Jeffrey Fong

Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study*

Objective: To compare the efficacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill patients requiring as-needed haloperidol. Design: Prospective, randomized, double-blind, placebo-controlled study. Setting: Three academic medical centers. Patients: Thirty-six adult intensive care unit patients with delirium (Intensive Care Delirium Screening Checklist score ≥4), tolerating enteral nutrition, and without a complicating neurologic condition. Interventions: Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Study drug was continued until the intensive care unit team discontinued it because of delirium resolution, therapy ≥10 days, or intensive care unit discharge. Measurements and Main Results: Baseline characteristics were similar between the quetiapine (n = 18) and placebo (n = 18) groups. Quetiapine was associated with a shorter time to first resolution of delirium [1.0 (interquartile range [IQR], 0.5–3.0) vs. 4.5 days (IQR, 2.0–7.0; p =.001)], a reduced duration of delirium [36 (IQR, 12–87) vs. 120 hrs (IQR, 60–195; p =.006)], and less agitation (Sedation-Agitation Scale score ≥5) [6 (IQR, 0–38) vs. 36 hrs (IQR, 11–66; p =.02)]. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%; p =.06). Subjects treated with quetiapine required fewer days of as-needed haloperidol [3 [(IQR, 2–4)] vs. 4 days (IQR, 3–8; p = .05)]. Whereas the incidence of QTc prolongation and extrapyramidal symptoms was similar between groups, more somnolence was observed with quetiapine (22% vs. 11%; p = .66). Conclusions: Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation. Future studies should evaluate the effect of quetiapine on mortality, resource utilization, post-intensive care unit cognition, and dependency after discharge in a broader group of patients.

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study

IntroductionWhile propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol.MethodsCritically ill adults from 11 academic medical centers administered an infusion of propofol for [>/=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS.ResultsAmong 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>/=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar.ConclusionsDespite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.

Predictors of mortality in patients with suspected propofol infusion syndrome

Objectives:To identify predictors of mortality in patients with suspected propofol infusion syndrome and to develop a simple scoring system to identify patients with suspected propofol infusion syndrome who are most at risk of death. Design:Retrospective, database analysis. Setting:MEDWATCH system. Participants:Reports (1989–2005) where propofol was associated with ≥1 of 24 published propofol infusion syndrome clinical manifestations. Interventions:None. Measurements and Main Results:After comparison of demographic and clinical manifestations between survivors and nonsurvivors, a multivariate logistic regression model was built through a stepwise selection process and then used to develop a simplified mortality scoring system. Of 1139 patients with suspected propofol infusion syndrome, 342 (30%) were fatal. Death was more likely if patients were ≤18 yrs (odds ratio [95% confidence interval], 2.3 [1.7–3.2]), male (1.3 [1.1–1.7]), received a vasopressor (1.8 [1.3–2.5)]), or had the following clinical manifestations: cardiac (3.8 [2.88–4.91]), metabolic acidosis (3.7 [2.7–5.0]), renal failure (1.9 [1.4–2.6]), hypotension (1.8 [1.3–2.3]), rhabdomyolysis (1.8 [1.3–2.3]), or dyslipidemia (2.0 [1.2–3.4]). The multivariable modeling process found that cardiac symptoms, rhabdomyolosis, hypotension, metabolic acidosis, renal failure, and age each affected survival, although significant interactions existed between some of these factors. Based on the combination of the presence or absence of the six factors in the multivariate model, a propofol infusion syndrome mortality risk score of 0 to 4 resulted in a predicted %/observed % mortality for each score of 0 (10%/10%), 1 (24%/24%), 2 (47%/44%), 3 (72%/81%), and 4 (89%/83%). Conclusions:A number of characteristics are independently associated with higher mortality in patients with suspected propofol infusion syndrome, only some of which are currently reflected in the package insert. Further research should focus on prospectively evaluating the mortality scoring system in patients with suspected propofol infusion syndrome.

Introduction to Drug Pharmacokinetics in the Critically III Patient

Despite regular use of drugs for critically ill patients, overall data are limited regarding the impact of critical illness on pharmacokinetics (PK). Designing safe and effective drug regimens for patients with critical illness requires an understanding of PK. This article reviews general principles of PK, including absorption, distribution, metabolism, and elimination, and how critical illness can influence these parameters. In the area of drug absorption, we discuss the impact of vasopressor use, delayed gastric emptying and feeding tubes, and nutrient interactions. On the topic of drug distribution, we review fluid resuscitation, alterations in plasma protein binding, and tissue perfusion. With drug metabolism, we discuss hepatic enzyme activity, protein binding, and hepatic blood flow. Finally, we review drug elimination in the critically ill patient and discuss the impact of augmented renal clearance and acute kidney injury on drug therapies. In each section, we highlight select literature reviewing the PK impact of these conditions on a drug PK profile and, where appropriate, provide general suggestions for clinicians on how to modify drug regimens to manage PK challenges.

Survey of sedation practices during noninvasive positive-pressure ventilation to treat acute respiratory failure.

Objectives:Noninvasive positive-pressure ventilation (NPPV) is increasingly used in patients with acute respiratory failure, but few data exist regarding current sedation practices during NPPV. We sought to characterize current practices and attitudes regarding sedation during NPPV. Design:Cross-sectional Web-based survey. Setting:Medical institutions. Participants:Physician members of the American College of Chest Physicians Critical Care Network (n = 2,656) and the European Respiratory Societys Assembly of Critical Care (n = 339). Interventions:Survey. Measurements and Main Results:Of the 790 of 2,985 (27%) of physicians who responded, 15%, 6%, and 28% never used sedation, analgesia, or hand restraints any of the time for NPPV patients, respectively, and the large majority reported using these interventions in ≤25% of patients. Sedation, analgesia, and hand restraints were more commonly used by North Americans than Europeans (41% vs. 24% for sedation, 48% vs. 35% for analgesia, and 27% vs. 16% for hand restraints, all p < .01) and critical care vs. noncritical care physicians (42% vs. 24% for sedation and 50% vs. 34% for analgesia, all p < .01). A benzodiazepine alone was the most preferred (33%), followed by an opioid alone (29%). Europeans were less likely to use a benzodiazepine alone (25% vs. 39%, p < .001) but more likely to use an opioid alone (37% vs. 26%, p < .009). Sedation was usually administered as an intermittent intravenous bolus, outside of a protocol, and was assessed by nurses using clinical end points rather than a sedation scale. Conclusions:Most physicians infrequently use sedation and analgesic therapy for NPPV to treat acute respiratory failure, but practices vary widely within and between specialties and geographic regions.

Use of a validated delirium assessment tool improves the ability of physicians to identify delirium in medical intensive care unit patients

Objective: Although medical intensive care unit nurses at our institution routinely use the Intensive Care Delirium Screening Checklist (ICDSC) to identify delirium, physicians rely on traditional diagnostic methods. We sought to measure the effect of physicians’ use of the ICDSC on their ability to detect delirium. Design: Before–after study. Setting: Medical intensive care unit of an academic medical center Patients and Participants: A total of 25 physicians with >=1 month of clinical experience in the medical intensive care unit conducted 300 delirium assessments in 100 medical intensive care unit patients. Measurements and Main Results: Physicians sequentially evaluated two patients for delirium using whatever diagnostic method preferred. Following standardized education regarding ICDSC use, each physician evaluated two different patients for delirium using the ICDSC. Each physician assessment was preceded by consecutive, but independent, evaluations for delirium by the patients nurse and then a validated judge using the ICDSC. Before (PRE) physician ICDSC use, the validated judge identified delirium in five patients; the physicians and nurses identified delirium in zero and four of these patients, respectively. The physicians incorrectly identified delirium in four additional patients. After (POST) physician ICDSC use, the validated judge identified delirium in 11 patients; the physicians and nurses identified delirium in eight and ten of these patients, respectively. The physicians incorrectly identified delirium in one patient. After physician ICDSC use, agreement improved between both the physicians and validated judge (PRE [kappa] = ‐0.14 [95% confidence interval {CI} = ‐0.27 to ‐0.02] to POST [kappa] = 0.67 [95% CI = 0.38 to 0.96]) and physicians and nurses (PRE [kappa] = ‐0.15 [95% CI = ‐0.29 to ‐0.02] to POST [kappa] = 0.58 [95% CI = 0.25 to 0.91]). Nurses vs. validated judge agreement was strong in both periods (PRE [kappa] = 0.65 [95% CI = 0.29 to 1.00] and POST [kappa] = 0.92 [95% CI = 0.76 to 1.00]). Conclusions: Use of the ICDSC, along with education supporting its use, improves the ability of physicians to detect delirium in the medical intensive care unit.

Atypical antipsychotics versus haloperidol for treatment of delirium in acutely ill patients.

Delirium is common in acutely ill patients and can result in substantial morbidity if left untreated. Atypical antipsychotics have been postulated to be safer and more effective than haloperidol for treatment of this condition. To evaluate the role of atypical antipsychotics versus haloperidol for treatment of delirium in hospitalized acutely ill adults, we searched MEDLINE (1977–September 2006) and International Pharmaceutical Abstracts (1997–September 2006) for English‐language publications of clinical trials that compared atypical antipsychotics and haloperidol. Four comparative studies were identified: one double‐blind, randomized study (risperidone vs haloperidol), one single‐blind, randomized study (olanzapine vs haloperidol), and two retrospective studies (olanzapine vs haloperidol and quetiapine vs haloperidol). These studies demonstrated that atypical antipsychotics are as efficacious as haloperidol. In addition, they appear to be associated with a lower frequency of extrapyramidal effects, and thus are safer than haloperidol. However, these conclusions are based on a limited number of studies; larger comparative trials are needed to elucidate the role of atypical antipsychotics for treating delirium in this population.

Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: a post-hoc analysis of a double-blind, randomized, placebo-controlled study

IntroductionWe hypothesized that delirium symptoms may respond differently to antipsychotic therapy. The purpose of this paper was to retrospectively compare duration and time to first resolution of individual delirium symptoms from the database of a randomized, double-blind, placebo-controlled study comparing quetiapine (Q) or placebo (P), both with haloperidol rescue, for critically ill patients with delirium.MethodsData for 10 delirium symptoms from the eight-domain, intensive care delirium screening checklist (ICDSC) previously collected every 12 hours were extracted for 29 study patients. Data between the Q and P groups were compared using a cut-off P- value of ≤0.10 for this exploratory study.ResultsBaseline ICDSC scores (5 (4 to 7) (Q) vs 5 (4 to 6)) (median, interquartile range (IQR)) and % of patients with each ICDSC symptom were similar in the two groups (all P > 0.10). Among patients with the delirium symptom at baseline, use of Q may lead to a shorter time (days) to first resolution of symptom fluctuation (4 (Q) vs. 14, P = 0.004), inattention (3 vs. 8, P = .10) and disorientation (2 vs. 10, P = 0.10) but a longer time to first resolution of agitation (3 vs. 1, P = 0.04) and hyperactivity (5 vs. 1, P = 0.07). Among all patients, Q-treated patients tended to spend a smaller percent of time with inattention (47 (0 to 67) vs. 78 (43 to 100), P = 0.025), hallucinations (0 (0 to 17) vs. 28 (0 to 43), P = 0.10) and symptom fluctuation (47 (19 to 67) vs. 89 (33 to 00), P = 0.04] and there was a trend for Q-treated patients to spend a greater percent of time at an appropriate level of consciousness (26% (13 to 63%) vs. 14% (0 to 33%), P = 0.17].ConclusionsOur exploratory analysis suggests that quetiapine may resolve several intensive care unit (ICU) delirium symptoms faster than the placebo. Individual symptom resolution appears to differ in association with the pharmacologic intervention (that is, P vs Q, both with as needed haloperidol). Future studies evaluating antipsychotics in ICU patients with delirium should measure duration and resolution of individual delirium symptoms and their relation to long-term outcomes.

Impact of an Institution-Specific Hospital-Acquired Pneumonia Protocol on the Appropriateness of Antibiotic Therapy and Patient Outcomes

Study Objective. To evaluate the impact of a hospital‐acquired pneumonia (HAP) protocol on appropriateness of empiric antibiotic therapy, antibiotic deescalation, antibiotic duration, patient mortality, and length of stay.

Sofosbuvir: A Nucleotide NS5B Inhibitor for the Treatment of Chronic Hepatitis C Infection

OBJECTIVE To review the use of sofosbuvir for the treatment of chronic hepatitis C virus (HCV). DATA SOURCES Review and nonreview articles were identified through MEDLINE (1996-April 2014), citations of articles, and meeting abstracts using keywords, including NS5B polymerase inhibitor, GS-7977, sofosbuvir, direct-acting antiviral (DAA), and others. STUDY SELECTION AND DATA EXTRACTION Phase 1, 2, and 3 studies describing dose-ranging potential, pharmacokinetics, efficacy, safety, and tolerability of sofosbuvir were identified. DATA SYNTHESIS Sofosbuvir is an NS5B polymerase inhibitor that was approved for use by the Food and Drug Administration in December 2013 for the treatment of chronic HCV in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for genotype 1. Additionally, it has been evaluated with other oral DAAs, such as simeprevir and others in the pipeline. It is not recommended as monotherapy because of lower sustained virological response (SVR) rates in clinical studies. Most of the treatment regimens are 12 weeks in duration; however, certain populations require a longer duration. Sofosbuvir has activity against all 6 genotypes, although most clinical trials evaluated genotypes 1 to 3. Sofosbuvir has a favorable safety and tolerability profile, making it a recommended first-line agent for chronic HCV infection. CONCLUSION In clinical trials, 12 weeks of sofosbuvir with concomitant peg-IFN and RBV therapy in treatment-naïve and experienced HCV genotype 1 patients resulted in SVR rates of >90%. An all-oral regimen of sofosbuvir and RBV is highly effective for genotype 2 and 3 patients. Sofosbuvir was found to be tolerable with minimal adverse effects (AEs), and no treatment discontinuations occurred secondary to drug related AEs..Objective: To review the use of sofosbuvir for the treatment of chronic hepatitis C virus (HCV). Data Sources: Review and nonreview articles were identified through MEDLINE (1996-April 2014), citations of articles, and meeting abstracts using keywords, including NS5B polymerase inhibitor, GS-7977, sofosbuvir, direct-acting antiviral (DAA), and others. Study Selection and Data Extraction: Phase 1, 2, and 3 studies describing dose-ranging potential, pharmacokinetics, efficacy, safety, and tolerability of sofosbuvir were identified. Data Synthesis: Sofosbuvir is an NS5B polymerase inhibitor that was approved for use by the Food and Drug Administration in December 2013 for the treatment of chronic HCV in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for genotype 1. Additionally, it has been evaluated with other oral DAAs, such as simeprevir and others in the pipeline. It is not recommended as monotherapy because of lower sustained virological response (SVR) rates in clinical studies. Most of the treatment regimens are 12 weeks in duration; however, certain populations require a longer duration. Sofosbuvir has activity against all 6 genotypes, although most clinical trials evaluated genotypes 1 to 3. Sofosbuvir has a favorable safety and tolerability profile, making it a recommended first-line agent for chronic HCV infection. Conclusion: In clinical trials, 12 weeks of sofosbuvir with concomitant peg-IFN and RBV therapy in treatment-naïve and experienced HCV genotype 1 patients resulted in SVR rates of >90%. An all-oral regimen of sofosbuvir and RBV is highly effective for genotype 2 and 3 patients. Sofosbuvir was found to be tolerable with minimal adverse effects (AEs), and no treatment discontinuations occurred secondary to drug related AEs..