Charting the course for improved outcomes in chronic critical illness: therapeutic strategies for persistent inflammation, immunosuppression, and catabolism syndrome (PICS).

Enhanced critical care delivery has led to improved survival rates in critically ill patients, yet sepsis remains a leading cause of multiorgan failure with variable recovery outcomes. Chronic critical illness, characterised by prolonged ICU stays and persistent end-organ dysfunction, presents a significant challenge in patient management, often requiring multifaceted interventions. Recent research, highlighted in a comprehensive review in the British Journal of Anaesthesia, focuses on addressing the pathophysiological drivers of chronic critical illness, such as persistent inflammation, immunosuppression, and catabolism, through targeted therapeutic strategies including immunomodulation, muscle wasting prevention, nutritional support, and microbiome modulation. Although promising avenues exist, challenges remain in patient heterogeneity, treatment timing, and the need for multimodal approaches.

Disparities in insurance status negatively affect patients with infantile hypertrophic pyloric stenosis.

PURPOSE: Infantile hypertrophic pyloric stenosis (IHPS) is suspected to have worse outcomes when length of illness prior to presentation is prolonged. Our objective was to evaluate how social determinants of health influence medical care and outcomes for babies with IHPS. METHODS: A retrospective review was performed over 10 years. Census data were used as proxy for socioeconomic status via Geo-Identification codes and correlated with food access and social vulnerability variables. The cohort was subdivided to understand the impact of Medicaid Managed Care (MMC). RESULTS: The cohort (279 cases) was divided into two groups; early group from 2011 to 2015 and late from 2016 to 2021. Cases in the late group were older at the time of presentation (41.5 vs. 36.5 days; p = 0.022) and presented later in the disease course (12.8 vs. 8.9 days; p = 0.021). There was no difference in race (p = 0.282), gender (p = 0.874), or length of stay. CONCLUSIONS: Patients who presented with IHPS after implementation of phased MMC were older, had a longer symptomatic course, and shorter pylorus measurements. Patients with public insurance after the implementation of MMC were more likely to follow-up with an outpatient pediatrician within a month of hospitalization. These results suggest that MMC may have improved access to care for infants with IHPS.

Exploring Limited English Proficiency in the Clinical Outcomes of Pediatric Burn Patients.

INTRODUCTION: Limited English proficiency (LEP) is linked to lower health care access and worse clinical outcomes. This study aims to explore the potential role of LEP on clinical outcomes of pediatric burn patients. METHODS: We conducted a single-institution retrospective study of burn patients presenting at a tertiary pediatric burn referral program between January 2016 and December 2020. Patient demographics, burn mechanism, severity, interventions, and primary patient language were abstracted from the electronic health record. Clinical outcomes (length of stay [LOS], clinic follow-up, and 30-day readmission) of patients with LEP were compared to patients with English as primary language (EPL). RESULTS: Thirty-five (4.2%) patients with LEP were identified of 840 total patients. On univariate analysis, there was no difference in mean total body surface area (6.5% versus 6.1%), report of physical abuse (2.9% versus 8.9%), or need for grafting (14.3% versus 15.0%) comparing patients with LEP to those with EPL. Patients with LEP were more likely to have a scald burn (68.6% versus 48.9%, P = 0.025) and less likely to have a flame/fire burn (20.0% versus 37.6%, P = 0.047). On multivariate analysis, there was no difference between patients with LEP compared to patients with EPL for LOS (2.9 versus 3.5 d), 30-day readmissions (5.6% versus 5.7%), or clinic follow-up (80.6% versus 75.0%). In patients with >10% total body surface area, patients with LEP had a longer emergency department LOS (277 min versus 145 min, P = 0.06) but no difference in outcome measures. CONCLUSIONS: Pediatric patients with LEP were not found to have worse burn outcomes compared to EPL patients in our patient sample. However, a true association is difficult to determine given the small sample size of LEP patients and the potential underestimation of language discordancy as recorded in the electronic medical record. Further research is needed to better explore the role of primary language and health communication as a social determinant of health in pediatric burn patients.

Medical Student Career Choice: Who Is the Influencer?

BACKGROUND: While many factors influence medical student career choice, interactions with attending and resident physicians during clinical rotations are particularly important. To evaluate the influence of attending and resident physicians on medical students' career choices, particularly for those pursuing surgical careers, we quantified their respective influence in the context of other known influences. METHODS: Rising fourth-year medical students and new graduates were given an IRB-exempt, 14-item online survey. Descriptive statistics were performed on the demographic information. Chi-square analysis was used, as were Kruskal-Wallis and Mann-Whitney analyses on the Likert responses (α = 0.05). RESULTS: Survey response was 24%. Students pursuing general surgery rated residents greater than or equal to attendings on 7 of 8 key mentoring characteristics. Of students choosing a different specialty than the one they intended to pursue upon entering medical school, the influence of residents was cited by 100% of the students pursuing general surgery, compared to 59% of the entire cohort. Identification of a role model and perceived personality fit were significantly more important than other factors (P < 0.0001). Students pursuing general surgery rated the importance of identifying a role model and perceived personality fit greater than their peers. CONCLUSIONS: Residents have greater influences on medical students' career choice compared to attendings. Students pursuing a surgical specialty, particularly general surgery, considered the influence of role models and perceived personality fit to be the most important factors in their specialty decision. These findings provide valuable insights to improve student experiences and career recruitment in surgical specialties, particularly general surgery.

Monocyte anisocytosis increases during multisystem inflammatory syndrome in children with cardiovascular complications.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication that can develop weeks to months after an initial SARS-CoV-2 infection. A complex, time-consuming laboratory evaluation is currently required to distinguish MIS-C from other illnesses. New assays are urgently needed early in the evaluation process to expedite MIS-C workup and initiate treatment when appropriate. This study aimed to measure the performance of a monocyte anisocytosis index, obtained on routine complete blood count (CBC), to rapidly identify subjects with MIS-C at risk for cardiac complications. METHODS: We measured monocyte anisocytosis, quantified by monocyte distribution width (MDW), in blood samples collected from children who sought medical care in a single medical center from April 2020 to October 2020 (discovery cohort). After identifying an effective MDW threshold associated with MIS-C, we tested the utility of MDW as a tier 1 assay for MIS-C at multiple institutions from October 2020 to October 2021 (validation cohort). The main outcome was the early screening of MIS-C, with a focus on children with MIS-C who displayed cardiac complications. The screening accuracy of MDW was compared to tier 1 routine laboratory tests recommended for evaluating a child for MIS-C. RESULTS: We enrolled 765 children and collected 846 blood samples for analysis. In the discovery cohort, monocyte anisocytosis, quantified as an MDW threshold of 24.0, had 100% sensitivity (95% CI 78-100%) and 80% specificity (95% CI 69-88%) for identifying MIS-C. In the validation cohort, an initial MDW greater than 24.0 maintained a 100% sensitivity (95% CI 80-100%) and monocyte anisocytosis displayed a diagnostic accuracy greater that other clinically available hematologic parameters. Monocyte anisocytosis decreased with disease resolution to values equivalent to those of healthy controls. CONCLUSIONS: Monocyte anisocytosis detected by CBC early in the clinical workup improves the identification of children with MIS-C with cardiac complications, thereby creating opportunities for improving current practice guidelines.

Heterogeneity in the evaluation of suspected MIS-C: a cross-sectional vignette-based survey.

BACKGROUND AND OBJECTIVES: Multisystem Inflammatory Syndrome in Children (MIS-C) is an emerging complication of COVID-19 which lacks a definitive diagnostic test and evidence-based guidelines for workup. We sought to assess practitioners' preferences when initiating a workup for pediatric patients presenting with symptoms concerning for MIS-C. METHODS: In a cross-sectional vignette-based survey, providers were presented with clinical vignettes of a patient presenting with 24 h of fever from a community with high rates of COVID-19. Respondents were asked about their general practices in pursuing a workup for potential MIS-C including testing obtained, criteria for diagnosis, and timing to confirm or rule out the diagnosis. RESULTS: Most of the 174 respondents were physicians from the United States at academic medical centers. The majority of providers would not initiate MIS-C workup for fever and non-specific symptoms unless the fever lasted more than 72 h. Skin rash, abdominal pain, and shortness of breath were symptoms that raised greatest concern for MIS-C. Most providers would obtain COVID-19 PCR or antigen testing, plus blood work, in the initial workup. The list of laboratory studies providers would obtain is extensive. Providers primarily rely on cardiac involvement to confirm a MIS-C diagnosis, and establishing a diagnosis takes 24-48 h. CONCLUSIONS: Significant heterogeneity exists amongst providers as to when to initiate the MIS-C workup, the order and content of the workup, and how to definitively diagnose MIS-C. A diagnostic test with high sensitivity and specificity for MIS-C and refined evidence-based guidelines are needed to expedite diagnosis and treatment.

Outcomes After Prehospital Endotracheal Intubation in Suburban/Rural Pediatric Trauma.

BACKGROUND: Trauma is the leading cause of death in pediatric patients over 1 y of age. Controversy exists regarding prehospital airway management for these patients, with some studies suggesting that endotracheal intubation in the field or at a referring hospital is associated with increased mortality and complication rate. These studies were largely performed at urban centers, and it is unclear whether the results apply to suburban/rural networks with longer transport times and more stops at referring hospitals. The purpose of this study is to evaluate differential outcomes in pediatric trauma patients who underwent endotracheal intubation at the scene of injury, referring hospital, or pediatric trauma center in a predominantly rural/suburban setting. MATERIALS AND METHODS: A retrospective review was performed evaluating trauma patients age 18 y or younger at a single institution over 10 y (2004-2014). Patients were selected who underwent endotracheal intubation and were classified based on location of intubation (scene, referring hospital, or trauma center). Fischer's exact test and t-tests were performed for comparison. Univariate and multivariate regression analyses were performed. RESULTS: 288 patients were identified. 155 (53.8%) were intubated at the scene of injury, 55 (19.1%) at a referring hospital, and 72 (25%) at the trauma center. Overall mortality was 21.9%, which was highest in the scene intubation group (29.7%) compared with the referring hospital (20%) and trauma center (5.6%) groups (P < 0.01). Patients intubated at the scene had higher Injury Severity Scores and lower Glasgow Coma Scale scores (P < 0.01). Duration of intubation was lowest in the trauma center group (P < 0.01). Complication rate was highest in the referring hospital group (P < 0.05). Multivariate analysis revealed that age, injury severity, and neurologic status were the key drivers of mortality rather than location of intubation. CONCLUSIONS: Mortality and duration of intubation were lowest in trauma patients intubated at a pediatric trauma center. However, location of intubation was not a significant independent predictor of mortality or complications on multivariate analysis, suggesting that age, injury severity, and neurologic status are the main indicators of prognosis in severe pediatric trauma.

Long-term outcomes of antegrade continence enema in children with chronic encopresis and incontinence: what is the optimal flush to use?

PURPOSE: Severe constipation and encopresis are significant problems in the pediatric population. Medical management succeeds in 50-70%; however, surgical considerations are necessary for the remainder such as the antegrade continence enema (ACE). The purpose of this study is to assess the long-term outcomes following the ACE procedure. METHODS: All patients undergoing an ACE over a 14-year period were included. Data on clinical conditions, treatments, and outcomes were collected. A successful outcome was defined as remaining clean with ≤ 1 accident per week. Comparative data were analyzed using the Fisher's exact test, Mann-Whitney U test, or Student's t test. RESULTS: There were 42 ACE patients, and overall, 79% had improvement in their bowel regimens. Encopresis rates decreased from 79 to 5% (P < 0.001). Admissions for cleanouts decreased from 52 to 19% (P = 0.003). All cases of Hirschsprung's, functional constipation and spina bifida were successful. Rates of success varied for other diseases such as slow-transit constipation (60%) and cerebral palsy (33%). A majority (85%) required a change in the enema composition for improvement. CONCLUSION: In our study, ACE reduced soiling, constipation, and need for fecal disimpaction. Higher volume saline flushes used once a day was the optimal solution and most preferred option. LEVEL OF EVIDENCE: Level 4 (retrospective case series or cohort).

Inguinal hernias in premature neonates: exploring optimal timing for repair.

PURPOSE: Inguinal hernias have been reported in as many as 10-30% premature neonates, making inguinal herniorrhaphy (IHR) one of the most commonly performed surgical procedures. The timing of surgery remains controversial. The purpose of this report is to compare outcomes of IHR while in the NICU (inpatient) versus repair following discharge (outpatient) to determine optimal timing. METHODS: Premature neonates having undergone IHR over a 5-year period were identified and a retrospective case cohort analysis was performed. RESULTS: 263 patients underwent IHR during the 5-year study period with 115 (43.7%) having surgical repair inpatient (IP; prior to discharge) and 148 having outpatient herniorrhaphy (OP). Patients with IHR performed IP had significantly lower birth weight (p < 0.001), gestational age (p < 0.001), longer duration of surgery (p = 0.01) and were more likely to have post-operative ventilator dependence following repair; however, there were no differences in the rate of recurrence (p = 0.44) and incarceration (p = 0.45). CONCLUSION: Our study demonstrated no significant differences in the rates of incarceration or recurrence, following in- or out-patient IHR. These findings suggest that IHR can potentially be offered as an outpatient procedure following hospital discharge in appropriate patients. The optimal timing of IHR in premature infants remains elusive and will likely require additional multicenter investigation.

Microbial recognition and danger signals in sepsis and trauma.

Early host recognition of microbial invasion or damaged host tissues provides an effective warning system by which protective immune and inflammatory processes are initiated. Host tissues responsible for continuous sampling of their local environment employ cell surface and cytosolic pattern recognition receptors (PRRs) that provide redundant and overlapping identification of both microbial and host alarmins. Microbial products containing pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs) serve as principle ligands for recognition by these PRRs. It is this interaction which plays both an essential survival role in response to infection and injury, as well as the pathologic role in tissue and organ injury associated with severe sepsis and trauma. Elucidating the interaction between ligands and their respective PRRs can provide both a better understanding of the host response, as well as a rational basis for therapeutic intervention. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.

Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis.

Controversy remains whether the leukocyte genomic response to trauma or sepsis is dependent upon the initiating stimulus. Previous work illustrated poor correlations between historical models of murine trauma and sepsis (i.e., trauma-hemorrhage and lipopolysaccharide injection, respectively). The aim of this study is to examine the early genomic response in improved murine models of sepsis [cecal ligation and puncture (CLP)] and trauma [polytrauma (PT)] with and without pneumonia (PT+Pp). Groups of naïve, CLP, PT, and PT+Pp mice were killed at 2 h, 1 or 3 days. Total leukocytes were isolated for genome-wide expression analysis, and genes that were found to differ from control (false discovery rate adjusted P < 0.001) were assessed for fold-change differences. Spearman correlations were also performed. For all time points combined (CLP, PT, PT+Pp), there were 10,426 total genes that were found to significantly differ from naïve controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (rs) of 0.446 (P < 0.0001) but were less positive thereafter. Correlations were significantly improved when we limited the analysis to common genes whose expression differed by a 1.5 fold-change. Both pathway and upstream analyses revealed the activation of genes known to be associated with pathogen-associated and damage-associated molecular pattern signaling, and early activation patterns of expression were very similar between polytrauma and sepsis at the earliest time points. This study demonstrates that the early leukocyte genomic response to sepsis and trauma are very similar in mice.

Pediatric sepsis.

PURPOSE OF REVIEW: Sepsis is the leading cause of pediatric death worldwide. In the United States alone, there are 72 000 children hospitalized for sepsis annually with a reported mortality rate of 25% and an economic cost estimated to be $4.8 billion. However, it is only recently that the definition and management of pediatric sepsis has been recognized as being distinct from adult sepsis. RECENT FINDINGS: The definition of pediatric sepsis is currently in a state of evolution, and there is a large disconnect between the clinical and research definitions of sepsis which impacts the application of research findings into clinical practice. Despite this, it is the speed of diagnosis and the timely implementation of current treatment guidelines that has been shown to improve outcomes. However, adherence to treatment guidelines is currently low and it is only through the implementation of protocols that improved care and outcomes have been demonstrated. SUMMARY: The current management of pediatric sepsis is largely based on adaptations from adult sepsis treatment; however, distinct physiology demands more prospective pediatric trials to tailor management to the pediatric population. Adherence to current and emerging practice guidelines will require that protocolized care pathways become a commonplace.

Improved emergency myelopoiesis and survival in neonatal sepsis by caspase-1/11 ablation.

Over one million newborns die annually from sepsis with the highest mortality in premature and low-birthweight infants. The inflammasome plays a central role in the regulation of innate immunity and inflammation, and is presumed to be involved in protective immunity, in large part through the caspase-1-dependent activation of interleukin-1ß (IL-1ß) and IL-18. Studies in endotoxic shock, however, suggest that endogenous caspase-1 activity and the inflammasome contribute to mortality primarily by promoting excessive systemic inflammatory responses. We examined whether caspase-1 and the inflammasome also regulate neonatal inflammation, host protective immunity and myelopoiesis during polymicrobial sepsis. Neonatal (5-7 days) C57BL/6 and caspase-1/11(-/-) mice underwent a low-lethality caecal slurry model of intra-abdominal sepsis (LD25-45 ). Ablation of caspase-1/11, but not apoptosis-associated speck-like protein containing a CARD domain or nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), improved neonatal survival following septic challenge compared with wild-type mice (P < 0·001), with decreased concentrations of inflammatory cytokines in the serum and peritoneum. Surprisingly, caspase-1/11(-/-) neonates also exhibited increased bone marrow and splenic haematopoietic stem cell expansion (P < 0·001), and increased concentrations of granulocyte and macrophage colony-stimulating factors in the peritoneum (P < 0·001) after sepsis. Ablation of caspase-1/11 signalling was also associated with increased recruitment of peritoneal macrophages and neutrophils (P < 0·001), increased phagocytosis by neutrophils (P = 0·003), and decreased bacterial colonization (P = 0·02) in the peritoneum. These findings suggest that endogenous caspase-1/11 activity, independent of the NLRP3 inflammasome, not only promotes the magnitude of the inflammatory response, but also suppresses protective immunity in the neonate, so contributing to innate immune dysfunction and poor survival in neonatal sepsis.

Appendiceal carcinoids in children--management and outcomes.

BACKGROUND: Appendiceal carcinoid tumors are very rare in children, and management has been guided by adult presentations and outcomes. Here, we present our experience with pediatric appendiceal carcinoid tumors. METHODS: We undertook a retrospective review of all cases of appendiceal carcinoids in children over a 20-y period. Data regarding clinical presentation, diagnosis, pathology, follow-up, and outcomes were collected and analyzed. RESULTS: We identified 13 cases of appendiceal carcinoids. All cases were diagnosed after appendectomy for presumed appendicitis (nine acute and four interval;), with no patient having carcinoid syndrome. Mean age at diagnosis was 13.7 y, and all but one case was female. Tumor size ranged from microscopic foci of tumor cells to 2.1 cm (mean, 0.93 cm). Seven cases had invasion of the mesoappendix, three of which underwent a subsequent right hemicolectomy. The patient with the largest tumor (2.1 cm) had evidence of lymphatic invasion with three nodes positive for tumor after right colectomy. No patient had elevation of 5-hydroxyindoleacetic acid or serum chromogranin A, and surveillance computed tomographic scans did not reveal any liver metastases. CONCLUSIONS: This is a relatively large series of carcinoids of the appendix in children. We found no evidence of carcinoid syndrome or metastatic disease in these cases other than lymphatic. The need for a secondary colectomy is perhaps questionable.

Social determinants of health in pediatric trauma: Associations with injury mechanisms and outcomes in the context of the COVID-19 pandemic.

BACKGROUND: Relationships between social determinants of health and pediatric trauma mechanisms and outcomes are unclear in context of COVID-19. METHODS: Children <16 years old injured between 2016 and 2021 from ten pediatric trauma centers in Florida were included. Patients were stratified by high vs. low Social Vulnerability Index (SVI). Injury mechanisms studied were child abuse, ATV/golf carts, and firearms. Mechanism incidence trends and mortality were evaluated by interrupted time series and multivariable logistic regression. RESULTS: Of 19,319 children, 68% and 32% had high and low SVI, respectively. Child abuse increased across SVI strata and did not change with COVID. ATV/golf cart injuries increased after COVID among children with low SVI. Firearm injuries increased after COVID among children with high SVI. Mortality was predicted by injury mechanism, but was not independently associated with SVI, race, or COVID. CONCLUSION: Social vulnerability influences pediatric trauma mechanisms and COVID effects. Child abuse and firearm injuries should be targeted for prevention.

Golf cart injuries have similar severity to all-terrain vehicle injuries in children: a multicenter comparison over a 5-year period.

Background: Golf carts (GCs) and all-terrain vehicles (ATVs) are popular forms of personal transport. Although ATVs are considered adventurous and dangerous, GCs are perceived to be safer. Anecdotal experience suggests increasing numbers of both GC and ATV injuries, as well as high severity of GC injuries in children. This multicenter study examined GC and ATV injuries and compared their injury patterns, resource utilization, and outcomes. Methods: Pediatric trauma centers in Florida submitted trauma registry patients age <16 years from January 2016 to June 2021. Patients with GC or ATV mechanisms were identified. Temporal trends were evaluated. Injury patterns, resource utilization, and outcomes for GCs and ATVs were compared. Intensive care unit admission and immediate surgery needs were compared using multivariable logistic regression. Results: We identified 179 GC and 496 ATV injuries from 10 trauma centers. GC and ATV injuries both increased during the study period (R2 0.4286, 0.5946, respectively). GC patients were younger (median 11 vs 12 years, p=0.003) and had more intracranial injuries (34% vs 19%, p<0.0001). Overall Injury Severity Score (5 vs 5, p=0.27), intensive care unit (ICU) admission (20% vs 16%, p=0.24), immediate surgery (11% vs 11%, p=0.96), and mortality (1.7% vs 1.4%, p=0.72) were similar for GCs and ATVs, respectively. The risk of ICU admission (OR 1.19, 95% CI 0.74 to 1.93, p=0.47) and immediate surgery (OR 1.04, 95% CI 0.58 to 1.84, p=0.90) remained similar on multivariable logistic regression. Conclusions: During the study period, GC and ATV injuries increased. Despite their innocuous perception, GCs had a similar injury burden to ATVs. Heightened safety measures for GCs should be considered. Level of evidence: III, prognostic/epidemiological.

Transcriptomic Differences in Peripheral Monocyte Populations in Septic Patients Based on Outcome.

ABSTRACT: Post-sepsis early mortality is being replaced by survivors who experience either a rapid recovery and favorable hospital discharge or the development of chronic critical illness (CCI) with suboptimal outcomes. The underlying immunological response that determines these clinical trajectories remains poorly defined at the transcriptomic level. As classical and non-classical monocytes are key leukocytes in both the innate and adaptive immune systems, we sought to delineate the transcriptomic response of these cell types. Using single-cell RNA sequencing and pathway analyses, we identified gene expression patterns between these two groups that are consistent with differences in TNFα production based on clinical outcome. This may provide therapeutic targets for those at risk for CCI in order to improve their phenotype/endotype, morbidity, and long-term mortality.

The post-septic peripheral myeloid compartment reveals unexpected diversity in myeloid-derived suppressor cells.

Introduction: Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. Methods: Cellular Indexing of Transcriptomes and Epitopes by Sequencing and transcriptomic analysis are used to describe MDSC subpopulations based on differential gene expression, RNA velocities, and biologic process clustering. Results: We identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome. Discussion: The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity.

Long-term maturation of congenital diaphragmatic hernia treatment results: toward development of a severity-specific treatment algorithm.

OBJECTIVES: To assess the impact of varying approaches to congenital diaphragmatic hernia (CDH) repair timing on survival and need for ECMO when controlled for anatomic and physiologic disease severity in a large consecutive series of patients with CDH. BACKGROUND: Our publication of 60 consecutive patients with CDH in 1999 showed that survival was significantly improved by limiting lung inflation pressures and eliminating hyperventilation. METHODS: We retrospectively reviewed 268 consecutive patients with CDH, combining 208 new patients with the 60 previously reported. Management and ventilator strategy were highly consistent throughout. Varying approaches to surgical timing were applied as the series matured. RESULTS: Patients with anatomically less severe left liver-down CDH had significantly increased need for ECMO if repaired in the first 48 hours, whereas patients with more severe left liver-up CDH survived at a higher rate when repair was performed before ECMO. Overall survival of 268 patients was 78%. Survival was 88% for those without lethal associated anomalies. Of these, 99% of left liver-down CDH survived, 91% of right CDH survived, and 76% of left liver-up CDH survived. CONCLUSIONS: This study shows that patients with anatomically less severe CDH benefit from delayed surgery whereas patients with anatomically more severe CDH may benefit from a more aggressive surgical approach. These findings show that patients respond differently across the CDH anatomic severity spectrum and lay the foundation for the development of risk-specific treatment protocols for patients with CDH.