Andrew A. Quartin

Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study.

BACKGROUND The American Thoracic Society and Infectious Diseases Society of America provide guidelines for management of hospital-acquired, ventilator-associated, and health-care-associated pneumonias, consisting of empirical antibiotic regimens for patients at risk for multidrug-resistant pathogens. We aimed to improve compliance with these guidelines and assess outcomes. METHODS We implemented a performance-improvement initiative in four academic medical centres in the USA with protocol-based education and prospective observation of outcomes. Patients were assessed for severity of illness and followed up until death, hospital discharge, or day 28. We included patients in intensive-care units who were at risk for multidrug-resistant pneumonia and were treated empirically. FINDINGS 303 patients at risk for multidrug-resistant pneumonia were treated empirically, and prescribed treatment was guideline compliant in 129 patients and non-compliant in 174 patients. 44 (34%) patients died before 28 days in the compliance group and 35 (20%) died in the non-compliance group. Five patients in the compliance group and seven in the non-compliance group were lost to follow-up after day 14. Kaplan-Meier estimated survival to 28 days was 65% in the compliance group and 79% in the non-compliance group (p=0·0042). This difference persisted after adjustment for severity of illness. Median length of stay and duration of mechanical ventilation did not differ between groups. Compliance failures included non-use of dual treatment for Gram-negative pathogens in 154 patients and absence of meticillin-resistant Staphylococcus aureus coverage in 24 patients. For patients in whom pathogens were subsequently identified, empirical treatment was active in 79 (81%) of 97 of patients receiving compliant therapy compared with 109 (85%) of 128 of patients receiving non-compliant therapy. INTERPRETATION Because adherence with empirical treatment was associated with increased mortality, we recommend a randomised trial be done before further implementation of these guidelines. FUNDING Pfizer, US Medical.

Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients.

Objective:To demonstrate that a new immediate-release omeprazole oral suspension is effective in preventing upper gastrointestinal bleeding in critically ill patients. Design:A noninferiority analysis was used to compare rates of clinically significant upper gastrointestinal bleeding in a prospective, phase 3, double-blind trial with parallel omeprazole suspension and cimetidine treatment groups. Setting:A total of 47 intensive care units in the United States. Patients:A total of 359 critically ill patients who required mechanical ventilation for ≥48 hrs, had an Acute Physiology and Chronic Health Evaluation score of ≥11 at baseline, had an intact stomach with a nasogastric or orogastric tube in place, and had at least one additional risk factor for upper gastrointestinal bleeding. Interventions:Patients were randomized to treatment with omeprazole suspension (two 40-mg doses on day 1, via orogastric or nasogastric tube, and 40 mg each day thereafter) or intravenous cimetidine (300-mg bolus and 50 mg/hr thereafter) for up to 14 days. Gastric aspirates were sampled for bleeding and pH. Medication doses were doubled for failure of pH control (two successive aspirates with pH ≤ 4). Measurements and Main Results:Clinically significant upper gastrointestinal bleeding (bright red blood not clearing after 5–10 mins of lavage or persistent Gastroccult-positive “coffee-grounds” material for 8 hrs on days 1–2 or for 2–4 hrs on days 3–14 and not clearing with ≥100 mL of lavage) was the primary end point of the trial. The rate of clinically significant bleeding in the per-protocol population was 4.5% with omeprazole suspension and 6.8% with cimetidine, meeting the criteria for the noninferiority of omeprazole suspension. Median gastric pH was ≥6 on all trial days with omeprazole suspension treatment and on 50% of days with cimetidine treatment (p < .001, all trial days). In the omeprazole suspension group, median gastric pH was >4 on each trial day in 95% of patients. Conclusions:Immediate-release omeprazole suspension is effective in preventing upper gastrointestinal bleeding and more effective than intravenous cimetidine in maintaining gastric pH of >4 in critically ill patients.

Feasibility of Shortening Respiratory Isolation with a Single Sputum Nucleic Acid Amplification Test

RATIONALE Serial smear analysis to guide respiratory isolation (RI) of patients with suspected tuberculosis (TB), the majority of whom will be found not to have TB, leads to expensive and unnecessary isolation, and may potentially result in decreased vigilance of subjects with respiratory compromise. OBJECTIVES To compare the performance of a single first-sputum, Mycobacterium tuberculosis-specific nucleic acid amplification (NAA) test with three sputum smears for assessing the need for RI. METHODS Prospective evaluation of 493 patients with suspected TB (74% HIV positive) admitted to RI in a major county hospital in the United States, who had at least three sputum smears and material available from the first sample for additional NAA testing. MEASUREMENTS AND MAIN RESULTS Accuracy of the first sputum NAA result and serial smears for identifying patients with potentially infectious TB who truly require RI was determined. Forty-six patients (9.3%) had TB confirmed by culture. First-sputum NAA test detected all patients with TB who had a positive smear (n = 35), even when the first of the three specimens was smear negative. In addition, when compared with serial smears, the first-sputum NAA had a higher sensitivity (0.87; 95% confidence interval [CI], 0.74-0.95) and specificity (1.0) in the detection of subjects with positive M. tuberculosis cultures (smear sensitivity, 0.76; 95% CI, 0.61-0.87; and specificity, 0.96; 95% CI, 0.94-0.98). CONCLUSIONS A single first-sputum NAA testing can rapidly and accurately identify the subset of patients with suspected TB who require RI according to serial sputum smears. Its potential use to shorten RI time does not preclude the need to obtain subsequent specimens for culture.

An evaluation of the hemodynamic effects of HA-1A human monoclonal antibody.

We sought to determine whether there might be acute changes in hemodynamics attributable to HA-1A, a monoclonal antibody to endotoxin, in patients with presumed Gramnegative sepsis. Design: Post hocanalysis of a multicenter, randomized, double-blind, placebo-controlled study. Patients:A total of 543 patients with severe sepsis presumed to be caused by Gram-negative bacteria who were enrolled in a clinical trial to evaluate the efficacy and safety of HA-1A human monoclonal antibody. Interventions:Patients were randomly assigned to receive either 100 mg of HA-1A or placebo. Measurement and Main Results:Patients were grouped by the study drug, HA-1A, or placebo, and the presence or absence of Gram-negative bacteremia. Hemodynamic variables were monitored from before, until 72 hrs after infusion of the study drug. For the entire study population (n = 543), no changes over time attributable to study drug were noted in the mean arterial pressure (p > .19), heart rate (p > .53) or the need for vasopressor administration (p > .62). One hundred ninety-seven patients underwent pulmonary artery catheterization and had hemodynamic data available from before the infusion of HA-1A or placebo until at least 12 hrs after infusion. Evaluating all 197 patients on an intent to treat basis demonstrated no significant differences over time in cardiac index (p > .15), oxygen delivery index (p > .43), or left ventricular stroke work index (p > .48) between patients who received HA-1A and those patients receiving placebo. Grouping patients by the presence of Gram-negative bacteremia and study drug received also failed to demonstrate any significant difference attributable to HA-1A in mean arterial pressure (p > .54), heart rate (p > .84), cardiac index (p > .13), oxygen delivery index (p > .05), or left ventricular stroke work index (p > .48) between populations. Conclusion:There is no apparent relationship between the administration of HA-1A, the presence of Gram-negative bacteremia, and hemodynamic profiles over the 72-hr study period. (Crit Care Med 1994; 22:1227–1234)

Influence of critical illness on physicians' prognoses for underlying disease: a randomized study using simulated cases.

Objective: During critical illness, physicians often provide estimates of the severity of underlying disease to aid patients and families when formulating care directives. We sought to determine whether factors such as the superimposed acute illness, the prognoses of other patients cared for by the same physician, or the phrasing of inquiry influence these assessments of underlying disease. Design, Setting, and Subjects: Internal medicine attending and resident physicians participated in a computerized, Web-available survey that described two case vignettes, one with cardiomyopathy and the other with lung cancer as underlying diseases. Using random assignment, each respondent was presented one case as having septic shock, and the other as an uneventful clinic visit. Respondents were explicitly asked to ignore the context and to assess the severity of the underlying disease alone to predict survival time and quality of life. The order in which subjects encountered the cases and phrasing of the survival question also were varied through randomization. Measurements and Main Results: Mortality predictions for the cardiomyopathy case at 5 yrs were sensitive to both context (predicted survival, 39% ± 23% when presented as septic vs. 52% ± 24% when presented as a clinic patient; p < .001) and to whether a lung cancer case was presented before it (39% ± 23% when presented after lung cancer vs. 52% ± 24% when presented before; p < .001). These effects were independent and led to mean predicted 5-yr survival probabilities ranging from 31% to 59%. Predicted 1-yr survival from lung cancer was sensitive to phrasing (p < .05) but not to context. Quality of life predictions were also sensitive to context and case order. Conclusions: Physician appraisal of underlying disease severity is potentially vulnerable to a number of biases that may be relevant in the critical care setting. These biases appear to vary with the nature of the underlying disease.

Use of intensive care, mechanical ventilation, both, or neither by patients with acute lung injury.

Objective:Reports of acute lung injury and acute respiratory distress syndrome have generally been restricted to mechanically ventilated intensive care unit patients, creating an incomplete picture of the epidemiologies of the syndromes. We sought to determine the incidence and outcomes of acute lung injury and acute respiratory distress syndromes throughout an entire hospital population. Design:Retrospective cohort study. Setting:A Department of Veterans Affairs medical center. Patients:All patients satisfying criteria for acute lung injury or acute respiratory distress syndrome during a 2-yr period. Interventions:None. Measurements and Main Results:There were 11,465 acute medical and surgical admissions during the study period; 156 patients had acute lung injury or acute respiratory distress syndrome. Only 74 (47%) were invasively ventilated in an intensive care unit for acute lung injury. Another 15 (10%) patients were ventilated for other reasons, 41 (26%) were admitted to an intensive care unit at approximately the time of acute lung injury onset but were not invasively ventilated, and 26 (17%) were managed with neither invasive ventilation nor admission to an intensive care unit. Four-week mortality differed by group (p = .023), ranging from 22% among those managed in an intensive care unit without invasive ventilation to 50% among those ventilated for acute lung injury or acute respiratory distress syndrome. By 2 yrs, differences in survival between groups were no longer significant. Notably, only 53 (34%) patients would have been eligible for widely cited acute lung injury intervention trials. Ten patients had a second episode of acute lung injury during the study period, equating to a 16%-per-year risk of recurrence. Conclusions:Acute lung injury and acute respiratory distress syndrome studies restricted to patients mechanically ventilated in intensive care units substantially underestimate the incidence of the syndromes. Nonventilated patients and those cared for outside of intensive care units may still be at substantial risk for death. Further characterization of previously overlooked acute lung injury and acute respiratory distress syndrome patients may suggest new therapeutic opportunities.

Prior healthcare utilization as a predictor of survival for medical intensive care unit patients

ObjectiveTo determine whether measures of inpatient care utilization from the year preceding admission to a medical intensive care unit (MICU) improve physiology-based predictions of hospital and 1-yr survival. DesignInception cohort study with a validation cohort. SettingThe MICU in university-affiliated Department of Veterans Affairs Medical Center. PatientsA total of 1,200 consecutive patients admitted to the MICU. Measurements and Main ResultsIncreased use of inpatient health care before MICU admission was associated with increased mortality. However, inpatient utilization data failed to improve physiology-based logistic models for hospital and 1-yr survival (p > .15 for improvement in the area under the receiver operating characteristic curve for both end points in the validation cohort), whereas physiologic data improved models derived from measures of inpatient care (p < .001 for both end points). Empirically derived inpatient care models used only information from the few days preceding MICU admission, despite the availability of a full year of data. ConclusionsChronic illness, as gauged by a need for frequent inpatient care in the year before MICU admission, is not independently predictive of poor short- or long-term survival. Clinicians should not attempt to predict survival of prospective MICU patients by the extent of previous inpatient care.

Candidemia in the critically ill: initial therapy and outcome in mechanically ventilated patients

BackgroundMortality among critically ill patients with candidemia is very high. We sought to determine whether the choice of initial antifungal therapy is associated with survival among these patients, using need for mechanical ventilatory support as a marker of critical illness.MethodsCohort analysis of outcomes among mechanically ventilated patients with candidemia from the 24 North American academic medical centers contributing to the Prospective Antifungal Therapy (PATH) Alliance registry. Patients were included if they received either fluconazole or an echinocandin as initial monotherapy.ResultsOf 5272 patients in the PATH registry at the time of data abstraction, 1014 were ventilated and concomitantly had candidemia, with 689 eligible for analysis. 28-day survival was higher among the 374 patients treated initially with fluconazole than among the 315 treated with an echinocandin (66% versus 51%, P < .001). Initial fluconazole therapy remained associated with improved survival after adjusting for non-treatment factors in the overall population (hazard ratio .75, 95% CI .59–.96), and also among patients with albicans infection (hazard ratio .62, 95% CI .44–.88). While not statistically significant, fluconazole appeared to be associated with higher mortality among patients infected with glabrata (HR 1.13, 95% CI .70–1.84).ConclusionsAmong ventilated patients with candidemia, those receiving fluconazole as initial monotherapy were significantly more likely to survive than those treated with an echinocandin. This difference persisted after adjustment for non-treatment factors.

Effects of exogenous lipids on blood gas measurements

ObjectiveNumerous reports have appeared describing the effects of intravenous lipid administration on the pulmonary function of the critically ill patient. Our study was undertaken to determine whether the lipid content of an arterial blood gas specimen affects the measurement of arterial pH, Pao2, Paco2, or arterial oxygen saturation. DesignProspective, in vitro controlled study. SettingMedical and cardiac intensive care units. PatientsCritically ill patients undergoing clinically-directed blood gas sampling via indwelling arterial catheters. InterventionsNone. MeasurementsArterial blood gas specimens were modified in vitro by dividing the sample and adding a known amount of lipid emulsion to half of the sample, resulting in a difference between the plasma triglyceride concentrations of the two halves. Two series of experiments were run: one series was run with a predicted plasma triglyceride difference of 400 mg/dL (4.5 mmol/L) between the two samples; the other series was run with a predicted plasma triglyceride difference of 800 mg/dL (9.0 mmol/L) between the two samples. Blood gas measurements were performed on each half of a sample, and the results were compared. Because some studies have only noted changes in patients with the adult respiratory distress syndrome (ARDS), samples from these patients were also analyzed as a separate group. ResultsNo significant changes were found in arterial pH, Pao2, Paco2, or arterial oxygen saturation between the two halves of the sample. With 95% confidence, differences as small as 1.5 torr (0.2 kPa) for Pao2 and Paco2,0.5% for arterial oxygen saturation, and 0.005 for pH, would have been detected. No differences were found in the ARDS subgroup. ConclusionsThe addition of clinically relevant amounts of lipid to blood samples does not affect blood gas measurements. Any observed changes in blood gas values after lipid feeding are presumably due to products of lipid metabolism or alterations in pulmonary function.

Does iodinated radiocontrast material pose an appreciable risk for kidney injury in the critically Ill

To the Editor: In a recent issue of Critical Care Medicine, we read with interest the article by Ehrmann et al (1) examining the incidence of nephropathy induced by iodinated radiocontrast material (RCM) in the critically ill. Their result that modern RCM agents administered IV pose at most a minimal risk for kidney injury in this population complements and extends our findings (2) regarding this important clinical question. We examined measured creatinine clearances before and after CT in critically ill patients, comparing changes in kidney function among patients scanned with RCM with matched patients scanned without RCM enhancement. Like Ehrmann et al (1), we found many instances of worsened renal function after RCM exposure but at a rate no higher than among similar patients imaged without RCM. We used measured clearance because it is unaffected by the variability of creatinine production and volume of distribution common among the critically ill and better accounts for dynamic changes in renal function. The price of this precision was the need for prescan timed urine collections, impractical outside the setting of a prospective study and effectively preventing study around the time of ICU admission. Ehrmann et al (1) in effect went the opposite route, capturing a larger and more completely representative picture of the ICU population by using serum creatinine to assess changes in renal function. This approach is much more practicable, if less refined than measured clearance, and has the advantage of permitting the inclusion of patients scanned shortly before or after ICU admission. Compared to our patients, those in the study by Ehrmann were also much less likely to have received putative contrast nephropathy prophylaxis agents, clarifying interpretation. We believe Jacobs (3) understates the weight of evidence provided by ours and Ehrmann’s investigations, the only studies of contrast nephropathy among critically ill patients to include control groups. Both found nephropathy after RCM exposure occurred frequently, comparable to reports by others (4), suggesting populations representative of ICU patients in general. However, with matching controls, it becomes apparent that RCM exposure was seldom, if ever, the cause of these events. There is little reason at this point to suppose that RCM is a major culprit in the renal injury intensivists so often manage. When matching or risk adjustment is employed, there is always the possibility that unmeasured confounders may lead to erroneous conclusions. That we and Ehrmann et al (1) performed our studies in different ICUs on different continents and used different variables for matching suggests the findings are robust. Complete removal of any confounding factors, necessary to accurately quantify the relatively weak (or possibly absent) signal from contrast nephropathy, would require a very large randomized trial, an unlikely prospect when looking for toxicity. the committee deemed a grade 2, rather than a grade 1 recommendation, was in order. At least we did not ignore the issue, and we are happy to see this critical topic being openly debated and carefully analyzed. If SDD does indeed prove to reduce antibiotic resistance development among the microbial ecology within the unit, it might actually be used as a tool to reduce the prevalence of MDR infections in ICU patients in the future. Dr. Opal is a board member with Arsanis and Bioaegous; consulted for Sanofi Pasteur; receives royalties from Elsevier; and is a data and safety monitoring board member with Spectral (lipopolysaccharide inhibitor), Tetraphase (new antibiotic), and Sangart (plasma expander). Dr. Opal’s institution received grant support from Sirtris (preclinical studies on new therapies for septic shock), GlaxoSmithKline (preclinical studies on epigenetic modulators for systemic inflammation), and Asahi Kasei (Clinical coordinating center for the sponsor’s phase 3 clinical trial in sepsis). Dr. Opal’s institution has a patent with the University of Maryland Med Center (patent on vaccine strategy against bacterial endotoxin) and Prothera biologics (patent on inter alpha inhibitor as a treatment for anthrax). Dr. Dellinger has disclosed that he does not have any potential conflicts of interest.