Abstract
Introduction
Shock is a common and life-threatening condition in pediatric intensive care units (PICUs). In catecholamine-resistant shock, current guidelines suggest adjunctive therapies such as hydrocortisone, vasopressin, angiotensin II, or extracorporeal membrane oxygenation (ECMO). Methylene blue (MB) has emerged as a potential alternative or adjunct therapy. We report our clinical experience administering MB to children who had refractory shock unresponsive to standard inotropes and vasopressors.
Methods
We retrospectively reviewed children who were treated with MB between March and November 2023 at a tertiary PICU. Pre- and post-MB variables included vasoactive-inotropic score (VIS), systolic blood pressure (SBP), vasopressor requirements, concurrent continuous renal replacement therapy/ECMO use, and mortality. Hemodynamic parameters were evaluated before MB administration and up to 24 hours thereafter.
Results
Ten patients were included (mean age 9.4 years; 70% with chronic comorbidities). Baseline VIS was 116.4±90.5 and SBP was 81.3±19 mmHg. At 24 hours after MB administration, VIS decreased to 109.9±74.6 and SBP increased to 96.5±18.2 mmHg, corresponding to an average absolute change of -6.5 points in VIS and +15 mmHg in SBP. Hemodynamic responses were heterogeneous: VIS decreased in five patients, remained unchanged in two, and increased in three, while SBP improved in all patients. No MB-related adverse effects were observed. Overall survival to hospital discharge was 10%.
Conclusion
In children with catecholamine-resistant shock, MB administration was associated with short-term improvement in blood pressure, although the reduction in vasoactive burden was inconsistent and mortality remained high. Larger prospective studies are needed to define the optimal timing, dosing, safety, and efficacy of MB in pediatric vasodilatory shock.
Introduction
Shock is a life-threatening syndrome of acute circulatory failure that results in inadequate oxygen delivery to tissues. It affects nearly one-third of patients admitted to intensive care units and is associated with high mortality.1-4 Four major types of shock—distributive, hypovolemic, cardiogenic, and obstructive—may occur alone or in combination.4, 5 Distributive shock, most commonly due to sepsis, predominates in pediatric intensive care units (PICUs). Early recognition and stabilization, including airway, breathing, and circulation assessment, prompt antibiotic therapy, intravenous fluid resuscitation, and initiation of vasopressors when indicated, remain the standard of care.6
Despite these measures, a subset of patients develops catecholamine-resistant shock, in which hemodynamic stability cannot be achieved even with escalating doses of conventional vasopressors. Because prolonged exposure to high-dose catecholamines is associated with significant adverse effects, interest has grown in alternative or adjunctive therapies aimed at improving vascular responsiveness.7, 8
Methylene blue (MB), a heterocyclic aromatic compound, interferes with nitric oxide-dependent signaling pathways by inhibiting soluble guanylate cyclase (sGC), thereby reducing cyclic guanosine monophosphate production and attenuating pathological vasodilation.9, 10 In addition, MB inhibits inducible nitric oxide synthase and scavenges nitric oxide, typically producing measurable hemodynamic effects within 30-60 minutes of intravenous administration.11-13 Because it is inexpensive, widely available, and generally well tolerated, MB has been proposed as a adjunctive therapy in catecholamine-resistant shock. However, pediatric data remain limited, and its role in routine clinical practice has not been clearly defined.14, 15
This study aimed to evaluate our clinical experience with MB administration in critically ill children with catecholamine-resistant shock, focusing on short-term hemodynamic effects and clinical outcomes in a highly selected, severely ill patient population.
Materials and Methods
This retrospective observational study was conducted in the PICU of Ankara University between March and November 2023. Children with catecholamine-resistant shock who received MB were included. Demographic and clinical data, including age, sex, underlying conditions, inotrope and vasopressor dosages, MB administration details (loading and maintenance doses, duration), and concurrent therapies were recorded.
Catecholamine-resistant shock was defined as persistent hypotension and/or clinical signs of inadequate tissue perfusion despite adequate fluid resuscitation and treatment with vasoactive agents. Persistent catecholamine-resistant shock was operationally defined as ongoing hemodynamic instability despite the administration of two or more vasoactive agents at escalating doses. In our clinical practice, MB administration was considered when high-dose vasoactive support was required, typically corresponding to a vasoactive-inotropic score (VIS) greater than 30, despite optimization of conventional therapies.16, 17
The VIS and systolic blood pressure (SBP) were documented before MB initiation and at 4, 8, 12, and 24 hours post-treatment. Mortality outcomes were recorded. Disease severity was assessed using the pediatric risk of mortality III (PRISM III) and pediatric logistic organ dysfunction (PELOD) scores.18-23 The VIS was calculated as follows: VIS=dopamine (µg/kg/min)+dobutamine(µg/kg/min)+100×epinephrine (µg/kg/min)+10×milrinone (µg/kg/min)+10.000×vasopressin (U/kg/min)+100×norepinephrine (µg/kg/min).
Patients who received continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation (ECMO) during their PICU stay were also evaluated.24-26
Blood pressure measurements were obtained as part of routine clinical monitoring; however, the use of invasive versus non-invasive measurement methods was not standardized across patients and was not consistently documented. Diastolic blood pressure and mean arterial pressure values were not systematically available for all patients and were therefore not included in the analysis.
Ethical Considerations
The study protocol was approved by the Ankara University Human Research Ethics Committee (approval no: I04-406-24, date: 11.06.2024). Written informed consent for treatment and data use was obtained from the families of all participants.
Statistical Analysis
Analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Normality of continuous variables was assessed using the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± standard deviation and/or median with interquartile range, as appropriate. Changes in VIS and SBP before and after MB were analyzed using the Wilcoxon signed-rank test, and time-dependent variations at 0, 4, 8, 12, and 24 h were analyzed using the Friedman test with Dunn-Bonferroni correction. Correlations between MB dose, duration, and hemodynamic changes were examined using Spearman’s rho. A two-sided p<0.05 was considered statistically significant.
Results
Ten children with catecholamine-resistant shock received MB therapy during the study period. Seven patients (70%) were female; the mean age was 9.4 years (range: 3 months-19 years). Most patients (70%) had chronic comorbidities, including bone marrow transplantation, neuromuscular disease with multiple organ dysfunction syndrome, liver transplantation, cystic fibrosis, cerebral palsy, and severe congenital or acquired infections. Baseline clinical characteristics, treatments, and outcomes are summarized in Table 1; mean values are presented in Table 2.
At PICU admission, the mean PRISM III score was 9.0±3.3, and the mean PELOD score was 10.6±5.9, indicating high disease severity. All patients were receiving multiple vasopressors, including norepinephrine, epinephrine, dopamine, and hydrocortisone before MB initiation. The mean baseline VIS was 116.4±90.5, and the mean SBP was 81.3±19.0 mmHg.
Following MB administration, SBP demonstrated a consistent upward trend over the 24-hour observation period, whereas changes in VIS were variable. At 24 hours post-treatment, the mean VIS decreased to 109.9±75.8, corresponding to a mean relative reduction of 6.5%, while mean SBP increased to 96.5±17.3 mmHg, representing a mean relative increase of 18.7%. Statistical testing demonstrated a significant increase in SBP (Wilcoxon signed-rank test, Z=-2.03, p=0.04), whereas the change in VIS did not reach statistical significance (Z=-1.06, p=0.29). A time-series analysis using the Friedman test showed a significant rise in SBP across time points [χ2(4)=9.6, p=0.048], whereas variations in VIS were not significant [χ2(4)=5.3, p=0.26].
Individual hemodynamic responses varied: VIS decreased in 5 patients (50%), remained unchanged in 2 patients (20%), and increased in 3 patients (30%). However, SBP improved in all patients, with the greatest relative increase (+142.8%) observed in a patient with amlodipine intoxication. No MB-related adverse effects (e.g., hemolysis, serotonin syndrome, methemoglobinemia) were observed.
The duration of MB therapy ranged from 1 to 6 days (mean 2.6±1.4). A loading dose (1-2 mg/kg) was administered to 6 patients, followed by a continuous infusion at 0.25-1 mg/kg/h. Six patients (60%) underwent CRRT, and four (40%) received venoarterial ECMO. In all patients receiving CRRT or ECMO, SBP increased after MB administration, whereas reductions in VIS were inconsistent. Two ECMO patients demonstrated reductions in VIS and improvements in perfusion parameters, while others required stable vasopressor support. Despite short-term hemodynamic improvement, overall mortality remained high. Nine patients (90%) died during their PICU stay, whereas one patient—diagnosed with amlodipine intoxication—survived and was discharged in good clinical condition.
Figures 1 and 2 illustrate individual temporal changes in VIS and SBP following MB administration over the first 24 hours.
Discussion
This study describes one of the few pediatric series evaluating MB in catecholamine-resistant shock. MB administration was associated with a statistically significant short-term increase in SBP, whereas the reduction in the VIS was modest and was not statistically significant. Taken together, these findings indicate a transient hemodynamic improvement without evidence of a sustained reduction in vasoactive support, and they should be interpreted cautiously, given the small sample size and the lack of a control group.
The hemodynamic response observed after MB use is consistent with its mechanism of action through inhibition of nitric oxide synthase and sGC, which helps restore vascular tone and catecholamine responsiveness.12, 13 However, in our cohort, the limited improvement in VIS and the persistently high mortality rate (90%) likely reflect the advanced stage of shock and extensive multi-organ dysfunction at the time of MB initiation rather than treatment inefficacy.
Although a statistically significant increase in SBP was observed, this improvement did not translate into a survival benefit. This apparent discrepancy between short-term hemodynamic improvement and high mortality highlights the clinical context in which MB was used. In our study, MB was administered predominantly as a late rescue therapy in a highly selected population of critically ill children, many of whom required CRRT and/or ECMO support. Under these circumstances, MB may provide temporary physiological stabilization without altering the overall disease trajectory.
Previous pediatric studies evaluating MB in refractory shock have reported heterogeneous outcomes. Otero Luna et al.27 reported improved blood pressure and reduced vasopressor requirements following MB administration, with lower reported mortality rates and limited use of advanced organ support. Similarly, Bitterman et al.28 described favorable short-term hemodynamic responses in selected pediatric patients, most of whom did not require ECMO or CRRT at the time of MB initiation. In contrast, our cohort was characterized by a markedly greater severity of illness, a frequent need for ECMO and CRRT, and predominantly late administration of MB as rescue therapy. These differences likely explain the higher mortality observed in our study and highlight the unique contribution of our series, which reflects real-world use of MB in the most critically ill pediatric patients.
The timing of MB appears to be crucial. Early administration, before irreversible endothelial injury occurs, may enhance efficacy.7, 9, 12 In our cohort, MB was mostly used as a late rescue therapy, which may have limited its benefit. Nonetheless, no MB-related complications were observed, consistent with previous safety reports.10, 12, 27 Particular caution should be exercised in patients with glucose-6-phosphate dehydrogenase deficiency or in those receiving serotonergic medications, as MB may precipitate hemolysis or serotonin syndrome.
MB administration in children with catecholamine-resistant shock was associated with a short-term improvement in SBP, without an observable survival benefit. Larger prospective studies are needed to clarify the optimal timing, dosing, and patient selection for MB therapy in pediatric shock.
Study Limitations
This study has several limitations. It was a retrospective, single-center analysis with a small sample size, thereby limiting the generalizability of the findings and precluding causal inference. The absence of a control group further restricts the interpretation of treatment effects. In addition, the timing and dosing of MB were not standardized, and concomitant therapies such as corticosteroids, vasopressin, CRRT, and ECMO may have influenced outcomes. Hemodynamic assessment was primarily based on changes in SBP and VIS; diastolic blood pressure and mean arterial pressure were not systematically recorded or compared; perfusion or biochemical markers were not available. Furthermore, blood pressure measurements were not standardized with respect to invasive versus noninvasive monitoring, and the cohort’s small, heterogeneous composition with respect to inotrope selection and dosing precluded meaningful within-group comparisons of the MB effect. Finally, long-term follow-up data on survival or organ recovery were not available. Larger prospective multicenter studies are needed to confirm the safety and efficacy of MB in pediatric catecholamine-resistant shock.
Conclusion
Methylene blue was associated with a short-term increase in systolic blood pressure in children with catecholamine-resistant shock, but its effect on vasoactive support was inconsistent and mortality remained high. Although no treatment-related adverse events were observed, larger prospective studies are needed to determine its optimal timing, dosing, safety, and clinical benefit.
