Inotropes for Pediatric Septic Shock (PLS): Scoping Review

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ILCOR staff

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This Review is a draft version prepared by ILCOR, with the purpose to allow the public to comment and is labeled “Draft for Public Comment". The comments will be considered by ILCOR. The next version will be labelled “draft" to comply with copyright rules of journals. The final Review will be published on this website once a summary article has been published in a scientific Journal and labeled as “final”.

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

Table 1: Comparison of Vasoactive agent A vs Vasoactive agent B in pediatric septic shock

Double-blind randomized controlled studies

Author; Year

Design, country

Population

Intervention/Comparator

Main findings

Ramaswasw-amy 2016 e502

Double-blind randomized controlled pilot study

India

Study; N=60

Fluid refractory (> 40 mls/kg isotonic crystalloid) hypotensive septic shock in consecutive children 3 months to 12 years age. Pediatric emergency and ICU departments in a tertiary care teaching hospital in India

Dopamine or epinephrine given in incremental doses given as first line vasoactive therapy until end points of resolution of shock were achieved. Primary outcome were resolution of shock within first hour of resuscitation. Secondary outcomes were organ function, adverse events and mortality.

Resolution of shock within first hour was achieved in greater proportion of children receiving epinephrine (n = 12; 41%) than dopamine (n = 4; 13%) (odds ratio, 4.8; 95% CI, 1.3-17.2; p = 0.019); the trend persisted even at 6 hours (48.3% vs 29%; p = 0.184). Children in epinephrine group had lower Sequential Organ Function Assessment score on day 3 (8 vs 12; p = 0.05) and more organ failure-free days (24 vs 20 d; p = 0.022). 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

Epinephrine is more effective than dopamine in achieving resolution of fluid-refractory hypotensive cold shock within the first hour of resuscitation and improving organ functions.

Ventura 2015

2292

Double-blind prospective randomized controlled trial

Brazil

Study: N= 120

Fluid refractory septic shock (> 40 mls/kg isotonic crystalloid) in children 1 month to 15 years age in a PICU in a University Hospital in Brazil

The primary outcome was to compare the effects of dopamine or epinephrine in severe sepsis on 28-day mortality; secondary outcomes were the rate of healthcare-associated infection, the need for other vasoactive drugs, and the multiple organ dysfunction score. Dopamine was associated with death (odds ratio, 6.5; 95% CI, 1.1-37.8; p=0.037) and healthcare-associated infection (odds ratio, 67.7; 95% CI, 5.0-910.8; p=0.001). The use of epinephrine was associated with a survival odds ratio of 6.49.

Dopamine was associated with an increased risk of death and healthcare-associated infection. Early administration of peripheral or intraosseous epinephrine was associated with increased survival in this population. Limitations should be observed while interpreting these results.

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

1

"Shock, Septic"/ or septic shock/ or ("septic shock" or "toxic shock" or "endotoxic shock" or "endo-toxic shock").ti,ab,kf,kw.

99216

2

(exp Sepsis/ or (sepsis or septic or pyemia* or pyaemia* or pyohemia* or septicemia* or "blood poisoning*").ti,ab,kf,kw.) and ("Hypotension"/ or (hypotension or hypotensive or ((low or lowered) adj2 "blood pressure") or hypoperfusion or hypo-tension or hypo-tensive or hypo-perfusion or "cardiovascular compromise").ti,ab,kf,kw.)

19277

3

1 or 2 [SEPTIC SHOCK]

109982

4

exp Vasoconstrictor Agents/ or vasoconstrictor agent/ or (vasoconstrictor* or vasoactive or vasopressor* or vaso-constrictor* or vaso-active or vaso-pressor* or vasoconstrictive or vasoconstricting or vaso-constrictive or vaso-constricting or "blood vessel constrictor*" or angiotensin or endothelin or norephedrine).ti,ab,kf,kw.

713708

5

exp Vasodilator Agents/ or vasodilator agent/ or (vasodilator* or vaso-dilator* or vasorelaxant* or vaso-relaxant* or vasodilatant* or vasodilating or vaso-dilatant* or vaso-dilating).ti,ab,kf,kw.

1087128

6

Dopamine/ or (dopamine or hydroxytyramine or intropin or cardiopal or cardiosteril or catabon or dopamine or dopaminex or dopamimum or dopastat or dopinga or dopmin or dopme or drynalken or dunatra or dynos or giludop or levodopamine or revivan or tensamin or uramin).ti,ab,kf,kw.

342980

7

exp Epinephrine/ or Norepinephrine/ or (epinephrine or adrenaline or epitrate or lyophrin or epifrin or norepinephrine or noradrenaline or levarterenol or levophed or arterenol or levonor).ti,ab,kf,kw.

378484

8

inotropic agent/ or (inotrope* or inotropic).ti,ab,kf,kw.

81804

9

Cardiotonic Agents/ or (cardiotonic or ((cardiac or myocardial or cardioactive or cardio-active or cardioprotective or cardio-protective or myocardial or myo-cardial) adj2 (drug or drugs or agent* or medicine* or medication* or stimulant*))).ti,ab,kf,kw.

42111

10

exp Vasopressins/ or vasopressin derivative/ or (vasopressin* or pitressin or beta-hypophamine or "antidiuretic hormone*" or argipressin* or lypressin or diapid or postacton or felypressin* or octopressin or phelypressin or PLV-2 or octapressin or terlipressin* or glycylpressin or TGLVP or terypressin or glipressin or glypressin or triglycylvasopressin or remestyp or omnipressin* or POR-8 or "argipressionic acid").ti,ab,kf,kw.

124421

11

or/4-10 [VASOACTIVE AGENTS]

2208597

12

3 and 11 [SEPTIC SHOCK + VASOACTIVE AGENTS]

21453

13

exp Pediatrics/ or exp Infant/ or exp Child/ or Adolescent/

6939002

14

(pediatric* or paediatric* or child or children or childhood or adolescen* or preadolescen* or pre-adolescen* or infant or infants or baby or babies or toddler* or youngster* or teen or teens or teenager* or youth* or juvenile* or preteen* or pre-teen* or girl or girls or boy or boys or PICU).ti,ab,kf,kw.

4834091

15

exp "Infant, Newborn"/ or "Premature Birth"/ or "Term Birth"/ or "Live Birth"/ or "Birth Injuries"/ or "Gestational Age"/ or "newborn"/ or "prematurity"/ or exp "birth weight"/ or "birth injury"/ or (newborn* or "newly born" or neonat* or infant or infants or preterm or pre-term or premature or "prematurely born" or "postmature" or "post-mature" or "small for gestational age" or birth or births or birthed or birthing).ti,ab,kf,kw.

2641338

16

or/13-15 [PEDIATRIC]

8988235

17

12 and 16 [PEDIATRIC SEPTIC SHOCK + VASOACTIVE AGENTS]

2956

18

(Animals/ or "Animal Experimentation"/ or "Models, Animal"/ or "Disease Models, Animal"/ or Manikin/) not (Humans/ or "Human Experimentation"/)

8024793

19

(exp "animal model"/ or exp "animal experiment"/ or "nonhuman"/ or exp "vertebrate"/ or "manikin"/ or "patient simulator"/) not (exp "human"/ or exp "human experiment"/)

9942246

20

17 not (18 or 19) [PEDIATRIC SEPTIC SHOCK + VASOACTIVE AGENTS, human]

2833

21

(editorial or comment or letter or "newspaper article" or news or note or lecture or "case reports").pt.

6346877

22

20 not 21 [PEDIATRIC SEPTIC SHOCK + VASOACTIVE AGENTS, human, substantive]

2580

23

(conference or "conference abstract" or "conference paper" or "conference review" or congresses).pt.

4414043

24

22 not 23 [PEDIATRIC SEPTIC SHOCK + VASOACTIVE AGENTS, human, substantive, conferences removed]

EBM Reviews - Cochrane Database of Systematic Reviews <2005 to November 20, 2019>

EBM Reviews - ACP Journal Club <1991 to October 2019>

EBM Reviews - Database of Abstracts of Reviews of Effects <1st Quarter 2016>

EBM Reviews - Cochrane Clinical Answers <October 2019>

EBM Reviews - Cochrane Central Register of Controlled Trials <October 2019>

EBM Reviews - Cochrane Methodology Register <3rd Quarter 2012>

EBM Reviews - Health Technology Assessment <4th Quarter 2016>

EBM Reviews - NHS Economic Evaluation Database <1st Quarter 2016>

Embase <1974 to 2019 November 22>

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to November 22, 2019>

2114

0

0

0

0

134

0

0

0

1394

586

25

remove duplicates from 24

EBM Reviews - Cochrane Database of Systematic Reviews <2005 to November 20, 2019>

EBM Reviews - ACP Journal Club <1991 to October 2019>

EBM Reviews - Database of Abstracts of Reviews of Effects <1st Quarter 2016>

EBM Reviews - Cochrane Clinical Answers <October 2019>

EBM Reviews - Cochrane Central Register of Controlled Trials <October 2019>

EBM Reviews - Cochrane Methodology Register <3rd Quarter 2012>

EBM Reviews - Health Technology Assessment <4th Quarter 2016>

EBM Reviews - NHS Economic Evaluation Database <1st Quarter 2016>

Embase <1974 to 2019 November 22>

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to November 22, 2019>

1645

0

0

0

0

59

0

0

0

1003

583


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