Exploring the Possible Role of Cannabinoids in Managing Post-cardiac Surgery Complications: A Narrative Review of Preclinical Evidence and a Call for Future Research Directions.

ABSTRACT: Open-heart surgery with cardiopulmonary bypass often leads to complications including pain, systemic inflammation, and organ damage. Traditionally managed with opioids, these pain relief methods bring potential long-term risks, prompting the exploration of alternative treatments. The legalization of cannabis in various regions has reignited interest in cannabinoids, such as cannabidiol, known for their anti-inflammatory, analgesic, and neuroprotective properties. Historical and ongoing research acknowledges the endocannabinoid system's crucial role in managing physiological processes, suggesting that cannabinoids could offer therapeutic benefits in postsurgical recovery. Specifically, cannabidiol has shown promise in managing pain, moderating immune responses, and mitigating ischemia/reperfusion injury, underscoring its potential in postoperative care. However, the translation of these findings into clinical practice faces challenges, highlighting the need for extensive research to establish effective, safe cannabinoid-based therapies for patients undergoing open-heart surgery. This narrative review advocates for a balanced approach, considering both the therapeutic potential of cannabinoids and the complexities of their integration into clinical settings.

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.

The Reviewer Academy of the Society of Critical Care Medicine: Key Principles and Strategic Plan.

The Society of Critical Care Medicine (SCCM) Reviewer Academy seeks to train and establish a community of trusted, reliable, and skilled peer reviewers with diverse backgrounds and interests to promote high-quality reviews for each of the SCCM journals. Goals of the Academy include building accessible resources to highlight qualities of excellent manuscript reviews; educating and mentoring a diverse group of healthcare professionals; and establishing and upholding standards for insightful and informative reviews. This manuscript will map the mission of the Reviewer Academy with a succinct summary of the importance of peer review, process of reviewing a manuscript, and the expected ethical standards of reviewers. We will equip readers to target concise, thoughtful feedback as peer reviewers, advance their understanding of the editorial process and inspire readers to integrate medical journalism into diverse professional careers.

Perioperative Care Models for Neonates With Congenital Heart Disease: Evolving Role of Neonatology Within the Cardiac Intensive Care Unit.

A multidisciplinary team is needed to optimally care for infants with congenital heart disease (CHD). Different compositions of teams trained in cardiology, critical care, cardiothoracic surgery, anesthesia, and neonatology have been identified as being primarily responsible for perioperative care of this high-risk population in dedicated cardiac intensive care units (CICUs). Although the specific role of cardiac intensivists has become more well defined over the past two decades, the responsibilities of neonatologists remain highly variable in the CICU with neonatologists providing care along with a unique spectrum of primary, shared, or consultative care. The neonatologist can function as the primary physician and assume all or share responsibility with the cardiac intensivists for the management of infants with CHD. A neonatologist can provide care as a secondary consultant physician in a supportive role for the primary CICU team. Additionally, neonates with CHD can be mixed with older children in a CICU, cohorted in a dedicated space within the CICU or placed in a stand-alone infant CICU without older children. Although variations exist between centers on which model of care is deployed and the location within a CICU, characterization of current practice patterns represents the initial step required to determine optimal best practices to improve the quality of care for neonates with cardiac disease. In this manuscript, we present four models utilized in the United States in which the neonatologist provides neonatal-cardiac-focused care in a dedicated CICU. We also outline the different permutations of location where neonates can be cared for in dedicated pediatric/infant CICUs.

Beyond Conventional Hemodynamic Monitoring-Monitoring to Improve Our Understanding of Disease Process and Interventions.

Monitoring the hemodynamic state of patients is a hallmark of any intensive care environment. However, no single monitoring strategy can provide all the necessary data to paint the entire picture of the state of a patient; each monitor has strengths and weaknesses, advantages, and limitations. We review the currently available hemodynamic monitors used in pediatric critical care units using a clinical scenario. This provides the reader with a construct to understand the progression from basic to more advanced monitoring modalities and how they serve to inform the practitioner at the bedside.

Association of Social Determinants of Health With Rapid Response Events: A Retrospective Cohort Trial in a Large Pediatric Academic Hospital System.

Background: Social determinants of health (SDH) are known to impact hospital and intensive care unit (ICU) outcomes. Little is known about the association between SDH and pediatric rapid response (RR) events and understanding this impact will help guide future interventions aimed to eliminate health disparities in the inpatient setting. Objectives: The primary objective of this study is to describe the association between SDH and RR utilization (number of RR events, time to RR event, shift of event and caller). The secondary objective is to determine if SDH can predict hospital length of stay (LOS), ICU transfer, critical deterioration (CD), and mortality. Methods: A retrospective cohort study was conducted. We reviewed all RR events from 2016 to 2019 at a large, academic, pediatric hospital system including a level 1 trauma center and two satellite community campuses. All hospitalized patients up to age 25 who had a RR event during their index hospitalization were included. Exposure variables included age, gender, race/ethnicity, language, income, insurance status, chronic disease status, and repeat RR event. The primary outcome variables were hospital LOS, ICU transfer, CD, and mortality. The odds of mortality, CD events and ICU transfer were assessed using unadjusted and multivariable logistic regression. Associations with hospital LOS were assessed with unadjusted and multivariable quantile regression. Results: Four thousand five hundred and sixty-eight RR events occurred from 3,690 unique admissions and 3301 unique patients, and the cohort was reduced to the index admission. The cohort was largely representative of the population served by the hospital system and varied according to race and ethnicity. There was no variation by race/ethnicity in the number of RR events or the shift in which RR events occurred. Attending physicians initiated RR calls more for event for non-Hispanic patients of mixed or other race (31.6% of events), and fellows and residents were more likely to be the callers for Hispanic patients (29.7% of events, p = 0.002). Families who are non-English speaking are also less likely to activate the RR system (12% of total RR events, p = 0.048). LOS was longest for patients speaking languages other than Spanish or English and CD was more common in patients with government insurance. In adjusted logistic regression, Hispanic patients had 2.5 times the odds of mortality (95% CI: 1.43-4.53, p = 0.002) compared with non-Hispanic white patients. Conclusion: Disparities exist in access to and within the inpatient management of pediatric patients. Our results suggest that interventions to address disparities should focus on Hispanic patients and non-English speaking patients to improve inpatient health equity. More research is needed to understand and address the mortality outcomes in Hispanic children compared to other groups.

Comparison of Laboratory and Hemodynamic Time Series Data Across Original, Alpha, and Delta Variants in Patients With Multisystem Inflammatory Syndrome in Children.

OBJECTIVES: To compare the clinical, laboratory, and hemodynamic parameters during hospitalization for patients with multisystem inflammatory syndrome in children (MIS-C), across the Original/Alpha and the Delta variants of severe acute respiratory syndrome coronavirus 2 infection. DESIGN: Retrospective cohort study. SETTING: Single-center quaternary children's hospital. PATIENTS: Children with MIS-C admitted from May 2020 to February 2021(Original and Alpha variant cohort) and August 2021 to November 2021 (Delta variant cohort). MEASUREMENTS AND MAIN RESULTS: Continuous vital sign measurements, laboratory results, medications data, and hospital outcomes from all subjects were evaluated. Of the 134 patients (102 with Original/Alpha and 32 with Delta), median age was 9 years, 75 (56%) were male, and 61 (46%) were Hispanics. The cohort with Original/Alpha variant had more males (61% vs 41%; p = 0.036) and more respiratory/musculoskeletal symptoms on presentation compared with the Delta variant ( p < 0.05). More patients in the Original/Alpha variant cohort received mechanical ventilation (16 vs 0; p = 0.009). Median hospital length of stay (LOS) was 7 days, and ICU LOS was 3 days for the entire cohort. ICU LOS was shorter in cohort with the Delta variant compared with the Original/Alpha variant (4 vs 2 d; p = 0.001). Only one patient had cardiac arrest, two needed extracorporeal membrane oxygenation, and two needed left ventricular assist device (Impella, Danvers, MA), all in the Original/Alpha variant cohort; no mortality occurred in the entire cohort. MIS-C cohort associated with the Delta variant had lower INR, prothrombin time, WBCs, sodium, phosphorus, and potassium median values ( p < 0.05) during hospitalization compared with the Original/Alpha variants. Hemodynamic assessment showed significant tachycardia in the Original/Alpha variants cohort compared with the Delta variant cohort ( p < 0.05). INTERVENTIONS: None. CONCLUSIONS: Patients with MIS-C associated with the Delta variants had lower severity during hospitalization compared with the Original/Alpha variant. Analysis of distinct trends in clinical and laboratory parameters with future variants of concerns will allow for potential modification of treatment protocol.

Opioid Weaning Protocol Using Morphine Compared With Nonprotocolized Methadone Associated With Decreased Dose and Duration of Opioid After Norwood Procedure.

OBJECTIVES: Opioids are used to manage pain, comfort, maintain devices, and decrease oxygen consumption around Norwood palliation (NP), but in high dose and prolonged exposure, they increase risk of tolerance and iatrogenic withdrawal syndrome (IAWS). Variability in practice for IAWS prevention potentially increases opioid dose and duration. We hypothesize that protocolized weaning with morphine (MOR) versus nonprotocolized methadone (MTD) is associated with reduction in opioid exposure. DESIGN: A before-versus-after study of outcomes of patients weaned with protocolized MOR versus nonprotocolized MTD including subset analysis for those patients with complications postoperatively. Primary endpoints include daily, wean phase, and total morphine milligram equivalent (MMEq) dose, duration, and, secondarily, length of stay (LOS). SETTING: Quaternary-care pediatric cardiac ICU. PATIENTS: Neonates undergoing single-ventricle palliation. INTERVENTIONS: Introduction of IAWS prevention protocol. MEASUREMENTS AND MAIN RESULTS: Analysis included 54 patients who underwent the NP in 2017-2018 including the subset analysis of 34 who had a complicated postoperative course. The total and wean phase opioid doses for the MTD group were significantly higher than that for the MOR group: 258 versus 22 and 115 versus 6 MMEq/kg; p < 0.001. Duration of opioid exposure was 63 days in the MTD group and 12 days in MOR group (p < 0.001). Subanalysis of the complicated subset also identifies higher total and wean dose for MTD group (293 vs 41 and 116 vs 7 MMEq/kg; p < 0.001) with a longer duration (65 vs 22 days; p = 0.001). Within the subset, LOS was 55% longer in the MTD group than that in the MOR group (150 vs 67 d; p = 0.01) and not different in the uncomplicated group. CONCLUSIONS: After complex NP, a protocolized opioid weaning using MOR versus MTD is associated with 65% shorter opioid duration, 10-fold decreased dose, and shortened LOS.

Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Contemporary Organ Dysfunction Criteria: Executive Summary.

Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.

Cardiovascular Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

CONTEXT: Cardiovascular dysfunction is associated with poor outcomes in critically ill children. OBJECTIVE: We aim to derive an evidence-informed, consensus-based definition of cardiovascular dysfunction in critically ill children. DATA SOURCES: Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020 using medical subject heading terms and text words to define concepts of cardiovascular dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION: Studies were included if they evaluated critically ill children with cardiovascular dysfunction and assessment and/or scoring tools to screen for cardiovascular dysfunction and assessed mortality, functional status, organ-specific, or other patient-centered outcomes. Studies of adults, premature infants (≤36 weeks gestational age), animals, reviews and/or commentaries, case series (sample size ≤10), and non-English-language studies were excluded. Studies of children with cyanotic congenital heart disease or cardiovascular dysfunction after cardiopulmonary bypass were excluded. DATA EXTRACTION: Data were abstracted from each eligible study into a standard data extraction form, along with risk-of-bias assessment by a task force member. RESULTS: Cardiovascular dysfunction was defined by 9 elements, including 4 which indicate severe cardiovascular dysfunction. Cardiopulmonary arrest (>5 minutes) or mechanical circulatory support independently define severe cardiovascular dysfunction, whereas tachycardia, hypotension, vasoactive-inotropic score, lactate, troponin I, central venous oxygen saturation, and echocardiographic estimation of left ventricular ejection fraction were included in any combination. There was expert agreement (>80%) on the definition. LIMITATIONS: All included studies were observational and many were retrospective. CONCLUSIONS: The Pediatric Organ Dysfunction Information Update Mandate panel propose this evidence-informed definition of cardiovascular dysfunction.

Hemodynamic Response to Calcium Chloride Boluses in Single-Ventricle Patients with Parallel Circulation.

The purpose of this study is to assess the effect of calcium bolus in response to a hypotensive episode by assessing high-fidelity hemodynamic data obtained from children with single-ventricle physiology with parallel circulation. Single-center, retrospective analysis of hemodynamic data after calcium bolus administrations within the first 2 weeks post-surgery. Time intervals were the baseline (- 60 to - 10 min); the hypotensive episode (- 10 to 0 min); time point zero at the bolus administration; and the response (0 to 60 min). The main responses assessed were the peak increase in mean blood pressure (mBP), duration of the response after the bolus, and markers of oximetric effects. These analyses included 128 boluses in 63 patients. Of the total boluses analyzed, 80% increased the mBP by 5 mmHg or higher with the effect lasting at least 10 min, whereas 10% of the boluses analyzed increased the mBP by 20 mmHg or higher with the effect lasting at least 50 min. The boluses induced a significant increase in arterial oxygen saturation and an upward trend in pulmonary-to-systemic flow ratio, without increasing renal or cerebral oxygen extraction ratios. Calcium chloride boluses are an effective rescue medication for hypotensive episodes in children with parallel circulation. They lead to an improvement in mBP, as well as an increase in pulmonary-to-systemic blood flow ratio. More importantly, these boluses do not compromise systemic oxygen delivery.

RBC Transfusion Induced ST Segment Variability Following the Norwood Procedure.

The transfusion of stored RBCs decreases nitric oxide bioavailability, which may have an adverse effect on vascular function. We assessed the effects of RBC transfusion on coronary vascular function by evaluating the relationship between myocardial oxygen delivery and demand as evidenced by ST segment variability. DESIGN: Retrospective case-control study. SETTING: Nine-hundred seventy-three-bed pediatric hospital with a 54-bed cardiovascular ICU. PATIENTS: Seventy-three neonates with hypoplastic left heart syndrome following the Norwood procedure, 38 with a Blalock-Taussig shunt and 35 with a right ventricle to pulmonary artery shunt. INTERVENTIONS: RBC transfusion. MATERIALS AND MAIN RESULTS: High-frequency physiologic data were captured 30 minutes prior to the initiation of (baseline) and during the 120 minutes of the transfusion. A rate pressure product was calculated for each subject and used as an indicator of myocardial oxygen demand. Electrocardiogram leads (aVL, V1, II) were used to construct a 3D ST segment vector to assess ST segment variability and functioned as a surrogate indicator of myocardial ischemia. One-hundred thirty-eight transfusions occurred in the Blalock-Taussig shunt group and 139 in the right ventricle to pulmonary artery shunt group. There was no significant change in the rate pressure product for either group; however, ST segment variability progressively increased for the entire cohort during the transfusion, becoming statistically significant by the end of the transfusion. Upon subgroup analysis, this finding was noted with statistical significance in the Blalock-Taussig shunt group and trending toward significance in the right ventricle to pulmonary artery shunt group. CONCLUSIONS: We found a significant increase in the ST segment variability and evidence of myocardial ischemia temporally associated with RBC transfusions in neonates following the Norwood procedure, specifically among those in the Blalock-Taussig shunt group, which may impact immediate and long-term outcomes.

Altered metabolic and inflammatory transcriptomics after cardiac surgery in neonates with congenital heart disease.

The study examines the whole blood transcriptome profile before and after cardiopulmonary bypass (CPB) in neonates with hypoplastic left heart syndrome (HLHS), a severe form of congenital heart disease, that can develop low cardiac output syndrome (LCOS). Whole blood mRNA transcriptome profiles of 13 neonates with HLHS before and after their first palliative surgery were analyzed to determine differentially expressed genes and pathways. The median age and weight at surgery were 4 days and 3.2 kg, respectively. Of the 13 patients, 8 developed LCOS. There was no significant difference between CPB, aortic cross clamp, deep hypothermic cardiac arrest times between patients that develop LCOS and those that do not. Upon comparing differential gene expression profiles between patients that develop LCOS and those that do not in pre-operative samples, 1 gene was up-regulated and 13 were down regulated. In the post-operative samples, 4 genes were up-regulated, and 4 genes were down regulated when patients that develop LCOS were compared to those that do not. When comparing post-operative samples to pre-operative samples in the patients that do not develop LCOS, 1484 genes were up-regulated, and 1388 genes were down regulated; while patients that developed LCOS had 2423 up-regulated genes, and 2414 down regulated genes for the same pre to post-operative comparison. Pathway analysis revealed differential regulation of inflammatory pathways (IL signaling, PDGF, NOTCH1, NGF, GPCR) and metabolic pathways (heme metabolism, oxidative phosphorylation, protein metabolism including amino acid and derivatives, fatty acid metabolism, TCA cycle and respiratory electron transport chain). By identifying altered transcriptome profiles related to inflammation and metabolism in neonates with HLHS who develop LCOS after CPB, this study opens for exploration novel pathways and potential therapeutic targets to improve outcomes in this high-risk population.

Impact of Corticosteroids on Cardiopulmonary Bypass Induced Inflammation in Children: A Meta-Analysis.

BACKGROUND: Corticosteroids suppress the inflammatory response to cardiopulmonary bypass in children undergoing cardiac surgery. What is less clear is the impact of corticosteroids on the postoperative course. METHODS: A systematic review and meta-analysis was made of prospective randomized blinded placebo-controlled trials of pediatric patients who received corticosteroids or saline placebo before surgery was performed. Ten studies met inclusion criteria for a total of 768 patients. In a prespecified subgroup analysis, studies that either were limited to The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery congenital heart surgery mortality categories 1 and 2 or excluded neonates were eliminated and a secondary analysis was conducted, which consisted of seven studies and 555 patients. RESULTS: Corticosteroids were associated with a significant improvement in fluid balance at 24 and 36 hours after surgery, with a mean difference of -15.2 mL/kg (95% confidence interval, 25.3 to -5.1 mL/kg; P < .01) and -5.7 mL/kg (95% confidence interval, -9.8 to -1.6 mL/kg; P < .01), respectively. Corticosteroids had no impact on the incidence of infection or mortality. With the secondary analysis, corticosteroids were associated with a trend toward significance in shortening the duration of mechanical ventilation (mean difference -0.7 days; 95% confidence interval, -1.7 to 0.1; P = .08). CONCLUSIONS: Corticosteroids were found to have a favorable impact on postoperative fluid balance and may be associated with shortening the duration of mechanical ventilation. Although corticosteroids had no impact on mortality, they may be beneficial particularly for neonates and patients undergoing highly complex surgery.

Xanthine Derivatives for Kidney Protection in the Critically Ill Pediatric Population: A Systematic Review.

Different types of diuretics have been used to minimize fluid overload after resuscitation. This meta-analysis determined the effects of xanthine derivatives on creatinine, creatinine clearance, and urine output. Studies included data from pediatric patients, whoused theophylline or aminophylline, and included pre- and postxanthine data for at least one of the outcomes of interest. A total of 13 studies with 198 patients were included in the pooled analyses. The study recorded data prior, and a mean of 36 hours after xanthine administration. This meta-analysis demonstrates that xanthine derivatives in critically ill children, using a dose of approximately5 mg/kg, lead to a statistically significant increase in creatinine clearance and urine output without significantly altering serum creatinine. Xanthine derivatives may be beneficial for fluid management in critically ill children. Further studies are warranted assessing the association with additional clinical outcomes.