Michael J. Armahizer

Analgosedation: A Paradigm Shift in Intensive Care Unit Sedation Practice

Objective: To critically evaluate the use of analgosedation in the management of agitation in critically ill mechanically ventilated patients. Data Sources: Literature was accessed through MEDLINE (1948-November 2011) and Cochrane Library (2011, issue 1) using the terms analgosedation, analgosedation, or analgesia-based sedation alone or in combination with intensive care unit or critically ill. Reference lists of related publications were also reviewed. Study Selection and Data Extraction: All articles published in English were evaluated. Randomized controlled trials examining critically ill mechanically ventilated patients older than 18 years were included. Data Synthesis: Limitations of current sedation practices include serious adverse drug events, prolonged mechanical ventilation time, and intensive care unit (ICU) length of stay. Studies have demonstrated that analgosedation, a strategy that manages patient pain and discomfort first, before providing sedative therapy, results in improved patient outcomes compared to standard sedative-hypnotic regimens. Nine randomized controlled trials comparing remifentanil-based analgosedation to other commonly used agents (fentanyl, midazolam, morphine, and propofol) for ICU sedation and 1 trial comparing morphine to daily sedation interruption with propofol or midazolam were reviewed. Remifentanil is an ideal agent for analgosedation due to its easy titratability and organ-in dependent metabolism. When compared to sedative-hypnotic regimens, remifentanil-based regimens were associated with shorter duration of mechanical ventilation, more rapid weaning from the ventilator, and shorter ICU length of stay. Compared to fentanyl-based regimens, remifentanil had similar efficacy with the exception of increased pain requirements upon remifentanil discontinuation. Analgosedation was well tolerated, with no significant differences in hemodynamic stability compared to sedative-hypnotic regimens. Conclusions: Analgosedation is an efficacious and well-tolerated approach to management of ICU sedation with improved patient outcomes compared to sedative-hypnotic approaches. Additional well-designed trials are warranted to clarify the role of analgosedation in the management of ICU sedation, including trials with nonopioid analgesics.

Drug-drug interactions contributing to QT prolongation in cardiac intensive care units

PURPOSE To determine the most common drug-drug interaction (DDI) pairs contributing to QTc prolongation in cardiac intensive care units (ICUs). MATERIALS AND METHODS This retrospective evaluation included patients who were admitted to the cardiac ICUs between January 2009 and July 2009 aged ≥ 18 years with electrocardiographic evidence of a QTc ≥ 500 ms. Patients receiving at least two concomitant drugs known to prolong the QT interval were considered to experience a pharmacodynamic DDI. Drugs causing CYP450 inhibition of the metabolism of QT prolonging medications were considered to cause pharmacokinetic DDIs. The causality between drug and QTc prolongation was evaluated with an objective scale. RESULTS One hundred eighty-seven patients experienced QT prolongation out of a total of 501 patients (37%) admitted during the study period. Forty-three percent and 47% of patients experienced 133 and 179 temporally-related pharmacodynamic and pharmacokinetic interactions, respectively. The most common medications related to these DDIs were ondansetron, amiodarone, metronidazole, and haloperidol. CONCLUSION DDIs may be a significant cause of QT prolongation in cardiac ICUs. These data can be used to educate clinicians on safe medication use. Computerized clinical decision support could be applied to aid in the detection of these events.

Evaluation of Adjunctive Ketamine to Benzodiazepines for Management of Alcohol Withdrawal Syndrome

Background: Adjunctive medications to manage alcohol withdrawal syndrome (AWS) in patients not adequately responding to escalating doses of benzodiazepines (BZDs) are limited. The use of the N-methyl-d-aspartate antagonist ketamine, may serve as an effective adjunct agent; however, no published data currently exist for this practice. Objective: To determine the safety and efficacy of adjunct ketamine for management of AWS. Methods: The study was a retrospective review of adult patients from April 2011 to March 2014 who were administered ketamine specifically for management of AWS. Outcomes included changes in BZD requirements and ketamine-related adverse reactions. Results: Of 235 patients screened, 23 patients met study eligibility. Ketamine was initiated primarily with toxicology consultation for significant BZD requirements or delirium tremens. The mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively. Mean initial infusion dose and median total infusion rate during therapy were 0.21 and 0.20 mg/kg/h, respectively. There was no change in sedation or alcohol withdrawal scores in patients within 6 hours of ketamine initiation. The median change in BZD requirements at 12 and 24 hours post–ketamine initiation were −40.0 and −13.3 mg, respectively. The mean time to AWS resolution was 5.6 days. There was one documented adverse reaction of oversedation, requiring dose reduction. Conclusions: Ketamine appears to reduce BZD requirements and is well tolerated at low doses. Prospective dose range evaluations in the management of AWS would be helpful in determining its place as an adjunctive agent.

QT prolongation in the intensive care unit: commonly used medications and the impact of drug–drug interactions

Importance of the field: Critically ill patients are at an increased risk to develop drug–drug interactions (DDIs). DDIs that increase the risk of QT prolongation, and ultimately torsades de pointes, can result in a medical emergency. Many clinicians are unaware of the risk of certain drug combinations that may precipitate QT prolongation in the intensive care unit (ICU). Additional DDI education and a review of management strategies could assist with prevention of future adverse outcomes. Areas covered in this review: This review focuses on some commonly used medications in the ICU that may be involved in pharmacokinetic and/or pharmacodynamic DDIs leading to the development of QT prolongation and possibly torsades de pointes. Also, appropriate management strategies are discussed. What the reader will gain: The ICU clinician will gain a better understanding of common medications used in the ICU and DDIs that put patients at risk for the development of QT prolongation and torsades de pointes. Take home message: Medications that may cause QT prolongation are common in the ICU and DDIs need to be identified and prevented by the clinician to avoid a potentially life-threatening dysrrhythmia.

Comparing Drug-Drug Interaction Severity Ratings between Bedside Clinicians and Proprietary Databases

Purpose. The purpose of this project was to compare DDI severity for clinician opinion in the context of the patient’s clinical status to the severity of proprietary databases. Methods. This was a single-center, prospective evaluation of DDIs at a large, tertiary care academic medical center in a 10-bed cardiac intensive care unit (CCU). A pharmacist identified DDIs using two proprietary databases. The physicians and pharmacists caring for the patients evaluated the DDIs for severity while incorporating their clinical knowledge of the patient. Results. A total of 61 patients were included in the evaluation and experienced 769 DDIs. The most common DDIs included: aspirin/clopidogrel, aspirin/insulin, and aspirin/furosemide. Pharmacists ranked the DDIs identically 73.8% of the time, compared to the physicians who agreed 42.2% of the time. Pharmacists agreed with the more severe proprietary database scores for 14.8% of DDIs versus physicians at 7.3%. Overall, clinicians agreed with the proprietary database 20.6% of the time while clinicians ranked the DDIs lower than the database 77.3% of the time. Conclusions. Proprietary DDI databases generally label DDIs with a higher severity rating than bedside clinicians. Developing a DDI knowledgebase for CDSS requires consideration of the severity information source and should include the clinician.

Comparing Drug-Drug Interaction Severity for Clinician Opinion to Proprietary Databases

Purpose: Commercial clinical decision support software (CDSS) may overestimate the severity of drug-drug interactions (DDI) because of their broad application; whereas, clinicians with knowledge of the patient should be able to better assess DDI severity. The purpose of this project was to compare DDI severity for clinician opinion in the context of the patient’s clinical status to the severity of proprietary databases. Methods: This was a single-center, prospective evaluation of DDIs at a large, tertiary care academic medical center between October 11, 2010 and November 5, 2010 in a 10-bed cardiac intensive care unit (CCU). A pharmacist identified DDIs using two proprietary databases. The physicians (fellow and attending) and pharmacists (rounding and distribution) caring for the patients evaluated the DDIs for severity while incorporating their clinical knowledge of the patient. Severity was ranked on a scale ranging from A to D and X. Results: A total of 61 patients were included in the evaluation and experienced 769 DDIs. The most common DDIs included: aspirin/clopidogrel (n=21, 2.7%), aspirin/insulin (n=21, 2.7%) and aspirin/furosemide (n=19, 2.5%). Pharmacists ranked the DDIs identically 73.8% of the time, compared to the physicians who agreed 42.2% of the time. Pharmacists agreed with the more severe proprietary database scores for 14.8% of DDIs versus physicians at 7.3%. Among the five contraindicated DDIs, two were rated as category B (minor severity/no action needed) and three as category C (moderate severity/monitor therapy) by the majority of the reviewers. Overall, clinicians agreed with the proprietary database 20.6% of the time while clinicians ranked the DDIs lower than the database 77.3% of the time. Conclusions: Proprietary DDI databases generally label DDIs with a higher severity rating as compared to clinicians who are caring for patients. Developing a DDI knowledgebase for CDSS requires careful consideration of the source of the severity information and should include clinician input in order to create clinically meaningful alerts.

Drug Class Combination–Associated Acute Kidney Injury

Objective: To evaluate the quality of available evidence of drug class combinations and their association with the development of acute kidney injury (AKI). Data Sources: A search of MEDLINE and Embase databases was completed using the following terms: “risk factor AND (acute kidney injury or acute kidney failure) AND (drug or medication).” Study Selection and Data Extraction: Inclusion criteria were the following: English language, full-text availability, and at least 1 drug-combination. Each citation was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. The literature was evaluated using the quality of evidence component of GRADE. No standardized definition of AKI was applied throughout.. Data Synthesis: Out of 2139 total citations, 151 were assessed for full-text review, with 121 citations (6%) meeting inclusion criteria, producing76 unique drug class combinations. Overall, 56 combinations (73.7%) were considered very low quality; 12 (15.8%) were considered low quality. There were 8 (10.5%) of moderate quality, and no combination was considered high quality. 58 (76%) combinations that had a single citation,with a mean of 1.6 citations per drug class combination. The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics was reported in 10 citations, the largest number of citations. Conclusions: Our study demonstrates a lack of well-designed studies addressing drug class combination–associated AKI. The combination of NSAIDs and diuretics with or without additional renin-angiotensin aldosterone agents had the strongest level of evidence. Despite limitations, the information included in this review may result in additional scrutiny about combining certain individual nephrotoxic drugs.

Lacosamide Pharmacokinetics in a Critically Ill Patient Receiving Continuous Venovenous Hemofiltration

Lacosamide is a new‐generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high‐performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5–12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half‐life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH.

Evaluation of Pharmacist Utilization of a Poison Center as a Resource for Patient Care

The objective of this study was to evaluate pharmacist use of a Regional Poison Information Center (RPIC), identify potential barriers to utilization, and provide strategies to overcome these barriers. All calls placed to a RPIC by a pharmacist, physician, or nurse over a 5-year period were retrieved. These data were analyzed to assess the pharmacist utilization of the RPIC and the variation of call types. Additionally, a survey, designed to assess the past and future use of the RPIC by pharmacists, was distributed to pharmacists in the region. Of the 37 799 calls made to the RPIC, 26 367 (69.8%) were from nurses, 8096 (21.4%) were from physicians, and 3336 (8.8%) were from pharmacists. Among calls initiated by pharmacists, the majority involved medication identification (n = 2391, 71.7%). The survey had a 38.9% response rate (n = 715) and revealed a trend toward less RPIC utilization by pharmacists with more formal training but less practice experience. The utilization of the RPIC was lowest among pharmacists as compared to other health care professionals. This may be due to pharmacists’ unfamiliarity with the poison center’s scope of services and resources. Therefore, it is important that pharmacists are educated on the benefit of utilizing poison centers in clinical situations.

A Retrospective Analysis of Prolonged Empiric Antibiotic Therapy for Pneumonia Among Adult Neurocritical Care Patients

Background and Purpose: Current literature reports that half of critically ill patients are continued on broad-spectrum antibiotics beyond 72 hours despite no confirmed infection. The purpose of this retrospective study was to identify the incidence of and risk factors for prolonged empiric antimicrobial therapy (PEAT) in adult neurocritical care (NCC) patients treated for pneumonia, hypothesizing that NCC patients will have a higher incidence of PEAT. Methods: This is a retrospective chart review of adult NCC patients treated for pneumonia. Antibiotic therapy was classified as restrictive, definitive, or PEAT based on culture results and timing of discontinuation or de-escalation. Results: A total of 95 patients (median age: 57 years; 28.4% female; admission diagnosis: 73.7% cerebrovascular, 10.5% neuromuscular, and 15.8% seizure-related) were included in this study. Overall, 59% of antibiotic regimens were considered PEAT, with vancomycin and piperacillin/tazobactam being most commonly prescribed. Median duration of therapy was 6.8 days, with shorter duration in patients with negative culture results compared to those with positive culture results (6.1 days [interquartile range, IQR 4.0-8.3] vs 7.2 days [IQR 5.8-10.3], P < .05). On multivariable analysis, elevated baseline white blood cell count, meeting Centers for Disease Control criteria for pneumonia, and negative bacterial culture were significantly associated with PEAT. Conclusion: The incidence of prolonged empiric antibiotic use was high in the NCC population. Patients are at particular risk for PEAT if they have negative cultures. All but one patient did not meet criteria for central fever, highlighting the challenges in identifying fever etiology in the NCC population.