be assessed and followed closely (Mecham, 2005).To make a definitive NMS diagnostic, the following criteria must be met (UpToDate.com, 2005):

  1. Administration of neuroleptics (May be from 24 hrs to 30 days after drug given)
  2. Hyperthermia- core temperatures may exceed 40º
  3. Muscle rigidity-lead pipe or cogwheel in nature
  4. At least five of the following symptoms:
    • mental status changes
    • tachycardia
    • incontinence
    • labile blood pressure
    • metabolic acidosis
    • tachypnea/hypoxia
    • rhabdomyolysis
    • diaphoresis
    • excessive salivation
    • leukocytosis
  5. Other causes of hyperthermia have been eliminated

Treatment

Even before a diagnosis is completely formulated treatment must begin. The extremely high temperatures that patients present with constitute a medical emergency. These temperatures must be dealt with swiftly and decisively in order to avert permanent damage to vital organs

The basic management of NMS is quite straight forward. First of all if an offending drug has been identified it must be discontinued immediately. The early diagnosis of NMS is important so that the temperature extremes of hyperthermia may be avoided. Intensive medical and nursing care must be provided to deal with the possible complications.

(UpToDate.com, 2005)

The specific treatment of NMS must be individualized and based empirically on the character, duration, and severity of clinical signs and symptoms of each patient (Caroff, www.nmsis.org). The treatment of NMS can be divided into four areas:

  1. supportive care
  2. rapid cooling
  3. specific drug therapy/ECT
  4. identification and treatment of complications.

As always the ABC’s of critical care must be addressed and the patient stabilized as soon as possible. If severe hypertension is present, the use of nitroprusside (Nipride®) can be extremely helpful as its potent vasodilatation aids in bringing blood to the skin and assists in cooling. Conversely, if hypotension is a problem, fluid resuscitation is preferred over potent vasoconstrictors like dopamine which could hamper cooling by shunting blood away from the skin. If temp is high cooled IV fluids may be used to help treat hyperthermia while addressing hypotension at the same time.

Rapid cooling of the patient is essential to avoid permanent damage. “Temperature elevation is accompanied by an increase in oxygen consumption and metabolic rate, resulting in hyperpnea and tachycardia. Above 42ºC (108ºF), oxidative phosphorylation becomes uncoupled, and a variety of enzymes cease to function. Hepatocytes, vascular endothelium, and neural tissue are most sensitive to these effects, but all organs may be involved. As a result, these patients are at risk of multiorgan system failure” (Mecham, 2005, p. 1).

Cooling measures

Augmentation of evaporative cooling is the treatment modality of choice because it is effective, noninvasive, and easily performed. Spray the naked patient with a mist of lukewarm water while air is circulated by large fans. Shivering may be suppressed with intravenous benzodiazepines such as diazepam 5 mg IV or Lorazepam 1-2 mg IV.

Other effective cooling methods are used less commonly. Immersing the patient in ice water results in rapid cooling, but complicates monitoring and access. Applying ice packs to the axillae, neck, and groin is effective, but is poorly tolerated in the awake patient. Cold peritoneal lavage results in rapid cooling, but it is an invasive technique that is contraindicated in pregnant patients or those with previous abdominal surgery. Cold oxygen, cold gastric lavage, cooling blankets, and cold intravenous fluids may be helpful adjuncts (Mecham, 2005). Alcohol sponge baths should be avoided because large amounts of the drug may be absorbed through dilated cutaneous vessels and produce toxicity (Khosla, 1999).

If supportive care and cooling measures are not successful in reversing the syndrome, drug therapy may be considered. “The efficacy of pharmacologic treatment of NMS has not been demonstrated in controlled trials, but the results of several case reports support their use. The major drugs that have been given are the dopaminergic agonist bromocriptine 2.5 to 7.5 mg PO every eight hours and dantrolene 0.8 to 3 mg/kg IV every six hours, up to a maximum of 10 mg/kg per day” (Mechem, 2005 p. 1). Dantrolene is beneficial primarily in cases of NMS involving significant rigidity and hyperthermia. It rapidly reduces extreme temperature elevations. These medications are effective during the first few days of treatment of NMS and are unlikely to show a delayed response (Caroff, www.mnsis.org).

ECT remains effective even late in the course of NMS, even after other interventions have failed. ECT is preferred if idiopathic lethal catatonia cannot be excluded, if NMS symptoms are refractory to other measures, in patients with prominent catatonic features, and in patients who develop a residual catatonic state or remain psychotic after NMS has resolved (Caroff, 2001).

It may take up to 7-10 days for NMS to completely resolve. Even longer for some of the many complications that can arise. The labs must be diligently monitored. The patient must be watched for developing complications such as DIC, rhabdomyolysis, or organ failure. Each complication must be treated appropriately in order to insure a positive patient outcome.

Prevention

Considerable progress has been achieved in recognizing, managing, and understanding this drug reaction since it was first described over 40 years ago. Development of innovative neuroleptics, conservative prescribing guidelines, reduction of proposed risk factors, and education of staff can result in a reduced incidence of this disorder (Caroff, 2001).

Conclusion

Awareness of the diagnosis, cessation of medications, early medical intervention, and consideration of specific remedies can reduce morbidity and mortality when NMS occurs. It is therefore essential for all physicians and nurses to become familiar with the diagnosis and management of this unusual but fascinating drug reaction (Caroff, 2001).

References

Mechem, C.Crawford MD, FACEP, Severe Hyperthermia: Heat stroke; neuroleptic malignant syndrome; and malignant hyperthermia www.UptoDateonline.com (UptoDate®2004)

Caroff, Stanley N. M.D. Neuroleptic Malignant Syndrome, Adverse Drug Reaction Bulletin, August 2001 No. 209, Pgs799-802 Lippincott Williams &Wilkins (found at www.mnsis.org)

Caroff, Stanley N. MD, FACEP, Neuroleptic malignant syndrome: Still a risk, but which patients may be in danger? Current Psychiatry Online Vol.2, No12/December 2003 (found at www.currentpsychiatry.com or thru link @ www.mnsis.org

Khosla, R, Guntapalli, KK. Heat-related illness. Crit Care Clin 1999; 15:251

Hsing-Chen Tsai, MD, Fever, Consciousness Disturbance, and Muscle Rigidity in a 68-Year-Old Man With Depressive Disorder

Chest 2003; 124:1598-1601