BRIEF REPORT Efficacy and Safety of Analgosedation with Fentanyl Compared with Traditional Sedation with Propofol Kristen M. Tedders,1,* Kelly N. McNorton,2 and Stephanie B. Edwin,2 1

Department of Pharmacy, St. John Macomb-Oakland Hospital, Warren, Michigan; 2Department of Pharmacy, St. John Hospital and Medical Center, Detroit, Michigan

OBJECTIVES To compare the efficacy and safety of analgosedation with fentanyl versus traditional sedation with propofol in critically ill patients receiving mechanical ventilation. METHODS Retrospective, observational study evaluating adult critically ill patients on mechanical ventilation at a community teaching hospital who received continuous infusion fentanyl (n=50) or propofol (n=50) from September 2011–March 2013. RESULTS Median duration of mechanical ventilation was similar between patients receiving propofol and fentanyl infusions (46.7 hr vs 46.0 hr, p=0.19). No difference was noted in median intensive care unit length of stay between groups (p=0.42). A larger percentage of patients receiving propofol required rescue opioids compared with patients receiving fentanyl (56% vs 34%, p=0.04). Furthermore, patients receiving propofol required significantly more rescue opioid therapy during the course of mechanical ventilation as calculated by fentanyl equivalents (150 lg vs 100 lg, p=0.03). No difference in the rate of intensive care unit delirium was noted between groups (fentanyl 23% vs propofol 27%, p=0.80). CONCLUSION Analgosedation with fentanyl appears to be a safe and effective strategy to facilitate mechanical ventilation. This regimen does not appear to affect duration of mechanical ventilation when compared with propofol, but may allow for more optimal pain management in critically ill patients. KEY WORDS analgosedation, fentanyl, propofol, sedation, critical care. (Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1429

Sedation and analgesia are often required for patients receiving mechanical ventilation in the intensive care unit (ICU) in order to control pain, agitation, and to facilitate ventilation.1 Historically, a sedative approach with benzodiazepines or propofol has been employed.2–6 The quick onset and short duration of propofol make for an attractive option not associated with accumulation. Propofol, however, lacks analgesic activity, which may result in the under treatPresented as an abstract at Society of Critical Care Medicine Annual Congress in San Francisco, California, from January 9 to 13, 2014. Disclosures: No financial support to disclose for any authors. *Address for correspondence: Kristen M. Tedders, 11800 East 12 Mile Road, Warren, MI 48093; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.

ment of pain if not used concurrently with opioids. Inadequate pain management has been associated with significant psychologic consequences for patients during hospitalization and over the long term.7 Analgesia-based sedation, known as analgosedation, has been compared with traditional sedation in several recent studies.8–12 This strategy emphasizes the initial use of an opioid to control pain and agitation, followed by the addition of a sedative as needed for residual agitation.8 Previous studies comparing analgosedation and traditional sedation regimens have reported decreased duration of mechanical ventilation, decreased ICU length of stay, and an increase in the amount of time patients are within goal sedation and pain scores.9, 10 Analgosedation has also been shown to reduce the requirements for hypnotics, decreasing the

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number of adverse reactions associated with these agents.10, 11 Based on these data, the Society of Critical Care Medicine upgraded its pain, agitation, and delirium clinical practice guideline in 2013 to recommend the use of analgesia-first sedation in critically ill mechanically ventilated patients (+2B).1 Current analgosedation literature has noted limitations. As-needed morphine was assessed in a previous analgosedation study, however, this agent is less frequently used in the ICU due to concerns of hypotension resulting from histamine release.12 Remifentanil is the only continuous-infusion opioid studied to date against traditional agents for sedation. It is an attractive choice due to high potency, fast onset, short half-life, and metabolism independent of renal or hepatic systems.13 Remifentanil, however, is more costly than other opioids and has been associated with increased frequency of pain and supplementary opioid requirements during the postextubation phase.14, 15 In contemporary practice, fentanyl is the most frequently utilized opioid analgesic in critically ill patients.5, 6 Due to larger volumes of distribution and an increased half-life, fentanyl may have altered pharmacokinetics in critically ill patients that could result in potential accumulation, especially in patients with end organ dysfunction.16 A variety of sedation regimens are used in patients receiving mechanical ventilation at our institution. Propofol infusion is a frequently selected option for sedation due to the short duration of action, making it desirable for patients who need frequent neurologic examinations or a perceived short duration of mechanical ventilation. Fentanyl infusions are also often utilized, as the drug is associated with less hypotension and bradycardia compared with propofol. There are currently no studies comparing outcomes of analgosedation with fentanyl infusion versus continuous infusion propofol. The purpose of this study was to compare the efficacy and safety of analgosedation with fentanyl versus propofol in critically ill patients receiving mechanical ventilation. Methods This retrospective, observational study was performed at St. John Hospital and Medical Center, a 772-bed community teaching hospital in Detroit, Michigan, with 52 adult intensive care beds (medical, surgical, and cardiovascular). Institutional review board approval was granted

before data collection; informed consent was waived due to the retrospective nature of the study. For patients receiving mechanical ventilation, institutional guidelines recommend pain assessment at minimum every 4 hours using the Critical Care Pain Observation Tool (CPOT) with a goal score less than 3.17 Agitation is assessed using the Richmond Agitation Sedation Scale (RASS) at least every 4 hours with a goal score 0 to 1.18 Delirium is assessed using the Confusion Assessment Method for the ICU (CAM-ICU) at minimum every 24 hours with a goal of negative for delirium.19 All patients receive a spontaneous awakening and breathing trial daily as tolerated, unless a contraindication is present.20 Patients greater than 18 years of age receiving mechanical ventilation for a minimum of 24 hours between September 2011 and March 2013 were eligible for inclusion in this study. Patients were required to have received either continuous infusion sedation with propofol or fentanyl. Breakthrough intravenous (IV) push opioids and benzodiazepines were administered on an as-needed basis by nurse or prescriber discretion based on pain and sedation scores. A list of eligible patients was generated from the pharmacy information system and data were collected from the electronic medical record. Only the initial ICU admission for each patient was evaluated for inclusion. Exclusion criteria included patients with weight over 120 kg, pregnancy or lactation, or hepatic impairment (Child-Pugh score > 10). Patients with stroke, traumatic brain injury, status epilepticus, subdural hematoma, or coma defined as Glasgow Coma Score less than 6 for more than 24 hours off sedation were also excluded. Patients were also excluded if they required paralytics or epidural anesthesia, if they switched study agents, had an additional continuous infusion analgesic or sedative added onto their regimen during ICU admission, were hypothermic, or had a history of drug abuse. Baseline demographics, social history, and laboratory data regarding organ dysfunction and severity of illness were collected. Data collection also included admission and discharge date from the ICU, days on mechanical ventilation, doses of fentanyl and propofol, and doses of rescue opioids or benzodiazepines used as needed. All opioids were converted to fentanyl equivalents (10 mg morphine = 100 lg fentanyl) and benzodiazepines were converted to midazolam equivalents (1 mg lorazepam = 2 mg midazolam).1, 21 CPOT, RASS, and CAM-ICU scores

ANALGOSEDATION COMPARED WITH PROPOFOL Tedders et al were collected for the duration of ICU admission. The frequency of adverse events was determined by episodes of bradycardia (heart rate < 50 beats per min), hypotension within 4 hours of sedation initiation (systolic blood pressure < 90 mm Hg measured at two consecutive times or decrease in systolic blood pressure > 40 mm Hg), delirium, and incidence of constipation and/or ileus. The primary end point of this study was the duration of mechanical ventilation in patients receiving continuous sedation with fentanyl compared with those patients receiving propofol. Secondary end points included ICU length of stay, percent of pain and sedation scores at goal, and frequency of adverse events between groups. Data are reported using descriptive statistics. Continuous variables were described as median with interquartile range; categorical variables were described as frequency distributions. Kruskal–Wallis test was used to determine the difference in medians. Fisher’s exact test and v2 test were used to find the difference in proportions. All data were analyzed with SPSS v. 22.0 (IBM, Pittsburgh, PA) and a p value