ABSTRACT

1. The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock Anand Kumar, Daniel Roberts, Kenneth Wood, Bruce Light, Joseph E. Parrillo, Satendra Sharma, Robert Suppes, Daniel Feinstein, Sergio Zanotti, Leo Taibert, David Gurka, Aseem Kumar, and Mary Cheang ABSTRACT Background. Current guidelines recommend antimicrobial initiation within one hour of presentation of severe sepsis and septic shock but no clinical studies are available to support this recommendation. 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, Setting and Patients: A retrospective cohort study using the medical records of 2731 adult patients with septic shock spread among 14 intensive care units (4 medical, 4 surgical, 6 mixed medical/surgical) and 10 hospitals (4 academic, 6 community) in Canada and the United States between July 1989 and June 2004 was performed. Main Outcome Measure: Survival to hospital discharge. Results: Among the 2154 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<0.0001). 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 hours was associated with an average decrease in survival of 7.6%. By the 2nd hour after onset of persistent/recurrent hypotension, in-hospital mortality 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 APACHE 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 hours (25-75th percentile, 2.0-15.0 hrs.) Conclusion: Effective antimicrobial administration within the first hour of documented hypotension is associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality with increasing delays, only 50% pf septic shock patients receive effective antimicrobial therapy within 6 hours of documents hypotension. (Crit Care Med 2006;34(6):1589-1596

2. 1.0 Survival fraction Cumulative effective antimicrobial initiation 0.8 0.6 Fraction of total patients 0.4 0.2 0.0 >36 6-8.99 3-3.99 4-4.99 2-2.99 0.5-.99 1-1.99 5-5.99 9-11.99 0-0-.49 24-35.99 12-23.99 Time from hypotension onset (hrs) The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock Cumulative effective antimicrobial initiation following onset of septic shock-associated hypotension and associated survival. X axis represents time (hrs) following first documentation of septic shock-associated hypotension. Kumar et al. Crit Care Med2006;34(6)1589-1596

3. 100 Odds Ratio of Death (95% Confidence Interval) 10 1 >36 6-8.99 4-4.99 3-3.99 1-1.99 5-5.99 2-2.99 9-11.99 24-35.99 12-23.99 Time (hrs) The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock Mortality risk (expressed as adjusted odds ratio of death) with increasing delays in initiation of effective antimicrobial therapy. Bars represent 95% confidence interval. Increased risk of death is already present by the 2nd hour post-hypotension onset (compared to the first hour post-hypotension). The risk of death continues to climb through to > 36 hours post-hypotension onset. Kumar et al. Crit Care Med2006;34(6)1589-1596

4. N all 2154 documented 1695 suspected 459 culture + 1546 culture - 608 bacteremia + 769 bacteremia - 1385 community 1242 nosocomial 912 gram + 584 gram - 768 fungal 131 respiratory 838 urinary tract 230 Intra-abdominal 641 skin/soft tissue 156 1.0 1.1 1.2 1.3 The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock Relationship of antimicrobial delay to hospital mortality in major subgroups (expressed as adjusted odds ratio of death with time as a continuous variable). Bars represent 95% confidence intervals. All major subgroups demonstrate a highly significant increase in mortality risk with increasing delays in administration of effective antimicrobial therapy following onset of sepsis-associated hypotension. For the overall group, mortality risk increases approximately 12% every hour relative to the risk in the previous hour. P values <0.0001 for all subgroups. Kumar et al. Crit Care Med2006;34(6)1589-1596

5. % Survival % Total receiving antibiotics Only 50% of patients in Septic Shock received antibiotics w/in 6 hrs. Septic Shock: Timing of Antibiotics Percent 1.00 14 ICUs; n = 2,731 .80 .60 .40 .20 0.0 .5 – 1.0 1 - 2 2 - 3 3-4 4 - 5 5 - 6 6 - 9 9 - 12 12 - 24 24 - 36 > 36 0 - .5 Time, hrs Kumar Crit Care Med 2006