Sepsis is a major childhood disease in terms of frequency and severity (1). The incidence of sepsis is increasing in the pediatric population, mainly due to the higher survival of very low-birth-weight infants and children with chronic conditions (1). Studies have shown that 30–62% of patients are currently treated according to guidelines. The implementation of managed protocols contributes to a systematized approach and to a continuous evaluation of results, always focusing on improving clinical practice and outcomes (2–4). Protocols might help clinicians treat sepsis because they make a systematic approach, early diagnosis, and treatment easier and through. But how to implement a pediatric sepsis protocol successfully?

This is a narrative review that includes the history of sepsis protocols, the importance of its utilization, barriers to implementation, and proposed solutions.

Guidelines are communications, developed by methodology, to support the best care of a specific disease (5).

Bundle is a concept developed by the Institute of Healthcare Improvement (IHI). It is a small set of evidence-based interventions for a defined patient segment/population and care setting that, when implemented together, will result in significantly better outcomes than when applied individually (6).

In 2001, IHI developed the concept of a bundle at a partnership with 13 hospitals to rethink intensive care and to discover how to achieve the highest levels of reliability in critical care processes. The bundle design guidelines are as follows: (1) The bundle has three to five interventions (elements), with strong clinician agreement; (2) Each bundle element is relatively independent; (3) The bundle is used with a defined patient population in one location; (4) The multidisciplinary care team develops the bundle; (5) Bundle elements should be descriptive rather than prescriptive, to allow for local customization and appropriate clinical judgment. According to IHI, success is not only related to following the steps of a care bundle but to the redesign of work processes, to improve communication strategies, and infrastructure, along with sustained measurement and vigilance (6).

In 2003, the Surviving Sepsis Campaign (SSC) started a partnership with IHI to disseminate sepsis bundles for resuscitation and management in adult patients (6, 7).

In 2014, The SSC for children recommended that institutions participate in the process by adopting recognition, resuscitation, management, and performance bundles, as follows: (1) recognition bundle to screen patients with sepsis, collect laboratory exams and blood culture, and initiate treatment within 15 min of diagnosis; (2) resuscitation bundle to start crystalloid infusion within 30 min and antibiotics and vasoactive drugs within 60 min of diagnosis; (3) Management bundle with multimodal monitoring; (4) a performance bundle to provide guidance on measuring adherence to recognition, resuscitation, and stabilization bundles. In addition, there is a recommendation to apply root cause analysis to identify adherence barriers (8).

Finally, the 2020 SSC panel supports that these guidelines should constitute a general scheme of “best practice,” but that translation to treatment algorithms or bundles and standards of care will need to account for variation in the availability of local healthcare resources (9).

The first step to implement a protocol is the elaboration of a written protocol. Surveys applied in France and Saudi Arabia to pediatric intensivists showed that an absence of a written protocol was one of greatest barrier to adoption of systematic treatment according to SSC guidelines (10, 11).

For protocol elaboration and measurement of performance, there are quality-improvement (QI) tools such as Ishikawa diagram and plan-do-study-act (PDSA) or plan-do-check-act (PDCA) cycles.

Ishikawa diagram is a good diagnostic tool to apply root-cause analysis. Cruz et al. applied a root-cause analysis to identify barriers to SSC guidelines and began a QI project named “Shock Protocol” that helped to re-think and re-design the process of treatment (12).

Rodrigues-Santos et al. used PDCA improvement cycles to implement protocol in a pediatric hospital in Brazil, which resulted in some of the following actions: (a) availability of crystalloid stock in the inpatient unit; (b) implementation of an assistance sheet to guide the steps of the 1-h bundle; (c) standardization of antibiotic regimens for the treatment of sepsis; (d) implementation of a manual antibiotic prescription sheet to enable the immediate dispensation of the drug; (e) provision of a device for remote activation of the attending physician in cases of suspected sepsis; (f) distribution of posters presenting the protocol, clarifying the diagnostic criteria, and the objectives to be achieved during the first hour; (g) distribution of cards for healthcare professionals, with ranges of normal vital signs by age group and warning signs for sepsis recognition; (h) training the multidisciplinary team in simulations with patients with suspected sepsis every 6 months; (i) scheduling of a semiannual meeting to disseminate sepsis care indicators (13).

Long et al. also implemented a local sepsis guideline at a Melbourne, Australia. The group identified quality gaps in ED sepsis management through sentinel events reviewed during monthly departmental morbidity and mortality meetings, and a local guideline was developed through a Clinical Practice Guideline Committee, comprising representatives from state-wide critical care and medical teams (14).

Plan-do-study-act is a tool to implement improvement cycles. Damiani et al. performed a systematic review of 50 studies in an adult population evaluating the impact of performance improvement programs on compliance with the SSC guideline-based bundles and/or mortality. They concluded that, despite high inconsistency across studies, performance improvement programs were associated with increased compliance with the complete 6-h bundle (OR = 4.12 [95% confidence interval 2.95–5.76], I² = 87.72%, k = 25, N = 50,081) and the complete 24-h bundle (OR = 2.57 [1.74–3.77], I² = 85.22%, k = 11, N = 45,846) and with a reduction in mortality (OR = 0.66 [0.61–0.72], I² = 87.93%, k = 48, N = 434,447) (15).

A multidisciplinary team is important to any QI initiative. Cruz et al. pointed that leadership support and the work of a multidisciplinary team with emergence department (ED) and pediatric intensive care unit (PICU) physicians and nurses were important for implementation. The team identified obstacles such as variability in experience of staff in performing initial evaluations; lack of adequate nursing staff for resource-intensive patients; difficulty obtaining frequent vital-sign measurements; lack of standardization of empiric antibiotics and diagnostic tests; lack of medication prioritization; and barriers to patient flow through the institution (12).

Lamba et al. implemented multiples PDSA cycles to increase compliance to late onset sepsis and antimicrobial stewardship in a neonatal intensive care unit (NICU) in Tampa (USA). A multidisciplinary team was formed and included physicians (neonatology fellows and attendings, infectious disease attendings), nurse practitioners, nurses, nurse educators, pharmacists, administrators (NICU nurse manager, NICU medical director), business intelligence, and information technology. They achieved ≥75% compliance, after interventions. The authors identified Key elements for successful implementation: (1) team composition, (2) meeting huddle efficiency, and (3) providing actionable feedback and education on identified opportunities following best practices for QI (16).

Paul et al., Fernandez-Sarmiento et al., Long et al., and Cruz et al. found a reduction in starting time of fluids and antibiotics administration after protocol implementation and education (2, 12, 14, 17).

Ackan Arikan et al. reported a reduction on kidney dysfunction, and Balamuth et al. related reduction on organ dysfunction after starting a protocolized treatment (18, 19).

Larsen et al. observed a reduction on length of stay (20).

In studies of Evans et al. on New York State and Rodrigues-Santos et al. in Brazil, there was reduction on mortality (13, 21).

The 2020 SSC were developed not taking into account the healthcare resources involved and the guidelines constitute a general “best practice.”

The choice of protocol to be implemented depends on the institution. In Latin America, for example, the protocol of the Latin American Sepsis Institute (ILAS) is available, with all the established implementation guidelines (43).

Some causes of sepsis and resources of treatment may differ in Low-Middle-Income Countries (LMIC) from high-income countries. We recognize that some studies developed in LMIC evaluating a sepsis protocol implementation showed different results compared to high income countries. Maitland et al. reported an increase in mortality after fluids bolus in African children with severe infection (44). Studies by Kortz et al. (Tanzania) and Vekaria-Hirani et al. (Naroby) did not observe reduction on mortality after a protocol implementation (34, 45). Kortz et al. even observed an increase in length of stay after protocol implementation caused by complications of treatment (34). On the other hand, de Oliveira et al. (Brazil) showed that using the ACCM/PALS guidelines associated with ScvO (2) goal-directed therapy improved mortality and new organ dysfunction in children with severe sepsis (46).

Hence, while we acknowledge that following the steps proposed by the Survival Sepsis Campaign are of extreme importance, the findings above re-enforce the fact that each protocol can be personalized to a certain degree locally, according to the most frequent diseases, disposable resources, scientific evidence and training, and expertise of the healthcare professionals. Local protocols must take into account the physiopathology of the most prevalent causes of septic shock in that population.

Protocols recommend the same treatment to all patient populations to improve treatment and allow for the most important parts of the therapy to be performed reliably at a population care level. In the individual care, studies suggest that different genetic profiles are related to different morbidity and mortality in sepsis and septic shock, possibly with different inflammation mechanisms and physiopathology (47–52). These findings suggest that a personalized approach, in addition to the protocolized treatment, may be available in the future treatment of sepsis, with earlier identification of genetic/receptors variants and targeted treatments.

We resumed this review with some clues to help on successful implementation of pediatric sepsis protocols.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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