Reviews

The FDA extended warning for intravenous haloperidol and torsades de pointes: How should institutions respond?

Abstract

Abstract

BACKGROUND:

In September 2007, the Food and Drug Administration (FDA) strengthened label warnings for intravenous (IV) haloperidol regarding QT prolongation (QTP) and torsades de pointes (TdP) in response to adverse event reports. Considering the widespread use of IV haloperidol in the management of acute delirium, the specific FDA recommendation of continuous electrocardiogram (ECG) monitoring in this setting has been associated with some controversy. We reviewed the evidence for the FDA warning and provide a potential medical center response to this warning.

METHODS:

Cases of intravenous haloperidol‐related QTP/TdP were identified by searching PubMed, EMBASE, and Scopus databases (January 1823 to April 2009) and all FDA MedWatch reports of haloperidol‐associated adverse events (November 1997 to April 2008).

RESULTS:

A total of 70 of IV haloperidol‐associated QTP and/or TdP were identified. There were 54 reports of TdP; 42 of these events were reportedly preceded by QTP. When post‐event QTc data were reported, QTc was prolonged >450 msec in 96% of cases. Three patients experienced sudden cardiac arrest. Sixty‐eight patients (97%) had additional risk factors for TdP/prolonged QT, most commonly receipt of concomitant proarrhythmic agents. Patients experiencing TdP received a cumulative dose of 5 mg to 645 mg, patients with QTP alone received a cumulative dose of 2 mg to 1540 mg.

CONCLUSIONS:

While administration of IV haloperidol can be associated with QTP/TdP, this complication most often took place in the setting of concomitant risk factors. Importantly, the available data suggest that a total cumulative dose of IV haloperidol of <2 mg can safely be administered without ongoing electrocardiographic monitoring in patients without concomitant risk factors. Journal of Hospital Medicine 2010;5:E8–E16. © 2010 Society of Hospital Medicine.

Copyright © 2010 Society of Hospital Medicine

Haloperidol is Food and Drug Administration (FDA)‐approved in the United States for the management of acute and chronic psychotic disorders and widely used in the management of delirium‐associated agitation in hospitalized patients.1 Delirium in the hospital is an acute confusional state that frequently arises from multiple complex factors and may affect up to 30% of hospitalized patients.2 Although the first step in the management of delirium involves identification and treatment of underlying causes and offering supportive behavioral care; medications may be needed to control severe agitation.2 Low dose intravenous (IV) haloperidol (ie, 0.250.5 mg every 4 hours) is a commonly used medication in this setting as recommended by expert‐groups including the Cochrane Collaboration and the American Psychiatric Association.2, 3

Although injectable haloperidol, a butyrophenone‐derived antipsychotic agent pharmacologically related to the piperazine phenothiazines,4 is approved for IV use in many countries (Table 1), parenteral use is approved only for intramuscular (IM) administration in the US. Thus, IV administration of the drug in the US is considered an off‐label use.5

Package Information of Officially Approved Haloperidol IV Products
Indication Country
Canada24 France29 Germany25 Great Britain37 Italy30 Switzerland31
  • Abbreviations: ECG, electrocardiogram; IV, intravenous; max, maximum; PO, by mouth; PRN, medication as needed; TdP, torsades de pointes; VT, ventricular tachycardia.

Mainly delirium (schizophrenia, other psychosis, short‐term management of psychomotor agitation, excitement, violent or dangerously impulsive behavior, vomiting, hiccup) Short term treatment of agitation and aggressiveness during an acute or chronic psychotic episode, vomiting along with antimitotic post‐radiotherapy treatment Acute and chronic schizophrenia, psycho‐motorical agitation of psychotic genesis Schizophrenia, other psychosis, short‐term adjunctive management if psychomotor agitation, violent or dangerous impulsive behavior Resistant forms of psycho‐motorical excitement, acute delirious and/or hallucinatory psychosis' chronic psychosis High doses restrictions: syndrome of psycho‐motorical excitement, acute delirious and/or hallucinatory psychosis, chronic psychosis Acute schizophrenic episode, mania, vomiting
IV dosing in adults 12 mg every 24 hours The use is limited to adult patients and the drug can be administered IM or IV. The IV route is restricted to the treatment of vomiting. 510 mg/day, daily max.: 30(100) mg 210 mg initially, PRN every 48 hours, daily max. 18 mg 510 mg initially, PRN every hour, daily max. 60 mg 5 mg PRN every 30 minutes
IV dosing in geriatric care 0.250.5 mg Single dose of 0.51.5 mg, daily max. 5 mg Half adult dose Adjust to appropriate dose 0.5 mg, than PRN
Risk factors for the development of cardiac adverse events QT prolonging drugs, diabetes, obesity, hypokalemia, congenital long QT syndrome Bradycardia <55 beats per minute, hypokalemia, congenital QT prolongation, other medications provoking bradycardia, deceleration of the intra‐cardiac transition or prolonged QT interval QT syndrome, hypokalemia, other electrolyte imbalance, cardiovascular diseases, QT prolongation in the family history Cardiovalscular disease, drugs that can prolong the QTc, diabetes, obesity, hypokalemia, congenital long QT syndrome Contraindications: recent cardiac infarction, uncompensated cardiac insufficiency, cardiac arrhythmias, antiarrhythmic drugs, pre‐existing QT prolongation, cases of arrhythmia or torsades de pointes in the family history, untreated potassium imbalance, QTc prolonging drugs QT syndrome, hypokalemia, hypomagnesemia, other electrolyte imbalances, cardiovascular diseases, hypothyreosis, QT prolongation in the family history
Monitoring recommendations Electrolytes ECG monitoring at admission time, electrolytes ECG monitoring, electrolytes Metabolic parameters ECG at baseline and regular ECG monitoring, electrolytes Close ECG monitoring, electrolytes
General recommendations Regular reevaluation in long‐term use Apply the lowest effective dose Apply the lowest effective dose Application per mouth is the route of choice Decrease dose if QTc >500 msec Switch to PO as soon as possible

Haloperidol is often preferred over other antipsychotics as a result of its effectiveness, low rate of anticholinergic side effects, familiarity with dosing and usage, and minimal respiratory or sedative properties.6 Use of the IV route in patients with acute delirium has several advantages over the IM or oral route,7 including rapid onset, immediate bioavailability, and ease and safety of administration.

Prior to September 2007, the package insert for haloperidol alerted healthcare professionals to the risk of cardiovascular side effects. Based on case reports of potentially fatal cardiac events, the FDA revised the label, warning that the QT prolongation (QTP) and risk of torsades de pointes (TdP) were increased with IV administration of haloperidol or administration of the drug at greater than recommended doses. Unfortunately, neither the typical dosing range nor the minimum dose associated with these cardiac side effects were specified in this recommendation.5

It is well‐established that haloperidol may prolong the QT interval by blocking the repolarizing potassium IKr current.8 Although drugs that block the IKr channel can produce arrhythmia in healthy individuals, additional risk factors, such as underlying heart conditions, electrolyte imbalances (ie, hypokalemia and hypomagnesemia), concomitant proarrhythmic drug use, and mechanical ventilation may increase this risk.9 Prolongation of the QT interval has been associated with subsequent malignant cardiac arrhythmias including ventricular fibrillation and TdP.10 Prolongation of the QT interval is considered the strongest risk factor for TdP, particularly with a baseline QTc > 450 msec.9

Based on the increased risk for QTP and TdP and the case reports of cardiac events, the FDA advisory recommended continuous electrocardiogram (ECG) monitoring in patients receiving IV haloperidol.5 However, such monitoring may be impractical and costly in hospitalized patients who require low doses of IV haloperidol to manage acute delirium and who are not in telemetry or intensive care units.

The aim of this review was to evaluate the case reports leading to the recent FDA warning for IV haloperidol, specifically focusing on the presence of risk factors for arrhythmias. Based upon the evidence, an additional aim was to provide an institutional response to this warning toward the optimal use of this agent.

Method

Two search pathways were used to evaluate reports of haloperidol‐associated TdP and/or QT prolongation:

Literature Review

We searched for published literature in humans indexed in Pubmed (1966April 2009), EMBASE (1972April 2009), and Scopus (1823April 2009) using the search terms haloperidol or Haldol combined with intravenous or infusion and at least one of the following terms: QT prolongation, TdP, torsades de pointes, torsades with a specific focus on case reports.

References from the retrieved articles were also reviewed to search for additional case reports.

In addition to cases reported in English journals, several of our reports originated from Japan11 (translation provided by the FDA), Spain12 and Germany13 (translated by the primary author).

Search of the FDA Database

We reviewed all adverse drug events reported through MedWatch or those submitted by the manufacturer from November 1997 to April 2008 through the Freedom of Information Act (FOIA) request. The FDA provided a full‐text summary of 5944 reports involving oral, intramuscular and IV use of haloperidol. The FDA data were transferred to a Microsoft Access database and screened for the key terms torsade, QT, prolongation, wave. Incident report number, date of report, age, gender, origin of report, medication name, role of drug as categorized by the FDA (suspect, concomitant, primary suspect, secondary suspect), route, dose, units, duration, symptoms and FDA outcome category (death, life‐threatening, hospitalization initial or prolonged, disability, congenital anomaly, required intervention to prevent permanent damage, other) were recorded. Only those reports in which IV haloperidol was considered by the reporter to be the primary causative agent for the adverse event were reviewed. Available information included diagnosis, laboratory parameters, QTc measurement, cardiac symptoms, outcomes and a description of recovery. No peer review was applied to the MedWatch reports and the data reported in this publication reflect the original information from the FDA MedWatch database. Baseline QTc was either the value defined as such in the original report or the lowest QTc reported. Haloperidol doses administered were defined as cumulative dose at event, encompassing all doses administered during the hospital stay until the occurrence of the adverse cardiac event.

The drugs listed in the case reports were assessed for proarrhythmic potential using 2 references: the individual package insert and the website of the Arizona Center for Education and Research on Therapeutics.14

The drugs were only considered proarrhythmic when the 2 resources were in agreement.

Duplicates and/or previously published cases, as well as reports involving adverse cardiac effects not associated with QTP or TdP, were identified and excluded.

In their advisory, the FDA does not state the exact origin of the reports, their specific search strategy to identify haloperidol‐associated adverse events, or the role IV haloperidol played in the individual events included in the extended warning. Consequently, the number of events identified in this review may differ from that published in the FDA extended warning.

Results

A total of 70 reported cases of IV haloperidol associated TdP and/or QTP were identified. Of these 70, 41 were identified through the PubMed/EMBASE/Scopus review, while an additional 29 cases were identified through the FDA database search.

Of the 29 cases in the FDA database, 21 were reported by health care professionals and 8 by manufacturers.

A total of 35 publications described cases originating from the US. Three cases took place in Japan and 1 case each in Canada, Germany and Spain. Several cases in the MedWatch database were reported outside the US: 1 case each originated from Austria, Canada, France, Japan, Spain, Switzerland and the United Kingdom. A summary of the published case reports is displayed in Table 2 and the FDA cases are summarized in Table 3.

Summary of Case Reports of Intravenous Haloperidol‐associated QTP/TdP Published in Pubmed, Embase and/or Scopus (182304/2009)
Case Source (reference#) Date Age, Years Gender Drugs Pro‐arrhyth. Venti‐ lated Max. Daily Dose (mg) Total Dose at Event (mg) Time to Event Prolonged QT QTc Maximal (baseline), msec Change in QTc (msec) TdP ECG Normalization, Outcome
  • Abbreviations: ECG, electrocardiogram; IM: intramuscular; IV, intravenous; max, maximum; PO, per os; PRN, medication as needed; QTP, QT prolongation; TdP, torsades de pointes, VT, ventricular tachycardia.

  • Five of 8 patients in this case series received concomitant proarrhythmic drugs. The individual patients were unspecified.

  • Estimated.

1 35 1991 56 m No Yes 1200 1540 NR Yes 584 (400) 184 NR NR, uneventful
2 13 1992 36 m Yes No 11.5 11.5 20 hours after start Yes 714 (428) 286 Yes QTc normalization (440 msec), NR
3 38 1993 39 f Yes Yes NR 580 Max. QTc 72 hours after start Yes 650 (420) 230 Yes QTc normalization after 6 days, uneventful
4 38 1993 19 f Yes No 170 170 Max. QT 12 hours after start Yes 600 (480) 120 Yes QTc normalization after 8 days, uneventful
5 38 1993 63 f Yes No NR 489 Max. QT 48 hours after start Yes 670 (520) 150 Yes QTc normalization after 8 days, uneventful
6 38 1993 74 f Yes Yes NR 10 NR No 430 (410) 20 Yes QTc unchanged after 8 days, uneventful
7 17 1993 39 m Yes Yes NR >490 NR Yes 457 (348) 109 Yes QTc normalization within 2 to 3 days, no further TdP, NR
8 17 1993 61 m Yes Yes 115 211 NR Yes 500 (390) 110 NR QTc normalization within 2 days, death
9 17 1993 48 m Yes Yes 825 825 NR Yes 538 (441) 97 NR QTc normalization in 3 days, rehabilitation
10 39 1994 23 f Yes Yes 120 300 12 hours after dose increase Yes NR (550) NR Yes NR, uneventful, extubation after 5 days, discharge after 10 days
11 39 1994 28 m Yes Yes 300 >300 24 hours after dose increase Yes NR (>520) NR Yes No recurrence of arrhythmia, patient death (multi‐organ failure)
12 40 1994 65 m Yes NR 230 410 Worsening from day 2 to day 5 Yes 594 (490) 104 Yes QTc normalization (406 msec), no cardiac problems at discharge
13 40 1994 65 f Yes NR 500 980 After the last 60mg Yes 628 (403) 225 Yes QTc normalization (<400 msec), recurrence with oral haloperidol, rehabilitation
14 40 1994 76 f Yes NR 21 26 Day 2 after several boluses Yes 670 (450) 220 Yes QTc normalization within several days (412 msec), rehabilitation
15 41 1994 59 m NR Yes 865 1013 NR Yes 640 (480) 160 NR QTc normalization in 24 hours, survived
16 16 1995 76 f Yes No NR 44.5 plus 1 PO 15 minutes Yes 670 (409) 261 Yes ECG normalized the next morning, no further events
17 16 1995 49 m Yes No NR 1150 plus 20 IM 45 minutes Yes 648 (380) 268 Yes QTc normalization in 24 hours, anoxic brain insult/rehabilitation
18 16 1995 65 f Yes No 600 965 30 minutes Yes 628 (403) 225 Yes 3 more episodes of TdP in 3 hours, QTc normalization in 2 days, no recurrence with further haloperidol, NR
19 42 1995 42 m Yes No 28 28 20 minutes Yes 610 (533) 77 Yes QTc normalization in 5 days, uneventful, ECG normal
20 42 1995 39 m Yes No 45 45 5 minutes Yes 654 (NR) NR Yes QTc normalization after 24 hours, uneventful
21 11 1997 56 f No No 10 10 Shortly after NR NR (NR) NR Yes TdP resolved after 8 hours, NR
22 11 1997 82 f NR No 10 10 Shortly after Yes 680 (NR) NR Yes QTc normalization on day 6 after admission (470 msec), NR
23 11 1997 35 m NR No NR 90 After 20 mg Yes 520 (NR) NR Yes TdP disappeared 12 hours later, NR
24 43,44 1998 45 m NR Yes* NR 9 203 minutes Yes 638 (560) 78 Yes NR, overall survival 100%, significantly prolonged hospital stay
25 43,44 1998 64 f NR NR 115 220 minutes Yes 605 (424) 181 Yes
26 43,44 1998 75 f NR NR 85 60 minutes Yes 567 (508) 59 Yes
27 43,44 1998 71 f NR NR 55 120 minutes Paced Paced Paced Yes
28 43,44 1998 58 f NR NR 75 38 minutes Yes 657 (542) 115 Yes
29 43,44 1998 40 m NR NR 35 15 minutes Yes 679 (475) 204 Yes
30 43,44 1998 71 m NR NR 70 58 minutes Yes 521 (478) 43 Yes
31 43,44 1998 47 m NR 400 400 79 minutes Yes 574 (444) 130 Yes
32 21 1999 41 f Yes Yes 320 915 55 minutes Yes 610 (426) 184 Yes QTc normalization after 5 day, uneventful
33 21 1999 31 m Yes Yes 480 1700 40 minutes Yes 599 (491) 108 Yes QTc normalized in 4 days, NR
34 18 2000 64 f Yes Yes 175 175 NR No 413 (418) (‐5) Yes QTc remained unchanged, uneventful
35 8 2000 75 m No NR >2 >2 NR Yes 615 (435) 180 No QTc normalization in 48 hours, uneventful
36 8 2000 68 m Yes Yes >2 >2 NR Yes 650 (407) 243 No QTc normalization after 4 day, uneventful after extubation
37 8 2000 77 m NR NR (4) 2 NR Yes 550 (393) 157 No QTc normalization in 24 to 36 hours, NR
38 12 2004 34 m Yes NR 24.5 24.5 20 minutes Yes 560 (420) 140 Yes QTc normalization (440 msec), ECG normal
39 23 2004 58 f Yes NR 340 1010 NR Yes 533 (460) 73 Yes QTc normalization 7 days later discharge after 27days
40 45 2008 86 f Yes No 2 mg 2 mg 8 hours after last dose Yes 524 (NR) Probably 79 No QTc normalization (445 msec), NR
41 46 2009 74 m Yes No 2 2 Shortly after Yes NR (579) NR Yes Pre‐existing heart block and fibrillation resolved, nursing home/rehabilitation
Summary of FDA MedWatch Reports of Intravenous Haloperidol‐associated QTP/TdP, 11/199704/2008
Report MedWatch Identifier Report Date Age, Years Gender Drugs Pro‐arrh. Maximum Daily Dose (mg) Total Dose at Event (mg) Prolonged QT QTc Maximal (baseline), msec Change in QTc (msec) TdP Outcome; Recovery
  • Abbreviations: FDA, Food and Drug Administration; f, female; m, male; NA, not applicable, NR, not reported; QTP, QT prolongation; VT, ventricular tachycardia.

1 3122988‐1 1998 61 m No 48 48 Yes NR NR Yes Intervention; NR
2 3157827‐6 1998 44 f No 160 160 Yes 550 (440) 110 Yes Intervention; uneventful
3 3178715‐5 1999 60 m NR 415 645 Yes NR NR Yes Life‐threatening; QTc normalization in 1 day, no recurrence
4 3271261‐X 1999 56 m NR NR 20 Yes NR NR Yes Life‐threatening; QTc normalization
5 3271080‐4 1999 35 m Yes 7 7 NR NR NR Yes NR; event abated after dose stopped/reduced, hospitalization prolonged
6 3325391‐4 1999 55 f Yes 75 75 NR NR NR Yes Life‐threatening; event abated after dose stopped/reduced
7 3381921‐8 1999 52 m No 320 634 Yes 458 (430) 28 Yes Death; NA
8 3483869‐7 2000 18 m No >200 >310 Yes NR NR Yes Intervention; no recurrence after haloperidol reinstitution
9 3516342‐8 2000 NR NR NR NR NR NR NR NR Yes NR; NR
10 3516320‐9 2000 34 m Yes 5 5 Yes NR NR No Life‐threatening; event abated after dose stopped
11 3552263‐2 2000 46 f Yes NR 97.5 Yes NR NR Yes Life‐threatening; event abated after dose stopped/reduced
12 3574705‐9 2000 78 m Yes NR 160 Yes 603 (453) 50 Yes Intervention; event abated after dose stopped/reduced
13 3703871‐7 2001 27 m NR 530 530 Yes NR NR Yes Death, NA
14 3724567‐1 2001 31 m Yes 6 6 Yes 496 (449) 47 No Life‐threatening; ECG returned to baseline
15 3851984‐1 2002 72 f NR 18 18 NR NR NR Yes Hospitalization; NR
16 3942407‐2 2002 51 m Yes 14 14 Yes 461 (444) 17 Yes Life‐threatening; no recurrence
17 4066580‐3 2003 >60 f NR 50 50 Yes >600 (480) >120 No Hospitalization; QTc normalization, patient recovered
18 4126280‐8 2003 47 f NR 60 180 Yes 550 (450) 100 No (bradycardia) Hospitalization; patient recovered
19 4150700‐6 2003 NR m NR 5 5 NR NR NR Yes NR; event abated after dose stopped/reduced
20 4340092‐1 2004 52 m Yes 5 5 Yes >500 (490) >10 NR (polymorphous VT) Life‐threatening; NR
21 4714692‐0 2005 NR m NR NR NR Yes NR NR Yes Hospitalization; event abated after dose stopped/reduced
22 4881813‐9 2006 NR m NR NR 40 NR NR NR Yes Hospitalization; event abated after dose stopped/reduced
23 4892225‐6 2006 NR f Yes 10 >10 Yes 493 (300) 193 No Hospitalization; QTc normalization (403 msec)
24 4911873‐8 2006 69 m Yes 6 6 NR NR NR Yes Cardiac arrest, death; NA
25 5366448‐6 2007 53 m Yes NR 35 Yes NR NR NR Cardiac arrest, life‐threatening; patient recovered
26 5563440‐3 2007 58 m Possible 5 5 Yes NR NR Yes Life‐threatening; event abated after dose stopped/reduced
27 5642929‐2 2008 42 m Yes 165 165 Yes 640 (350) 290 Yes Death; NA
28 5697758‐0 2008 38 m Yes NR 620 NR NR NR Yes Hospitalization; patient recovered
29 5254840‐X 2008 19 f Possible 15 25 Yes 461 NR NR Cardiac arrest, hospitalization; patient recovered

Of the 70 cases, 54 cases of TdP were reported. The remaining 16 of 70 cases involved cases of QTP, 9 of which did not progress to TdP and 7 of which the progression to TdP was unclear. Of note, 42 of 54 of the cases of TdP were reported as preceded by documented QTP. Presence of QTP was unknown in the other 12 original reports. Three out of 70 patients experienced sudden cardiac arrest, 1 of which was fatal. One arrest was preceded by TdP and 2 by QTP (Figure 1).

Figure 1

Distribution of cardiac adverse events among unpublished and published case reports of intravenous haloperidol‐associated QTP/TdP, 1997–2008.

The patient ages ranged from 18 years to 86 years. Of note, 17 patients experiencing TdP and/or QTP were <40 years old, and 2 of those patients were <30 years old.

Haloperidol‐associated QTP and/or TdP were observed in 27 female and 42 male patients; the gender was not stated in one report. Of the 54 patients experiencing TdP (with or without report of previous QTP), 22 were female and 31 were male (1 gender unknown).

A total of 68 of 70 patients were determined to have associated risk factors15 for QTP/TdP (see Table 4). The circumstances of the remaining 2 patients were not described in sufficient detail to identify associated risk factors.

Presence of Risk Factors Associated With QTP and/or TdP in the Published Case Reports and the FDA MedWatch Database
Risk Factor Patients, n (%)
  • Abbreviations: FDA, Food and Drug Administration; QTc, ; QT, QT prolongation; TdP, torsades de pointes.

Any risk factor 68/70 (97)
Unknown 2/70 (3)
Specific risk factors
Electrolyte imbalance 27/68 (40)
Underlying cardiac disease 32/68 (47)
Concomitant proarrhythmic agents 39/68 (57)
Other drugs influencing cardiac function 23/68 (34)
Baseline QTc >450 msec 18/68 (26)
QTc known: 44 patients 18/44 (41)

Overall, 32 patients had underlying heart conditions. Electrolyte imbalances, including hypokalemia, hypomagnesemia, and hypocalcemia, were present in 17 patients. At least 39 patients were receiving potentially proarrhythmic agents (1‐8 proarrhythmic drugs per patient) in addition to IV haloperidol. At least 23 patients were receiving additional drugs with a potential for other cardiac adverse events than QTP and TdP.

A wide range of other disease states previously reported to be associated with QTP15 were identified in these patients: asthma (5 patients), diabetes (5 patients), obesity (3 patients), impaired renal and/or liver function (3 patients each), human immunodeficiency virus (HIV) (2 patients); chronic obstructive pulmonary disease (COPD), pancreatitis and hypothyroidism (1 patient each). A total of 22 patients had a history of substance abuse (alcohol and/or drugs), and 4 patients were smokers.

The administered doses of IV haloperidol varied widely. Considering that information regarding the maximal daily dose was missing in 22 reports and ambiguous in another 20 cases, the results have been presented using cumulative IV haloperidol doses. Patients experiencing TdP without preceding QTP received a cumulative dose (= total dose at event) ranging from 5 mg to 645 mg. Patients with both confirmed QTP and TdP were administered a cumulative dose of 2 mg to 1700 mg. Patients who experienced QTP without TdP received a cumulative dose of 2 mg to 1540 mg of IV haloperidol.

Sudden cardiac arrest following administration of IV haloperidol was observed in cumulative doses ranging from 6 mg to 35 mg. The cardiac arrest leading to a fatal outcome was preceded by an administration of at least 6 mg of IV haloperidol. Overall, 14 out of 70 patients received cumulative doses of 10 mg IV haloperidol.

The time from administration to documentation of QTP and/or TdP ranged from immediately post administration to 8 hours after administration of the last dose of IV haloperidol.

Baseline QTc was known in 44 patients. Baseline QTc was >450 msec in 18 of these 44 patients.

The change from baseline QTc varied widely from 20 msec to 286 msec; 36 patients demonstrated a prolongation of >50 msec.

In those patients with reported haloperidol‐associated QTP, 25 patients demonstrated a QTc >600 msec and 38 patients >520 msec.9 Of the cases with known specific QTc values, the QTc was prolonged >450 msec in 48 out of 50 cases. The lowest reported QTc leading to TdP was 413 msec.

A total of 20 patients were reported as having a normalization of QTc (as defined by the original reports) within several hours to 8 days; minimal QTP was reported as persisting in 2 patients. The specifics of the other patients were unknown, although 25 patients were categorized as recovered, 13 were stated as having an uneventful remainder of hospitalization, and 5 patients were discharged to a rehabilitation facility or a nursing home.

Discussion

The current review was performed in response to the FDA warning recommending the use of continuous ECG monitoring associated with the administration of intravenous haloperiodol.5 This warning has resulted in substantial dilemmas for health care organizations, additional resource allocation, and increased scrutiny from regulatory agencies. The results of our review reveal that intravenous haloperidol‐associated QTP and TdP almost uniformly take place in patients with concomitant risk factors and with cumulative doses 2 mg. In light of these findings, it is possible that hospitals may be able to administer intravenous haloperidol in patients without risk factors without continuous ECG monitoring. In reviewing these published reports, it is important to note that the FDA identified 28 published cases of haloperidol‐associated QTP and TdP, while our review yielded a total of 41 published case reports.

The FDA database included 73 cases of haloperidol‐associated TdP in their database. However, these cases included both oral as well as IV administration; using our methodology, we identified 29 additional case reports associated with intravenous haloperidol from this database. Consequently, our review included 41 published case reports and 29 FDA database cases, resulting in the total of 70 patients.

Our review revealed a number of practical findings. First, our summary demonstrated that neither QTP nor TdP has been documented with a cumulative dose of IV haloperidol of <2 mg. The majority of patients (80%) received cumulative IV doses 10 mg. The lowest dose associated with sudden cardiac arrest was 6 mg and this took place in a 69‐year‐old male patient. Second, the majority (97%) of our patients had additional risk factors for QTP and/or TdP. Pre‐existing heart disease,1619 electrolyte imbalance,17, 1921 concomitant proarrhythmic drugs16, 17, 1922 and mechanical ventilation17, 23 were identified as the most commonly observed risk factors (Table 4). Lastly, in those cases in which the data were reported, baseline QTc was >450 msec in 41% of the patients, and 96% had a QTc at the time of the event >450 msec. Therefore, we conclude that patients: (1) receiving low cumulative doses (<2 mg) with (2) no risk factors for prolonged QTc or TdP, and (3) with a normal QTc on baseline EKG can safely be given IV haloperidol in the hospital setting.

This dosage range is consistent with the labelling for IV haloperidol dosing in Canada24 and Germany25 (Table 1), where single doses of 0.25 mg to 1.5 mg are recommended for the treatment of delirium or acute agitation in the geriatric population.24, 25

In a recent Cochrane review, low‐dose IV haloperidol (<3 mg per day) was concluded to be as safe and effective as atypical antipsychotics in the treatment of acute delirium with respect to extrapyramidal adverse effects.2

The American Psychiatric Association recommends an initial IV dose of 12 mg every 24 hours as needed (0.250.50 mg every 4 hours as needed for elderly patients), with titration to higher doses for patients who continue to be agitated for the treatment of patients with delirium (issued 1999, updated 2004).3

While several expert‐groups and investigators currently consider IV haloperidol as an important therapeutic option for treating acute delirium and agitation in the dose range presented above, less consensus exists regarding monitoring requirements.2, 3, 26, 27

The American Psychiatric Association recommends IV haloperidol only after a baseline ECG is obtained. These guidelines have not been updated since the release of the FDA extended warning.3 In their recent review, Morandi et al.28 support the dosage recommendation of the 1999 American Psychiatric Association's practice guidelines for treatment of delirium,3 ie, administration of IV haloperidol in single doses of 0.5 mg to 2 mg in elderly patients, however, only after a baseline ECG is obtained.28 While the package insert of IV haloperidol in France29 recommends a baseline ECG, Germany,25 Italy30 and Switzerland's31 package information states the need for regular ECG monitoring. Guidelines for the treatment of delirium in the intensive care unit published by the American College of Critical Care Medicine and the Society of Critical Care Medicine in collaboration with the American Society of Health‐System Pharmacists consider IV haloperidol as the preferred agent for the treatment of delirium in critically ill patients (grade of recommendation = C). These expert groups recommend that patients should be monitored for electrocardiographic changes (QT interval prolongation and arrhythmias) when receiving haloperidol (Grade of recommendation = B).32

Nevertheless, continuous ECG monitoring (ie, telemetry) is expensive, labor‐intensive and, potentially overutilized.33, 34 Requiring clinicians to place all patients receiving intravenous haloperidol on telemetry is impractical and potentially costly. Mandating telemetry could also lead to unintended harm, ie, use of a less effective or less safe drug to avoid compliance with the telemetry mandate.

Based on our findings and the current recommendations in the literature, inpatient providers should be thoughtful and deliberate in the use of haloperidol to treat acute delirium with agitation. Patients requiring pharmacologic management of their delirium should be screened for risk factors for QTP and TdP (Table 4) and a baseline ECG should be obtained prior to haloperidol administration. If significant risk factors exist or the baseline ECG reveals a prolonged QTc, then the patient should receive continuous ECG monitoring. Similarly, if cumulative doses of 2 mg are needed, the patient should be placed on telemetry.

There are some limitations to our study design. Our findings are based upon previously published case reports or data submitted to the FDA MedWatch. While the content of the FDA's MedWatch database is accessible to the public via the Freedom of Information Act (FOIA), the events are neither categorized nor peer‐reviewed upon entry into the database. Consequently, information may be incomplete or inaccurate. In addition, the denominator representing the overall use of IV haloperidol is unknown, thus a rate of event cannot be assigned and the true scope of the problem cannot be determined. Despite these limitations, this summary represents the most comprehensive review of the literature to date, expanding on the analysis performed by the FDA. Of note, in our review of the FDA database, we noted several cases of haloperidol‐associated QTP or TdP associated with other routes of administration. Thus, it is unknown whether this complication is any greater with IV vs. the IM or per os (PO) routes of administration.

Conclusion

Although the proarrhythmic potential of haloperidol and other antipsychotics has been well established in the literature, IV haloperidol has been considered relatively safe with respect to this complication from the time of its approval in 1967.5, 1722, 35, 36 In reviewing all reported cases of cardiac complications associated with IV haloperidol, as well as the current literature, an association with QTP and TdP is likely. However, the case reports reveal that QTP and TdP generally occur in the setting of concomitant risk factors, and no cases have been reported utilizing a cumulative IV dose of <2 mg. It may therefore be safe to administer a cumulative dose of IV haloperidol of <2 mg without ECG monitoring in patients without risk factors for QTP. However, ECG monitoring should take place with IV haloperidol doses 2 mg and/or in those patients with additional risk factors of developing QTP and/or TdP.

Based on the findings of this review complemented by the guidelines of various expert‐groups and the official labelling information of different countries, the Pharmacy & Therapeutics Committee of the UCSF Medical Center revised the IV haloperidol policy: administration of a total dose of <2 mg IV haloperidol without concurrent telemetry is allowed in a noncritical care setting in patients without risk factors for QTP and TdP.

Acknowledgements

The authors acknowledge Gloria Won of the Fishbon Library at UCSF Medical Center at Mount Zion for her support.

References

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