Objective To describe the safety of sildenafil based on hypotension in premature infants with bronchopulmonary dysplasia (BPD). Study design We conducted a multicenter, randomized, double-blind, placebo-controlled, dose-escalating trial of sildenafil. Infants born < 29 weeks’ gestation and at 32-44 weeks postmenstrual age with severe BPD were randomized sequentially into 3 cohorts to receive up to 34 days of intravenous or enteral sildenafil citrate vs placebo (3:1) in a dose-escalating approach. Safety was determined by the incidence of hypotension through 28 days following the last dose of study drug. Pulmonary hypertension by serial echocardiography and daily respiratory severity scores were obtained to assess preliminary efficacy. Results A total of 122 infants received sildenafil (N=92) or placebo (N=30). The incidence of hypotension did not differ between the sildenafil (1/92) and placebo (0/30) groups. Serious adverse events occurred in 8% of the sildenafil group and 13% of the placebo group; retinopathy of prematurity requiring treatment in 17% and 30%, abnormal hearing results in 8% and 7%, direct hyperbilirubinemia in 4% and 3%, alanine aminotransferase elevation in 3% and 0, and escalation in respiratory support in 7% and 20%, respectively. There were no differences in daily respiratory severity scores between groups. Conclusions Among premature infants with severe BPD, enteral sildenafil citrate did not increase the incidence of hypotension or retinopathy of prematurity. Although we found possible differences between groups in the development of BPD-associated pulmonary hypertension diagnosed by echocardiography in high-risk infants, a larger, randomized controlled trial is needed to assess efficacy.

Background: Pulmonary hypertension in children is progressive with wide variability in prognosis. This document provides an evidence-based clinical practice guideline for the management of children with progressive pulmonary hypertension despite optimal therapy. Methods: A multidisciplinary panel identified pertinent questions regarding the management of children with pulmonary hypertension that has progressed despite optimal therapy, conducted systematic reviews of the relevant literature, and applied the Grading of Recommendations, Assessment, Development and Evaluation approach to develop clinical recommendations. Results: After reviewing the research evidence, the panel considered the balance of desirable (benefits) and undesirable (harms and burdens) effects of the interventions in each proposed question. Valuation of our main outcomes was also considered, together with resources required, equity, acceptability, and feasibility. Recommendations were developed for or against interventional strategies specific to children with pulmonary hypertension that has progressed despite optimal therapy. Conclusions: Although there is a growing population of children with pulmonary hypertension, there is a striking lack of empirical evidence regarding management of those whose disease has progressed despite optimal pharmacotherapy. The panel formulated and provided the rationale for clinical recommendations for or against interventional strategies on the basis of this limited empirical evidence, coupled with expert opinion, to aid clinicians in the management of these complex pediatric patients. In addition, we identified important areas for future research.

Prenatal diagnosis of cardiac defects can significantly aid postnatal care. We present 2 cases of a rare anomaly of the right superior vena cava draining into the left atrium, one postnatally diagnosed and one prenatally diagnosed, to highlight the differences in care and the benefits of prenatal diagnosis. The patient who received the postnatal diagnosis was born at a community hospital with hypoxemia. There was a delay in diagnosis, which resulted in escalation of critical care support including the use of extracorporeal membrane oxygenation. The prenatally diagnosed patient presented with concern of a dilated left atrium in the fetus. After the diagnosis, there was coordinated delivery with cardiology presence and immediate transfer to the cardiac care center. This patient was stabilized using minimal support, had timely postnatal imaging studies, and successful surgical repair with an uncomplicated clinical course. Prenatal diagnosis resulted in coordinated high-quality care because of a shared cognitive framework.

Pulmonary veno-occlusive disease has no definitive cure apart from lung transplant. The reverse Potts shunt can be a palliative bridge to transplant. A post-arrest 14-year-old with severe pulmonary veno-occlusive disease on extracorporeal membrane oxygenation support was decannulated after reverse Potts shunt and survived to lung transplant. Reverse Potts shunt should be considered as a rescue in select patients with end-stage pulmonary veno-occlusive disease.

BACKGROUND:Surveillance for heart transplant rejection by endomyocardial biopsy is invasive and may yield false negatives. T1 and T2 mapping from cardiac magnetic resonance can demonstrate elevations with rejection. We sought to evaluate longitudinal changes in T1 and T2 mapping in pediatric patients with heart transplant. METHODS AND RESULTS:A cohort study was performed of pediatric patients with heart transplant who underwent concurrent endomyocardial biopsy and cardiac magnetic resonance with T1 and T2 mapping from December 2019 to July 2024. Segmental values were measured and subsegmental elevations (ie, hotspots) were identified. Subjects were categorized as either treated rejection or no rejection. Peak and mean T1 and T2 values and number of hotspots at/between each time point for patient dyads were compared between the groups. A total of 21 subjects (7 treated rejection, 14 no rejection) with 68 total encounters met inclusion criteria. Peak and mean T1 values were higher in treated rejection patients during the rejection period and decreased with treatment (peak, 1086 versus 1052; mean, 1028 versus 1021), such that at last follow-up when their rejection had resolved, there was no significant difference in values when compared with no rejection patients (peak, 1066; mean, 1016). The number of T1 hotspots decreased after rejection treatment (2 versus 1). There were no changes in peak or mean T2 values in the treated rejection group despite treatment, and peak and mean T2 values were similar to patients with no rejection through last follow-up. CONCLUSIONS:Elevated T1 values and hotspots observed during cardiac allograft rejection decline in response to treatment. Cardiac magnetic resonance may serve as a noninvasive monitoring tool for the development and resolution of rejection, as well as the effectiveness of rejection therapy.

Background: Resuscitation with chest compressions and positive pressure ventilation in Bidirectional Glenn (BDG) or Fontan physiology may compromise passive venous return and accentuate neurologic injury. We hypothesized that arterial pressure and survival would be better in BDG than Fontan patients. Methods: Secondary analyses of the Pediatric Intensive Care Quality of CPR and Improving Outcomes from Pediatric Cardiac Arrest databases. P-values were considered significant if < 0.05. Results: In total, 64 patients had either BDG (42/64, 66%) or Fontan (22/64, 34%) anatomy. Return of spontaneous circulation was achieved in 76% of BDG patients versus 59% of Fontan patients and survival with favorable neurologic outcome in 22/42 (52%) BDG versus 6/22 (27%) Fontan patients, p = 0.067. Twelve of 24 (50%) BDG and 2/7 (29%) Fontan patients who survived to discharge suffered new morbidity as defined by worsening Functional Status Score. More BDG patients achieved adequate DBP (>= 25 mmHg for neonates and infants; >= 30 mmHg for children) than Fontan patients (21/23 (91%) vs. 5/11 (46%), p = 0.007). Conclusions: Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after CPR, likely driven by inadequate diastolic blood pressure during resuscitation. One half of the BDG patients who survived to hospital discharge had new neurologic morbidity. BackgroundCardiac arrest in patients with congenital heart disease (CHD) may present challenges to resuscitation based on the unique cardiovascular physiology resulting from surgical palliation. Recent resuscitation guidelines for CHD patients highlight the lack of data surrounding these special patient populations.1 Univentricular heart disease is palliated by a series of cardiac surgeries that stepwise result in passive pulmonary perfusion from the systemic venous system directly to the pulmonary vascular bed. The bidirectional Glenn (BDG) palliation directly anastomoses the superior vena cava (SVC) to the pulmonary arterial system and leaves normal inferior vena cava (IVC) venous return to the heart.2 The Fontan palliation baffles IVC flow directly to the pulmonary vascular bed which relieves cyanosis due to right to left shunting, but requires systemic ventricular preload to be directly dependent upon pulmonary vascular resistance and intrathoracic pressures.3 Impact statementHemodynamic waveforms from 2 large prospective observational studies now allow for exploration of physiology during cardiopulmonary resuscitation for unique anatomy associated with single ventricle congenital heart disease.Fewer patients with Fontan physiology (46%) achieved an adequate diastolic blood pressure (defined as >= 25 mmHg for neonates and infants and >= 30 mmHg for children) than bidirectional Glenn patients during cardiopulmonary resuscitation (91%, = 0.007).Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after cardiopulmonary resuscitation.Of the bidirectional Glenn patients who survived, 50% developed a new morbidity as quantified by the Functional Status Score.

Background: Cardiovascular magnetic resonance (CMR) derived T1 parametric mapping offers quantitative, regional assessments of myocardial edema and fibrosis. Pediatric cardiac allografts are subject to fibrosis due to rejection inflammation, coronary vasculopathy, cardiopulmonary bypass and graft failure. The role of CMR parametric mapping in identifying clinically important myocardial fibrosis in this population remains unknown. Thus, the aim of this study was to correlate endomyocardial biopsy (EMB)-derived fibrosis measurements with local T1 values in PHTx patients. Methods: PHTx pts undergoing EMB also underwent simultaneous cardiac MRI including T1 parametric mapping in 6 short axis slices at 1.5 T. Segmental T1 values were measured and the segments corresponding to EMB sites were noted from overlay registration. Trichrome-stained EMBs were digitally scanned and analyzed for fibrosis content. Encounters were divided into low and high fibrosis groups, and clinical variables from echocardiography, clinical treatment, and cardiac catheterization were compared using student’s t-test and linear regression. Results: Thirty-three PHTx pts (age of 12.8 + 4.9 years) underwent 94 surveillance encounters, for a total of 283 EMB samples. 75 encounters had no active rejection and 19 encounters had active rejection requiring treatment. Average T1 was significantly higher in active rejection group (1056 vs 1018 ms, p<0.01), and there was no difference in fibrosis score between the 2 groups, thus identifying rejection as the main driver of T1 elevation. In the group with no active rejection, the T1 value from the EMB site was elevated in the high fibrosis score group (1023 vs 1011 ms, p=0.01). Of these patients without rejection, the higher fibrosis group had higher BNP (626 vs 145, p=0.04), higher lateral mitral E/e’ (8 vs 6.6, p=0.03) and higher RVEDP (11 vs 9 mmHg, p=0.05), all suggestive of more significant diastolic dysfunction. Conclusions: CMR derived segmental T1 value can detect clinically significant graft rejection. In the absence of rejection, elevated T1 correlates with clinically significant fibrosis on EMB, which correlates with markers of diastolic dysfunction.

Background: Heart transplantation remains definitive therapy for children with heart failure, but the burden of acute graft rejection remains. While adult data has shown cardiac magnetic resonance (CMR) offers reliable, non-invasive identification of graft rejection1-3, endo-myocardial biopsy (EMB) continues to be the gold-standard in children. Hypothesis: CMR can establish the presence/absence of rejection, guiding need for EMB and rejection therapy. Aims: To assess the (1) strength of CMR parametric mapping in discriminating presence of rejection (defined as need for new therapy), and (2) the ability of CMR to identify patients without rejection, negating the need for EMB. Methods: Pediatric heart transplant patients referred for EMB underwent concurrent noncontrast CMR with volumetry, flows, MOLLI T1 and T2 parametric mapping at 1.5T. Average and peak segmental native T1 and T2 were measured in 6 slices, and regions of sub-segmental ‘hotspot’ elevation (3 continuous voxels T1>1050 ms or T2>60 ms) were identified. Rejection treatment was per institutional protocol, blinded to CMR results, categorized as (A)new IV therapy, (B)oral augmentation of maintenance, or (C) no change. Sensitivity, specificity and ROC analyses were performed. Results: 95 encounters in 34 patients (median age 13.1y (IQR 7.5-16.3), BSA 1.37 m2 (1.1-1.6), 47% female) were completed, with treatment groups A 13%, B 5%, and C 82%. Significantly higher T1 and T2 values were found in the rejection groups. ROC curve analysis identified elevated peak T1 levels as the strongest predictor of rejection (AUC = 0.848, 95% CI: 0.746, 0.950, p<0.001), with optimal cutoff T1 >1099 ms. Subsegmental hotspots were present in all encounters with rejection requiring new therapy (100% sensitivity), however the type/ number of hotspots did not correlate with rejection. New rejection therapy was not initiated in any patient encounter without hotspots (NPV 100%). Conclusions: Elevated segmental T1 CMR values can identify children with graft rejection, and absence of subsegmental hotspot elevations can reliably identify patients without rejection. CMR is a promising non-invasive test to aid in graft surveillance and direct invasive testing and therapy.

To determine associations between anticoagulation practices and bleeding and thrombosis during pediatric extracorporeal membrane oxygenation (ECMO), we performed a secondary analysis of prospectively collected data which included 481 children (<19 years), between January 2012 and September 2014. The primary outcome was bleeding or thrombotic events. Bleeding events included a blood product transfusion >80 ml/kg on any day, pulmonary hemorrhage, or intracranial bleeding, Thrombotic events included pulmonary emboli, intracranial clot, limb ischemia, cardiac clot, and arterial cannula or entire circuit change. Bleeding occurred in 42% of patients. Five percent of subjects thrombosed, of which 89% also bled. Daily bleeding odds were independently associated with day prior activated clotting time (ACT) (OR 1.03, 95% CI= 1.00, 1.05, p=0.047) and fibrinogen levels (OR 0.90, 95% CI 0.84, 0.96, p <0.001). Thrombosis odds decreased with increased day prior heparin dose (OR 0.88, 95% CI 0.81, 0.97, p=0.006). Lower ACT values and increased fibrinogen levels may be considered to decrease the odds of bleeding. Use of this single measure, however, may not be sufficient alone to guide optimal anticoagulation practice during ECMO.

Background: Previous studies have identified pulmonary hypertension (PH) as a relatively common diagnosis in children with in-hospital cardiac arrest (IHCA), and preclinical laboratory studies have found poor outcomes and low systemic blood pressures during CPR for PH-associated cardiac arrest. The objective of this study was to determine the prevalence of PH among children with IHCA and the association between PH diagnosis and intra-arrest physiology and survival outcomes.Methods: This was a prospectively designed secondary analysis of patients enrolled in the ICU-RESUS clinical trial (NCT02837497). The primary exposure was a pre-arrest diagnosis of PH. The primary survival outcome was survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline). The primary physiologic outcome was event-level average diastolic blood pressure (DBP) during CPR. Results: Of 1276 patients with IHCAs during the study period, 1129 index IHCAs were enrolled; 184 (16.3%) had PH and 101/184 (54.9%) were receiving inhaled nitric oxide at the time of IHCA. Survival with favorable neurologic outcome was similar between patients with and without PH on univariate (48.9% vs. 54.4%; p = 0.17) and multivariate analyses (aOR 0.82 [95%CI: 0.56, 1.20]; p = 0.32). There were no significant differences in CPR event outcome or survival to hospital discharge. Average DBP, systolic BP, and end-tidal carbon dioxide during CPR were similar between groups.Conclusions: In this prospective study of pediatric IHCA, pre-existing PH was present in 16% of children. Pre-arrest PH diagnosis was not associated with statistically significant differences in survival outcomes or intra-arrest physiologic measures.

T1/T2 parametric mapping may reveal patterns of elevation (“hotspots”) in myocardial diseases, such as rejection in orthotopic heart transplant (OHT) patients. This study aimed to evaluate the diagnostic accuracy of free-breathing (FB) multi-parametric SAturation recovery single-SHot Acquisition (mSASHA) T1/T2 mapping in identifying hotspots present on conventional Breath-held Modified Look-Locker Inversion recovery (BH MOLLI) T1 and T2-prepared balanced steady-state free-precession (BH T2p-bSSFP) maps in pediatric OHT patients. Pediatric OHT patients underwent noncontrast 1.5T CMR with BH MOLLI T1 and T2p-bSSFP and prototype FB mSASHA T1/T2 mapping in 8 short-axis slices. FB and BH T1/T2 hotspots were segmented using semi-automated thresholding (ITK-SNAP) and their 3D coordinate locations were collected (3-Matic, Materialise, Leuven, Belgium). Receiver operator characteristic curve analysis and measures of central tendency were utilized. 40 imaging datasets from 23 pediatric OHT patients were obtained. FB mSASHA yielded a sensitivity of 82.8% for T1 and 80% for T2 maps when compared to the standard BH MOLLI, as well as 100% specificity for both T1 and T2 maps. When identified on both FB and BH maps, hotspots overlapped in all cases, with an average long axis offset between FB and BH hotspot centers of 5.8 mm (IQR 3.5–8.2) on T1 and 5.9 mm (IQR 3.5–8.2) on T2 maps. FB mSASHA T1/T2 maps can identify hotspots present on conventional BH T1/T2 maps in pediatric patients with OHT, with high sensitivity, specificity, and overlap in 3D space. Free-breathing mapping may improve patient comfort and facilitate OHT assessment in younger patient populations.

Introduction: Endomyocardial biopsy (EMB) drives rejection diagnosis in pediatric heart transplant patients but is subject to false negatives and carries risk. Cardiac MRI can detect and quantify myocardial fibrosis and edema with T1 and T2 mapping. Hypothesis: Cardiac MRI may improve discernment of acute rejection in pediatric transplant patients. Methods: Pediatric heart transplant patients referred for clinically indicated EMB underwent noncontrast MRI with T1 +T2 mapping prior to EMB. Segmental T1 and T2 values were measured for base/mid/apex segments. Mean and peak T1+ T2 were quantified per encounter. Rejection treatment was per institutional protocol, and categorized as (A) no changes, (B) oral therapy initiated, or (C) IV therapy initiated. Treatment decisions were blinded to MRI results. Treatment category and T1+T2 were compared with Fisher’s exact test and logistic regression. Results: 89 encounters in 34 patients (median age 13.2y (IQR 8.3-16.8), BSA 1.39 m2 (1.09-1.65), 44.1% female) were successfully completed, with treatment groups A 11%, B 8%, C 81%. Median T1 mean and T1 peak values were (1022 ms (994-1040) and 1077 ms (1056, 1113)), respectively. Median T2 mean and T2 peak values were (50.4 ms (48.4-53.2) and 57.4 ms (53.1-60.8)), respectively. Higher T2 mean and T2 peak predict need for IV therapy; the strongest discriminator was T2 mean > 54.5 (AUC = 0.801, 95% CI: 0.630, 0.972) Table 1. T1 mean and T1 peak were not significant in predicting rejection requiring IV therapy. Adding T1 mean to T2 mean did not improve the AUC (0.804 (95% CI: 0.637, 0.971), DeLong p=0.74). Finally, the odds ratio of new IV rejection therapy for T2 mean values > 54.5 ms is 16.1 (95% confidence interval: 3.6 - 72.6, p<0.001). Conclusions: Average T2 values (cutoff > 54.5 ms) were efficacious at identifying need for IV treatment for rejection in pediatric heart transplant patients, regardless of T1 values. MRI is a promising noninvasive test to identify children at risk of rejection.

Background Cardiovascular magnetic resonance (CMR) is emerging as an important tool for cardiac allograft assessment. Native T1 mapping may add value in identifying rejection and in assessing graft dysfunction and myocardial fibrosis burden. We hypothesized that CMR native T1 values and features of textural analysis of T1 maps would identify acute rejection, and in a secondary analysis, correlate with markers of graft dysfunction, and with fibrosis percentage from endomyocardial biopsy (EMB). Methods Fifty cases with simultaneous EMB, right heart catheterization, and 1.5 T CMR with breath-held T1 mapping via modified Look-Locker inversion recovery (MOLLI) in 8 short-axis slices and subsequent quantification of mean and peak native T1 values, were performed on 24 pediatric subjects. A single mid-ventricular slice was used for image texture analysis using nine gray-level co-occurrence matrix features. Digital quantification of Masson trichrome stained EMB samples established degree of fibrosis. Markers of graft dysfunction, including serum brain natriuretic peptide levels and hemodynamic measurements from echocardiography, catheterization, and CMR were collated. Subjects were divided into three groups based on degree of rejection: acute rejection requiring new therapy, mild rejection requiring increased ongoing therapy, and no rejection with no change in treatment. Statistical analysis included student's t-test and linear regression. Results Peak and mean T1 values were significantly associated with acute rejection, with a monotonic trend observed with increased grade of rejection. Texture analysis demonstrated greater spatial heterogeneity in T1 values, as demonstrated by energy, entropy, and variance, in cases requiring treatment. Interestingly, 2 subjects who required increased therapy despite low grade EMB results had abnormal peak T1 values. Peak T1 values also correlated with increased BNP, right-sided filling pressures, and capillary wedge pressures. There was no difference in histopathological fibrosis percentage among the 3 groups; histopathological fibrosis did not correlate with T1 values or markers of graft dysfunction. Conclusion In pediatric heart transplant patients, native T1 values identify acute rejection requiring treatment and may identify graft dysfunction. CMR shows promise as an important tool for evaluation of cardiac grafts in children, with T1 imaging outperforming biopsy findings in the assessment of rejection.

OBJECTIVES: Characterize the use of inhaled nitric oxide (iNO) for pediatric cardiac patients and assess the relationship between patient characteristics before iNO initiation and outcomes following cardiac surgery. DESIGN: Observational cohort study. SETTING: PICU and cardiac ICUs in seven Collaborative Pediatric Critical Care Research Network hospitals. PATIENTS: Consecutive patients, less than 18 years old, mechanically ventilated before or within 24 hours of iNO initiation. iNO was started for a cardiac indication and excluded newborns with congenital diaphragmatic hernia, meconium aspiration syndrome, and persistent pulmonary hypertension, or when iNO started at an outside institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four-hundred seven patients with iNO initiation based on cardiac dysfunction. Cardiac dysfunction patients were administered iNO for a median of 4 days (2–7 d). There was significant morbidity with 51 of 407 (13%) requiring extracorporeal membrane oxygenation and 27 of 407 (7%) requiring renal replacement therapy after iNO initiation, and a 28-day mortality of 46 of 407 (11%). Of the 366 (90%) survivors, 64 of 366 patients (17%) had new morbidity as assessed by Functional Status Scale. Among the postoperative cardiac surgical group (n = 301), 37 of 301 (12%) had a superior cavopulmonary connection and nine of 301 (3%) had a Fontan procedure. Based on echocardiographic variables prior to iNO (n = 160) in the postoperative surgical group, right ventricle dysfunction was associated with 28-day and hospital mortalities (both, p < 0.001) and ventilator-free days (p = 0.003); tricuspid valve regurgitation was only associated with ventilator-free days (p < 0.001), whereas pulmonary hypertension was not associated with mortality or ventilator-free days. CONCLUSIONS: Pediatric patients in whom iNO was initiated for a cardiac indication had a high mortality rate and significant morbidity. Right ventricular dysfunction, but not the presence of pulmonary hypertension on echocardiogram, was associated with ventilator-free days and mortality.

OBJECTIVE:Tracheobronchomalacia (TBM) is common in neonates with bronchopulmonary dysplasia (BPD) and is associated with higher morbidity. This study evaluates the value of a CT protocol to assess the degree of TBM and gauge the adequacy of prescribed PEEP.STUDY DESIGN:Four infants with severe BPD on invasive mechanical ventilation underwent a chest CT protocol, including limited reduced-dose expiratory scans with varying PEEP levels.RESULTS:Baseline PEEP was adjusted in all subjects after performing the Dynamic PEEP CT. In two infants, the PEEP was increased due to significant TBM and in the other two without signs of TBM PEEP was decreased. The clinical course improved in all patients after adjusting PEEP.CONCLUSION:A "Dynamic PEEP" study may be reliable and non-invasive imaging modality for the evaluation of adequate ventilator settings in infants with severe BPD who are not optimal candidates for bronchoscopy.

Successful separation of a pediatric patient from extracorporeal membrane oxygenation (ECMO) support requires careful planning. The etiology of a patient’s cardiopulmonary compromise should direct the ECMO provider to develop a timeline for weaning and separation as early as the time of ECMO deployment and cannulation. This chapter reviews common methods of weaning and decannulation of pediatric patients from veno-arterial ECMO support. It also describes difficulties encountered in the weaning process, highlighting scenarios pertinent to the pediatric and pediatric cardiac surgery populations. A case discussion followed by a critical review of the literature, as well as critical care board-type, multiple-choice questions summarizing the chapter, are provided to aid the learner.

OBJECTIVES:To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock. DESIGN:Multicenter, double-blinded, randomized controlled trial. SETTING:One academic medical ICU and four community ICUs. PATIENTS:Of 167 adult patients within 24 hours of vasopressor initiation for septic shock, 126 consented to participation, and 124 received study drug and were included in analysis. INTERVENTIONS:IV vitamin C (10 mg/mL in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr for 96 hours or placebo of equal volumes of normal saline. MEASUREMENTS AND MAIN RESULTS:Of 124 subjects receiving study drug and included in analysis, 60 received vitamin C and 64 placebo. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; p = 0.10) was lower in the vitamin C arm but did not reach statistical significance. Initiation of renal replacement therapy was higher in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; p = 0.015), as was volume of fluid administration within 6 hours of study drug initiation (vitamin C, 1.07 L; placebo, 0.76 L; p = 0.03). There were no statistically significant differences in other secondary outcomes. In post hoc subgroup analysis, there was a decrease in 28-day mortality in the vitamin C arm among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; p = 0.05). This trial is registered at clinicaltrials.gov under identifier NCT03338569. CONCLUSIONS:Vitamin C monotherapy failed to significantly reduce mortality in septic shock patients as hypothesized. Our findings do not support its routine clinical use for this purpose.