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.

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data.

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. The final combined dataset consisted of 266 plasma drug concentrations in 45 subjects with a median (interquartile range) postnatal age of 40.1 (11.0-120.4) days and weight of 3.9 (3.1-5.1) kg. Since the median sampling time after the first dose was short (study: 95 h; literature: 72 h) relative to the terminal half-life estimated in adult PopPK studies, values of the deep compartment volume and flow were fixed to literature values. A 3-compartment model best described the data and was validated by visual predictive checks and non-parametric bootstrap analysis. The final model included body weight as a covariate on all volumes and on both inter-compartmental and elimination clearances. The empiric Bayesian estimates for clearance (CL), volume of distribution at steady state, and terminal half-life were 0.25 (90% CL 0.14-0.36) L/kg/h, 93 (68-174) L/kg, and 266 (197-477) h, respectively. These studies will provide useful information for future PopPK studies of amiodarone in infants and children that could improve dosage regimens.

Asthma across the ages: knowledge gaps in childhood asthma.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act. The overall goal of the Best Pharmaceuticals for Children Act Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug-labeling changes. Although significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled for use in children. In general, the younger the child, the less information there is available to guide clinicians. Because asthma often begins in early childhood, it is incumbent on us to continue to address the primary questions raised in this review and carefully evaluate the medications used to manage asthma in children. Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.

Estimation of Body Fat Percentage for Clinical Pharmacokinetic Studies in Children.

Obesity is a prevalent childhood condition and the degree of adiposity appears likely to be an important covariate in the pharmacokinetics (PKs) of many drugs. We undertook these studies to facilitate the evaluation and, where appropriate, quantification of the covariate effect of body fat percentage (BF%) on PK parameters in children. We examined two large databases to determine the values and variabilities of BF% in children with healthy body weights and in those with obesity, comparing the accuracy and precision of BF% estimation by both clinical methods and demographically derived techniques. Additionally, we conducted simulation studies to evaluate the utility of the several methods for application in clinical trials. BF% was correlated with body mass index (BMI), but was highly variable among both children with healthy body weights and those with obesity. Bio-impedance and several demographically derived techniques produced mean estimates of BF% that differed from dual x-ray absorptiometry by < 1% (accuracy) and a SD of 5% or less (precision). Simulation studies confirmed that when the differences in precision among the several methods were small compared with unexplained between-subject variability of a PK parameter, the techniques were of similar value in assessing the contribution of BF%, if any, as a covariate for that PK parameter. The combination of sex and obesity stage explained 68% of the variance of BF% with BMI. The estimation of BF% from sex and obesity stage can routinely be applied to PK clinical trials to evaluate the contribution of BF% as a potential covariate.

Preventing Home Medication Administration Errors.

Medication administration errors that take place in the home are common, especially when liquid preparations are used and complex medication schedules with multiple medications are involved; children with chronic conditions are disproportionately affected. Parents and other caregivers with low health literacy and/or limited English proficiency are at higher risk for making errors in administering medications to children in their care. Recommended strategies to reduce home medication errors relate to provider prescribing practices; health literacy-informed verbal counseling strategies (eg, teachback and showback) and written patient education materials (eg, pictographic information) for patients and/or caregivers across settings (inpatient, outpatient, emergency care, pharmacy); dosing-tool provision for liquid medication measurement; review of medication lists with patients and/or caregivers (medication reconciliation) that includes prescription and over-the-counter medications, as well as vitamins and supplements; leveraging the medical home; engaging adolescents and their adult caregivers; training of providers; safe disposal of medications; regulations related to medication dosing tools, labeling, packaging, and informational materials; use of electronic health records and other technologies; and research to identify novel ways to support safe home medication administration.

Dosage Regimens for Meropenem in Children with Pseudomonas Infections Do Not Meet Serum Concentration Targets.

There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high-risk children and adults. We evaluated this observation in children using literature studies conducted in infants and children. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). A population pharmacokinetic model was fit to the data and then used to simulate the recommended dosing regimens and estimate the proportion of subjects achieving recommended target exposures. A two-compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. The US Food and Drug Administration (FDA)-approved dosing regimens achieved targets in ~ 90% or more of subjects less than 3 months of age for organisms with minimum inhibitory concentration (MIC)'s of 2 and 4 mg/L; however, only 68.4% and 41.7% of subjects older than 3 months and weighing < 50 kg achieved target exposures for organisms with MIC's of 2 and 4 mg/L, respectively [Correction added on January 23, 2020, after first online publication: "> 3 months" corrected to "less than 3 months".]. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Simulation studies were used to explore the impact of changing dose, dosing interval, and infusion duration on the likelihood of achieving therapeutic targets in these groups. Our findings illustrate that current dosing recommendations for children over 3 months of age fail to meet therapeutic targets in an unacceptable fraction of patients. Further investigation is needed to develop new dosing strategies in these patients.

Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials.

OBJECTIVE: To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19). METHODS: We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2. RESULTS: The average total serum/plasma HCQ concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/l in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/l), all studies had about one-tenth the necessary concentration for in vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose. CONCLUSION: We found that the average patient receiving treatment with HCQ for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in vitro. Nevertheless, patients receiving HCQ long term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for HCQ in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for HCQ.

Hydroxychloroquine Levels throughout Pregnancies Complicated by Rheumatic Disease: Implications for Maternal and Neonatal Outcomes.

OBJECTIVE: Pregnancies in women with active rheumatic disease often result in poor neonatal outcomes. Hydroxychloroquine (HCQ) reduces disease activity and flares; however, pregnancy causes significant physiologic changes that may alter HCQ levels and lead to therapeutic failure. Therefore, our objective was to evaluate HCQ concentrations during pregnancy and relate levels to outcomes. METHODS: We performed an observational study of pregnant patients with rheumatic disease who were taking HCQ from a single center during 2013-2016. Serum samples were analyzed using high-performance liquid chromatography/mass spectrometry. Primary HCQ exposure was categorized as nontherapeutic (≤ 100 ng/ml) or therapeutic (> 100 ng/ml). Categorical outcomes were analyzed using Fisher's exact test and continuous outcomes using linear regression models, Wilcoxon signed-rank test, Kruskal-Wallis test, t test, and ANOVA. RESULTS: We analyzed 145 samples from 50 patients with rheumatic disease, 56% of whom had systemic lupus erythematosus (SLE). HCQ concentration varied widely among individuals at each trimester. Mean physician's global assessment scores in patients with SLE were significantly higher in those with average drug levels ≤ 100 ng/ml compared to > 100 ng/ml (0.93 vs 0.32, p = 0.01). Of patients with SLE, 83% with average drug levels ≤ 100 ng/ml delivered prematurely (n = 6), compared to only 21% with average levels > 100 ng/ml (n = 19; p = 0.01). HCQ levels were not associated with prematurity or disease activity in non-SLE patients. CONCLUSION: With both high and low HCQ levels associated with preterm birth and disease activity in SLE, further study is necessary to understand HCQ disposition throughout pregnancy and to clarify the relationship between drug levels and outcomes.

Pharmacokinetics of Hydroxychloroquine in Pregnancies with Rheumatic Diseases.

BACKGROUND: Hydroxychloroquine is an oral drug prescribed to pregnant women with rheumatic disease to reduce disease activity and prevent flares. Physiologic changes during pregnancy may substantially alter drug pharmacokinetics. However, the effect of pregnancy on hydroxychloroquine disposition and the potential need for dose adjustment remains virtually unknown. METHODS: We performed a population-pharmacokinetic analysis using samples from the Duke Autoimmunity in Pregnancy Registry from 2013 to 2016. We measured hydroxychloroquine concentration using high-performance liquid chromatography/tandem mass spectrometry and analyzed data using non-linear mixed-effect modeling. We calculated differences between pregnancy and postpartum empirical Bayesian estimates using paired t tests. We computed steady-state concentration profiles for hydroxychloroquine during pregnancy and postpartum using individual clinical data and empirical Bayesian estimates developed from the final pharmacokinetic model. RESULTS: We obtained 145 serum samples from 50 patients, 25 of whom had paired pregnancy and postpartum specimens. Five subjects had average concentrations (pregnancy and postpartum) < 100 ng/mL, consistent with medication non-adherence, and were excluded. The population estimated apparent volume of distribution was 1850 L/70 kg and estimated apparent clearance was 51 L/h. Compared with postpartum, median apparent volume of distribution increased significantly during pregnancy (p < 0.001), whereas apparent clearance and 24-h area under the curve did not change. CONCLUSIONS: We developed a one-compartment population-pharmacokinetic model for hydroxychloroquine in pregnant women with rheumatic disease. Estimates for serum CL were within the expected range for plasma in non-pregnant adults. Because CL and 24-h area under the curve did not change during pregnancy compared with postpartum, our modeling in this small cohort does not support adjusting hydroxychloroquine dose during pregnancy.

A review of the natriuretic hormone system's diagnostic and therapeutic potential in critically ill children.

OBJECTIVE: To review the natriuretic hormone system and discuss its diagnostic, prognostic, and therapeutic potential in critically ill children. DATA SOURCE: A thorough literature search of MEDLINE was performed using search terms including heart defects, congenital; cardiopulmonary bypass, atrial natriuretic factor; natriuretic peptide, brain; carperitide; nesiritide. Preclinical and clinical investigations and review articles were identified that describe the current understanding of the natriuretic hormone system and its role in the regulation of vascular tone and fluid balance in healthy adults and children and in those with underlying cardiac, pulmonary, and renal disease. RESULTS: A predictable activation of the natriuretic hormone system occurs in children with congenital heart disease and congestive heart failure. Further study is needed to confirm preliminary reports that measurement of natriuretic hormone levels in critically ill children provides diagnostic and prognostic information, as has been demonstrated in adult cardiac populations. Natriuretic hormone infusions provide favorable hemodynamic changes and symptomatic relief when used in adults with decompensated congestive heart failure, and uncontrolled case series suggest that similar benefits may exist in children. The biological activity of the natriuretic hormone system may be decreased following pediatric cardiopulmonary bypass, and additional studies are needed to determine whether natriuretic hormone infusions provide clinical benefit in the postoperative period. Preliminary reports suggest that natriuretic hormone infusions cause physiologic improvements in adults with acute lung injury and asthma but not in those with acute renal failure. CONCLUSIONS: Although important perturbations of the natriuretic hormone system occur in critically ill infants and children, further investigation is needed before the measurement of natriuretic peptides and the use of natriuretic hormone infusions are incorporated into routine practice.

Codeine: Time to Say "No".

Codeine has been prescribed to pediatric patients for many decades as both an analgesic and an antitussive agent. Codeine is a prodrug with little inherent pharmacologic activity and must be metabolized in the liver into morphine, which is responsible for codeine's analgesic effects. However, there is substantial genetic variability in the activity of the responsible hepatic enzyme, CYP2D6, and, as a consequence, individual patient response to codeine varies from no effect to high sensitivity. Drug surveillance has documented the occurrence of unanticipated respiratory depression and death after receiving codeine in children, many of whom have been shown to be ultrarapid metabolizers. Patients with documented or suspected obstructive sleep apnea appear to be at particular risk because of opioid sensitivity, compounding the danger among rapid metabolizers in this group. Recently, various organizations and regulatory bodies, including the World Health Organization, the US Food and Drug Administration, and the European Medicines Agency, have promulgated stern warnings regarding the occurrence of adverse effects of codeine in children. These and other groups have or are considering a declaration of a contraindication for the use of codeine for children as either an analgesic or an antitussive. Additional clinical research must extend the understanding of the risks and benefits of both opioid and nonopioid alternatives for orally administered, effective agents for acute and chronic pain.

Low inferior vena caval catheters for hemodynamic and pulmonary function monitoring in pediatric critical care patients.

OBJECTIVE: To assess the value of low inferior vena caval (LIVC) catheters for estimating central venous pressure in pediatric intensive care patients and to assess influences of intra-abdominal pressures and mean airway pressure on these measurements. DESIGN: Prospective cohort of consecutive patients. SETTING: Pediatric intensive care unit. PATIENTS: Thirty patients ranging in age (18, 0-1 yrs; four, 1-3 yrs; four, 3-10 yrs; four, > or =10 yrs). INTERVENTIONS: Interventions included catheterizations via internal jugular, subclavian, and common femoral veins, as well as direct right atrial catheterization during surgery; arterial catheter placement; airway pressure monitoring during mechanical ventilation; indirect intra-abdominal pressure monitoring via bladder catheter pressure readings; and arterial and central venous blood gas analysis. LIVC vein catheters were placed below the origin of the renal veins. MEASUREMENTS AND MAIN RESULTS: LIVC pressure was highly correlated with central venous pressure (n=30, r2=.965, p=.0001). LIVC pressure did not correlate with intra-abdominal pressure (n=18, r2=.000). Mean airway pressure did not correlate with central venous pressure (n=11, r2=.106). The pH of LIVC blood was similar to that of central venous blood (n=18, r2=.941, p=.0001). PCO2 values of inferior vena cava and central venous blood correlated (r2=.945, p=.0001). However, agreement between inferior vena cava and central venous PO2 and oxyhemoglobin saturation was poor (PO2, r2=.066; oxyhemoglobin saturation, r2=.000). CONCLUSIONS: LIVC catheters whose tips lie below the origin of the renal veins predict central venous pressure in pediatric intensive care unit patients. Intra-abdominal pressure and mean airway pressure do not affect this relationship, within the wide range of values for these variables included in this study. Blood samples drawn from femoral venous catheters can be used to monitor acid-base balance and partial pressure of carbon dioxide.

Noninvasive positive-pressure ventilation in children with lower airway obstruction.

STUDY OBJECTIVES: Mechanical ventilation of patients with severe lower airway obstruction presents significant risks; therefore, avoiding the intubation in these patients has been a principal goal of clinical management. Noninvasive positive-pressure ventilation has been shown to be effective in treating adults with chronic obstructive pulmonary disease, but its use has not been studied prospectively in children with acute obstructive lower airways disease. The objective of this study was to determine whether noninvasive mask ventilation improved respiratory function in children with asthma and other obstructive lower airways diseases. STUDY DESIGN: A prospective, randomized, crossover study. PATIENTS: A total of 20 children admitted to the pediatric intensive care unit with acute lower airway obstruction. METHODS: Children were randomized to receive either 2 hrs of noninvasive ventilation followed by crossover to 2 hrs of standard therapy or 2 hrs of standard therapy followed by 2 hrs of noninvasive ventilation. RESULTS: Using a Clinical Asthma Score, we found that noninvasive ventilation decreased signs of work of breathing such as respiratory rate, accessory muscle use, and dyspnea as compared with standard therapy. There was no serious morbidity associated with noninvasive ventilation. CONCLUSIONS: We conclude that noninvasive ventilation can be an effective treatment for children with acute lower airway obstruction.

Off-label use of drugs in children.

The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than 500 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term "off-label" does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient.

Dexamethasone reduces postoperative troponin levels in children undergoing cardiopulmonary bypass.

OBJECTIVE: We previously demonstrated that dexamethasone treatment before cardiopulmonary bypass in children reduces the postoperative systemic inflammatory response. The purpose of this study was to test the hypothesis that dexamethasone administration before cardiopulmonary bypass in children correlates with a lesser degree of myocardial injury as measured by a decrease in cardiac troponin I release. DESIGN: A prospective, randomized, double-blind study. SETTING: The cardiac surgery operating room and intensive care unit of a pediatric referral hospital. SUBJECTS: Twenty-eight patients who underwent open-heart surgery for congenital heart defects. INTERVENTIONS: Patients received either placebo (group I, n = 13) or dexamethasone, 1 mg/kg iv (group II, n = 15), 1 hr before initiation of cardiopulmonary bypass. Plasma cardiac troponin I samples were obtained at three time points: immediately before study agent (sample 1), 10 mins after protamine sulfate administration after cardiopulmonary bypass (sample 2), and 24 hrs postoperatively (sample 3). MEASUREMENTS AND MAIN RESULTS: Mean cardiac troponin I levels (+/-sd) were significantly lower at sample time 3 in group II (dexamethasone; 33.4 +/- 20.0 ng/mL) vs. group I (control; 86.9 +/- 81.1) (p =.04). CONCLUSION: Dexamethasone administration before cardiopulmonary bypass in children resulted in a significant decrease in cardiac troponin I levels at 24 hrs postoperatively. We postulate that this may represent a decrease in myocardial injury, and, thus, a possible cardioprotective effect produced by dexamethasone.