Australasian

Remember the Side Effects of Haloperidol: A Case Report G. F. ALVAREZ, G. A. SKOWRONSKIDepartment of Intensive Care, The St George Hospital, Kogarah, NEW SOUTH WALES
ABSTRACT
An eighteen-year-old man who had a laminectomy and subtotal excision of a lipomyelomeningocele,
received a single dose of haloperidol for post-operative pain and agitation. The patient suffered an acute
dystonic reaction and was extensively investigated before the correct diagnosis and treatment was
instituted. This case illustrates the ease with which extrapyramidal side effects following treatment with
haloperidol may be overlooked in complicated medical or surgical cases. (Critical Care and
Resuscitation 2003; 5: 266-269)

Key words: Haloperidol, benztropine, antipsychotic, neuroleptic drug, adverse drug effect, extrapyramidal
Haloperidol is a psychotropic drug of the butyro- phenone family and is used for both chronic and short- An eighteen-year male with an unremarkable past term therapy. Long-term therapy is commonly used for medical history presented with a 2-month history of psychotic disorders such as schizophrenia, senile disabling back and leg pain. Initially, his pain was psychosis or the manic phase of bipolar disorders. controlled with gabapentin, dexamethasone and oral Physicians not dealing with psychiatric patients are analgesics. However, his pain became unresponsive and more familiar with the short-term indications in acutely magnetic resonance imaging (MRI) of his spine confused states including the relief of delusions, revealed an intradural lipoma extending from the delirium and aggressive behavior. Although haloperidol lumbar vertebra (L2, L3) to the sacral vertebra (L5, S1) appears to function by blocking dopaminergic neuro- which measured 8 cm in length and 3.5 cm in diameter. transmission in the central nervous system, the precise There was encasement of the nerve roots of the cauda mechanism for its therapeutic effects remains equina, with the conus adherent to the superior border unknown.1 Antipsychotic drugs also have the potential of the lipoma. The MRI of the cervicothoracic spine and to cause the extrapyramidal syndrome (EPS), which a computed tomography (CT) scan of the head were includes a group of movement disorders of dystonia, akathisia, tardive dyskinesia and parkinsonism.2 An L2-L4 laminectomy and subtotal excision of the Antipsychotic drug-induced EPS is thought to be lipomyelomeningocele were performed to untether the caused by the blockage of central dopamine D2 spinal cord. While the patient did not sustain any receptors.3 Serious complications include neuroleptic additional neurologic deficits, because of the extensive malignant syndrome4,5 and torsades de points6-8 and dissection of his cauda equina he developed post- demand the clinician pay close attention to patients operative radicular leg pain which was treated with analgesia, gabapentin and decreasing doses of The following case report illustrates a common dexamethasone. Postoperatively he remained afebrile adverse drug effect to haloperidol that was not with no haemodynamic or respiratory compromise. recognised early, causing unnecessary investigations On the third post-operative day, the patient began complaining of escalating episodes of right shoulder Correspondence to: Dr. G. Alvarez, Intensive Care Unit, The Prince of Wales Hospital, Randwick, New South Wales 2031 (e-mail: g.alvarez@unsw.edu.au) Critical Care and Resuscitation 2003; 5: 266-269 and neck pain causing involuntary neck flexion on the neoplasms to be carefully considered. The effect of right side. He was orientated, cooperative and haloperidol may also be exacerbated in the critically ill responded appropriately to command. Sensory, motor, patient with multiple organ dysfunction as the agent is cerebellar and cranial nerve examinations were within metabolised by the cytochrome P450 system which may normal limits. The patient was described as having be compromised during surgical stress.28 "neck muscle spasms and persistent upward gaze." A et al,29 defined the extrapyramidal synd- diagnosis of atypical convulsions was made and he was rome (EPS) as the adverse effects of neuroleptic drugs admitted to the intensive care unit. A CT of his head that include hyperkinetic (akathisia, acute dystonia, and and a lumbar puncture were performed, both of which acute dyskinesia), and hypokinetic Parkinson-like revealed no abnormalities. However, on review of his symptoms (e.g. bradykinesia, rigidity, and tremor). medical chart, it was noted that twenty-four hours While, they found that elderly patients and duration of previously, the patient had received an extra dose of 8 neuroleptic treatment were positive predictors of the mg of dexamethasone and 5 mg of haloperidol (intra- EPS,29 a United Kingdom study showed that extrapyr- muscularly) for radicular leg pain. He was given 2 mg amidal reactions reported for haloperidol (predom- of benztropine intravenously with complete resolution inantly dystonia-dyskinesia) occurred within the first 3 days of treatment and the highest incidence was in younger patients, especially under 20 years of age.30 They speculated that the incidence was higher in Haloperidol is widely used, in part because of the younger patients because of the reduction in D2 lack of cardiovascular side effects. There is a common receptors in the substantia nigra with increasing age.30 perception that it controls agitation with virtually no Other retrospective studies have quoted between 20% to adverse respiratory, cardiac, renal or haematopoietic 30% extrapyridimal adverse drug effects with effects. However, numerous reports illustrate that haloperidol and agree that younger age appears to be a serious side effects can occur in all of these systems,9-14 risk factor for haloperidol-induced EPS.31,32 and dystonia of the larngopharyngeal muscles can cause et al, identified 424 patients who throat tightness and dysphagia prompting inappropriate started haloperidol for the first time, who had a 13.3% and hazardous medical interventions.15-18 incidence of drug-induced EPS requiring benztropine.3 Hennessy and coworkers performed a cohort study Kurz et al,33 also examined 59 first time users of of psychiatric outpatients to determine the rates of haloperidol and reported that 73% required anticholin- cardiac arrest and ventricular arrhythmia in patients ergic therapy to treat parkinsonian symptoms and 24% using antipsychotic drugs.10 Compared with the control required beta adrenergic-blockers to counteract neuro- groups, patients taking antipsychotic drugs (mostly leptic-induced akathisia. They found that 10.2% of haloperidol) had a rate ratio of cardiac arrest or ventric- haloperidol-treated patients developed dystonia during ular arrhythmia ranging from 1.7 to 3.2 and rate ratio their first two weeks of treatment. Rosebush et al,34 for death ranging from 2.6 to 5.8. While the literature is prospectively studied the neuroleptic side effect profile replete with reports of the potential cardiovascular of 350 consecutive neuroleptic-naïve patients admitted consequences of haloperidol,6-8,19,20 not all sudden death to an acute care psychiatric hospital. Despite a low episodes in patients taking neuroleptic drugs are average daily dose of haloperidol (e.g. 3.7 mg), more attributable to the effect of the drug.21 than 50% of patients suffered extrapyramidal side Haloperidol has long been used in the management effects with 127 episodes of acute dystonia that required of the critically ill patient,22-24 and is often used during immediate benztropine treatment. While the study weaning from mechanical ventilation. It is also used in included neuroleptic-naïve patients only, many patients critically ill agitated and delirious patients who are were on concurrent medications known to cause EPS unresponsive to high doses of narcotics and benzodiaz- (e.g. selective serotonin reuptake inhibitors, tricyclic epines. Two studies have demonstrated that continuous antidepressants). Ramaekers et al,35 recruited twenty- infusions are safe and efficient in reducing nursing care one volunteers aged 18 to 35 years without any time and to facilitate weaning.25,26 Both studies noted significant past medical or psychiatric history. They prolongation of the QTc interval in some patients that conducted tests of psychomotor, cognitive and resolved with decreasing the drug infusion rate. extrapyramidal functions one hour before and 3 and 6 Critically ill patients can also experience movement hours after haloperidol on days 1 and 5. Two subjects disorders (e.g. tongue, hand or leg tremor) upon withdrew from the study, one because of akathisia after withdrawal of haloperidol,27 requiring a differential a 2 mg dose, the other subject suffered an acute diagnosis of metabolic disturbances, cerebral infections dystonic reaction on day two. Approximately 65% of as well as structural lesions following trauma, strokes or the volunteers experienced EPS requiring Critical Care and Resuscitation 2003; 5: 266-269 anticholinergic medication during the first five days. Wilt JL, Minnema AM, Johnson RF, Rosenblum AM. Torsade de pointes associated with the use of Haloperidol also significantly interfered with the intravenous haloperidol. Ann Intern Med 1993;119:391- subjects' concentration causing increased somnolence 9. Abdullah N, Voronovitch L, Taylor S, Lippmann S. As the elimination half-life of haloperidol is 17 to 18 Olanzapine and haloperidol: potential for neutropenia? hours36 it may exert prolonged effects. Anderson et al,37 described a patient with akathisia 5 days after and 10. Hennessy S, Bilker WB, Knauss JS, et al. Cardiac arrest dysphoria 6 weeks after receiving a single haloperidol and ventricular arrhythmia in patients taking dose of 5 mg. Alternatively, patients can experience a antipsychotic drugs: cohort study using administrative nearly immediate adverse drug effect.38 Patients who have experienced drug-induced EPS are more likely to 11. Mahutte CK, Nakasato SK, Light RW. Haloperidol and have future episodes if antipsychotic medications are re- sudden death due to pulmonary edema. Arch Intern Med introduced.39 However, compared with oral haloperidol intravenous haloperidol may be associated with an EPS 12. Marsh SJ, Dolson GM. Rhabdomyolysis and acute renal failure during high-dose haloperidol therapy. Ren Fail Haloperidol is easy to use and effective in 13. Sato T, Takeichi M. Drug-induced pneumonitis controlling acute delirium and combative states. associated with haloperidol. A case report. Gen Hosp However, it has important adverse side effects that may be misinterpreted especially in complex medical or surgical patients. Our report illustrates the ease with bronchospasm. Can J Psychiatry 1991;36:525-526. which inappropriate investigations and management 15. Barach E, Dubin LM, Tomlanovich MC, Kottamasu S. occurs because a common adverse drug event was not Dystonia presenting as upper airway obstruction. J recognised. One ampoule of benztropine costs $2.40 16. Fines RE, Brady WJ Jr, Martin ML. Acute laryngeal (AUD). This patient's intensive care unit stay, medical dystonia related to neuroleptic agents. Am J Emerg Med fees, investigations (e.g. CT head, lumbar puncture, cerebrospinal fluid analysis), antibiotic course and one 17. Flaherty JA, Lahmeyer HW. Laryngeal-pharyngeal extra day in hospital, cost an extra $2715.00 (AUD). dystonia as a possible cause of asphyxia with We should mention the added distress the patient and haloperidol treatment. Am J Psychiatry 1978;135:1414- 18. Ilchef R. Neuroleptic-induced laryngeal dystonia can mimic anaphylaxis. Aust NZ J Psychiatry 1997;31:877- 19. Huyse F, van Schijndel RS. Haloperidol and cardiac 20. Lawrence KR, Nasraway SA. Conduction disturbances associated with administration of butyrophenone 1. Sigma Pharmaceuticals Pty Ltd. Product Monograph. antipsychotics in the critically ill: a review of the literature. Pharmacotherapy 1997;17:531-537. 2. Gerlach J, Korsgaard S. Classification of abnormal involuntary movements in psychiatric patients. 21. Raju GV, Kumar TC, Khanna S. Sudden death following neuroleptic administration due to hemoperitoneum resulting from physical restraint. Can J 3. Schillevoort I, de Boer A, Herings RM, Roos RA, Jansen PA, Leufkens HG. Risk of extrapyramidal syndromes with haloperidol, risperidone, or olanzapine. 22. Crippen DW. The role of sedation in the ICU patient with pain and agitation. Crit Care Clin 1990;6:369-392. 23. Fish DN. Treatment of delirium in the critically ill Levitt AJ, Midha R, Craven JL. Neuroleptic malignant syndrome with intravenous haloperidol. Can J Psychiatry 1990;35:789. 24. Moulaert P. Treatment of acute nonspecific delirium with i.v. haloperidol in surgical intensive care patients. Town IG. Haloperidol: neuroleptic malignant syndrome. 25. Riker RR, Fraser GL, Cox PM. Continuous infusion of 6. Kriwisky M, Perry GY, Tarchitsky D, Gutman Y, haloperidol controls agitation in critically ill patients. Kishon Y. Haloperidol-induced torsades de pointes. 26. Seneff MG, Mathews RA. Use of haloperidol infusions Metzger E, Friedman R. Prolongation of the corrected to control delirium in critically ill adults. Ann QT and torsades de pointes cardiac arrhythmia associated with intravenous haloperidol in the medically ill. J Clin Psychopharmacol 1993;13:128-132. 27. Riker RR, Fraser GL, Richen P. Movement disorders associated with withdrawal from high-dose intravenous Critical Care and Resuscitation 2003; 5: 266-269 haloperidol therapy in delirious ICU patients. Chest 34. Rosebush PI, Mazurek MF. Neurologic side effects in neuroleptic-naive patients treated with haloperidol or 28. Haas CE, Kaufman DC, Jones CE, Burstein AH, Reiss W. Cytochrome P450 3A4 activity after surgical stress. 35. Ramaekers JG, Louwerens JW, Muntjewerff ND, et al. Psychomotor, Cognitive, extrapyramidal, and affective 29. Muscettola G, Barbato G, Pampallona S, Casiello M, functions of healthy volunteers during treatment with an Bollini P. Extrapyramidal syndromes in neuroleptic- atypical (amisulpride) and a classic (haloperidol) treated patients: prevalence, risk factors, and association antipsychotic. J Clin Psychopharmacol 1999;19:209- with tardive dyskinesia. J Clin Psychopharmacol 36. Froemming JS, Lam YW, Jann MW, Davis CM. Pharmacokinetics of haloperidol. Clin Pharmacokinet Extrapyramidal reactions to prochlorperazine and haloperidol in the United Kingdom. Q J Med 37. Anderson BG, Reker D, Cooper TB. Prolonged adverse effects of haloperidol in normal subjects. N Engl J Med 31. Miller CH, Hummer M, Oberbauer H, Kurzthaler I, DeCol C, Fleischhacker WW. Risk factors for the 38. Barnes TR, Braude WM, Hill DJ. Acute akathisia after development of neuroleptic induced akathisia. Eur oral droperidol and metoclopramide preoperative 32. Addonizio G, Alexopoulos GS. Drug-induced dystonia 39. Keepers GA, Casey DE. Use of neuroleptic-induced in young and elderly patients. Am J Psychiatry extrapyramidal symptoms to predict future vulnerability to side effects. Am J Psychiatry 1991;148:85-89. 33. Kurz M, Hummer M, Oberbauer H, Fleischhacker WW. 40. Menza MA, Murray GB, Holmes VF, Rafuls WA. 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Source: http://cicm.org.au/journal/2003/december/Case3a.pdf