Pharmacokinetics of an extended 4-hour infusion of piperacillin-tazobactam in critically ill patients undergoing continuous renal replacement therapy.

STUDY OBJECTIVE: To evaluate the pharmacokinetic and pharmacodynamic profiles of piperacillin-tazobactam administered as a 4-hour infusion in critically ill patients undergoing continuous renal replacement therapy (CRRT). DESIGN: Prospective, observational, pharmacokinetic study. SETTING: Intensive care unit of a tertiary care hospital in Montréal, Canada. PATIENTS: Twenty critically ill adults who were undergoing continuous venovenous hemodiafiltration and receiving a 4-hour infusion of piperacillin 4 g-tazobactam 0.5 g every 8 hours for a documented or suspected infection. INTERVENTION: Blood samples were collected every hour over an 8-hour dosing interval. Prefilter and postfilter blood samples, and effluent and urine samples were also collected. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of patients who achieved an unbound piperacillin plasma concentration above a target minimum inhibitory concentration (MIC) of 64 mg/L (MIC that inhibits 90% of isolates for Pseudomonas aeruginosa) for at least 50% of the dosing interval; 18 (90%) of the 20 patients achieved this outcome. In all patients, the free piperacillin concentrations were above the Pseudomonas aeruginosa breakpoint of 16 mg/L for the entire time interval. Regarding piperacillin pharmacokinetic parameters, the median (interquartile range) minimum unbound plasma concentration was 65.15 mg/L (51.30-89.30), maximum unbound plasma concentration was 141.3 mg/L (116.75-173.90), sieving coefficient was 0.809 (0.738-0.938), total clearance was 65.82 ml/minute (53.79-102.87), and renal clearance was 0.16 ml/minute (0.05-3.04). The median CRRT dose was 32.0 ml/kg/h (25.0-39.8). CONCLUSIONS: Administration of a 4-hour infusion of piperacillin-tazobactam was associated with a favorable pharmacodynamic profile in patients undergoing CRRT. Concentrations associated with maximal activity were attained in our patients.

Alcohol, nicotine, and iatrogenic withdrawals in the ICU.

OBJECTIVES: The neurophysiology, risk factors, and screening tools associated with alcohol withdrawal syndrome in the ICU are reviewed. Alcohol withdrawal syndrome assessment and its treatment options are discussed. Description of nicotine withdrawal and related publications specific to the critically ill are also reviewed. A brief comment as to sedative and opiate withdrawal follows. DATA AND SUMMARY: The role of currently published alcohol withdrawal syndrome pharmacologic strategies (benzodiazepines, ethanol, clomethiazole, antipsychotics, barbiturates, propofol, and dexmedetomidine) is detailed. Studies on nicotine withdrawal management in the ICU focus mainly on the safety (mortality) of nicotine replacement therapy. Study characteristics and methodological limitations are presented. CONCLUSION: We recommend a pharmacologic regimen titrated to withdrawal symptoms in ICU patients with alcohol withdrawal syndrome. Benzodiazepines are a reasonable option; phenobarbital appears to confer some advantages in combination with benzodiazepines. Propofol and dexmedetomidine have not been rigorously tested in comparative studies of drug withdrawal treatment; their use as additional or alternative strategies for managing withdrawal syndromes in ICU patients should therefore be individualized to each patient. Insufficient data preclude recommendations as to nicotine replacement therapy and management of iatrogenic drug withdrawal in ICU patients.

Alcohol withdrawal and delirium tremens in the critically ill: a systematic review and commentary.

INTRODUCTION: Alcohol withdrawal is common among intensive care unit (ICU) patients, but no current practice guidelines exist. We reviewed published manuscripts for prevalence, risk factors, screening tools, prophylactic and treatment strategies, and outcomes for alcohol withdrawal syndrome (AWS) and delirium tremens (DT) in the critically ill. METHODS: The following databases: PubMed, MEDLINE, Embase, Cochrane Database of Systematic Reviews and Central Register of Controlled Trials, CINAHL, Scopus, Web of Knowledge, pain, anxiety and delirium (PAD) Guidelines REFWORKS, International Pharmaceutical Abstracts and references for published papers were searched. Publications with high or moderate Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Oxford levels of evidence were included. RESULTS: Reported AWS rates range from <1 % in 'all ICU comers' to 60 % in highly selected alcohol-dependent ICU patients. Alcohol dependence and a history of withdrawal are significant risk factors for AWS occurrence. No screening tools for withdrawal have been validated in the ICU. The benefit of alcohol withdrawal prophylaxis is unproven, and proposed regimens appear equivalent. Early and aggressive titration of medication guided by symptoms is the only feature associated with improved treatment outcome. CONCLUSIONS: Treatment of AWS is associated with higher ICU complication rates and resource utilization. The optimal means of identification, prevention and treatment of AWS in order to establish evidence-based guidelines remain to be determined.

I-SAVE study: impact of sedation, analgesia, and delirium protocols evaluated in the intensive care unit: an economic evaluation.

BACKGROUND: Intensive care units (ICUs) account for considerable health care costs. Adequate pain and sedation management is important to clinical care. OBJECTIVE: To determine whether implementing a protocol for management of analgesia, sedation, and delirium in the ICU would save costs. METHODS: With data from the I-SAVE (Impact of Sedation, Analgesia and Delirium Protocols Evaluated in the Intensive Care Unit: an Economic Evaluation) study, a prospective pre- and postprotocol design was used. Between the 2 periods, protocols for systematic management of sedation, analgesia, and delirium were implemented. Cost-effectiveness was calculated by associating the variation of cost and effectiveness measures (proportion of patients within targeted pain, sedation, and delirium goals). Total costs (in 2004 Canadian dollars), by patient, consisted of the sum of sedation, analgesia, and delirium drug acquisition costs during the ICU stay and the cost of the ICU stay. RESULTS: A total of 1214 patients, 604 in the preprotocol group and 610 in the postprotocol group, were included. The mean (SD) ICU length of stay and the duration of mechanical ventilation were shorter among patients of the postprotocol group compared with those of the preprotocol group (5.43 [6.43] and 6.39 [8.05] days, respectively; p = 0.004 and 5.95 [6.80] and 7.27 [9.09] days, respectively; p < 0.009). The incidence of delirium remained the same. The proportion of patients with Richmond Agitation and Sedation (RASS) scores between -1 and +1 increased from 57.0% to 66.2% (p = 0.001), whereas the proportion of patients with a numeric rating scale (NRS) score of 1 or less increased from 56.3% to 66.6% (p < 0.001). The mean total cost of ICU hospitalization decreased from $6212.64 (7846.86) in the preprotocol group to $5279.90 (6263.91) in the postprotocol group (p = 0.022). The cost analyses for pain and agitation management improved; the proportion of patients with RASS scores between -1 and +1 or NRS scores of 1 or less increased significantly in the postprotocol group while costing, on average, $932.74 less per hospitalization. CONCLUSIONS: Establishing protocols for patient-driven management of sedation, analgesia, and delirium is a cost-effective practice and allows savings of nearly $1000 per hospitalization.

Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates.

BACKGROUND: Sedatives and analgesics, in doses that alter consciousness in the intensive care unit (ICU), contribute to delirium and mortality. Pain, agitation, and delirium can be monitored in ICU patients. These symptoms were noted before (PRE) and after (POST) a protocol to alleviate undesirable symptoms. Analgesia and sedation levels, the incidence of coma, delirium, length of stay (LOS), discharge location, and mortality were then compared. We hypothesized that the likely reduction in iatrogenic coma would result in less delirium, because these 2 morbid conditions seem to be linked. METHODS: All patients were consecutively admitted to an ICU PRE-protocol (August 2003 to February 2004, 610 patients) and POST-protocol (April 2005 to November 2005, 604 patients). Between February 2004 and April 2005, we piloted and taught individualized nonpharmacologic strategies and titration of analgesics, sedatives, and antipsychotics based on sedation, analgesia, and delirium scores. We measured the following outcomes: coma, delirium, LOS, mortality, and discharge location. RESULTS: The POST group benefited from better analgesia, received less opiates (90.72 + or - 207.45 vs 22.93 + or - 40.36 morphine equivalents/d, P = <0.0001), and, despite comparable sedation, had shorter duration of mechanical ventilation. Medication-induced coma rates (18.1%vs 7.2%, P < 0.0001), ICU and hospital LOS, and dependency at discharge were lower in the POST-protocol group. Subsyndromal delirium was significantly reduced; delirium was similar. The 30-day mortality risk in the PRE cohort was 29.4% vs 22.9% in the POST cohort (log-rank test, P = 0.009). CONCLUSION: Educational initiatives incorporating systematic management protocols with nonpharmacologic measures and individualized titration of sedation, analgesia, and delirium therapies are associated with better outcomes.