Major Observational Studies Assessing Time-to-Antibiotics and Mortality in Adult Patients With Sepsis
| Reference . | Study Design and Setting . | Sample Size . | % ICU Patients . | % Septic Shock . | Main Findings: Time-To-Antibiotics and Mortality (or Other Outcome) . | Effect Estimate: Septic Shock . | Effect Estimate: Sepsis Without Shock . | Comments . |
|---|---|---|---|---|---|---|---|---|
| Barie et al, Surg Infect (Larchmt), 2005 [37] | Prospective: 1 surgical ICU in New York | 356 | 100% | Not reported | OR 1.021 [1.003–1.038] for in-hospital death with each 30-minute delay | Not reported | Not reported | Time zero based on suspected infection rather than any physiologic criteria |
| Kumar et al, Crit Care Med, 2006 [38] | Retrospective: 14 ICUs in 10 hospitals in Canada | 2154 | 100% | 100% | OR 1.119 [1.103–1.136] for in-hospital death with each hr delay | Same as primary finding (all patients had septic shock) | N/A | Time-to-antibiotics measured after onset of persistent or recurrent hypotension |
| Gaieski et al, Crit Care Med, 2010 [39] | Retrospective: 1 university hospital ED | 261 | 100% | 100% | OR 0.30 [0.11–0.83] for in-hospital death if antibiotics given <1 hr from triage; OR 0.50 [0.27–0.92] if given <1 hr from qualifying for EGDT | Same as primary finding (all patients had septic shock) | N/A | No significant association between time- to-antibiotics and mortality at different hourly cutoffs other than <1 hr |
| Ferrer et al, Crit Care Med, 2014 [40] | Retrospective: 165 ICUs in the Surviving Sepsis Campaign database | 17 990 | 100% | 64% | OR for in-hospital death: hr 1–2, 1.07 [0.97–1.18]; hr 2–3, 1.14 [1.02– 1.26]; hr 3–4, 1.19 [1.04–1.35]; hr 4–5, 1.24 [1.06–1.45]; hr 5–6, 1.47 [1.22–1.76]; hr > 6, 1.52 [1.36–1.70] | Not reported | Not reported | Statistically significant signal for mortality only seen after hr 2 |
| Liu et al, Am J Resp Crit Care Med, 2017 [41] | Retrospective: 21 EDs in Northern California | 35 000 | 21% | 13% | OR 1.09 [1.05–1.13] for in-hospital death with each hr delay | OR 1.14 [1.06–1.23] | OR 1.07 [1.01–1.24] | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 6 hrs but increase in mortality was not linear; increase in absolute mortality per hr delay much higher with septic shock (1.8%, vs severe sepsis [0.4%] and sepsis [0.3%]) |
| Whiles et al, Crit Care Med, 2017 [42] | Retrospective: 1 ED in Kansas | 3929 | 59% | 0% | OR 1.08 [1.06–1.10] for progression from severe sepsis to septic shock with each hr delay; OR 1.05 [1.03–1.07] for in-hospital death with each hr delay | N/A | Same as primary finding (all patients had no shock on presentation) | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 24 hrs but no change in proportion of severe sepsis patients progressing to septic shock with antibiotic delays until after hr 5 |
| Seymour et al, N Engl J Med, 2017 [43] | Retrospective: 149 hospitals in New York | 49 331 | Not reported | 45% | OR 1.04 [1.03–1.06] for in-hospital death with each hr delay | OR 1.07 [1.05–1.09] for patients who required vasopressors | OR 1.01 [0.99–1.04] for no vasopressors | Risk-adjustment model had modest performance (AUROC = 0.77); ORs represented linearized estimates across 12 hrs but increase in mortality was not linear |
| Peltan et al, Chest, 2019 [44] | Retrospective: 4 hospitals in Utah | 10 811 | 29% | 8% | OR 1.10 [1.05–1.14] for 1-year mortality with each hr delay OR 1.12 [1.06–1.18] for in-hospital death with each hr delay | OR 1.13 [1.00–1.28] for patients with hypotension | OR 1.09 [1.05–1.13] for no hypotension | ORs represented linearized estimates across >15 hrs but increase in mortality was not linear; No significant increase in 1-year mortality seen until hr 3; no increase in in-hospital mortality until hr 5 |
| Ko et al, Am J Med, 2019 [45] | Prospective: 10 EDs in South Korea | 2229 | Not reported | 100% | OR for in-hospital death: hr 1–2, 1.248 [1.053– 1.478]; hr 2–3, 1.186 [0.999–1.408]; hr > 3, 1.419 [1.203–1.675] | Same as primary finding (all patients had septic shock) | N/A | No clear linear association between each hour delay and in-hospital mortality |
| Reference . | Study Design and Setting . | Sample Size . | % ICU Patients . | % Septic Shock . | Main Findings: Time-To-Antibiotics and Mortality (or Other Outcome) . | Effect Estimate: Septic Shock . | Effect Estimate: Sepsis Without Shock . | Comments . |
|---|---|---|---|---|---|---|---|---|
| Barie et al, Surg Infect (Larchmt), 2005 [37] | Prospective: 1 surgical ICU in New York | 356 | 100% | Not reported | OR 1.021 [1.003–1.038] for in-hospital death with each 30-minute delay | Not reported | Not reported | Time zero based on suspected infection rather than any physiologic criteria |
| Kumar et al, Crit Care Med, 2006 [38] | Retrospective: 14 ICUs in 10 hospitals in Canada | 2154 | 100% | 100% | OR 1.119 [1.103–1.136] for in-hospital death with each hr delay | Same as primary finding (all patients had septic shock) | N/A | Time-to-antibiotics measured after onset of persistent or recurrent hypotension |
| Gaieski et al, Crit Care Med, 2010 [39] | Retrospective: 1 university hospital ED | 261 | 100% | 100% | OR 0.30 [0.11–0.83] for in-hospital death if antibiotics given <1 hr from triage; OR 0.50 [0.27–0.92] if given <1 hr from qualifying for EGDT | Same as primary finding (all patients had septic shock) | N/A | No significant association between time- to-antibiotics and mortality at different hourly cutoffs other than <1 hr |
| Ferrer et al, Crit Care Med, 2014 [40] | Retrospective: 165 ICUs in the Surviving Sepsis Campaign database | 17 990 | 100% | 64% | OR for in-hospital death: hr 1–2, 1.07 [0.97–1.18]; hr 2–3, 1.14 [1.02– 1.26]; hr 3–4, 1.19 [1.04–1.35]; hr 4–5, 1.24 [1.06–1.45]; hr 5–6, 1.47 [1.22–1.76]; hr > 6, 1.52 [1.36–1.70] | Not reported | Not reported | Statistically significant signal for mortality only seen after hr 2 |
| Liu et al, Am J Resp Crit Care Med, 2017 [41] | Retrospective: 21 EDs in Northern California | 35 000 | 21% | 13% | OR 1.09 [1.05–1.13] for in-hospital death with each hr delay | OR 1.14 [1.06–1.23] | OR 1.07 [1.01–1.24] | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 6 hrs but increase in mortality was not linear; increase in absolute mortality per hr delay much higher with septic shock (1.8%, vs severe sepsis [0.4%] and sepsis [0.3%]) |
| Whiles et al, Crit Care Med, 2017 [42] | Retrospective: 1 ED in Kansas | 3929 | 59% | 0% | OR 1.08 [1.06–1.10] for progression from severe sepsis to septic shock with each hr delay; OR 1.05 [1.03–1.07] for in-hospital death with each hr delay | N/A | Same as primary finding (all patients had no shock on presentation) | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 24 hrs but no change in proportion of severe sepsis patients progressing to septic shock with antibiotic delays until after hr 5 |
| Seymour et al, N Engl J Med, 2017 [43] | Retrospective: 149 hospitals in New York | 49 331 | Not reported | 45% | OR 1.04 [1.03–1.06] for in-hospital death with each hr delay | OR 1.07 [1.05–1.09] for patients who required vasopressors | OR 1.01 [0.99–1.04] for no vasopressors | Risk-adjustment model had modest performance (AUROC = 0.77); ORs represented linearized estimates across 12 hrs but increase in mortality was not linear |
| Peltan et al, Chest, 2019 [44] | Retrospective: 4 hospitals in Utah | 10 811 | 29% | 8% | OR 1.10 [1.05–1.14] for 1-year mortality with each hr delay OR 1.12 [1.06–1.18] for in-hospital death with each hr delay | OR 1.13 [1.00–1.28] for patients with hypotension | OR 1.09 [1.05–1.13] for no hypotension | ORs represented linearized estimates across >15 hrs but increase in mortality was not linear; No significant increase in 1-year mortality seen until hr 3; no increase in in-hospital mortality until hr 5 |
| Ko et al, Am J Med, 2019 [45] | Prospective: 10 EDs in South Korea | 2229 | Not reported | 100% | OR for in-hospital death: hr 1–2, 1.248 [1.053– 1.478]; hr 2–3, 1.186 [0.999–1.408]; hr > 3, 1.419 [1.203–1.675] | Same as primary finding (all patients had septic shock) | N/A | No clear linear association between each hour delay and in-hospital mortality |
Abbreviations: AUROC, area under the receiver operating characteristic curve; ED, emergency department; EGDT, early goal-directed therapy; hr, hour; ICU, intensive care unit; N/A, not applicable; OR, odds ratio; pts, patients.
Major Observational Studies Assessing Time-to-Antibiotics and Mortality in Adult Patients With Sepsis
| Reference . | Study Design and Setting . | Sample Size . | % ICU Patients . | % Septic Shock . | Main Findings: Time-To-Antibiotics and Mortality (or Other Outcome) . | Effect Estimate: Septic Shock . | Effect Estimate: Sepsis Without Shock . | Comments . |
|---|---|---|---|---|---|---|---|---|
| Barie et al, Surg Infect (Larchmt), 2005 [37] | Prospective: 1 surgical ICU in New York | 356 | 100% | Not reported | OR 1.021 [1.003–1.038] for in-hospital death with each 30-minute delay | Not reported | Not reported | Time zero based on suspected infection rather than any physiologic criteria |
| Kumar et al, Crit Care Med, 2006 [38] | Retrospective: 14 ICUs in 10 hospitals in Canada | 2154 | 100% | 100% | OR 1.119 [1.103–1.136] for in-hospital death with each hr delay | Same as primary finding (all patients had septic shock) | N/A | Time-to-antibiotics measured after onset of persistent or recurrent hypotension |
| Gaieski et al, Crit Care Med, 2010 [39] | Retrospective: 1 university hospital ED | 261 | 100% | 100% | OR 0.30 [0.11–0.83] for in-hospital death if antibiotics given <1 hr from triage; OR 0.50 [0.27–0.92] if given <1 hr from qualifying for EGDT | Same as primary finding (all patients had septic shock) | N/A | No significant association between time- to-antibiotics and mortality at different hourly cutoffs other than <1 hr |
| Ferrer et al, Crit Care Med, 2014 [40] | Retrospective: 165 ICUs in the Surviving Sepsis Campaign database | 17 990 | 100% | 64% | OR for in-hospital death: hr 1–2, 1.07 [0.97–1.18]; hr 2–3, 1.14 [1.02– 1.26]; hr 3–4, 1.19 [1.04–1.35]; hr 4–5, 1.24 [1.06–1.45]; hr 5–6, 1.47 [1.22–1.76]; hr > 6, 1.52 [1.36–1.70] | Not reported | Not reported | Statistically significant signal for mortality only seen after hr 2 |
| Liu et al, Am J Resp Crit Care Med, 2017 [41] | Retrospective: 21 EDs in Northern California | 35 000 | 21% | 13% | OR 1.09 [1.05–1.13] for in-hospital death with each hr delay | OR 1.14 [1.06–1.23] | OR 1.07 [1.01–1.24] | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 6 hrs but increase in mortality was not linear; increase in absolute mortality per hr delay much higher with septic shock (1.8%, vs severe sepsis [0.4%] and sepsis [0.3%]) |
| Whiles et al, Crit Care Med, 2017 [42] | Retrospective: 1 ED in Kansas | 3929 | 59% | 0% | OR 1.08 [1.06–1.10] for progression from severe sepsis to septic shock with each hr delay; OR 1.05 [1.03–1.07] for in-hospital death with each hr delay | N/A | Same as primary finding (all patients had no shock on presentation) | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 24 hrs but no change in proportion of severe sepsis patients progressing to septic shock with antibiotic delays until after hr 5 |
| Seymour et al, N Engl J Med, 2017 [43] | Retrospective: 149 hospitals in New York | 49 331 | Not reported | 45% | OR 1.04 [1.03–1.06] for in-hospital death with each hr delay | OR 1.07 [1.05–1.09] for patients who required vasopressors | OR 1.01 [0.99–1.04] for no vasopressors | Risk-adjustment model had modest performance (AUROC = 0.77); ORs represented linearized estimates across 12 hrs but increase in mortality was not linear |
| Peltan et al, Chest, 2019 [44] | Retrospective: 4 hospitals in Utah | 10 811 | 29% | 8% | OR 1.10 [1.05–1.14] for 1-year mortality with each hr delay OR 1.12 [1.06–1.18] for in-hospital death with each hr delay | OR 1.13 [1.00–1.28] for patients with hypotension | OR 1.09 [1.05–1.13] for no hypotension | ORs represented linearized estimates across >15 hrs but increase in mortality was not linear; No significant increase in 1-year mortality seen until hr 3; no increase in in-hospital mortality until hr 5 |
| Ko et al, Am J Med, 2019 [45] | Prospective: 10 EDs in South Korea | 2229 | Not reported | 100% | OR for in-hospital death: hr 1–2, 1.248 [1.053– 1.478]; hr 2–3, 1.186 [0.999–1.408]; hr > 3, 1.419 [1.203–1.675] | Same as primary finding (all patients had septic shock) | N/A | No clear linear association between each hour delay and in-hospital mortality |
| Reference . | Study Design and Setting . | Sample Size . | % ICU Patients . | % Septic Shock . | Main Findings: Time-To-Antibiotics and Mortality (or Other Outcome) . | Effect Estimate: Septic Shock . | Effect Estimate: Sepsis Without Shock . | Comments . |
|---|---|---|---|---|---|---|---|---|
| Barie et al, Surg Infect (Larchmt), 2005 [37] | Prospective: 1 surgical ICU in New York | 356 | 100% | Not reported | OR 1.021 [1.003–1.038] for in-hospital death with each 30-minute delay | Not reported | Not reported | Time zero based on suspected infection rather than any physiologic criteria |
| Kumar et al, Crit Care Med, 2006 [38] | Retrospective: 14 ICUs in 10 hospitals in Canada | 2154 | 100% | 100% | OR 1.119 [1.103–1.136] for in-hospital death with each hr delay | Same as primary finding (all patients had septic shock) | N/A | Time-to-antibiotics measured after onset of persistent or recurrent hypotension |
| Gaieski et al, Crit Care Med, 2010 [39] | Retrospective: 1 university hospital ED | 261 | 100% | 100% | OR 0.30 [0.11–0.83] for in-hospital death if antibiotics given <1 hr from triage; OR 0.50 [0.27–0.92] if given <1 hr from qualifying for EGDT | Same as primary finding (all patients had septic shock) | N/A | No significant association between time- to-antibiotics and mortality at different hourly cutoffs other than <1 hr |
| Ferrer et al, Crit Care Med, 2014 [40] | Retrospective: 165 ICUs in the Surviving Sepsis Campaign database | 17 990 | 100% | 64% | OR for in-hospital death: hr 1–2, 1.07 [0.97–1.18]; hr 2–3, 1.14 [1.02– 1.26]; hr 3–4, 1.19 [1.04–1.35]; hr 4–5, 1.24 [1.06–1.45]; hr 5–6, 1.47 [1.22–1.76]; hr > 6, 1.52 [1.36–1.70] | Not reported | Not reported | Statistically significant signal for mortality only seen after hr 2 |
| Liu et al, Am J Resp Crit Care Med, 2017 [41] | Retrospective: 21 EDs in Northern California | 35 000 | 21% | 13% | OR 1.09 [1.05–1.13] for in-hospital death with each hr delay | OR 1.14 [1.06–1.23] | OR 1.07 [1.01–1.24] | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 6 hrs but increase in mortality was not linear; increase in absolute mortality per hr delay much higher with septic shock (1.8%, vs severe sepsis [0.4%] and sepsis [0.3%]) |
| Whiles et al, Crit Care Med, 2017 [42] | Retrospective: 1 ED in Kansas | 3929 | 59% | 0% | OR 1.08 [1.06–1.10] for progression from severe sepsis to septic shock with each hr delay; OR 1.05 [1.03–1.07] for in-hospital death with each hr delay | N/A | Same as primary finding (all patients had no shock on presentation) | Cohort identified by sepsis billing codes; ORs represented linearized estimates across 24 hrs but no change in proportion of severe sepsis patients progressing to septic shock with antibiotic delays until after hr 5 |
| Seymour et al, N Engl J Med, 2017 [43] | Retrospective: 149 hospitals in New York | 49 331 | Not reported | 45% | OR 1.04 [1.03–1.06] for in-hospital death with each hr delay | OR 1.07 [1.05–1.09] for patients who required vasopressors | OR 1.01 [0.99–1.04] for no vasopressors | Risk-adjustment model had modest performance (AUROC = 0.77); ORs represented linearized estimates across 12 hrs but increase in mortality was not linear |
| Peltan et al, Chest, 2019 [44] | Retrospective: 4 hospitals in Utah | 10 811 | 29% | 8% | OR 1.10 [1.05–1.14] for 1-year mortality with each hr delay OR 1.12 [1.06–1.18] for in-hospital death with each hr delay | OR 1.13 [1.00–1.28] for patients with hypotension | OR 1.09 [1.05–1.13] for no hypotension | ORs represented linearized estimates across >15 hrs but increase in mortality was not linear; No significant increase in 1-year mortality seen until hr 3; no increase in in-hospital mortality until hr 5 |
| Ko et al, Am J Med, 2019 [45] | Prospective: 10 EDs in South Korea | 2229 | Not reported | 100% | OR for in-hospital death: hr 1–2, 1.248 [1.053– 1.478]; hr 2–3, 1.186 [0.999–1.408]; hr > 3, 1.419 [1.203–1.675] | Same as primary finding (all patients had septic shock) | N/A | No clear linear association between each hour delay and in-hospital mortality |
Abbreviations: AUROC, area under the receiver operating characteristic curve; ED, emergency department; EGDT, early goal-directed therapy; hr, hour; ICU, intensive care unit; N/A, not applicable; OR, odds ratio; pts, patients.
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