Results
We enrolled 112 patients in the study (Fig. 1). Two patients not meeting the eligibility criteria were excluded within hours of enrollment. One patient was excluded within 1 hour of randomization because informed consent was verbal and not written. The remaining 109 patients were included in intention to treat analysis. In-hospital survival was available for all patients. The 28-day survival outcome was not ascertained in six patients who were lost to follow-up after discharge.
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Figure 1.
Selection and follow-up of study patients. During the study period, 382 patients presenting to the emergency department were screened for eligibility. Of those, 112 patients with severe sepsis were enrolled and randomized to either Simplified Severe Sepsis Protocol (SSSP) or usual care. Three patients were excluded within hours of randomization due to not meeting all elibility criteria (2) or improper consent (1) and were not included in the final analysis.
Eighty-eight patients (80.7%) were HIV positive, with median CD4 count of 49 cells/mm. Median time from admission to enrollment was 2.5 hours (interquartile range [IQR], 0.9–6.4 hr). In 100 patients for whom JVP was assessable, 88 (88%) had below-normal JVP, including 28 with expiratory JVP at the level of the sternal angle (0 cm) and 60 with a JVP that was below the sternal angle and only visible in the supine position. Mean respiratory rate was very high in both the intervention and control groups, 38.2 and 37.7 breaths/min, respectively. Pulmonary infection was the most commonly suspected source of sepsis, occurring in 63 of 109 participants (57.8%). Eighty-one patients (74.3%) were nonambulatory at the time of admission with a median time of 5 days (IQR, 3–7) since last walking. Baseline characteristics are summarized in Table 1.
Management
Treatment of the two groups is summarized in Table 2. Slightly over half of patients received a third-generation cephalosporin, either alone or as part of a combination. Antituberculous therapy was given to 21 patients in SSSP (39.6%) and 14 control patients (25.0%). Median time to first dose of antibiotics was 1.4 hours (IQR, 0.5–3.1) from time of admission and 0 hour (IQR, –1.3–2.0) from time of enrolment. Patients in the SSSP group received significantly more IV fluids in the first 6 hours compared with control (2.8 L vs 1.6 L, p < 0.001). Of 53 patients in the SSSP group, 30 patients (56.6%) received at least 3 L in the first 6 hours, and 14 of 53 (26.4%) received at least 4 L. The most common reasons for stopping fluids included tachypnea or decreased SpO2 (in eight patients), raised JVP (7), lost IV access (2), blood transfusion (5), and poor urine output in suspected oliguric renal failure (1). The SSSP group received more fluid in the first 72 hours (5.5 L vs 4.3 L; p = 0.02). Regressing 6-hour IV fluid administration on date of admission in the control group resulted in no meaningfully different fluid administration over the study period (–0.005/d; 95% CI, –0.013 to 0.003), suggesting that usual practices were not substantially impacted by a Hawthorne-like effect during the study period.
Only three patients in the SSSP group and one patient in the control group received dopamine. Sixteen patients (30.2%) in the intervention group and 11 control patients (19.6%) received blood transfusion (p = 0.20). Median number of units transfused was identical between the two groups (two units). The majority of patients received antibiotics within 1 hour of enrollment, although antibiotics start time was missing for 12 patients. Only two patients, one in each group, were treated in the ICU. For both patients, the indication for ICU transfer was mechanical ventilation. The local conventions for ICU use are described in Discussion section.
Clinical Outcomes
Overall, 68 patients (62.4%) died prior to discharge. In-hospital mortality was not significantly different between the two groups. Of 53 patients in the intervention group, 34 patients (64.2%) died in hospital compared with 34 of 56 (60.7%) in controls (relative risk, 1.05; 95% CI, 0.79–1.41; SAPS-3-adjusted risk ratio, 1.01; 95% CI, 0.76–1.33). The 28-day mortality was 71.4% in the intervention group compared with 66.7% for controls (relative risk, 1.07 [0.83–1.39]; adjusted relative risk, 1.03 [0.81–1.32]). We failed to detect differences between intervention and control for the prespecified subgroups (Table 3). Because categorizing continuous predictors into intervals may lead to loss of power, models were rerun with continuous exposures (i.e., not categorized into a priori subgroups) with similar results (not shown). Median survival was 4 days in the SSSP group versus 9 days in the control group, but the IQR was 2–28 days in both groups and Kaplan-Meier estimates showed little difference (log-rank p = 0.57) (Fig. 2).
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Figure 2.
Kaplan-Meier survival estimates for Simplified Severe Sepsis Protocol (SSSP) intervention versus usual care in patients with severe sepsis.
Bacteriologic Findings
Twenty-six patients (23.9%) had positive aerobic blood cultures. The most common organisms were Staphylococcus aureus (seven) and Streptococcus pneumoniae and Salmonella typhi (three each). Mycobacterial blood cultures were collected from HIV-positive patients only; 31 of 82 patients had tuberculosis mycobacteria (37.8%). Two patients had coinfection with TB and S. aureus. The other 29 patients with TB bacteremia had no other identifiable etiology for their sepsis. Among 46 patients with CD4 count less than 75 cells/mm, 22 patients (47.8%) had positive TB blood cultures. Four patients, all in the control group, had evidence of Cryptococcus neoformans in the cerebrospinal fluid. Two patients, one in each group, had blood-slide-positive malaria.
Decision to Stop Study
The study was stopped early by the investigators prior to the scheduled interim analysis, in communication with UNZA BREC and Vanderbilt IRB, due to the observation that patients with hypoxemic respiratory distress at baseline might be at increased risk from the intervention. Because only two of 109 patients were transferred to ICU for mechanical ventilation, the investigators initiated an unscheduled analysis of participants with baseline respiratory rate above 40/min and oxygen saturation less than 90%. In this group, 15 of 18 patients (83.3%) died during hospitalization, including eight of eight in the intervention group (100%) and seven of 10 in the control group (70%, p = 0.09). Based on these findings, the decision was made to stop the study.