External validation of a clinical mathematical model estimating post-operative urine output following cardiac surgery in children.

BACKGROUND: This study aims to externally validate a clinical mathematical model designed to predict urine output (UOP) during the initial post-operative period in pediatric patients who underwent cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Children aged 0-18 years admitted to the pediatric cardiac intensive care unit at Cleveland Clinic Children's from April 2018 to April 2023, who underwent cardiac surgery with CPB were included. Patients were excluded if they had pre-operative kidney failure requiring kidney replacement therapy (KRT), re-operation or extracorporeal membrane oxygenation or KRT requirement within the first 32 post-operative hours or had indwelling urinary catheter for fewer than the initial 32 post-operative hours, or had vasoactive-inotrope score of 0, or those with missing data in the electronic health records. RESULTS: A total of 213 encounters were analyzed; median age (days): 172 (IQR 25-75th%: 51-1655), weight (kg): 6.1 (IQR 25-75th%: 3.8-15.5), median UOP ml/kg/hr in the first 32 post-operative hours: 2.59 (IQR 25-75th%: 1.93-3.26) and post-operative 30-day mortality: 1, (0.4%). The mathematical model achieved the following metrics in the entire dataset: mean absolute error (95th% Confidence Interval (CI)): 0.70 (0.67-0.73), median absolute error (95th% CI): 0.54 (0.52-0.56), mean squared error (95th% CI): 0.97 (0.89-1.05), root mean squared error (95th% CI): 0.99 (0.95-1.03) and R2 Score (95th% CI): 0.29 (0.24-0.34). CONCLUSIONS: This study provides encouraging external validation results of a mathematical model predicting post-operative UOP in pediatric cardiac surgery patients. Further multicenter studies must explore its broader applicability.

Association of enteral feeds in critically ill bronchiolitis patients supported by high-flow nasal cannula with adverse events and outcomes.

To study association of enteral feeds in bronchiolitis patients supported by different levels of high flow nasal cannula (HFNC) with adverse events, nutritional goals, and clinical outcomes. Bronchiolitis patients ≤ 24 months of age treated with < 1 L/kg/min, 1-2 L/kg/min and > 2 L/kg/min of HFNC between January 2014 and December 2021 were studied retrospectively at a tertiary care children's hospital. Adverse events (aspiration pneumonia, emesis, and respiratory support escalation), nutritional goals (initiation of enteral feeds, achievement of nutritional goal volume and goal calories, percentage weight change during hospital stay) and clinical outcomes (HFNC duration, oxygen supplementation duration after HFNC, length of hospital stay following HFNC support, total length of hospital stay and follow-up for 1 month after hospital discharge) were compared between fed and non-fed patients on HFNC. Six hundred thirty-six (489 fed and 147 not-fed) bronchiolitis patients on HFNC studied. 260 patients, 317 patients and 59 patients were supported by < 1 L/kg/min, 1-2 L/kg/min and > 2 L/kg/min of HFNC, respectively. Enterally fed patients had significantly less adverse events (OR = 0.14, 95% CI 0.083 - 0.23, p < 0.001), significantly better nutritional goals: earlier initiation of enteral feeds by 65% in time (mean ratio = 0.35, 95% CI 0.28 - 0.43, p < 0.001), earlier achievement of goal volume and goal calorie needs by 14% in time (mean ratio = 0.86, 95% CI 0.78 to 0.96, p = 0.005) and significantly better clinical outcomes: shorter HFNC duration by 29.75 h (95% CI 20.19 -39.31, p < 0.001), shorter oxygen supplementation duration after HFNC by 12.14 h (95% CI 6.70 -17.59, p < 0.001), shorter length of hospital stay after HFNC support by 21.35 h (95% CI 14.71-27.98, p < 0.001) and shorter total length of hospital stay by 51.10 h (95% CI 38.65 -63.55, p < 0.001), as compared to non-fed patients, after adjusting for age, weight, prematurity, comorbidities, admission time, admission bronchiolitis score, admission respiratory rate, and HFNC levels. The number of revisits and readmissions at 7 and 30 days after hospital discharge were not significantly different (p > 0.05) between the fed and non-fed groups.    Conclusion: Enteral feeding of bronchiolitis patients supported by different levels of HFNC is associated with less adverse events and better nutrition goals and clinical outcomes. What is Known: •There is general apprehension to feed critically ill bronchiolitis patients supported by high flow nasal cannula. What is New: •Our study reveals that enteral feeding of critically ill bronchiolitis patients supported by different levels of high flow nasal cannula is associated with minimal adverse events, better nutritional goals and improved clinical outcomes as compared to non-fed patients.

A Novel Method to Improve Perfusion of Ex Vivo Pumped Human Kidneys.

OBJECTIVE: To determine if addition of the S-nitrosylating agent ethyl nitrite (ENO) to the preservation solution can improve perfusion parameters in pumped human kidneys. BACKGROUND: A significant percentage of actively stored kidneys experience elevations in resistance and decreases in flow rate during the ex vivo storage period. Preclinical work indicates that renal status after brain death is negatively impacted by inflammation and reduced perfusion-processes regulated by protein S-nitrosylation. To translate these findings, we added ENO to the preservation solution in an attempt to reverse the perfusion deficits observed in nontransplanted pumped human kidneys. METHODS: After obtaining positive proof-of-concept results with swine kidneys, we studied donated human kidneys undergoing hypothermic pulsatile perfusion deemed unsuitable for transplantation. Control kidneys continued to be pumped a 4°C (ie, standard of care). In the experimental group, the preservation solution was aerated with 50 ppm ENO in nitrogen. Flow rate and perfusion were recorded for 10 hours followed by biochemical analysis of the kidney tissue. RESULTS: In controls, perfusion was constant during the monitoring period (ie, flow rate remained low and resistance stayed high). In contrast, the addition of ENO produced significant and sustained reductions in resistance and increases in flow rate. ENO-treated kidneys had higher levels of cyclic guanosine monophosphate, potentially explaining the perfusion benefits, and increased levels of interleukin-10, suggestive of an anti-inflammatory effect. CONCLUSIONS: S-Nitrosylation therapy restored the microcirculation and thus improved overall organ perfusion. Inclusion of ENO in the renal preservation solution holds promise to increase the number and quality of kidneys available for transplant.

Fever without a source in children with congenital heart disease.

Two paediatric congenital heart disease patients presented with a brief history of low-grade fever without any focal symptoms. Their clinical features and laboratory tests were unremarkable; however, their blood cultures were positive that prompted further work-up. Infective endocarditis should be considered in any paediatric congenital heart disease patient who presents with fever without any other associated clinical features.

Lung Ultrasound Utility in the Management of the Neurologically Deceased Organ Donor.

CONTEXT: Lung transplantation is limited by donor lung availability with ∼20% of deceased donor lungs transplanted. Diagnostic testing identifying pulmonary derangements guide donor management strategies to maximize lung transplantation. Lung ultrasound (LUS) identifies pathology in critically ill patients equivalent or superior to chest radiograph (CXR) or computed tomography (CT) scans. No published studies have reported on LUS in neurologically deceased donors (DNDDs). OBJECTIVE: We evaluated LUS in identifying abnormal lung pathology in DNDDs and related these findings to the standard approach. DESIGN: Prospective pilot study. SETTING: Intensive care units, university-associated teaching hospital. PARTICIPANTS: Six DNDDs evaluated during donor management. INTERVENTIONS: Deceased donors were enrolled based on the availability of ultrasound operators (USOs). Bedside LUS was performed using Lichtenstein 3- or Volpicelli 4-zone method based on the operator preference. Lungs were evaluated for sliding, A/B profile, consolidation, or pleural fluid. Ultrasound operators were blinded to donor management data. Lung ultrasound interpretations were compared for interindividual variability. Ultrasound and anteroposterior portable CXR (AP-CXR) results were compared by Organ Procurement Organization medical directors. MEASUREMENTS AND MAIN RESULTS: Bedside LUS compared well to AP-CXRs during donor management. There was no interindividual variability noted among USOs. Lung ultrasound identified all findings on AP-CXR and additional clinical pathology not reported on AP-CXR. Reports on AP-CXRs took a median 202 (13-696) minutes to occur, with LUS results available immediately. CONCLUSIONS: Lung ultrasound may play a significant role in donor management providing real-time clinical data, allowing for rapid identification of abnormalities, and leading to management interventions that may increase the number of transplanted lungs.

Pediatric Intensive Care Unit Length of Stay Prediction by Machine Learning.

Purpose: To develop and validate machine learning models for predicting the length of stay (LOS) in the Pediatric Intensive Care Unit (PICU) using data from the Virtual Pediatric Systems (VPS) database. Methods: A retrospective study was conducted utilizing machine learning (ML) algorithms to analyze and predict PICU LOS based on historical patient data from the VPS database. The study included data from over 100 North American PICUs spanning the years 2015-2020. After excluding entries with missing variables and those indicating recovery from cardiac surgery, the dataset comprised 123,354 patient encounters. Various ML models, including Support Vector Machine, Stochastic Gradient Descent Classifier, K-Nearest Neighbors, Decision Tree, Gradient Boosting, CatBoost, and Recurrent Neural Networks (RNNs), were evaluated for their accuracy in predicting PICU LOS at thresholds of 24 h, 36 h, 48 h, 72 h, 5 days, and 7 days. Results: Gradient Boosting, CatBoost, and RNN models demonstrated the highest accuracy, particularly at the 36 h and 48 h thresholds, with accuracy rates between 70 and 73%. These results far outperform traditional statistical and existing prediction methods that report accuracy of only around 50%, which is effectively unusable in the practical setting. These models also exhibited balanced performance between sensitivity (up to 74%) and specificity (up to 82%) at these thresholds. Conclusions: ML models, particularly Gradient Boosting, CatBoost, and RNNs, show moderate effectiveness in predicting PICU LOS with accuracy slightly over 70%, outperforming previously reported human predictions. This suggests potential utility in enhancing resource and staffing management in PICUs. However, further improvements through training on specialized databases can potentially achieve better accuracy and clinical applicability.

Temporary Veno-Venous ECMO for Acute Respiratory Illness in Pediatric Berlin Heart Patient.

We report the unique case of a 2-year-old male with severe heart failure requiring mechanical circulatory support with a left ventricular assist device, who developed adenovirus pneumonitis infection requiring veno-venous extracorporeal membrane oxygenation (ECMO) support. He progressed to acute respiratory failure and refractory hypoxemia despite intubation with maximum respiratory support. The patient was placed on ECMO with improvement in lung function over four days with subsequent successful decannulation. During the ECMO run, anticoagulation required escalation given the increased circuit surface area. Patient has since recovered and undergone heart transplantation.

Inhaled nitric oxide therapy for severe hypoxemia in hyperinflated mechanically ventilated bronchiolitis patient.

Management of hospitalized bronchiolitis patients comprises supportive care including non-invasive and invasive mechanical ventilation. Inhaled nitric oxide (iNO) therapy has been used in bronchiolitis patients to manage pulmonary hypertension, acute respiratory distress syndrome, bronchoconstriction or inflammation. We report the role of iNO in management of severe hypoxemia in a 7-month-old mechanically ventilated bronchiolitis patient on 100% oxygen and high ventilator settings who had hyperinflation on chest x-ray, and diffuse bronchospasm on clinical assessment. We believe iNO improved hypoxemia in our patient by optimizing the ventilation/perfusion mismatch, decreasing dead space ventilation and relieving elevated pulmonary vascular resistance associated with alveolar overdistention. Inhaled nitric oxide therapy for severe hypoxemia in hyperinflated mechanically ventilated bronchiolitis patient.

Streptococcus Pneumoniae-Associated Hemolytic Uremic Syndrome in the Era of Pneumococcal Vaccine.

Streptococcus pneumoniae-associated hemolytic uremic syndrome (Sp-HUS) is a serious complication of invasive pneumococcal disease that is associated with increased mortality in the acute phase and morbidity in the long term. Recently, Sp-HUS definition has undergone revision and cases are categorized as definite, probable, and possible, based on less invasive serological investigations that evaluate Thomsen-Friedenreich crypt antigen (T-antigen) activation. In comparison to the pre-vaccine era, Sp-HUS incidence seems to be decreasing after the introduction of 7-serotype valence and 13-serotype valence pneumococcal vaccines in 2000 and 2010, respectively. However, Sp-HUS cases continue to occur secondary to vaccine failure and emergence of non-vaccine/replacement serotypes. No single hypothesis elucidates the molecular basis for Sp-HUS occurrence, although pneumococcal neuraminidase production and formation of T-antigen antibody complexes on susceptible endothelial and red blood cells continues to remain the most acceptable explanation. Management of Sp-HUS patients remains supportive in nature and better outcomes are being reported secondary to earlier recognition, better diagnostic tools and improved medical care. Recently, the addition of eculizumab therapy in the management of Sp-HUS for control of dysregulated complement activity has demonstrated good outcomes, although randomized clinical trials are awaited. A sustained pneumococcal vaccination program and vigilance for replacement serotypes will be the key for persistent reduction in Sp-HUS cases worldwide.

Simplified Pediatric Index of Mortality 3 Score by Explainable Machine Learning Algorithm.

Pediatric Index of Mortality 3 is a validated tool including 11 variables for the assessment of mortality risk in PICU patients. With the recent advances in explainable machine learning algorithms, we aimed to assess feasibility of application of these machine learning models to simplify the Pediatric Index of Mortality 3 scoring system in order to decrease time and labor required for data collection and entry for Pediatric Index of Mortality 3. DESIGN: Single-center, retrospective cohort study. Data from the Virtual Pediatric Systems for patients admitted to Cleveland Clinic Children`s PICU between January 2008 and December 2019 was obtained. Light Gradient Boosting Machine Regressor (a gradient boosting decision tree algorithm) was used for building the machine learning models. Variable importance was analyzed by SHapley Additive exPlanations. All of the 11 Pediatric Index of Mortality 3 variables were used as input variables in the machine learning models to predict Pediatric Index of Mortality 3 risk of mortality as the outcome variable. Mean absolute error, root mean squared error, and R-squared were calculated for each of the 11 machine learning models as model performance parameters. SETTING: Quaternary children's hospital. PATIENTS: PICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five-thousand sixty-eight patients were analyzed. The machine learning models were able to maintain similar predictive error until the number of input variables decreased to four. The machine learning model with five input variables (mechanical ventilation in the first hour of PICU admission, very-high-risk diagnosis, surgical recovery from a noncardiac procedure, low-risk diagnosis, and base excess) produced lowest mean root mean squared error of 1.49 (95% CI, 1.05-1.93) and highest R-squared of 0.73 (95% CI, 0.6-0.86) with mean absolute error of 0.43 (95% CI, 0.35-0.5) among all the 11 machine learning models. CONCLUSIONS: Explainable machine learning methods were feasible in simplifying the Pediatric Index of Mortality 3 scoring system with similar risk of mortality predictions compared to the original Pediatric Index of Mortality 3 model tested in a single-center dataset.

Acute Tracheal Necrosis After Intubation in a Childhood Onset Systemic Lupus Erythematosus.

Upper airway involvement in systemic lupus erythematosus (SLE) disease process is uncommon. A 15-year-old girl, a known patient with class IVA lupus nephritis, presented in acute renal failure due to flare-up of SLE. She underwent an uneventful elective intubation procedure for placement of a hemodialysis catheter. After 36 hours of extubation, she developed biphasic stridor and severe shortness of breath that was unresponsive to multiple medications. Prompt airway evaluation by laryngoscopy and confirmation of acute tracheal necrosis by histopathology along with reintubation and high-dose steroid therapy resulted in good outcome and recovery.

A CLUE for better assessment of donor lungs: Novel technique in clinical ex vivo lung perfusion.

BACKGROUND: The direCt Lung Ultrasound Evaluation (CLUE) technique was proven to be an accurate method for monitoring extravascular lung water in donor lungs during ex vivo lung perfusion (EVLP) in an experimental model. The aim of this study was to examine the application of CLUE in the clinical setting. METHODS: Lungs were evaluated using acellular EVLP protocol. Ultrasound images were obtained directly from the lung surface. Images were graded according to the percentage of B-lines seen on ultrasound. CLUE scores were calculated at the beginning and end of EVLP for the whole lung, each side, and lobe based on the number (No.) of images in each grade and the total No. of images taken and evaluated retrospectively. RESULTS: A total of 23 EVLP cases were performed resulting in 13 lung transplants (LTxs) with no hospital mortality. Primary graft dysfunction (PGD) occurred in only 1 recipient (PGD3, no PGD2). Significant differences were found between suitable and non-suitable lungs in CLUE scores (1.03 vs 1.85, p < 0.001), unlike the partial pressure of oxygen/fraction of inspired oxygen ratio. CLUE had the highest area under the receiver operating characteristic curve (0.98) compared with other evaluation parameters. The initial CLUE score of standard donor lungs was significantly better than marginal lungs. The final CLUE score in proned lungs showed improvement when compared with initial CLUE score, especially in the upper lobes. CONCLUSIONS: The CLUE technique shows the highest accuracy in evaluating donor lungs for LTx suitability compared with other parameters used in EVLP. CLUE can optimize the outcomes of LTx by guiding the decision making through the whole process of clinical EVLP.

DireCt Lung Ultrasound Evaluation (CLUE): A novel technique for monitoring extravascular lung water in donor lungs.

BACKGROUND: Extravascular lung water (EVLW) could change in donor lungs in a time-dependent fashion during procurement or ex-vivo lung perfusion (EVLP) and may vary across different zones. Current techniques for EVLW assessment are either subjective, general estimation, or not feasible in the clinical setting. An accurate and non-invasive diagnostic tool for EVLW would be desirable for donor lung assessment and management. Therefore, we studied the feasibility and accuracy of direCt Lung Ultrasound Evaluation (CLUE) technique. METHODS: Eleven lungs were utilized for the human model and 6 lungs for the porcine model. Lungs underwent EVLP for 2 hours. In CLUE, ultrasound images were taken directly from the lungs. A scoring system was created for each point based on the percentage of B-lines. Images were graded according to the degree of edema. An equation was used to calculate total lung and lobe scores based on number of images of each grade. RESULTS: CLUE point score correlated with wet/dry ratio in human and porcine models (n = 99, r = 0.863, p < 0.001; and n = 31, r = 0.916, p < 0.001, respectively). CLUE total lung score correlated with lung weight (n = 19, r = 0.812, p < 0.001; and n = 12, r = 0.895, p < 0.001, respectively). CLUE lobe score correlated negatively with partial pressure of oxygen/fraction of inspired oxygen ratio in the human model (n = 20, r = -0.775, p < 0.001). CONCLUSIONS: EVLW monitoring in donor lungs with CLUE after procurement is feasible and CLUE scores were found to be significantly correlated with lung weight, wet/dry, and PaO2/FIO2 ratio.

Varicella with stridor: think group A streptococcal epiglottitis.

Bacterial superinfection complicating varicella is not uncommon, but airway complications are rare. We report a case of varicella in a 2-year-old boy complicated by life-threatening stridor secondary to group A streptococcal epiglottitis.

Interleukin 10 extends the effectiveness of standard therapy during late sepsis with serum interleukin 6 levels predicting outcome.

Patients with septic shock often display features of T cell hyporesponsiveness and immune suppression, which, if persistent, are associated with increased mortality. In the murine cecal ligation and puncture (CLP) model of sepsis, we previously reported that early treatment with the anti-inflammatory cytokine interleukin 10 (IL-10) delays the onset of irreversible shock, defined as the time at which rescue surgery to remove the necrotic cecum is no longer effective. Because IL-10 can be immunostimulatory for T cells, we hypothesized that in the CLP model, late IL-10 treatment after removal of the infectious nidus at the onset of irreversible shock would restore T cell responsiveness and increase survival. C57BL/6J mice were subjected to lethal CLP with and without rescue surgery, concurrent with IL-10 treatment, at the onset of irreversible shock. Survival and serum IL-6 levels were measured as markers of the response to treatment. Ten hours after intervention, all groups exhibited T cell hyporesponsiveness marked by impaired interferon (IFN)-gamma production by Con A-stimulated splenocytes. IL-6 levels at 10 h were related to outcome independent of treatment. By 25 h after intervention, only the dual treatment group of cecal removal and IL-10 exhibited T cell responsiveness that was similar to pre-CLP levels (P = 0.26) and had a 7-day survival of 90% (P < or = 0.002 compared with all other groups). Thus, even in the advanced stages of septic shock when standard therapies fail, treatment with IL-10 extends the therapeutic window. For an individual mouse, the efficacy of such treatment may be predicted by an early postintervention IL-6 level.

Ischemia/reperfusion: a clinically relevant model of intestinal injury yielding systemic inflammation.

BACKGROUND/PURPOSE: Multisystem organ failure (MSOF) is a major cause of morbidity and mortality in the critically ill patient. Animal models of endotoxin-induced sepsis were used to develop therapeutic regimens, which thus far have failed in clinical trials. Because multiple etiologies of MSOF affect the intestine, the authors hypothesized that during sepsis the gut may act as a possible trigger of the inflammatory cascade. As ischemia and reperfusion of the small intestine disrupts gut barrier function, thereby activating systemic inflammatory responses, the authors evaluated a murine model of ischemia/reperfusion to investigate these systemic responses to local mucosal and epithelial injury. METHODS: C57BL/10 and Balb/c mice underwent variable amounts of gut ischemia by superior mesenteric artery occlusion. Animals were evaluated for survival as well as gross and microscopic intestinal damage. RESULTS: Maximal ischemic damage occurred in the distal jejunum and proximal ileum. More severe epithelial damage and transmural inflammation were observed in C57BL/10 mice, which correlated with a higher mortality. CONCLUSIONS: This model mimics what is observed clinically with intestinal injury resulting from a progressive ischemic insult with eventual systemic manifestations. This reproducible model of systemic inflammation elicits variable responses from genetically different animals, the results of which may lead to a better understanding of MSOF.

Interleukin-10 controls the onset of irreversible septic shock.

Lethality from sepsis is believed to be mediated by a proinflammatory cytokine cascade, yet blocking the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) fails to prevent mortality in human disease and a mouse model of sepsis induced by cecal ligation and puncture (CLP). The role of the antiinflammatory cytokine IL-10 in the CLP model of sepsis is unclear, with either protective or harmful effects demonstrated, depending upon the time of intervention. We therefore hypothesize that IL-10 functions as a temporal regulator of the transition from early reversible sepsis to the late phase of irreversible shock. Transition from reversible sepsis to irreversible shock in the CLP model was defined as the time when removal of the necrotic cecum by rescue surgery is no longer effective. We subjected IL-10-deficient (IL-10(-/-)) and wild-type (IL-10(+/+)) mice to CLP and monitored the progression of sepsis, the onset of irreversible shock, and mortality. Onset of lethality in IL-10(-/-) mice occurred significantly earlier than in IL-10(+/+) mice and was associated with 15-fold-higher serum levels of TNF-alpha and IL-6. Consistent with these findings, the efficacy of rescue surgery after lethal CLP is lost 10 h earlier in IL-10(-/-) mice than in IL-10(+/+) mice. Treatment with recombinant human IL-10 5 h after CLP significantly improved survival and lengthened the therapeutic window for rescue surgery in both strains of mice. These results demonstrate that IL-10 controls the onset of irreversible septic shock after CLP.

Persistent elevation of serum interleukin-6 in intraabdominal sepsis identifies those with prolonged length of stay.

BACKGROUND/PURPOSE: Elevated serum interleukin-6 (IL-6) levels in patients with intraabdominal sepsis have been associated with increased morbidity and mortality. The authors hypothesized that after surgical intervention a persistent elevation of IL-6 would more accurately reflect the inflammatory state and thus predict the subsequent time to recovery better than the preoperative value alone. METHODS: Nineteen consecutive children with peritonitis and manifestations of the systemic inflammatory response syndrome were enrolled prospectively. IL-6 levels were determined from pre- and postoperative serum samples (within 12 to 24 hours) by enzyme-linked immunosorbant assay (ELISA). Patient postoperative length of stay (LOS) was recorded. RESULTS: Before surgery, patient serum IL-6 levels ranged from 48 to 132,546 pg/mL. LOS ranged from 4 to 60 days, with subjects falling into 2 groups of < or =11 (n = 14) and > or =25 (n = 5) days. Using an IL-6 level greater than 500 pg/mL to predict a prolonged LOS (>11 days), a persistent elevation of IL-6 postoperatively appears to increase the likelihood of a prolonged LOS. CONCLUSIONS: Persistent IL-6 levels greater than 500 pg/mL may be useful in identifying pediatric intraabdominal sepsis patients with prolonged LOS and presumably greater morbidity. Rapid identification of these patients may allow for novel therapeutic interventions.