Ketorolac Dosing and Outcomes in Neonates Following Congenital Heart Surgery: A Retrospective Analysis.

BACKGROUND: Pain management is essential for postoperative surgery. Given the association of opioids with adverse outcomes, interest in the use of nonopioid analgesics, such as ketorolac, has increased. Published data on use in neonates are limited. OBJECTIVES: To describe ketorolac dosing and safety and efficacy outcomes in the first 48 hours postcardiac surgery in neonates. DESIGN: We performed a single-center retrospective cohort study of neonates (ages < 28 d) who received ketorolac following cardiac surgery from November 2020 to July 2023 (inclusive). The primary safety outcome was a clinically significant decline in renal function, as defined by the composite of an increase in serum creatinine by greater than or equal to 0.3 mg/dL from baseline within 96 hours of ketorolac initiation and urine output less than or equal to 0.5 mL/kg/hr for 6 hours. The secondary safety outcome was clinically significant bleeding, defined as the composite of major bleeding by the International Society on Thrombosis and Hemostasis pediatric criteria and severe/fatal bleeding by the criteria of Nellis et al (2019). Efficacy was measured by opioid utilization based on a standardized pain score-driven analgesia protocol. INTERVENTIONS: Ketorolac was administered at 0.5 mg/kg every 6 hours as per an institutional clinical management algorithm. MEASUREMENTS AND MAIN RESULTS: Thirty-nine patients met the eligibility criteria. The median ketorolac dose was 0.5 mg/kg/dose, and median (interquartile range [IQR]) duration of therapy was 48 hours (6-48 hr). No patients experienced a significant decline in renal function, and there were no clinically significant bleeding events. The median (IQR) IV morphine milligram equivalents (MMEs)/kg/d of opioid administration was 0.2 MME/kg/d (0.1-0.25 MME/kg/d) at the time of ketorolac initiation and 0.1 MME/kg/d (0.1-0.2 MME/kg/d) at 48 hours post-ketorolac initiation. CONCLUSIONS: If validated prospectively, these findings suggest that a ketorolac regimen of 0.5 mg/kg/dose every 6 hours in neonates postcardiac surgery may be safe with regard to renal function and bleeding risk. Additional randomized studies would be needed to determine efficacy with regard to opioid-sparing capacity.

Higher Cumulative Dose of Opioids and Other Sedatives are Associated with Extubation Failure in Norwood Patients.

BACKGROUND: The primary purpose of this study is to evaluate the relationship between sedation usage and extubation failure, and to control for the effects of hemodynamic, oximetric indices, clinical characteristics, ventilatory settings pre- and post-extubation, and echocardiographic (echo) findings in neonates with hypoplastic left heart syndrome (HLHS) post-Norwood procedure. METHODS: Single-center, retrospective analysis of Norwood patients during their first extubation post-surgery from January 2015 to July 2021. Extubation failure was defined as reintubation within 48 h of extubation. Demographics, clinical characteristics, ventilatory settings, echo findings (right ventricular function, tricuspid regurgitation), and cumulative dose of sedation medications before extubation were compared between patients with successful or failed extubation. RESULTS: The analysis included 130 patients who underwent the Norwood procedure with 121 (93%) successful and 9 (7%) failed extubations. Univariate analyses showed that vocal cord anomaly (p = 0.05), lower end-tidal CO2 (p < 0.01), lower pulse-to-respiratory quotient (p = 0.02), and ketamine administration (p = 0.04) were associated with extubation failure. The use of opioids, benzodiazepines, dexmedetomidine, and ketamine are mutually correlated in this cohort. On multivariable analysis, the vocal cord anomaly (OR = 7.31, 95% CI 1.25-42.78, p = 0.027), pre-extubation end-tidal CO2 (OR = 0.80, 95% CI 0.65-0.97, p = 0.025), and higher cumulative dose of opioids (OR = 10.16, 95% CI 1.25-82.43, p = 0.030) were independently associated with extubation failure while also controlling for post-extubation respiratory support (CPAP/BiPAP/HFNC vs NC), intubation length, and echo results. CONCLUSION: Higher cumulative opioid doses were associated with a greater incidence of extubation failure in infants post-Norwood procedure. Therefore, patients with higher cumulative doses of opioids should be more closely evaluated for extubation readiness in this population. Low end-tidal CO2 and low pulse-to-respiratory quotient were also associated with failed extubation. Consideration of the pulse-to-respiratory quotient in the extubation readiness assessment can be beneficial in the Norwood population.

Pediatric Extracorporeal Membrane Oxygenation Anticoagulation and Monitoring: Where We Were and Where Are We Now?

Extracorporeal membrane oxygenation (ECMO) support in neonates and pediatric patients has continued to advance. In addition to technologic progress, there is a growing interest in the anticoagulation agents and laboratory monitoring strategies used in children requiring ECMO support. This review summarizes current available evidence and provides guidance for clinicians regarding anticoagulation agents and monitoring.

Dosing, Monitoring, Blood Product Utilization, and Thromboembolic Complications of Four-Factor Prothrombin Complex Concentrate as Part of an Institutional Protocol in Pediatric Cardiac Surgery: A Retrospective Cohort Study.

Pediatric cardiac surgery patients are predisposed to blood loss. Blood product administration can lead to complications. Prothrombin complex concentrates (PCCs) offer potential advantages of factor composition, small volume, decreased immunogenicity/infectious risks, and accessibility. The objective of this study was to describe dosing, monitoring, blood product utilization, and thromboembolic complications of administering four-factor PCC (4F-PCC) in pediatric cardiac surgery. We performed a retrospective review of patients aged <18 years undergoing cardiac surgery from June 2020 to May 2022 (inclusive) who received 4F-PCC. Outcomes of interest included 4F-PCC dosing (units/kg) and number of doses administered, chest tube output, blood product administration, donor exposure, length of stay, and thromboembolic events. Eighty-six patients met eligibility criteria. The median (range) age and weight were 0.37 (0.01-16.3) years and 5.3 (1.6-98) kg, respectively. Median (range) total 4F-PCC dose per patient was 25 (9.2-50) units/kg, with 6 patients (7%) receiving a total of two doses. Median (range) 24-hour postoperative packed red blood cells, platelet, plasma, and cryoprecipitate administration volumes were 0 (0-2.57) mL/kg/24 h, 0 (0-1.09), 0 (0-2.64), and 0 (0-0.28 mL/kg/24 h), respectively. Median (range) length of stay and 24-hour postoperative chest tube output were 10 (6-26) days and 1.1 (0.1-4.2) mL/kg/h, respectively. Two (2%) patients experienced a thromboembolic event within 30 days of 4F-PCC administration. These retrospective findings suggest no worsening of hemostatic parameters, a mild median improvement in fibrinogen, low blood product utilization, and low thromboembolism rates following 4F-PCC use in pediatric cardiac surgery.

Ketorolac in neonates and infants following congenital heart surgery: a retrospective review.

INTRODUCTION: Pain management is essential in the immediate post-surgical period. We sought to describe the ketorolac dose regimen in neonates and infants following cardiac surgery. Secondary outcomes included renal dysfunction, bleeding, and pain management. METHODS: We performed a single-centre retrospective cohort study of neonates and infants (aged < 12 months) who received ketorolac following cardiac surgery, from November 2020 through November 2021 (inclusive). Ketorolac was administered at 0.5 mg/kg every 6 hours. Safety was defined by absence of a clinically significant decline in renal function (i.e., increase in serum creatinine [SCr] by ≥ 0.3 mg/dL from baseline within 48 hours and/or urine output ≤ 0.5 mL/kg/hour for 6 hours) and absence of clinically significant bleeding defined as major by International Society on Thrombosis and Hemostasis paediatric criteria or Severe/Fatal Bleeding Events by Nellis et al. Efficacy measures included pain scores and opioid utilisation. RESULTS: Fifty-five patients met eligibility criteria. The median (range) dose and duration of ketorolac administration was 0.5 mg/kg/dose for 48 (6-90) hours. Among all patients, there was not a statistically significant difference observed in median SCr within 48 hours of baseline (p > .9). There were no major or severe bleeding events. The median (range) opioid requirements (morphine intravenous equivalents per kg per day) at 48 hours post-ketorolac initiation was 0.1 (0-0.8) mg/kg/day. CONCLUSIONS: If validated prospectively, these findings suggest that a ketorolac regimen 0.5 mg/kg/dose every 6 hours in neonates and infants post-cardiac surgery may be safe with regard to renal function and bleeding risk, and effective regarding opioid-sparing capacity.

Pharmacist Avoidance or Reductions in Medical Costs in Critically and Emergently Ill Pediatrics: PHARM-PEDS Study.

OBJECTIVES: To comprehensively classify interventions performed by pediatric critical care clinical pharmacists and quantify cost avoidance (CA) generated through their accepted interventions. DESIGN: A multicenter, prospective, observational study performed between August 2018 and January 2019. SETTING: Academic and community hospitals in the United States with pediatric critical care units. SUBJECTS: Pediatric clinical pharmacists. INTERVENTIONS: Pharmacist recommendations were classified into one of 38 total intervention categories associated with CA. MEASUREMENTS AND MAIN RESULTS: Nineteen pediatric pharmacists at five centers documented 1,458 accepted interventions during 112 shifts on 861 critically ill pediatric patients. This calculated to an associated CA of $450,590. The accepted interventions and associated CA in the six established categories included as follows: adverse drug event prevention (155 interventions, $118,901 CA), resource utilization (267 interventions; $59,020), individualization of patient care (898 interventions, $217,949 CA), prophylaxis (8 interventions, $453 CA), hands-on care (30 interventions, $35,509 CA), and administrative/supportive tasks (108 interventions, $18,758 CA). The average associated CA was $309 per accepted intervention, $523 per patient day, and $4,023.13 per pediatric clinical pharmacist shift. The calculated potential annualized CA of accepted interventions from a pediatric pharmacist was $965,550, resulting in a potential monetary-associated CA-to-pharmacist salary ratio between $1.5:1 and $5.2:1. CONCLUSIONS: There is potential for significant avoidance of healthcare costs when pediatric pharmacists are involved in the care of critically and emergently ill pediatric patients, with a monetary potential CA-to-pediatric pharmacist salary ratio to be between $1.5:1 and $5.2:1.

Anticoagulation with Intravenous Direct Thrombin Inhibitors in Pediatric Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature.

Although intravenous (IV) direct thrombin inhibitors (DTI) have gained interest in pediatric extracorporeal membrane oxygenation (ECMO), dosing and safety information is limited. The objective of this systematic review was to characterize DTI types, dosing, monitoring, and outcomes (bleeding and thromboembolic) in pediatric ECMO patients managed with IV DTIs. We conducted searches of MEDLINE (Ovid) and Embase (Elsevier) from inception through December 2022. Case reports, retrospective studies, and prospective studies providing per-patients or summary data for patient(s) <18 years of age receiving IV DTI for ECMO anticoagulation were included. Study selection and data extraction were conducted independently by two reviewers. A total of 28 studies: 14 case reports, 13 retrospective studies, and 1 prospective study were included, totaling 329 patients. Bivalirudin was utilized in 318 (96.7%), argatroban in 9 (2.7%), and lepirudin in 2 (0.6%) patients. Infusion dosing included: bivalirudin 0.14 ± 0.37 mg/kg/h, argatroban 0.69 ± 0.73 µg/kg/min, lepirudin 0.14 ± 0.02 mg/kg/h. Laboratory monitoring tests utilized were the activated clotting time, activated partial thromboplastin time (aPTT), diluted thrombin time, and thromboelastography measures. The aPTT was utilized in most patients (95%). Thromboembolism, bleeding, or death were observed in 17%, 17%, and 23% of bivalirudin, argatroban, and lepirudin patients, respectively. Bivalirudin appears to be the most frequently used DTI in pediatric ECMO. Dosing and laboratory monitoring varied, and bleeding and thromboembolic events were reported in 17% of patients. Prospective studies are warranted to establish dosing, monitoring, safety, and efficacy of bivalirudin and other IV DTI in pediatric ECMO.

Sotalol in neonates for arrhythmias: Dosing, safety, and efficacy.

INTRODUCTION: Various agents may be utilized to manage supraventricular tachycardia (SVT) in neonates and infants. Recently, sotalol has piqued interest given its reported success in managing neonates and infants with SVTs, especially with the intravenous formulation. While the manufacturer recommends using an age-related nomogram in neonates and young infants to guide doses, clinical reports describe various dosing based on weight (mg/kg) or on body surface area (BSA) in mg/m2 . Given the reported variation in clinical practice with regard to dosing in neonates, there is a gap in the literature and translation into clinical practice regarding applicability of the nomogram into clinical practice. The purpose of this study was to describe sotalol doses based on body weight and BSA in neonates for SVT. METHODS: This is a single center retrospective study evaluating effective sotalol dosing from January 2011 and June 2021 (inclusive). Neonates who received intravenous (IV) or oral (PO) sotalol for SVT were eligible for inclusion. The primary outcome was to describe sotalol doses based on body weight and BSA. Secondary outcomes include comparison of doses to the manufacturer nomogram, description of dose titrations, reported adverse outcomes, and change in therapy. Two-sided Wilcoxon signed-rank tests were used to determine statistically significant differences. RESULTS: Thirty-one eligible patients were included in this study. The median (range) age and weight were 16.5 (1-28) days and 3.2 (1.8-4.9) kg, respectively. The median initial dose was 7.3 (1.9-10.8) mg/kg or 114.3 (30.9-166.7) mg/m2 /day. Fourteen (45.2%) of patients required a dose increase for SVT control. The median dose required for rhythm control was 8.5 (2-14.8) mg/kg/day or 120.7 (30.9-225) mg/m2 /day. Of note, the median recommended dose per manufacturer nomogram for our patients would have been 51.3 (16.2-73.8) mg/m2 /day, which is significantly lower than both the initial dose (p < .001) and final doses (p < .001) utilized in our study. A total of 7 (22.9%) patients were uncontrolled on sotalol monotherapy using our dosing regimen. Two patients (6.5%) had reports of hypotension and one patient (3.3%) had a report of bradycardia requiring discontinuation of therapy. The average change in baseline QTC following sotalol initiation was 6.8%. Twenty-seven (87.1%), 3 (9.7%), 1 (3.3%) experienced prolongation, no change, or a decrease in QTc, respectively. CONCLUSIONS: This study demonstrates that a sotalol strategy significantly higher than the manufacture dose recommendations are required for rhythm control in neonates with SVT. There were few adverse events reported with this dosing. Further prospective studies would be advantageous to confirm these findings.

Basiliximab therapy for immune-mediated bowel disease in a pediatric heart transplant patient.

In pediatric patients who undergo heart transplantation, severe immune-mediated bowel disease has been reported. Management is complex, and there are little data discussing the use of basiliximab for immune-mediated bowel disease. This case report discusses a pediatric patient who developed immune-mediated bowel disease following heart transplantation and was successfully managed with basiliximab.

Venous Thromboembolism among Noncritically Ill Hospitalized Children: Key Considerations for the Pediatric Hospital Medicine Specialist.

Venous thromboembolism (VTE) is a leading cause of morbidity and preventable harm among noncritically ill hospitalized children. Several clinical factors relevant to the noncritically ill hospitalized child significantly increase the risk of VTE including the presence of central venous catheters, systemic inflammation, and prolonged immobilization. Although risk mitigation strategies have been described, the diagnosis, treatment, and prevention of VTE require standardization of institutional practices combined with multidisciplinary collaboration among pediatric hospitalists, hematologists, and other care providers. In this narrative review, we summarize the epidemiology of VTE, risk models identifying high-risk conditions associated with VTE, and prevention and treatment strategies. We further describe successful quality improvement efforts implementing institutional VTE risk stratification and thromboprophylaxis procedures. Finally, we highlight unique challenges facing pediatric hospital medicine specialists in the era of the COVID-19 pandemic, including caring for adults admitted to pediatric hospital units, and describe future research opportunities for VTE in the noncritically ill hospitalized child.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature.

Venous thromboembolism (VTE) in children can lead to significant morbidity and mortality. Traditionally, treatment for thrombotic events in pediatric patients has been limited mainly to unfractionated heparin, low-molecular-weight heparin (LMWH), or vitamin K antagonists. Since the first non-vitamin K antagonist oral anticoagulant (NOAC) was approved for adult use, these agents have gained popularity for a variety of indications. This is largely due to their ease of administration, favorable pharmacokinetic and pharmacodynamic profile, decreased food interactions, and decreased need for therapeutic drug monitoring. Treating and preventing VTE with traditional anticoagulants in pediatric patients presents many challenges. This systematic review evaluated the current literature regarding pediatric NOAC trials. Additionally, based on an up-to-date query of clinicaltrials.gov, we detail current ongoing and as-yet unpublished clinical trials, study outcomes, and projected completion dates. Published pediatric NOAC trials have included 1,007 total children to date and have ranged from phase 1 to 4, with "indications" including both thromboembolism prophylaxis and VTE treatment. Three recent phase 3 trials, specifically involving rivaroxaban and dabigatran, have shown the agents to be at least as effective as traditional anticoagulants for acute and/or extended VTE treatment, with low frequency of recurrent thrombosis and clinically significant bleeding rates. Additionally, specially developed and tested pediatric formulations have allowed for accurate and reliable dosing, oral administration, stable pharmacokinetics and pharmacodynamics, and fewer drug or food interactions. Ongoing trials, anticipated for completion in the next few years, will reveal important information with regard to thromboembolism prophylaxis in special pediatric subpopulations and settings.

Expanded utilization of rituximab in paediatric cardiac transplant patients.

WHAT IS KNOWN AND OBJECTIVE: Epstein-Barr virus (EBV) viraemia and autoimmune cytopenias (AICs) are significant complications that occur following paediatric solid organ transplantation. A variety of treatment methods have been investigated but limited research has focused on the utilization of rituximab in paediatric cardiac transplant recipients for these indications. Rituximab is a monoclonal antibody that binds the CD20 antigen on the surface of B-type lymphocytes resulting in B-cell cytotoxicity. It is considered a second-line therapy for treatment of autoimmune cytopenias and EBV viraemia following adult solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT). However, data for its use in the paediatric population for treatment of autoimmune cytopenias are lacking. Dosing is based on adult studies, and the frequency and length of therapy associated with resolution of EVB viraemia and AICs in paediatric cardiac transplant recipients is unknown. The objective of this retrospective study was to describe the dosing and length of therapy of expanded off-label use of rituximab for the management of refractory EBV viraemia and AICs, specifically in paediatric cardiac transplant patients. METHODS: A retrospective chart review was conducted evaluating children <18 years of age who underwent cardiac transplantation, were diagnosed with EBV viraemia or autoimmune cytopenia, and subsequently received treatment with rituximab between June 1995 and October 2018. Data were analysed descriptively. RESULTS AND DISCUSSION: Of all (n = 188) paediatric cardiac transplant recipients since 1995, 10 patients met the inclusion/exclusion criteria. Primary diagnoses were EBV viraemia (n = 6), immune haemolytic anaemia (n = 3) and immune thrombocytopenic purpura (n = 1). Complete responses were observed in 83.3% and 100% of patients with EVB viraemia and AICs treated with rituximab, respectively. All patients (n = 10) received rituximab 325 mg/m2 at weekly intervals. The number of total doses associated with complete resolution was 4-6 doses for EBV viraemia and 2-4 doses for AICs. The most common adverse events reported were neutropenia (n = 3), thrombocytopenia (n = 4), infusion reactions (n = 1) and significant anaemia (n = 2). WHAT IS NEW AND CONCLUSION: Although the efficacy of rituximab for treatment of EBV viraemia and autoimmune cytopenia in the paediatric cardiac transplant population remains unclear, our study supported the benefit of rituximab when added to therapy for treatment of EBV viraemia and ACIs.

Use of cidofovir with extracorporeal membrane oxygenation to treat adenovirus-associated acute respiratory distress syndrome in paediatric patients- a case series.

WHAT IS KNOWN AND OBJECTIVE: Reports of cidofovir dosing with extracorporeal membrane oxygenation (ECMO) support are limited. This case series describes our clinical experience and provides a literature review regarding cidofovir dosing in paediatric patients requiring ECMO support. CASE SUMMARY: Three patients with adenovirus-associated acute respiratory distress syndrome (ARDS) were treated with cidofovir while requiring ECMO support. A 27-month-old patient was treated with cidofovir 1 mg/kg/dose three times weekly, and a 19-month-old patient and an 18-year-old patient were treated with cidofovir 5 mg/kg/dose weekly. WHAT IS NEW AND CONCLUSION: This case series describes the dosing and positive clinical response of cidofovir in paediatric patients with adenovirus-associated ARDS requiring ECMO support.

Analgesia and Sedation Strategies in Mechanically Ventilated Adults with COVID-19.

Evidence-based management of analgesia and sedation in COVID-19-associated acute respiratory distress syndrome remains limited. Non-guideline recommended analgesic and sedative medication regimens and deeper sedation targets have been employed for patients with COVID-19 due to exaggerated analgesia and sedation requirements with extended durations of mechanical ventilation. This, coupled with a desire to minimize nurse entry into COVID-19 patient rooms, marked obesity, altered end-organ function, and evolving medication shortages, presents numerous short- and long-term challenges. Alternative analgesic and sedative agents and regimens may pose safety risks and require judicious bedside management for appropriate use. The purpose of this commentary is to provide considerations and solutions for designing safe and effective analgesia and sedation strategies for adult patients with considerable ventilator dyssynchrony and sedation requirements, such as COVID-19.