Bruce Light

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

Objective:To determine the prevalence and impact on mortality of delays in initiation of effective antimicrobial therapy from initial onset of recurrent/persistent hypotension of septic shock. Design:A retrospective cohort study performed between July 1989 and June 2004. Setting:Fourteen intensive care units (four medical, four surgical, six mixed medical/surgical) and ten hospitals (four academic, six community) in Canada and the United States. Patients:Medical records of 2,731 adult patients with septic shock. Interventions:None. Measurements and Main Results:The main outcome measure was survival to hospital discharge. Among the 2,154 septic shock patients (78.9% total) who received effective antimicrobial therapy only after the onset of recurrent or persistent hypotension, a strong relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted (adjusted odds ratio 1.119 [per hour delay], 95% confidence interval 1.103–1.136, p < .0001). Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital mortality rate was significantly increased relative to receiving therapy within the first hour (odds ratio 1.67; 95% confidence interval, 1.12–2.48). In multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest predictor of outcome. Median time to effective antimicrobial therapy was 6 hrs (25–75th percentile, 2.0–15.0 hrs). Conclusions:Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension.

Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.

OBJECTIVE Our goal was to determine the impact of the initiation of inappropriate antimicrobial therapy on survival to hospital discharge of patients with septic shock. METHODS The appropriateness of initial antimicrobial therapy, the clinical infection site, and relevant pathogens were retrospectively determined for 5,715 patients with septic shock in three countries. RESULTS Therapy with appropriate antimicrobial agents was initiated in 80.1% of cases. Overall, the survival rate was 43.7%. There were marked differences in the distribution of comorbidities, clinical infections, and pathogens in patients who received appropriate and inappropriate initial antimicrobial therapy (p < 0.0001 for each). The survival rates after appropriate and inappropriate initial therapy were 52.0% and 10.3%, respectively (odds ratio [OR], 9.45; 95% CI, 7.74 to 11.54; p < 0.0001). Similar differences in survival were seen in all major epidemiologic, clinical, and organism subgroups. The decrease in survival with inappropriate initial therapy ranged from 2.3-fold for pneumococcal infection to 17.6-fold with primary bacteremia. After adjustment for acute physiology and chronic health evaluation II score, comorbidities, hospital site, and other potential risk factors, the inappropriateness of initial antimicrobial therapy remained most highly associated with risk of death (OR, 8.99; 95% CI, 6.60 to 12.23). CONCLUSIONS Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Efforts to increase the frequency of the appropriateness of initial antimicrobial therapy must be central to efforts to reduce the mortality of patients with septic shock.

Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis.

Background:Septic shock represents the major cause of infection-associated mortality in the intensive care unit. The possibility that combination antibiotic therapy of bacterial septic shock improves outcome is controversial. Current guidelines do not recommend combination therapy except for the express purpose of broadening coverage when resistant pathogens are a concern. Objective:To evaluate the therapeutic benefit of early combination therapy comprising at least two antibiotics of different mechanisms with in vitro activity for the isolated pathogen in patients with bacterial septic shock. Design:Retrospective, propensity matched, multicenter, cohort study. Setting:Intensive care units of 28 academic and community hospitals in three countries between 1996 and 2007. Subjects:A total of 4662 eligible cases of culture-positive, bacterial septic shock treated with combination or monotherapy from which 1223 propensity-matched pairs were generated. Measurements and Main Results:The primary outcome of study was 28-day mortality. Using a Cox proportional hazards model, combination therapy was associated with decreased 28-day mortality (444 of 1223 [36.3%] vs. 355 of 1223 [29.0%]; hazard ratio, 0.77; 95% confidence interval, 0.67-0.88; p = .0002). The beneficial impact of combination therapy applied to both Gram-positive and Gram-negative infections but was restricted to patients treated with &bgr;-lactams in combination with aminoglycosides, fluoroquinolones, or macrolides/clindamycin. Combination therapy was also associated with significant reductions in intensive care unit (437 of 1223 [35.7%] vs. 352 of 1223 [28.8%]; odds ratio, 0.75; 95% confidence interval, 0.63-0.92; p = .0006) and hospital mortality (584 of 1223 [47.8%] vs. 457 of 1223 [37.4%]; odds ratio, 0.69; 95% confidence interval, 0.59-0.81; p < .0001). The use of combination therapy was associated with increased ventilator (median and [interquartile range], 10 [0-25] vs. 17 [0-26]; p = .008) and pressor/inotrope-free days (median and [interquartile range], 23 [0-28] vs. 25 [0-28]; p = .007) up to 30 days. Conclusion:Early combination antibiotic therapy is associated with decreased mortality in septic shock. Prospective randomized trials are needed.

Risk factors for acquisition of endemic blastomycosis

BACKGROUND Blastomycosis is potentially fatal, but environmental risk factors for acquiring blastomycosis are not well established. METHOD Matched cross-sectional questionnaire of 112 patients with history of blastomycosis and 118 control subjects in Manitoba and northwestern Ontario. RESULTS The most common tissues involved with blastomycosis were pulmonary, skin and soft tissues, and bone. A significantly greater proportion of patients with blastomycosis than control subjects were involved in outdoor occupations. A significantly greater percentage of patients with blastomycosis were immunosuppressed either from collagen vascular disease or immunosuppressive therapy, or had hypothyroidism. A significant association between canine and human blastomycosis was not observed. CONCLUSIONS Independent risk factors for development of blastomycosis included immunosuppression for any reason (including drugs or disease), collagen vascular disease, being an outdoor worker, and having a coworker with blastomycosis. Canine blastomycosis was not a risk factor for human disease in dog owners.

Time required to initiate outbreak and pandemic observational research

Purpose Observational research focused upon emerging infectious diseases such as Ebola virus, Middle East respiratory syndrome, and Zika virus has been challenging to quickly initiate. We aimed to determine the duration of start‐up procedures and barriers encountered for an observational study focused upon such infectious outbreaks. Materials and methods At 1 pediatric and 5 adult intensive care units, we measured durations from protocol receipt to a variety of outbreak research milestones, including research ethics board (REB) approval, data sharing agreement (DSA) execution, and patient study screening initiation. Results The median (interquartile range) time from site receipt of the protocol to REB submission was 73 (30‐126) days; to REB approval, 158 (42‐188) days; to DSA completion, 276 (186‐312) days; and to study screening initiation, 293 (269‐391) days. The median time from REB submission to REB approval was 43 (13‐85) days. The median time for all start‐up procedures was 335 (188‐335) days. Conclusions There is a lengthy start‐up period required for outbreak‐focused research. Completing DSAs was the most time‐consuming step. A reactive approach to newly emerging threats such as Ebola virus, Middle East respiratory syndrome, and Zika virus will likely not allow sufficient time to initiate research before most outbreaks are advanced. HighlightsStart‐up period required for observational studies focused on outbreak surveillance is time consuming.The median time for all start‐up procedures was 335 (188‐335) days.Completing data sharing agreements was the most time‐consuming step, taking 9 months on average.There is a need to have a nationally and internationally coordinated approach, with context‐appropriate, tiered case report forms and preparatory work—protocol and case report form generation, data sharing agreements, and REB submissions—completed during the pre‐ and interoutbreak periods.A reactive approach to newly emerging threats will likely not allow sufficient time to initiate research before most outbreaks are advanced or completed.

Influenza A (H1N1pdm09)-Related Critical Illness and Mortality in Mexico and Canada, 2014.

Objectives:The 2009–2010 influenza A (H1N1pdm09) pandemic caused substantial morbidity and mortality among young patients; however, mortality estimates have been confounded by regional differences in eligibility criteria and inclusion of selected populations. In 2013–2014, H1N1pdm09 became North America’s dominant seasonal influenza strain. Our objective was to compare the baseline characteristics, resources, and treatments with outcomes among critically ill patients with influenza A (H1N1pdm09) in Mexican and Canadian hospitals in 2014 using consistent eligibility criteria. Design:Observational study and a survey of available healthcare setting resources. Setting:Twenty-one hospitals, 13 in Mexico and eight in Canada. Patients:Critically ill patients with confirmed H1N1pdm09 during 2013–2014 influenza season. Interventions:None. Measurements and Main Results:The main outcome measures were 90-day mortality and independent predictors of mortality. Among 165 adult patients with H1N1pdm09-related critical illness between September 2013 and March 2014, mean age was 48.3 years, 64% were males, and nearly all influenza was community acquired. Patients were severely hypoxic (median PaO2-to-FIO2 ratio, 83 mm Hg), 97% received mechanical ventilation, with mean positive end-expiratory pressure of 14 cm H2O at the onset of critical illness and 26.7% received rescue oxygenation therapy with prone ventilation, extracorporeal life support, high-frequency oscillatory ventilation, or inhaled nitric oxide. At 90 days, mortality was 34.6% (13.9% in Canada vs 50.5% in Mexico, p < 0.0001). Independent predictors of mortality included lower presenting PaO2-to-FIO2 ratio (odds ratio, 0.89 per 10-point increase [95% CI, 0.80–0.99]), age (odds ratio, 1.49 per 10 yr increment [95% CI, 1.10–2.02]), and requiring critical care in Mexico (odds ratio, 7.76 [95% CI, 2.02–27.35]). ICUs in Canada generally had more beds, ventilators, healthcare personnel, and rescue oxygenation therapies. Conclusions:Influenza A (H1N1pdm09)-related critical illness still predominantly affects relatively young to middle-aged patients and is associated with severe hypoxemic respiratory failure. The local critical care system and available resources may be influential determinants of patient outcome.

Global research preparedness for outbreak-related critical illness

We thank authors Gobat, Butler, Webb and Nichol for their thoughtful and practical suggestions to advance our ability to perform practiceinforming research in the context of outbreaks and pandemics. We too have been encouraged by the progress made with the Platform foR European Preparedness Against Re-emerging Epidemics (PREPARE) initiative a model for well-resourced health care systems to consider in preparing for the certainty of uncertain emerging infectious threats. While focused upon European preparedness, one additional promising aspect of PREPARE, is the provision to assist in addressing threats wherever they emerge. Novel viral pathogens often arise at the human-animal interface. Avian influenza, Ebola virus, Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome coronaviruses are but a few recent examples. While no region is protected, this interface frequently occurs in lowand middle-income countries, where preparedness funding and activities by necessity come after everyday urgent population and individual healthcare needs. We must encourage proactive humanitarian research preparedness from global regions with the luxury of this capacity. One such example is the freely available World Health Organization – International Severe Acute Respiratory & Emerging Infection Consortium (ISARIC) clinical characterization protocol [1], developed to provide clinicians and researchers with a case