Kumar A et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589–96.
Introduction
In the summer of 1928, Alexander Fleming, on his return from holidays, was disconcerted by a mold that had contaminated his Petri dishes. On examination under the microscope, he noted that the mold had suppressed the growth of staphylococci all around. Little did he realize that he had stumbled upon one of the most groundbreaking discoveries in the history of medicine. In less than three decades since the discovery of penicillin, life-expectancy had risen by nearly 8 years; patients suffering from seemingly minor injuries or severe illnesses like pneumonia no longer had to languish, hoping for a miracle.
Although sepsis was recognized from time immemorial, considerable discordance existed in the interpretation. Roger Bone and colleagues came up with a consensus definition at the Society of Critical Care Medicine (SCCM) – American College of Chest Physicians (ACCP) meeting of 1991 (1). A bundled approach towards the expeditious care of septic patients was proposed by the Surviving Sepsis Guidelines in 2004 (2). The 3- and 6-hour bundles were revamped to a 1-hour bundle in 2018 (3). One of the key elements of the 1-hour bundle was the administration of broad-spectrum antibiotics. Timely administration of antibiotics is intuitive in patients with sepsis; however, no robust evidence had supported a timeframe for the initiation of therapy. In contrast, hemodynamic stabilization with fluid resuscitation and vasopressors were firmly entrenched in the initial management of sepsis. Kumar et al. in their landmark study of 2004, asked the question – does a delay in antimicrobial administration lead to increased mortality in septic shock?
Setting and design
The retrospective cohort study included patients who were admitted to 14 ICUs in Canada and the US (4). Three patient cohorts were included – two between 1999–2004 and one between 1989–1999. Patients were screened to confirm septic shock based on the 1991 SCCM/ACCP consensus statement (1). Hypotension was defined as a mean arterial pressure of <65 mm Hg, a systolic BP <90 mm Hg, or a decrease in systolic BP by >40 mm Hg from the baseline. Septic shock was deemed to have occurred if hypotension persisted despite fluid resuscitation or improved transiently, for less than 1 hour. Antimicrobial therapy was considered effective if it was appropriate for the pathogen isolated. In culture negative septic shock, antimicrobial therapy was considered effective if it was in concordance with accepted national guidelines. Besides, antimicrobial therapy had to be administered within 6 h of the onset of septic shock to be considered effective.
Results
Patient characteristics
The study included 2731 patients who fulfilled the criteria for septic shock. All three patient cohorts had a similar distribution of infections, APACHE II scores, and time to effective antimicrobial therapy following hypotension; hence the data were combined and analyzed. The mean age of the cohort was 62.7±16.4 years, and 54.3% were male patients. The mean APACHE II score was 26±8.6. Community-acquired infections occurred in 58.1% of patients, while the infection was considered nosocomial in 41.9%.
Infections were documented in 77.9% of cases; in the rest, infection was suspected – no pathogens were isolated was isolated on cultures, nor could infection be confirmed otherwise. The most common foci of infection were the lungs (37.2%), followed by abdomen (29.3%), and genitourinary (10.7%). Gram-negative infections were more common, with E. coli being the most frequently isolated organism (22.4%).
In the whole cohort of 2731 patients, 19 did not receive effective antimicrobial therapy until death; 558 patients received effective therapy before the onset of hypotension. The remaining 2,154 patients received effective antimicrobial therapy only after the onset of hypotension; the mortality among this group was 58.0%. The median time to effective antimicrobial therapy following the onset of hypotension was 6 (2.0–15.0) hours.
Outcomes
The time interval between recurrent or persistent hypotension and commencement of effective antimicrobial therapy was a critical determinant of survival to ICU or hospital discharge. Increasing delays with the initiation of effective therapy was associated with higher mortality. The mortality rate with initiation of effective antimicrobial therapy at two hours after the onset of hypotension was significantly higher compared with initiation of therapy within the first hour (adjusted odds ratio 1.67; 95% confidence interval, 1.12–2.48). There was a continuous increase in the odds ratio of death with increasing delay – to a maximum level at 36 hours after the onset of hypotension. Each 1-h delay in the commencement of effective antimicrobials was associated with decrease in survival by 7.6% during the first 6 hours after the onset of hypotension.
The authors performed multivariate analysis including effectiveness of antimicrobial therapy, the volume and type of initial fluid resuscitation, monotherapy vs. combination antibiotic therapy, and vasopressor support. Among all these variables, the time to effective antibiotic therapy was most strongly associated with survival. The strong association between time to effective therapy and survival persisted after inclusion of the APACHE II score, the number of organ failures, and site of infection to the model. On subgroup analysis, the increase in hospital mortality associated with longer delays in antimicrobial administration was evident regardless of the focus of infection, and whether the infection was documented or suspected. The findings were also consistent across patients with positive or negative cultures, gram positive, negative, or fungal infections, and regardless of community acquired or nosocomial infection.
Strengths
The importance of timely antimicrobial therapy in conjunction with source control as appropriate cannot be overemphasized. However, a key clinical conundrum lies in the definitive diagnosis of sepsis within a reasonable time frame, considering the paucity of information available at an early stage. In their desperation to conform to a bundled approach, clinicians may often be under pressure to administer antibiotics even if the diagnosis of sepsis is uncertain. This approach may lead to an inappropriate overuse of antibiotics, leading to an adverse impact on the gut microbiome, overgrowth with resistant organisms, and superinfections including Clostridium difficile diarrhea. A randomized controlled trial comparing early with delayed antimicrobial therapy is unrealistic considering the ethical implications of such a study. Kumar et al. embarked upon their retrospective study based on information from databases involving three cohorts of patients. Their landmark study conveyed the powerful message that the key to survival may lie in the time interval between the onset of septic shock and antibiotic administration. Every hour of delay following the onset of hypotension led to an increase in mortality. The study was highly impactful and led to the bundled approach to sepsis recommended by the Surviving Sepsis Guidelines, with early antibiotic administration being pivotal (3).
Limitations
The study was based on retrospective data of three patient cohorts from Canada and the US. It was a long drawn-out period of data collection – between 1989 to 2004, during which many aspects of care among critically ill patients may have undergone far-reaching changes. Infection was just “suspected” in 22.1% of cases, with neither a plausible pathogen grown on culture, nor was the presence of infection confirmed by any other modality of investigation. The likelihood of non-infectious mimics (e.g., cardiogenic shock) as a confounding variable was not considered. The timing and effectiveness of antimicrobial therapy was based on predefined rules; however, in doubtful scenarios, the decision was based on physician review and judgment, which could have led to bias. In the absence of a positive culture, appropriateness of therapy was based on available guidelines, casting ambiguity on the effectiveness of the agents used. No information was available on the performance of source control interventions and their timing, often more important than punctilious antibiotic administration in severe sepsis. The study did not consider the use of sedative agents in mechanically ventilated patients as a possible cause for hypotension. Information was not available on the incidence and severity of organ dysfunction, a major determinant of mortality in critically ill patients. Antibiotics were commenced prior to the onset of hypotension in 558 patients; however, inexplicably, survival in this subgroup of patients was lower than those who received antimicrobial agents within 5 hours of the onset of hypotension. The study was also supported by grants from pharmaceutical companies leading to conflicts of interest.
Subsequent evidence
A prospective observational study included 2,796 patients with severe sepsis; the hospital mortality was 41.6% among the cohort. Early broad-spectrum antibiotics resulted in lower hospital mortality (5). Seymour et al. evaluated patients with septic shock reported to the New York health department. Among this cohort, 82.5% of patients revealed adherence to the 3-hour bundle including blood cultures, administration of broad-spectrum antibiotics, and measurement of lactate levels. Among those who completed the bundle in 12 hours, a delay in commencement of antibiotics was associated with higher risk-adjusted in-hospital mortality. Intriguingly, a longer time to completion of an intravenous fluid bolus was not associated with higher mortality (6). Liu et al. retrospectively studied 35,000 randomly selected patients with sepsis who received antibiotics within 6 hours of registration in the emergency department. Each hour of delay in antibiotic administration resulted in an increase in absolute mortality by 0.4% in patients with severe sepsis and 1.8% in those with septic shock (7). Another prospective observational study evaluated in-hospital mortality among patients who presented to the emergency department with sepsis. In patients with septic shock who received antibiotics within 3 hours of presentation, every hour of delay was associated with an increased risk of mortality. The association was not observed in patients with sepsis without shock (8).
Key highlights of the study
Although guidelines recommended antimicrobial therapy within an hour of presentation in patients with severe sepsis and septic shock, no clinical studies had been carried out to support this recommendation. Specifically, likely adverse outcomes consequent to delayed administration of antibiotics had not been rigorously evaluated during the period when Kumar et al. embarked upon their landmark study. The authors had previously demonstrated that the onset of septic shock is a key determinant of outcome in a murine model. Against this background, they conducted a retrospective study including data from ICUs in the US and Canada. They set out to evaluate the impact of delays in effective antimicrobial therapy among patients with septic shock. Among patients with septic shock, effective antimicrobial therapy was administered in approximately 50% of patients within 6 hours of onset of hypotension The authors observed a strong association between delays in the initiation of effective antimicrobials and in-hospital mortality. Survival was highest when effective antimicrobials were commenced within an hour of the onset of hypotension; mortality increased with every hour of delay. The findings of this retrospective study underlined the urgency of effective antibiotic administration in patients with septic shock and provided the impetus for further research.
References
1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644–55.
2. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858–73.
3. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 Update. Crit Care Med. 2018 Jun;46(6):997–1000.
4. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589–96.
5. Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, et al. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med. 2009 Nov 1;180(9):861–6.
6. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017 Jun 8;376(23):2235–44.
7. Liu VX, Fielding-Singh V, Greene JD, Baker JM, Iwashyna TJ, Bhattacharya J, et al. The Timing of Early Antibiotics and Hospital Mortality in Sepsis. Am J Respir Crit Care Med. 2017 Oct 1;196(7):856–63.
8. Im Y, Kang D, Ko RE, Lee YJ, Lim SY, Park S, et al. Time-to-antibiotics and clinical outcomes in patients with sepsis and septic shock: a prospective nationwide multicenter cohort study. Crit Care. 2022 Jan 13;26(1):19.
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