Sepsis care bundles were associated with consistent and significant increases in survival across eight studies. Two of three measures of antibiotic use were also consistently and significantly improved across the studies reporting such data. In contrast, there was significant heterogeneity in the effect of bundled care on the use of all remaining bundle components analyzed. Insulin therapy and lung protective strategies were insufficiently reported and, therefore, not analyzed.
Numerous studies over the past 20 yrs have demonstrated improved outcomes in life-threatening infections with early administration of appropriate antibiotics, and multiple clinical guidelines emphasize such care (31
). In a recent, large, retrospective study in septic patients with hypotension (n = 2731), every hour of delay in appropriate antibiotic administration was associated with a significant increase in mortality (32
). Based on such evidence supporting the critical need for early appropriate antibiotics in treating serious infections, the Surviving Sepsis Campaign gave this treatment a strong rating (Grade 1B) in their updated 2008 guidelines (31
). Importantly, use of early appropriate antibiotics for sepsis meets the stated requirement of the Joint Commission and Institute for Healthcare Improvement that bundle components be proven and well-accepted interventions (1
Resuscitation fluid volumes and the percentage of patients receiving vasopressors were not consistently altered by bundled care. This heterogeneity was not related to any individual study. Although bundles in each of these studies targeted a central venous pressure goal of 8 mm Hg to 12 mm Hg for fluid administration and an MAP of ≥65 mm Hg for vasopressors, levels outside of this range were likely employed clinically in some patients and may have contributed to heterogeneity. Notably, only one trial provided data regarding the levels of central venous pressure and MAP actually reached with bundled treatment and these exceeded the stipulated goals in many patients (22
Hemodynamic support with fluids and vasopressors is as important as antibiotics in reducing mortality from septic shock (58
). Nonetheless, differences in physician practice and among patient populations could lead to heterogeneity in application of these interventions. There is considerable variation in the ranges of central venous pressure and MAP which physicians believe should be targeted in septic patients (59
). Furthermore, a central venous pressure goal of 8 mm Hg to 12 mm Hg may be too low in some septic patients or unnecessarily high in others (60
). Many experts recommend fluid titration based on the response to carefully monitored boluses, rather than using arbitrary targets (63
). Although the Surviving Sepsis Campaign guidelines provide a strong recommendation for these target numbers (Grade 1C), they also stipulate the importance of individualizing care (31
). A single center trial that used the same central venous pressure and MAP targets in both study arms to titrate crystalloids and vasopressors is cited as the primary evidence to support these targets (22
). As such, these targets were not tested and their use is questioned (64
). Importantly, the effectiveness of these targets is now being reevaluated in large, multicentered randomized controlled trials (69
) ( and ). Although rapid fluid and vasopressor resuscitation is indispensable for sepsis, optimal goals for such therapy may differ in patients based on underlying medical conditions, and their use should be individualized (67
Administration of PRBC and inotropes to obtain an ScvO2
of ≥70% was also not consistently altered with bundles over the eight studies. Although PRBC use became consistent after removal of one trial (22
), it was not significantly different with bundled care. In contrast, removal of another trial (27
) did consistently increase inotrope use significantly. Of note, however, the efficacy of administering PRBC and inotropes to achieve an ScvO2
of ≥70% in patients with sepsis is unclear. How often this goal was reached with bundled care in seven of the eight trials analyzed is not reported. The 2008 Surviving Sepsis Campaign guidelines give such treatment during the early resuscitation of septic shock a weak recommendation (Grade 2C). Inotropic support and PRBC transfusions targeted to ScvO2
are being further tested in ongoing randomized controlled trials to determine their efficacy in sepsis (69
) ( and ). Accordingly, at present, these interventions do not meet Joint Commission and Institute for Healthcare Improvement criteria for inclusion in a bundle (1
Bundled care did not uniformly change low-dose corticosteroid and rhAPC use across trials and this may also relate to variations in practice or patient populations (70
). However, as questions persist regarding the risks and benefits of these therapies for sepsis, either when administered individually or together, they continue to undergo investigation (77
) ( and ). The Surviving Sepsis Campaign guidelines gave these therapies a weak recommendation for use in patients with severe sepsis and septic shock (Grade 2C for steroids, and 2B/2C for rhAPC). Although these agents may benefit some septic patients, until such subgroups are clear, their inclusion in care bundles is inappropriate.
Consistent use of earlier and appropriate antibiotics with care bundles could plausibly have contributed to the consistent increases in survival noted across these studies. However, other factors may have also contributed, independent of component therapies. Importantly, six of the trials described education or treatment aids to improve bundle utilization (22
). Consequently, unmeasured effects (e.g., earlier recognition of patients requiring surgical intervention or more readily available nonbundled therapies, such as respiratory support) may have changed outcomes. A large, multicentered, sepsis trial in Spain tested the effects of an intense educational program on bundle treatment goals and outcome first early (immediately after education) and then later (1 yr after education). Although attainment of treatment goals increased early but not later, survival was improved throughout (80
Limitations of this meta-analysis include lack of methodologic rigor in the studies analyzed (lack of blinding, before-after study designs, retrospectively identified historical controls, potential selection bias, duration of sepsis, completeness of data collection, use of unadjusted data), which may confound their findings. Variation in factors, such as participating healthcare workers and patients studied, as well as the natural trend for general care to improve over time in hospitals, may have favored better outcomes with bundled care (81
). Also, consistency per se as used in our analysis may not be a strong indicator of cause and effect. Finally, this analysis included both nonrandomized and randomized studies.
Lung protective mechanical ventilation and strict glucose control with intravenous insulin have been included in some sepsis bundles (12
). However, these therapies were either not assessed or insufficient data were available to determine their application in the analyzed studies. Primary evidence to support intravenous insulin control of glucose in septic patients came from a single trial, which reported that intensive insulin therapy improved survival in cardiac surgery patients. Subsequent controlled trials in critically ill patients, including those with sepsis, have not reproduced this benefit, and have suggested such therapy increases the frequency of hypoglycemia and may worsen outcome (83
). This experience with intensive insulin therapy demonstrates the risks of incorporating therapies into bundles before sufficient evidence supports such practice.
Although bundle use to ensure timely delivery of therapies with recognized benefit may be important in the Emergency Department and intensive care unit, institution of current sepsis bundles may force physicians to provide unproven or even harmful care. As administered and studied to date, only antibiotics meet the stated criteria of proof for bundle inclusion (1
). Furthermore, despite acknowledgment that the performance of care bundles should be assessed both as a whole and based on the contribution of individual components, methodology for such assessment has not been developed. At this time, reliance on nonrandomized designs and the absence of detailed results regarding application of bundle components and ancillary changes in management severely limit our ability to interpret clinical trials of bundled care.