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Psychosomatics 50:8-15, January-February 2009
doi: 10.1176/appi.psy.50.1.8
© 2009 Academy of Psychosomatic Medicine
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Review

Neuroleptic Malignant Syndrome Complicating Antipsychotic Treatment of Delirium or Agitation in Medical and Surgical Patients: Case Reports and A Review of the Literature

Dallas P. Seitz, M.D., and Sudeep S. Gill, M.Sc., M.D., FRCPC

Received October 30, 2007; revised February 3, 2008; accepted February 5, 2008. From the Dept. of Psychiatry, Queen’s University, Kingston, Ont., Canada; and the Dept. of Medicine, Queen’s University, Kingston, Ont., Canada. Send correspondence and reprint requests to Dr. Dallas Seitz, Dept. of Psychiatry, Hotel Dieu Hospital, 166 Brock St., Kingston, Ontario, Canada, K7L 5G3. e-mail: seitzd{at}hdh.kari.net
© 2009 The Academy of Psychosomatic Medicine


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 CASE REPORTS
 LITERATURE SEARCH
 Results of Literature Review
 DISCUSSION
 REFERENCES
 
BACKGROUND: Neuroleptic malignant syndrome (NMS) is a potentially fatal adverse event associated with the use of antipsychotics. OBJECTIVE: The authors provide information on the development and outcome of NMS during antipsychotic treatment of delirium or agitation in medically ill patients. METHOD: The authors present case reports and a literature review of NMS arising during antipsychotic treatment of delirium. RESULTS: A total of 25 cases of NMS occurring in patients with delirium or agitation were identified. Most cases involved men with agitated delirium who received relatively high doses of parenteral haloperidol. The signs and symptoms of NMS episodes were similar to those reported in other settings, and most patients had a complete recovery. CONCLUSION: Clinicians utilizing antipsychotics in managing delirium or agitation are advised to be vigilant for NMS. Further study is required to determine whether certain patient characteristics or medications present greater risk for this serious adverse event.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
CASE REPORTS
 LITERATURE SEARCH
 Results of Literature Review
 DISCUSSION
 REFERENCES
 
Neuroleptic malignant syndrome (NMS) is a potentially fatal adverse event associated with the use of antipsychotics. The incidence of NMS in patients with psychiatric disorders treated with antipsychotics is 0.01% to 0.02% per year.1,2 The most frequent signs and symptoms of NMS include fever, muscle rigidity, autonomic dysfunction (e.g., tachycardia, labile blood pressure, tachypnea), and mental status changes, including delirium.3 The most consistently abnormal laboratory finding is elevated serum creatine kinase (CK). The diagnosis of NMS is made clinically, and several criteria exist for diagnosing NMS.4 A variety of medical conditions may present with features similar to NMS.5,6 Because of the antidopaminergic properties of medications that cause NMS and the condition’s response to dopamine-agonists such as bromocriptine,2,7 the pathophysiology of NMS is believed to be related to central dopaminergic receptor-blockade. NMS is associated with several adverse outcomes, including persistent neuropsychiatric complications8 and death.9 Early recognition of the disorder by clinicians may help by limiting further exposure to offending medications and expediting specific treatments for NMS. The incidence of NMS10 and mortality rates during NMS episodes9 appear to have decreased recently. These reductions may be attributable to increased vigilance and earlier diagnosis of this condition.2

Typical antipsychotic agents are most frequently reported as contributing to NMS in the literature, although NMS may also occur in association with atypical antipsychotic medications, as well.11,12 NMS is most frequently reported during treatment of schizophrenia, mood disorders, mental retardation, and substance-induced conditions,13,14 although it may occur in the absence of primary psychiatric illness. Risk factors for developing NMS after antipsychotic exposure include intramuscular administration of medication, the medication being newly administered, a rapid dose increase, psychomotor agitation, and dehydration.15–18 Some of these risk factors are especially common among hospitalized patients with delirium, a population for whom antipsychotic drugs are routinely prescribed.

NMS may have increased importance in the setting of antipsychotic management of delirium. Many patients with delirium are treated with antipsychotics, both typical and atypical, in clinical practice.19–21 The most commonly utilized medication is haloperidol, which continues to be recommended in professional guidelines22,23 and review articles24,25 as the gold-standard treatment for delirium. Haloperidol is frequently utilized in high doses through parenteral routes of administration during the treatment of delirium in critically ill patients, and most individuals complete treatment without any untoward effects. However, because both high doses and parenteral administration of antipsychotics are known risk factors for NMS,26 individuals with delirium may be particularly vulnerable to this adverse effect. Agitation is a frequent symptom of delirium and likely increases an individual’s likelihood both of receiving antipsychotics and developing NMS. Diagnosing and managing NMS in the setting of preexisting delirium poses additional challenges for clinicians. Delirium is present in the majority of NMS episodes,1,27 and delirium, agitation, and other behavioral symptoms are often the earliest symptoms of NMS.28 These difficulties make it likely that NMS is underrecognized and underreported, especially in critical-care environments.29 NMS was not reported as an adverse event during trials of antipsychotics in the treatment of delirium, although most clinical trials in this area suffer from poor assessment of adverse events and small sample sizes.30 With only a few prospective trials of antipsychotics in treating delirium, clinicians may have difficulty in assessing potential worsening of delirium during antipsychotic treatment, and this worsening of delirium may indicate incipient NMS.

We briefly report on two cases of NMS at our institution and present a review of the literature for cases of NMS that occurred during treatment of delirium or agitation in medical or surgical patients. We describe patient characteristics, medications, and clinical features of NMS in this population and offer suggestions for minimizing the risk of NMS during the treatment of delirium with antipsychotics.


  CASE REPORTS

 
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
LITERATURE SEARCH
 Results of Literature Review
 DISCUSSION
 REFERENCES
 
Case 1: "Mr. A," a 52-year-old man, was admitted to the hospital for treatment of intractable migraine headaches. Treatment of his migraine began with intravenous meperidine, which was not effective. Hydromorphone 2 mg po q3 hours was subsequently substituted for meperidine. Shortly after the administration of hydromorphone, Mr. A became agitated and developed symptoms of delirium. Vital signs revealed an elevated blood pressure of 190/100. Laboratory investigations revealed an elevated serum creatine kinase (CK) level, at 264 U/liter, with a normal MB fraction and negative troponin. Hydromorphone was discontinued, and the patient was monitored carefully.

The next day, Mr. A continued to show delirium and developed persecutory delusions with visual hallucinations. Haloperidol 5 mg intramuscularly was administered once. Quetiapine 12.5 mg po od was also initiated to manage the symptoms of his delirium. His agitation improved after the injection, although his medical condition deteriorated.

The day after receiving haloperidol, the patient was found to have a low-grade fever of 99.3°F, a heart rate of 120, and blood pressure of 120/100. He was noted to have a decreased level of consciousness, and he was disoriented. A neurological exam revealed rigidity in all extremities and dysarthria, but no localizing signs. Laboratory investigations revealed a white blood-cell count (WBC) of 18.8 x 109 cells/mm3 and a serum CK level of 872 U/liter. Within hours, his temperature was 103.6°F; heart rate was between 120 and 180 bpm; respiratory rate was 30; and blood pressure was 140/87. Serum CK also increased to 1,265 U/liter during this time.

A preliminary diagnosis of neuroleptic malignant syndrome (NMS) was made, and all antipsychotic medications were discontinued. Aggressive hydration with intravenous normal saline was initiated, along with dantrolene and bromocriptine. He eventually recovered completely from the episode, was free of migraine, and subsequently was transferred to his home hospital for rehabilitation because he was quite deconditioned from his episode of NMS.

Case 2: "Ms. B," a 38-year-old woman, was admitted to the hospital after a generalized tonic–clonic seizure and decreased level of consciousness. Her medications included venlafaxine 150 mg daily and acetaminophen with codeine before admission.

She showed delirium on admission, and she was frequently agitated. Treatment of her delirium included risperidone 1 mg po bid with additional boluses of intravenous haloperidol 5 mg–10 mg intermittently for increased agitation. Psychiatric consultation was provided for management of her delirium, and risperidone therapy was discontinued because the patient developed symptoms consistent with akathisia while on this agent. Quetiapine therapy was initiated because she continued to have delirium with significant agitation.

Five days after the initiation of quetiapine, her delirium and agitation worsened, and she was given 10 mg of haloperidol IV. At this time, she was noted to have possible seizure activity and was also noted to be diaphoretic. Her vital signs at the time included a heart rate of 190 bpm, blood pressure of 180/120, respiratory rate of 36, and temperature of 99.3°F. She continued to receive haloperidol 10 mg IV twice daily in addition to her quetiapine, and she was transferred to the intensive care unit for decreased level of consciousness and increasing oxygen requirements. Investigations, including an EEG, were negative as to any medical causes of her condition.

Two days later, vitals signs revealed a temperature of 102.6°F, blood pressure of 135/85, heart rate of 140, and respiratory rate of 24. A neurological exam indicated lead-pipe muscular rigidity in all extremities, as well as tremor, and no localizing signs. Laboratory investigations indicated a WBC of 14.9 x 109 and CK level of 1,103 IU/liter. A diagnosis of NMS was made, and all antipsychotics were discontinued. Supportive therapies, including external cooling and intravenous hydration with normal saline, were initiated. Dantrolene 60 mg IV every 6 hours was also initiated at this time. Lorazepam 2 mg IV every 6 hours for muscular rigidity and agitation were also used. Serum CK peaked the next day, at 2,197, and she remained febrile and rigid for 2 more days. She recovered completely from the episode within 5 days.


  LITERATURE SEARCH

 
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
 LITERATURE SEARCH
Results of Literature Review
 DISCUSSION
 REFERENCES
 
Using the keywords and subject headings "neuroleptic malignant syndrome" or "NMS," combined with "delirium," "acute confusional state," "confusion," or "encephalopathy," electronic databases, including CINAHL (1982–July 2006), EMBASE (1980–2006), PsychINFO (1967–2006), and MEDLINE (1966–2006), were searched for relevant articles. Reference lists of articles and a textbook on neuroleptic malignant syndrome31 were also searched for potentially relevant articles. Cases reports were included in the review if the individual developed NMS after antipsychotic treatment of delirium or agitation arising during any acute medical or surgical illness. Cases were excluded if the individual was receiving antipsychotics for treatment of an underlying psychiatric illness (e.g., schizophrenia, bipolar disorder, personality disorders, dementia, etc.) or for another, nonpsychiatric condition (e.g., nausea, insomnia).


  Results of Literature Review

 
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
 LITERATURE SEARCH
 Results of Literature Review
DISCUSSION
 REFERENCES
 
An additional 23 cases of NMS occurring during the treatment of delirium or agitation in medically ill patients were described in the literature (Table 1). The mean age for all patients was 48.36 years (standard deviation [SD]: 21.28; range: 20–90 years). Men accounted for 21 of 25 cases reported (84%). The majority of cases (15 of 25) occurred in patients undergoing various surgical procedures, often in the setting of trauma. Symptoms of agitation or aggression were noted in 21 patients, and these behaviors appeared to be the indication for initiating antipsychotic treatment in the majority of cases.


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TABLE 1. Case Reports of Neuroleptic Malignant Syndrome (NMS) During Antipsychotic Treatment of Delirium or Agitation



A variety of medications were implicated in causing NMS in these instances. Haloperidol, either alone, or in combination with other medications, was implicated in 22 of 25 cases. Atypical antipsychotics were used in three cases, and only one case of NMS occurred during monotherapy with atypical antipsychotics. Haloperidol was utilized in 84% of all cases, and parenteral administration of haloperidol was reported in 71% of all cases that occurred during haloperidol treatment. Atypical antipsychotics were infrequently used in these cases (12%), and only one case of NMS occurred in a patient who received only atypical antipsychotics. Dosage of medication was not consistently reported in all cases, and the mean dose of medications administered was highly variable. In the 20 cases with complete information on medications and dosage, 11 cases reported dosages of medications in excess of those recommended in delirium guidelines.22

The signs of NMS in this group of patients were consistent with those of NMS reported in other settings. Elevated temperature was reported in 23 cases, and the average temperature was 102.9°F. Muscle rigidity was noted in 80% of cases; additional signs of extrapyramidal side effects (e.g., tremor, dysarthria) were noted in 36% of cases. Tachycardia, tachypnea, and blood pressure abnormalities were noted in 72%, 32%, and 60% of cases, respectively. Elevations of serum CK were noted in 80% of cases, with an average peak serum CK of 5,403 IU/liter. Elevated WBC was reported in 64% of cases, with an average WBC of 19.2 x 109 cell/mm3. Other associated features of NMS observed in these cases included diaphoresis (36%), dysarthria (8%), and urinary symptoms (12%).

In addition to supportive therapies, the most frequently utilized treatments for NMS included benzodiazepines (20% of cases), bromocriptine (52%), dantrolene (44%), and other dopamine agonists (16%). The majority of cases recovered from their NMS episodes without complication, although one patient suffered from depression after the episode, and two patients died at some time remote from the NMS episode.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
 LITERATURE SEARCH
 Results of Literature Review
 DISCUSSION
REFERENCES
 
NMS is a potential complication of using antipsychotics to treat delirium or agitation in medically ill patients. Despite the widespread use of antipsychotics in delirium management, NMS arising in this context is reported infrequently in the published literature. The clinical features of NMS in patients with delirium appear to be similar to NMS found in other settings.

Patients with delirium may be at particular risk for NMS because the delirium may present with agitation, confusion, and disorganized behavior, all known risk factors for developing NMS after antipsychotic exposure in psychiatric populations without delirium.15,17 Certain medical conditions, such as dehydration, are also known risk factors for delirium32 and NMS.18 Rapid dose-escalation of antipsychotics and intramuscular administration of medication are frequently utilized in delirium management and are also risk factors for NMS.15,17 The doses of antipsychotics reported in case reports of NMS during delirium treatment were also often in excess of the dosages recommended in delirium treatment guidelines22,23 and greater than the average doses of antipsychotics reported in trials of antipsychotic medications for delirium.30,33 Guidelines and trial data for delirium management recommend treatment with low-dose haloperidol (1 mg–2 mg po q4 hours) or similar doses of risperidone (0.5 mg–1.0 mg), or olanzapine (2.5 mg–5.0 mg daily). Given that the majority of individuals with delirium respond to low-dose antipsychotic monotherapy in delirium trials,30 patients’ failure to respond to initial monotherapy may prompt clinicians to consider a switch to a second monotherapy or adjunctive therapy with non-antipsychotic medications, as opposed to excessive dose-escalation of the initial medication. Unfortunately, many patients with treatment-refractory delirium may require higher doses of medication, particularly in the critically ill population, where the medical precipitants of the delirium may not be easily or promptly reversed. In critically ill patients with refractory delirium, it is most likely that haloperidol is used as the antipsychotic of choice, given its availability in numerous formulations and familiarity to clinicians. This may also account for the frequent implication of haloperidol in the preceding case reports of NMS arising during antipsychotic treatment of delirium.

Despite limited evidence from randomized, controlled trials, antipsychotics remain the best supported pharmacological treatment for delirium and a mainstay of delirium management along with non-pharmacological interventions. The majority of physicians manage delirium with antipsychotics, and haloperidol continues to be recommended as the first-line treatment.19,20 Recent reviews30,55 have found no difference in the efficacy of atypical antipsychotics in treating the symptoms of delirium, although rates of extrapyramidal symptoms appear to be less frequent during treatment of delirium with atypical antipsychotics as compared with haloperidol. Intravenous haloperidol may be associated with fewer extrapyramidal symptoms than oral or intramuscular formulations,34 although this potential benefit needs to be weighed against the increased risk of QTc prolongation and cardiac arrhythmias associated with intravenous use.35 The current study also suggests that NMS may also be more frequently associated with haloperidol than are atypical antipsychotics, although prospective studies would be required to determine whether this is related to haloperidol’s increased propensity to cause extrapyramidal symptoms and possibly NMS, or simply that haloperidol is most frequently used in managing refractory delirium in critically ill patients.

Further complicating the assessment of delirium and potential medication-related side effects is the fact that delirium is also a frequent symptom of NMS. Delirium or confusion may be an early symptom of NMS, often preceding other symptoms such as rigidity or fever.28 NMS has been reported to manifest as a protracted episode of delirium.36 NMS may present without fever, prominent muscle rigidity, or autonomic instability, which may obscure the diagnosis and delay treatment,5,14 and a spectrum of NMS-related illnesses has been proposed.37 Akathisia may also present with a clinical picture similar to agitated or hyperactive delirium, prompting clinicians to escalate antipsychotic medication dosage inappropriately.38 Worsening delirium or agitation during antipsychotic treatment of delirium should prompt clinicians to consider NMS or other medication-related adverse effects as potential contributors to the clinical presentation.

Once NMS is identified during treatment of delirium with antipsychotics, several measures should be taken. First, all antipsychotic medications must be discontinued, and supportive care aimed at maintaining adequate hydration, renal functioning, and temperature regulation should be implemented. Additional treatment with agents such as dantrolene, bromocriptine, and benzodiazepines may also be implemented, although there is limited evidence from the literature that the addition of these agents may also improve outcomes,39 and some authors have suggested that these treatments may also be associated with worse outcomes.40 After an episode of NMS, at least 2 weeks should elapse before a rechallenge with antipsychotic medications, and the second medication should be different from the medication implicated in the initial NMS episode.41 Although not recommended as monotherapy treatment of delirium,22 benzodiazepines may have a role in managing agitation in delirium related to NMS as well as in treating the other symptoms of NMS.2,42,43 Refractory cases of NMS may also respond to ECT,44 although caution is required for individuals with acute medical conditions.

Management of the medically ill delirium patient is challenging and requires a multifaceted approach, including pharmacologic and non-pharmacologic interventions. When delirium is managed with antipsychotics, clinicians should be aware of the risk of NMS and monitor for this adverse event. Strategies that may minimize the risk of NMS in patients with delirium or agitated medically ill patients may include using low-dose medications, oral administration of medications, and perhaps the preferential use of atypical antipsychotics over haloperidol. Further study is required to determine the frequency and risk factors for NMS in the medically ill population with delirium.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
 LITERATURE SEARCH
 Results of Literature Review
 DISCUSSION
 REFERENCES
 

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