Search

IMPORTANCE: It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS). OBJECTIVE: To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial, conducted from September 1, 2014, through August 20, 2017, including patients without ARDS expected to not be extubated within 24 hours after start of ventilation from 6 intensive care units in the Netherlands. INTERVENTIONS: Invasive ventilation using low tidal volumes (n = 477) or intermediate tidal volumes (n = 484). MAIN OUTCOMES AND MEASURES: The primary outcome was the number of ventilator-free days and alive at day 28. Secondary outcomes included length of ICU and hospital stay; ICU, hospital, and 28- and 90-day mortality; and development of ARDS, pneumonia, severe atelectasis, or pneumothorax. RESULTS: In total, 961 patients (65% male), with a median age of 68 years (interquartile range [IQR], 59-76), were enrolled. At day 28, 475 patients in the low tidal volume group had a median of 21 ventilator-free days (IQR, 0-26), and 480 patients in the intermediate tidal volume group had a median of 21 ventilator-free days (IQR, 0-26) (mean difference, –0.27 [95% CI, –1.74 to 1.19]; P = .71). There was no significant difference in ICU (median, 6 vs 6 days; 0.39 [–1.09 to 1.89]; P = .58) and hospital (median, 14 vs 15 days; –0.60 [–3.52 to 2.31]; P = .68) length of stay or 28-day (34.9% vs 32.1%; hazard ratio [HR], 1.12 [0.90 to 1.40]; P = .30) and 90-day (39.1% vs 37.8%; HR, 1.07 [0.87 to 1.31]; P = .54) mortality. There was no significant difference in the percentage of patients developing the following adverse events: ARDS (3.8% vs 5.0%; risk ratio [RR], 0.86 [0.59 to 1.24]; P = .38), pneumonia (4.2% vs 3.7%; RR, 1.07 [0.78 to 1.47]; P = .67), severe atelectasis (11.4% vs 11.2%; RR, 1.00 [0.81 to 1.23]; P = .94), and pneumothorax (1.8% vs 1.3%; RR, 1.16 [0.73 to 1.84]; P = .55). CONCLUSIONS AND RELEVANCE: In patients in the ICU without ARDS who were expected not to be extubated within 24 hours of randomization, a low tidal volume strategy did not result in a greater number of ventilator-free days than an intermediate tidal volume strategy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02153294

This pooled cohort analysis assesses the association of quick Sequential (Sepsis-Related Organ Failure Assessment (qSOFA) score with excess hospital death among patients with suspected infection in low- to middle-income countries and compares the mortality association using qSOFA vs systemic inflammatory response syndrome (SIRS) criteria.

The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown.To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill.Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States.Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76).The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days.Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54).Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting.clinicaltrials.gov Identifier: NCT01335932.

Importance Drug shortages in the United States are common, but their effect on patient care and outcomes has rarely been reported. Objective To assess changes to patient care and outcomes associated with a 2011 national shortage of norepinephrine, the first-line vasopressor for septic shock. Design, Setting, and Participants Retrospective cohort study of 26 US hospitals in the Premier Healthcare Database with a baseline rate of norepinephrine use of at least 60% for patients with septic shock. The cohort included adults with septic shock admitted to study hospitals between July 1, 2008, and June 30, 2013 (n = 27 835). Exposures Hospital-level norepinephrine shortage was defined as any quarterly (3-month) interval in 2011 during which the hospital rate of norepinephrine use decreased by more than 20% from baseline. Main Outcomes and Measures Use of alternative vasopressors was assessed and a multilevel mixed-effects logistic regression model was used to evaluate the association between admission to a hospital during a norepinephrine shortage quarter and in-hospital mortality. Results Among 27 835 patients (median age, 69 years [interquartile range, 57-79 years]; 47.0% women) with septic shock in 26 hospitals that demonstrated at least 1 quarter of norepinephrine shortage in 2011, norepinephrine use among cohort patients declined from 77.0% (95% CI, 76.2%-77.8%) of patients before the shortage to a low of 55.7% (95% CI, 52.0%-58.4%) in the second quarter of 2011; phenylephrine was the most frequently used alternative vasopressor during this time (baseline, 36.2% [95% CI, 35.3%-37.1%]; maximum, 54.4% [95% CI, 51.8%-57.2%]). Compared with hospital admission with septic shock during quarters of normal use, hospital admission during quarters of shortage was associated with an increased rate of in-hospital mortality (9283 of 25 874 patients [35.9%] vs 777 of 1961 patients [39.6%], respectively; absolute risk increase = 3.7% [95% CI, 1.5%-6.0%]; adjusted odds ratio = 1.15 [95% CI, 1.01-1.30]; P = .03). Conclusions and Relevance Among patients with septic shock in US hospitals affected by the 2011 norepinephrine shortage, the most commonly administered alternative vasopressor was phenylephrine. Patients admitted to these hospitals during times of shortage had higher in-hospital mortality.

IMPORTANCE: Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.OBJECTIVE: To evaluate and, as needed, update definitions for sepsis and septic shock.PROCESS: A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).KEY FINDINGS FROM EVIDENCE SYNTHESIS: Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.RECOMMENDATIONS: Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.CONCLUSIONS AND RELEVANCE: These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

Expanded abstract Citation Prasad M, Holmboe ES, Lipner RS, Hess BJ, Christie JD, Bellamy SL, Rubenfeld GD, Kahn JM. Clinical Protocols and Trainee Knowledge About Mechanical Ventilation. JAMA. 2011; 306(9):935-941. PubMed PMID: 21900133 This is available on http://www.pubmed.gov Background Clinical protocols are associated with improved patient outcomes; however, they may negatively affect medical education by removing trainees from clinical decision making. Methods Objective: To study the relationship between critical care training with mechanical ventilation protocols and subsequent knowledge about ventilator management. Design: A retrospective cohort equivalence study linking a national survey of mechanical ventilation protocol availability with knowledge about mechanical ventilation. Exposure to protocols was defined as high intensity if an intensive care unit had 2 or more protocols for at least 3 years and as low intensity if 0 or 1 protocol. Setting: Accredited US pulmonary and critical care fellowship programs. Subjects: First-time examinees of the American Board of Internal Medicine (ABIM) Critical Care Medicine Certification Examination in 2008 and 2009. Intervention: N/A Outcomes: Knowledge, measured by performance on examination questions specific to mechanical ventilation management, calculated as a mechanical ventilation score using item response theory. The score is standardized to a mean (SD) of 500 (100), and a clinically important difference is defined as 25. Variables included in adjusted analyses were birth country, residency training country, and overall first-attempt score on the ABIM Internal Medicine Certification Examination. Results The 90 of 129 programs (70%) responded to the survey. Seventy seven programs (86%) had protocols for ventilation liberation, 66 (73%) for sedation management, and 54 (60%) for lung-protective ventilation at the time of the survey. Eighty eight (98%) of these programs had trainees who completed the ABIM Critical Care Medicine Certification Examination, totaling 553 examinees. Of these 88 programs, 27 (31%) had 0 protocols, 19 (22%) had 1 protocol, 24 (27%) had 2 protocols, and 18 (20%) had 3 protocols for at least 3 years. 42 programs (48%) were classified as high intensity and 46 (52%) as low intensity, with 304 trainees (55%) and 249 trainees (45%), respectively. In bi-variable analysis, no difference in mean scores was observed in high-intensity (497; 95% CI, 486-507) vs low-intensity programs (497; 95% CI, 485-509). Mean difference was 0 (95% CI, -16 to 16), with a positive value indicating a higher score in the high-intensity group. In multivariable analyses, no association of training was observed in a high-intensity program with mechanical ventilation score (adjusted mean difference, -5.36; 95% CI, -20.7 to 10.0). Conclusions Among first-time ABIM Critical Care Medicine Certification Examination examinees, training in a high-intensity ventilator protocol environment compared with a low-intensity environment was not associated with worse performance on examination questions about mechanical ventilation management.

ACUTE LUNG INJURY (ALI) IS A COMMON, LETHAL, AND complex syndrome. Estimates of attributable mortality from ALI or its more severe form, acute respiratory distress syndrome (ARDS), in the United States place it above asthma and human immunodeficiency virus infection as a cause of death. The current mortality of 35% associated with ALI is roughly 3-fold higher than that associated with ST-segment elevation myocardial infarction. Most of the salient features of ARDS, including the therapeutic use of positive end-expiratory pressure (PEEP), were described by Ashbaugh et al in their classic description of the syndrome: “ventilation without positive end-expiratory pressure resulted in immediate hypoxaemia. . . . Collapsed alveoli require greater pressures for reopening, thus explaining the notable loss of compliance. Positive end-expiratory pressure would theoretically prevent complete collapse and improve oxygenation by maintaining alveolar ventilation.” Ashbaugh et al thought that mechanical ventilation merely prevented hypoxemic death, thereby providing clinicians with time to treat the underlying cause of ARDS. However, recent research has focused on the degree to which mechanical ventilation is injurious, depending on how it is applied, by causing inflammation and multiple organ failure. There is little disagreement about the principles of mechanical ventilation in patients with ALI: a PEEP sufficient to recruit collapsed lung areas should be used while delivering small tidal volumes to protect the uninjured lung from overdistention. These basic concepts do not provide any of the details required to manage the care of patients at the bedside. Although the use of PEEP is a simple physiological intervention, it has potentially deleterious effects on right and left ventricular function, pulmonary vascular resistance, and thoracic compliance, leading to unpredictable effects on gas exchange and hemodynamics in individual patients. Airway pressures necessary to recruit collapsed lung areas can improve oxygenation but also can overdistend normal areas of pulmonary parenchyma, worsen inflammation, and reduce cardiac output. Therefore, identifying the optimal PEEP to use in ALI has been the focus of a substantial amount of clinical investigation. Many strategies exist: clinicians can increase PEEP to achieve the maximal improvement in oxygenation, sacrificing overdistention of normal alveoli; balance oxygenation benefits against cardiac output or blood pressure; use pressure-volume curves or dynamic stress indices to identify a trade-off point of lung recruitment; or use sophisticated imaging techniques to assess how much lung has been opened. However, in clinical practice, patients with ALI do not appear to benefit from any of these strategies. Large cohorts of patients receiving mechanical ventilation show that patients with ALI, ARDS, acute respiratory failure that is neither ALI nor ARDS, and patients with chronic obstructive pulmonary disease all receive, on average, about 8 cm H2O of PEEP. Current practice may reflect the lack of evidence demonstrating a patient-centered outcome benefit of any specific approach to titrating PEEP. Four recent clinical trials address the question of “How much PEEP in acute lung injury?”: ALVEOLI, LOVS, EXPRESS, and EPVENT. All of these investigations were designed to measure the benefits of a protocolized higher PEEP strategy in a broad range of patients with ALI receiving tidal volumes thought to be protective. The protocols tested were related only in that they delivered approximately 14.5 to 18 cm H2O of PEEP on day 1 to patients in the intervention groups. The usual set of explanations were invoked to interpret the results of high-quality, wellconceived, but statistically negative trials; ie, the wrong patients were enrolled; too few patients were enrolled because of overly optimistic projections of the effect of PEEP on mortality; and unlucky randomization led to sicker patients in the intervention groups and to investigators not using the right approach to setting PEEP. In this issue of JAMA, a meta-analysis of individualpatient data by Briel and colleagues addresses 3 of these 4 important limitations. Using primary data from the actual trials, the authors demonstrated that, after adjusting for individual patient covariates, higher PEEP was associated with

Despite skilled palliative care, some dying patients experience distressing symptoms that cannot be adequately relieved. A patient with metastatic breast cancer, receiving high doses of opioids administered to relieve pain, developed myoclonus. After other approaches proved ineffective, palliative sedation was an option of last resort. The doctrine of double effect, the traditional justification for palliative sedation, permits physicians to provide high doses of opioids and sedatives to relieve suffering, provided that the intention is not to cause the patient's death and that certain other conditions are met. Such high doses are permissible even if the risk of hastening death is foreseen. Because intention plays a key role in this doctrine, clinicians must understand and document which actions are consistent with an intention to relieve symptoms rather than to hasten death. The patient or family should agree with plans for palliative sedation. The attending physician needs to explain to them, as well as to the medical and nursing staff, the details of care and the justification for palliative sedation. Because cases involving palliative sedation are emotionally stressful, the patient, family, and health care workers can all benefit from talking about the complex medical, ethical, and emotional issues they raise.

Context Severe acute respiratory syndrome (SARS) is a newly recognized infectious disease capable of causing severe respiratory failure. Objective To determine the epidemiological features, course, and outcomes of patients with SARS-related critical illness. Design, Setting, and Patients Retrospective case series of 38 adult patients with SARS-related critical illness admitted to 13 intensive care units (ICUs) in the Toronto area between the onset of the outbreak and April 15, 2003. Data were collected daily during the first 7 days in the ICUs, and patients were followed up for 28 days. Main Outcome Measures The primary outcome was mortality at 28 days after ICU admission. Secondary outcomes included rate of SARS-related critical illness, number of tertiary care ICUs and staff placed under quarantine, and number of health care workers (HCWs) contracting SARS secondary to ICU-acquired transmission. Results Of 196 patients with SARS, 38 (19%) became critically ill, 7 (18%) of whom were HCWs. The median (interquartile range [IQR]) age of the 38 patients was 57.4 (39.0-69.6) years. The median (IQR) duration between initial symptoms and admission to the ICU was 8 (5-10) days. Twenty-nine (76%) required mechanical ventilation and 10 of these (34%) experienced barotrauma. Mortality at 28 days was 13 (34%) of 38 patients and for those requiring mechanical ventilation, mortality was 13 (45%) of 29. Six patients (16%) remained mechanically ventilated at 28 days. Two of these patients had died by 8 weeks' follow-up. Patients who died were more often older, had preexisting diabetes mellitus, and on admission to hospital were more likely to have bilateral radiographic infiltrates. Transmission of SARS in 6 study ICUs led to closure of 73 medical-surgical ICU beds. In 2 university ICUs, 164 HCWs were quarantined and 16 (10%) developed SARS. Conclusions Critical illness was common among patients with SARS. Affected patients had primarily single-organ respiratory failure, and half of mechanically ventilated patients died. The SARS outbreak greatly strained regional critical care resources.

The quality of medical care at the end of life is receiving increased attention in both the popular press 1 and professional journals. 2,3 This interest has developed in part because of the perception that people die with ineffective, painful, expensive, and unwanted medical interventions that deprive them of their dignity, personal interactions, and family savings. This perception is not wholly unfounded. Approximately 60% of Americans die in hospitals. 4 Among the deaths of hospitalized patients in the SUPPORT study, 5 half died after receiving mechanical ventilation for more than 1 week. Many families of dying patients report that their loved ones experience moderate to severe pain during most or all of the loved ones' last few days. Many of the families of dying patients experience severe caregiving and financial burdens. 6 Efforts to improve the quality of end-of-life care through advance directives, education, and more accurate prognostic information have