Median age was 69 years (interquartile range [IQR], 55–80 yr) for PB and 67 years (IQR, 56–79 yr) for the NP group. Majority of sepsis patients were identified at the emergency room (60.9% in PB, 53.2% in NP) and required vasopressor therapy (80.9% in PB, 75.8% in NP). The respiratory tract was the most common site of infection in both groups (65.9% in PB, 63.7% in NP).
Hospital mortality was higher for the NP group (44.7%) compared with the PB group (28.4%; odds ratio [OR], 0.5; p = 0.00) (Table 2).
As cohort characteristics showed differences in the proportions of female patients, cirrhosis and urosepsis, and because pathway activation rate varied over time, a propensity-matched analysis was performed post hoc. Using program year, gender, comorbid status, initial vital signs, patient origin, and sepsis source as predictors for protocolized therapy, a propensity-matched cohort of 380 patients was developed (Appendix G, Supplemental Digital Content 1, http://links.lww.com/CCX/A117). Analysis of mortality rates showed 43.2% for NP, and 33.2% for PB (p = 0.045), consistent with the primary outcome analysis.
ICU mortality was also higher in the NP group (31.6% vs 24.2%; OR, 0.69; p = 0.038). There were no significant differences in the other secondary outcomes (Table 2): ICU stay was 3–4 days (IQR, 2–7 d), hospital stay was 8–9 days (IQR, 4–17 d), duration of mechanical ventilation was 3–4 days (IQR, 2–8 d), and duration of vasoactive therapy was 2 days (IQR, 1–4 d).
Logistic regression showed that an APACHE II score greater than or equal to 25 and lactate greater than or equal to 4 mmol were independently associated with mortality, with OR 5.3 (95% CI, 3.9–7.2; sig = 0.00) and 2.6 (95% CI, 1.9–3.7; p = 0.00), respectively. PB management was independently associated with decreased mortality, OR 0.5 (95% CI, 0.4–0.7; p = 0.00; Appendix H, Supplemental Digital Content 1, http://links.lww.com/CCX/A117).
The RA-CUSUM chart of the whole population (Fig. 2) revealed a halving of mortality rate in July 2009 until May 2011, then in April 2012 until the end of the study period. This second downward inflection of the slope of RA-CUSUM appeared six months following the introduction of a radiofrequency identification (RFID)-based solution for improving hand hygiene in ICU. There was a decrease in mortality below the lower CL for the PB group starting June 2009 until the end of the study (Appendix E, Supplemental Digital Content 1, http://links.lww.com/CCX/A117; and Fig. 2).
The RA-EWMA chart showed that the expected mortality of the entire population decreased over time. Actual mortality remained below the upper CL since May 2008, and breached the lower CL starting January 2015 (Fig. 3). However, the observed mortality of the NP group remained above the upper CL throughout the study (Appendix E, Supplemental Digital Content 1, http://links.lww.com/CCX/A117).
This single-center retrospective cohort study represents the largest dataset of sepsis patients in the Philippines. We found that PB management was associated with decreased hospital mortality (OR, 0.5; p = 0.00) and ICU mortality (OR, 0.69; p = 0.038) in patients with sepsis admitted to ICU. This association was consistent over 10 years, over three protocol iterations.
EGDT, the first model of PB sepsis management, achieved lower mortality and less severe organ dysfunction compared with standard therapy (5). However, three large multicenter studies (6–8) done to validate EGDT showed no survival benefit over usual care, but only an increased patient exposure to invasive procedures. It has been argued that the differences in results may be attributed to the 15-year gap between Rivers and the newer trials, such that the “usual care” in the studies were not comparable.
The ProCESS trial reported a third patient group, who were randomized to receive “Protocol-Based Standard Therapy” (6). This differed with EGDT in some aspects: central venous catheter placement only if peripheral access was insufficient, fluids and vasoactive agents titrated to goals for systolic blood pressure and shock index, and conservative red cell transfusions.
During the first years of implementation, our clinical pathway was patterned after EGDT. Its most recent iteration is similar to the Protocol-Based Standard Therapy in ProCESS: initial fluid resuscitation of 30 mL/kg followed by reassessment of fluid status using dynamic variables. Interestingly, we note that the absolute amount of fluid given in the first 6 hours was greatest in the first protocol era (1.9 ± 1.3 L vs 1.5 ± 0.8 L vs 1.6 ± 1 L).
Antibiotic therapy was started within 30 minutes in 74.7% in the NP group and 77.1% in the PB group (p = 0.4). These and other process variables are reported in the Appendix F (Supplemental Digital Content 1, http://links.lww.com/CCX/A117).
The RA-CUSUM analysis of all patients showed an improved mortality trend after pathway implementation, but the lower CL was only breached after 1 year, suggesting a year-long run-in period for this complex intervention. A second lower CL breach appeared after the institution of an RFID-based program that improved baseline hand hygiene compliance rates from ~40% to ~80%.
In the RA-EWMA charts, the observed mortality of the NP group exceeded predicted mortality throughout the duration of the study (Appendix E, Supplemental Digital Content 1, http://links.lww.com/CCX/A117; and Fig. 6). This suggests that unlike in other settings, where “institutional learning” was posited as a mechanism for better outcomes in “usual care” groups, patients in our system seemed to benefit from a degree of protocolization or, conversely, appeared to be harmed by “usual care.”
Our findings also differ from the study on hypotensive septic patients in Zambia, where protocolized hemodynamic resuscitation led to significantly increased in-hospital mortality (14). This has led to the suggestion that protocolization may be harmful in resource-limited settings. Our results suggest that the benefits of protocolization follows a nonlinear curve whose inflection points reflect differences in baseline healthcare delivery capability.
APACHE II scores in this study (20, IQR 14–27 in PB and 21, IQR 16–28 in NP) are similar to that of the three groups on ProCESS (mean ± sd 20.8 ± 8.1 in EGDT, 20.6 ± 7.4 in protocol-based standard therapy, and 20.7 ± 7.5 in usual care) (6), indicating similar severity of illness. Mortality in ProCESS was only 19.3% (vs 32% in our population); 18.2% for their protocol-based standard therapy (28.4% in PB), suggesting that further gains are still possible for our model of protocolized care, while also recognizing that some attributable mortality lies outside the scope of the clinical pathway.
There were no significant differences in ICU or hospital LOS, mechanical ventilation days, or duration of vasoactive therapy between groups.
There are several limitations of this study beyond those intrinsic to a single-center retrospective cohort design:
The annual pathway activation compliance was 75–87% of all eligible patients throughout the study (Appendix I, Supplemental Digital Content 1, http://links.lww.com/CCX/A117). Clinician resistance to the complete pathway did not appear to influence the early administration of broad-spectrum antibiotics: 74.7% of the NP and 77.1% PB patients received broad-spectrum antibiotics within 30 minutes of sepsis diagnosis (p = 0.4), suggesting that at least this component was widely accepted.
The most cited reasons for nonactivation included perceived costs of care, healthcare being a substantial out-of-pocket expenditure for many in the Philippines (15), perceived poor prognosis upon admission, and physician disagreement with the sepsis diagnosis. Nonactivation occurred in spite of hospital policies requiring reporting (and administrative sanction) of physician noncompliance with clinical pathways, continuous education programs regarding sepsis, and advocacy activities (such as the World Sepsis Day). This illustrates the challenge faced by healthcare organizations in our setting to administer a complex clinical pathway.
A substantial number of patients (n = 609) in the ICU had limitations to therapy (including DNR or do-not-intubate orders) requested upon or shortly after admission and were excluded from our analysis, as our original intent was to compare the outcomes of patients with full commitment to critical care. However, we recognize that these excluded patients could be the subject of a follow-up report.
This study was also not designed to identify the specific components of the Sepsis Alert Pathway that were critical in improving mortality. Besides the stipulated therapies within the pathways, many treatments or procedures (e.g., stress-dose steroids, recruitment maneuvers for acute respiratory distress syndrome) were performed or foregone in a nonsystematic fashion over a decade. Furthermore, the 2001 International Sepsis Definitions (9) were used throughout the duration of the study. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) (16) have not yet been applied.
This 10-year single-center retrospective cohort showed that the use of PB management of severe sepsis and septic shock was associated with a decreased hospital mortality for patients. This mortality benefit was preserved over time and through three iterations of the protocol. Protocolized management of sepsis appears to be advantageous, while a reliance on “usual care” may be detrimental, in our setting. Finally, unit- or hospital-level interventions can impact the performance of our clinical pathways.
We would like to thank the members of The Medical City Sepsis Alert Group for administrative support for The Medical City Sepsis Alert Pathway.
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intensive care unit; quality improvement; resuscitation; retrospective; sepsis
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