Russel Roberts

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.

Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids.

Opioids, benzodiazepines, and propofol remain the mainstay by which to optimize patient comfort and facilitate mechanical ventilation in patients who are critically ill. Unfortunately none of these agents share all of the characteristics of the ideal sedative or analgesic agent: rapid onset, rapid recovery, a predictable dose response, a lack of drug accumulation, and no toxicity. To optimize care, critical care clinicians should be familiar with the many pharmacokinetic, pharmacodynamic, and pharmacogenetic variables that can affect the safety and efficacy of these sedatives and analgesics.

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.

Efficacy and Safety of Early Dexmedetomidine During Noninvasive Ventilation for Patients With Acute Respiratory Failure: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

BACKGROUND Successful application of noninvasive ventilation (NIV) for acute respiratory failure (ARF) requires patient cooperation and comfort. The efficacy and safety of early IV dexmedetomidine when added to protocolized, as-needed IV midazolam and fentanyl remain unclear. METHODS Adults with ARF and within 8 h of starting NIV were randomized to receive IV dexmedetomidine (0.2 μg/kg/h titrated every 30 min to 0.7 μg/kg/h to maintain a Sedation-Agitation Scale [SAS] score of 3 to 4) or placebo in a double-blind fashion up to 72 h, until NIV was stopped for ≥ 2 h, or until intubation. Patients with agitation (SAS ≥ 5) or pain (visual analog scale ≥ 5 of 10 cm) 15 min after each dexmedetomidine and placebo increase could receive IV midazolam 0.5 to 1.0 mg or IV fentanyl 25 to 50 μg, respectively, at a minimum interval of every 3 h. RESULTS The dexmedetomidine (n = 16) and placebo (n = 17) groups were similar at baseline. Use of early dexmedetomidine did not improve NIV tolerance (score, 1 of 4; OR, 1.44; 95% CI, 0.44-4.70; P = .54) nor, vs. placebo, led to a greater median (interquartile range) percent time either tolerating NIV (99% [61%-100%] vs. 67% [40%-100%], P = .56) or remaining at the desired sedation level (SAS score = 3 or 4, 100% [86%-100%] vs. 100% [100%-100%], P = .28], or fewer intubations (P = .79). Although use of dexmedetomidine was associated with a greater duration of NIV vs placebo (37 [16-72] vs. 12 [4-22] h, P = .03), the total ventilation duration (NIV + invasive) was similar (3.3 [2-4] days vs. 3.8 [2-5] days, P = .52). More patients receiving dexmedetomidine had one or more episodes of deep sedation vs placebo (SAS ≤ 2, 25% vs. 0%, P = .04). Use of midazolam (P = .40) and episodes of either severe bradycardia (heart rate ≤ 50 beats/min, P = .18) or hypotension (systolic BP ≤ 90 mm Hg, P = .64) were similar. CONCLUSIONS Initiating dexmedetomidine soon after NIV initiation in patients with ARF neither improves NIV tolerance nor helps to maintain sedation at a desired goal. Randomized, multicenter trials targeting patients with initial intolerance are needed to further elucidate the role for dexmedetomidine in this population.

Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low-Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study.

Objective:To compare the efficacy and safety of scheduled low-dose haloperidol versus placebo for the prevention of delirium (Intensive Care Delirium Screening Checklist ≥ 4) administered to critically ill adults with subsyndromal delirium (Intensive Care Delirium Screening Checklist = 1–3). Design:Randomized, double-blind, placebo-controlled trial. Setting:Three 10-bed ICUs (two medical and one surgical) at an academic medical center in the United States. Patients:Sixty-eight mechanically ventilated patients with subsyndromal delirium without complicating neurologic conditions, cardiac surgery, or requiring deep sedation. Interventions:Patients were randomly assigned to receive IV haloperidol 1 mg or placebo every 6 hours until delirium occurred (Intensive Care Delirium Screening Checklist ≥ 4 with psychiatric confirmation), 10 days of therapy had elapsed, or ICU discharge. Measurements and Main Results:Baseline characteristics were similar between the haloperidol (n = 34) and placebo (n = 34) groups. A similar number of patients given haloperidol (12/34 [35%]) and placebo (8/34 [23%]) developed delirium (p = 0.29). Haloperidol use reduced the hours per study day spent agitated (Sedation Agitation Scale ≥ 5) (p = 0.008), but it did not influence the proportion of 12-hour ICU shifts patients spent alive without coma (Sedation Agitation Scale ⩽ 2) or delirium (p = 0.36), the time to first delirium occurrence (p = 0.22), nor delirium duration (p = 0.26). Days of mechanical ventilation (p = 0.80), ICU mortality (p = 0.55), and ICU patient disposition (p = 0.22) were similar in the two groups. The proportion of patients who developed corrected QT-interval prolongation (p = 0.16), extrapyramidal symptoms (p = 0.31), excessive sedation (p = 0.31), or new-onset hypotension (p = 1.0) that resulted in study drug discontinuation was comparable between the two groups. Conclusions:Low-dose scheduled haloperidol, initiated early in the ICU stay, does not prevent delirium and has little therapeutic advantage in mechanically ventilated, critically ill adults with subsyndromal delirium.

Predictors for daily interruption of sedation therapy by nurses: A prospective, multicenter study☆

PURPOSE The aim of the study was to identify the nurse and patient-related factors predicting daily interruption of sedation (DIS) performance by nurses in the intensive care unit (ICU). METHODS Nurses, caring for a mechanically ventilated patient receiving 24 hours or more of a continuously infused sedative, were interviewed at the bedside to determine their willingness to perform DIS on this patient and to determine the influence of 20 nurse- and 47 patient-related factors on DIS completion. RESULTS The 57 (44%) of 130 of nurses willing to perform DIS had performed DIS at least once in the past (P < .0001) and were not targeting deep sedation (ie, Sedation Agitation Scale [SAS] ≤ 2 [P = .03]). The DIS performance was less likely with use of higher-dose continuous midazolam (P = .006), a fraction of inspired oxygen (Fio(2)) greater than 50% (P = .03), or positive end-expiratory pressure greater than 5 mm Hg (P = .006) and in patients either deeply sedated (SAS ≤ 2) (P = .05) or agitated (SAS ≥ 5) in the past 24 hours (P = .003). Prior DIS experience (odds ratio [OR], 2.54; P = .004), hours of sedation-related continuing education (OR, 1.13; P = .02), and a target of deep sedation (OR, 0.49; P = .02) were independent nurse-related factors for DIS performance. Nurses willingness to conduct DIS ranged from 45% to 80% based on the interaction between patient sex, current Fio(2), and agitation in past 24 hours. CONCLUSIONS Educational strategies and institutional protocols focused on improving use of DIS need to consider the various nurse- and patient-related factors that affect DIS performance by nurses in the ICU.

Impact of a national propofol shortage on duration of mechanical ventilation at an academic medical center.

Objective: To measure the impact of a national propofol shortage on the duration of mechanical ventilation. Design: Before–after study. Setting: Three, noncardiac surgery, adult intensive care units at a 320-bed academic medical center. Patients: Consecutive patients requiring mechanical ventilation ≥48 hrs, administered a continuously infused sedative ≥24 hrs, extubated, and successfully discharged from the intensive care unit were compared between before (December 1, 2008 to May 31, 2009) and after (December 1, 2009, to May 31, 2010) a propofol shortage. Intervention: None. Measurements and Main Results: Sedation drug use and common factors affecting time on mechanical ventilation were collected and if found either to differ significantly (p ⩽ .10) between the two groups or to have an unadjusted significant association (p ⩽ .10) with time on mechanical ventilation were included in a multivariable model. The unadjusted analyses revealed that the median (interquartile range) duration of mechanical ventilation increased from 6.7 (9.8; n = 153) to 9.6 (9.5; n = 128) days (p = .02). Fewer after-group patients received ≥24 hrs of continuously infused propofol (94% vs. 15%, p < .0001); more received ≥24 hrs of continuously infused lorazepam (7% vs. 15%, p = .037) and midazolam (30% vs. 81%, p < .0001). Compared with the before group, the after group was younger, had a higher admission Acute Physiology and Chronic Health Evaluation II score, was more likely to be admitted by a surgical service, have acute alcohol withdrawal, and be managed with pressure-controlled ventilation as the primary mode of mechanical ventilation. Of these five factors, only the Acute Physiology and Chronic Health Evaluation II score, admission service, and use of a pressure-controlled ventilation affected duration of mechanical ventilation across both groups. Although a regression model revealed that Acute Physiology and Chronic Health Evaluation II score (p < .0001), admission by a medical service (p = .009), and use of pressure-controlled ventilation (p = .02) each affected duration of mechanical ventilation in both groups, inclusion in either the before- or after-propofol shortage groups (i.e., high vs. low use of propofol) did not affect duration of mechanical ventilation (p = .35). Conclusions: An 84% decrease in propofol use in the adult intensive care units at our academic institution as a result of a national shortage did not affect duration of mechanical ventilation.

Corticosteroids for Prevention of Postextubation Laryngeal Edema in Adults

Objective: To evaluate the efficacy and safety of prophylactic corticosteroid therapy in preventing postextubation laryngeal edema (PELE) and the need for reintubation in adults. Data Sources: Literature was accessed through MEDLINE (1966-January 2008) and the Cochrane Library using the terms laryngeal edema, airway obstruction, postextubation stridor, intubation, glucocorticoids, and corticosteroids. Bibliographies of cited references were reviewed and a manual search of abstracts from recent pulmonary and critical care meetings was completed. Study Selection and Data Extraction: All English-language, placebo-controlled, randomized studies evaluating the use of prophylactic corticosteroids for the prevention of postextubation laryngeal edema or postextubation stridor (PES) in adults were reviewed. Data Synthesis: Although laryngoscopy is the gold standard method for diagnosing PELE, PES is more commonly used for diagnosis in clinical practice. While 3 older studies failed to demonstrate benefit with the prophylactic administration of corticosteroid therapy in terms of reducing PELE, PES, or the need for reintubation, each of these studies evaluated only a single dose of steroid therapy that was initiated only 30-60 minutes prior to a planned extubation in a population of patients at low-risk for PELE. In comparison, 3 newer studies, each using 4 doses of corticosteroid therapy initiated 12-24 hours prior to a planned extubation in patients deemed to be at high baseline risk for developing PELE, demonstrated a reduction in PELE, PES, and the need for reintubation; no safety concerns were identified. Current evidence therefore suggests that prophylactic intravenous methylprednisolone therapy (20-40 mg every 4-6 h) should be considered 12-24 hours prior to a planned extubation in patients at high-risk for PELE (eg, mechanical ventilation >6 days). Conclusions: Data from the most recent well-designed clinical trials suggest that prophylactic corticosteroid therapy can reduce the incidence of PELE and the subsequent need for reintubation in mechanically ventilated patients at high-risk for PELE. Based on this information, clinicians should consider initiating prophylactic corticosteroid therapy in this population. Further studies are needed to establish the optimal dosing regimens as well as the subgroups of patients at high risk for PELE who will derive the greatest benefit from this preventive steroid therapy.

Patterns of antihypertensive treatment in patients with acute severe hypertension from a nonneurologic cause: Studying the Treatment of Acute Hypertension (STAT) registry.

Study Objective. To assess antihypertensive treatment practices and outcomes for patients with acute severe hypertension requiring hospitalization.