William T. McGee

Linezolid in Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study

BACKGROUND Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. METHODS This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare-associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. RESULTS Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). CONCLUSIONS For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.

Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient

Objective:To update the 2002 version of “Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.” Design:A Task Force comprising 17 members of the Society of Critical Medicine with particular expertise in the use of neuromuscular-blocking agents; a Grading of Recommendations Assessment, Development, and Evaluation expert; and a medical writer met via teleconference and three face-to-face meetings and communicated via e-mail to examine the evidence and develop these practice guidelines. Annually, all members completed conflict of interest statements; no conflicts were identified. This activity was funded by the Society for Critical Care Medicine, and no industry support was provided. Methods:Using the Grading of Recommendations Assessment, Development, and Evaluation system, the Grading of Recommendations Assessment, Development, and Evaluation expert on the Task Force created profiles for the evidence related to six of the 21 questions and assigned quality-of-evidence scores to these and the additional 15 questions for which insufficient evidence was available to create a profile. Task Force members reviewed this material and all available evidence and provided recommendations, suggestions, or good practice statements for these 21 questions. Results:The Task Force developed a single strong recommendation: we recommend scheduled eye care that includes lubricating drops or gel and eyelid closure for patients receiving continuous infusions of neuromuscular-blocking agents. The Task Force developed 10 weak recommendations. 1) We suggest that a neuromuscular-blocking agent be administered by continuous intravenous infusion early in the course of acute respiratory distress syndrome for patients with a PaO2/FIO2 less than 150. 2) We suggest against the routine administration of an neuromuscular-blocking agents to mechanically ventilated patients with status asthmaticus. 3) We suggest a trial of a neuromuscular-blocking agents in life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise. 4) We suggest that neuromuscular-blocking agents may be used to manage overt shivering in therapeutic hypothermia. 5) We suggest that peripheral nerve stimulation with train-of-four monitoring may be a useful tool for monitoring the depth of neuromuscular blockade but only if it is incorporated into a more inclusive assessment of the patient that includes clinical assessment. 6) We suggest against the use of peripheral nerve stimulation with train of four alone for monitoring the depth of neuromuscular blockade in patients receiving continuous infusion of neuromuscular-blocking agents. 7) We suggest that patients receiving a continuous infusion of neuromuscular-blocking agent receive a structured physiotherapy regimen. 8) We suggest that clinicians target a blood glucose level of less than 180 mg/dL in patients receiving neuromuscular-blocking agents. 9) We suggest that clinicians not use actual body weight and instead use a consistent weight (ideal body weight or adjusted body weight) when calculating neuromuscular-blocking agents doses for obese patients. 10) We suggest that neuromuscular-blocking agents be discontinued at the end of life or when life support is withdrawn. In situations in which evidence was lacking or insufficient and the study results were equivocal or optimal clinical practice varies, the Task Force made no recommendations for nine of the topics. 1) We make no recommendation as to whether neuromuscular blockade is beneficial or harmful when used in patients with acute brain injury and raised intracranial pressure. 2) We make no recommendation on the routine use of neuromuscular-blocking agents for patients undergoing therapeutic hypothermia following cardiac arrest. 3) We make no recommendation on the use of peripheral nerve stimulation to monitor degree of block in patients undergoing therapeutic hypothermia. 4) We make no recommendation on the use of neuromuscular blockade to improve the accuracy of intravascular-volume assessment in mechanically ventilated patients. 5) We make no recommendation concerning the use of electroencephalogram-derived parameters as a measure of sedation during continuous administration of neuromuscular-blocking agents. 6) We make no recommendation regarding nutritional requirements specific to patients receiving infusions of neuromuscular-blocking agents. 7) We make no recommendation concerning the use of one measure of consistent weight over another when calculating neuromuscular-blocking agent doses in obese patients. 8) We make no recommendation on the use of neuromuscular-blocking agents in pregnant patients. 9) We make no recommendation on which muscle group should be monitored in patients with myasthenia gravis receiving neuromuscular-blocking agents. Finally, in situations in which evidence was lacking or insufficient but expert consensus was unanimous, the Task Force developed six good practice statements. 1) If peripheral nerve stimulation is used, optimal clinical practice suggests that it should be done in conjunction with assessment of other clinical findings (e.g., triggering of the ventilator and degree of shivering) to assess the degree of neuromuscular blockade in patients undergoing therapeutic hypothermia. 2) Optimal clinical practice suggests that a protocol should include guidance on neuromuscular-blocking agent administration in patients undergoing therapeutic hypothermia. 3) Optimal clinical practice suggests that analgesic and sedative drugs should be used prior to and during neuromuscular blockade, with the goal of achieving deep sedation. 4) Optimal clinical practice suggests that clinicians at the bedside implement measure to attenuate the risk of unintended extubation in patients receiving neuromuscular-blocking agents. 5) Optimal clinical practice suggests that a reduced dose of an neuromuscular-blocking agent be used for patients with myasthenia gravis and that the dose should be based on peripheral nerve stimulation with train-of-four monitoring. 6) Optimal clinical practice suggests that neuromuscular-blocking agents be discontinued prior to the clinical determination of brain death.

ACCURATE PLACEMENT OF CENTRAL VENOUS CATHETERS: A PROSPECTIVE, RANDOMIZED, MULTICENTER TRIAL

Objectivesa) To define the frequency of dangerous (intracardiac) central venous catheter placement in a multicenter study of large community hospital intensive care units (ICUs) and to evaluate physician responses to this finding. b) To validate right atrial electrocardiography as a technique to assure adherence with recent Food and Drug Administration (FDA) guidelines regarding the location of central venous catheter tips. c) To conduct a literature review of vascular cannulation and its associated potentially lethal complications. DesignProspective, randomized, blinded, multicenter study. SettingMultidisciplinary ICUs in five large community teaching hospitals. PatientsConsecutive patients (n = 112) who required a central venous catheter by either internal jugular vein or subclavian vein at four separate hospitals were assessed using 30-cm catheters. Consecutive patients (n = 50) in a fifth hospital who subsequently required a central venous catheter via the internal jugular vein or subclavian vein route were prospectively randomized to receive a 20-cm central venous catheter with either conventional surface-landmark guidance, or with the right atrial electrocardiography-guided technique. Main Outcome Measuresa) Occurrence rate of malpositioned central venous catheters. b) Ability of right atrial electrocardiography to aid in the accurate placement of central venous catheters. Resultsa) Using conventional placement techniques with a 30-cm catheter, 53 (47%) of 112 initial central venous catheter placements resulted in location of the catheter tip within the heart. Catheter tips were not repositioned to locations outside the right atrium after this finding was identified on initial postprocedure films. b) Using the right atrial electrocardiography technique to place 20-cm central venous catheters resulted in no catheter tip locations within the heart (0/25) vs. 14 (56%) of 25 (p < .0001) intracardiac placements using conventional techniques. c) The literature suggests that serious mechanical complications of central venous catheterization, although uncommon, are associated with a high mortality rate. Deaths are associated with intracardiac placement. Conclusionsa) The FDA guidelines regarding catheter tip location (catheter tip should not be in the right atrium) have not been widely publicized. b) The average safe insertion depth for a central venous catheter from the left or right internal jugular vein or subclavian vein is 16.5 cm for the majority of adult patients; a central venous catheter should not be routinely inserted to a depth of >20 cm. Catheters longer than this size are rarely needed, and potentially dangerous. Catheter tip location is important to document following central venous catheter insertion. Thirty-centimeter central venous catheters should not be used when accessing the central circulation via internal jugular or subclavian veins. c) Right atrial electrocardiography is a technique that assures initial tip position outside the heart in accordance with FDA guidelines. This technique would virtually eliminate the major risk of death (i.e., cardiac perforation) associated with this procedure. d) Recently available, 15− and 16-cm central venous catheters have significant potential to minimins

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

ObjectivePlatelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DesignA prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SettingOne hundred forty-six intensive care units from nine countries. PatientsApproximately 2,522 patients were planned to be enrolled ≤12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. Measurements and Main ResultsThe study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85–1.25; p = .80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. ConclusionsrPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

Validation of a continuous, arterial pressure-based cardiac output measurement: a multicenter, prospective clinical trial

IntroductionThe present study compared measurements of cardiac output by an arterial pressure-based cardiac output (APCO) analysis method with measurement by intermittent thermodilution cardiac output (ICO) via pulmonary artery catheter in a clinical setting.MethodsThe multicenter, prospective clinical investigation enrolled patients with a clinical indication for cardiac output monitoring requiring pulmonary artery and radial artery catheters at two hospitals in the United States, one hospital in France, and one hospital in Belgium. In 84 patients (69 surgical patients), the cardiac output was measured by analysis of the arterial pulse using APCO and was measured via pulmonary artery catheter by ICO; to establish a reference comparison, the cardiac output was measured by continuous cardiac output (CCO). Data were collected continuously by the APCO and CCO technologies, and at least every 4 hours by ICO. No clinical interventions were made as part of the study.ResultsFor APCO compared with ICO, the bias was 0.20 l/min, the precision was ± 1.28 l/min, and the limits of agreement were -2.36 l/m to 2.75 l/m. For CCO compared with ICO, the bias was 0.66 l/min, the precision was ± 1.05 l/min, and the limits of agreement were -1.43 l/m to 2.76 l/m. The ability of APCO and CCO to assess changes in cardiac output was compared with that of ICO. In 96% of comparisons, APCO tracked the change in cardiac output in the same direction as ICO. The magnitude of change was comparable 59% of the time. For CCO, 95% of comparisons were in the same direction, with 58% of those changes being of similar magnitude.ConclusionIn critically ill patients in the intensive care unit, continuous measurement of cardiac output using either APCO or CCO is comparable with ICO. Further study in more homogeneous populations may refine specific situations where APCO reliability is strongest.

Effects of clinical maneuvers on sonographically determined internal jugular vein size during venous cannulation.

We sought to define variations in internal jugular vein (IJV) anatomy and the effect of recommended cannulation maneuvers on a population of ICU patients. Maneuvers that decreased IJV lumen cross-sectional area were carotid artery palpation (1.48 to 0.82 cm2, p less than .05) and advancement of the needle (1.57 to 0.75 cm2, p less than .001). The head-down (modified Trendelenburg) position increased IJV lumen cross-sectional area (1.18 to 1.62 cm2, p less than .05). There was wide variability in IJV anatomic features, although most patients had patent veins.

A simple physiologic algorithm for managing hemodynamics using stroke volume and stroke volume variation: Physiologic optimization program

Intravascular volume status and volume responsiveness continue to be important questions for the management of critically ill or injured patients. Goal-directed hemodynamic therapy has been shown to be of benefit to patients with severe sepsis and septic shock, acute lung injury and adult respiratory distress syndrome, and for surgical patients in the operating room. Static measures of fluid status, central venous pressure (CVP), and pulmonary artery occlusion pressure (PAOP) are not useful in predicting volume responsiveness. Stroke volume variation and pulse pressure variation related to changes in stroke volume during positive pressure ventilation predict fluid responsiveness and represent an evolving practice for volume management in the intensive care unit (ICU) or operating room. Adoption of dynamic parameters for volume management has been inconsistent. This manuscript reviews some of the basic physiology regarding the use of stroke volume variation to predict fluid responsiveness in the ICU and operating room. A management algorithm using this physiology is proposed for the critically ill or injured in various settings.

Defining a High-Performance ICU System for the 21st Century: A Position Paper

In the fall of 1997 George D. Lundberg and John E. Wennberg wrote an editorial in JAMA calling for comprehensive quality improvement programs to become the driver of the American health care system. The suggestion came during the Second European Forum on Quality Improvement in Health Care held in Paris, France, in April 1997 and was based on comments made by Donald Berwick. The concept was to focus on an organized response to problem identification and proposed solutions to improve patient care and protect the health of the public. Critical care medicine represents a large segment of health care and is undergoing dramatic changes during our managed care revolution. General ICU severity of illness models have been developed, tested, and shown to provide a useful estimate of hospital mortality for populations of critically ill patients. These systems have captured the imagination of clinical researchers and have become an integral component of a large number of publications as well as a part of many ICU databases. These risk adjustment severity models are remarkably robust for heterogeneous patient populations but the models have not been shown to validate well in new settings. We feel that by focusing on the episode of critical illness rather than each individual ICU admission and by going beyond the traditional acute hospital discharge to determine whether the patient lives or dies, we can better evaluate critical care system performance and cost-effectiveness. The incentives for high quality/low cost should favor integrated comprehensive critical care delivery systems. Programs that score well should be identified as high quality and be honored as medallion level 1 ICUs. We challenge national and international critical care societies to evaluate and then debate the described definitions and recommendations as a call to action.

The pulmonary artery catheter in critical care.

Pulmonary artery catheterization has been a routine part of care for critically ill patients over the past 25 years. Primary hemodynamic data regarding cardiac output and pulmonary pressures can be utilized to make diagnoses and guide therapy. Tissue oxygen delivery and utilization allow inferences about the efficiency of the cardiopulmonary system and the impact of disease and medical therapies on tissue metabolism. Goals of high level invasive monitoring of cardiopulmonary function with pulmonary artery catheterization are organ salvage and minimizing complications associated with critical illness. Optimizing renal perfusion and minimizing pulmonary congestion with precise volume titration are common reasons for performing pulmonary artery catheterization in the intensive care unit. Despite being reassuring to clinicians that hemodynamic therapy is optimal, multiple data from well conducted clinical studies have not demonstrated outcome benefits to patients related to pulmonary artery catheterization. Less invasive techniques to obtain data regarding hemodynamic function are now entering the clinical arena and are being actively investigated.

Accurate placement of central venous catheters using a 16-cm catheter.

We determine if use of 16-cm central venous catheters (CVC) minimizes dangerous intracardiac catheter placements. We conducted a prospective study in a large community teaching hospital. Consecutive patients (n = 127) who required a CVC via either the internal jugular (IJV) or the subclavian vein (SCV) were assessed using 16 (n = 102) or 20-cm (n = 25) catheters. The main outcome measurements were (1) intracardiac placement of central venous catheters, and (2) relationship of right- or left-sided internal jugular or subclavian vein insertions to intracardiac catheter placement. Use of a 20-cm CVC resulted in 14 of 25 (56%) intracardiac placements compared with 11 of 102 (11%) using a 16-cm catheter (p < 0.0001). All intracardiac placements with the 16-cm CVC were from right-sided approaches: IJV 7 of 38 (16%), SCV 4 of 18 (18%). Use of a 16-cm CVC to access the central circulation from either the SCV or the IJV results in a significantly greater proportion of safe catheter placements than using longer CVCs, and it should become the standard of care.