The Duration of Hypotension Prior to Initiation of The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical

Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock 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

The Duration of Hypotension Prior to Initiation of The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock 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.

1.0 Fraction of total patients 0.8 0.6 0.4 0.2 0.0

Survival fraction Cumulative effective antimicrobial initiation

6 >3 99 5. -3 24 99 3. -2 12 9 .9 11 9- 9 9 8. 699 5. 5- 9 9 4. 499 3. 399 2. 2- 9 9 1. 19 .9

50.

Kumar et al. Crit Care Med 2006;34(6)1589-1596

.4 00-

Time from hypotension onset (hrs)

The Duration of Hypotension Prior to Initiation of The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock 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 posthypotension). The risk of death continues to climb through to > 36 hours post-hypotension onset.
(95% Confidence Interval)

Odds Ratio of Death

100

10

Kumar et al. Crit Care Med 2006;34(6)1589-1596

6 >3 .99 5 -3 24 99 3. -2 12 9 .9 11 999 8. 699 5. 599 4. 499 3. 399 2. 29 .9

1 1-

Time (hrs)

The Duration of Hypotension Prior to Initiation of The Duration of Hypotension Prior to Initiation of Effective Antimicrobial Therapy is the Critical Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock 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.
N all documented suspected culture + culture bacteremia + bacteremia community nosocomial gram + gram fungal respiratory urinary tract Intra-abdominal skin/soft tissue 1.0 1.1 1.2 2154 1695 459 1546 608 769 1385 1242 912 584 768 131 838 230 641 156 1.3

Kumar et al. Crit Care Med 2006;34(6)1589-1596

Septic Shock: Timing of Antibiotics

Percent
1.00 .80 .60 Only 50% of patients in Septic Shock received antibiotics w/in 6 hrs. .40 .20 % Survival % Total receiving antibiotics 14 ICUs; n = 2,731

0.0

.5 0-

.0 1 5

2 1-

3 2-

3-4

5 4-

6 5-

9 6-

2 -1 9

4 -2 12

6 -3 24

6 >3

Time, hrs

Kumar Crit Care Med 2006