Wildt, S.N. de

Prevalence of renal dysfunction in tacrolimus-treated pediatric transplant recipients: A systematic review (Article)

2013-05-01T00:00:00Z

Renal dysfunction after non-renal transplantation in adult tacrolimus-treated transplant patients is well documented. Little is known about its prevalence in children. Age-related changes in both disposition and effect of tacrolimus as well as renal function may preclude extrapolation of adult data to children. To systematically review the literature on renal dysfunction in non-renal pediatric transplant recipients treated with tacrolimus. PubMed/Medline, Embase, and Google were searched from their inception until April 19, 2012, with the search terms "tacrolimus," "renal function," "transplantation," and "children." Eighteen of 385 retrieved papers were considered relevant. Twelve dealt with liver, four with heart transplant, one with heart and lung transplant, and one with intestinal recipients. Reported prevalences of mild and severe chronic kidney disease ranged from 0% to 39% and 0% to 71.4%, respectively, for liver, and from 22.7% to 40% and 6.8% to 46%, respectively, for heart and/or lung transplant recipients. Ranges remained wide after adjusting for follow-up time and disease severity. Possible explanations are inclusion bias and definitions used for renal dysfunction. A considerable proportion of pediatric non-renal transplant patients who receive tacrolimus-based immunosuppression, appear to suffer from chronic kidney disease. This conclusion warrants further research into the real risk, its risk factors, and individualization of immunosuppressant therapy.

Review: Ontogeny of oral drug absorption processes in children (Article)

2012-06-12T00:00:00Z

A large proportion of prescribed drugs to children are administered orally. Age-related change in factors affecting oral absorption can have consequences for drug dosing. Areas covered: For each process affecting oral drug absorption, a systematic search has been performed using Medline to identify relevant articles (from inception till February 2012) in humans. This review presents the findings on age-related changes of the following processes affecting oral drug absorption: gastric pH, gastrointestinal motility, bile salts, pancreatic function, intestinal pH, intestinal drug-metabolizing enzymes and transporter proteins. Expert opinion: Clinicians should bear in mind the ontogeny of oral drug absorption processes when prescribing oral drugs to children. The authors’ review shows large information gaps on almost all drug absorption processes. It is important that more knowledge is acquired on intestinal transit time, intestinal pH and the ontogeny of intestinal drug-metabolizing enzymes and drug transporter proteins. Furthermore, the ultimate goal in this field should be to predict more precisely the oral disposition of drugs in children across the entire pediatric age range.

Biomarkers and clinical tools in critically ill children: are we heading toward tailored drug therapy? (Article)

2012-06-01T00:00:00Z

In pediatric critical care, validated biomarkers are essential for guiding drug therapy. The aim of this article is to present examples of current biomarker developments in its full breadth, including biochemical substances, physiological measurements and clinical scoring tools, with a focus on the field of circulatory, renal and neurophysiologic failure. Within each field we consecutively discuss the rationale for the selected biomarkers, studies in critically ill children, biomarker validation stage and biomarker use or potential use in drug studies and clinical drug dosing. This article demonstrates that there is paucity of properly validated biomarkers. Nevertheless, recent developments in, for instance, the field of sepsis, point us toward a future wherein, for critically ill children, drug therapy may be personalized using proteomic profiling instead of a small number of biomarkers, in order to establish a personal and dynamic disease profile.

The status of paediatric medicines initiatives around the world-what has happened and what has not? (Article)

2012-01-01T00:00:00Z

Purpose: This review was conducted to examine the current status of paediatric medicines initiatives across the globe. Methods: The authors made a non-systematic descriptive review of current world situation. Results: Two regions, the United States (US) and the European Union (EU), and the World Health Organization (WHO) have introduced strong paediatric initiatives to improve children's health through improving access to better paediatric medicines. The experience from the US initiative indicates that it is possible to stimulate development and study of paediatric medicines and provide important new information for improvement of paediatric therapy. The early results from the EU initiative are similarly encouraging. In Canada, Japan, Australia and other developed countries, specific paediatric medicines initiatives have been less extensive and weaker, with modest results. Disappointingly, current evidence suggests that results from clinical trials outside the US often do not benefit children in the country in which the trials were largely conducted. Pharmaceutical companies that have derived a financial benefit commensurate with the cost of doing the paediatric trials in one country do not seem to be making the results of these trials available to all countries if there is no financial incentive to the company. The WHO campaign 'make medicines child size' has produced substantive accomplishments in building improved foundations to improve mechanisms that will enhance children's access to critical medicines in resource-limited settings. However, practically all of this work has been performed using an amalgamation of short-term funding from a variety of sources as opposed to a sustained, programmatic commitment. Conclusions: Although much still needs to be done, it's clear that with concerted efforts and appropriate resources, change is possible but slow. Retaining and fostering public and political interest in paediatric medicines is challenging, but pivotal for success.

Daily interruption of sedation in critically ill children (Article)

2012-01-01T00:00:00Z

The effect of critical illness and inflammation on midazolam therapy in children (Article)

2012-01-01T00:00:00Z

OBJECTIVE:: To determine the effect of inflammation and disease severity on midazolam pharmacokinetics (as surrogate marker of cytochrome 3A activity) and pharmacodynamics in critically ill children. DESIGN:: Analysis of prospectively collected pharmacokinetic and pharmacodynamic data from a midazolam study in critically ill children. SETTING:: Pediatric intensive care unit of a university hospital. PATIENTS:: Twenty-one critically ill children who needed midazolam for sedation. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: We determined the relationship between inflammation (using C-reactive protein and leukocyte count as surrogate markers) and disease severity (Pediatric Logistic Organ Dysfunction and Pediatric Risk of Mortality scores) vs. the pharmacokinetics (clearance) and pharmacodynamics (COMFORT score, dose requirement) of midazolam. We found a significant negative correlation between disease severity and midazolam clearance corrected for body weight (r =-0.49, p = .02). Midazolam clearance was significantly lower in children with multiple organ failure (defined as Pediatric Logistic Organ Dysfunction ≥10, n = 11) compared with children without multiple organ failure (Pediatric Logistic Organ Dysfunction <10, n = 10) (median 0.14 [interquartile range, 0.11-0.23] vs. 0.28 [interquartile range, 0.14-0.43]) L/kg/h, p = .035). No other significant correlations were found. CONCLUSIONS:: Results from this pilot study suggest that increased disease severity is associated with reduced midazolam clearance in critically ill children, most likely as a result of reduced cytochrome 3A activity. In contrast, reduced midazolam clearance does not seem to result in decreased midazolam dose requirements.

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation (Article)

2011-12-01T00:00:00Z

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07-0.20) vs. 0.09 (0.02-0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15-0.32) vs. 0.11 (0.01-0.25) mg/kg/12h, p = 0.013]. Conclusion: CYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition.

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients (Article)

2011-12-01T00:00:00Z

Background: Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. Method: We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. Results: Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (rs= 0.447, p = 0.004) and the concentration/dose ratio (rs= 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R2= 0.351, p = 0.001 and R2= 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. Conclusion: Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.

Prevention of low cardiac output syndrome in children: Where is the evidence? (Article)

2011-12-01T00:00:00Z

Protocolized post-operative pain management in infants; do we stick to it? (Article)

2011-10-28T00:00:00Z

Background: The American Academy of Pediatrics states that ongoing assessment of pain is essential for adequate pain treatment. Pain assessment by means of the COMFORT behaviour scale and the Numeric Rating Scale is therefore an important component of the post-operative pain treatment protocol for neonates and infants in our intensive care unit (ICU). Aim: The study aims to determine degrees of staff compliance with this protocol. Patients and methods: This retrospective chart review concerned post-surgical patients under the age of 3 years admitted to our level III ICU over a 1-year period. The degree of compliance to the post-operative pain protocol was measured by the frequency of deviations from protocol-dictated drug treatment and pain assessments. Results: Records of 200 children with a median age at surgery of 98 days (interquartile range 6–320) were analysed. A mean of 11 assessments in the first 72 h post-operatively per patient had been recorded. A total of 2103 pain assessments were retrieved, of which 1675 (79.7%) suggested comfort. Compliance to the protocol (reassessment and correct medication) was provided in 66 (15.4%) of the 428 assessments suggesting pain or distress. Conclusion: The post-operative pain protocol applied in our ICU appears to be effective; however, full compliance to the protocol was marginal, possibly leading to under-treatment of pain.

Application to Add Midazolam to the Model List of Essential Medicines (Research Paper)

2011-08-01T00:00:00Z

Summary statement of the proposal for inclusion The benzodiazepine midazolam has proven sedative, anxiolytic and amnesic properties. It is extensively used for premedication and procedural sedation in both adults and children. In comparison to other benzodiazepine and non-benzodiazepine drugs, midazolam is equally or more effective for premedication/preoperative sedation. No evidence exists that premedication with midazolam prolongs discharge time from hospital. Its efficacy and safety have been extensively studied in both adults and children. This contrasts its comparator drug, diazepam for which data in children and elderly are scarce or lacking. Midazolam is also effective for procedural sedation as a single drug or in combination with an opioid. As a single drug, adequate sedation for procedures in the emergency room, is achieved in over 90% of all procedures. Comparative efficacy was shown for propofol. Data are insufficient to determine comparative efficacy for procedural sedation for other drugs. When administered with the appropriate precautions, e.g. titration to effect, adequate monitoring and personnel to support ventilation, midazolam is very safe. No major adverse events were seen in 847 adults who received midazolam for procedural sedation. Also, adverse effects can be antagonized with an effective antagonist, flumazenil. As midazolam is off-patent, drug costs are relatively low. Drug costs per procedure range from approximately 0.15 US$ to 2.6 US$ in an adult, depending on dose and country, with significantly lower costs in developing countries.

CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: A pilot study (Article)

2011-08-01T00:00:00Z

Background: Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into morphine than normal individuals can. In contrast, poor metabolizers (PMs), individuals who have no active CYP2D6 genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine without attaining analgesia. Objective: The aim was to study the relationship between CYP2D6 genotype and codeine analgesia among women recovering from c-section. Methods: Forty-five mothers prescribed codeine provided a blood sample for CYP2D6 genotyping and recorded their pain level 4 times a day for 3 days immediately after a c-section. Codeine was used on an as-needed basis; doses and times were recorded. The relationship between CYP2D6 genotype, pain scores, need for codeine, and adverse events was studied. Theoretical morphine dose, based on CYP2D6 genotype, was estimated. Results: Women at the genotypic extremes reported codeine effects consistent with their genotype: the 2 PMs of codeine reported no analgesia as a result of taking codeine, whereas 2 of the 3 Ums reported immediate pain relief from codeine but stopped taking it due to dizziness and constipation. Much larger numbers are needed to study similar correlations among extensive and intermediate metabolizers. Conclusions: In this pilot study, the extreme CYP2D6 genotypes (PMs and UMs) seemed to predict pain response and adverse events. Larger sample sizes are needed to correlate the range of genotypes with pain response. Copyright

Drug dosing in pediatric intensive care and in pediatrics in general (Article)

2011-07-01T00:00:00Z

The effect of distant reiki on pain in women after elective Caesarean section: A double-blinded randomised controlled trial (Article)

2011-05-17T00:00:00Z

Introduction: Approximately 25% of all babies in North America are delivered via Caesarean section (C-section). Though a common surgical procedure, C-section recovery can be painful. Opioids, specifically codeine, are commonly used to ease pain; however, its active metabolite, morphine, passes into breast milk, and may produce unwanted side effects in neonates; therefore, alternatives to opioids are being sought. Reiki is an ancient Japanese form of healing where practitioners transfer healing energy through light touch and positive healing intention. Although 1.2 million Americans use reiki to reduce pain or depression, there is a lack of strong evidence supporting its effectiveness. A recent systematic review showed existing studies to be of poor methodological quality, with the common limitation of lack of blinding. To overcome this issue, the authors used distant reiki to assess its effectiveness in reducing pain following an elective C-section. Methods: In this randomised, double-blinded study, women who underwent an elective C-section were allocated to either usual care (control, n=40) or three distant reiki sessions in addition to usual care (n=40). Pain was assessed using a visual analogue scale (VAS). The primary endpoint was the Area Under the VAS-Time Curve (AUC) for days 1-3. Secondary measures included: The proportion of women who required opioid medications and dose consumed, rate of healing and vital signs. Results: AUC for pain was not significantly different in the distant reiki and control groups (mean±SD; 212.16104.7 vs 223.16117.8; p=0.96). There were no significant differences in opioid consumption or rate of healing; however, the distant reiki group had a significantly lower heart rate (74.368.1 bpm vs 79.867.9 bpm, p=0.003) and blood pressure (106.469.7 mm Hg vs 111.9611.0 mm Hg, p=0.02) post surgery. Conclusion: Distant reiki had no significant effect on pain following an elective C-section.

The effect of inflammation on drug metabolism: A focus on pediatrics (Article)

2011-05-01T00:00:00Z

Inflammation is associated with downregulation of the expression and activity of cytochrome P450 enzymes (CYP450) involved in hepatic drug metabolism. Elevated plasma drug levels and increased toxicity might be the consequences of this downregulation. Few clinical studies have investigated these consequences of inflammation in children, who are prescribed many off-label or unlicensed drugs. This review describes the impact of inflammation on CYP450 drug metabolism and drug effect in children, with the consequent implications for drug studies and clinical therapy in this group.

Acute liver failure after recommended doses of acetaminophen in patients with myopathies (Article)

2011-04-01T00:00:00Z

Objective: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Design: Retrospective analysis. Setting: Level III pediatric intensive care unit. Patients: Two pediatric patients with myopathies and acute liver failure. CLINICAL INVESTIGATIONS:: We determined acetaminophen protein adduct levels, in combination with a literature review and systematic evaluation of the cases, using the Roussel Uclaf Causality Assessment Method for drug-induced liver injury to assess causality between recommended acetaminophen dosing and acute liver failure in two children with myopathies. MAIN RESULTS:: The serum adduct levels were consistent with the values previously reported in children with acute liver injury following acetaminophen overdose. We found four similar cases of acute liver failure in pediatric and adult patients with myopathies following recommended acetaminophen doses in the literature (n = 3) and personal communication (n = 1). The Roussel Uclaf Causality Assessment Method suggested a probable relationship between acetaminophen use at recommended doses and acute liver failure in our myopathy patients. Conclusion: Our data suggest that some patients with myopathies who are receiving recommended doses of acetaminophen may be at increased risk for the development of toxicity resulting in acute liver failure. More studies are needed to corroborate these findings. In the meantime, we would advise physicians to be alert in these patients while taking acetaminophen, especially when critically ill or postoperative. Copyright

Evaluation of drug formularies for pediatric intensive care (Article)

2011-01-01T00:00:00Z

Objectives: To evaluate availability and reliability of pediatric drug dosing guidelines in selected formularies for intensive care patients. Most drugs used in the pediatric intensive care unit are prescribed off-label, often on the guidance of limited information from commonly used drug formularies. Design: Availability of dosing information on prescribed drugs in a Dutch intensive care unit from January 1, 2005 to December 31, 2006 was compared among four selected formularies (Micromedex, Lexi-Comp, Drug Formulary for Children, Drug Doses). Reliability of dosing guidelines was assessed by evaluating labeling status and literature data for the three most (midazolam, acetaminophen, and amoxicillin/clavulanic acid) and the three least (bosentan, ketanserin, and iloprost) prescribed drugs. Measurements and Main Results: The selected formularies covered 68% to 86% of all 257 prescribed drugs. Guidelines differ widely on daily doses per kilogram, dose description, dosing regimen, and age ranges. For the three most prescribed and one of the least prescribed drugs (bosentan), dosing guidelines adequately reflected labeling status and existing (but scarce) literature. No dosing guidelines were available for iloprost, and only one dosing guideline was available for ketanserin. Conclusions: This study shows that four commonly used drug formularies give few and widely differing dosing guidelines for drugs prescribed in the intensive care unit. If guidelines exist, they seem to reflect labeling status (if present) and limited literature available. Findings from this study likely reflect the scarcity of drug studies in this population. Physicians should be aware of the limitations of these formularies for daily practice in this group of vulnerable patients. Copyright

Feasibility of sedation and analgesia interruption following cannulation in neonates on extracorporeal membrane oxygenation (Article)

2010-09-01T00:00:00Z

Purpose: In most extracorporeal membrane oxygenation (ECMO) centers patients are heavily sedated to prevent accidental decannulation and bleeding complications. In ventilated adults not on ECMO, daily sedation interruption protocols improve short- and long-term outcome. This study aims to evaluate safety and feasibility of sedation interruption following cannulation in neonates on ECMO. Methods: Prospective observational study in 20 neonates (0.17-5.8 days of age) admitted for ECMO treatment. Midazolam (n = 20) and morphine (n = 18) infusions were discontinued within 30 min after cannulation. Pain and sedation were regularly assessed using COMFORT-B and visual analog scale (VAS) scores. Midazolam and/or morphine were restarted and titrated according to protocolized treatment algorithms. Results: Median (interquartile range, IQR) time without any sedatives was 10.3 h (5.0-24.1 h). Median interruption duration for midazolam was 16.5 h (6.6-29.6 h), and for morphine was 11.2 h (6.7-39.4 h). During this period no accidental extubations, decannulations or bleeding complications occurred. Conclusions: This is the first study to show that interruption of sedatives and analgesics following cannulation in neonates on ECMO is safe and feasible. Interruption times are 2-3 times longer than reported for adult ICU patients not on ECMO. Further trials are needed to substantiate these findings and evaluate short- and long-term outcomes.

Ontogeny of midazolam glucuronidation in preterm infants (Article)

2010-02-01T00:00:00Z

Purpose: In preterm infants, the biotransformation of midazolam (M) to 1-OH-midazolam (OHM) by cytochrome P450 3A4 (CYP3A4) is developmentally immature, but it is currently unknown whether the glucuronidation of OHM to 1-OH-midazolam glucuronide (OHMG) is also decreased. The aim of our study was to investigate the urinary excretion of midazolam and its metabolites OHM and OHMG in preterm neonates following the intravenous (IV) or oral (PO) administration of a single M dose. Methods: Preterm infants (post-natal age 3-13 days, gestational age 26-34 4/7 weeks) scheduled to undergo a stressful procedure received a 30-min IV infusion (n=15) or a PO bolus dose (n=7) of 0.1 mg/kg midazolam. The percentage of midazolam dose excreted in the urine as M, OHM and OHMG up to 6 h post-dose was determined. Results: The median percentage of the midazolam dose excreted as M, OHM and OHMG in the urine during the 6-h interval after the IV infusion was 0.44% (range 0.02-1.39%), 0.04% (0.01-0.13%) and 1.57% (0.36-7.7%), respectively. After administration of the PO bolus dose, the median percentage of M, OHM and OHMG excreted in the urine was 0.11% (0.02-0.59%), 0.02% (0.00-0.10%) and 1.69% (0.58-7.31%), respectively. The proportion of the IV midazolam dose excreted as OHMG increased significantly with postconceptional age (r=0.73, p <0.05). Conclusion: The glucuronidation of OHM appears immature in preterm infants less than 2 weeks of age. The observed increase in urinary excretion of OHMG with postconceptional age likely reflects the combined maturation of glucuronidation and renal function.

A systematic review of the therapeutic effects of Reiki (Article)

2009-11-01T00:00:00Z

Introduction: Reiki is an ancient form of Japanese healing. While this healing method is widely used for a variety of psychologic and physical symptoms, evidence of its effectiveness is scarce and conflicting. The purpose of this systematic review was to try to evaluate whether Reiki produces a significant treatment effect. Methods: Studies were identified using an electronic search of Medline, EMBASE, Cochrane Library, and Google Scholar. Quality of reporting was evaluated using a modified CONSORT Criteria for Herbal Interventions, while methodological quality was assessed using the Jadad Quality score. Data extraction: Two (2) researchers selected articles based on the following features: placebo or other adequate control, clinical investigation on humans, intervention using a Reiki practitioner, and published in English. They independently extracted data on study design, inclusion criteria, type of control, sample size, result, and nature of outcome measures. Results: The modified CONSORT Criteria indicated that all 12 trials meeting the inclusion criteria were lacking in at least one of the three key areas of randomization, blinding, and accountability of all patients, indicating a low quality of reporting. Nine (9) of the 12 trials detected a significant therapeutic effect of the Reiki intervention; however, using the Jadad Quality score, 11 of the 12 studies ranked "poor." Conclusions: The serious methodological and reporting limitations of limited existing Reiki studies preclude a definitive conclusion on its effectiveness. High-quality randomized controlled trials are needed to address the effectiveness of Reiki over placebo.

Morphine-induced muscle rigidity in a term neonate (Article)

2009-10-01T00:00:00Z

OBJECTIVE: To describe a potentially fatal adverse drug event after administration of morphine to a term neonate. CASE SUMMARY: A 2-day-old term neonate experienced generalized muscle rigidity and laryngeal spasm resulting in acute respiratory failure on 2 separate occasions after morphine administration. The first occasion was after administration of bolus doses of fentanyl and morphine 100 μg/kg in the operating theater; administration of intravenous propofol 2 mg/kg resulted in relief of muscle rigidity. The second occasion occurred a few hours later, when the patient received a continuous infusion of morphine 4.4 μg/kg/h in the intensive care unit and experienced generalized muscle rigidity with respiratory compromise. The opioid antagonist naloxone 30 μg/kg was administered intravenously, which immediately resulted in a patent airway and spontaneous breathing. An objective causality assessment using the Naranjo probability scale revealed that the likelihood of morphine causing the patient's muscle rigidity on the second occasion was highly probable to definite. It is not clear whether the first occurrence of muscle rigidity was morphine-induced. DISCUSSION: We searched PubMed and EMBASE (through August 2009) for previous reports of morphine-related muscle rigidity and/or laryngeal spasm, using the search terms (muscle rigidity OR chest rigidity OR laryngeal spasm) AND (morphine OR fentanyl OR opioid). Sudden onset of muscle rigidity and laryngeal spasm is described in the literature as a rare but serious adverse event after infusion of fentanyl and similar opioids in both adults and young infants. However, there are no reports of this potentially fatal adverse event after administration of morphine. To our knowledge this is the first case reported of life-threatening muscle rigidity and laryngeal spasm after therapeutic doses of morphine in humans. CONCLUSIONS: A serious adverse event consisting of generalized muscle rigidity and laryngospasm can occur after bolus administration of morphine as well as during continuous infusion. Clinicians should be aware of this possibility.

Knowledge of developmental pharmacology and modeling approaches should be used to avoid useless trials in children (Article)

2009-08-01T00:00:00Z

Tailor-made drug treatment for children. Creation of an infrastructure for data-sharing and population PK-PD modeling (Article)

2009-03-01T00:00:00Z

Rational dosing guidelines for drugs in pediatrics are urgently needed. To develop these guidelines, we use population pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation by: (i) optimization of clinical trial designs based on preliminary data; (ii) development and internal validation of population PK-PD models using sparse data; (iii) external validation using independent data; and (iv) prospective clinical evaluation. Optimized dosing regimens for specific drugs may then serve as a basis to develop dosing guidelines for existing or newly developed drugs with similar disposition and/or effect. In addition to modeling of drug disposition (PK) pathways, we emphasize the need for modeling of effect (PD) pathways and the use of a multidisciplinary infrastructure for data-sharing.

Probability of rash related to gabapentin therapy in a child (Article)

2009-02-01T00:00:00Z

OBJECTIVE: To describe a child who developed a skin reaction during gabapentin therapy and discuss how we evaluated the probability of an adverse drug reaction. CASE SUMMARY: An 8-year-old boy with a neurodegenerative disease of unknown origin and an epilepsy disorder developed an urticarial rash and irritability 10 and 4 days, respectively, after the start of gabapentin 20 mg/kg 3 times a day for epilepsy control. Otherwise, the child was well; no changes in other medication or diet had recently been made. After gabapentin discontinuation and administration of one dose of methylprednisolone 10 mg/kg intravenously and diphenhydramine 1 mg/kg every 4 hours via gastric tube, the rash disappeared over 3 weeks. DISCUSSION: In contrast to other antiepileptic drugs, skin reactions to gabapentin are considered uncommon. In adults, reported prevalence of rash possibly related to gabapentin range from 1% to 10%. A postmarketing surveillance study reported gabapentin treatment failure as a consequence of rash in 0.4% of 3000 patients. The product monograph does not mention rash in children. In our patient, assessment using an objective causality scale revealed that the rash was probably caused by gabapentin. CONCLUSIONS: This case, and limited literature data, suggest that gabapentin may cause rash that is severe enough to necessitate discontinuation in a small percentage of children. Further research is needed to determine the actual incidence and severity of gabapentin-related rash in this population.

Unintended pregnancy during radiotherapy for cancer (Article)

2009-01-28T00:00:00Z

Background: A 27-year-old woman with upper mediastinum stage IIA Hodgkin lymphoma was treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. Two months later she received a total of 4,250 cGy to the upper mediastinum and left clavicular region over a 1-month period. One week after completion of radiotherapy she was found to be 13-weeks pregnant. Her physician advised her to terminate pregnancy. She contacted a teratology information service for further information regarding the risks of radiation exposure for her fetus. Investigations: Estimation of fetal radiation exposure, literature review and synthesis of published cases and effects of fetal radiation exposure. Diagnosis: Estimated fetal radiation dose between 5 and 18 cGy. Management: Counseling on the possible risks to the fetus as a result of radiation exposure.

Challenges for drug studies in children: CYP3A phenotyping as example (Article)

2009-01-01T00:00:00Z

A paucity of data exists on the disposition and effect of drugs in young children. This information gap can be reduced by elucidating developmental principles of absorption, distribution, metabolism and excretion (ADME) in vivo. Such knowledge might enable the prediction of the disposition of individual drugs in children over the whole pediatric age range. CYP3A, the most abundant human drug metabolizing enzyme, is involved in the metabolism of more than 50% of all marketed drugs. Hence, elucidating the developmental pattern of CYP3A in relation to genetic background, disease and comedications might greatly enhance our knowledge on drug disposition in children. Several methods have been used to determine in vivo CYP3A activity in human adults, while similar studies in children face several ethical, practical and scientific challenges. The aim of this review is to identify these challenges and offer feasible solutions for studying drugs in young children, with an emphasis on CYP3A phenotyping as an example.

Authors' reply [4] (Article)

2008-03-01T00:00:00Z

13C-Erythromycin breath test as a noninvasive measure of CYP3A activity in newborn infants: A pilot study (Article)

2007-04-01T00:00:00Z

The intravenous C-erythromycin breath test (EBMT) has been largely used in adults as a validated probe to measure hepatic cytochrome P450 3A4 and 3A5 (CYP3A4/5) activity in vivo. Additionally, the oral EBMT has been suggested to measure combined hepatic and intestinal CYP3A4/5 activity. Both hepatic and intestinal CYP3A4/5 activities are low in neonates, but the exact developmental pattern is not known. Also, a knowledge gap exists on the impact of comedication or disease state on CYP3A4/5 activity in this population. However, to use the radioactive test in newborns is not feasible, for obvious ethical reasons. Hence, the aim of this pilot study was to determine if stable isotope-labeled C-erythromycin could be used alternatively. Preterm infants who needed treatment with erythromycin for ureaplasma infection were given an oral 10 to 15 mg/kg C-(N-dimethyl)-erythromycin dose. Pharmacy regulations did not permit intravenous administration. Exhaled air samples were collected predose and up to 24 hours post-dose and analyzed for CO2 and CO2 with gas chromatography-mass spectrometry. Three patients received oral C-erythromycin. CO2 did not change significantly from baseline, showed a maximum blood concentration at 20 hours (+12%), and decreased over 24 hours (-16%) in these patients, respectively. Because none of these patients showed a consistent peak in C enrichment, in accordance with maximum blood concentration of oral erythromycin in preterms, we stopped this pilot trial after 3 patients. In conclusion, the lack of a consistent change in exhaled CO2 after oral C-erythromycin in this pilot study precludes the routine use of oral 13C-EBMT in preterm infants as a noninvasive probe of CYP3A4/5 activity. We speculate that this lack of change is due to developmentally low intestinal and hepatic CYP3A activity.

Developmental aspects of midazolam metabolism (Doctoral Thesis)

2001-09-26T00:00:00Z

From fetal life through adolescence, dramatic changes in pharmacokinetics and pharmacodynamics occur as a consequence of organ maturation and changes in body composition associated with normal development. Accordingly, effective and safe drug therapy in preterm infants, neonates, infants,children and adolescents requires a thorough understanding of human developmental biology and the ontogeny of the processes that govern absorption, distribution, metabolism, excretion, and action of drugs. Physicians must be aware of these interindividual differences, when prescribing drugs. The research presented by this thesis provides an example of an integrated approach to critically examine the pharmacokinetics and pharmacodynamics of midazolam, a benzodiazepine that is finding expanded use in neonatal intensive care units.

The CYP3A4*3 allele: is it really rare? (Article)

2001-01-01T00:00:00Z

CYP3A4-V polymorphism detection by PCR-restriction fragment length polymorphism analysis and its allelic frequency among 199 Dutch Caucasians (Article)

2000-01-01T00:00:00Z