Hydrocortisone Dosing for Hypotension in Neonates: A Systematic Review & Meta-Analysis

Hydrocortisone Dosing for Hypotension in Neonates: A Systematic Review & Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Hydrocortisone Dosing for Hypotension in Neonates: A Systematic Review & Meta-Analysis Abdihafid Mohamed Abdullahi, Jiaming Li, Xuyanping xu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8024256/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Hypotension is common in neonates, particularly those who are preterm or very-low-birth-weight (VLBW) and is associated with poor outcomes, including brain injury and increased mortality. Relative adrenal insufficiency is a key contributor, with hydrocortisone (HC) often used to support cardiovascular stability. However, the optimal dosing strategy remains uncertain. Aim This meta-analysis evaluated the efficacy and safety of different hydrocortisone dosing regimens for treating hypotension in neonates including both preterm and term infants, focusing on blood pressure response, organ perfusion, and adverse effects. Methods Following PRISMA guidelines, randomized controlled trials (RCTs) published up to 2024 were systematically reviewed. RevMan 5.4 software was used for meta-analysis. Outcomes included improvement in blood pressure and perfusion, mortality, bronchopulmonary dysplasia (BPD), and adverse events such as hyperglycemia. Results Nine RCTs involving 2,044 neonates were included. Hydrocortisone (0.5 mg/kg every 6 hours to 5 mg/kg/day) significantly improved mean arterial pressure (mean increase: ~4 mmHg; OR = 0.43, 95% CI: 0.20–0.92, P = 0.03) and reduced inotrope requirements. HC reduced mortality prior to discharge (15.5% vs 23.7% in controls; OR = 0.08, 95% CI: 0.02–0.27, P < 0.0001) and lowered the incidence of BPD (OR = 0.32, 95% CI: 0.11–0.95, P = 0.04). However, treatment was associated with a higher risk of hyperglycemia (OR = 4.07, 95% CI: 1.04–15.90, P = 0.04). No consistent evidence was found for increased risk of gastrointestinal or neurosensory complications. Conclusion Hydrocortisone improves blood pressure, reduces inotrope use, and may lower mortality and BPD in both preterm and term neonates with hypotension. Lower-dose regimens appear effective with fewer metabolic complications, while higher doses increase hyperglycemia risk. Large, well-designed RCTs are still needed to define optimal dosing strategies. Neonatal Hypotension Hydrocortisone Dosing Preterm Infants Very Low Birth Weight (VLBW) Adrenal Insufficiency Corticosteroid Therapy Meta-Analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Introduction Hypotension in neonates especially those born with preterm or with very low birth weight (VLBW), or with perinatal complications remains a significant challenge in neonatal intensive care units (NICUs). This condition, affecting 20–40% of VLBW infants, is often linked with poor outcomes, including brain injury and increased mortality ( 1 ). Neonatal hypotension is generally classified as refractory when it persists despite maximum treatment with volume expanders and inotropes. One of the key factors contributing to hypotension in neonates is relative adrenal insufficiency (RAI), a condition in which the adrenal glands fail to produce adequate amounts of cortisol in response to stress, as well as low blood volume, impaired vascular tone, and persistent pulmonary hypertension ( 2 ). This impairment is believed to be related to the developmental immaturity of the adrenal cortex particularly in preterm infants, particularly those born before 30 weeks of gestation, who have limited capacity for cortisol synthesis. As a result, these infants are at increased risk for poor cardiovascular adaptation and organ perfusion, which can lead to clinical instability ( 3 , 4 ). Neonatal hypotension, is a critical condition that requires prompt and effective management to ensure adequate organ perfusion and prevent long-term complications. The first-line treatment strategies for neonatal hypotension typically involve inotropic agents such as dopamine, dobutamine, and epinephrine, which are used to treat volume-responsive hypotension ( 5 ). However, in cases of refractory hypotension where blood pressure remains low despite adequate fluid resuscitation and inotropic support corticosteroids have become increasingly advocated as an adjunctive therapy ( 6 ). The rationale for corticosteroid use lies in their ability to restore adrenal function, enhance catecholamine effectiveness, and improve cardiovascular stability ( 7 ). Despite these potential benefits, concerns persist regarding the long-term effects of corticosteroid use, particularly on neurodevelopmental outcomes and the risk of gastrointestinal complications, such as intestinal perforation when combined with indomethacin ( 8 ). Among corticosteroids, hydrocortisone has emerged as the most commonly used agent for managing hypotension in neonates, especially in those with impaired adrenal function. Hydrocortisone stabilizes blood pressure by supporting cardiovascular function and reducing the need for vasopressor medications ( 5 ). However, the dosing of hydrocortisone remains a topic of debate, with significant variability in regimens used across institutions. Kumbhat et al. (2020) and Dasgupta et al. (2016) suggest that low doses of hydrocortisone, as little as 2 mg/kg per day, can effectively raise cortisol levels to stress levels and improve organ perfusion without significant adverse effects ( 9 , 10 ). In contrast, higher doses of hydrocortisone are frequently employed, though there is limited evidence to support their superior efficacy. High-dose regimens carry an increased risk of adverse outcomes, such as potential long-term neurodevelopmental impairments ( 11 ). This has led to growing interest in the potential benefits of low-dose hydrocortisone, which may provide hemodynamic stability while minimizing side effects, though this approach remains underexplored in the current literature ( 12 ). More recently, the large multicenter RCT by Watterberg et al. (2022) evaluated hydrocortisone in very preterm infants, underscoring the ongoing debate about dosing and safety ( 13 ). Despite the widespread use of hydrocortisone, a clear consensus on the optimal dosing regimen for neonates remains lacking. Dosing protocols vary widely, with some studies administering hydrocortisone as a daily dose ranging from 2 mg/kg to 5 mg/kg, often with a tapering schedule ( 13 ). This variability underscores a significant gap in the current evidence base, with insufficient data on the pharmacokinetics and pharmacodynamics of hydrocortisone in neonates. Moreover, definitive clinical trials comparing the efficacy and safety of low-dose versus high-dose regimens are still lacking, highlighting the need for further research to guide optimal treatment strategies ( 12 , 14 ). The aim of this meta-analysis is to evaluate and compare different dosing strategies of hydrocortisone for treating hypotension in preterm neonates (both preterm and term), focusing on their impact on key outcomes such as blood pressure improvement, survival, and adverse effects. This comparison will help guide optimal and safe clinical use of hydrocortisone in neonatal care. Methods PICO Question The PICO (Population, Intervention, Comparator, Outcome) framework for this systematic review and meta-analysis and registered the study with PROSPERO (CRD42024616328),as follows (Table 1 ): Table 1 PICO Framework Component Description Population Preterm and term neonates with postmenstrual age ≤ 44 weeks and hypotension, defined as mean blood pressure lower than the gestational age or requiring fluid or vasoactive therapy. Intervention Intravenous hydrocortisone administered at any dose, duration, or timing as a primary or rescue treatment for hypotension. Comparator ( 1 ) Hydrocortisone compared with standard treatment, placebo, or any other vasoactive agent. ( 2 ) Low-dose hydrocortisone (≤ 1 mg/kg initial dose and ≤ 2 mg/kg/day thereafter) compared with high-dose hydrocortisone (> 1 mg/kg initial dose and > 2 mg/kg/day thereafter). Outcomes Primary : - Improvement in end-organ perfusion (increase in blood pressure, urine output, or reduction in serum lactate within 12 hours) - Mortality prior to discharge. Secondary : - Development of bronchopulmonary dysplasia. - Major neurosensory disabilities (moderate to severe motor or cognitive impairment, cerebral palsy, or severe visual or hearing impairment). - Occurrence of adverse events (e.g., hypertension, hyperglycemia, gastrointestinal complications, hospital-acquired infections) within 2 weeks of hydrocortisone administration. Search Strategy A comprehensive and systematic search was conducted in four major electronic databases: MEDLINE, Scopus, PubMed, and the Cochrane Central Register of Controlled Trials, covering publications from 2014 to 2024. We used a combination of MeSH terms and keywords such as "preterm infants," "term infants," "neonates," "hypotension," " hydrocortisone," and "neonates" to ensure a wide retrieval of relevant studies. Boolean operators (AND, OR) were applied to combine search terms and refine results. For example, the query "premature infants AND corticosteroids AND hypotension" was used. The search was tailored to each database using appropriate subject headings and text word terms. Additionally, we conducted a manual search of reference lists from relevant systematic reviews and meta-analyses and included studies from ongoing or unpublished clinical trials (ClinicalTrials.gov, WHO International Clinical Trials Registry, and others). We limited our search to studies published between January 2014 and March 2024 to ensure inclusion of the most contemporary evidence. Earlier trials were excluded because neonatal intensive care practices, definitions of hypotension, and hydrocortisone dosing strategies have evolved significantly over the last decade, making older studies less comparable to current clinical standards. Eligibility Criteria Randomized controlled trials (RCTs) involving neonates (both preterm and term, postmenstrual age ≤ 44 weeks) who were treated with hydrocortisone for hypotension were included. Studies involving methylprednisolone or term neonates were excluded unless dosing data were specifically extractable for preterm subgroups. Included studies had to report at least one primary outcome or relevant adverse effects. One study using methylprednisolone in combination with hydrocortisone was included due to its relevance to stress-dose corticosteroid regimens, but sensitivity analysis was performed with and without this study. Selection Process Following PRISMA guidelines, the study selection process involved two-tier screening procedure. Firstly, two reviewers independently screened titles and abstracts of identified studies to determine their eligibility. The second stage involved full-text screening, where the complete articles were screened for final inclusion. Discrepancies between reviewers were resolved through involvement of third reviewer to reach consensus. The inter-rater reliability was assessed using Cohen’s Kappa coefficient, with value of 0.85 indicating substantial agreement between the reviewers. Data Extraction Data extraction was carried out by two independent reviewers using Covidence software. The information extracted included study design, population characteristics (including gestational age, birth weight, postmenstrual age), details of hydrocortisone intervention (dose, timing, duration), comparator treatment (placebo, other vasoactive agents), and reported outcomes (blood pressure changes, mortality, adverse events, etc.). A standardized data extraction form was developed and piloted to extract information on study design, patient characteristics, interventions, comparators, outcomes, and adverse events. Primary and Secondary Outcomes The primary outcomes for this review were: Improvement in end-organ perfusion, defined as a measurable increase in mean, systolic, or diastolic blood pressure within 12 hours of hydrocortisone treatment initiation, in addition to either an increase in urine output or a reduction in serum lactate. Mortality prior to discharge. Secondary outcomes included: Development of bronchopulmonary dysplasia. Incidence of major neurosensory disabilities, including cognitive, motor impairments, or severe visual or hearing impairments. The occurrence of adverse events (hypertension, hyperglycemia, gastrointestinal complications, and hospital-acquired infections) within two weeks of hydrocortisone administration. Quality Assessment The methodological quality of included studies was assessed using the Cochrane Risk of Bias 2 (ROB-2) tool, applied per outcome rather than per study in accordance with Cochrane recommendations. Data Synthesis and Analysis Meta-analysis was conducted using Review Manager (RevMan) version 5.4 software. The certainty of evidence was evaluated using GRADE criteria across key outcomes. Pooled estimates of Odds Ratio(OR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. Statistical heterogeneity was assessed using the I² statistic and Chi-square tests. A random-effects model was applied. Publication bias was evaluated using funnel plots and Egger’s test. Results Characteristics of the included studies A total of 9 full-text articles were included in this review and meta-analysis. These studies were identified from a total of 1,352 records, with 1327 records retrieved through database searching across PubMed (n = 571), Medline (n = 232), Embase (n = 142), Cochrane (n = 178), and Scopus (n = 204), along with an additional 25 records from other sources. After removing duplicates (n = 358) and screening 994 records, 540 full-text articles were assessed for eligibility. Of these, 531 were excluded for various reasons, including irrelevance, lack of control group, or no hydrocortisone outcomes. The final 9 studies met the criteria for inclusion based on relevance and reporting of hydrocortisone-related outcomes and adverse effects (Fig. 1 ). Some included trials (Onland 2019, Parikh 2015) primarily aimed to assess BPD prevention but provided relevant data on hemodynamics/hypotension outcomes, and were therefore included. Participant Data and Baseline characteristics A total of 2,044 participants were included in the review with mean age ranged from neonates ≤ 28 days old to extremely low birth weight (ELBW) infants (< 1000g), and term neonates requiring intensive care or those requiring mechanical ventilation. The studies focused on neonates—both preterm and term with conditions like pulmonary hypertension, hypoxic-ischemic encephalopathy (HIE) or congenital heart defects. Mean gestation age ranged from as low as 22 weeks to 37 weeks, reflecting a mix of preterm and term populations with focus on those at high risk for conditions like BPD, cardiovascular insufficiency or refractory hypotension. Randomized controlled trials, double-blind, placebo-controlled studies were included in the review. The interventions involved hydrocortisone in different dosages and regimens, such as hydrocortisone sodium succinate (2–5 mg/Kg/day), or stress-dose hydrocortisone, with some studies also using methylprednisolone perioperatively. Comparators included placebo (saline/mannitol) with interventions administered intravenously. Dosage regimens varied, with hydrocortisone administered as an initial bolus followed by tapered doses or on continuous schedule, ranging from 0.5mg/kg every 6 hours to 3-5mg/kg/day over series of days. Adverse effects reported included hyperglycemia (more frequent in hydrocortisone group), hypertension (with high-dose hydrocortisone), gastrointestinal complications, electrolyte disturbance and increased insulin requirements. Other outcomes included incidence of BPD, mortality, weight gain, extubation success and need for inotropic support (Table 2 ). Table 2 Data Extraction Sheet of the Included Studies Author & Year Study design Participant characteristics Intervention Comparator Dosing Regimen Adverse effects Main Results Hochwald et al. 2014 ( 37 ) Randomized controlled trial Total Number of Participants: 22 (11 in each group) Gestational Age (GA): ≤30 weeks Birth Weight (BW): ≤1250 g Gender: 6 females, 5 males in hydrocortisone group; 5 females, 6 males in placebo group Inborn: 9 hydrocortisone, 10 placebo Apgar at 5 minutes: Hydrocortisone group: 7.1 (SD 1.69), Placebo group: 6.67 (SD 2.18) Intravenous hydrocortisone (2 mg/kg initial dose, 1 mg/kg q6h for 3 doses, 0.5 mg/kg q6h for 4 doses) and concurrent dopamine infusion (5 mcg/kg/min, increased or decreased per protocol). Placebo (saline 0.9%) with concurrent dopamine infusion. Hydrocortisone: 2 mg/kg initial dose, 1 mg/kg q6h for 3 doses, 0.5 mg/kg q6h for 4 doses Dopamine: 5 mcg/kg/min, adjusted per protocol - Trend towards higher incidence of NEC and positive blood cultures in placebo group. - BPD: 36% in hydrocortisone group vs 63% in placebo group (proportion difference 0.27 [− 0.12–0.5]). - Survival without BPD: 54% in hydrocortisone group vs 18% in placebo group (proportion difference 0.46 [0.05–0.7]). - Dopamine Dose: Hydrocortisone group received significantly lower cumulative dose of dopamine (p = 0.07), fewer hours of treatment (p = 0.04). - Mortality: 36% mortality in placebo group, none in hydrocortisone group. Salasa et al. 2014 ( 38 ) Prospective, double-blind, randomised, placebo-controlled trial Total Number of Participants50 full-term infants Gender50 infants likely a mix of males and females) AgeFull-term infants (gestational age ≥ 37 weeks) Historical Background Primary reason for hospitalisation: pulmonary hypertension (n = 23), congenital heart defects (n = 9), and surgical treatment (n = 9). Hydrocortisone sodium succinate, 2.5 mg/kg intravenously every 12 hours for 2 days Isotonic saline 1.25 mL/kg intravenously every 12 hours for 2 days Hydrocortisone: 2.5 mg/kg/dose every 12 hours for 2 days (IV) Hyperglycemia (more frequent in the hydrocortisone group), gastrointestinal hemorrhage (1 case in placebo group) - Primary Outcome: Hydrocortisone significantly reduced the need for inotropic support compared to placebo, with 21 of the hydrocortisone group requiring reduced support versus 7 in the placebo group (p < 0.05). - Hemodynamic Outcomes: There was a trend toward improved ABP in the hydrocortisone group. Kovacs et al. 2019 ( 39 ) Double-blind, randomized, placebo-controlled clinical trial Total Number of Participants35 asphyxiated neonates Age: Neonates ≥ 36 weeks gestational age GenderBoth male and female neonates Historical Background - All neonates had hypoxic-ischemic encephalopathy (HIE) and underwent therapeutic hypothermia. - Volume-resistant hypotension was defined as MAP < gestational age in weeks despite volume resuscitation. - Dopamine was used as the primary inotrope during the study period. 0.5 mg/kg hydrocortisone intravenously every 6 hours for the duration of therapeutic hypothermia treatment (up to 72 hours). Placebo (saline) intravenously every 6 hours for the same duration as hydrocortisone Hydrocortisone: 0.5 mg/kg/dose every 6 hours IV during therapeutic hypothermia Placebo: 0.5 mL/kg saline every 6 hours IV Cortisol levels were low in both groups at baseline. - Primary Outcome: 94% of infants in the hydrocortisone group reached the target of ≥ 5 mmHg increase in MAP within 2 hours, vs 58% in the placebo group (P = 0.02). - Inotrope Requirements: The hydrocortisone group had a significantly shorter duration of cardiovascular support and lower cumulative and peak inotrope doses (P < 0.001). - MAP Increase: The hydrocortisone group had an average increase of 4 mmHg in MAP compared to placebo (P = 0.045). - Heart Rate: The hydrocortisone group had a lower heart rate over time (P < 0.001). Parikh et al. 2015 ( 40 ) Randomized, parallel group, double-blind clinical trial 64 extremely low birth weight (ELBW) infants (< 1000g birth weight), 57 with adequate data for primary outcome (89% follow-up rate) Age: 10–21 postnatal days at randomization, Gestational age: Extremely preterm infants Stress dose hydrocortisone sodium succinate (Solu-Cortef, Pfizer), tapering 7-day course administered intravenously Placebo (0.9% sterile saline) Hydrocortisone: 3 mg/kg/day for 4 days, 2 mg/kg/day for 2 days, 1 mg/kg/day for 1 day (total of 17 mg/kg over 7 days) no bilateral blindness, no severe neurosensory impairments other than mild hearing loss in one placebo infant) - No statistically significant difference in survival without neurodevelopmental impairment (RR: 0.83; 95% CI, 0.61 to 1.14) − 31% death in hydrocortisone group vs 41% in placebo group (P = 0.42) - Cognitive delay: 21% in hydrocortisone vs 47% in placebo (RR: 0.46, 95% CI 0.18 to 1.17) - Cerebral palsy (CP): 15% in hydrocortisone vs 6% in placebo (not statistically significant) Watterberg et al. 2017 ( 41 ) Randomized, multicenter, double-masked, placebo-controlled trial 932 infants screened; 257 eligible for inotropes, 12 enrolled over 10 months Gestational Age: ≥ 34 weeks Age at Enrollment: Median 37 hours (range: 2–46 hours) Historical Background: Mechanically ventilated, receiving inotropes (dopamine, dobutamine, epinephrine, norepinephrine) for cardiovascular insufficiency Hydrocortisone sodium succinate: 1 mg/kg loading dose followed by 0.5 mg/kg every 6 hours for 12 doses, 0.5 mg/kg every 12 hours for 4 doses, and 0.5 mg/kg daily for 1 dose, total treatment course of 7 days. Placebo: equal volume of normal saline Hydrocortisone: 1 mg/kg loading dose, 0.5 mg/kg every 6 hours for 12 doses, 0.5 mg/kg every 12 hours for 4 doses, 0.5 mg/kg daily for 1 dose (7-day total course). interactions with NSAIDs (indomethacin, ibuprofen) were not allowed during study drug treatment. − 932 infants screened, with 257 eligible for inotropes; however, 207 (81%) were excluded due to exclusionary diagnoses - Only 12 infants enrolled over 10 months (3 per month in final 3 months) − 81% of eligible infants had exclusionary diagnoses, leading to limited enrollment - Only 12 infants consented despite 21 families being approached Peeples et al 2017 ( 42 ) Retrospective case-control study conducted at a single-center (University of Washington) from 2011 to 2015. 106 infants: 50 high-dose HC (4 mg/kg/day), 20 low-dose HC (1–3 mg/kg/day), and 36 control infants receiving only vasoactive agents Gestational Age: ≤28 weeks Age: Preterm infants with hypotension requiring vasoactive infusions Historical Background: Infants with refractory hypotension, receiving vasoactive medications (dopamine, dobutamine, epinephrine) and/or HC for hypotension management. Hydrocortisone: high-dose (4 mg/kg/day) or low-dose (1–3 mg/kg/day), as part of clinical management for refractory hypotension. Control group: Infants treated with vasoactive medications alone, without hydrocortisone. High-dose HC: 4 mg/kg/day (1 mg/kg every 6 hours) Low-dose HC: 1–3 mg/kg/day (0.5 mg/kg every 6–12 hours, depending on regimen) - Increased incidence of hypertension (high-dose HC) - Increased hyperglycemia - Increased insulin therapy in HC-treated infants (though not statistically significant) - No significant differences in blood pressure or ability to wean off vasoactive medications between high- and low-dose HC. - High-dose HC group had significantly higher rates of hypertension compared to low-dose group (28.0% vs. 6.9%, P = 0.024). - HC therapy was associated with higher incidence of hyperglycemia (23.7%, P = 0.020) and insulin therapy (19.3%, P = 0.054), although insulin therapy difference was not significant. Neunhoeffer et al. 2015 ( 43 ) Retrospective, single-center study 166 children (out of 1,273 total patients) treated with HRT for refractory hypotension after CPB from 2000 to 2010. - Age: 150 infants ≤ 1 year (90.36%) and 16 children > 1 year (9.64%) - Background: Children with complex congenital heart defects who underwent CPB surgery and had refractory hypotension despite optimized medical management. Hydrocortisone rescue therapy (HRT): 100 mg/m²/day, initiated intravenously and continued for 2 days, followed by a taper over 2–5 days. Placebo: equal volume of normal saline Hydrocortisone: 100 mg/m²/day for 2 days, then tapered over 2–5 days. adverse effects were observed, such as electrolyte disturbances, hyperglycemia, or gastrointestinal perforation. - Hemodynamic Response: 82% of infants ≤ 1 year responded to HRT, with significant improvement in mean blood pressure, VIS, lactate, and urine output. - Non-responders: Non-responders were younger, had lower body weight, and higher PRISM and lactate levels. Mortality was significantly higher in non-responders (13.5% vs. 2.44%, p = 0.0008). - Mortality: Mortality was 13.5% in non-responders and 2.44% in responders. Suominen et al. 2017 ( 44 ) Randomized Controlled Trial (RCT) Total Participants: 40 neonates Age: Neonates (≤ 28 days old) undergoing elective open heart operations Stress-dose corticosteroid (SDC) Drug: Methylprednisolone (2 mg/kg) bolus perioperatively and hydrocortisone infusion (0.2 mg/kg/h for 48 hours, tapered dose for 5 days) Placebo (saline infusion) - Methylprednisolone: 2 mg/kg perioperatively - Hydrocortisone: 0.2 mg/kg/h for 48 hours, tapering doses for 5 days - Higher blood glucose levels (significantly higher at 6 hours post-op and first post-op morning) - Higher incidence of insulin infusion required in SDC group (12 of 14 patients) - IL-6 values were significantly lower in the SDC group postoperatively compared to placebo group - Inotropic scores were significantly lower in the SDC group on postoperative days (POD) 1, 3, and 6 - Sternal closure occurred significantly earlier in the SDC group (mean 2 days earlier) - Systemic ventricle delta strain (decrease in cardiac contractility) was significantly lower (less deterioration) in the SDC group postoperatively - C-reactive protein (CRP): Similar trend to IL-6 (lower in SDC group) Onland et al. 2019 ( 45 ) Double-blind, placebo-controlled, randomized trial 372 preterm infants (gestational age < 30 weeks or birth weight < 1250 g) on mechanical ventilation between 7–14 days of life, with high risk of BPD Hydrocortisone sodium succinate, 5 mg/kg/day for 7 days, then 3.75 mg/kg/day for 5 days, tapering frequency over 22 days (total dose: 72.5 mg/kg) Placebo (mannitol) with identical dosing schedule and duration to hydrocortisone Hydrocortisone: 5 mg/kg/day for 7 days (4 doses/day), 3.75 mg/kg/day for 5 days (3 doses/day), taper to 1 dose every 5 days for 22 days (total dose: 72.5 mg/kg) Significantly higher incidence of hyperglycemia requiring insulin therapy (18.2% hydrocortisone vs 7.9% placebo 1. No significant difference in death or BPD at 36 weeks (70.7% with hydrocortisone vs 73.7% with placebo; P = .54). 2. Reduced mortality at 36 weeks in hydrocortisone group (15.5% vs 23.7%, P = .048). 3. No significant difference in BPD (55.2% with hydrocortisone vs 50.0% placebo, P = .31). 4. Increased extubation success at 3, 7, and 14 days in the hydrocortisone group. Effectiveness of Hydrocortisone for Treating Hypotension across Key Clinical Parameters This study assessed hydrocortisone dosing for hypotension in neonates, comparing its effects to placebo across several clinical parameters. It also showed a strong protective effect in antenatal corticosteroid-treated infants (OR = 0.19, 95% CI: 0.07, 0.50, P = 0.0007, I² = 66%), likely due to enhanced adrenal function, and a moderate effect in pregnancy-induced hypertension (OR = 0.34, 95% CI: 0.12, 0.96, P = 0.04, I² = 69%) by stabilizing blood pressure. Hydrocortisone reduced hypotension risk in the dopamine dose subgroup (OR = 0.30, 95% CI: 0.10, 0.95, P = 0.04, I² = 54%) but showed no significant effect for infusion volume (P = 0.06, I² = 93%). Overall, hydrocortisone reduced hypotension events (OR = 0.43, 95% CI: 0.20, 0.92, P = 0.03), though significant subgroup variability (P = 0.005) suggests further exploration is needed (Fig. 2 ). Impact of Hydrocortisone Dosing on End-Organ Perfusion Significant differences between hydrocortisone and placebo were identified across several clinical parameters. Hydrocortisone shortened the time to achieve blood pressure stabilization compared with placebo (mean difference = 3.19 hours, 95% CI: 0.35–6.04, P = 0.03), with no heterogeneity (I² = 0%), suggesting consistency in treatment timing benefits. Hydrocortisone shortened the duration of inotrope therapy by ~ 25 hours (mean difference = -2.35 days, 95% CI: -4.28 to -0.42, P = 0.02), with no heterogeneity. Hydrocortisone also improved urine output (mean difference = -0.99 mL/kg/h, P = 0.02) and significantly increased mean arterial pressure (mean difference = -7.22 mmHg, P = 0.03). Subgroup differences (P = 0.002) suggested variability in response. These results indicate hydrocortisone’s effective role in managing hypotension in neonates(Fig. 3 ). Efficacy and Adverse Effects associated with Hydrocortisone Dosing Hydrocortisone reduced the risk of bronchopulmonary dysplasia (BPD) with an odds ratio (OR) of 0.32 (95% CI: 0.11–0.95, P = 0.04), indicating a protective effect, though moderate heterogeneity (I² = 63%) was noted. Regarding hyperglycemia, hydrocortisone significantly increased the risk (OR = 4.07, 95% CI: 1.04–15.90, P = 0.04), with moderate heterogeneity (I² = 54%). For arterial hypertension, hydrocortisone was associated with increased risk (OR = 0.31, 95% CI: 0.10–0.95, P = 0.04), with moderate heterogeneity (I² = 66%). Cognitive delay was also reduced in the hydrocortisone group (OR = 0.18, 95% CI: 0.05–0.65, P = 0.009), despite high heterogeneity (I² = 69%) (Fig. 4 ). Hydrocortisone treatment was associated with a reduced incidence of cerebral palsy (OR = 0.27, 95% CI: 0.06–1.18, P = 0.08) and language delay (OR = 0.27, 95% CI: 0.10–0.74, P = 0.01), though the effect on cerebral palsy did not reach statistical significance (P = 0.08). The incidence of mild gastrointestinal hemorrhage was significantly lower in the hydrocortisone group (OR = 0.16, 95% CI: 0.03–0.92, P = 0.04), indicating a protective effect. Hydrocortisone treatment also showed a significant reduction in the risk of death (OR = 0.08, 95% CI: 0.02–0.27, P < 0.0001), with a substantial decrease in sepsis risk (OR = 0.22, 95% CI: 0.06–0.80, P = 0.02) as shown in Fig. 5 . Hydrocortisone demonstrated significant benefits in reducing BPD and cognitive delay, but it also increased the risk of hyperglycemia, highlighting its complex effects on neonatal health. While it significantly reduced adverse outcomes like death and sepsis, moderate to high heterogeneity (I² = 61–83%) was observed across several parameters. Subgroup analyses revealed no significant differences (P = 0.60), suggesting a generally consistent treatment effect across studies, despite variability in responses. Publication Bias Publication bias in this study was assessed using a funnel plot and Egger's test. The funnel plot showed some asymmetry, suggesting potential publication bias, particularly in smaller studies (Fig. 6 – 9 ). Egger's test further confirmed this with a statistically significant result (P < 0.05). Despite the observed bias, the overall trend indicated that hydrocortisone had a positive impact on outcomes, though moderate heterogeneity (I² = 61–83%) was present, indicating variability in treatment effects across studies. The Cochrane risk of Bias (ROB 2) tool also showed moderate heterogeneity across the included studies as shown in Fig. 10 . Discussion This meta-analysis aimed to evaluate the effectiveness and safety of hydrocortisone dosing for treating hypotension in neonates (both preterm and term). The results identified that hydrocortisone significantly improved clinical outcomes, including a reduction in the incidence of bronchopulmonary dysplasia (BPD), cognitive delay, and mortality, while also lowering mean blood pressure and enhancing end-organ perfusion. Notably, the timing of hydrocortisone dosing was crucial, with earlier initiation linked to improved outcomes. Hydrocortisone also reduced the duration of inotrope therapy and improved urine output. However, it was associated with an increased risk of hyperglycemia. Subgroup analyses revealed variability in responses, and moderate to high heterogeneity (I² = 61–83%) was observed across several parameters, indicating inconsistent treatment effects. Despite some publication bias, the overall trend supports hydrocortisone as a beneficial intervention for preterm infants with hypotension, but further studies are needed to optimize dosing and minimize adverse effects. Our review included both preterm and term populations, reflecting the heterogeneity of clinical presentations (e.g., pulmonary hypertension in term infants, refractory hypotension in preterm infants). This broader inclusion increases generalizability but also contributes to heterogeneity. The use of hydrocortisone in the management of hypotension in critically ill neonates has garnered considerable attention due to its potential to stabilize hemodynamics, especially in cases where volume resuscitation and vasopressors are insufficient ( 17 ). Several studies have assessed the impact of hydrocortisone on blood pressure and hemodynamics in neonates, particularly in VLBW and term neonates exposed to adverse birth condition such as asphyxia ( 10 ). For instance, Dempsey et al. (2006) conducted a randomized controlled trial in VLBW infants with hypotension, finding that hydrocortisone improved blood pressure and reduced the need for inotropic support, similar to our study results ( 18 ). However, their study involved higher cumulative doses of hydrocortisone over a longer period, which may have contributed to differences in the observed adverse effects, particularly in terms of gastrointestinal complications such as intestinal perforation when combined with indomethacin. Our study, which used a lower dose, did not demonstrate such adverse outcomes, suggesting that careful dose titration can mitigate risks ( 7 , 19 ). Similarly, the work by Baker et al. (2008) examined a cohort of infants with refractory hypotension treated with hydrocortisone, showing consistent improvements in blood pressure, reduction in inotropic dose, and increased diuresis ( 11 ). In line with these findings, our study also observed a decrease in inotrope demand and an increase in urine output, further supporting the notion that hydrocortisone has a positive impact on neonatal hemodynamics. The study by Noori et al. (2012) also found that hydrocortisone led to a significant reduction in dopamine dosage and improved blood pressure, reinforcing the dopamine-sparing effects of hydrocortisone observed in our study ( 20 , 21 ). In contrast, the trial by Iijima et al. (2019) assessing stress-dose hydrocortisone in VLBW infants with adrenal insufficiency found that hydrocortisone administration led to a decrease in inotropic requirements and improved blood pressure within the first 48 hours of treatment ( 22 ). This study echoes our own results, which suggest that early intervention with hydrocortisone may be particularly beneficial in managing hypotension ( 23 ). However, the study did not observe significant improvements in long-term pulmonary outcomes, such as the incidence of bronchopulmonary dysplasia (BPD), which contrasts with our observation of a potential trend toward improved survival without BPD ( 24 , 25 ). One notable study by Kumbhat et al. (2020) found that approximately 70% of neonates with congenital diaphragmatic hernia who received hydrocortisone showed improved blood pressure and reduced reliance on vasopressors, indicating that steroids may help stabilize cardiovascular function in critically ill neonates ( 9 ). This supports our finding that hydrocortisone improves cardiovascular function in the context of neonatal hypotension. However, as in our study, Kumbhat et al. did not find significant differences in long-term neurodevelopmental outcomes, highlighting the need for further follow-up to evaluate the long-term safety of hydrocortisone ( 26 , 27 ). The role of hydrocortisone in neonatal adrenal insufficiency has been well-documented, neonates with prematurity or perinatal asphyxia. A study by Efird et al. (2005) demonstrated that hydrocortisone administration improved both blood pressure and survival in neonates with suspected adrenal insufficiency, which is consistent with our findings ( 28 ). Furthermore, the reduced serum cortisol levels observed in the placebo group in our study further support the hypothesis that relative adrenal insufficiency may play a role in hypotension and that hydrocortisone supplementation may address this deficiency ( 13 , 29 ). However, while hydrocortisone shows promise in improving hemodynamics and reducing inotrope dependency, the potential risk of corticosteroid therapy must be carefully considered ( 30 ). In line with previous research, our study did not observe any significant long-term adverse effects related to neurodevelopment, but other studies, such as those by Cartwright et al. (2019), suggest that early steroid treatment may carry risks for abnormal brain development and cognitive outcomes, particularly with higher doses. These concerns warrant further investigation, especially given the potential neurotoxic effects observed with dexamethasone in preterm infants ( 31 , 32 ). In terms of dosing, our study used relatively low doses of hydrocortisone, which is consistent with the practice of using stress doses in critically ill neonates. This aligns with findings from the meta-analysis by Ropp et al. (2024), which suggested that low-dose hydrocortisone administered early in the course of illness had a favorable impact on blood pressure and inotrope use without significant long-term harms ( 33 ). However, this strategy remains controversial, and there is still no consensus on the optimal dosing regimen. Studies such as those by Tang et al. (2022) ( 34 ) and Sushko et al. (2021) ( 35 ) highlight the need for further trials to establish definitive protocols for hydrocortisone use in neonatal hypotension. This meta-analysis is limited by its exclusive inclusion of randomized controlled trials (RCTs), which, while providing high-quality evidence, may limit the generalizability of our findings to broader, non-randomized populations. Additionally, the studies included in this analysis varied in terms of patient populations, dosing regimens, and treatment protocols, which may introduce some heterogeneity in the results. The duration of hydrocortisone treatment and its long-term effects, particularly on neurodevelopment, remain areas that require further investigation, as few studies have followed patients beyond the immediate neonatal period. Furthermore, while we observed significant improvements in hemodynamic stability and inotrope use, the absence of comprehensive data on long-term outcomes such as survival without BPD or neurodevelopmental impairment warrants caution in applying these results universally. Despite these limitations, this study is significant as it consolidates the evidence from high-quality RCTs to support the use of hydrocortisone in managing volume-resistant hypotension in neonates, emphasizing its potential as a valuable adjunct to current therapies, particularly in critically ill neonates( 36 ). Conclusion In conclusion, this meta-analysis demonstrates that hydrocortisone is an effective treatment for managing hypotension in in neonates including both preterm and term and those who are preterm or of very low birth weight, offering significant improvements in blood pressure, organ perfusion, and reduction in adverse outcomes such as bronchopulmonary dysplasia (BPD) and cognitive delay. However, the risk of hyperglycemia and other side effects, particularly with higher doses, underscores the need for careful dosing. Our findings highlight the potential benefits of low-dose hydrocortisone regimens, though the variability in treatment responses calls for further research to define the optimal dosing strategy. Future studies should focus on large, well-designed trials comparing low and high-dose hydrocortisone regimens to provide clearer guidance on balancing efficacy with safety and long-term neurodevelopmental outcomes. Declarations Author details First Author: Abdihafid Mohamed Abdullahi 1 Department of Pediatrics in NICU, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China. Email: [email protected] , [email protected] Second Author: Jiaming Li 2 1Department of Pediatrics in NICU, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China. 2 Zhejiang Shaoxing Shangyu Maternal and Child Health Hospital Email: [email protected] Affiliation: 1 Zhejiang University 2Department of Pediatrics in NICU, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China. Correspondence to Xuyanping * , MD, PhD. Department of Pediatrics in NICU, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China. Email: [email protected] Acknowledgements Not applicable. Author contributions Xu contributions to conception and design; Abdihafid and Li been involved in drafting the manuscript and revising it critically for important intellectual content; Abdihafid and Li made substantial contributions to acquisition of data; Abdihafid analysis and interpretation of data; and all authors given final approval of the version to be published. Funding None. Data availability The datasets generated and analysed during the current study are available in several major electronic databases, including PubMed, Cochrane Library, Embase, and Web of Science. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Dempsey EM. Challenges in treating low blood pressure in preterm infants. Children. 2015;2(2):272–88. Verma RP, Dasnadi S, Zhao Y, Chen HH. 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Effect of hydrocortisone therapy initiated 7 to 14 days after birth on mortality or bronchopulmonary dysplasia among very preterm infants receiving mechanical ventilation: a randomized clinical trial. JAMA. 2019;321(4):354–63. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":44992,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flow chart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/d14bc57f382b68f79da5a0cc.png"},{"id":100404654,"identity":"fbed14a8-99a2-44fb-988e-dd0def367d0d","added_by":"auto","created_at":"2026-01-16 12:04:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35824,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot showing the Effectiveness of Hydrocortisone versus Placebo for Treating Hypotension across Key Clinical Parameters.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/815974802d6f6110763482ab.png"},{"id":100404372,"identity":"5f7d23b2-19a0-4dc9-99a3-3fde6f492092","added_by":"auto","created_at":"2026-01-16 12:03:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42131,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot showing the Impact of Hydrocortisone Treatment on End-Organ Perfusion, including timing of first hydrocortisone dose, duration of therapy, mean blood pressure, and serum cortisol concentration at randomization.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/a0ee6b9584956d9ab9692126.png"},{"id":100404945,"identity":"05e36547-90f0-45ca-b375-20780bdca55b","added_by":"auto","created_at":"2026-01-16 12:04:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":30550,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot showing the Efficacy and Adverse Effects associated with Hydrocortisone Treatment, including bronchopulmonary dysplasia (BPD) development, hyperglycemia, arterial hypertension, and cognitive delay.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/b36b91b0730682cfc33c3ae8.png"},{"id":100404685,"identity":"ee4d64b6-8e01-483e-9fa6-66c2ae05dae9","added_by":"auto","created_at":"2026-01-16 12:04:11","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":36940,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot showing the Efficacy and Adverse Effects associated with Hydrocortisone Treatment, including cerebral palsy, language delay, mild gastrointestinal hemorrhage, mortality, and onset of sepsis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/2703f10a14462b213c082d11.png"},{"id":100404367,"identity":"c4d597c0-bc6c-4e13-b713-f950fb32b3f7","added_by":"auto","created_at":"2026-01-16 12:03:39","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":7657,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot showing heterogeneity in studies of the Effectiveness of Hydrocortisone versus Placebo for Treating Hypotension across Key Clinical Parameters.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/275b89cc39bdd384c977173e.png"},{"id":100405266,"identity":"c6beb2c3-1be5-40fe-9257-e8eb42d32aca","added_by":"auto","created_at":"2026-01-16 12:05:12","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":7524,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot showing heterogeneity in studies of the Impact of Hydrocortisone Treatment on End-Organ Perfusion, including timing of first dose, duration, mean blood pressure, and serum cortisol concentration at randomization.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/00e421cba8d628ff64f30671.png"},{"id":100405232,"identity":"01fdb338-46be-45a5-87bf-b30f2527ac73","added_by":"auto","created_at":"2026-01-16 12:05:08","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":6410,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot showing heterogeneity in studies of the Efficacy and Adverse Effects associated with Hydrocortisone Treatment, including BPD, hyperglycemia, arterial hypertension, and cognitive delay.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/5d3b917122c8f0195806afc7.png"},{"id":100404575,"identity":"e3d2a17b-ca4b-4dcd-97aa-6fdd74dc4586","added_by":"auto","created_at":"2026-01-16 12:03:58","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":6943,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot showing heterogeneity in studies of the Efficacy and Adverse Effects associated with Hydrocortisone Treatment, including cerebral palsy, language delay, mild GI hemorrhage, mortality, and onset of sepsis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image8.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/4e6423d43cdb36628ac805ee.png"},{"id":100405015,"identity":"6c5c6051-4e6a-4e67-91a5-8bf48d4c5151","added_by":"auto","created_at":"2026-01-16 12:04:33","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":184136,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCochrane Risk of Bias (ROB 2) for heterogeneity of the included studies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image9.png","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/cea9ab21de53b6d8a78fbd61.png"},{"id":104399751,"identity":"c23ab72e-c0e4-4d92-9360-f84cd0a1ceee","added_by":"auto","created_at":"2026-03-11 12:07:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2126663,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8024256/v1/7d45aa53-1cb2-4547-b6ee-29fd2fca4e08.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hydrocortisone Dosing for Hypotension in Neonates: A Systematic Review \u0026 Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHypotension in neonates especially those born with preterm or with very low birth weight (VLBW), or with perinatal complications remains a significant challenge in neonatal intensive care units (NICUs). This condition, affecting 20\u0026ndash;40% of VLBW infants, is often linked with poor outcomes, including brain injury and increased mortality (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Neonatal hypotension is generally classified as refractory when it persists despite maximum treatment with volume expanders and inotropes. One of the key factors contributing to hypotension in neonates is relative adrenal insufficiency (RAI), a condition in which the adrenal glands fail to produce adequate amounts of cortisol in response to stress, as well as low blood volume, impaired vascular tone, and persistent pulmonary hypertension (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). This impairment is believed to be related to the developmental immaturity of the adrenal cortex particularly in preterm infants, particularly those born before 30 weeks of gestation, who have limited capacity for cortisol synthesis. As a result, these infants are at increased risk for poor cardiovascular adaptation and organ perfusion, which can lead to clinical instability (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNeonatal hypotension, is a critical condition that requires prompt and effective management to ensure adequate organ perfusion and prevent long-term complications. The first-line treatment strategies for neonatal hypotension typically involve inotropic agents such as dopamine, dobutamine, and epinephrine, which are used to treat volume-responsive hypotension (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, in cases of refractory hypotension where blood pressure remains low despite adequate fluid resuscitation and inotropic support corticosteroids have become increasingly advocated as an adjunctive therapy (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The rationale for corticosteroid use lies in their ability to restore adrenal function, enhance catecholamine effectiveness, and improve cardiovascular stability (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Despite these potential benefits, concerns persist regarding the long-term effects of corticosteroid use, particularly on neurodevelopmental outcomes and the risk of gastrointestinal complications, such as intestinal perforation when combined with indomethacin (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmong corticosteroids, hydrocortisone has emerged as the most commonly used agent for managing hypotension in neonates, especially in those with impaired adrenal function. Hydrocortisone stabilizes blood pressure by supporting cardiovascular function and reducing the need for vasopressor medications (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, the dosing of hydrocortisone remains a topic of debate, with significant variability in regimens used across institutions. Kumbhat et al. (2020) and Dasgupta et al. (2016) suggest that low doses of hydrocortisone, as little as 2 mg/kg per day, can effectively raise cortisol levels to stress levels and improve organ perfusion without significant adverse effects (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In contrast, higher doses of hydrocortisone are frequently employed, though there is limited evidence to support their superior efficacy. High-dose regimens carry an increased risk of adverse outcomes, such as potential long-term neurodevelopmental impairments (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). This has led to growing interest in the potential benefits of low-dose hydrocortisone, which may provide hemodynamic stability while minimizing side effects, though this approach remains underexplored in the current literature (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMore recently, the large multicenter RCT by Watterberg et al. (2022) evaluated hydrocortisone in very preterm infants, underscoring the ongoing debate about dosing and safety (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the widespread use of hydrocortisone, a clear consensus on the optimal dosing regimen for neonates remains lacking. Dosing protocols vary widely, with some studies administering hydrocortisone as a daily dose ranging from 2 mg/kg to 5 mg/kg, often with a tapering schedule (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This variability underscores a significant gap in the current evidence base, with insufficient data on the pharmacokinetics and pharmacodynamics of hydrocortisone in neonates. Moreover, definitive clinical trials comparing the efficacy and safety of low-dose versus high-dose regimens are still lacking, highlighting the need for further research to guide optimal treatment strategies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe aim of this meta-analysis is to evaluate and compare different dosing strategies of hydrocortisone for treating hypotension in preterm neonates (both preterm and term), focusing on their impact on key outcomes such as blood pressure improvement, survival, and adverse effects. This comparison will help guide optimal and safe clinical use of hydrocortisone in neonatal care.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePICO Question\u003c/h2\u003e \u003cp\u003eThe PICO (Population, Intervention, Comparator, Outcome) framework for this systematic review and meta-analysis and registered the study with PROSPERO (CRD42024616328),as follows (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e):\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePICO Framework\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComponent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePopulation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreterm and term neonates with postmenstrual age\u0026thinsp;\u0026le;\u0026thinsp;44 weeks and hypotension, defined as mean blood pressure lower than the gestational age or requiring fluid or vasoactive therapy.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntervention\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntravenous hydrocortisone administered at any dose, duration, or timing as a primary or rescue treatment for hypotension.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComparator\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Hydrocortisone compared with standard treatment, placebo, or any other vasoactive agent. \u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Low-dose hydrocortisone (\u0026le;\u0026thinsp;1 mg/kg initial dose and \u0026le;\u0026thinsp;2 mg/kg/day thereafter) compared with high-dose hydrocortisone (\u0026gt;\u0026thinsp;1 mg/kg initial dose and \u0026gt;\u0026thinsp;2 mg/kg/day thereafter).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePrimary\u003c/b\u003e: \u003c/p\u003e \u003cp\u003e- Improvement in end-organ perfusion (increase in blood pressure, urine output, or reduction in serum lactate within 12 hours) \u003c/p\u003e \u003cp\u003e- Mortality prior to discharge. \u003c/p\u003e \u003cp\u003e\u003cb\u003eSecondary\u003c/b\u003e: \u003c/p\u003e \u003cp\u003e- Development of bronchopulmonary dysplasia. \u003c/p\u003e \u003cp\u003e- Major neurosensory disabilities (moderate to severe motor or cognitive impairment, cerebral palsy, or severe visual or hearing impairment). \u003c/p\u003e \u003cp\u003e- Occurrence of adverse events (e.g., hypertension, hyperglycemia, gastrointestinal complications, hospital-acquired infections) within 2 weeks of hydrocortisone administration.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch Strategy\u003c/h3\u003e\n\u003cp\u003eA comprehensive and systematic search was conducted in four major electronic databases: MEDLINE, Scopus, PubMed, and the Cochrane Central Register of Controlled Trials, covering publications from 2014 to 2024. We used a combination of MeSH terms and keywords such as \"preterm infants,\" \"term infants,\" \"neonates,\" \"hypotension,\" \" hydrocortisone,\" and \"neonates\" to ensure a wide retrieval of relevant studies. Boolean operators (AND, OR) were applied to combine search terms and refine results. For example, the query \"premature infants AND corticosteroids AND hypotension\" was used. The search was tailored to each database using appropriate subject headings and text word terms. Additionally, we conducted a manual search of reference lists from relevant systematic reviews and meta-analyses and included studies from ongoing or unpublished clinical trials (ClinicalTrials.gov, WHO International Clinical Trials Registry, and others).\u003c/p\u003e \u003cp\u003eWe limited our search to studies published between January 2014 and March 2024 to ensure inclusion of the most contemporary evidence. Earlier trials were excluded because neonatal intensive care practices, definitions of hypotension, and hydrocortisone dosing strategies have evolved significantly over the last decade, making older studies less comparable to current clinical standards.\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eRandomized controlled trials (RCTs) involving neonates (both preterm and term, postmenstrual age\u0026thinsp;\u0026le;\u0026thinsp;44 weeks) who were treated with hydrocortisone for hypotension were included. Studies involving methylprednisolone or term neonates were excluded unless dosing data were specifically extractable for preterm subgroups. Included studies had to report at least one primary outcome or relevant adverse effects. One study using methylprednisolone in combination with hydrocortisone was included due to its relevance to stress-dose corticosteroid regimens, but sensitivity analysis was performed with and without this study.\u003c/p\u003e\n\u003ch3\u003eSelection Process\u003c/h3\u003e\n\u003cp\u003e Following PRISMA guidelines, the study selection process involved two-tier screening procedure. Firstly, two reviewers independently screened titles and abstracts of identified studies to determine their eligibility. The second stage involved full-text screening, where the complete articles were screened for final inclusion. Discrepancies between reviewers were resolved through involvement of third reviewer to reach consensus. The inter-rater reliability was assessed using Cohen\u0026rsquo;s Kappa coefficient, with value of 0.85 indicating substantial agreement between the reviewers.\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eData extraction was carried out by two independent reviewers using Covidence software. The information extracted included study design, population characteristics (including gestational age, birth weight, postmenstrual age), details of hydrocortisone intervention (dose, timing, duration), comparator treatment (placebo, other vasoactive agents), and reported outcomes (blood pressure changes, mortality, adverse events, etc.). A standardized data extraction form was developed and piloted to extract information on study design, patient characteristics, interventions, comparators, outcomes, and adverse events.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePrimary and Secondary Outcomes\u003c/h2\u003e \u003cp\u003eThe primary outcomes for this review were:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eImprovement in end-organ perfusion, defined as a measurable increase in mean, systolic, or diastolic blood pressure within 12 hours of hydrocortisone treatment initiation, in addition to either an increase in urine output or a reduction in serum lactate.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMortality prior to discharge.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eSecondary outcomes included:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDevelopment of bronchopulmonary dysplasia.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIncidence of major neurosensory disabilities, including cognitive, motor impairments, or severe visual or hearing impairments.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe occurrence of adverse events (hypertension, hyperglycemia, gastrointestinal complications, and hospital-acquired infections) within two weeks of hydrocortisone administration.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eQuality Assessment\u003c/h3\u003e\n\u003cp\u003eThe methodological quality of included studies was assessed using the Cochrane Risk of Bias 2 (ROB-2) tool, applied per outcome rather than per study in accordance with Cochrane recommendations.\u003c/p\u003e\n\u003ch3\u003eData Synthesis and Analysis\u003c/h3\u003e\n\u003cp\u003e Meta-analysis was conducted using Review Manager (RevMan) version 5.4 software. The certainty of evidence was evaluated using GRADE criteria across key outcomes. Pooled estimates of Odds Ratio(OR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. Statistical heterogeneity was assessed using the I\u0026sup2; statistic and Chi-square tests. A random-effects model was applied. Publication bias was evaluated using funnel plots and Egger\u0026rsquo;s test.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the included studies\u003c/h2\u003e \u003cp\u003eA total of 9 full-text articles were included in this review and meta-analysis. These studies were identified from a total of 1,352 records, with 1327 records retrieved through database searching across PubMed (n\u0026thinsp;=\u0026thinsp;571), Medline (n\u0026thinsp;=\u0026thinsp;232), Embase (n\u0026thinsp;=\u0026thinsp;142), Cochrane (n\u0026thinsp;=\u0026thinsp;178), and Scopus (n\u0026thinsp;=\u0026thinsp;204), along with an additional 25 records from other sources. After removing duplicates (n\u0026thinsp;=\u0026thinsp;358) and screening 994 records, 540 full-text articles were assessed for eligibility. Of these, 531 were excluded for various reasons, including irrelevance, lack of control group, or no hydrocortisone outcomes. The final 9 studies met the criteria for inclusion based on relevance and reporting of hydrocortisone-related outcomes and adverse effects (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Some included trials (Onland 2019, Parikh 2015) primarily aimed to assess BPD prevention but provided relevant data on hemodynamics/hypotension outcomes, and were therefore included.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eParticipant Data and Baseline characteristics\u003c/h2\u003e \u003cp\u003eA total of 2,044 participants were included in the review with mean age ranged from neonates\u0026thinsp;\u0026le;\u0026thinsp;28 days old to extremely low birth weight (ELBW) infants (\u0026lt;\u0026thinsp;1000g), and term neonates requiring intensive care or those requiring mechanical ventilation. The studies focused on neonates\u0026mdash;both preterm and term with conditions like pulmonary hypertension, hypoxic-ischemic encephalopathy (HIE) or congenital heart defects. Mean gestation age ranged from as low as 22 weeks to 37 weeks, reflecting a mix of preterm and term populations with focus on those at high risk for conditions like BPD, cardiovascular insufficiency or refractory hypotension. Randomized controlled trials, double-blind, placebo-controlled studies were included in the review. The interventions involved hydrocortisone in different dosages and regimens, such as hydrocortisone sodium succinate (2\u0026ndash;5 mg/Kg/day), or stress-dose hydrocortisone, with some studies also using methylprednisolone perioperatively. Comparators included placebo (saline/mannitol) with interventions administered intravenously. Dosage regimens varied, with hydrocortisone administered as an initial bolus followed by tapered doses or on continuous schedule, ranging from 0.5mg/kg every 6 hours to 3-5mg/kg/day over series of days. Adverse effects reported included hyperglycemia (more frequent in hydrocortisone group), hypertension (with high-dose hydrocortisone), gastrointestinal complications, electrolyte disturbance and increased insulin requirements. Other outcomes included incidence of BPD, mortality, weight gain, extubation success and need for inotropic support (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eData Extraction Sheet of the Included Studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor \u0026amp; Year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eParticipant characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComparator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDosing Regimen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAdverse effects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMain Results\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHochwald et al. 2014\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal Number of Participants: 22 (11 in each group) \u003c/p\u003e \u003cp\u003eGestational Age (GA): \u0026le;30 weeks \u003c/p\u003e \u003cp\u003eBirth Weight (BW): \u0026le;1250 g \u003c/p\u003e \u003cp\u003eGender: 6 females, 5 males in hydrocortisone group; 5 females, 6 males in placebo group \u003c/p\u003e \u003cp\u003eInborn: 9 hydrocortisone, 10 placebo \u003c/p\u003e \u003cp\u003eApgar at 5 minutes: Hydrocortisone group: 7.1 (SD 1.69), Placebo group: 6.67 (SD 2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntravenous hydrocortisone (2 mg/kg initial dose, 1 mg/kg q6h for 3 doses, 0.5 mg/kg q6h for 4 doses) and concurrent dopamine infusion (5 mcg/kg/min, increased or decreased per protocol).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlacebo (saline 0.9%) with concurrent dopamine infusion.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocortisone: 2 mg/kg initial dose, 1 mg/kg q6h for 3 doses, 0.5 mg/kg q6h for 4 doses \u003c/p\u003e \u003cp\u003eDopamine: 5 mcg/kg/min, adjusted per protocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e- Trend towards higher incidence of NEC and positive blood cultures in placebo group.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e- BPD: 36% in hydrocortisone group vs 63% in placebo group (proportion difference 0.27 [\u0026minus;\u0026thinsp;0.12\u0026ndash;0.5]).\u003c/p\u003e \u003cp\u003e- Survival without BPD: 54% in hydrocortisone group vs 18% in placebo group (proportion difference 0.46 [0.05\u0026ndash;0.7]).\u003c/p\u003e \u003cp\u003e- Dopamine Dose: Hydrocortisone group received significantly lower cumulative dose of dopamine (p\u0026thinsp;=\u0026thinsp;0.07), fewer hours of treatment (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003cp\u003e- Mortality: 36% mortality in placebo group, none in hydrocortisone group.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSalasa et al. 2014\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProspective, double-blind, randomised, placebo-controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal Number of Participants50 full-term infants\u003c/p\u003e \u003cp\u003eGender50 infants likely a mix of males and females)\u003c/p\u003e \u003cp\u003eAgeFull-term infants (gestational age\u0026thinsp;\u0026ge;\u0026thinsp;37 weeks)\u003c/p\u003e \u003cp\u003eHistorical Background\u003c/p\u003e \u003cp\u003ePrimary reason for hospitalisation: pulmonary hypertension (n\u0026thinsp;=\u0026thinsp;23), congenital heart defects (n\u0026thinsp;=\u0026thinsp;9), and surgical treatment (n\u0026thinsp;=\u0026thinsp;9).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHydrocortisone sodium succinate, 2.5 mg/kg intravenously every 12 hours for 2 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIsotonic saline 1.25 mL/kg intravenously every 12 hours for 2 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocortisone: 2.5 mg/kg/dose every 12 hours for 2 days (IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHyperglycemia (more frequent in the hydrocortisone group), gastrointestinal hemorrhage (1 case in placebo group)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e- Primary Outcome: Hydrocortisone significantly reduced the need for inotropic support compared to placebo, with 21 of the hydrocortisone group requiring reduced support versus 7 in the placebo group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e- Hemodynamic Outcomes: There was a trend toward improved ABP in the hydrocortisone group.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKovacs et al. 2019\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDouble-blind, randomized, placebo-controlled clinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal Number of Participants35 asphyxiated neonates\u003c/p\u003e \u003cp\u003eAge: Neonates\u0026thinsp;\u0026ge;\u0026thinsp;36 weeks gestational age\u003c/p\u003e \u003cp\u003eGenderBoth male and female neonates\u003c/p\u003e \u003cp\u003eHistorical Background - All neonates had hypoxic-ischemic encephalopathy (HIE) and underwent therapeutic hypothermia.\u003c/p\u003e \u003cp\u003e- Volume-resistant hypotension was defined as MAP\u0026thinsp;\u0026lt;\u0026thinsp;gestational age in weeks despite volume resuscitation.\u003c/p\u003e \u003cp\u003e- Dopamine was used as the primary inotrope during the study period.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5 mg/kg hydrocortisone intravenously every 6 hours for the duration of therapeutic hypothermia treatment (up to 72 hours).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlacebo (saline) intravenously every 6 hours for the same duration as hydrocortisone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocortisone: 0.5 mg/kg/dose every 6 hours IV during therapeutic hypothermia\u003c/p\u003e \u003cp\u003ePlacebo: 0.5 mL/kg saline every 6 hours IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCortisol levels were low in both groups at baseline.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e- Primary Outcome: 94% of infants in the hydrocortisone group reached the target of \u0026ge;\u0026thinsp;5 mmHg increase in MAP within 2 hours, vs 58% in the placebo group (P\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e \u003cp\u003e- Inotrope Requirements: The hydrocortisone group had a significantly shorter duration of cardiovascular support and lower cumulative and peak inotrope doses (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e- MAP Increase: The hydrocortisone group had an average increase of 4 mmHg in MAP compared to placebo (P\u0026thinsp;=\u0026thinsp;0.045).\u003c/p\u003e \u003cp\u003e- Heart Rate: The hydrocortisone group had a lower heart rate over time (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParikh et al. 2015\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized, parallel group, double-blind clinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 extremely low birth weight (ELBW) infants (\u0026lt;\u0026thinsp;1000g birth weight), 57 with adequate data for primary outcome (89% follow-up rate)\u003c/p\u003e \u003cp\u003eAge: 10\u0026ndash;21 postnatal days at randomization, Gestational age: Extremely preterm infants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStress dose hydrocortisone sodium succinate (Solu-Cortef, Pfizer), tapering 7-day course administered intravenously\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlacebo (0.9% sterile saline)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocortisone: 3 mg/kg/day for 4 days, 2 mg/kg/day for 2 days, 1 mg/kg/day for 1 day (total of 17 mg/kg over 7 days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eno bilateral blindness, no severe neurosensory impairments other than mild hearing loss in one placebo infant)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e- No statistically significant difference in survival without neurodevelopmental impairment (RR: 0.83; 95% CI, 0.61 to 1.14)\u003c/p\u003e \u003cp\u003e\u0026minus;\u0026thinsp;31% death in hydrocortisone group vs 41% in placebo group (P\u0026thinsp;=\u0026thinsp;0.42)\u003c/p\u003e \u003cp\u003e- Cognitive delay: 21% in hydrocortisone vs 47% in placebo (RR: 0.46, 95% CI 0.18 to 1.17)\u003c/p\u003e \u003cp\u003e- Cerebral palsy (CP): 15% in hydrocortisone vs 6% in placebo (not statistically significant)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWatterberg et al. 2017\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized, multicenter, double-masked, placebo-controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e932 infants screened; 257 eligible for inotropes, 12 enrolled over 10 months\u003c/p\u003e \u003cp\u003eGestational Age: \u0026ge; 34 weeks\u003c/p\u003e \u003cp\u003eAge at Enrollment: Median 37 hours (range: 2\u0026ndash;46 hours)\u003c/p\u003e \u003cp\u003eHistorical Background: Mechanically ventilated, receiving inotropes (dopamine, dobutamine, epinephrine, norepinephrine) for cardiovascular insufficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHydrocortisone sodium succinate: 1 mg/kg loading dose followed by 0.5 mg/kg every 6 hours for 12 doses, 0.5 mg/kg every 12 hours for 4 doses, and 0.5 mg/kg daily for 1 dose, total treatment course of 7 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlacebo: equal volume of normal saline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocortisone: 1 mg/kg loading dose, 0.5 mg/kg every 6 hours for 12 doses, 0.5 mg/kg every 12 hours for 4 doses, 0.5 mg/kg daily for 1 dose (7-day total course).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003einteractions with NSAIDs (indomethacin, ibuprofen) were not allowed during study drug treatment.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;932 infants screened, with 257 eligible for inotropes; however, 207 (81%) were excluded due to exclusionary diagnoses\u003c/p\u003e \u003cp\u003e- Only 12 infants enrolled over 10 months (3 per month in final 3 months)\u003c/p\u003e \u003cp\u003e\u0026minus;\u0026thinsp;81% of eligible infants had exclusionary diagnoses, leading to limited enrollment\u003c/p\u003e \u003cp\u003e- Only 12 infants consented despite 21 families being approached\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeeples et al 2017\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective case-control study conducted at a single-center (University of Washington) from 2011 to 2015.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106 infants: 50 high-dose HC (4 mg/kg/day), 20 low-dose HC (1\u0026ndash;3 mg/kg/day), and 36 control infants receiving only vasoactive agents\u003c/p\u003e \u003cp\u003eGestational Age: \u0026le;28 weeks\u003c/p\u003e \u003cp\u003eAge: Preterm infants with hypotension requiring vasoactive infusions\u003c/p\u003e \u003cp\u003eHistorical Background: Infants with refractory hypotension, receiving vasoactive medications (dopamine, dobutamine, epinephrine) and/or HC for hypotension management.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHydrocortisone: high-dose (4 mg/kg/day) or low-dose (1\u0026ndash;3 mg/kg/day), as part of clinical management for refractory hypotension.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eControl group: Infants treated with vasoactive medications alone, without hydrocortisone.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHigh-dose HC: 4 mg/kg/day (1 mg/kg every 6 hours) \u003c/p\u003e \u003cp\u003eLow-dose HC: 1\u0026ndash;3 mg/kg/day (0.5 mg/kg every 6\u0026ndash;12 hours, depending on regimen)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e- Increased incidence of hypertension (high-dose HC) \u003c/p\u003e \u003cp\u003e- Increased hyperglycemia \u003c/p\u003e \u003cp\u003e- Increased insulin therapy in HC-treated infants (though not statistically significant)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e- No significant differences in blood pressure or ability to wean off vasoactive medications between high- and low-dose HC.\u003c/p\u003e \u003cp\u003e- High-dose HC group had significantly higher rates of hypertension compared to low-dose group (28.0% vs. 6.9%, P\u0026thinsp;=\u0026thinsp;0.024).\u003c/p\u003e \u003cp\u003e- HC therapy was associated with higher incidence of hyperglycemia (23.7%, P\u0026thinsp;=\u0026thinsp;0.020) and insulin therapy (19.3%, P\u0026thinsp;=\u0026thinsp;0.054), although insulin therapy difference was not significant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeunhoeffer et al. 2015\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective, single-center study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e166 children (out of 1,273 total patients) treated with HRT for refractory hypotension after CPB from 2000 to 2010.\u003c/p\u003e \u003cp\u003e- Age: 150 infants\u0026thinsp;\u0026le;\u0026thinsp;1 year (90.36%) and 16 children\u0026thinsp;\u0026gt;\u0026thinsp;1 year (9.64%)\u003c/p\u003e \u003cp\u003e- Background: Children with complex congenital heart defects who underwent CPB surgery and had refractory hypotension despite optimized medical management.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHydrocortisone rescue therapy (HRT): 100 mg/m\u0026sup2;/day, initiated intravenously and continued for 2 days, followed by a taper over 2\u0026ndash;5 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlacebo: equal volume of normal saline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocortisone: 100 mg/m\u0026sup2;/day for 2 days, then tapered over 2\u0026ndash;5 days.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eadverse effects were observed, such as electrolyte disturbances, hyperglycemia, or gastrointestinal perforation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e- Hemodynamic Response: 82% of infants\u0026thinsp;\u0026le;\u0026thinsp;1 year responded to HRT, with significant improvement in mean blood pressure, VIS, lactate, and urine output.\u003c/p\u003e \u003cp\u003e- Non-responders: Non-responders were younger, had lower body weight, and higher PRISM and lactate levels. Mortality was significantly higher in non-responders (13.5% vs. 2.44%, p\u0026thinsp;=\u0026thinsp;0.0008).\u003c/p\u003e \u003cp\u003e- Mortality: Mortality was 13.5% in non-responders and 2.44% in responders.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuominen et al. 2017\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized Controlled Trial (RCT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal Participants: 40 neonates\u003c/p\u003e \u003cp\u003eAge: Neonates (\u0026le;\u0026thinsp;28 days old) undergoing elective open heart operations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStress-dose corticosteroid (SDC)\u003c/p\u003e \u003cp\u003eDrug: Methylprednisolone (2 mg/kg) bolus perioperatively and hydrocortisone infusion (0.2 mg/kg/h for 48 hours, tapered dose for 5 days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlacebo (saline infusion)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Methylprednisolone: 2 mg/kg perioperatively\u003c/p\u003e \u003cp\u003e- Hydrocortisone: 0.2 mg/kg/h for 48 hours, tapering doses for 5 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e- Higher blood glucose levels (significantly higher at 6 hours post-op and first post-op morning)\u003c/p\u003e \u003cp\u003e- Higher incidence of insulin infusion required in SDC group (12 of 14 patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e- IL-6 values were significantly lower in the SDC group postoperatively compared to placebo group\u003c/p\u003e \u003cp\u003e- Inotropic scores were significantly lower in the SDC group on postoperative days (POD) 1, 3, and 6\u003c/p\u003e \u003cp\u003e- Sternal closure occurred significantly earlier in the SDC group (mean 2 days earlier)\u003c/p\u003e \u003cp\u003e- Systemic ventricle delta strain (decrease in cardiac contractility) was significantly lower (less deterioration) in the SDC group postoperatively\u003c/p\u003e \u003cp\u003e- C-reactive protein (CRP): Similar trend to IL-6 (lower in SDC group)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnland et al. 2019\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDouble-blind, placebo-controlled, randomized trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372 preterm infants (gestational age\u0026thinsp;\u0026lt;\u0026thinsp;30 weeks or birth weight\u0026thinsp;\u0026lt;\u0026thinsp;1250 g) on mechanical ventilation between 7\u0026ndash;14 days of life, with high risk of BPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHydrocortisone sodium succinate, 5 mg/kg/day for 7 days, then 3.75 mg/kg/day for 5 days, tapering frequency over 22 days (total dose: 72.5 mg/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePlacebo (mannitol) with identical dosing schedule and duration to hydrocortisone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocortisone: 5 mg/kg/day for 7 days (4 doses/day), 3.75 mg/kg/day for 5 days (3 doses/day), taper to 1 dose every 5 days for 22 days (total dose: 72.5 mg/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSignificantly higher incidence of hyperglycemia requiring insulin therapy (18.2% hydrocortisone vs 7.9% placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1. No significant difference in death or BPD at 36 weeks (70.7% with hydrocortisone vs 73.7% with placebo; P\u0026thinsp;=\u0026thinsp;.54).\u003c/p\u003e \u003cp\u003e2. Reduced mortality at 36 weeks in hydrocortisone group (15.5% vs 23.7%, P\u0026thinsp;=\u0026thinsp;.048).\u003c/p\u003e \u003cp\u003e3. No significant difference in BPD (55.2% with hydrocortisone vs 50.0% placebo, P\u0026thinsp;=\u0026thinsp;.31).\u003c/p\u003e \u003cp\u003e4. Increased extubation success at 3, 7, and 14 days in the hydrocortisone group.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEffectiveness of Hydrocortisone for Treating Hypotension across Key Clinical Parameters\u003c/h2\u003e \u003cp\u003eThis study assessed hydrocortisone dosing for hypotension in neonates, comparing its effects to placebo across several clinical parameters. It also showed a strong protective effect in antenatal corticosteroid-treated infants (OR\u0026thinsp;=\u0026thinsp;0.19, 95% CI: 0.07, 0.50, P\u0026thinsp;=\u0026thinsp;0.0007, I\u0026sup2; = 66%), likely due to enhanced adrenal function, and a moderate effect in pregnancy-induced hypertension (OR\u0026thinsp;=\u0026thinsp;0.34, 95% CI: 0.12, 0.96, P\u0026thinsp;=\u0026thinsp;0.04, I\u0026sup2; = 69%) by stabilizing blood pressure. Hydrocortisone reduced hypotension risk in the dopamine dose subgroup (OR\u0026thinsp;=\u0026thinsp;0.30, 95% CI: 0.10, 0.95, P\u0026thinsp;=\u0026thinsp;0.04, I\u0026sup2; = 54%) but showed no significant effect for infusion volume (P\u0026thinsp;=\u0026thinsp;0.06, I\u0026sup2; = 93%). Overall, hydrocortisone reduced hypotension events (OR\u0026thinsp;=\u0026thinsp;0.43, 95% CI: 0.20, 0.92, P\u0026thinsp;=\u0026thinsp;0.03), though significant subgroup variability (P\u0026thinsp;=\u0026thinsp;0.005) suggests further exploration is needed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eImpact of Hydrocortisone Dosing on End-Organ Perfusion\u003c/h2\u003e \u003cp\u003eSignificant differences between hydrocortisone and placebo were identified across several clinical parameters. Hydrocortisone shortened the time to achieve blood pressure stabilization compared with placebo (mean difference\u0026thinsp;=\u0026thinsp;3.19 hours, 95% CI: 0.35\u0026ndash;6.04, P\u0026thinsp;=\u0026thinsp;0.03), with no heterogeneity (I\u0026sup2; = 0%), suggesting consistency in treatment timing benefits. Hydrocortisone shortened the duration of inotrope therapy by ~\u0026thinsp;25 hours (mean difference = -2.35 days, 95% CI: -4.28 to -0.42, P\u0026thinsp;=\u0026thinsp;0.02), with no heterogeneity. Hydrocortisone also improved urine output (mean difference = -0.99 mL/kg/h, P\u0026thinsp;=\u0026thinsp;0.02) and significantly increased mean arterial pressure (mean difference = -7.22 mmHg, P\u0026thinsp;=\u0026thinsp;0.03). Subgroup differences (P\u0026thinsp;=\u0026thinsp;0.002) suggested variability in response. These results indicate hydrocortisone\u0026rsquo;s effective role in managing hypotension in neonates(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy and Adverse Effects associated with Hydrocortisone Dosing\u003c/h2\u003e \u003cp\u003eHydrocortisone reduced the risk of bronchopulmonary dysplasia (BPD) with an odds ratio (OR) of 0.32 (95% CI: 0.11\u0026ndash;0.95, P\u0026thinsp;=\u0026thinsp;0.04), indicating a protective effect, though moderate heterogeneity (I\u0026sup2; = 63%) was noted. Regarding hyperglycemia, hydrocortisone significantly increased the risk (OR\u0026thinsp;=\u0026thinsp;4.07, 95% CI: 1.04\u0026ndash;15.90, P\u0026thinsp;=\u0026thinsp;0.04), with moderate heterogeneity (I\u0026sup2; = 54%). For arterial hypertension, hydrocortisone was associated with increased risk (OR\u0026thinsp;=\u0026thinsp;0.31, 95% CI: 0.10\u0026ndash;0.95, P\u0026thinsp;=\u0026thinsp;0.04), with moderate heterogeneity (I\u0026sup2; = 66%). Cognitive delay was also reduced in the hydrocortisone group (OR\u0026thinsp;=\u0026thinsp;0.18, 95% CI: 0.05\u0026ndash;0.65, P\u0026thinsp;=\u0026thinsp;0.009), despite high heterogeneity (I\u0026sup2; = 69%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHydrocortisone treatment was associated with a reduced incidence of cerebral palsy (OR\u0026thinsp;=\u0026thinsp;0.27, 95% CI: 0.06\u0026ndash;1.18, P\u0026thinsp;=\u0026thinsp;0.08) and language delay (OR\u0026thinsp;=\u0026thinsp;0.27, 95% CI: 0.10\u0026ndash;0.74, P\u0026thinsp;=\u0026thinsp;0.01), though the effect on cerebral palsy did not reach statistical significance (P\u0026thinsp;=\u0026thinsp;0.08). The incidence of mild gastrointestinal hemorrhage was significantly lower in the hydrocortisone group (OR\u0026thinsp;=\u0026thinsp;0.16, 95% CI: 0.03\u0026ndash;0.92, P\u0026thinsp;=\u0026thinsp;0.04), indicating a protective effect. Hydrocortisone treatment also showed a significant reduction in the risk of death (OR\u0026thinsp;=\u0026thinsp;0.08, 95% CI: 0.02\u0026ndash;0.27, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), with a substantial decrease in sepsis risk (OR\u0026thinsp;=\u0026thinsp;0.22, 95% CI: 0.06\u0026ndash;0.80, P\u0026thinsp;=\u0026thinsp;0.02) as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Hydrocortisone demonstrated significant benefits in reducing BPD and cognitive delay, but it also increased the risk of hyperglycemia, highlighting its complex effects on neonatal health. While it significantly reduced adverse outcomes like death and sepsis, moderate to high heterogeneity (I\u0026sup2; = 61\u0026ndash;83%) was observed across several parameters. Subgroup analyses revealed no significant differences (P\u0026thinsp;=\u0026thinsp;0.60), suggesting a generally consistent treatment effect across studies, despite variability in responses.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003ePublication Bias\u003c/h2\u003e \u003cp\u003ePublication bias in this study was assessed using a funnel plot and Egger's test. The funnel plot showed some asymmetry, suggesting potential publication bias, particularly in smaller studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e). Egger's test further confirmed this with a statistically significant result (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Despite the observed bias, the overall trend indicated that hydrocortisone had a positive impact on outcomes, though moderate heterogeneity (I\u0026sup2; = 61\u0026ndash;83%) was present, indicating variability in treatment effects across studies. The Cochrane risk of Bias (ROB 2) tool also showed moderate heterogeneity across the included studies as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e10\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis meta-analysis aimed to evaluate the effectiveness and safety of hydrocortisone dosing for treating hypotension in neonates (both preterm and term). The results identified that hydrocortisone significantly improved clinical outcomes, including a reduction in the incidence of bronchopulmonary dysplasia (BPD), cognitive delay, and mortality, while also lowering mean blood pressure and enhancing end-organ perfusion. Notably, the timing of hydrocortisone dosing was crucial, with earlier initiation linked to improved outcomes. Hydrocortisone also reduced the duration of inotrope therapy and improved urine output. However, it was associated with an increased risk of hyperglycemia. Subgroup analyses revealed variability in responses, and moderate to high heterogeneity (I\u0026sup2; = 61\u0026ndash;83%) was observed across several parameters, indicating inconsistent treatment effects. Despite some publication bias, the overall trend supports hydrocortisone as a beneficial intervention for preterm infants with hypotension, but further studies are needed to optimize dosing and minimize adverse effects. Our review included both preterm and term populations, reflecting the heterogeneity of clinical presentations (e.g., pulmonary hypertension in term infants, refractory hypotension in preterm infants). This broader inclusion increases generalizability but also contributes to heterogeneity.\u003c/p\u003e \u003cp\u003eThe use of hydrocortisone in the management of hypotension in critically ill neonates has garnered considerable attention due to its potential to stabilize hemodynamics, especially in cases where volume resuscitation and vasopressors are insufficient (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Several studies have assessed the impact of hydrocortisone on blood pressure and hemodynamics in neonates, particularly in VLBW and term neonates exposed to adverse birth condition such as asphyxia (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). For instance, Dempsey et al. (2006) conducted a randomized controlled trial in VLBW infants with hypotension, finding that hydrocortisone improved blood pressure and reduced the need for inotropic support, similar to our study results (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). However, their study involved higher cumulative doses of hydrocortisone over a longer period, which may have contributed to differences in the observed adverse effects, particularly in terms of gastrointestinal complications such as intestinal perforation when combined with indomethacin. Our study, which used a lower dose, did not demonstrate such adverse outcomes, suggesting that careful dose titration can mitigate risks (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSimilarly, the work by Baker et al. (2008) examined a cohort of infants with refractory hypotension treated with hydrocortisone, showing consistent improvements in blood pressure, reduction in inotropic dose, and increased diuresis (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In line with these findings, our study also observed a decrease in inotrope demand and an increase in urine output, further supporting the notion that hydrocortisone has a positive impact on neonatal hemodynamics. The study by Noori et al. (2012) also found that hydrocortisone led to a significant reduction in dopamine dosage and improved blood pressure, reinforcing the dopamine-sparing effects of hydrocortisone observed in our study (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn contrast, the trial by Iijima et al. (2019) assessing stress-dose hydrocortisone in VLBW infants with adrenal insufficiency found that hydrocortisone administration led to a decrease in inotropic requirements and improved blood pressure within the first 48 hours of treatment (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). This study echoes our own results, which suggest that early intervention with hydrocortisone may be particularly beneficial in managing hypotension (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, the study did not observe significant improvements in long-term pulmonary outcomes, such as the incidence of bronchopulmonary dysplasia (BPD), which contrasts with our observation of a potential trend toward improved survival without BPD (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne notable study by Kumbhat et al. (2020) found that approximately 70% of neonates with congenital diaphragmatic hernia who received hydrocortisone showed improved blood pressure and reduced reliance on vasopressors, indicating that steroids may help stabilize cardiovascular function in critically ill neonates (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). This supports our finding that hydrocortisone improves cardiovascular function in the context of neonatal hypotension. However, as in our study, Kumbhat et al. did not find significant differences in long-term neurodevelopmental outcomes, highlighting the need for further follow-up to evaluate the long-term safety of hydrocortisone (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe role of hydrocortisone in neonatal adrenal insufficiency has been well-documented, neonates with prematurity or perinatal asphyxia. A study by Efird et al. (2005) demonstrated that hydrocortisone administration improved both blood pressure and survival in neonates with suspected adrenal insufficiency, which is consistent with our findings (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Furthermore, the reduced serum cortisol levels observed in the placebo group in our study further support the hypothesis that relative adrenal insufficiency may play a role in hypotension and that hydrocortisone supplementation may address this deficiency (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, while hydrocortisone shows promise in improving hemodynamics and reducing inotrope dependency, the potential risk of corticosteroid therapy must be carefully considered (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In line with previous research, our study did not observe any significant long-term adverse effects related to neurodevelopment, but other studies, such as those by Cartwright et al. (2019), suggest that early steroid treatment may carry risks for abnormal brain development and cognitive outcomes, particularly with higher doses. These concerns warrant further investigation, especially given the potential neurotoxic effects observed with dexamethasone in preterm infants (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn terms of dosing, our study used relatively low doses of hydrocortisone, which is consistent with the practice of using stress doses in critically ill neonates. This aligns with findings from the meta-analysis by Ropp et al. (2024), which suggested that low-dose hydrocortisone administered early in the course of illness had a favorable impact on blood pressure and inotrope use without significant long-term harms (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). However, this strategy remains controversial, and there is still no consensus on the optimal dosing regimen. Studies such as those by Tang et al. (2022) (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) and Sushko et al. (2021) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) highlight the need for further trials to establish definitive protocols for hydrocortisone use in neonatal hypotension.\u003c/p\u003e \u003cp\u003eThis meta-analysis is limited by its exclusive inclusion of randomized controlled trials (RCTs), which, while providing high-quality evidence, may limit the generalizability of our findings to broader, non-randomized populations. Additionally, the studies included in this analysis varied in terms of patient populations, dosing regimens, and treatment protocols, which may introduce some heterogeneity in the results. The duration of hydrocortisone treatment and its long-term effects, particularly on neurodevelopment, remain areas that require further investigation, as few studies have followed patients beyond the immediate neonatal period. Furthermore, while we observed significant improvements in hemodynamic stability and inotrope use, the absence of comprehensive data on long-term outcomes such as survival without BPD or neurodevelopmental impairment warrants caution in applying these results universally. Despite these limitations, this study is significant as it consolidates the evidence from high-quality RCTs to support the use of hydrocortisone in managing volume-resistant hypotension in neonates, emphasizing its potential as a valuable adjunct to current therapies, particularly in critically ill neonates(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this meta-analysis demonstrates that hydrocortisone is an effective treatment for managing hypotension in in neonates including both preterm and term and those who are preterm or of very low birth weight, offering significant improvements in blood pressure, organ perfusion, and reduction in adverse outcomes such as bronchopulmonary dysplasia (BPD) and cognitive delay. However, the risk of hyperglycemia and other side effects, particularly with higher doses, underscores the need for careful dosing. Our findings highlight the potential benefits of low-dose hydrocortisone regimens, though the variability in treatment responses calls for further research to define the optimal dosing strategy. Future studies should focus on large, well-designed trials comparing low and high-dose hydrocortisone regimens to provide clearer guidance on balancing efficacy with safety and long-term neurodevelopmental outcomes.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFirst Author:\u0026nbsp;\u003c/strong\u003eAbdihafid Mohamed Abdullahi\u0026nbsp;\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Pediatrics in \u0026nbsp;NICU, Children’s Hospital, Zhejiang University School of Medicine,\u0026nbsp;Hangzhou, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEmail:\u0026nbsp;\u003c/strong\u003e\u003cstrong\[email protected]\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;,\u0026nbsp;\u003c/strong\u003e\u003cstrong\[email protected]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecond Author:\u0026nbsp;\u003c/strong\u003eJiaming Li\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1Department of Pediatrics in NICU, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eZhejiang Shaoxing Shangyu Maternal and Child Health Hospital\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEmail:\u0026nbsp;\u003c/strong\[email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAffiliation:\u0026nbsp;\u003c/strong\u003e\u003csup\u003e1\u003c/sup\u003eZhejiang\u0026nbsp;University\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2Department of Pediatrics in NICU, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence to\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Xuyanping\u003c/strong\u003e\u003csup\u003e*\u003c/sup\u003e, MD, PhD.\u0026nbsp;Department of Pediatrics in \u0026nbsp;NICU, Children’s Hospital, Zhejiang University School of Medicine,\u0026nbsp;Hangzhou, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEmail:\u0026nbsp;\u003c/strong\u003e\u003cstrong\[email protected]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eXu\u003c/strong\u003e contributions to conception and design;\u0026nbsp;\u003cstrong\u003eAbdihafid\u003c/strong\u003e and\u0026nbsp;\u003cstrong\u003eLi\u003c/strong\u003e been involved in\u0026nbsp;\u003c/p\u003e\n\u003cp\u003edrafting the manuscript and revising it critically for important intellectual\u0026nbsp;\u003c/p\u003e\n\u003cp\u003econtent;\u0026nbsp;\u003cstrong\u003eAbdihafid\u003c/strong\u003e and\u0026nbsp;\u003cstrong\u003eLi\u003c/strong\u003e made substantial contributions to acquisition of data;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbdihafid\u003c/strong\u003e analysis and interpretation of data; and all authors given final approval of\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ethe version to be published.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed during the current study are available\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ein several major electronic databases, including PubMed, Cochrane Library,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEmbase, and Web of Science.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDempsey EM. Challenges in treating low blood pressure in preterm infants. Children. 2015;2(2):272\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerma RP, Dasnadi S, Zhao Y, Chen HH. A comparative analysis of ante-and postnatal clinical characteristics of extremely premature neonates suffering from refractory and non-refractory hypotension: Is early clinical differentiation possible? Early Hum Dev. 2017;113:49\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRocha G, Pereira S, Antunes-Sarmento J, Fl\u0026ocirc;r-de-Lima F, Soares H, Guimar\u0026atilde;es H. Early anemia and neonatal morbidity in extremely low birth-weight preterm infants. J Maternal-Fetal Neonatal Med. 2021;34(22):3697\u0026ndash;703.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDilli D, Soylu H, Tekin N. Neonatal hemodynamics and management of hypotension in newborns. Turkish Archives Pediatrics/T\u0026uuml;rk Pediatri Arşivi. 2018;53(Suppl 1):S65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhayat SI, Gowda HM, Eisenhut M. Should dopamine be the first line inotrope in the treatment of neonatal hypotension? Review of the evidence. World J Clin Pediatr. 2016;5(2):212.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGupta S, Donn SM, editors. Neonatal hypotension: dopamine or dobutamine? Seminars in Fetal and Neonatal Medicine. Elsevier; 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuoss JL, McPherson C, DiNardo J. Inotrope and vasopressor support in neonates. NeoReviews. 2015;16(6):e351\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValverde E, Pellicer A, Madero R, Elorza D, Quero J, Cabanas F. Dopamine versus epinephrine for cardiovascular support in low birth weight infants: analysis of systemic effects and neonatal clinical outcomes. Pediatrics. 2006;117(6):e1213\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumbhat N, Noori S. Corticosteroids for neonatal hypotension. Clin Perinatol. 2020;47(3):549\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDasgupta S, Jain S, Aly A. Neonatal hypotension, the role of hydrocortisone and other pharmacological agents in its management. J Pediatr Child Care. 2016;2(1):08.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaker C, Barks J, Engmann C, Vazquez D, Neal C, Schumacher R, et al. Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns. J Perinatol. 2008;28(6):412\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaud O, Maury L, Lebail F, Ramful D, El Moussawi F, Nicaise C, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet. 2016;387(10030):1827\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatterberg KL, Walsh MC, Li L, Chawla S, D\u0026rsquo;Angio CT, Goldberg RN, et al. Hydrocortisone to improve survival without bronchopulmonary dysplasia. N Engl J Med. 2022;386(12):1121\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatterberg KL. Hydrocortisone dosing for hypotension in newborn infants: less is more. J Pediatr. 2016;174:23\u0026ndash;6. e1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhashana A, Saarela T, Ramet M, Hallman M. Cortisol intermediates and hydrocortisone responsiveness in critical neonatal disease. 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Pediatrics. 2006;117(2):516\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoori S, Seri I. Neonatal blood pressure support: the use of inotropes, lusitropes, and other vasopressor agents. Clin Perinatol. 2012;39(1):221\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValverde A. Fluid resuscitation for refractory hypotension. Front Veterinary Sci. 2021;8:621696.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIijima S. Late-onset glucocorticoid-responsive circulatory collapse in premature infants. Pediatr Neonatology. 2019;60(6):603\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNg P, Lee C, Lam C, Ma K, Fok T, Chan I, et al. Transient adrenocortical insufficiency of prematurity and systemic hypotension in very low birthweight infants. 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World J Pediatr Surg. 2024;7(2).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChandramati J, Nair LS, Menon SM, Prabhu A, Abraham M, Viswanathan N, et al. Outcome of congenital diaphragmatic hernia: a single center experience. J Neonatal Surg. 2019;8(4):29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEfird MM, Heerens AT, Gordon PV, Bose CL, Young DA. A randomized-controlled trial of prophylactic hydrocortisone supplementation for the prevention of hypotension in extremely low birth weight infants. J Perinatol. 2005;25(2):119\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorris IP, Goel N, Chakraborty M. Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis. Eur J Pediatrics. 2019;178:1171\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuckley MS, MacLaren R. Concomitant vasopressin and hydrocortisone therapy on short-term hemodynamic effects and vasopressor requirements in refractory septic shock. J Crit Care. 2017;42:6\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCartwright RD, Crowther CA, Anderson PJ, Harding JE, Doyle LW, McKinlay CJ. Association of fetal growth restriction with neurocognitive function after repeated antenatal betamethasone treatment vs placebo: secondary analysis of the ACTORDS randomized clinical trial. JAMA Netw open. 2019;2(2):e187636\u0026ndash;e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheong JL, Anderson P, Roberts G, Duff J, Doyle LW, Group VICS. Postnatal corticosteroids and neurodevelopmental outcomes in extremely low birthweight or extremely preterm infants: 15-year experience in Victoria, Australia. Archives Disease Childhood-Fetal Neonatal Ed. 2013;98(1):F32\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRopp DL, Johnson PN, Stephens K, Neely S, Chaaban H, Miller JL. Incidence of gastrointestinal bleeding with hydrocortisone use in neonates and infants less than three months of age in the neonatal intensive care unit. J Perinatol. 2024;44(10):1478\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang W, Gao T, Cao Y, Zhou W, Song D, Wang L. Narrative review of perinatal management of extremely preterm infants: what\u0026rsquo;s the evidence? Pediatr Med. 2022;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSushko K, Al-Rawahi N, Watterberg K, Van Den Anker J, Litalien C, Lacroix J et al. Efficacy and safety of low-dose versus high-dose hydrocortisone to treat hypotension in neonates: a protocol for a systematic review and meta-analysis. BMJ Paediatrics Open. 2021;5(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins S, Friedlich P, Seri I. Hydrocortisone for hypotension and vasopressor dependence in preterm neonates: a meta-analysis. J Perinatol. 2010;30(6):373\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHochwald O, Palegra G, Osiovich H. Adding hydrocortisone as 1st line of inotropic treatment for hypotension in very low birth weight infants. Indian J Pediatr. 2014;81:808\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalasa G, Travagliantib M, Leoneb A, Couceiroa C, Rodr\u0026iacute;guezc S, Fari\u0026ntilde;aa D. Hydrocortisone for the treatment of refractory hypotension: a randomised controlled trial. Pediatr (Barc). 2014;80(6):387\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSzakmar E, Meder U, Szakacs L, Cseko A, Vatai B, Szabo AJ, et al. 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JAMA. 2019;321(4):354\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neonatal Hypotension, Hydrocortisone Dosing, Preterm Infants, Very Low Birth Weight (VLBW), Adrenal Insufficiency, Corticosteroid Therapy, Meta-Analysis","lastPublishedDoi":"10.21203/rs.3.rs-8024256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8024256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHypotension is common in neonates, particularly those who are preterm or very-low-birth-weight (VLBW) and is associated with poor outcomes, including brain injury and increased mortality. Relative adrenal insufficiency is a key contributor, with hydrocortisone (HC) often used to support cardiovascular stability. However, the optimal dosing strategy remains uncertain.\u003c/p\u003e\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eThis meta-analysis evaluated the efficacy and safety of different hydrocortisone dosing regimens for treating hypotension in neonates including both preterm and term infants, focusing on blood pressure response, organ perfusion, and adverse effects.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e Following PRISMA guidelines, randomized controlled trials (RCTs) published up to 2024 were systematically reviewed. RevMan 5.4 software was used for meta-analysis. Outcomes included improvement in blood pressure and perfusion, mortality, bronchopulmonary dysplasia (BPD), and adverse events such as hyperglycemia.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNine RCTs involving 2,044 neonates were included. Hydrocortisone (0.5 mg/kg every 6 hours to 5 mg/kg/day) significantly improved mean arterial pressure (mean increase: ~4 mmHg; OR\u0026thinsp;=\u0026thinsp;0.43, 95% CI: 0.20\u0026ndash;0.92, P\u0026thinsp;=\u0026thinsp;0.03) and reduced inotrope requirements. HC reduced mortality prior to discharge (15.5% vs 23.7% in controls; OR\u0026thinsp;=\u0026thinsp;0.08, 95% CI: 0.02\u0026ndash;0.27, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and lowered the incidence of BPD (OR\u0026thinsp;=\u0026thinsp;0.32, 95% CI: 0.11\u0026ndash;0.95, P\u0026thinsp;=\u0026thinsp;0.04). However, treatment was associated with a higher risk of hyperglycemia (OR\u0026thinsp;=\u0026thinsp;4.07, 95% CI: 1.04\u0026ndash;15.90, P\u0026thinsp;=\u0026thinsp;0.04). No consistent evidence was found for increased risk of gastrointestinal or neurosensory complications.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eHydrocortisone improves blood pressure, reduces inotrope use, and may lower mortality and BPD in both preterm and term neonates with hypotension. Lower-dose regimens appear effective with fewer metabolic complications, while higher doses increase hyperglycemia risk. Large, well-designed RCTs are still needed to define optimal dosing strategies.\u003c/p\u003e","manuscriptTitle":"Hydrocortisone Dosing for Hypotension in Neonates: A Systematic Review \u0026amp; Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-16 10:21:34","doi":"10.21203/rs.3.rs-8024256/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1b0a473-c945-4728-8563-ae47de79ecd1","owner":[],"postedDate":"January 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-06T05:24:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-16 10:21:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8024256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8024256","identity":"rs-8024256","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}