Elevated serum tobramycin concentrations after treatment with tobramycin inhalation in a preterm infant.

High-dose inhaled tobramycin has been increasingly used for treatment and suppression of Pseudomonas aeruginosa pulmonary infections, especially in patients with cystic fibrosis. The advantage of inhalation over other routes of administration is minimal systemic absorption, which reduces the potential for adverse effects. However, cases of adults who had elevated serum concentrations and experienced systemic adverse effects due to excessive systemic absorption after inhaled tobramycin have been reported. We describe a prematurely born infant with numerous congenital and acquired disorders who required assisted mechanical ventilation and a 60-day stay in the neonatal intensive care unit (NICU). Tracheostomy and mechanical ventilatory support were required throughout the infant's hospital stay. The patient developed several pulmonary infections caused by various bacteria. He was treated with multiple antibiotics, including two different dose preparations of inhaled tobramycin 80 mg and 300 mg, administered through the tracheostomy and the ventilator. The infant was given a total of five preparations of tobramycin 80 mg/dose and three of 300 mg/dose, for a total cumulative dose of 1,300 mg over a 6-day period. His tobramycin concentrations increased, prompting discontinuation of the inhaled tobramycin. The infant died on day 60. To our knowledge, this is the first report of elevated tobramycin concentrations after inhalation in an infant. Although studies have found that tobramycin is safe and effective, certain patient populations are more at risk for toxicity. Tobramycin concentrations should be closely monitored in patients with significant underlying renal disorders, especially those in age-group extremes.

Topical anesthesia in neonates: clinical practices and practical considerations.

During the past two decades there has been a substantial increase in the number and types of topical anesthetics available. Options for the prevention of neonatal pain associated with skin-breaking procedures were previously limited to injections of lidocaine hydrochloride. Topical anesthetics are now available as creams, gels, and a heat-activated patch system. Although lidocaine injection continues to be widely used for pain associated with circumcision, lumbar puncture, or placement of central venous lines, practical information regarding the use of newer agents in the neonate is needed. This review seeks to expand the options for topical anesthesia in neonates.

Neonatal facial coding system scores and spectral characteristics of infant crying during newborn circumcision.

OBJECTIVE: To determine the relations between Neonatal Facial Coding System (NFCS) scores and measures of infant crying during newborn circumcision. METHODS: Video and audio recordings were made of infant facial activity and cry sounds, respectively, during the lysis phase of circumcisions of 44 healthy term males (<3 d of age). All infants received topical analgesia before circumcision. NFCS scores were determined by blinded assistant from video recordings of facial activity. Measures of infant crying were determined via spectrum analysis of audio recordings by a blinded, independent researcher. Pearson product-moment correlations were used to examine relationship between NFCS scores and measures of crying. Principal component factor analysis detected dimensions underlying related measures of crying. Factor scores from a factor analysis were used in stepwise linear regression to predict NFCS scores. RESULTS: Higher NFCS scores correlated with lower peak fundamental frequency of crying (P<0.01) and with higher amplitudes of crying at peak fundamental frequency and dominant frequency and in overall cry sample (P<0.01). The factor analysis showed 3 significant orthogonal dimensions underlying measures of crying: Power and Velocity (amplitude and rapidity), Pitch of Crying (frequency characteristics), and Infant Arousal (turbulence and intensity) accounting for 42.3%, 17.8%, and 14.6% of variance, respectively. A regression analysis showed all 3 factor scores accounted for significant and separate portions of variance (P<0.001). The best predictor of NFCS score was Power and Velocity (P<0.002), followed by Infant Arousal (P<0.002), and Pitch of Crying (P<0.007). DISCUSSION: These data provide some of the first known evidence linking specific measures of infant crying with an independent, validated measure of pain.

Can a Short Video Improve Inhaler Use in Urban Youth?

OBJECTIVE: The primary aim was to determine whether watching a short video in the inpatient setting could produce an immediate improvement in pediatric patients' asthma knowledge and inhaler technique. METHODS: This prospective, quasi-experimental, pre-post study was conducted in a single center, in Detroit, Michigan, which primarily serves an urban, African-American population. Patients were eligible if they were between 8- and 16-years-old, had asthma, and would be discharged with an albuterol metered-dose inhaler. The primary outcome was improvement in the composite score of a knowledge and technique assessment before and after watching a 5-minute video. The lead author developed the video with content validation by pharmacists, pediatricians, elementary school teachers, and a pediatric health education specialist. Secondary outcomes at 30 days included change in asthma control and whether the video was revisited after discharge. RESULTS: Thirty patients were enrolled. Their average age was 11 ± 2.1 years; they were primarily African American (83%), female (53%), and insured by Medicaid (87%). The composite score of technique assessment and written quiz increased by 3.53 (95% confidence interval [CI] 2.81 to 4.85) of a possible 16 points after watching the video. There was no significant change in asthma control at 30 days as measured by the asthma control test (2, 95% CI -0.53 to 4.53). Eight of 22 patients revisited the video after discharge. CONCLUSIONS: A brief educational video delivered during a pediatric inpatient visit in an urban medical center resulted in an immediate improvement in patients' disease knowledge and inhaler technique.

Vancomycin elimination in human infants with intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) results in substantial decrease in nephron number and renal and hepatic organ mass in experimental animals and newborn infants. Because the liver and the kidneys are the major organs for drug biotransformation and elimination, any decrease in their size and function may lead to impaired metabolism and elimination of drugs in newborns with IUGR. Our objective was to test the hypothesis that IUGR results in prolonged renal elimination of vancomycin in newborns. METHODS: Small for gestational age (SGA) infants (n = 20) were matched with appropriate for gestational age (AGA) infants (n = 123). Steady state peak and trough serum concentrations were used to calculate vancomycin clearance (Cl), volume of distribution (Vd) and half-life (t(1/2)) for each subject. Pharmacokinetic profiles were compared between groups. RESULTS: Overall, Cl, Vd and t(1/2) of vancomycin were the same between groups. However, stratification showed decreased Cl in those SGA versus AGA newborns 3-4 weeks old and in those newborns with a postconceptional age of 27-29 weeks. There was no difference in Vd, normalized for weight, between SGA and AGA babies. The half-life of vancomycin was similar across most groups but was prolonged in SGA newborns aged 3-4 weeks. CONCLUSIONS: Vancomycin Cl differs between SGA and AGA newborns. This difference is greatest early in life and normalizes between groups after the fourth week of life or after 29 weeks postconceptionally. Normalized Vd is similar between SGA and AGA newborns. The elimination of vancomycin is comparable between SGA and AGA infants, except before the fifth week of life, when SGA newborns may eliminate the drug more slowly. Specific vancomycin dose recommendations for SGA versus AGA neonates may therefore be justified during the first month of life.

Analgesia and local anesthesia during invasive procedures in the neonate.

BACKGROUND: Preterm and full-term neonates admitted to the neonatal intensive care unit or elsewhere in the hospital are routinely subjected to invasive procedures that can cause acute pain. Despite published data on the complex behavioral, physiologic, and biochemical responses of these neonates and the detrimental short- and long-term clinical outcomes of exposure to repetitive pain, clinical use of pain-control measures in neonates undergoing invasive procedures remains sporadic and suboptimal. As part of the Newborn Drug Development Initiative, the US Food and Drug Administration and the National Institute of Child Health and Human Development invited a group of international experts to form the Neonatal Pain Control Group to review the therapeutic options for pain management associated with the most commonly performed invasive procedures in neonates and to identify research priorities in this area. OBJECTIVE: The goal of this article was to review and synthesize the published clinical evidence for the management of pain caused by invasive procedures in preterm and full-term neonates. METHODS: Clinical studies examining various therapies for procedural pain in neonates were identified by searches of MEDLINE (1980-2004), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2004), the reference lists of review articles, and personal files. The search terms included specific drug names, infant-newborn, infant-preterm, and pain, using the explode function for each key word. The English-language literature was reviewed, and case reports and small case series were discarded. RESULTS: The most commonly performed invasive procedures in neonates included heel lancing, venipuncture, IV or arterial cannulation, chest tube placement, tracheal intubation or suctioning, lumbar puncture, circumcision, and SC or IM injection. Various drug classes were examined critically, including opioid analgesics, sedative/hypnotic drugs, nonsteroidal anti-inflammatory drugs and acetaminophen, injectable and topical local anesthetics, and sucrose. Research considerations related to each drug category were identified, potential obstacles to the systematic study of these drugs were discussed, and current gaps in knowledge were enumerated to define future research needs. Discussions relating to the optimal design for and ethical constraints on the study of neonatal pain will be published separately. Well-designed clinical trials investigating currently available and new therapies for acute pain in neonates will provide the scientific framework for effective pain management in neonates undergoing invasive procedures.

Analgesia and anesthesia for neonates: study design and ethical issues.

OBJECTIVE: The purpose of this article is to summarize the clinical, methodologic, and ethical considerations for researchers interested in designing future trials in neonatal analgesia and anesthesia, hopefully stimulating additional research in this field. METHODS: The MEDLINE, PubMed, EMBASE, and Cochrane register databases were searched using subject headings related to infant, newborn, neonate, analgesia, anesthesia, ethics, and study design. Cross-references and personal files were searched manually. Studies reporting original data or review articles related to these topics were assessed and critically evaluated by experts for each topical area. Data on population demographics, study characteristics, and cognitive and behavioral outcomes were abstracted and synthesized in a systematic manner and refined by group members. Data synthesis and results were reviewed by a panel of independent experts and presented to a wider audience including clinicians, scientists, regulatory personnel, and industry representatives at the Newborn Drug Development Initiative workshop. Recommendations were revised after extensive discussions at the workshop and between committee members. RESULTS: Designing clinical trials to investigate novel or currently available approaches for analgesia and anesthesia in neonates requires consideration of salient study designs and ethical issues. Conditions requiring treatment include pain/stress resulting from invasive procedures, surgical operations, inflammatory conditions, and routine neonatal intensive care. Study design considerations must define the inclusion and exclusion criteria, a rationale for stratification, the confounding effects of comorbid conditions, and other clinical factors. Significant ethical issues include the constraints of studying neonates, obtaining informed consent, making risk-benefit assessments, defining compensation or rewards for participation, safety considerations, the use of placebo controls, and the variability among institutional review boards in interpreting federal guidelines on human research. For optimal study design, investigators must formulate well-defined study questions, choose appropriate trial designs, estimate drug efficacy, calculate sample size, determine the duration of the studies, identify pharmacokinetic and pharmacodynamic parameters, and avoid drug-drug interactions. Specific outcome measures may include scoring on pain assessment scales, various biomarkers and their patterns of response, process outcomes (eg, length of stay, time to extubation), intermediate or long-term outcomes, and safety parameters. CONCLUSIONS: Much more research is needed in this field to formulate a scientifically sound, evidence-based, and clinically useful framework for management of anesthesia and analgesia in neonates. Newer study designs and additional ethical dilemmas may be defined with accumulating data in this field.

Patient-controlled analgesia for the pediatric patient.

Pediatric patients benefit from patient-controlled analgesia (PCA), which eliminates the need for painful intramuscular injections of opioids and improves the child's sense of control. Age is often used inappropriately as a criterion for PCA use in children. Children must be carefully screened for their cognitive and physical ability to manage their pain using PCA. Family-controlled analgesia and nurse-controlled analgesia may be considered in select cases as alternatives to PCA in children with cognitive or physical disabilities. PCA dosage regimens must be individualized on the basis of age. Monitoring parameters must be age appropriate. Potential adverse effects of PCA therapy, including respiratory depression, nausea, vomiting, and pruritus, can be prevented or controlled. Clinicians must become aware of age-related and developmental differences in the pharmacokinetic, pharmacodynamic, and monitoring parameters for the pediatric patient. The safety and efficacy of PCA in pediatric patients has been established, and its role has increased beyond postoperative pain management.

Respiratory depression in adult patients with intravenous patient-controlled analgesia.

Patient-controlled analgesia (PCA) has been widely implemented to provide better pain relief and increased patient satisfaction with relatively few side effects. However, patients using intravenous (i.v.) PCA are at increased risk for specific adverse effects, especially respiratory depression. A review of the literature from 1990 to present was done to identify the incidence and risk factors for respiratory depression and recommendations for care. Several studies have documented the incidence of respiratory depression with i.v. PCA; rates ranged from 0.19% to 5.2%. Variation in incidence existed because authors defined respiratory depression differently. Methods for monitoring oxygenation include sedation; respiratory rate, depth, and rhythm, and oxygen saturation using pulse oximetry. No single parameter is the single indicator for respiratory depression. Risk factors for respiratory depression with i.v. PCA include age greater than 70 years; basal infusion with i.v. PCA; renal, hepatic, pulmonary, or cardiac impairment; sleep apnea (suspected or history); concurrent central nervous system depressants; obesity; upper abdominal or thoracic surgery; and i.v. PCA bolus > 1 mg. Structures and processes should be in place to guide appropriate dosing, identify risk factors, and activate pertinent monitoring and frequency. Finally, respiratory depression occurs infrequently in comparison to the 10% of patients who are undertreated for pain.

Hepatotoxicity induced by trimethoprim-sulfamethoxazole in a child with cystic fibrosis.

Patients with cystic fibrosis (CF) have chronic and progressive lung infections with various bacterial organisms that require treatment with oral and intravenous antibiotics on a regular basis. Trimethoprim-sulfamethoxazole (TMP-SMX) is one of the medications used to treat acute pulmonary infectious exacerbations in patients with CF. Hepatic toxicity secondary to TMP-SMX was previously described in normal subjects but has not been reported in children with CF. Here we describe a 14-year-old female child with CF who was given oral TMP-SMX for an acute pulmonary infectious exacerbation. She developed a rash, severe constitutional symptoms, and significant elevation of liver enzyme concentrations secondary to immunity-mediated reaction to TMP-SMX. Discontinuation of TMP-SMX and supportive treatment led to resolution of her symptoms and normalization of liver enzyme concentrations.

Pharmacokinetics and pharmacodynamics of famotidine and ranitidine in critically ill children.

To characterize and compare acid suppression (pharmacodynamics) and pharmacokinetics of IV famotidine and ranitidine in critically ill children at risk for stress gastritis. Single-blind, randomized study in PICU patients 6 months to 18 years requiring mechanical ventilation with continuous gastric pH monitoring, randomized to IV famotidine 12 mg/m(2) or ranitidine 60 mg/m(2) when gastric pH < 4.0 >1 hour with serial blood sampling following first dose. Twenty-four children randomized to either famotidine (n = 12) or ranitidine (n = 12). Sixteen out of twenty-four completed both PK and PD study arms (7/12 famotidine; 4.7 ± 3.4 years; 9/12 ranitidine; 6.6 ± 4.7 years; p = 0.38). Time to gastric pH 4.0 and total time pH above 4.0 similar with no difference in pH at 6 and 12 hours (p > 0.2). No difference between drugs in clearance, volume of distribution and half-life (p > 0.05). Ratio of AUC pH to AUC drug concentration 0-12 hours after first dose was significantly greater for famotidine (0.06849 ± 0.01460 SD) than ranitidine (0.02453 ± 0.01448; p < 0.001) demonstrating greater potency of famotidine. pH lowering efficacy of both drugs is similar. Greater potency of famotidine may offer clinical advantage due to lower drug exposure and less frequent dosing to achieve same pH lowering effect.

An algorithm to detect adverse drug reactions in the neonatal intensive care unit.

Critically ill newborns in neonatal intensive care units (NICUs) are at greater risk of developing adverse drug reactions (ADRs). Differentiation of ADRs from reactions associated with organ dysfunction/immaturity is difficult. Current ADR algorithm scoring was established arbitrarily without validation in infants. The study objective was to develop a valid and reliable algorithm to identify ADRs in the NICU. Algorithm development began with a 24-item questionnaire for data collection on 100 previously suspected ADRs. Five pediatric pharmacologists independently rated cases as definite, probable, possible, and unlikely ADRs. Consensus "gold standard" was reached via teleconference. Logistic regression and iterative C programs were used to derive the scoring system. For validation, 50 prospectively collected ADR cases were assessed by 3 clinicians using the new algorithm and the Naranjo algorithm. Weighted kappa and intraclass correlation coefficient (ICC) were used to compare validity and reliability of algorithms. The new algorithm consists of 13 items. Kappa and ICC of the new algorithm were 0.76 and 0.62 versus 0.31 and 0.43 for the Naranjo algorithm. The new algorithm developed using actual patient data is more valid and reliable than the Naranjo algorithm for identifying ADRs in the NICU population. Because of the relatively small and nonrandom samples, further refinement and additional testing are needed.

An objective structured clinical examination to assess problem-based learning.

OBJECTIVES: To compare pharmacy students' performance on an objective structured clinical examination (OSCE) to their performance on a written examination for the assessment of problem-based learning (PBL); and to determine students' and faculty members' perceptions of OSCEs for PBL evaluations. DESIGN: Four OSCEs were added to the written examination to assess 4 PBL cases in a third-year pharmacotherapy course. OSCE scores were compared to written examination scores. Faculty members evaluated student performance. ASSESSMENT: OSCE performance did not correlate with the written-examination scores. Most students (≥ 75%) agreed that OSCEs reflected their learning from PBL and measured knowledge, communication, and clinical skills. A majority of faculty members (≥75%) agreed that OSCEs should be part of PBL assessment. CONCLUSIONS: Addition of an OSCE to written examinations was valued and provided a more comprehensive assessment of the PBL experience.

Lidocaine 4% cream compared with lidocaine 2.5% and prilocaine 2.5% or dorsal penile block for circumcision.

This study evaluated the efficacy and safety of lidocaine 4% cream (LMX4), compared with lidocaine 2.5% and prilocaine 2.5% (EMLA) or dorsal penile block (DPNB) for analgesia during circumcision. Healthy, term males (n = 54), younger than 1 week old undergoing circumcision were randomly assigned to open-label pretreatment with LMX4, EMLA, or DPNB. Heart rate (HR; beats per minute [bpm]), respiratory rate (RR; breaths/minute), and arterial oxygen saturation as measured by pulse oximetry (Sp O2; %) were monitored at baseline, and during drug application, circumcision, and recovery. Mean differences were compared using the general linear model. At the end of drug application, mean HR for infants receiving LMX4 (146 bpm; standard error of mean [SEM], 8.0 bpm) was lower than that for DPNB (176 bpm; SEM, 8.3 bpm; p < 0.05). No significant difference in mean HR was observed between treatments during circumcision. Mean RR was higher during circumcision for EMLA compared with LMX4 (p < 0.05) and DPNB (p < 0.05). At lysis, mean RR was significantly lower in DPNB than LMX4 and EMLA. The number of Sp O2 samples was too small for comparison. Three infants (one receiving LMX4 and two receiving EMLA) experienced local reactions (p = 0.54). No adverse effects were observed with DPNB. No difference in analgesic efficacy was observed between treatments according to HR. Differences in RR may reflect a varying level of analgesia. The safety profile was similar for all treatments. LMX4 is an effective analgesic for newborn circumcision.

Management of infiltration injury in neonates using duoderm hydroactive gel.

Neonates are at increased risk of injury from infiltration of intravenous fluids because of small vessel size and immature skin structure. Until recently, hyaluronidase injection was used to prevent tissue injury following the infiltration of intravenous solutions in neonates. The production of hyaluronidase injection was discontinued in 2001. The alternative, compounded hyaluronidase injection is not regulated by the U.S. Food and Drug Administration and is subject to variation in quality assurance practices. Amorphous hydrogels have been used as wound dressings for sloughy or necrotic wounds in a variety of clinical settings. Hydrogels facilitate autodebridement of the wound by rehydrating slough and enhancing the rate of autolysis. No adverse effects or increased infection rates have been associated with the use of hydrogel dressings. DuoDerm Hydroactive gel is a sterile, preservative-free, viscous, hydrating gel composed of natural hydrocolloids. We report our experience using DuoDerm Hydroactive gel for management of injury secondary to the infiltration of total parenteral nutrition solution and lipid emulsion in three neonates.