513559
research-article2013
AOPXXX10.1177/1060028013513559Annals of PharmacotherapyMichaud et al
Research Report
Early Pharmacological Treatment of Delirium May Reduce Physical Restraint Use: A Retrospective Study
Annals of Pharmacotherapy 2014, Vol. 48(3) 328–334 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013513559 aop.sagepub.com
Christopher J. Michaud, PharmD1, Wendy L. Thomas, PharmD1, and Karen J. McAllen, PharmD, FCCM1
Abstract Introduction: Evidence surrounding pharmacological treatment of delirium is limited. The negative impact of physical restraints on patient outcomes in the intensive care unit (ICU), however, is well published. The objective of this study was to evaluate whether initiating pharmacologic delirium treatment within 24 hours of a positive screen reduces the number of days in physical restraints and improves patient outcomes compared with delayed or no treatment. Methods: Patients from a mixed ICU with a documented positive delirium score using the Intensive Care Delirium Screening Checklist were retrospectively grouped based on having received pharmacologic treatment within 24 hours of the first positive screen or not. Primary end points were number of days spent in physical restraints and time to extubation after delirium onset. Secondary end points included hospital and ICU length of stay (LOS) and survival to discharge. Results: Two hundred intubated patients were either pharmacologically treated (n = 98) or not treated (n = 102) within 24 hours of the first positive delirium score. Patients receiving treatment spent a shorter median time in restraints compared with patients who were not treated (3 vs 6 days; P < .001), and had a shorter median time to extubation (3 vs 6.5 days; P < .001). The treatment group also experienced a shorter ICU LOS (9.5 vs 16 days; P < .001) and hospital LOS (14.5 vs 22 days; P < .001) compared with the no-treatment group. Conclusions: Delirious patients who received pharmacological treatment within 24 hours of the first positive screen spent fewer days in physical restraints and less time receiving mechanical ventilation compared with those who did not. Although delirium management is multifactorial, early pharmacological therapy may benefit patients diagnosed with delirium. Keywords delirium, physical restraints, antipsychotic, intensive care, mechanical ventilation, retrospective, Intensive Care Delirium Screening Checklist, ICDSC
Delirium remains a common, often elusive consequence of critical illness. Despite an increase in awareness and research, the incidence in the intensive care unit (ICU) is estimated to range from 20% to 50% in nonventilated patients and up to 80% in ventilated patients.1-4 There is a well-supported link between the development of ICU delirium and negative outcomes; its diagnosis has been associated with increased hospital and ICU length of stay (LOS), prolonged mechanical ventilation, long-term cognitive impairment, and increased costs.1,3,5-10 Additionally, it is accepted that delirium occurs in distinct motor subtypes, with the hypoactive form reportedly going unrecognized in 75% of patients and conferring worse clinical outcomes compared with the hyperactive subtype.11,12 These findings have heightened awareness of delirium in the ICU and
highlighted the importance of early identification and appropriate management of delirious patients. Of the many modifiable risk factors attributed to delirium development, use of physical restraints appears to play a uniquely detrimental role. Once thought to reduce falls and improve outcomes, data now link use of physical restraints to increased fracture risk,13-15 iatrogenic injury,16 hospital LOS,17 and mortality18 as well as sudden cardiac death19 and no reduced risk of falls in adult ICU patients.15,16 1
Spectrum Health, Grand Rapids, MI, USA
Corresponding Author: Christopher J. Michaud, PharmD, Spectrum Health Department of Pharmacy, 100 Michigan St NE MC 001, Grand Rapids, MI 49503, USA. Email: [email protected]
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Michaud et al First implicated as a risk factor in 1996, the use of physical restraints has repeatedly shown to increase the odds of developing delirium.20-24 Minimizing the use of physical restraints has been shown to decrease the risk of developing delirium and reduce delirium duration, possibly by allowing for earlier mobilization.25 To date, however, the impact of delirium treatment on physical restraint use has not been studied. Whereas trials have examined individual agents in the treatment of ICU delirium, there is also a gap in the literature regarding the impact of treatment as a whole. To date, no trials have included all accepted pharmacological treatments as an experiment arm and compared outcomes with nontreated patients. The 2013 Pain, Analgesia, and Delirium (PAD) Guidelines suggest that atypical antipsychotics may reduce the duration of delirium (level of evidence C) but make no recommendations for routine pharmacological treatment.26 As such, the pharmacological management of delirious patients varies greatly, with some receiving early drug therapy, some receiving late drug therapy, and some receiving none at all, at each medical team’s discretion. To the authors’ knowledge, only 1 prospective study has evaluated the impact of early versus delayed pharmacological treatment of delirium. In the trial, Heymann et al27 reported reduced mechanical ventilation, fewer nosocomial infections, and lower mortality when patients were treated within 24 hours of diagnosis. The goal of this retrospective analysis was to assess patient outcomes after prompt administration of any clinically accepted delirium treatment medication. The primary outcomes were patient-days spent in physical restraints and time to extubation after the first positive delirium screen. Secondary outcomes included ICU and hospital LOS, time to first delirium onset, presence of deliriogenic medications prior to a positive delirium screen, survival to discharge, and discharge outcomes scores.
Materials and Methods Patient Selection This study is a retrospective cohort analysis conducted at a nonacademic, tertiary community hospital. The institutional review board at Spectrum Health approved the study and waived consent because of its retrospective nature. Patients admitted to the 22-bed medical/surgical ICU from February 2009 to December 2012 were routinely screened for delirium by trained bedside nurses using the Intensive Care Delirium Screening Checklist (ICDSC). Any patient with at least 1 documented positive delirium screen (indicated by a score of ≥4 on the ICDSC) was eligible to be included in the study. Other inclusion criteria included age ≥18 years and mechanical ventilation at the time of the first positive delirium screen. Patients were excluded if they were pregnant,
incarcerated at the time of admission, or had insufficient medical records. Included patients were then consecutively selected by convenience sample for analysis. Quetiapine, olanzapine, risperidone, ziprasidone, haloperidol, and dexmedetomidine were the medications considered clinically acceptable for delirium treatment. If at least 1 dose of a pharmacological treatment medication was administered to a patient within 24 hours of the first positive delirium screen, the patient was placed in the “treatment” group. If the patient received pharmacological treatment >24 hours after the first positive delirium screen or did not receive any pharmacological treatment during their delirium course, they were placed in the “no-treatment” group.
Data Collection All patient information was collected via electronic medical administration records. Baseline demographics and admitting ICU diagnoses were obtained, and severity of illness was measured using the modified Acute Physiology and Chronic Health Evaluation II (APACHE II), with the earliest available patient data for that admission.28 Administration of deliriogenic medications in the 2 days prior to the first positive delirium screen was recorded, as was sedative and analgesic use during the 7 days after the first positive screen. A list of potential deliriogenic medications was predetermined using available ICU delirium literature,29,30 and analgesic doses were totaled by medication and converted to morphine equivalents.31 To account for the unpredictable onset of delirium, LOS was recorded in 2 formats: (1) total ICU and hospital LOS and (2) ICU and hospital LOS after the first positive delirium screen. Modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS) scores were assessed based on discharge summaries.32,33 During the study period, patients requiring physical restraints were assessed daily using an algorithm that included physical mobility and fall risk assessments (Modified Conley Score), subjective potential to remove lines or interfere with treatment, and behavioral guidelines required for discontinuation. If the algorithm indicated that the patient no longer required physical restraints, they were removed the same day.
Statistical Analysis A power and sample size analysis was performed a priori. To detect a 20% difference in the primary outcome of days spent in physical restraints with α = .05, an estimated 198 patients would need to be enrolled. Parametric and nonparametric data were expressed as mean ± standard deviation and median with range, respectively. Pearson’s χ2 or Fisher’s exact tests were used to analyze dichotomous data. Continuous demographic data were
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Annals of Pharmacotherapy 48(3)
Table 1. Demographics, Delirium Screen Information, and Primary Intensive Care Unit Admission Diagnosis of Treatment and NoTreatment Groups.a
Male gender Age Weight (kg) Admitting APACHE II ICU day of delirium onset First (+) ICDSC score Hypervigilance documented First (+) score ≥3 days after ICU admission Primary ICU admission diagnosis Neurological Respiratory Sepsis or ID Hepatic Renal Cardiovascular Gastrointestinal Endocrine
Treatment, n = 98
No Treatment, n = 102
P Value
46 (47) 58 ± 17 93 ± 32 17 ± 7 4.5 (0-34) 4 (4-8) 29 (30) 69 (70)
48 (47) 62 ± 15 94 ± 33 18 ± 8 5.0 (0-28) 4 (4-8) 10 (10) 73 (72)
.986 .061 .737 .377 .435 .136 .05 for each. b
lance component were more likely to receive pharmacological treatment than those without. Overall, the group that received early treatment had significant improvements in outcomes compared with a demographically similar group that did not. Furthermore, although the importance of clinical judgment could never be overstated, the literature supports that hypoactive delirium occurs more frequently, conveys a worse prognosis, and is best diagnosed using the CAM-ICU or ICDSC.11,49-51 Though we were unable to assess the incidence of hypoactive delirium in this cohort, the results suggest that we should rely more heavily on our validated screening tools and that pharmacological treatment may merit stronger consideration when patients screen positive for all subtypes of delirium. As part of the Awake and Breathing Coordination, Delirium Monitoring and Management, and Early Mobility (ABCDE) bundle (described in detail elsewhere30,52-54), early mobility is desired in mechanically ventilated patients to prevent the development of delirium and reduce deconditioning and physical dysfunction. Longer courses of mechanical ventilation and use of physical restraints both work against mobilizing ICU patients. In this cohort, the treatment group spent 50% fewer days in physical restraints and less than half the time receiving mechanical ventilation after delirium diagnosis compared with the no-treatment group. Though the ABCDE bundle is aimed at preventing delirium and providing general care to intubated patients, the reduction in physical restraint use and mechanical ventilation seen in the patients who received early pharmacological treatment may have enabled earlier mobility and may have contributed to the shorter LOS and reduced mortality in this group of delirious patients. This is only speculation, however, as data regarding mobility was not collected.
Although in-hospital outcomes did improve, the impact of early treatment on long-term functional outcomes is less clear. Though improvements in mRS and GOS scores were statistically significant favoring the treatment group, the clinical impact of these findings may be minimal. First, both scales were originally designed for a specific patient subset; we used them to assess a diverse patient population. Second, the changes in scores were not large enough to indicate a clinical improvement in functional outcome. The long-term consequences of delirium development have been well reported. Most recently, the BRAIN-ICU study correlated a longer duration of delirium with worse cognition and executive function scores at 3 and 12 months.55 The long-term effects of delirium treatment, however, have yet to be established. There were several limitations to this study. The retrospective nature of the trial limited our ability to collect data that could add substantially to our findings, such as motor subtype of delirium, side effects of treatment medications, and initial indication for physical restraint use. Although sleep/wake cycle promotion, daily sedation wake-ups, clear and frequent reorientation, and other nonpharmacological measures are considered the standard of care in our ICU, it was not formally documented and thus unable to be assessed. The format for treating delirium was also nonstandardized during the time of the study, in that there was no formal algorithm or protocol to dictate delirium management, and clinicians could pharmacologically treat or not treat at their discretion. Patients were routinely screened for delirium on ICU admission, but after the initial positive screen, not all patients received frequent, continued ICDSC monitoring. Thus, we were unable to assess duration of delirium or time to resolution of delirium as recommended
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Michaud et al by recent delirium study guidelines.56 Finally, some patients received their first pharmacological treatment agent more than 24 hours into their delirium and were thus placed, by design, in the no-treatment group. Although this precludes conclusions regarding pure treatment versus no treatment, the results may reflect the importance of initiating pharmacological therapy early in the course of delirium. More prospective, placebo-controlled trials are needed to determine the role of pharmacological treatment in the management of delirium. One phase 3 study—Modifying the Impact of ICU-Induced Neurological Dysfunction USA (MINDS USA)—is currently studying delirious, mechanically ventilated ICU patients to further determine the shortand long-term effects of pharmacological treatment with ziprasidone and haloperidol.57 Additionally, prospective studies that can delineate delirium motor subtype will be helpful in solidifying the impact of delirium and its treatment on use of physical restraints.
Conclusion Patients in a mixed ICU who received treatment with a clinically accepted medication within 24 hours of the first positive delirium screen spent fewer days in physical restraints and experienced reduced mechanical ventilation time compared with those who received delayed or no treatment. Though it is only 1 component of the multimodal approach to delirium management, pharmacological therapy may benefit patients when initiated soon after a validated positive delirium screen. Acknowledgments The authors acknowledge the pioneering efforts of the Spectrum Health Blodgett ICU nursing staff, whose independent dedication to delirium screening and exceptional patient care provided the foundation for this research.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Thomason JWW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 260 nonventilated patients. Crit Care. 2005;9:R375-R381. 2. Ely EW, Inouye SK, Benard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). JAMA. 2001;286:2703-2710.
3. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753-1762. 4. McNicoll L, Pisani MA, Zhang Y, Ely EW, Siegel MD, Inouye SK. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc. 2003;51:591-598. 5. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care. 2004;32:955-962. 6. Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27:1892-1900. 7. Lat I, McMIllian W, Taylor S, et al. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit Care. 2009;37:1898-1905. 8. McCusker J, Cole M, Abrahamowicz M, Primeau F, Belzile E. Delirium predicts 12-month mortality. Arch Intern Med. 2002;162:457-463. 9. McAvay GJ, Van Ness PH, Bogardus ST, et al. Older adults discharged from the hospital with delirium: 1 year outcomes. J Am Geriatr Soc. 2006;54:1245-1250. 10. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009;180:1092-1097. 11. Stransky M, Schmidt C, Ganslmeier P, et al. Hypoactive delirium after cardiac surgery as an independent risk factor for prolonged mechanical ventilation. J Cardiothorac Vasc Anesth. 2011;25:968-974. 12. O’Keeffe ST, Lavan JN. Clinical significance of delirium subtypes in older people. Age Ageing. 1999;28:115-119. 13. Evans D, Wood J, Lambert L. Patient injury and physi cal restraint devices: a systematic review. J Adv Nurs. 2003;41:274-282. 14. Luo H, Lin M, Castle N. Physical restraint use and falls in nursing homes: a comparison between residents with and without dementia. Am J Alzheimers Dis Other Demen. 2011;26:44-50. 15. Tinetti ME, Liu WL, Ginter SF. Mechanical restraint use and fall-related injuries among residents of skilled nursing facilities. Ann Intern Med. 1992;116:369-374. 16. Lofgren RP, MacPherson DS, Granieri R, Myllenbeck S, Sprafka JM. Mechanical restraints on the medical wards: are protective devices safe? Am J Public Health. 1989;79:735-738. 17. Frengley JD, Mion LC. Incidence of physical restraints on acute general medical wards. J Am Geriatr Soc. 1986;34:565-568. 18. Miles SH, Irvine P. Deaths caused by physical restraints. Gerontologist. 1992;32:762-766. 19. Mohr WK, Mohr BD. Mechanisms of injury and death proximal to restraint use. Arch Psychiatr Nurs. 2000;14:285-295. 20. Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability. JAMA. 1996;275:852-857. 21. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354:1157-1165. 22. McCusker J, Cole M, Abrahamowicz M, Han L, Podoba JE, Ramman-Haddad L. Environmental risk factors for delirium in hospitalized older people. J Am Geriatr Soc. 2001;49:13271334.
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23. Norkiene I, Ringaitiene D, Misiuriene I, et al. Incidence and precipitating factors of delirium after coronary artery bypass grafting. Scand Cardiovasc J. 2007;41:180-185. 24. McPherson JA, Wagner CE, Boehm LM, et al. Delirium in the cardiovascular ICU: exploring modifiable risk factors. Crit Care Med. 2013;41:405-413. 25. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomized controlled trial. Lancet. 2009;373:1874-1882. 26. Barr J, Fraser GL, Puntillo K, et al. American College of Critical Care Medicine clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:263-306. 27. Heymann A, Radtke F, Schiemann A, et al. Delayed treatment of delirium increases mortality rate in intensive care unit patients. J Int Med Res. 2010;38:1584-1595. 28. Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-829. 29. Alagiakrishnan K, Wiens C. An approach to drug induced delirium in the elderly. Postgrad Med J. 2004;80:388-393. 30. Brummel NE, Girard TD. Preventing delirium in the intensive care unit. Crit Care Clin. 2013;29:51-65. 31. Pereira J, Lawlor P, Vigano A, et al. Equianalgesic dose ratios for opioids: a critical review and proposals for long-term dosing. J Pain Symptom Manage. 2001;22:672-687. 32. Bonita R, Beaglehole R. Modification of Rankin Scale: recovery of motor function after stroke. Stroke. 1988;19:1497-1500. 33. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1(7905):480-484. 34. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38:428-437. 35. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38:419-427. 36. Skrobik YK, Bergeron N, Dumont M, et al. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004;30:444-449. 37. Devlin JW, Bhat S, Roberts RJ, Skrobik Y. Current perceptions and practices surrounding the recognition and treatment of delirium in the intensive care unit: a survey of 250 critical care pharmacists from eight states. Ann Pharmacother. 2011;45:1217-1229. 38. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebocontrolled trial. Lancet Respir Med. 2013;1:515-523. 39. Riker RR, Shehabi Y, Bokesch PM, et al. SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group: dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489-499. 40. Pandharipande P, Pun B, Herr D, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction
in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298:2644-2653. 41. Yapici N, Coruh T, Kehlibar T, et al. Dexmedetomidine in cardiac surgery patients who fail extubation and present with a delirium state. Heart Surg Forum. 2011;14:E93-E98. 42. Mo Y, Zimmermann AE. Role of dexmedetomidine for the prevention and treatment of delirium in intensive care unit patients. Ann Pharmacother. 2013;47:869-876. 43. Bergeron N, Dubois MJ, Dumon M, et al. Intensive care delirium screening checklist: evaluation of a new screening tool. Intensive Care Med. 2001;27:859-864. 44. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the intensive care unit (CAM-ICU). Crit Care Med. 2001;29:1370-1379. 45. Schweickert WD, Kress JP. Implementing early mobilization interventions in mechanically ventilated patients in the ICU. Chest. 2011;140:1612-1617. 46. Scott P, McIlveney F, Mallice M. Implementation of a validated delirium assessment tool in critically ill adults. Intensive Crit Care Nurs. 2013;29:96-102. 47. Riekerk B, Pen EJ, Hofhuis JG, Rommes JH, Schultz MJ, Spronk PE. Limitations and practicalities of CAM-ICU implementation, a delirium scoring system, in a Dutch intensive care unit. Intensive Crit Care Nurs. 2009;25:242-249. 48. Page VJ, Navarange S, Gama S, McAuley DF. Routine delirium monitoring in a UK critical care unit. Crit Care. 2009;13:R16. 49. Peterson JF, Pun BT, Dittus RS, et al. Delirium and its motoric subtypes: a study of 614 critically ill patients. J Am Geriatr Soc. 2006;54:479-484. 50. Robinson TN, Raeburn CD, Tran ZV, Brenner LA, Moss M. Motor subtypes of postoperative delirium in older adults. Arch Surg. 2011;146:295-300. 51. Spronk PE, Riekerk B, Hofhuis J, Rommes JH. Occurrence of delirium is severely underestimated in the ICU during daily care. Intensive Care Med. 2009;35:1276-1280. 52. Balas MC, Vasilevskis EE, Burke WJ, et al. Critical care nurses’ role in implementing the “ABCDE bundle” into practice. Crit Care Nurse. 2012;32:35-38, 40-47. 53. Pandharipande P, Banerjee A, McGrane S, Ely EW. Liberation and animation for ventilated ICU patients: the ABCDE bundle for the back-end of critical care. Crit Care. 2010;14:157. 54. Morandi A, Brummel NE, Ely EW. Sedation, delirium and mechanical ventilation: the “ABCDE” approach. Curr Opin Crit Care. 2011;17:43-49. 55. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306-1316. 56. Trzepacz PT, Bourne R, Zhang S. Designing clinical trials for the treatment of delirium. J Psychosom Res. 2008;65:299-307. 57. Ely EW; Vanderbilt University. The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MINDUSA) Study. http://clinicaltrials.gov/show/NCT01211522. Accessed November 7, 2013.
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research-article2013
AOPXXX10.1177/1060028013513559Annals of PharmacotherapyMichaud et al
Research Report
Early Pharmacological Treatment of Delirium May Reduce Physical Restraint Use: A Retrospective Study
Annals of Pharmacotherapy 2014, Vol. 48(3) 328–334 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013513559 aop.sagepub.com
Christopher J. Michaud, PharmD1, Wendy L. Thomas, PharmD1, and Karen J. McAllen, PharmD, FCCM1
Abstract Introduction: Evidence surrounding pharmacological treatment of delirium is limited. The negative impact of physical restraints on patient outcomes in the intensive care unit (ICU), however, is well published. The objective of this study was to evaluate whether initiating pharmacologic delirium treatment within 24 hours of a positive screen reduces the number of days in physical restraints and improves patient outcomes compared with delayed or no treatment. Methods: Patients from a mixed ICU with a documented positive delirium score using the Intensive Care Delirium Screening Checklist were retrospectively grouped based on having received pharmacologic treatment within 24 hours of the first positive screen or not. Primary end points were number of days spent in physical restraints and time to extubation after delirium onset. Secondary end points included hospital and ICU length of stay (LOS) and survival to discharge. Results: Two hundred intubated patients were either pharmacologically treated (n = 98) or not treated (n = 102) within 24 hours of the first positive delirium score. Patients receiving treatment spent a shorter median time in restraints compared with patients who were not treated (3 vs 6 days; P < .001), and had a shorter median time to extubation (3 vs 6.5 days; P < .001). The treatment group also experienced a shorter ICU LOS (9.5 vs 16 days; P < .001) and hospital LOS (14.5 vs 22 days; P < .001) compared with the no-treatment group. Conclusions: Delirious patients who received pharmacological treatment within 24 hours of the first positive screen spent fewer days in physical restraints and less time receiving mechanical ventilation compared with those who did not. Although delirium management is multifactorial, early pharmacological therapy may benefit patients diagnosed with delirium. Keywords delirium, physical restraints, antipsychotic, intensive care, mechanical ventilation, retrospective, Intensive Care Delirium Screening Checklist, ICDSC
Delirium remains a common, often elusive consequence of critical illness. Despite an increase in awareness and research, the incidence in the intensive care unit (ICU) is estimated to range from 20% to 50% in nonventilated patients and up to 80% in ventilated patients.1-4 There is a well-supported link between the development of ICU delirium and negative outcomes; its diagnosis has been associated with increased hospital and ICU length of stay (LOS), prolonged mechanical ventilation, long-term cognitive impairment, and increased costs.1,3,5-10 Additionally, it is accepted that delirium occurs in distinct motor subtypes, with the hypoactive form reportedly going unrecognized in 75% of patients and conferring worse clinical outcomes compared with the hyperactive subtype.11,12 These findings have heightened awareness of delirium in the ICU and
highlighted the importance of early identification and appropriate management of delirious patients. Of the many modifiable risk factors attributed to delirium development, use of physical restraints appears to play a uniquely detrimental role. Once thought to reduce falls and improve outcomes, data now link use of physical restraints to increased fracture risk,13-15 iatrogenic injury,16 hospital LOS,17 and mortality18 as well as sudden cardiac death19 and no reduced risk of falls in adult ICU patients.15,16 1
Spectrum Health, Grand Rapids, MI, USA
Corresponding Author: Christopher J. Michaud, PharmD, Spectrum Health Department of Pharmacy, 100 Michigan St NE MC 001, Grand Rapids, MI 49503, USA. Email: [email protected]
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Michaud et al First implicated as a risk factor in 1996, the use of physical restraints has repeatedly shown to increase the odds of developing delirium.20-24 Minimizing the use of physical restraints has been shown to decrease the risk of developing delirium and reduce delirium duration, possibly by allowing for earlier mobilization.25 To date, however, the impact of delirium treatment on physical restraint use has not been studied. Whereas trials have examined individual agents in the treatment of ICU delirium, there is also a gap in the literature regarding the impact of treatment as a whole. To date, no trials have included all accepted pharmacological treatments as an experiment arm and compared outcomes with nontreated patients. The 2013 Pain, Analgesia, and Delirium (PAD) Guidelines suggest that atypical antipsychotics may reduce the duration of delirium (level of evidence C) but make no recommendations for routine pharmacological treatment.26 As such, the pharmacological management of delirious patients varies greatly, with some receiving early drug therapy, some receiving late drug therapy, and some receiving none at all, at each medical team’s discretion. To the authors’ knowledge, only 1 prospective study has evaluated the impact of early versus delayed pharmacological treatment of delirium. In the trial, Heymann et al27 reported reduced mechanical ventilation, fewer nosocomial infections, and lower mortality when patients were treated within 24 hours of diagnosis. The goal of this retrospective analysis was to assess patient outcomes after prompt administration of any clinically accepted delirium treatment medication. The primary outcomes were patient-days spent in physical restraints and time to extubation after the first positive delirium screen. Secondary outcomes included ICU and hospital LOS, time to first delirium onset, presence of deliriogenic medications prior to a positive delirium screen, survival to discharge, and discharge outcomes scores.
Materials and Methods Patient Selection This study is a retrospective cohort analysis conducted at a nonacademic, tertiary community hospital. The institutional review board at Spectrum Health approved the study and waived consent because of its retrospective nature. Patients admitted to the 22-bed medical/surgical ICU from February 2009 to December 2012 were routinely screened for delirium by trained bedside nurses using the Intensive Care Delirium Screening Checklist (ICDSC). Any patient with at least 1 documented positive delirium screen (indicated by a score of ≥4 on the ICDSC) was eligible to be included in the study. Other inclusion criteria included age ≥18 years and mechanical ventilation at the time of the first positive delirium screen. Patients were excluded if they were pregnant,
incarcerated at the time of admission, or had insufficient medical records. Included patients were then consecutively selected by convenience sample for analysis. Quetiapine, olanzapine, risperidone, ziprasidone, haloperidol, and dexmedetomidine were the medications considered clinically acceptable for delirium treatment. If at least 1 dose of a pharmacological treatment medication was administered to a patient within 24 hours of the first positive delirium screen, the patient was placed in the “treatment” group. If the patient received pharmacological treatment >24 hours after the first positive delirium screen or did not receive any pharmacological treatment during their delirium course, they were placed in the “no-treatment” group.
Data Collection All patient information was collected via electronic medical administration records. Baseline demographics and admitting ICU diagnoses were obtained, and severity of illness was measured using the modified Acute Physiology and Chronic Health Evaluation II (APACHE II), with the earliest available patient data for that admission.28 Administration of deliriogenic medications in the 2 days prior to the first positive delirium screen was recorded, as was sedative and analgesic use during the 7 days after the first positive screen. A list of potential deliriogenic medications was predetermined using available ICU delirium literature,29,30 and analgesic doses were totaled by medication and converted to morphine equivalents.31 To account for the unpredictable onset of delirium, LOS was recorded in 2 formats: (1) total ICU and hospital LOS and (2) ICU and hospital LOS after the first positive delirium screen. Modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS) scores were assessed based on discharge summaries.32,33 During the study period, patients requiring physical restraints were assessed daily using an algorithm that included physical mobility and fall risk assessments (Modified Conley Score), subjective potential to remove lines or interfere with treatment, and behavioral guidelines required for discontinuation. If the algorithm indicated that the patient no longer required physical restraints, they were removed the same day.
Statistical Analysis A power and sample size analysis was performed a priori. To detect a 20% difference in the primary outcome of days spent in physical restraints with α = .05, an estimated 198 patients would need to be enrolled. Parametric and nonparametric data were expressed as mean ± standard deviation and median with range, respectively. Pearson’s χ2 or Fisher’s exact tests were used to analyze dichotomous data. Continuous demographic data were
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Table 1. Demographics, Delirium Screen Information, and Primary Intensive Care Unit Admission Diagnosis of Treatment and NoTreatment Groups.a
Male gender Age Weight (kg) Admitting APACHE II ICU day of delirium onset First (+) ICDSC score Hypervigilance documented First (+) score ≥3 days after ICU admission Primary ICU admission diagnosis Neurological Respiratory Sepsis or ID Hepatic Renal Cardiovascular Gastrointestinal Endocrine
Treatment, n = 98
No Treatment, n = 102
P Value
46 (47) 58 ± 17 93 ± 32 17 ± 7 4.5 (0-34) 4 (4-8) 29 (30) 69 (70)
48 (47) 62 ± 15 94 ± 33 18 ± 8 5.0 (0-28) 4 (4-8) 10 (10) 73 (72)
.986 .061 .737 .377 .435 .136 .05 for each. b
lance component were more likely to receive pharmacological treatment than those without. Overall, the group that received early treatment had significant improvements in outcomes compared with a demographically similar group that did not. Furthermore, although the importance of clinical judgment could never be overstated, the literature supports that hypoactive delirium occurs more frequently, conveys a worse prognosis, and is best diagnosed using the CAM-ICU or ICDSC.11,49-51 Though we were unable to assess the incidence of hypoactive delirium in this cohort, the results suggest that we should rely more heavily on our validated screening tools and that pharmacological treatment may merit stronger consideration when patients screen positive for all subtypes of delirium. As part of the Awake and Breathing Coordination, Delirium Monitoring and Management, and Early Mobility (ABCDE) bundle (described in detail elsewhere30,52-54), early mobility is desired in mechanically ventilated patients to prevent the development of delirium and reduce deconditioning and physical dysfunction. Longer courses of mechanical ventilation and use of physical restraints both work against mobilizing ICU patients. In this cohort, the treatment group spent 50% fewer days in physical restraints and less than half the time receiving mechanical ventilation after delirium diagnosis compared with the no-treatment group. Though the ABCDE bundle is aimed at preventing delirium and providing general care to intubated patients, the reduction in physical restraint use and mechanical ventilation seen in the patients who received early pharmacological treatment may have enabled earlier mobility and may have contributed to the shorter LOS and reduced mortality in this group of delirious patients. This is only speculation, however, as data regarding mobility was not collected.
Although in-hospital outcomes did improve, the impact of early treatment on long-term functional outcomes is less clear. Though improvements in mRS and GOS scores were statistically significant favoring the treatment group, the clinical impact of these findings may be minimal. First, both scales were originally designed for a specific patient subset; we used them to assess a diverse patient population. Second, the changes in scores were not large enough to indicate a clinical improvement in functional outcome. The long-term consequences of delirium development have been well reported. Most recently, the BRAIN-ICU study correlated a longer duration of delirium with worse cognition and executive function scores at 3 and 12 months.55 The long-term effects of delirium treatment, however, have yet to be established. There were several limitations to this study. The retrospective nature of the trial limited our ability to collect data that could add substantially to our findings, such as motor subtype of delirium, side effects of treatment medications, and initial indication for physical restraint use. Although sleep/wake cycle promotion, daily sedation wake-ups, clear and frequent reorientation, and other nonpharmacological measures are considered the standard of care in our ICU, it was not formally documented and thus unable to be assessed. The format for treating delirium was also nonstandardized during the time of the study, in that there was no formal algorithm or protocol to dictate delirium management, and clinicians could pharmacologically treat or not treat at their discretion. Patients were routinely screened for delirium on ICU admission, but after the initial positive screen, not all patients received frequent, continued ICDSC monitoring. Thus, we were unable to assess duration of delirium or time to resolution of delirium as recommended
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Michaud et al by recent delirium study guidelines.56 Finally, some patients received their first pharmacological treatment agent more than 24 hours into their delirium and were thus placed, by design, in the no-treatment group. Although this precludes conclusions regarding pure treatment versus no treatment, the results may reflect the importance of initiating pharmacological therapy early in the course of delirium. More prospective, placebo-controlled trials are needed to determine the role of pharmacological treatment in the management of delirium. One phase 3 study—Modifying the Impact of ICU-Induced Neurological Dysfunction USA (MINDS USA)—is currently studying delirious, mechanically ventilated ICU patients to further determine the shortand long-term effects of pharmacological treatment with ziprasidone and haloperidol.57 Additionally, prospective studies that can delineate delirium motor subtype will be helpful in solidifying the impact of delirium and its treatment on use of physical restraints.
Conclusion Patients in a mixed ICU who received treatment with a clinically accepted medication within 24 hours of the first positive delirium screen spent fewer days in physical restraints and experienced reduced mechanical ventilation time compared with those who received delayed or no treatment. Though it is only 1 component of the multimodal approach to delirium management, pharmacological therapy may benefit patients when initiated soon after a validated positive delirium screen. Acknowledgments The authors acknowledge the pioneering efforts of the Spectrum Health Blodgett ICU nursing staff, whose independent dedication to delirium screening and exceptional patient care provided the foundation for this research.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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