Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.

BACKGROUND: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT). METHODS: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort). RESULTS: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91). CONCLUSION: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources.

Lithium-Induced Awakening of Neural Cell Memory of Involuntary Dyskinesia: A Case Report.

Involuntary movement disorders include tremors, tics, myoclonus, athetosis, chorea, dystonia, and dyskinesia. Neuroleptic drugs have the propensity to cause extrapyramidal side effects. Lithium-induced coarse tremors are well documented and may occur at therapeutic serum concentrations (0.8-1.0 mEq/L) in the treatment of bipolar disorder. Treatment for coarse tremors due to lithium includes either dose reduction or non-selective beta-blockers. To our knowledge, there are only four case reports regarding the lithium-induced awakening of cell memory of involuntary movement disorders worldwide. In scientific literature, only two drugs have the propensity to reawaken past cell memory. These intriguing findings can have a wider application across fields such as past-life regression therapy, post-traumatic stress disorder, catharsis, or recall of sub-aural temporal high-frequency burst-erased memory-type of mind-altering techniques. We report a case of lithium-induced awakening of the cell memory of involuntary dyskinesia in a female who took treatment for bipolar disorder in the past.

Pediatric Swine Model of Methicillin-Resistant Staphylococcus aureus Sepsis-Induced Coagulopathy, Disseminated Microvascular Thrombosis, and Organ Injuries.

Sepsis-induced coagulopathy leading to disseminated microvascular thrombosis is associated with high mortality and has no existing therapy. Despite the high prevalence of Gram-positive bacterial sepsis, especially methicillin-resistant Staphylococcus aureus (MRSA), there is a paucity of published Gram-positive pediatric sepsis models. Large animal models replicating sepsis-induced coagulopathy are needed to test new therapeutics before human clinical trials. HYPOTHESIS: Our objective is to develop a pediatric sepsis-induced coagulopathy swine model that last 70 hours. METHODS AND MODELS: Ten 3 weeks old piglets, implanted with telemetry devices for continuous hemodynamic monitoring, were IV injected with MRSA (n = 6) (USA300, Texas Children's Hospital 1516 strain) at 1 × 109 colony forming units/kg or saline (n = 4). Fluid resuscitation was given for heart rate greater than 50% or mean arterial blood pressure less than 30% from baseline. Acetaminophen and dextrose were provided as indicated. Point-of-care complete blood count, prothrombin time (PT), activated thromboplastin time, d-dimer, fibrinogen, and specialized coagulation assays were performed at pre- and post-injection, at 0, 24, 48, 60, and 70 hours. Piglets were euthanized and necropsies performed. RESULTS: Compared with the saline treated piglets (control), the septic piglets within 24 hours had significantly lower neurologic and respiratory scores. Over time, PT, d-dimer, and fibrinogen increased, while platelet counts and activities of factors V, VII, protein C, antithrombin, and a disintegrin and metalloproteinase with thrombospondin-1 motifs (13th member of the family) (ADAMTS-13) decreased significantly in septic piglets compared with control. Histopathologic examination showed minor focal organ injuries including microvascular thrombi and necrosis in the kidney and liver of septic piglets. INTERPRETATIONS AND CONCLUSIONS: We established a 70-hour swine model of MRSA sepsis-induced coagulopathy with signs of consumptive coagulopathy, disseminated microvascular thrombosis, and early organ injuries with histological minor focal organ injuries. This model is clinically relevant to pediatric sepsis and can be used to study dysregulated host immune response and coagulopathy to infection, identify potential early biomarkers, and to test new therapeutics.

Elevated bile acids are associated with left ventricular structural changes in biliary atresia.

BACKGROUND: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood. METHODS: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5. RESULTS: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry. CONCLUSION: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.

The use of tracheostomy to support critically ill children receiving orthotopic liver transplantation: a single-center experience.

BACKGROUND: Children with end-stage liver disease and multi-organ failure, previously considered as poor surgical candidates, can now benefit from liver transplantation (LT). They often need prolonged mechanical ventilation (MV) post-LT and may need tracheostomy to advance care. Data on tracheostomy after pediatric LT are lacking. METHOD: Retrospective chart review of children who required tracheostomy in the peri-LT period in a large, freestanding quaternary children's hospital from 2014 to 2019. RESULTS: Out of 205 total orthotopic LTs performed in 200 children, 18 (9%) required tracheostomy in the peri-transplant period: 4 (2%) pre-LT and 14 (7%) post-LT. Among those 14 needing tracheostomy post-LT, median age was 9 months [IQR = 7, 14] at LT and 10 months [9, 17] at tracheostomy. Nine (64%) were infants and 12 (85%) were cirrhotic at the time of LT. Seven (50%) were intubated before LT. Median MV days prior to LT was 23 [7, 36]. Eight (57%) patients received perioperative continuous renal replacement therapy (CRRT). The median MV days from LT to tracheostomy was 46 [33, 56]; total MV days from initial intubation to tracheostomy was 57 [37, 66]. Four (28%) children died, of which 3 (21%) died within 1 year of transplant. Total ICU and hospital length of stay were 92 days [I72, 126] and 177 days [115, 212] respectively. Among survivors, 3/10 (30%) required MV at home and 8/10 (80%) were successfully decannulated at 400 median days [283, 584]. CONCLUSION: Tracheostomy though rare after LT remains a feasible option to support and rehabilitate critically ill children who need prolonged MV in the peri-LT period.

Two to Tango: Kidney-Lung Interaction in Acute Kidney Injury and Acute Respiratory Distress Syndrome.

Acute Kidney Injury (AKI) is an independent risk factor for mortality in hospitalized patients. AKI syndrome leads to fluid overload, electrolyte and acid-base disturbances, immunoparalysis, and propagates multiple organ dysfunction through organ "crosstalk". Preclinical models suggest AKI causes acute lung injury (ALI), and conversely, mechanical ventilation and ALI cause AKI. In the clinical setting, respiratory complications are a key driver of increased mortality in patients with AKI, highlighting the bidirectional relationship. This article highlights the challenging and complex interactions between the lung and kidney in critically ill patients with AKI and acute respiratory distress syndrome (ARDS) and global implications of AKI. We discuss disease-specific molecular mediators and inflammatory pathways involved in organ crosstalk in the AKI-ARDS construct, and highlight the reciprocal hemodynamic effects of elevated pulmonary vascular resistance and central venous pressure (CVP) leading to renal hypoperfusion and pulmonary edema associated with fluid overload and increased right ventricular afterload. Finally, we discuss the notion of different ARDS "phenotypes" and the response to fluid overload, suggesting differential organ crosstalk in specific pathological states. While the directionality of effect remains challenging to distinguish at the bedside due to lag in diagnosis with conventional renal function markers and lack of tangible damage markers, this review provides a paradigm for understanding kidney-lung interactions in the critically ill patient.

Comparison of In Vitro to In Vivo Extrapolation Approaches for Predicting Transporter-Mediated Hepatic Uptake Clearance Using Suspended Rat Hepatocytes.

Clearance (CL) prediction remains a significant challenge in drug discovery, especially when complex processes such as drug transporters are involved. The present work explores various in vitro to in vivo extrapolation (IVIVE) approaches to predict hepatic CL driven by uptake transporters in rat. Broadly, two different IVIVE methods using suspended rat hepatocytes were compared: initial uptake CL (PSu,inf) and intrinsic metabolic CL (CLint,met) corrected by unbound hepatocytes to medium partition coefficient (Kpuu). Kpuu was determined by temperature method (Temp Kpuu,ss), homogenization method (Hom Kpuu,ss), and initial rate method (Kpuu,V0). In addition, the impact of bovine serum albumin (BSA) on each of these methods was investigated. Twelve compounds, which are known substrates of organic anion-transporting polypeptides representing diverse chemical matter, were selected for these studies. As expected, CLint,met alone significantly underestimated hepatic CL for all the test compounds. Overall, predicted hepatic CL using PSu,inf with BSA, Hom Kpuu,ss with BSA, and Temp Kpuu,ss showed the most robust correlation with in vivo rat hepatic CL. Adding BSA improved hepatic CL prediction for selected compounds when using the PSu,inf and Hom Kpuu,ss methods, with minimal impact on the Temp Kpuu,ss and Kpuu,V0 methods. None of the IVIVE approaches required an empirical scaling factor. These results suggest that supplementing rat hepatocyte suspension with BSA may be essential in drug discovery research for novel chemical matters to improve CL prediction. SIGNIFICANCE STATEMENT: The current investigation demonstrates that hepatocyte uptake assay supplemented with 4% bovine serum albumin is a valuable tool for estimating unbound hepatic uptake clearance (CL) and Kpuu. Based upon the extended clearance concept, direct extrapolation from these in vitro parameters significantly improved the overall hepatic CL prediction for organic anion-transporting polypeptide substrates in rat. This study provides a practical in vitro to in vivo extrapolation strategy for predicting transporter-mediated hepatic CL in early drug discovery.

Minimal Change in Cardiac Index With Increasing PEEP in Pediatric Acute Respiratory Distress Syndrome.

Objective: To determine if increasing positive end expiratory pressure (PEEP) leads to a change in cardiac index in children with Pediatric Acute Respiratory Distress Syndrome ranging from mild to severe. Design: Prospective interventional study. Setting: Multidisciplinary Pediatric Intensive Care Unit in a University teaching hospital. Patients: Fifteen intubated children (5 females, 10 males) with a median age of 72 months (IQR 11, 132) and a median weight of 19.3 kg (IQR 7.5, 53.6) with a severity of Pediatric Acute Respiratory Distress Syndrome that ranged from mild to severe with a median lung injury score of 2.3 (IQR 2.0, 2.7). Measurements: Cardiac index (CI) and stroke volume (SV) were measured on baseline ventilator settings and subsequently with a PEEP 4 cmH2O higher than baseline. Change in CI and SV from baseline values was evaluated using Wilcoxon signed rank test. Results: A total of 19 paired measurements obtained. The median baseline PEEP was 8 cmH2O (IQR 8, 10) Range 6-14 cmH2O. There was no significant change in cardiac index or stroke volume with change in PEEP. Baseline median CI 4.4 L/min/m2 (IQR 3.4, 4.8) and PEEP 4 higher median CI of 4.3 L/min/m2 (IQR 3.6, 4.8), p = 0.65. Baseline median SV 26 ml (IQR 13, 44) and at PEEP 4 higher median SV 34 ml (IQR 12, 44) p = 0.63. Conclusion: There is no significant change in cardiac index or stroke volume with increasing PEEP by 4 cmH2O in a population of children with mild to severe PARDS. Clinical Trial Registration: The study is registered on Clinical trails.gov under the Identifier: NCT02354365.

Extracorporeal Cardiopulmonary Resuscitation After Diphenhydramine Ingestion.

INTRODUCTION: Diphenhydramine is a widely used first-generation histamine (H1) antagonist that can be obtained without prescription in many countries. Massive ingestions can result in severe toxicity and even death. We describe a case of diphenhydramine overdose leading to cardiac arrest, cardiopulmonary resuscitation (CPR), and extracorporeal membrane oxygenation (ECMO) cannulation for refractory ventricular fibrillation, a process we refer to as extracorporeal cardiopulmonary resuscitation (ECPR). CASE REPORT: Responding to a call for altered mental status, emergency medical service (EMS) personnel found an unconscious and seizing 17-year-old male. He had reportedly developed generalized tonic-clonic seizures and dysrhythmias after ingesting approximately 800 25-mg diphenhydramine tablets. He was transferred to our pediatric intensive care unit (PICU) after stabilization at a local emergency center. After approximately 7 hours of clinical stability and normalization of cardiac rhythm, electrolytes, and acidosis, he developed renewed seizure activity and accelerated ventricular rhythm leading to hemodynamic collapse and cardiac arrest. He was cannulated for veno-arterial extracorporeal membrane oxygenation (VAECMO) with CPR in progress. A pharmacobezoar located in his stomach was presumed to be the cause of his biphasic clinical deterioration. After 5 days, the patient was successfully weaned from ECMO support. Ten days later, his convalescence continued in the step-down unit and was discharged with good functional outcome. DISCUSSION: Significant ingestion of anticholinergic substances is often fatal. This case describes a favorable outcome after ECPR and aggressive supportive management following a large intentional overdose of diphenhydramine.

Change in Oxygen Consumption Following Inhalation of Albuterol in Comparison with Levalbuterol in Healthy Adult Volunteers.

BACKGROUND: Albuterol is the most commonly used ß agonist to treat reversible lower airway obstruction. Albuterol contains a racemic mixture of two enantiomers. Levalbuterol contains the single R form enantiomer. Levalbuterol is frequently prescribed to limit cardiovascular toxicity. OBJECTIVE: We examined changes in oxygen consumption (V'O2) and heart rate (HR) following administration of albuterol and levalbuterol. METHODS: This is a prospective, randomized, single-blinded, controlled study of healthy adult volunteers. Subjects separately received albuterol (5 mg) and levalbuterol (2.5 mg) aerosolized over 15 min. V'O2 and vital signs were measured before the medications and 5, 10, 20, 40, and 60 min after. RESULTS: We enrolled 24 volunteers with a median age of 32 years. Compared to baseline, there was a significant maximum increase in V'O2 following administration of both albuterol (median 17% (1, 3 IQR 9, 43%) p < 0.001) and levalbuterol (median 23% (1, 3 IQR 10, 32%) p < 0.001). There was no significant difference between the maximum increase in V'O2 following administration of albuterol compared to levalbuterol (p = 0.57). Compared to baseline, there was a significant maximal increase in HR with both albuterol (median 30% (1, 3 IQR 19, 43%) p < 0.001) and levalbuterol (median 23% (1, 3 IQR 19, 31%) p < 0.001). There was a statistically significant greater increase in maximal HR following administration of albuterol as compared to levalbuterol (p = 0.009). CONCLUSION: Albuterol and levalbuterol both cause a significant increase in V'O2 and HR. There was no significant difference between albuterol and levalbuterol regarding the maximum increase in V'O2. There was a statistically significant but likely clinically insignificant difference in maximum increase in HR in patients with adequate oxygen delivery when comparing albuterol to levalbuterol.