European Journal of Cardiovascular Medicine

Inotropes and vasoactive agents are indispensable in the management of critically ill children admitted to Pediatric Intensive Care Units (PICUs). These pharmacological agents enhance myocardial contractility, optimize systemic vascular resistance, and restore adequate tissue perfusion in circulatory shock states such as septic shock, cardiogenic shock, and post-operative cardiac dysfunction [1]. Early initiation of appropriate vasoactive support has been shown to reduce mortality and improve organ function outcomes in pediatric critical illness.

Globally, sepsis and shock remain leading causes of childhood mortality, particularly in low- and middle-income countries. The World Health Organization (WHO) has highlighted timely recognition and structured resuscitation, including fluid therapy and vasoactive drugs, as essential elements of pediatric emergency care [2]. Over time, clinical practice has evolved from empiric use of dopamine as the first-line agent to evidence-based algorithms that increasingly support norepinephrine and epinephrine as superior choices in pediatric shock [3,4].

Several randomized trials and systematic reviews have compared the efficacy and safety of commonly used agents. Dopamine, once widely accepted as a first-line drug, has been shown to be inferior to epinephrine in pediatric septic shock, with higher rates of treatment failure and mortality [5]. Similarly, norepinephrine has emerged as the preferred agent in distributive shock with profound vasoplegia, while dobutamine and milrinone continue to play a role in cardiogenic shock and post-operative low cardiac output syndromes [6].

In India, septic shock constitutes a major burden in PICUs, contributing significantly to mortality rates that range between 30–50% [7]. Variability in practice patterns persists, with many centers transitioning from dopamine toward adrenaline and noradrenaline as first-line choices, in alignment with global guidelines. However, regional disparities in drug availability, resource limitations, and physician preferences continue to influence management strategies [8].

In Hyderabad and other tertiary centers in South India, pediatric intensive care services have expanded rapidly. However, locally validated protocols on vasoactive support remain limited. Network meta-analysis offers a unique advantage by comparing multiple agents simultaneously and generating a ranking of efficacy and safety profiles, which is especially valuable when direct head-to-head trials are scarce.

The problem lies in the lack of region-specific guidelines informed by robust evidence synthesis. Adult critical care benefits from large-scale multicenter trials and systematic reviews, but pediatric data are often limited, heterogeneous, and extrapolated from adult populations. This creates uncertainty in clinical decision-making, increases risk of drug-related complications, and contributes to preventable pediatric mortality.

Hence, this study is designed as a systematic review and network meta-analysis to evaluate and compare the efficacy and safety of ionotropes and vasoactive therapies in pediatric critical care. By integrating global and Indian evidence, the findings will help refine clinical practice, guide evidence-based guidelines, and improve survival outcomes for critically ill children.

Table 1: Search Strategy

Figure 1: PRISMA Flow Diagram for Systemic Review and Network Meta- Analysis

This study was conducted as a systematic review and network meta-analysis in accordance with the PRISMA 2020 guidelines. The objective was to evaluate and compare the efficacy and safety of ionotropes and vasoactive agents in children admitted to Pediatric Intensive Care Units (PICUs). The review was carried out at Tx Children’s Hospitals, Hyderabad, during the period from July 2023 to August 2024.

The eligibility criteria were defined a priori. Studies were included if they involved pediatric patients aged 0–18 years admitted to PICUs and receiving ionotropes or vasoactive therapy. Eligible study designs consisted of randomized controlled trials, prospective or retrospective cohort studies, and systematic reviews. The interventions of interest included dopamine, epinephrine, norepinephrine, dobutamine, and milrinone, either as monotherapy or in comparison with each other, placebo, or standard care. Only studies reporting clinical outcomes such as mortality, hemodynamic stabilization, shock reversal, length of PICU stay, and adverse drug events were considered. Studies were excluded if they involved adults, were case reports or case series with fewer than 10 patients, narrative reviews, editorials, expert opinions, conference abstracts without full text, animal studies, or if they lacked relevant outcome data.

A comprehensive literature search was performed across major electronic databases including PubMed, Cochrane Library, Scopus, and Google Scholar, and this was supplemented by manual searches of bibliographies of relevant trials and guidelines. The search covered the period from July 2000 to August 2024 and was restricted to studies published in English involving human subjects. The strategy combined MeSH terms and free-text keywords such as inotropes, vasoactive agents, dopamine, epinephrine, norepinephrine, dobutamine, milrinone, septic shock, and pediatric intensive care. Boolean operators were used to maximize sensitivity.

The study selection process was conducted in two stages. First, titles and abstracts were screened independently by two reviewers, and then full-text articles of potentially eligible studies were assessed against inclusion and exclusion criteria. Disagreements were resolved by discussion or consultation with a third reviewer. The entire process was documented using a PRISMA flow diagram, which showed the number of studies identified, screened, excluded, and finally included.

Data were extracted independently by two reviewers using a predesigned proforma to ensure uniformity. Extracted information included study characteristics (author, year, country, design, and sample size), patient demographics, intervention type and dosage, comparator arm, and reported outcomes. Any discrepancies were resolved by consensus.

The risk of bias was assessed separately for different study designs. Randomized controlled trials were evaluated using the Cochrane Risk of Bias Tool (RoB 2.0), while observational studies were assessed using the Newcastle–Ottawa Scale. Inter-rater reliability was calculated, and disagreements were addressed through discussion.

Data synthesis followed a two-step approach. Pairwise meta-analyses were performed using a random-effects model to obtain pooled estimates for direct comparisons, and results were expressed as risk ratios or odds ratios for dichotomous outcomes and mean differences or standardized mean differences for continuous outcomes, all with 95% confidence intervals. A Bayesian network meta-analysis was then conducted to enable both direct and indirect comparisons of multiple interventions. Ranking of agents was presented using surface under the cumulative ranking curve (SUCRA) values. Heterogeneity was measured using the I² statistic, and sensitivity analyses were conducted by excluding studies at high risk of bias or methodological limitations. Publication bias was evaluated through funnel plots, Begg’s test, and Egger’s regression test when sufficient studies were available.

The primary outcome of this study was all-cause mortality among children admitted to the PICU. Secondary outcomes included time to shock reversal, duration of mechanical ventilation, length of PICU stay, adverse drug reactions, and treatment failure requiring escalation of therapy. All statistical analyses were conducted using RevMan, STATA, and R software packages.

Table 2: Data Extraction Framework

A total of 12 key studies, including randomized controlled trials, cohort studies, observational analyses, and international guideline syntheses, were reviewed to evaluate the role of ionotropes and vasoactive agents in pediatric septic shock. The included studies spanned multiple countries, with important contributions from the USA, Brazil, India, and multicenter international collaborations. Dopamine, epinephrine, norepinephrine, dobutamine, and milrinone were the most frequently studied agents, with mortality, hemodynamic stabilization, and treatment failure reported as the primary outcomes.

The pooled pairwise meta-analysis demonstrated that epinephrine significantly reduced mortality compared to dopamine (OR 0.65, 95% CI 0.45–0.92, p=0.01), with low heterogeneity (I²=20%). Norepinephrine also showed a favorable trend over dopamine (OR 0.70, 95% CI 0.50–1.05), though the results did not reach statistical significance (p=0.08). Dobutamine did not demonstrate a significant survival advantage compared to dopamine (OR 1.10, 95% CI 0.75–1.60), while milrinone, when compared to standard care, did not reduce mortality but improved hemodynamic stabilization in specific contexts (OR 0.80, 95% CI 0.55–1.18). Overall, epinephrine and norepinephrine consistently ranked superior to dopamine across multiple outcomes.

The network meta-analysis ranking based on SUCRA values further reinforced these findings. Epinephrine achieved the highest probability of being the most effective agent (85%), closely followed by norepinephrine (80%), both of which were associated with improved survival and faster reversal of shock. Milrinone (65%) ranked next, particularly beneficial in post-operative low cardiac output states, while dobutamine (50%) demonstrated moderate effects in cardiogenic shock. Dopamine (25%), in contrast, consistently ranked lowest, with higher adverse event rates and inferior survival outcomes compared to other agents.

In summary, the pooled evidence from both pairwise and network analyses clearly highlights epinephrine and norepinephrine as superior first-line vasoactive agents in pediatric septic shock, while dobutamine and milrinone retain important but adjunctive roles in specific clinical contexts. Dopamine, despite its historical use, is associated with poorer outcomes and should no longer be considered the agent of choice.

Table 3: Characteristics of Included Studies

Table 4: Summary of Pooled Outcomes (Pairwise Meta-analysis)

Table 5: Network Meta-analysis Ranking (SUCRA Values)

Figure 2: Forest Plot: Pair wise Meta- Analysis Results

Figure 3: Network Diagram of Comparisons Between Interventions

The present systematic review and network meta-analysis demonstrated that epinephrine and norepinephrine were superior to dopamine in the management of pediatric shock in PICU settings. The pooled results from randomized controlled trials showed that epinephrine significantly reduced mortality compared to dopamine, with an odds ratio favoring epinephrine. This finding is consistent with the randomized controlled trial by de Oliveira et al. (2008) in Brazil, which reported that early use of epinephrine resulted in improved survival and faster hemodynamic stabilization when compared to dopamine in children with septic shock [9]. Similarly, Ventura et al. (2015), in a multicenter RCT, found that dopamine was associated with higher treatment failure and mortality compared to epinephrine, reinforcing the evidence for adrenaline as the preferred first-line agent in pediatric septic shock [10].

The role of norepinephrine was also highlighted in this review, with evidence suggesting its superiority over dopamine in cases of distributive shock with vasoplegia. This aligns with the Surviving Sepsis Campaign Pediatric Guidelines (Weiss et al., 2020), which recommended norepinephrine as the vasopressor of choice in fluid-refractory septic shock characterized by low systemic vascular resistance [11]. An Indian cohort study by Sankar et al. (2008) also reported better outcomes with norepinephrine in children presenting with refractory septic shock, particularly in those unresponsive to dopamine [12]. The findings of this review therefore reinforce the gradual shift in practice from dopamine to catecholamines with stronger vasopressor effects, particularly in resource-rich settings.

Dobutamine and milrinone were assessed primarily in the context of cardiogenic shock and post-operative low cardiac output syndromes. The results indicated that while these agents were not superior in reducing mortality, they played an important role in improving cardiac output and facilitating hemodynamic stabilization. These findings are consistent with the observations by Samraj and Venkataraman (2019), who reported that dobutamine remains useful in cases with predominant myocardial dysfunction, although it does not independently reduce mortality [13]. In a regional context, Indian studies have demonstrated that milrinone is frequently used in post-cardiac surgery patients, where it improves hemodynamic parameters, although survival benefit remains unproven [14].

The SUCRA ranking in this network meta-analysis placed epinephrine as the most effective agent, closely followed by norepinephrine. This is supported by a global meta-analysis by Chong et al. (2016), which also demonstrated that catecholamines with potent α-adrenergic activity were associated with improved survival outcomes compared to dopamine [15]. The results of this study highlight a strong international consensus toward limiting dopamine use due to its higher adverse effect profile, including arrhythmias and increased mortality, as previously established by Carcillo and Fields (2002) [16].

In the Indian setting, practice patterns have historically favored dopamine due to its availability and cost-effectiveness. However, as highlighted in this review, evidence from both global and national studies strongly supports a paradigm shift toward epinephrine and norepinephrine as the primary agents for pediatric septic shock. Regional data from tertiary care centers in South India, including Hyderabad, also reflect this transition, although disparities in drug availability and physician preferences continue to influence prescribing behavior.

Overall, this systematic review and network meta-analysis provide robust evidence that epinephrine and norepinephrine are superior to dopamine in improving survival outcomes in pediatric shock. Dobutamine and milrinone remain important adjuncts in specific clinical contexts, particularly in cardiac dysfunction. These findings underscore the importance of updating pediatric critical care protocols in India and globally to align with emerging evidence, thereby ensuring timely and effective use of vasoactive support in critically ill children.

This systematic review and network meta-analysis was undertaken to evaluate and compare the effectiveness of ionotropes and vasoactive therapies in children admitted to PICUs. The primary objective was to assess their role in improving survival and hemodynamic outcomes. The analysis demonstrated that epinephrine and norepinephrine were superior to dopamine in reducing mortality and achieving faster hemodynamic stabilization in pediatric septic shock. This directly addresses the objective of identifying the most effective first-line vasoactive agents in critically ill children.

The secondary objective was to determine the relative effectiveness of other agents, including dobutamine and milrinone. The findings revealed that while these agents did not significantly reduce mortality, they played an important role in specific contexts such as cardiogenic shock and post-operative low cardiac output states. This supports their continued use as adjuncts rather than primary agents.

By synthesizing global, Indian, and regional data, the study provides evidence that clinical protocols should move away from dopamine as a first-line therapy and prioritize epinephrine or norepinephrine, thereby aligning practice with international guidelines. These findings fulfill the objectives of providing clarity on comparative efficacy and supporting evidence-based clinical decision-making in pediatric intensive care.

LIMITATIONS AND RECOMMENDATIONS

This systematic review and network meta-analysis had certain limitations. First, the number of high-quality randomized controlled trials in pediatric populations was relatively small compared to adult studies, which limited the strength of evidence for some comparisons. Second, heterogeneity existed across studies with respect to patient populations, severity of illness, and outcome definitions, which may have influenced pooled estimates. Third, some included studies were observational, which introduces the possibility of bias despite careful assessment. Fourth, regional data from low- and middle-income countries, including India, remained limited, thereby reducing the generalizability of findings to resource-constrained settings. Finally, publication bias could not be completely excluded, as negative or small studies may not have been published or indexed.

Based on the findings, several recommendations can be made. Epinephrine and norepinephrine should be preferred over dopamine as first-line agents in the management of pediatric septic shock, given their demonstrated survival benefits. Dobutamine and milrinone may be considered as adjuncts in specific conditions such as cardiogenic shock and post-operative low cardiac output syndrome, though not as primary agents for septic shock. Clinicians in India and similar settings should progressively update practice protocols to align with international guidelines while taking into account local resource availability. Future research should focus on large, multicenter randomized controlled trials in pediatric populations, especially in low- and middle-income countries, to strengthen the evidence base and establish region-specific treatment guidelines.

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