Inotropes for Pediatric Septic Shock (PLS): Scoping Review

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none applicable

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: none applicable)

Task Force Scoping Review Citation

Nuthall G, DeCaen A, Atkins DL, Maconochie I, Aickin R, Bingham R, Couto TB, de Caen AR Guerguerian AM, Nadkarni V, Ng KC, Nuthall G, Ong G, Reis A, Schexynader S, Tijssen J. behalf of the International Liaison Committee on Resuscitation Paediatric Life Support Task Force. In infants and children in any setting (in-hospital or out-of –hospital) with septic shock does the use of any specific inotropic agent improve patient outcomes. Scoping review and Task Force Insights: International Liaison Committee on resuscitation (ILCOR) Paediatric Life Support Task Force. ] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Education, Implementation, and Teams Task Force, 2020 January 09. Available from: http://ilcor.org

Methodological Preamble

The continuous evidence evaluation process started with a scoping review of vasoactive agent use in pediatric septic shock being conducted by the ILCOR PLS Task Force Scoping Review team. Evidence from pediatric literature was sought and considered by the PLS Task Force.

Scoping Review

Not available.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Infants and children in any setting (in-hospital or out-of-hospital) with septic shock

Intervention: Vasoactive agent A

Comparators: Vasoactive agent B

Outcomes: Mortality (survival to hospital discharge, 30 day survival), time to resolution of shock, , adverse events, neurologic outcomes, multi organ dysfunction (for example acute kidney injury, myocardial and respiratory failure) and organ failure free days/organ failure scores.

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) are excluded.

Case series may be included in the initial search as it is anticipated that there will be insufficient studies from which to draw a conclusion. The minimum number of cases for a case series to be included is ≥ 5).

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search 1946 to November 15, 2019.

Search Strategies

For details see appendix 1

Inclusion and Exclusion criteria

Inclusion: Only comparative studies of inotrope use for pediatric septic shock were included for analysis.

Exclusion: Premature infants, newly born, animal studies, single vasoactive/inotropic agent descriptive studies, manikin studies, editorials, letters to the editor and adult study. Studies not relevant to the PICOST.

Data Tables

Task Force Insights

1. Why this topic was reviewed.

This topic was last reviewed by ILCOR in 2009 (Peds-045A) and 2010 (Peds-045B). Septic shock is a common pediatric disease state seen in Emergency Departments and Critical Care settings. Attempts have been made to direct vasoactive therapy based upon “cold vs warm” shock appearances. The latest ACCM statement (2016) on Pediatric sepsis shock has suggested that epinephrine be used for vasoconstrictive shock while norepinephrine be used for vasodilatory shock. High quality supportive data was limited at that time. At least two pediatric RCTs have been published since that time comparing vasoactive use in septic shock. A systematic review will help make contemporary evidence-based recommendations.

The focus of this scoping review was looking for comparative studies (agent A vs. agent B). It is very unlikely that there will be studies of a single intervention compared to a placebo.

2. Narrative summary of evidence identified

Despite the librarian search identifying 1620 articles, after review of all the abstracts only two comparative studies were identified that were relevant. The two single center pediatric RCTs compared the use of the vasoactive agents Dopamine and Epinephrine as first-line vasoactive drugs in pediatric septic shock. These studies are both new since the last Worksheets in 2009 Peds-045A and 2010 Peds-045B.

Ramaswamy {Ramaswaswamy 2016 e502} included 60 patients comparing dopamine and epinephrine for pediatric Fluid-refractory (cold) hypotensive shock (> 40 mls/kg of isotonic crystalloid) in the pediatric emergency department (ED) and pediatric intensive care unit (PICU). Children were excluded from study if there was a history of preexisting heart disease or rhythm disturbance, were on vasoactive agent infusion at the time of screening, had raised intracranial pressure, had a known immune compromised state, or suffered from severe acute malnutrition. There was a question as to whether children may have had delayed presentations to the tertiary ED (76-80% of patients were referred from other hospitals, and only 13-17% of these patients had received any fluid resuscitation prior to tertiary care arrival). Most of the patients had community acquired septic shock (90-97%). Primary outcome was resolution of shock. Resolution of shock within the first hour was achieved in greater proportion of children receiving epinephrine (n=12;41%) than dopamine (n=4;13%) (OR, 4.8; 95% CI; 1.3-17.2; p=0.019). Children in the epinephrine group had lower Sequential organ Function Assessment (SOFA) score on day 3 (8 vs 12; p=0.05) and more organ free failure days (24 vs 20 d; p=0.22). No significant difference in adverse events (16.1% vs 13.8%; p=0.80) and mortality (58.1% vs 48.3%; p=0.605) was observed between the two groups (note is made that the study was not powered for mortality as a primary outcome).

Ventura {Ventura 2015 2292} included 120 children in a double-blind prospective randomized controlled trial of children with fluid refractory septic shock (not necessarily hypotensive) after having received > 40 mls/kg of isotonic crystalloid and were randomized to receive either dopamine or epinephrine. Children with congenital heart disease were excluded. Inotropes were delivered by either peripheral IV or intraosseous line (unclear as to how long via the IO route?). Primary outcome was 28 day mortality and secondary outcomes included the rate of healthcare-associated infection. The vast majority of the patients (89-94%) had community acquired septic shock. (There was an overall mortality of 14.2% (17/120). Dopamine was associated with increased mortality at 28 days (OR, 6.5; 95% CI, 1.1-37.8, p=0.037) and healthcare-associated infection (OR, 67.7: 95% CI, 5.0-910.8; p=0.001). The scoping reviewers were concerned that comparative doses of dopamine and epinephrine used in the study were not clinically accurate for clinical dose effects of each drug at each stage of the study.

Neonatal evidence that was identified included mixed populations of premature and/or newlyborn patients, so the initial intention to include older neonates as part of this analysis was not undertaken.

3. Narrative Reporting of the task force discussions

We identified many gaps in the literature. These included absence of other vasoactive agents in common use both in practice and in guidelines, most notably Norepinephrine, and that both studies are single center studies. The two studies both originate from low-middle income health care systems, so it is unclear how relevant the findings are to other health care systems. Both studies have significant limitations (as outlined above in study summaries). Note is also made that a greater number of patients in both arms of the Indian study required invasive ventilation and renal replacement therapy, suggesting that the patients in this study were potentially sicker than those in the Brazilian study (ie. different patient populations were studied). This might be as a result of all of the Indian patients being hypotensive upon study entry (Ramaswamy: mean BPs of both study arms low 70s; Ventura: mean BPs of both study arms mid-80s). Although a superficial analysis of the papers might lead readers to conclude that epinephrine is the superior inotrope to use for fluid refractory septic shock, the limitations in study designs and whether it is appropriate to extrapolate the findings to other health care settings leave a significant gap in our understanding of which vasoactive agent to use.

The task force felt that the pediatric population and epidemiology of septic shock is so different from that of adults, that papers looking at inotrope use for adult septic shock should not be included in this scoping review.

This scoping review has not identified sufficient new evidence to prompt a new systematic review or reconsideration of current resuscitation guidelines/treatment recommendations. The existing recommendation reads “There is insufficient evidence to recommend a specific inotrope or vasopressor to improve mortality in pediatric distributive shock. Selection of an inotrope or vasopressor to improve hemodynamics should be tailored to each patient’s physiology and adjusted as clinical status changes.”

Knowledge Gaps

Specific research is still required in this area: multicentre, resource-intensive setting, norepinephrine vs. epinephrine (a more relevant comparison in contemporary critical care practice); pre-designated analysis of patients with hypotension vs. maintained BP.

References

Ramaswamy KN, Singhi S, Jayashree M, Bansal A, Nallasamy K. Double-blind randomized clinical trial comparing dopamine and epinephrine in pediatric fluid-refractory hypotensive septic shock. Pediatric Critical Care Medicine. 2016 Nov 1;17(11):e502-12.

Ventura AM, Shieh HH, Bousso A, Góes PF, Iracema de Cássia FO, de Souza DC, Paulo RL, Chagas F, Gilio AE. Double-blind prospective randomized controlled trial of dopamine versus epinephrine as first-line vasoactive drugs in pediatric septic shock. Critical care medicine. 2015 Nov 1;43(11):2292-302.

Appendix 1 Search strategy details