Impact of Personal Protective Equipment on the Performance of Emergency Pediatric Procedures by Prehospital Providers.

BACKGROUND: Personal protective equipment (PPE) is worn by prehospital providers (PHPs) for protection from hazardous exposures. Evidence regarding the ability of PHPs to perform resuscitation procedures has been described in adult but not pediatric models. This study examined the effects of PPE on the ability of PHPs to perform resuscitation procedures on pediatric patients. METHODS: This prospective study was conducted at a US simulation center. Paramedics wore normal attire at the baseline session and donned full Level B PPE for the second session. During each session, they performed timed sets of psychomotor tasks simulating clinical care of a critically ill pediatric patient. The difference in time to completion between baseline and PPE sessions per task was examined using Wilcoxon signed-rank tests. RESULTS: A total of 50 paramedics completed both sessions. Median times for task completion at the PPE sessions increased significantly from baseline for several procedures: tracheal intubation (+4.5 s; P = 0.01), automated external defibrillator (AED) placement (+9.5 s; P = 0.01), intraosseous line insertion (+7 s; P < 0.0001), tourniquet (+8.5 s; P < 0.0001), intramuscular injection (+21-23 s, P < 0.0001), and pulse oximetry (+4 s; P < 0.0001). There was no significant increase in completion time for bag-mask ventilation or autoinjector use. CONCLUSIONS: PPE did not have a significant impact on PHPs performing critical tasks while caring for a pediatric patient with a highly infectious or chemical exposure. This information may guide PHPs faced with the situation of resuscitating children while wearing Level B PPE.

Endoscopic Ultrasound Quality Metrics in Clinical Practice.

Recent advances in endoscopic ultrasound (EUS), particularly EUS-guided tissue acquisition, may have affected EUS procedural performance as measured by current American Society for Gastrointestinal Endoscopy (ASGE)/American College of Gastroenterology (ACG) quality indicators. Our study aims to assess how these quality metrics are met in clinical practice. We retrospectively analyzed 732 EUS procedures; data collected were procedural indications, technical aspects and outcomes, completeness of documentation, and malignancy staging. EUS was performed in 660 patients for a variety of indications. All ASGE/ACG EUS procedural quality metrics were met or exceeded. Intervention was successful in 97.7% (715/732) of cases, with complication rate of 0.4% (3/732). EUS outcomes changed clinical management in 58.7% of all cases and in 91.2% of malignancy work-up cases; in 26.0% of suspected choledocholithiasis cases, endoscopic retrograde cholangiopancreatography (ERCP) was avoided after EUS. Locoregional EUS staging was accurate in 61/65 (93.8%) cases of non-metastatic disease and in 15/22 (68.2%) cases of metastatic disease. Pancreatic mass malignancy detection rate with EUS-guided fine needle aspiration (FNA) or fine needle biopsy (FNB) was 75.8%, with a sensitivity of 96.2%; a significant increase in detection rate from 46.2% (6/13) to 95.0% (19/20) (p = 0.0026) was observed with a transition to the predominant use of FNB for tissue acquisition. All ASGE/ACG EUS quality metrics were met or exceeded for EUS procedures performed for a wide variety of indications in a diverse patient population. EUS was instrumental in changing clinical management, with a low complication rate. The malignancy detection rate in pancreatic masses significantly increased with FNB use.

Improved diagnostic yield of endoscopic ultrasound-fine needle biopsy with histology specimen processing.

BACKGROUND: Endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) has emerged as a safe, efficacious alternative to fine needle aspiration (FNA) for tissue acquisition. EUS-FNB is reported to have higher diagnostic yield while preserving specimen tissue architecture. However, data on the optimal method of EUS-FNB specimen processing is limited. AIM: To evaluate EUS-FNB with specimen processing as histology vs EUS-FNA cytology with regards to diagnostic yield and specimen adequacy. METHODS: All EUS-FNA and EUS-FNB performed at our institution from July 1, 2016, to January 31, 2018, were retrospectively analyzed. We collected data on demographics, EUS findings, pathology, clinical outcomes, and procedural complications in two periods, July 2016 through March 2017, and April 2017 through January 2018, with predominant use of FNB in the second data collection time period. FNA specimens were processed as cytology with cell block technique and reviewed by a cytopathologist; FNB specimens were fixed in formalin, processed for histopathologic analysis and immunohistochemical staining, and reviewed by an anatomic pathologist. Final diagnosis was based on surgical pathology when available, repeat biopsy or imaging, and length of clinical follow up. RESULTS: One hundred six EUS-FNA and EUS-FNB procedures were performed. FNA alone was performed in 17 patients; in 56 patients, FNB alone was done; and in 33 patients, both FNA and FNB were performed. For all indications, diagnostic yield was 47.1% (8/17) in FNA alone cases, 85.7% (48/56) in FNB alone cases, and 84.8% (28/33) in cases where both FNA and FNB were performed (P = 0.0039). Specimens were adequate for pathologic evaluation in 52.9% (9/17) of FNA alone cases, in 89.3% (50/56) of FNB alone cases, and 84.8% (28/33) in cases where FNA with FNB were performed (P = 0.0049). Tissue could not be aspirated for cytology in 10.0% (5/50) of cases where FNA was done, while in 3.4% (3/89) of FNB cases, tissue could not be obtained for histology. In patients who underwent FNA with FNB, there was a statistically significant difference in both specimen adequacy (P = 0.0455) and diagnostic yield (P = 0.0455) between the FNA and FNB specimens (processed correspondingly as cytology or histology). CONCLUSION: EUS-FNB has a higher diagnostic yield and specimen adequacy than EUS-FNA. In our experience, specimen processing as histology may have contributed to the overall increased diagnostic yield of EUS-FNB.

Atypical Presentation of Acquired Hypoganglionosis in a Patient Taking Clozapine.

Acquired hypoganglionosis (HG) is a rare enteric gastrointestinal neuromuscular disorder previously associated with chronic inflammation that can lead to constipation, ileus, and even death. There is little known about the pathophysiology of acquired hypoganglionosis, and it is unclear if medications are related to the development of the disease. Clozapine is an atypical antipsychotic used to treat refractory schizophrenia that is well known for its side effects including agranulocytosis and gastrointestinal dysmotility. This is an unusual case of acquired hypoganglionosis in a patient with anticholinergic toxicity on clozapine therapy.

Wide variation in caffeine discontinuation timing in premature infants.

OBJECTIVE: To assess site variability and concomitant respiratory support related to the timing of caffeine discontinuation, and compare clinical characteristics of infants who discontinued caffeine before vs. within the last week of hospitalization. STUDY DESIGN: Cohort study of 81,110 infants <35 weeks gestational age and <1500 g birth weight discharged from 304 neonatal intensive care units from 2001-2016. RESULTS: The mean postmenstrual age at caffeine discontinuation ranged from 32 to 37 weeks among sites. Respiratory support at the time of discontinuation was common, but variable, with 0-57% of infants receiving positive airway pressure at caffeine discontinuation by site. Infants who discontinued caffeine within the last week of hospitalization had longer total duration of caffeine, but were discharged from the hospital at an earlier postmenstrual age. CONCLUSION: There was substantial variability among sites in the timing of caffeine discontinuation before discharge and respiratory support at the time of caffeine discontinuation.

Evaluating the risk of adverse events with interventional endoscopic retrograde cholangiopancreatography and endoscopic ultrasound procedures in cirrhotic patients.

BACKGROUND: Hepatic cirrhosis is associated with greater adverse event rates following surgical procedures and is thought to have a higher risk of complications with interventional procedures in general. However, these same patients often require interventional gastrointestinal procedures such as endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS). While studies examining this scenario exist, the overall body of evidence for adverse event rates associated with ERCP/EUS procedures is more limited. We sought add to the literature by examining the incidence of adverse events after ERCP/EUS procedures in our safety-net hospital population with the hypothesis that severity of cirrhosis correlates with higher adverse event rates. AIM: To examine whether increasing severity of cirrhosis is associated with greater incidence of adverse events after interventional ERCP/EUS procedures. METHODS: We performed a retrospective study of patients diagnosed with hepatic cirrhosis who underwent ERCP and/or EUS-guided fine needle aspirations/fine needle biopsies from January 1, 2016 to March 14, 2019 at our safety net hospital. We recorded Child-Pugh and Model for End-stage Liver Disease (MELD-Na) scores at time of procedure, interventions completed, and 30-day post-procedural adverse events. Statistical analyses were done to assess whether Child-Pugh class and MELD-Na score were associated with greater adverse event rates and whether advanced techniques (single-operator cholangioscopy, electrohydraulic lithotripsy/laser lithotripsy, or needle-knife techniques) were associated with higher complication rates. RESULTS: 77 procedures performed on 36 patients were included. The study population consisted primarily of middle-aged Hispanic males. 30-d procedure-related adverse events included gastrointestinal bleeding (7.8%), infection (6.5%), and bile leak (2%). The effect of Child-Pugh class C vs class A and B significantly predicted adverse events (ß = 0.55, P < 0.01). MELD-Na scores also significantly predicted adverse events (ß = 0.037, P < 0.01). Presence of advanced techniques was not associated with higher adverse events (P > 0.05). When MELD-Na scores were added as predictors with the effect of Child-Pugh class C, logistic regression showed MELD-Na scores were a significant predictor of adverse events (P < 0.01). The findings held after controlling for age, gender, ethnicity and repeat cases. CONCLUSION: Increasing cirrhosis severity predicted adverse events while the presence of advanced techniques did not. MELD-Na score may be more useful in predicting adverse events than Child-Pugh class.

Dosing and Safety of Off-label Use of Caffeine Citrate in Premature Infants.

OBJECTIVE: To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants. STUDY DESIGN: We used electronic health records (2010-2013) from 4 neonatal intensive care units to identify infants of ≤28 weeks of gestational age exposed to caffeine citrate. Safety outcomes included death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events. RESULTS: Of 410 infants with a median (IQR) gestational age of 26 (24-27) weeks, 95% received caffeine citrate for >0 days. Infants received a median (IQR) daily dose of 8 (5-10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis. CONCLUSIONS: Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose, or therapy duration was not associated with increased risk of necrotizing enterocolitis.

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus.

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200-600 ng/mL.

Prolonged furosemide exposure and risk of abnormal newborn hearing screen in premature infants.

BACKGROUND: At very high doses, furosemide is linked to ototoxicity in adults, but little is known about the risk of hearing loss in premature infants exposed to furosemide. AIMS: Evaluate the association between prolonged furosemide exposure and abnormal hearing screening in premature infants. STUDY DESIGN: Using propensity scoring, infants with prolonged (≥28 days) exposure to furosemide were matched to infants never exposed. The matched sample was used to estimate the impact of prolonged furosemide exposure on the probability of an abnormal hearing screen prior to hospital discharge. SUBJECTS: A cohort of infants 501-1250 g birth weight and 23-29 weeks gestational age discharged home from 210 neonatal intensive care units in the United States (2004-2013). OUTCOME MEASURES: We defined abnormal hearing screen as a result of either "fail" or "refer" for either ear. RESULTS: Altogether, 1020 infants exposed to furosemide for ≥28 days were matched to 790 unique infants never exposed, yielding a total of 1042 matches due to sampling with replacement and propensity score ties. Matching resulted in a population similar in baseline characteristics. After adjusting for covariates, the proportion of infants with an abnormal hearing screen in the furosemide-exposed group was not significantly higher than the never-exposed group (absolute difference 3.0% [95% CI -0.2-6.2%], P = 0.07). CONCLUSIONS: Prolonged furosemide exposure was associated with a positive, but not statistically significant, difference in abnormal hearing screening in premature infants. Additional studies with post-hospital discharge audiology follow-up are needed to further evaluate the safety of furosemide in this population.

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants.

BACKGROUND: Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. METHODS: To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to τ (AUCss,0-τ) and steady state maximal drug concentration (Cmaxss). Next, we used multivariable logistic regression to evaluate the association between simulated AUCss,0-τ and Cmaxss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUCss,0-τ and Cmaxss were reported. RESULTS: We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26-33) and postnatal age of 11 days (6-25). The median (interquartile range) piperacillin dose was 225 mg/kg/d (176-300). No significant associations were found between simulated piperacillin exposure (AUCss,0-τ and Cmaxss) and clinical and laboratory AEs. CONCLUSIONS: We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.

Safety of Enalapril in Infants Admitted to the Neonatal Intensive Care Unit.

Enalapril is used to treat hypertension and congestive heart failure in infants. However, enalapril is not labeled for neonates, and safety data in infants are sparse. To evaluate the safety of enalapril in young infants, we conducted a retrospective cohort study of infants who were exposed to enalapril in the first 120 days of life and were cared for in 348 neonatal intensive care units from 1997 to 2012. We determined the proportion of exposed infants who developed adverse events, including death, hypotension requiring pressors, hyperkalemia, and elevated serum creatinine. Using multivariable logistic regression, we examined risk factors for adverse events, including postnatal age at first exposure, exposure duration, gestational age group, small for gestational age status, race, sex, 5-min Apgar score, and inborn status. Of a cohort of 887,910 infants, 662 infants (0.07%) were exposed to enalapril. Among exposed infants, 142 infants (21%) suffered an adverse event. The most common adverse event was hyperkalemia (13%), followed by elevated serum creatinine (5%), hypotension (4%), and death (0.5%). Significant risk factors for adverse events included postnatal age <30 days at first exposure and longer exposure duration. This study is the largest to date examining the safety of enalapril in young term and preterm infants without significant structural cardiac disease.

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine.

BACKGROUND: Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. METHODS: Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. RESULTS: For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. CONCLUSIONS: This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration-response relationships.

Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach.

OBJECTIVES: Our study aimed to determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate. METHODS: We performed a literature search using PubMed and EMBASE to collect published safety, efficacy, and therapeutic monitoring data for 5 AEDs and extracted all relevant information into a drug- and study-specific drug database. For each AED, we summarized (1) type, severity, and incidence of toxicity-related adverse events and toxicity-associated range of drug doses or concentrations; (2) effective versus toxic concentration and dose (therapeutic range); and (3) therapeutic drug monitoring practices. We defined therapeutic index as the ratio of the minimum toxic concentration to the minimum effective concentration. RESULTS: We reviewed a total of 810 full-text articles and extracted data from 163. The literature suggests that the therapeutic index of phenytoin is 2. The therapeutic indices of phenobarbital and valproate exceed 2. There were insufficient data to precisely quantify the therapeutic indices of carbamazepine and lamotrigine. CONCLUSIONS: For some drugs, this approach offers a low-cost method of therapeutic index estimation. Our results can serve as preliminary data for future trials and as guidance for US Food and Drug Administration decision making regarding narrow therapeutic index classification.

Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal Transplant Patients.

BACKGROUND: Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially because of inconsistencies in sirolimus exposure-response relationships. METHODS: The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary health care system from 2008 to 2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to simulate sirolimus concentrations, and (3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors determined relationships between sirolimus exposure and adverse events (AEs) (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal function) and the composite efficacy end point of graft loss or rejection. RESULTS: The developed 2-compartment population PK model showed appropriate goodness of fit. In a late-phase (>12 months), postrenal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (P = 0.018) and decline in renal function (P = 0.006), respectively. CONCLUSIONS: Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function. However, the method was limited in its assessment of other AEs. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly transplanted patients with a higher propensity toward AEs or efficacy failure.

Hepatic decompensation/serious adverse events in post-liver transplantation recipients on sofosbuvir for recurrent hepatitis C virus.

AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection. METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome. RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m(2), 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases. CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.

Sedatives and Analgesics Given to Infants in Neonatal Intensive Care Units at the End of Life.

OBJECTIVE: To describe the administration of sedatives and analgesics at the end of life in a large cohort of infants in North American neonatal intensive care units. STUDY DESIGN: Data on mortality and sedative and analgesic administration were from infants who died from 1997-2012 in 348 neonatal intensive care units managed by the Pediatrix Medical Group. Sedatives and analgesics of interest included opioids (fentanyl, methadone, morphine), benzodiazepines (clonazepam, diazepam, lorazepam, midazolam), central alpha-2 agonists (clonidine, dexmedetomidine), ketamine, and pentobarbital. We used multivariable logistic regression to evaluate the association between administration of these drugs on the day of death and infant demographics and illness severity. RESULTS: We identified 19 726 infants who died. Of these, 6188 (31%) received a sedative or analgesic on the day of death; opioids were most frequently administered, 5366/19 726 (27%). Administration of opioids and benzodiazepines increased during the study period, from 16/283 (6%) for both in 1997 to 523/1465 (36%) and 295/1465 (20%) in 2012, respectively. Increasing gestational age, increasing postnatal age, invasive procedure within 2 days of death, more recent year of death, mechanical ventilation, inotropic support, and antibiotics on the day of death were associated with exposure to sedatives or analgesics. CONCLUSIONS: Administration of sedatives and analgesics increased over time. Infants of older gestational age and those more critically ill were more likely to receive these drugs on the day of death. These findings suggest that drug administration may be driven by severity of illness.

Bacterial meningitis in infants.

Neonatal bacterial meningitis is uncommon but devastating. Morbidity among survivors remains high. The types and distribution of pathogens are related to gestational age, postnatal age, and geographic region. Confirming the diagnosis is difficult. Clinical signs are often subtle, lumbar punctures are frequently deferred, and cerebrospinal fluid (CSF) cultures can be compromised by prior antibiotic exposure. Infants with bacterial meningitis can have negative blood cultures and normal CSF parameters. Promising tests such as the polymerase chain reaction require further study. Prompt treatment with antibiotics is essential. Clinical trials investigating a vaccine for preventing neonatal Group B Streptococcus infections are ongoing.

Dosing in neonates: special considerations in physiology and trial design.

Determining the right dose for drugs used to treat neonates is critically important. Neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination that make extrapolating dosages from adults and older children inappropriate. In spite of recent legislative efforts requiring drug studies in this population, most drugs given to neonates remain insufficiently studied. Many ethical and logistical concerns make designing studies in this age group difficult. Fortunately, specialized analytical techniques, such as the use of dried blood spots, scavenged sampling, population pharmacokinetics analyses, and sparse sampling, have helped investigators better define doses that maximize efficacy and safety. Through the use of these methods, successful clinical trials have resulted in recent changes to drug dosing in this population.