Effect of a tailored sepsis treatment protocol on patient outcomes in the Tikur Anbessa Specialized Hospital, Ethiopia: results of an interrupted time series analysis

Design

Our overall project design employed a concurrent nested mixed methods design [16]. An interrupted times series (ITS) study, and pre-post knowledge testing, was used to evaluate the effectiveness of the tailored sepsis treatment protocol in improving care and reducing sepsis mortality. An interrupted time series design was chosen to provide a rigorous evaluation of the intervention effect, as randomization was not possible due to the risk of contamination with implementation at a single site. In addition, we completed a process evaluation (to be reported separately) using interviews and a document review, to assess implementation, to identify barriers to and facilitators of scalability and sustainability, and to assess the potential of the approach to address other common high burden clinical presentations in the TASH-ED and other LMICs and in low-resource health-care settings within HICs.

This study is part of a larger project informed by the knowledge-to-action framework [17], with prior work conducted to identify the gap [18] and to understand barriers and facilitators to knowledge use [19]. An integrated KT approach has been employed throughout this project with stakeholders and knowledge users, including frontline clinicians and trainees, department managers, and leadership, engaged in all aspects of the project [20]. Stakeholder and knowledge user engagement has included participation of stakeholders as co-investigators in formative studies [17, 18], in person meetings with leadership and frontline clinicians throughout project development, usability testing, and implementation. They were full project partners who brought context-specific experience and expertise, and their input was incorporated in each stage of the research.

Setting and participants

The study was conducted in the TASH-ED. TASH is the largest publicly funded academic referral hospital and is owned by the Addis Ababa University (AAU). It is the site of the first emergency medicine (EM) residency program in Ethiopia and the Masters Nursing Program in Critical Care and EM. The TASH-ED has an estimated 20,000 patient visits annually, with 20–25% of patients’ critically ill and requiring emergent care. Sepsis is the second leading cause of mortality, accounting for 19% of deaths within 72 h of presentation to the TASH-ED [18]. Children ≤ 12 years of age and obstetrical emergencies are managed in other EDs. The TASH-ED is staffed by EM and off-service residents supervised by 6 EM faculty. The majority of nursing staff have bachelor’s degree training.

All TASH-ED staff and trainees rotating through the department during the implementation and post-implementation period were introduced to the study and sepsis protocol and encouraged to participate. All patients with suspected or proven sepsis presenting for care during the study period were eligible for inclusion and approached to participate.

InterventionSepsis protocol development

The surviving sepsis campaign [21] led the development of evidence-based guidance for sepsis management in LMICs [10, 19, 22, 23]. These guidelines formed the basis of our sepsis management protocol with adaption to the TASH-ED context, based on our preparatory data including a prospective cohort study of mortality patterns and qualitative study of barriers to and facilitators of development and utilization of evidence-based clinical algorithms in The TASH-ED [18, 24], stakeholder consultation, and recent TASH-ED data on pathogens and antimicrobial sensitivity [25].

The protocol includes a flow chart beginning with diagnostic criteria, followed by a stepwise approach to management of patients meeting diagnostic criteria (Fig. 1). Sepsis was diagnosed as suspected or confirmed infection and the presence of 2 or more quick sepsis-related organ failure assessment (qSOFA) criteria [26]. In order to facilitate early recognition and intervention, a trigger was posted at triage, with triage nursing staff asked to flag and notify a physician if the triage criteria were met. The protocol included standard components, such as obtaining blood cultures before initiation of antibiotics, fluid resuscitation, and early initiation of antibiotic therapy. Management was adapted to common pathogens and antibiotic sensitivities based on recent local data, included first- and second-line recommendations to address medication availability and patient ability to pay, and provided a reminder to consider and modify treatment for proven/or suspected tuberculosis and/or malaria. Additionally, as ICU capacity is limited at TASH, in order to avoid over-resuscitation necessitating ventilator support unnecessarily, ultrasound assessment of fluid status conducted by senior clinicians was incorporated into the protocol to guide fluid administration and initiation of vasopressor therapy.

Fig. 1figure 1

Sepsis protocol flow chart

The protocol was circulated widely to emergency medicine and ICU physicians and senior nurses based at or with experience working at TASH, and revised iteratively, with input from a human factors engineer with expertise in user-centered design throughout the process. The protocol was then usability tested with TASH-ED clinical staff with a range of clinical training and experience. Usability testing conducted in person employed a think out loud approach with participants asked to use the protocol to manage 3 clinical scenarios, with the PI (LPR) and a research assistant (RA) observing and taking notes. At the end of the think-aloud process, participants were asked to rate the tool using the System Usability Scale [27] and probed regarding any queries that arose during observations of the think-aloud process. Three rounds of usability testing were conducted with scores ranging from 80 to 87.5, with 3 consecutive scores above 68 considered above average [25].

Implementation strategy

Study design and flow are outlined in Fig. 2. The pre-implementation phase began on June 26, 2017, and included 13 4-week blocks, during which no changes were made with care of sepsis patients left to the discretion of the provider. During the 4-week implementation phase (June 25 to July 22, 2018), the protocol (intervention) and implementation strategy were finalized and introduced to the staff. The post-implementation phase also consisted of 13 4-week blocks, from July 23, 2018, to July 20, 2019.

Fig. 2figure 2

Study design and flow. Legend: = 4 weeks

The implementation plan was developed by mapping identified barriers and facilitators to evidence-based implementation strategies. An initial list of barriers and facilitators to use of evidence-based protocols in the TASH-ED was developed based on barriers and facilitators identified in our previous study [24] and informed by the Theoretical Domains Framework [28] for individual level and Consolidate Framework for advancing implementation science (CFIR) [29] for context-level barriers/facilitators. The list was supplemented with sepsis-specific considerations through stakeholder consultation with TASH-ED staff from the range of clinical backgrounds and experience, as well as colleagues from Toronto with experience working in the TASH-ED. Barriers and facilitators identified through this process were mapped to implementation strategies using the COM-B and the CFIR-ERIC [30, 31], and the final strategy was selected based both on evidence for effectiveness and considerations of feasibility and sustainability (see Table 1).

Table 1 Implementation strategies mapped to barriers/facilitators

A detailed description of the sepsis protocol intervention and implementation strategy, which follows the template for intervention description and replication (TIDieR) format [32], appears in Table 2 (see TIDieR checklist, Additional file 1).

Table 2 Detailed description of sepsis protocol intervention and implementation strategy

The implementation strategy initially included the following: adaptation of the evidence-based sepsis protocol to local pathogen and antibiotic sensitivities and resource availability, tailoring of the implementation strategies to context including engagement of local opinion leaders indentified through our earlier work to support implementation, and educational meetings and hard copy reminder tools. The protocol was introduced, and an education session was provided by the study PI at regularly scheduled in-person physician and nursing meetings during the 4-week implementation phase, with local leadership in attendance to encourage participation and address any questions or concerns arising. Sessions began with a didactic introduction to the project, followed by an opportunity for questions and discussion. The didactic portion included presentation of goals and objectives of the project, TASH-ED sepsis mortality data and findings of the barriers/facilitator study that informed the implementation plan, description of the process for development of the sepsis protocol including incorporation of local antibiotic resistance data and tailoring to the local context, and step-by-step approach to care of patients with suspected or proven sepsis beginning with trigger for urgent assessment at triage. Given the high turnover of physician trainees rotating through the emergency department, a short power-point presentation was developed and presented during trainee orientation sessions. Additional meetings were held in conjunction with weekly staff meetings late in the first and last quarters of the implementation phase during visits from the Toronto-based study team, and ad hoc as needed, tailored to assess and address implementation challenges as needed. Endorsement by local opinion leaders was noted during all meetings, and they attended when available.

Three hard copy clinical reminder tools were developed and employed to support implementation. The first was a large poster (approximately 4 by 3 ft), placed on the wall in the triage area. The poster included criteria to trigger notification of the physician team for urgent assessment for suspected sepsis. The second were large posters (approximately 3 by 5 ft) of the sepsis protocol, placed for easy reference in the resuscitation and acute care areas of the department. The third were laminated pocket cards, with the sepsis protocol on one side, and antibiotic recommendations and special considerations for tuberculosis and malaria, on the reverse side.

Data collection and outcome measures

The primary ITS outcome was the proportion of patients receiving appropriate sepsis care, defined as blood culture collection before antibiotics and initiation of appropriate antibiotics within 1 h of clinical assessment. Secondary outcomes included the following: time to antibiotic administration, early sepsis mortality (within 72 h of presentation), and 90-day all-cause mortality.

ITS outcomes were abstracted from patient charts (triage, physician and nursing notes), by local nursing staff trained as RAs and supervised by the local study team, using a standardized data collection form to identify and follow sepsis cases to hospital discharge. 90-day mortality was assessed from patient charts for admitted patients and by telephone for those discharged before 90 days. Calls to patients or their alternate contact, provided at the time of enrolment, continued for up to 2 weeks beginning at 90-day post-presentation. Due to turnover of the data collection team during the study period, double data entry was not possible. As patient records are paper based, charts were digitized to allow for verification of abstracted outcome data by a second study team member, with all abstracted outcome data reviewed and verified by a second study team member.

Sepsis knowledge was assessed using a brief paper-based questionnaire at the start of the pre-implementation period and at the end of the post-implementation period. The knowledge test was developed collaboratively with EM faculty members of the study team, using common clinical presentations to develop clinical scenarios representing a range of sepsis and non-sepsis clinical presentation. The knowledge test was introduced during regular staff meetings and available for pick up at the meetings and in a folder next to a locked drop box on the wall in the ED near the education center and rest areas. Reminders were given weekly for 2 weeks at regular staff meetings. Basic demographic data including clinical role, training, and years experience was collected at the start of the knowledge test, followed by the standardized clinical scenarios used to assess recognition and management. Participants were asked to make a unique mark on their paper to allow linking of pre- and posttests for analysis. Consent for participation in the pre-post knowledge test was implied by completion of the test.

Process evaluation data (unpublished data) was collected throughout the study using qualitative methods and included interviews with TASH-ED staff and a document review of study team notes. The detailed methods and findings of the process evaluation will be reported separately, with only key challenges to implementation and collection of ITS outcomes reported here to provide context to the ITS findings.

Consent/ethics approval

Written consent was obtained from patients/guardians (for patients < 18 years of age) or substitute decision-makers (for patients deemed incompetent by the treating physician) and assent obtained from patients < 18 years of age at the time of enrolment. For participants initially incapable, consent was obtained directly from patients in person if they became competent prior to discharge or by telephone at 90-day follow-up as appropriate.

Sample size estimation

Sample size for interrupted time series analysis is derived by the number of time points. At study initiation, we estimated that < 10% of sepsis patients received optimal care. We aimed to improve this by at least 10% (double the baseline rate selected by knowledge users as a clinically meaningful level of improvement). The precision of our estimates and the power of ITS in detecting the protocols impact depend on how precise the primary outcome is estimated and indirectly on the number of sepsis patients within the 2-week block.

Based on a pre-study estimate of 10–15 sepsis cases per week, the primary outcome was estimated with 12% margin of error for a 2-week block and 8% margin of error for a 4-week block. For an ITS analysis based on biweekly data, 44 time points provide > 95% power in detecting a mean difference of 10% in proportion of sepsis patients receiving optimal care between pre- and post-implementation phases. Analysis based on monthly data (22 months, 11 months in each phase) provides 90% power in detecting 10% increase in optimal care of sepsis patients.

We estimate that approximately 50% of the 100 TASH-ED staff regularly care for patients in a clinical capacity; with an estimated 50% pre-post testing participation rate, we expected 25 clinicians to complete the pre-post knowledge survey at each of the 2 time points.

AnalysisInterrupted time series

Patients were categorized into pre-implementation, and post-implementation periods according to ED visit date. As the number of patients within the 2-week blocks was too limited to validly estimate the proportions, the primary outcome was summarized monthly, with 13 4-week blocks before and after implementation included in the analysis.

Descriptive statistics of patient characteristics (age, sex, comorbidities) were calculated pre- and post-implementation.

Due to poor charting of time to antibiotic, our primary outcome and time to antibiotic administration could not be reliably assessed or analyzed.

Autocorrelation was assessed using autocorrelation and partial autocorrelation plots and the Durbin-Watson test and found not to be significant for either secondary outcome. Segmented regression with outcome as a binomial proportion without inclusion of an autoregressive term was therefore used to assess the impact of the intervention on 72-h sepsis mortality and 90-day all-cause mortality. Inclusion of covariates was precluded by the low number of cases per time block. In addition, we conducted a worst-case sensitivity analysis with missing outcomes included as dead (felt to be the most likely outcome) to assess the potential impact of missing outcomes.

Pre-post knowledge test

Pre-post knowledge test scores were analyzed using the Student’s t-test to compare group means for percentage of scenarios with correct diagnosis.

Process evaluation

Interviews and study team notes were analyzed independently by at least two study team members, using qualitative content analysis [33], with preliminary analyses occurring concurrent with data collection.

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