Haloperidol Use in Acute Traumatic Brain Injury: A Safety Analysis

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1 Research Article imedpub Journals htt:// Journal of Intensive and Critical Care ISSN DOI: / Haloeridol Use in Acute Traumatic Brain Injury: A Safety Analysis Abstract Background: The association of delirium with oor outcomes creates a comlex icture in traumatic brain injury atients by exacerbating an already increased risk for neurobehavioral sequelae. Haloeridol is commonly used for agitation and delirium; however, adverse events are concerns associated with its use in traumatic brain injury atients. The objective of this study was to assess the safety of haloeridol for the management of agitation and delirium in acute traumatic brain injury. Methods: A retrosective cohort study was conducted of adult ICU atients admitted from January 2007 to October 2009 with traumatic brain injury and admission Glasgow Coma Score 12. Incidence of comlications (seizures, neuroletic malignant syndrome, QTc rolongation, extrayramidal symtoms, hematologic disturbances) and haloeridol rescribing atters were assessed. Results: A total of 101 atients were included (56 non-haloeridol, 45 haloeridol). There was no difference in tyes of brain injury. Haloeridol was initiated on average day 8 of admission, and the median daily dose was 9 mg for a median duration of 4 days. The haloeridol grou received more analgesics (morhine equivalents) [714 vs. 252 mg, ], and more atients in the haloeridol grou received benzodiazeines comared to non-haloeridol grou [98% vs. 79%, = 0.005]. There was no significant increase in adverse events associated with haloeridol use. Patients in the haloeridol grou who develoed comlications received a higher mean daily dose [ = 0.013]. There was no difference in length of mechanical ventilation but the haloeridol grou had a longer hosital length of stay. Conclusion: Treatment of agitation and delirium with haloeridol in acute traumatic brain injury atients is not associated with an increased incidence of comlications. Keywords: Agitation; Delirium; Traumatic brain injury; Haloeridol Rebecca L Anderson 1, Kara L Birrer 2 and Xi Liu-DeRyke 3 1 Lakeland Regional Health, Deartment of Pharmacy, USA 2 Orlando Regional Medical Center, Deartment of Pharmacy, USA 3 Florida Hosital, Deartment of Pharmacy, USA Corresonding authors: Rebecca L Anderson Xi Liu-DeRyke rebecca.anderson@mylrh.org xi.liu@flhos.org PharmD, BCPS, Lakeland Regional Health, Deartment of Pharmacy, 1324 Lakeland Hills Boulevard, Lakeland, FL 33805, USA. Pharm D, FCCM, Florida Hosital, Deartment of Pharmacy, 601 E Rollins Street Orlando, FL 32803, USA. Tel: Citation: Anderson RL, Birrer KL, Liu-DeRyke X. Haloeridol Use in Acute Traumatic Brain Injury: A Safety Analysis. J Intensive & Crit Care, 2:2. Received: March 08, ; Acceted: March 16, ; Published: March 23, Background Recognition of delirium in the intensive care unit (ICU) and its imact on hositalization, short-term and long-term outcomes has gained increased awareness in the ast decade [1]. The management of delirium is more comlicated in atients with traumatic brain injuries (TBI) due to the injury-associated increased risk for neurobehavioral sequelae, including agitation, aggression, and disinhibition [2]. Early recognition and management of delirium is necessary due to the associated morbidity and mortality. It is imortant to use an agent that is safe for the management of agitation and delirium in the ICU. Haloeridol is a commonly used neuroletic agent for the management of agitation and delirium in critically ill atients. Haloeridol inhibits doamine recetors (D2) in the mesolimbic system, which regulates feelings of reward, motivation, and reinforcement [3]. There is concern with the use of haloeridol in TBI atients due to its adverse event rofile including neuroletic Under License of Creative Commons Attribution 3.0 License This article is available in: htt://criticalcare.imedub.com/archive.h 1

2 malignant syndrome (NMS), lowered seizure threshold, and imaired long-term cognitive recovery. NMS is thought to be caused by reduced central doamine neurotransmission [2]. This is significant in TBI atients because they have decreased doamine transmission at baseline which may be further exacerbated by haloeridol inhibition. The incidence of NMS varies from 0.02 to 12.2% based on atient oulation, with an unknown frequency in TBI atients [2]. TBI atients are also at an increased risk of ost-traumatic seizures which can worsen brain injury and haloeridol can exacerbate this risk by lowering the seizure threshold [3, 4]. Haloeridol may also rolong the length of osttraumatic amnesia, extend the time to return of cognitive function, and increase behavioral and cognitive deficits in TBI atients [2]. Increased awareness of delirium in the ICU has resulted in an increased use of haloeridol. Additional information is needed due to the limited literature available concerning the safety and efficacy of haloeridol in critically ill TBI atients. The urose of this study was to assess the safety of haloeridol for the treatment of agitation or delirium in atients with acute TBI. Methods This retrosective cohort study was conducted at a Level I trauma center and was aroved by the Institutional Review Board. Consecutive TBI atients admitted to the ICU between January 2007 and October 2009 were identified using ICD-9 codes. Patients who were 18 years of age or older and had an admission Glasgow Coma Score (GCS) of 12 or less were retained initially for the study. Those excluded had isolated skull fractures on comuted tomograhy (CT) scan, exired within 72 hours of admission, were actively going through alcohol withdrawal, had a diagnosis of Parkinson s disease, or had a home medication that included an antisychotic or mood stabilizer. Patients were stratified into two grous, those who received haloeridol and those who did not receive haloeridol during their hosital stay. Pertinent data were retrieved from the hosital electronic medical record. Demograhics collected included age, gender, race, and ast medical. Tye of TBI, extracranial injuries, GCS, Abbreviated Injury Scale (AIS) Head score, and Injury Severity Score (ISS) were recorded. Concurrent use of sedatives, analgesics, and quetiaine were reviewed. Sedatives were converted to midazolam equivalents and analgesics were converted to morhine equivalents [5]. The rimary outcomes were to describe the incidence of comlications and the rescribing atterns associated with the use of haloeridol in acute TBI atients. Five comlications were assessed during the entire hosital stay including seizures, NMS, QT c rolongation, extrayramidal symtoms (EPS), and hematologic disturbances. The resence of seizures was determined by documentation of occurrence and/or results of an electroencehalograhy (EEG) if available. NMS was characterized by the develoment of hyerthermia, severe extrayramidal dysfunction, alterations in consciousness, altered mental status, and/or autonomic instability [2]. Symtoms of NMS also include an increased serum creatine kinase (CK), acute renal failure, and leukocytosis (WBC 10,500/mm 3 ) [3]. The resence of NMS was 2 determined by documentation rovided in the medical chart. The QT c interval (QT interval corrected for heart rate) is considered at increased risk for rolongation if > 430 msec for men and > 450 msec for women and rolonged if > 450 msec for men and > 470 msec for women [6]. QT c rolongation was determined by documentation in the medical chart and/or the results of an electrocardiogram (ECG) if available. EPS was defined by the resence of Parkinson-like symtoms, akathisia, and/or dystonia and was determined by documentation available from the medical chart. Hematologic disturbances [leukoenia (WBC 4,000/mm 3 ) and/or neutroenia (neutrohils < 40.3%)] were determined by comlete blood counts (CBC) drawn during haloeridol treatment as comared to baseline rior to haloeridol initiation. The rescribing ractice atterns of haloeridol use included total dose, average daily dose, total number of haloeridol doses, and duration of haloeridol treatment. Clinical outcome data were assessed including ICU and hosital length of stay (LOS), number of days on mechanical ventilation (MV), and discharge disosition. Normally distributed data were assessed using Student s t-test. For non-arametric testing, the Mann-Whitney U test was erformed. Dichotomous variables were tested using Pearson s Chi-square or Fisher exact test. A -value of < 0.05 was used to determine statistical significance. A logistic regression analysis was erformed to identify indeendent risk factors associated with the develoment of comlications. All statistical analyses were erformed with Microsoft Excel for Windows and SPSS for Windows (version 16.0; SPSS, Inc., Chicago IL). Results A total of 309 TBI atients admitted from January 2007 to October 2009 were screened for inclusion. Eighty-two atients were excluded due to isolated skull fractures on CT scan. Of the 227 atients with a CT scan confirmed TBI, 126 atients were excluded: 100 exired within 72 hours, 11 were going through alcohol withdrawal, 7 had GCS > 12, 5 had home medications that included antisychotics, 2 charts could not be accessed, and 1 had Parkinson s disease. A total of 101 atients were retained for data analysis: 56 in the non-haloeridol grou and 45 in the haloeridol grou. Demograhics and clinical outcomes There were few differences in baseline demograhic characteristics between the two grous (Table 1). Patients in the haloeridol grou were younger than those in the non-haloeridol grou. The haloeridol grou had a higher median ISS score. There were no differences in the tye of TBI, with the majority in both grous diagnosed with a traumatic subarachnoid hemorrhage (SAH). Over 70% of atients had concurrent systemic injuries which may have necessitated the use of analgesics or benzodiazeines. Haloeridol usage and concomitant medications Haloeridol was initiated aroximately 8 (4-17) days following atient s admission. Patients in the haloeridol grou received a median daily dose of 9 (5-14) mg for duration of 4 (1-7) days. The median total dose received throughout the hosital stay was 35 (10-83) mg. A majority of atients received intravenous (IV) This article is available in: htt://criticalcare.imedub.com/archive.h

3 Table 1 Baseline demograhics. Non-haloeridol Haloeridol (n = 56) (n = 45) Age (years), median (IQR) 47 (28-67) 32 (24-43) Gender (male) 34 (61) 39 (87) Past medical history Psychiatric Seizures Stroke Traumatic brain injury 6 (11) 4 (7) 5 (9) 2 (4) 1 (2) 1 (2) GCS, median (IQR) 5 (3-7) 4 (3-7) ISS, median (IQR) 17 (9-24) 22 (16-27) AIS Head, median (IQR) 3 (3-4) 3 (3-4) Traumatic brain injury Eidural hemorrhage Intracranial hemorrhage Intraventricular hemorrhage Subarachnoid hemorrhage Subdural hemorrhage 3 (5) 28 (50) 11 (20) 39 (70) 31 (55) 5 (11) 19 (42) 5 (11) 29 (64) 19 (42) Systemic injury 38 (68) 37 (82) n (%) unless otherwise noted GCS: Glasgow Coma Scale; ISS: Injury Severity Score; AIS: Abbreviated Injury Scale haloeridol (64%) comared to IV and enteral (18%), enteral only (9%), or intramuscular (4%). In evaluating concomitant medications (Table 2), all atients received analgesics throughout the hosital stay. However, the haloeridol grou had a significantly longer length of treatment and higher total analgesic dose ( ). Although a majority of atients in both grous received benzodiazeines, significantly more atients in the haloeridol grou received benzodiazeines, required higher daily dose, and received longer duration of theray. The difference in analgesic and benzodiazeine use rior to and following the initiation of haloeridol was comared and no differences were found (data not shown). There was no significant difference in the number of atients who received roofol between the two grous. The haloeridol grou had a longer length of treatment ( = 0.033), greater average daily dose ( = 0.017), and larger total dose ( = 0.003). A higher ercentage of atients in the haloeridol grou did receive quetiaine ( ) but there was no difference in length of treatment or average daily dose. A majority of atients in both grous received rohylactic antieiletic theray (haloeridol 76% vs. no haloeridol 84%, = 0.324) with henytoin being the most commonly used medication. Adverse events and comlications Haloeridol use in acute TBI atients was not associated with an increase in the incidence of comlications (Tables 3). All three atients who develoed seizures during the study eriod required intervention. Of the two atients in the haloeridol grou, one atient seized on day two of haloeridol theray with a cumulative haloeridol dose of 20 mg given rior to the seizure. The other atient seized rior to receiving any haloeridol theray. QT c rolongation occurred in eleven atients in the non-haloeridol grou versus six atients in the haloeridol grou ( = 0.537). The six atients in Under License of Creative Commons Attribution 3.0 License the haloeridol grou received between two to six days of haloeridol theray before develoing QT c rolongation. The total dose of haloeridol administered rior to the onset of QT c rolongation ranged from 10 to 170 mg. None of the atients in the haloeridol grou required an intervention for their QT c rolongation. There was no documented NMS, EPS, or hematologic disturbances in either grou. A subgrou analysis assessing indeendent risk factors for develoing comlications was erformed in haloeridol atients only (n = 45). Of these atients, eight develoed comlications and 37 did not. Average daily dose was significantly higher in the grou who develoed comlications in a univariate analysis (14 mg vs. 7 mg) (Table 4). A logistic regression confirmed that an increase in average daily dose of haloeridol was a significant risk factor for develoing comlications after controlling for age, injury severity, and duration of theray [OR 1.145, 95% CI , = 0.02]. Clinical outcomes Clinical outcomes including LOS and mortality were evaluated (Table 5). While no difference was found in ICU LOS and duration of MV, atients who received haloeridol had a longer hosital LOS but a lower mortality rate. Discussion This is the first study to assess the safety of haloeridol for the treatment of agitation and delirium in acute TBI atients. Low to moderate haloeridol use was not associated with an increased incidence of comlications which suorts the short-term use of haloeridol in atients with acute TBI. Although no studies have been conducted to secifically assess haloeridol use in TBI atients, literature is available evaluating its use in general critically ill atients. Girard et al. evaluated the 3

4 Table 2 Concomitant medications. Analgesics, n (%) Length of treatment (days) Average dose (mg/day) Total dose (mg) Benzodiazeines, n (%) Length of treatment (days) Average dose (mg/day) Total dose (mg) Quetiaine, n (%) Length of treatment (days Average dose (mg/day) Total dose (mg) Median (IQR) unless otherwise noted Non-haloeridol (n = 56) Haloeridol (n = 45) 56 (100) 45 (100) 9 (6-18) 20 (13-29) 25 (17-51) 34 (18-60) ( ) 714 ( ) 44 (79) 3 (1-6) 8 (4-14) 24 (9-75) 9 (16) 7 (5-13) 96 (68-160) 625 ( ) Analgesics are reorted in morhine equivalents. Benzodiazeines are reorted in midazolam equivalents. 44 (98) 17 (8-24) 14 (6-32) 186 (77-476) 32 (71) 10 (7-20) 87 (45-177) 800 ( ) develoment of comlications in atients treated with haloeridol in the ICU comared to zirasidone and lacebo [7]. Thirty-five atients received a median haloeridol dose of 15 mg er day for seven days comared to 10 mg daily for four days in our study. In line with our study, there was no significant difference in serious adverse events, including QT c rolongation and NMS. A retrosective case-control study of 223 critically ill atients showed that 3.6% (eight atients) develoed torsades de ointes secondary to IV haloeridol use [8]. The comlication was considered drug related if it develoed within 24 hours of haloeridol use. Authors reorted that a total daily dose greater than 35 mg was associated with increased risk for QT rolongation. Of six atients who develoed QT rolongation in our study, one atient had an event five days following haloeridol administration. While this event may not be related to haloeridol use, we took a conservative aroach to include it in our results. Three of the five remaining atients received a total daily dose greater than 30 mg rior to exeriencing QT rolongation ( mg). This is in line with what has been reorted in the literature where QT rolongation is associated with a higher total daily haloeridol dose. None of our atients required an intervention for QT rolongation. A literature review of the develoment of NMS in TBI atients treated with haloeridol revealed nine cases [2]. The cumulative dose of haloeridol received rior to the develoment of NMS was reorted in six of these cases, ranging from 10 to 210 mg. A majority (five out of six) received 30 mg er dose. In our study, the cumulative doses ranged from 4 to 563 mg without any evidence of the develoment of NMS. However, none of our atients received single doses as high as 30 mg. The incidence of seizures with antisychotic use in TBI atients is unknown. However, haloeridol is one of the few antisychotic agents available in arenteral formulation and associated with lower seizure risk comared to other antiyschotics [3]. Our study suorts this low risk, with only one atient develoing a seizure after receiving haloeridol. Several differences were noted in our study including mortality, hosital LOS, and benzodiazeine use. Although our study is not 4 owered to detect statistical significance in clinical outcomes, a higher mortality was found in atients who did not receive haloeridol comared to those who did. While this finding is similar to what was reorted by Milbrandt et al, we susect this is a coincidental finding due to our small samle size [9]. Additionally, haloeridol is tyically given in the later course of a TBI atients hositalization in our institution, which may contribute to more haloeridol use in the atients who survived. It should be noted, however, that the difference in baseline severity of injury between the two study grous did not suggest that atients in the no haloeridol grou were more likely to exire making the increased mortality an unexected finding. Ely et al. reorted delirium as an indeendent redictor of longer hosital LOS which suorts the result seen in our study [10]. However, the difference in hosital LOS may also be attributed to the higher survival rate in the haloeridol grou. This increase in the survival and the hosital LOS may also exlain higher benzodiazeine requirements in the haloeridol grou. Due to the retrosective nature of this study, limitations exist which require discussion. The researchers relied on reorted laboratory findings and clinical indicators for identification of comlications associated with haloeridol administration. Lack of documentation may lead to a low reorted incidence of adverse events; however, the documentation does allow cature of clinically relevant adverse events. Additionally, an assessment of concurrent medications for otential QT c rolongation was not made when evaluating this adverse event. Another limitation to this study was the relatively small samle size. This samle size may not have been large enough to detect a difference between the grous in the develoment of comlications associated with haloeridol use in TBI atients. A fourth limitation to this study was the lack of a screening tool to differentiate between delirium and agitation in the TBI oulation. The diagnosis and treatment of delirium and agitation was at the discretion of the managing hysician. Therefore, it could not be determined if the increased use of analgesics and benzodiazeines noted in the haloeridol grou was due to the lack of early recognition of delirium or if the use of these agents contributed to the develoment of delirium. Finally, since atients were only followed for the duration of their hositalization, no assessment could be made regarding the imact of haloeridol use on long-term functional recovery. The limited animal and human studies on long-term functional This article is available in: htt://criticalcare.imedub.com/archive.h

5 Table 3 Primary outcome-comlications. Non-haloeridol Haloeridol (n = 56) (n = 45) Comlication occurred, n (%) 12 (21) 8 (18) Seizures, n (%) 1 (2) 2 (4) QT c rolongation, n (%) 11 (20) 6 (13) Neuroletic malignant syndrome, extrayramidal symtoms, or hematologic disturbances did not occur A seizure occurred on day two of haloeridol theray after a cumulative dose of 20 mg; the other occurred rior to haloeridol administration. QT c rolongation occurred in the haloeridol grou between days two to six of haloeridol theray with a cumulative dose ranging from 10 to 170 mg; only one atient required an intervention and was in the nonhaloeridol. Table 4 Haloeridol usage by comlications. No Comlications Comlications (n = 37) (n = 8) Hosital day initiated 10 (5-18) 5 (3-13) Average dose (mg/day) 7 (5-13) 14 (10-27) Total dose (mg) 30 (9-73) 75 (24-294) Duration of theray (days) 3 (1-7) 6 (2-8) Median (IQR) unless otherwise noted recovery after haloeridol administration resent conflicting results [11-13]. The use of haloeridol for the treatment of agitation and delirium in atients with acute TBI was not associated with an increased incidence of comlications. The comlications that did occur in the haloeridol grou were associated with higher average daily doses. Prosective studies are needed to further evaluate the relationshi between haloeridol and safety outcomes in atients with acute TBI. Table 5 Clinical outcomes. Non-haloeridol Haloeridol (n = 56) (n = 45) ICU LOS (days) 7 (4-11) 7 (6-11) Hosital LOS (days) 11 (7-22) 22 (15-33) Duration of MV (days) 7 (2-12) 6 (4-9) Mortality, n (%) 14 (25) 1 (2) Median (IQR) unless otherwise noted ICU: Intensive Care Unit; LOS: Length of Stay; MV: Mechanical Ventilation Withdrawal of 11 in the non-haloeridol grou and one in the haloeridol grou Under License of Creative Commons Attribution 3.0 License 5

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