Charles D. Gomersall

International Study of the Prevalence and Outcomes of Infection in Intensive Care Units

CONTEXT Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections. OBJECTIVE To provide an up-to-date, international picture of the extent and patterns of infection in ICUs. DESIGN, SETTING, AND PATIENTS The Extended Prevalence of Infection in Intensive Care (EPIC II) study, a 1-day, prospective, point prevalence study with follow-up conducted on May 8, 2007. Demographic, physiological, bacteriological, therapeutic, and outcome data were collected for 14,414 patients in 1265 participating ICUs from 75 countries on the study day. Analyses focused on the data from the 13,796 adult (>18 years) patients. RESULTS On the day of the study, 7087 of 13,796 patients (51%) were considered infected; 9084 (71%) were receiving antibiotics. The infection was of respiratory origin in 4503 (64%), and microbiological culture results were positive in 4947 (70%) of the infected patients; 62% of the positive isolates were gram-negative organisms, 47% were gram-positive, and 19% were fungi. Patients who had longer ICU stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species, and Candida species. The ICU mortality rate of infected patients was more than twice that of noninfected patients (25% [1688/6659] vs 11% [ 682/6352], respectively; P < .001), as was the hospital mortality rate (33% [2201/6659] vs 15% [ 942/6352], respectively; P < .001) (adjusted odds ratio for risk of hospital mortality, 1.51; 95% confidence interval, 1.36-1.68; P < .001). CONCLUSIONS Infections are common in patients in contemporary ICUs, and risk of infection increases with duration of ICU stay. In this large cohort, infection was independently associated with an increased risk of hospital death.

Continuous Infusion of Beta-Lactam Antibiotics in Severe Sepsis: A Multicenter Double-Blind, Randomized Controlled Trial

BACKGROUND Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. METHODS This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival. RESULTS Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). CONCLUSIONS Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

Prospective evaluation of patients refused admission to an intensive care unit: triage, futility and outcome

Abstract.Objectives: To evaluate factors associated with decisions to refuse ICU admission and to assess the outcome of refused patients. Design and setting: Prospective, descriptive evaluation in a multi-disciplinary intensive care unit, university referral hospital. Patients and participants: All adult emergency referrals over a 7-month period. Interventions: The number of beds available at the time of referral, the patients age, gender, diagnosis, mortality probability model score and hospital survival were documented. The outcome of the referral and the reason for refusal were recorded. Measurements and results: Of 624 patients 388 were admitted and 236 (38%) refused. Reasons for refusal were triage (n=104), futility (n=82) and inappropriate referral (too well; n=50). The standardised mortality ratio (SMR) for refused and admitted groups was 1.24 (95% CI 1.05–1.46) and 0.93 (0.78–1.09) respectively. The SMR ratio (refused SMR/admitted SMR) was highest in the middle range of illness (1.95, 1.19–3.20). Inappropriate referrals had a better than expected outcome despite refusal, with a SMR ratio of 0.39 (0.11–0.99). Excluding inappropriate referrals, multivariate analysis demonstrated that refusal was associated with older age, diagnostic group and severity of illness. Triage decisions were associated with a diagnosis of sepsis, and futility decisions with greater severity of illness and recent cardiac arrest. Conclusions: Refusal of admission to our ICU is common. Excess mortality of patients refused is most marked in the middle range of severity of illness. Age, diagnostic group, and severity of illness are important in decision making. Strategies should be developed to create admission criteria that would identify patients in the middle range of severity of illness who should benefit most from ICU care.

Principles of antibacterial dosing in continuous renal replacement therapy

Objectives: To outline the concepts involved in optimizing antibacterial dosing in critically ill patients with acute renal failure undergoing continuous renal replacement therapy (CRRT), provide a strategy for optimizing dosing, and summarize the data required to implement the strategy. Data Sources: MEDLINE search from February 1986 to 2008. Data Extraction and Synthesis: Optimal dosing of antibacterials is dependent on achieving pharmacokinetic targets associated with maximal killing of bacteria and improved outcomes. The initial dose is dependent on the volume of distribution. Maintenance doses are dependent on clearance. Both should be adjusted according to the pharmacokinetic target associated with optimal bacterial killing, when known. The volume of distribution of some antibacterials is altered by critical illness or acute renal failure or both. Clearance by CRRT is dependent on the dose and mode of CRRT and the sieving or saturation coefficient of the drug. Both sieving and saturation coefficient are related to the plasma protein binding and thus may be altered in renal failure. Conclusions: Appropriate dose calculation requires knowledge of the pharmacokinetic target and the usual minimum inhibitory concentration of the suspected organism in the patients locality (or if unavailable, the break point for the organism), published pharmacokinetic data (volume of distribution, non-CRRT clearance) on critically ill patients receiving CRRT (which may differ substantially from noncritically ill patients or those without renal failure), the sieving or saturation coefficient of the relevant drug in critically ill patients, the dose and mode of CRRT being used, and the actual dose of CRRT that is delivered. This large number of variables results in considerable inter- and intrapatient heterogeneity in dose requirements. This article provides basic principles and relevant data to guide the clinician in prescribing individualized dosing regimes.

Resuscitation of critically ill patients based on the results of gastric tonometry: a prospective, randomized, controlled trial.

Objective: To determine whether additional therapy aimed at correcting low gastric intramucosal pH (pHi) improves outcome in conventionally resuscitated, critically ill patients. Design: Prospective, randomized, controlled study. Setting: General intensive care unit (ICU) of a university teaching hospital. Patients: A total of 210 adult patients, with a median Acute Physiology and Chronic Health Evaluation II score of 24 (range, 8‐51). Interventions: All patients were resuscitated according to standard guidelines. After resuscitation, those patients in the intervention group with a pHi of <7.35 were treated with additional colloid and then dobutamine (5 μg/kg/min then 10 μg/kg/min) until 24 hrs after enrollment. Measurements and Main Results: There were no significant differences (p > .05) in ICU mortality (39.6% in the control group vs. 38.5% in the intervention group), hospital mortality (45.3% in the control group vs. 42.3% in the intervention group), and 30‐day mortality (43.7% in the control group vs. 40.2 in the intervention group); survival curves; median modified maximal multiorgan dysfunction score (10 points in the control group vs. 13 points in the intervention group); median modified duration of ICU stay (12 days in the control group vs. 11.5 days in the intervention group); or median modified duration of hospital stay (60 days in the control group vs. 42 days in the intervention group). A subgroup analysis of those patients with gastric mucosal pH of ≥7.35 at admission revealed no difference in ICU mortality (10.3% in the control group vs. 14.8% in the intervention group), hospital mortality (13.8% in the control group vs. 29.6% in the intervention group), or 30‐day mortality (10.3% in the control group vs. 26.9% in the intervention group). Conclusions: The routine use of treatment titrated against pHi in the management of critically ill patients cannot be supported. Failure to improve outcome may be caused by an inability to produce a clinically significant change in pHi or because pHi is simply a marker of disease rather than a factor in the pathogenesis of multiorgan failure.

Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study.

Objectives To assess the compliance of Asian intensive care units and hospitals to the Surviving Sepsis Campaign’s resuscitation and management bundles. Secondary objectives were to evaluate the impact of compliance on mortality and the organisational characteristics of hospitals that were associated with higher compliance. Design Prospective cohort study. Setting 150 intensive care units in 16 Asian countries. Participants 1285 adult patients with severe sepsis admitted to these intensive care units in July 2009. The organisational characteristics of participating centres, the patients’ baseline characteristics, the achievement of targets within the resuscitation and management bundles, and outcome data were recorded. Main outcome measure Compliance with the Surviving Sepsis Campaign’s resuscitation (six hours) and management (24 hours) bundles. Results Hospital mortality was 44.5% (572/1285). Compliance rates for the resuscitation and management bundles were 7.6% (98/1285) and 3.5% (45/1285), respectively. On logistic regression analysis, compliance with the following bundle targets independently predicted decreased mortality: blood cultures (achieved in 803/1285; 62.5%, 95% confidence interval 59.8% to 65.1%), broad spectrum antibiotics (achieved in 821/1285; 63.9%, 61.3% to 66.5%), and central venous pressure (achieved in 345/870; 39.7%, 36.4% to 42.9%). High income countries, university hospitals, intensive care units with an accredited fellowship programme, and surgical intensive care units were more likely to be compliant with the resuscitation bundle. Conclusions While mortality from severe sepsis is high, compliance with resuscitation and management bundles is generally poor in much of Asia. As the centres included in this study might not be fully representative, achievement rates reported might overestimate the true degree of compliance with recommended care and should be interpreted with caution. Achievement of targets for blood cultures, antibiotics, and central venous pressure was independently associated with improved survival.

A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis

RATIONALE Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with intermittent dosing. OBJECTIVES To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis. METHODS We conducted a randomized controlled trial in 25 intensive care units (ICUs). Participants commenced on piperacillin-tazobactam, ticarcillin-clavulanate, or meropenem were randomized to receive the prescribed antibiotic via continuous or 30-minute intermittent infusion for the remainder of the treatment course or until ICU discharge. The primary outcome was the number of alive ICU-free days at Day 28. Secondary outcomes were 90-day survival, clinical cure 14 days post antibiotic cessation, alive organ failure-free days at Day 14, and duration of bacteremia. MEASUREMENTS AND MAIN RESULTS We enrolled 432 eligible participants with a median age of 64 years and an Acute Physiology and Chronic Health Evaluation II score of 20. There was no difference in ICU-free days: 18 days (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24). CONCLUSIONS In critically ill patients with severe sepsis, there was no difference in outcomes between β-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).

Randomized Controlled Trial Comparing Adaptive-support Ventilation with Pressure-regulated Volume-controlled Ventilation with Automode in Weaning Patients after Cardiac Surgery

Background:Adaptive-support ventilation (ASV) is a minute ventilation–controlled mode governed by a closed-loop algorithm. With ASV, tidal volume and respiratory rate are automatically adjusted to minimize work of breathing. Studies indicate that ventilation in ASV enables more rapid weaning. The authors conducted a randomized controlled trial to determine whether ventilation in ASV results in a shorter time to extubation than pressure-regulated volume-controlled ventilation with automode (PRVCa) after cardiac surgery. Methods:Fifty patients were randomly assigned to ASV or PRVCa after elective coronary artery bypass grafting. Respiratory weaning progressed through three phases: phase 1 (controlled ventilation), phase 2 (assisted ventilation), and phase 3 (T-piece trial), followed by extubation. The primary outcome was duration of intubation (sum of phases 1–3). Secondary outcomes were duration of mechanical ventilation (sum of phases 1 and 2), number of arterial blood gas samples, and manual ventilator setting changes made before extubation. Results:Forty-eight patients completed the study. The median duration of intubation was significantly shorter in the ASV group than in the PRVCa group (300 [205–365] vs. 540 [462–580] min; P < 0.05). This difference was due to a reduction in the duration of mechanical ventilation (165 [120–195] vs. 480 [360–510] min; P < 0.05). There were no significant differences between the ASV and PRVCa groups in the number of arterial blood gas samples taken or manual ventilator setting changes made. Conclusions:ASV is associated with earlier extubation, without an increase in clinician intervention, when compared with PRVCa in patients undergoing uncomplicated cardiac surgery.

Increase in Methicillin-Resistant Staphylococcus aureus Acquisition Rate and Change in Pathogen Pattern Associated with an Outbreak of Severe Acute Respiratory Syndrome

Abstract Background. An outbreak of severe acute respiratory syndrome (SARS) occurred in our 22-bed intensive care unit (ICU; Prince of Wales Hospital, Hong Kong, HKSAR, China) from 12 March to 31 May 2003, when only patients with SARS were admitted. This period was characterized by the upgrading of infection control precautions, which included the wearing of gloves and gowns all the time, an extensive use of steroids, and a change in antibiotic prescribing practices. The pattern of endemic pathogenic organisms, the rates of acquisition of methicillin-resistant Staphylococcus aureus (MRSA), and the rates of ventilator-associated pneumonia (VAP) were compared with those of the pre-SARS and post-SARS periods. Methods. Data on pathogenic isolates were obtained from the microbiology department (Prince of Wales Hospital). Data on MRSA acquisition and VAP rates were collected prospectively. MRSA screening was performed for all ICU patients. A case of MRSA carriage was defined as an instance in which MRSA was recovered from any site in a patient, and cases were classified as imported or ICU-acquired if the first MRSA isolate was recovered within 72 h of ICU admission or after 72 h in the ICU, respectively. Results. During the SARS period in the ICU, there was an increase in the rate of isolation of MRSA and Stenotrophomonas and Candida species but a disappearance of Pseudomonas and Klebsiella species. The MRSA acquisition rate was also increased: it was 3.53% (3.53 cases per 100 admissions) during the pre-SARS period, 25.30% during the SARS period, and 2.21% during the post-SARS period (P < .001). The VAP rate was high, at 36.5 episodes per 1000 ventilator-days, and 47% of episodes were caused by MRSA. Conclusions. A SARS outbreak in the ICU led to changes in the pathogen pattern and the MRSA acquisition rate. The data suggest that MRSA cross-transmission may be increased if gloves and gowns are worn all the time.

A systematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: do current studies supply sufficient data?

BACKGROUND Drug dosing for septic patients with acute renal failure receiving continuous renal replacement therapy (CRRT) is complicated, and failure to correctly dose may result in either drug toxicity or treatment failure and development of antibiotic resistance. The aim of this study was to establish an ideal dataset that needs to be reported when presenting pharmacokinetic data for these patients and review current literature for completeness of this dataset. METHODS An ideal dataset was established of the parameters that should be reported when calculating a drug dosing regimen from first principles. A Medline search was performed of relevant literature producing 64 citations from which completeness of the specified criteria was examined. RESULTS None of the studies analysed presented the full dataset that we established as necessary. Of concern, basic pharmacokinetic parameters such as volume of distribution (V(d)) and clearance (CL) were specified in only 79% and 81% of studies, respectively. CONCLUSIONS A large proportion of current studies do not report key information necessary to devise a rational dosing regimen for patients with acute renal failure receiving CRRT, and we hope this dataset will be a useful guide when reporting future pharmacokinetic data.