Best evidence in critical care medicine - Early antibiotics and survival from septic shock: it's about time

Background: International guidelines recommend appropriate antimicrobial therapy within an hour of recognizing severe sepsis and septic shock.(1) Unfortunately, delays are common.(2,3) This study was undertaken to quantify the association between mortality and time to administration of effective antibiotics following hypotension in septic shock. Question: What is the relationship between delay of effective antibiotics from the initial onset of hypotension and survival-to-hospital-discharge in adult patients with suspected or confirmed septic shock? Design: A retrospective cohort review of the medical records of 2,731 adult patients with septic shock (and with no other obvious cause of shock), conducted between July 1989 and June 2004 and involving 14 intensive care units in Canada and the United States. Patients: Hypotension was defined as a mean arterial pressure (MAP) < 65 mmHg, a systolic blood pressure (SBP) < 90 mmHg, or a fall in SBP of 40 mmHg from the patient's baseline. These criteria were consistent with the 1991 Society of Critical Care Medicine/American College of Chest Physicians Consensus Statement on Sepsis Definitions.' Time zero was determined to be either 1) the first episode of hypotension that persisted despite at least two litres of crystalloid resuscitation (so called "persistent hypotension"), or 2) hypotension that resolved for less than one hour following fluid resuscitation (so called "recurrent hypotension"). Hypotension that resolved without therapy or with less than two litres normal saline (or equivalent) did not qualify. Potential pathogens had to be isolated within 48 hr of the onset of shock. The effectiveness of antimicrobials was deter-mined by an extensive list of predetermined rules that included broadly accepted guidelines for known and suspected infections. Intervention: No intervention. Instead, medical charts were reviewed and the antimicrobial used, the time of initial administration, the source of infection, patient demographics and the APACHE II score were collected. Primary endpoint: Survival to hospital-discharge. Results: Of 2,731 patients with septic shock, 2,154 (79%) patients did not receive effective antimicrobial therapy until after the onset of hypotension. Amongst these 2,154, the in-hospital mortality rate was 56.2%. After the onset of hypotension, each hour of delay was associated with a mean decrease in survival of 7.6% (range 3.6-9.9%). Survival was 79.9% if antibiotics were administered in the first hour, and 42% by the sixth hour. The median time to effective antibiotics was six hours after onset of hypotension. Multivariate analysis showed that time to administration of effective antimicrobial therapy was the single strongest predictor of outcome. The delay from onset of persistent/recurrent hypotension to initiation of effective antibiotics accounted for 28.1% of variance in survival to discharge while APACHE II only explained 24.6% and the volume of fluid infused in the first hour accounted for < 2%. Subgroup analysis showed the relationship of survival and antibiotic-delay following hypotension held regardless of site of infection; whether gram-negative, gram-positive or fungal, whether bacteremia was present or not; or whether the infection was documented or suspected. Conclusions. Effective antimicrobial therapy for adult patients with septic shock provided within the first hour of hypotension was associated with increased survival to hospital discharge. Only 50% of these patients received such therapy within the first six hours of documented hypotension.