Caffeine dosing in premature neonates: impact of birth weight on a pharmacokinetic simulation study.

BACKGROUND: The optimal caffeine dosing in extremely premature neonates remains elusive. This study aimed to evaluate the impact of birth weight on caffeine pharmacokinetics and various dosing regimens. METHODS: In this pharmacokinetic simulation study, we generated the body weights (0-49 days of postnatal age [PNA]) of neonates <28 weeks gestational age with different birth weights (550, 750, and 1050 g). Their pharmacokinetic parameters were determined based on published pharmacokinetic models. Then, we simulated and compared the caffeine base concentration-time profiles of standard versus off-label caffeine citrate dose regimens. RESULTS: The half-life decreased and the weight-adjusted clearance increased more significantly in neonates with lower birth weights, resulting in lower caffeine plasma concentrations. The neonate with the lowest birth weight did not achieve a threshold trough concentration of 15 mg/L after receiving the standard dose (5 mg/kg/day), while the higher-birth-weights (≥750 g) had trough concentrations below the threshold around the second week of life. Higher caffeine doses (10 mg/kg/day) resulted in peak concentrations of <36 mg/L by 10-14 days of PNA while maintaining trough concentrations above 15 mg/L throughout the 49 days PNA. CONCLUSION: Higher-than-standard caffeine dosing may be needed for extremely premature neonates, especially for those with lower birth weights. IMPACT: Extremely premature neonates with a lower birth weight may require a higher weight-based caffeine dosing due to their higher weight-adjusted clearance and shorter half-lives. Not only do these extremely premature neonates have a higher risk of developing bronchopulmonary dysplasia due to their structurally underdeveloped lungs, but the low birth weight-related underdosing may further contribute to the reduced caffeine effectiveness. Higher-than-standard caffeine citrate dosing (e.g., 10 mg/kg/day maintenance dose) may be needed to further prevent bronchopulmonary dysplasia.

Vasopressin-Induced Hyponatremia in Infants Following Cardiovascular Surgery.

BACKGROUND: Vasopressin is increasingly used in infants following cardiac surgery. Hyponatremia is a noted adverse event, but incidence and risk factors remain undefined. OBJECTIVE: The primary objective was to identify the incidence of vasopressin-induced hyponatremia. Secondary objectives included comparing baseline and change in serum sodium concentrations between infants receiving vasopressin with and without hyponatremia, and comparing vasopressin dose, duration, and clinical characteristics in those with and without hyponatremia. METHODS: This Institutional Review Board-approved, retrospective case-control study included infants <6 months following cardiac surgery receiving vasopressin for ≥6 hours at a tertiary care, academic hospital. Patients who developed hyponatremia, cases, were matched to controls in a 1:2 fashion. Demographics and clinical characteristics were collected. Descriptive and inferential statistics were employed. A conditional logistic regression was used to assess odds of hyponatremia. RESULTS: Of the included 142 infants, 20 (14.1%) developed hyponatremia and were matched with 40 controls. There was significant difference in median nadir between controls and cases, 142.0 versus 128.5 mEq/L (<0.001). A significantly higher number of cases received corticosteroids, loop diuretics, and chlorothiazide versus controls. The regression analysis demonstrated that each additional hour of vasopressin increased the odds of developing hyponatremia by 5% (adjusted odds ratio 1.05 [confidence interval 1-1.1]). CONCLUSIONS AND RELEVANCE: Vasopressin-induced hyponatremia incidence was <15%. Vasopressin duration was independently associated with hyponatremia development.

The Medication Possession Ratio as a Predictor of Longitudinal HIV-1 Viral Suppression.

BACKGROUND: Antiretroviral adherence is essential to achieve viral suppression and limit HIV-related morbidity and mortality; however, antiretroviral adherence thresholds to achieve viral suppression in clinical practice have not been fully characterized using administrative claims data. OBJECTIVE: The purpose of this study was to assess the relationship between medication adherence and viral suppression among adult persons with HIV/AIDS (PWH) receiving antiretroviral therapy (ART) for ≥6 months. METHODS: This historical cohort, real-world investigation assessed maintenance of viral load suppression and viral load area-under-the-curve (vAUC) in PWH ≥18 years of age based on ART adherence. A marginal effects model was used to determine the predicted probabilities of final plasma HIV-1 RNA <50 copies/mL or vAUC <1,000 copy-days/mL according to the medication possession ratio (MPR), estimated using a Jackknife model variance estimator and a delta-method for marginal effects standard error. Tests for statistical significance used a Sidák method to correct for multiple comparisons. RESULTS: The mean MPR for ART was 86.7% (95% CI: 85.0%-88.4%) for the 372 PWH included in the study. The marginal effects analysis indicated that an MPR ≥82% was associated with a predicted probability of viral suppression <50 copies/mL (P < 0.05). Significant predicted probabilities for vAUC <1,000 copy-days/mL were observed with an MPR ≥90% (P < 0.05). CONCLUSION AND RELEVANCE: Medication possession ratio as a proxy for drug exposure was significantly and consistently associated with viral suppression using a longitudinal measure of HIV viremia. These findings can aid clinicians in the clinical management of PWH and inform future studies of adherence-viral suppression relationships with contemporary antiretroviral regimens.

Evaluation of Ceftazidime Use in the Neonatal Intensive Care Unit and Association With Cephalosporin-Resistant Gram-Negative Bacteria.

BACKGROUND: Cefotaxime shortage in 2015 led to increased ceftazidime use in the neonatal intensive care unit (NICU). OBJECTIVE: The purpose was to explore whether ceftazidime increases risk for development of resistant gram-negative organisms. METHODS: Retrospective evaluation of NICU patients with cultures positive for Escherichia coli, Pseudomonas aeruginosa, Klebsiella species, or Stenotrophomonas maltophilia between January1, 2015 and August 31, 2020. Isolates were excluded if obtained from same patient and source within 90 days or if patient ≤7 days of life or admitted from a referring hospital. Data collection included demographics and clinical parameters, and culture/susceptibility data. The primary objective was comparison of pathogens and clinical parameters in those with and without third-generation cephalosporin resistance. The secondary objectives included a comparison between those with and without ceftazidime exposure and identification of factors associated with resistance. Comparisons were made using χ2, Fisher exact tests, or Wilcoxon tests. A logistic regression was used to identify risk factors for resistance. RESULTS: Overall, 349 isolates, representing 215 patients, were included. The most common source was endotracheal (n = 192, 55.0%) and pathogens were E coli (31.8%) and P aeruginosa (29.2%). Overall, 12.3% (n = 43) were resistant and these were obtained after longer parenteral nutrition (PN), central line access, and antibiotic days versus susceptible isolates. Higher resistance was noted after ceftazidime exposure versus no exposure, 19.1% versus 6.6%. Each day of ceftazidime was associated with 13% greater odds of P aeruginosa resistance (adjusted odds ratio: 1.13 [95% confidence interval: 1.03-1.23]). CONCLUSION AND RELEVANCE: Ceftazidime duration was associated with increased risk for P aeruginosa resistance. Additional studies are needed to confirm these findings.

Ampicillin Dose for Early and Late-Onset Group B Streptococcal Disease in Neonates.

Ampicillin is frequently used in neonates for early- and late-onset group B streptococcal (GBS) disease. In 2019, the American Academy of Pediatrics (AAP) published guidelines for GBS which included updated dosing recommendations for ampicillin for bacteremia and provided specific dosing recommendations for meningitis. The dosing recommendations in the guidelines were based off the 2018 Report of the Committee on Infectious Diseases (i.e., Red Book), which differed from the 2015 Red Book. For bacteremia, no dosing changes were recommended for ampicillin dosing in neonates ≤ 7 days of postnatal age (PNA), but less frequent dosing intervals were recommended for neonates > 7 days PNA. For meningitis, increased dosing recommendations were provided in the update. However, the rationale and supporting evidence for these changes were not provided. A literature search was performed to review articles pertaining to the pharmacokinetics (PK), pharmacodynamics (PD) and safety of ampicillin in neonates. The ampicillin dosing recommendations in the AAP guidelines were mainly supported by a 2014 publication that evaluated the PK and PD of ampicillin in neonates with gestational age (GA) of 24 to 41 weeks and PNA of 0 to 25 days. The proposed dosing from this study for bacteremia is included in the 2018 Red Book and 2019 guidelines. For meningitis, no supporting evidence was identified for the dosing recommendations in the 2018 Red Book and 2019 guidelines. Only one study has evaluated ampicillin concentrations in cerebrospinal fluid, but proposed dosing from this study was much lower than that included in the guidelines. The high ampicillin doses for GBS meningitis should be used with caution, as high ampicillin concentrations have been associated with seizures and no studies have evaluated efficacy of this dosing strategy. The purpose of this review is to identify key pieces of literature regarding dosing recommendations and safety of ampicillin in neonates. KEY POINTS: · Recent guidelines provide dosing recommendations for ampicillin, but the supporting evidence is not included.. · Literature supporting evidence for ampicillin dosing for bacteremia is available, but not for dosing for meningitis.. · Recommended meningitis dose may result in supratherapeutic concentrations and increase seizure risk..

Frequency and Severity of Chlorothiazide-Induced Hyponatremia in the Neonatal Intensive Care Unit.

OBJECTIVE: Although thiazide diuretics are commonly used in the neonatal intensive care unit (NICU), the risk of thiazide-induced hyponatremia in infants has not been well documented. The primary objective of this study was to determine the frequency and severity of hyponatremia in neonates and infants receiving enteral chlorothiazide. Secondary objectives included identifying: (1) percent change in serum sodium from before chlorothiazide initiation to nadir, (2) time to reach nadir serum sodium concentration, and (3) percentage of patients on chlorothiazide receiving sodium supplementation. STUDY DESIGN: This was a retrospective cohort study of NICU patients admitted between July 1, 2014, and July 31, 2019, who received ≥1 dose of enteral chlorothiazide. Mild, moderate, and severe hyponatremia were defined as serum sodium of 130 to 134 mEq/L, 120 to 129 mEq/L, and less than 120 mEq/L, respectively. Data including serum electrolytes, chlorothiazide dosing, and sodium supplementation were collected for the first 2 weeks of therapy. Descriptive and inferential statistics were performed in SAS software, Version 9.4. RESULTS: One hundred and seven patients, receiving 127 chlorothiazide courses, were included. The median gestational age at birth and postmenstrual age at initiation were 26.0 and 35.9 weeks, respectively. The overall frequency of hyponatremia was 35.4% (45/127 courses). Mild, moderate, and severe hyponatremia were reported in 27 (21.3%), 16 (12.6%), and 2 (1.6%) courses. The median percent decrease in serum sodium from baseline to nadir was 2.9%, and the median time to nadir sodium was 5 days. Enteral sodium supplements were administered in 52 (40.9%) courses. Sixteen courses (12.6%) were discontinued within the first 14 days of therapy due to hyponatremia. CONCLUSION: Hyponatremia occurred in over 35% of courses of enteral chlorothiazide in neonates and infants. Given the high frequency of hyponatremia, serum sodium should be monitored closely in infants receiving chlorothiazide. Providers should consider early initiation of sodium supplements if warranted. KEY POINTS: · One-third of infants on chlorothiazide develop hyponatremia.. · Nadir serum sodium typically occurs within 5 days.. · Monitor sodium closely after chlorothiazide initiation..

Infant Essential Fatty Acid Status Is Not Associated With Postoperative Wound Complication Severity.

BACKGROUND: Neonates are susceptible to postoperative wound complications (POWCs), as prematurity, hypoxia, steroid use, immunosuppression, and malnutrition are all common comorbidities. Critically ill infants, dependent on parenteral nutrition, are at even further risk of developing essential fatty acid deficiency (EFAD). We hypothesized that POWC severity and EFAD were associated because of increased susceptibility to infections and impaired wound healing seen with EFAD. METHODS: Institutional review board-approved (OUHSC10554), retrospective review from our academic Level IV Neonatal Intensive Care Unit. Infants aged <1 y who underwent a fascial-compromising gastrointestinal surgery from June 1, 2015, to March 15, 2019, and who had essential fatty acids (EFAs) measured ±2 wk from surgery were included. Three blinded investigators independently categorized POWC using the World Union of Wound Healing Society Surgical Wound Grading System. Infants were categorized into three groups: no POWC, POWC Grades 1 and 2 (superficial tissue nonintegrity), and POWC Grades 3 and 4 (deep tissue nonintegrity and complete dehiscence). EFA status and other possible POWC-associated factors were analyzed to determine any association with wound severity. RESULTS: Fifty infants met the inclusion criteria. Half (25/50) had no POWC, 30% (15/50) had Grade 1 or 2, and 20% (10/50) had Grade 3 or 4. We found no association between EFAD and POWC severity. CONCLUSIONS: In our cohort, EFA status did not predict POWC severity. At this time, we cannot suggest delaying elective surgical procedures to correct EFAD as an approach to preventing POWC.

Conversion From Continuous Infusion Fentanyl to Continuous Infusion Hydromorphone in the Pediatric Intensive Care Unit.

BACKGROUND: Opioid rotations from fentanyl to hydromorphone may reduce opioid/sedative exposure in critically ill children. OBJECTIVE: The primary objective was to determine the conversion percentage from fentanyl to hydromorphone infusions using equianalgesic conversions (0.1 mg fentanyl = 1.5 mg hydromorphone). Secondary objectives included identification of the median time and hydromorphone rate at stabilization (defined as the first 24-hour period no hydromorphone rates changed, 80% of State Behavioral Scale [SBS] scores between 0 and -1, and <3 hydromorphone boluses administered). Additional outcomes included a comparison of opioid/sedative requirements on the day of conversion versus the three 24-hour periods prior to conversion. METHODS: This retrospective study included children <18 years old converted from fentanyl to hydromorphone infusions over 6.3 years. Linear mixed models were used to determine if the mean cumulative opioid/sedative dosing differed from the day of conversion versus three 24-hour periods prior to conversion. RESULTS: A total of 36 children were converted to hydromorphone. The median conversion percentage of hydromorphone was 86% of their fentanyl dose (interquartile range [IQR] = 67-100). The median hydromorphone rate at stabilization was 0.08 mg/kg/h (IQR = 0.05-0.1). Eight (22%) were stabilized on their initial hydromorphone rate; 8 (22%) never achieved stabilization. Patients had a significant decrease in opioid dosing on the day of conversion versus the 24-hour period prior to conversion but no changes in sedative dosing following conversion. CONCLUSION AND RELEVANCE: A median 14% fentanyl dose reduction was noted when transitioning to hydromorphone. Further exploration is needed to determine if opioid rotations with hydromorphone can reduce opioid/sedative exposure.

Comparison of Clinical Outcomes and Medication Use of Obese Versus Nonobese Children Admitted to the Pediatric Intensive Care Unit.

Background: Few studies have compared clinical outcomes and medication use between obese and nonobese children in the pediatric intensive care unit (PICU). Objectives: The primary objective was to compare clinical outcomes including mortality, PICU length of stay (LOS), and mechanical ventilation (MV) requirement between obese and nonobese children. Secondary objectives included analysis of factors associated with these outcomes and medication use between groups. Methods: This retrospective study included children 2 to 17 years old admitted to the PICU over a 1-year time frame. Patients were categorized as obese, body mass index (BMI) ≥ 95th percentile, and nonobese (BMI < 95th percentile). Three binary regression models assessed the impact of obesity on clinical outcomes. Results: There were 834 admissions, with 22.1% involving obese children. There was no difference in mortality, MV requirement, or PICU LOS between groups. There were no associations with obesity and clinical outcomes found, but an association was noted for medication classes and receipt of continuous infusions on clinical outcomes. There was no difference noted in the median number (interquartile range [IQR]) of medications between obese and nonobese children, 8 (6-13) versus 9 (6-15), P = .38, but there was a difference in patients receiving a continuous infusion between obese and nonobese children, 24.4% versus 8.8%, P < .01. The 15 most used medications in both groups included analgesics, antimicrobials, corticosteroids, bronchodilators, and gastrointestinal agents. Conclusions: One-fifth of all admissions included obese children. Obesity was not associated with mortality, PICU LOS, and MV requirement, but the number of medication classes and continuous infusions were associated with these outcomes.

Hyponatremia With Intravenous Sulfamethoxazole/Trimethoprim in Children.

Background: Intravenous (IV) sulfamethoxazole/trimethoprim (SMX/TMP) has been associated with hyponatremia in adults. Objective: The primary objective was to identify the number of patients with a serum sodium <135 mEq/L. Secondary objectives between the hyponatremic versus nonhyponatremic groups included demographic comparisons, median serum sodium concentrations, SMX/TMP cumulative dose, number of diuretics, and other medications causing hyponatremia. Methods: This was a retrospective study of children <18 years receiving IV SMP/TMX. Comparisons were conducted via Mann-Whitney-Wilcoxon and Mantel-Haenszel χ2 tests with an a priori P value <0.05. Results: Sixty-one patients received 66 total courses; 20 courses (30.3%) were associated with hyponatremia with a decrease in the median nadir serum sodium concentration of 133 and 138 mEq/L in the hyponatremic and nonhyponatremic groups, respectively (P<0.001). The median age (interquartile range) was lower in the hyponatremic versus nonhyponatremic group, but this was not statistically significant: 0.6 (0.1-5.5) versus 3.9 (0.3-11.0) years; P=0.077. There was no significant difference in the median cumulative dose (mg/kg) between groups; P=0.104. In addition, there was a significant difference in the number of children in the hyponatremic versus nonhyponatremic groups receiving diuretics (16 [80.0%] vs 23 [50.0%], P=0.023) and other medications that cause hyponatremia (7 [35.0%] vs 5 [10.9%], P=0.034), respectively. Furosemide was noted to be the medication most associated with hyponatremia. Conclusion and Relevance: Approximately one-third administered IV SMX/TMP developed hyponatremia. Concomitant furosemide administration was one of the most common risk factors. Clinicians should be aware of this potential adverse event when initiating IV SMX/TMP in children.

Prediction and Comparison of Fentanyl Infusion Pharmacokinetics in Obese and Nonobese Children.

OBJECTIVES: To compare fentanyl infusion pharmacokinetic variables in obese children and nonobese children. DESIGN: A pharmacokinetic simulation study. SETTING: We used a semi-physiologically based pharmacokinetic model to generate fentanyl pharmacokinetic variables. SUBJECTS: Simulations of pharmacokinetic variables were based on historical inpatient demographic data in less than 18-year-olds. INTERVENTIONS: Obese children were defined as children less than 2 years with weight-for-length greater than or equal to 97.7th percentile or body mass index-for-age greater than or equal to 95th percentile for greater than or equal to 2-17-year-olds. MEASUREMENTS AND MAIN RESULTS: Overall, 4,376 patients were included, with 807 (18.4%) classified as obese children. The majority (52.9%) were male, with a median age of 8.1 years (interquartile range, 4.3-13.0 yr). The differences in total clearance (CLS), volume of distribution at steady-state values, weight-normalized CLS, and weight-normalized volume of distribution at steady state were assessed in obese children and nonobese children. Multivariable analyses indicated that obesity was significantly associated with a higher CLS in obese children greater than 6-year-olds (p < 0.0375). However, there was an 11-30% decrease in weight-normalized CLS in obese children versus nonobese children in all age groups (p < 0.05). Both volume of distribution at steady state and weight-normalized volume of distribution at steady state increased significantly in obese children compared with nonobese children (p < 0.05). Fentanyl plasma concentration-time profiles of obese children and nonobese children pairs (ages 4, 9, and 15) receiving 1 µg/kg/hr using total body weight were also compared. Steady-state concentrations of the obese children using similar weight-based dosing increased by 25%, 77%, and 44% in comparison to nonobese children 4-, 9-, and 15-year-olds, respectively. Time to steady state and elimination half-lives were two- to four-fold longer in obese children. An additional simulation was conducted for 15-year-old obese children and nonobese children using a fixed dose of 50 µg/hr and it provided similar pharmacokinetic profiles. CONCLUSIONS: CLS may increase less than proportional to weight in obese children greater than 6-year-olds, while volume of distribution at steady state increases more than proportional to weight in all obese children compared with nonobese children. Weight-based dosing in obese children may cause an increase in steady-state concentration while prolonging the time to steady state. Exploring alternative dosing strategies for obese children is warranted.

Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy.

BACKGROUND: Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients. OBJECTIVE: To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin. METHODS: This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile-associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications. RESULTS: Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 ± 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007). CONCLUSION: Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed.

Off-Label Medication use in Children, More Common than We Think: A Systematic Review of the Literature.

CONTENT: Clinician prescribing of off-label medications is common due to a lack of pediatric-specific data regarding the dosing, efficacy and safety of medications regularly prescribed to children. OBJECTIVE: This systematic review summarizes the published incidence of off-label medication use in children from the past 10 years. We also performed a retrospective chart review to determine the incidence of off-label prescriptions for children seen in the OU Physicians clinics. DATA SOURCES: We conducted a literature search of PubMed and OVID Medline from 2007 to 2017. Search terms included off-label use of medications and all child. For the local review, the outpatient electronic medical record (EMR) was queried. STUDY SELECTION: Studies were eligible for inclusion if the study included children < 18 years of age, defined off-label use in the paper, and included the incidence of off-label drug use. DATA EXTRACTION: Each review author extracted the study data from their assigned studies. For the retrospective chart review, the EMR was queried for patients <21 years of age who had a clinic visit and received a new prescription during 2017. RESULTS: We identified 31 studies, with off-label prescription rates from 3.2 % to 95%. The local retrospective chart review included 1,323 prescriptions; 504 were off-label (38.1%) and 819 were approved. The frequency of off-label prescriptions does not differ significantly between the meta-analysis from the systematic review and the local retrospective chart review (30.9% vs 38.1%). CONCLUSIONS: The use of off-label medications in children remains a common practice for pediatric providers.

Detectable Concentrations of Inhaled Tobramycin in Critically Ill Children Without Cystic Fibrosis: Should Routine Monitoring Be Recommended?

OBJECTIVES: To determine the percentage of detectable tobramycin troughs and acute kidney injury in critically ill children without cystic fibrosis on inhaled therapy. DESIGN: Historic cohort. SETTING: Academic hospital. PATIENTS: Forty children less than 18 years receiving inhaled tobramycin across 6.5 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary objective was to determine the percentage of detectable tobramycin troughs greater than or equal to 0.5 µg/mL. Secondary objectives included a comparison of acute kidney injury in children with and without detectable troughs. Twenty-two (55%) had trough concentrations obtained. Ten of these (45.5%) had detectable concentrations, with a median of 0.85 µg/mL (interquartile range, 0.5-2.0). There was no statistical significance between the detectable and nondetectable groups in age, gender, and method of administration. However, patients in the detectable group tended to be younger than nondetectable group and more likely to have a tracheotomy. There was a clinically significant decrease in estimated glomerular filtration rate in the detectable trough group. CONCLUSIONS: Detectable troughs were noted in almost half of patients with concentrations obtained. A clinically significant decrease in estimated glomerular filtration rate was noted in patients with detectable concentrations. Continued work should be directed to better understand outcomes and monitoring in children requiring inhaled tobramycin.

Review of Metronidazole Dosing in Preterm Neonates.

Metronidazole dosing recommendations vary significantly for premature infants in pediatric dosing references and can result in confusion for prescribers. We performed a literature search identifying articles evaluating the pharmacokinetics and dosing of metronidazole in premature infants. The search was limited to English-language articles in MEDLINE (January 1946 to December 2016), EMBASE (January 1974 to December 2016), and International Pharmaceutical Abstracts (January 1970 to December 2016). Reference citations from relevant articles were also reviewed. Six pharmacokinetic studies, representing 152 neonates, were included; however, only three of the well-defined studies were reviewed in depth, and the other three studies were considered foundational. The pharmacokinetic studies included in this review indicate that some published dosing recommendations in pediatric dosing references may result in subtherapeutic metronidazole concentrations. Therefore, postmenstrual age based dosing recommendations were provided by the authors of these pharmacokinetic studies based on a pharmacodynamic target of 6 to 8 mg/L; yet, these dosing recommendations differ from one another. The pharmacokinetic studies included in this review provide some guidance to dosing; however, a major limitation is that outcomes of clinical efficacy and safety were not evaluated. Future studies targeting the optimal dosing and serum concentrations required for clinical efficacy are needed.

Ketamine Continuous Infusions in Critically Ill Infants and Children.

OBJECTIVE: To review the role of ketamine continuous infusions (CINs) in critically ill children for sedation and analgesia, withdrawal, and bronchospasm. DATA SOURCES: Relevant articles were identified using MEDLINE (1946 to December 2015), EMBASE (1988 to December 2015), International Pharmaceutical Abstracts (1970 to December 2015), and the Cochrane Library (1996 to December 2015) using the terms ketamine, children, and CIN. STUDY SELECTION AND DATA EXTRACTION: All English-language articles in humans identified from data sources were evaluated. Three studies and 8 case reports/series representing 74 patients were included. DATA SYNTHESIS: Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that blocks glutamate in the limbic system, resulting in sedation and analgesia. Additionally, it provides bronchodilation by increasing catecholamine transmission and stimulation of ß2 receptors. The majority of reports evaluated ketamine for bronchospasm in children with status asthmaticus or bronchospasm refractory to conventional treatments. A total of 72 patients (97.3%) received a loading dose ranging from 0.2 to 2 mg/kg prior to CIN initiation. The CIN dosing range was 0.2 to 3.6 mg/kg/h. Children who received ketamine for sedation or opioid withdrawal received a lower dose than children initiated on it for bronchospasm: 0.24 to 0.9 versus 0.2 to 3.6 mg/kg/h, respectively. Duration of use ranged from 1 to 96 hours. Six of the reports mentioned that the ketamine CIN was tapered prior to discontinuation. Approximately 10.8% of patients included in the analysis experienced adverse events, with only 3 children (4.1%) experiencing emergence phenomenon. CONCLUSIONS: Limited evidence was noted, so ketamine CINs could be considered an adjunct therapy at this time. Further prospective studies should be conducted to determine ketamine's role in sedation and analgesia, withdrawal treatment, and bronchospasm treatment.

Caregiver Perception, Self-efficacy, and Knowledge of Methadone Tapers for Children With Iatrogenic Opioid Abstinence Syndrome.

Background: There are no definitive guidelines regarding the management of iatrogenic opioid abstinence syndrome (IOAS), but methadone tapers are one common approach. Methadone tapers can be complex for caregivers to manage, and there is a paucity of data about caregiver experiences administering medication tapers postdischarge. Objective: The primary objective was to describe caregiver perception, self-efficacy, and knowledge of administering methadone tapers. Secondary objectives included an assessment of the change in self-efficacy and knowledge of methadone and IOAS before and after discharge as well as clinical outcomes occurring postdischarge. Methods: This was an exploratory, descriptive, institutional review board-approved study surveying caregivers of children receiving methadone tapers for IOAS. Caregivers were included if they had a child ≤12 years of age discharged to home on a methadone taper. The study consisted of 2 phases: a questionnaire and observation/counseling session predischarge and a telephone interview after taper completion. Univariate descriptive statistics were utilized for data analysis. Results: Phase 1 of the study was completed by 12 caregivers, and only 5 completed phase 2. The majority of caregivers were completely confident predischarge (83.3%) and postdischarge (80%) in administering methadone as prescribed. However, some caregivers were confused about the purpose of the taper and experienced difficulty in measuring oral solutions. Conclusions: Despite high self-efficacy, caregivers experienced difficulties in understanding taper management and during the observation session. The results of this study suggest presenting information to caregivers utilizing minimal medical jargon, conducting a counseling/observation session predischarge, and utilizing the teach-back method with caregivers to assess for understanding.

External validation of the medication taper complexity score for methadone tapers in children with opioid abstinence syndrome.

BACKGROUND: Methadone is commonly prescribed for children with opioid abstinence syndrome (OAS) as a taper schedule over several days to weeks. The Medication Taper Complexity Score (MTCS) was developed to evaluate outpatient methadone tapers. OBJECTIVE: To further validate the MTCS and determine if it is a reliable tool for clinicians to use to assess the complexity of methadone tapers for OAS. METHODS: An expert panel of pediatric clinical pharmacists was convened. Panel members were provided 9 methadone tapers (ie, "easy," "medium," and "difficult") to determine construct and face validity of the MTCS. The primary objective was to further establish reliability and construct/face validity of the MTCS. The secondary objective was to assess the reliability of the MTCS within and between tapers. Instrument reliability was assessed using a Pearson correlation coefficient; with 0.8 as the minimum acceptable coefficient. Construct (divergent) validity was assessed via a repeated-measures ANOVA analysis (Bonferroni post hoc analyses) of the mean scores provided by panel members. RESULTS: Six panel members were recruited from various geographical locations. Panel members had 18.3 ± 5.5 years of experience, with practice expertise in general pediatrics, hematology/oncology, and the pediatric and neonatal intensive care unit. The MTCS had a reliability coefficient of .9949. There was vivid discrimination between the easy, medium, and difficult tapers; P = .001. The panel recommended minor modifications to the MTCS. CONCLUSIONS: The MTCS was found to be a reliable and valid tool. Overall, the panel felt that the MTCS was easy to use and had potential applications in both practice and research.

Association of fentanyl with neurodevelopmental outcomes in very-low-birth-weight infants.

BACKGROUND: Opioids are commonly used in the neonatal intensive care unit (NICU). Negative neurodevelopmental effects in the short-term setting have been associated with opioids ; however, long-term studies have been limited. OBJECTIVE: The primary objective was to determine if there is a dose relationship between fentanyl and neurodevelopmental outcomes, as measured by Bayley Scales of Infant and Toddler Development (Bayley-III) composite scores for language, cognition, and motor skills. Secondary objectives included comparison of Bayley-III scores and neurodevelopmental impairment classification based on fentanyl exposure. METHODS: A retrospective evaluation of 147 very-low-birth-weight infants with Bayley-III scores obtained at a chronological age of 6 months to 2 years at clinic follow-up was conducted. Univariate and multivariable linear regression analyses were used to determine if there was a dose-related association between fentanyl and neurodevelopmental outcomes. To evaluate secondary outcomes, patients were divided based on cumulative fentanyl dose ("high-dose" versus "low/no-dose"). RESULTS: The univariate analysis found a statistically significant decrease in cognition (P = .034) and motor skills scores (P = .006). No association was found in the multi-variable regression between fentanyl cumulative dose and Bayley-III scores. There was a significant decrease in the motor skills score between the high-dose versus low/no-dose group, 94 ± 20 versus 102 ± 15, respectively (P = .026); however, no statistical differences were noted for language or cognition scores or neurological impairment classification. CONCLUSIONS: When controlling for other variables, the cumulative fentanyl dose did not correlate with neurodevelopmental outcomes. Further evaluation of benefits and risks of opioids in premature infants are needed.

Pharmacologic Management of Sialorrhea in Neonatal and Pediatric Patients.

Sialorrhea, defined as an excess flow of saliva or excessive secretions, is common in patients with cerebral palsy and other neurologic disorders and is associated with clinical complications such as increased risk of local skin reactions, infections, aspiration, pneumonia, and dehydration. Upon failure of non-pharmacologic measures, clinicians have several noninvasive pharmacologic options available to manage sialorrhea. This review of the literature provides detailed descriptions of medications used, efficacy, safety, and practical considerations for use of non-injectable pharmacologic agents. The literature search included published -human studies in the English language in PubMed and Google Scholar from 1997 to 2022. Relevant citations within articles were also screened. A total of 15 studies representing 719 pediatric patients were included. Glycopyrrolate, atropine, scopolamine, and trihexyphenidyl all have a potential role for sialorrhea management in children; however, glycopyrrolate remains the most studied option with 374 (n = 52.0%) of the 719 patients included in the systematic review receiving this medication. Overall, glycopyrrolate showed similar efficacy but higher tolerability than its comparators in 2 comparative studies and is often considered the first-line agent. Patient-specific (age, route of administration) and medication-specific (dosage formulation, medication strength) considerations must be weighed when initiating a new therapy or switching to another medication upon treatment failure. Owing to the high propensity of adverse events with all agents, clinicians should consider initiating doses at the lower end of the dosage range, as previous studies have noted a dose-dependent relationship.