Hoog, M. de

Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance (Article)

2012-01-23T00:00:00Z

Background and Objectives: During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin. Methods: Population pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24-43 weeks; postnatal age 1-30 days; birthweight 385-4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally. Results: Postmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived. Conclusions: Amikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates.

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.

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

2011-07-01T00:00:00Z

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.

Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extracorporeal membrane oxygenation support (Article)

2010-08-09T00:00:00Z

Introduction: To evaluate the effect of extracorporeal membrane oxygenation (ECMO) support on pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in children. Methodology: Steady state 0-12 hour pharmacokinetic sampling was performed in new influenza A (H1N1) infected children treated with oseltamivir while on ECMO support. Cmax, Cmin and AUC0-12 hwere calculated. The age-specific oseltamivir dosage was doubled to counter expected decreased plasma drug concentrations due to increased volume of distribution on ECMO support. Principal Findings: Three patients were enrolled aged 15, 6 and 14 years in this pharmacokinetic case series. For two children the OC plasma concentrations were higher than those found in children and adults not on ECMO. These increased plasma concentrations related to the increased oseltamivir dosage and decreased kidney function. In one patient suboptimal plasma concentrations coincided with a decreased gastric motility. Conclusion: Oseltamivir pharmacokinetics do not appear to be significantly influenced by ECMO support. Caution is required in case of nasogastric administration and decreased gastric motility. Due to the limited number of (paediatric) patients available further multicenter studies are warranted.

Severe acute asthma (Article)

2009-12-01T00:00:00Z

Severe acute asthma (SAA) is life threatening and warrants fast and effective intervention. The severity of SAA can be assessed through a focused and concise clinical examination. Important signs of a life threatening attack are decreased consciousness, imminent exhaustion, oxygen saturation below 85% and diminished air movement on auscultation (silent chest). The severity of SAA can be expressed in an asthma score. The relative contribution of airway inflammation, bronchoconstriction and mucusplugging must be weighed for treatment choices. The pillars of treatment of SAA in the general pediatric practice are oxygen, continuous nebulization of salbutamol, systemic corticosteroids, intravenous magnesium sulphate and perhaps intravenous salbutamol. Further steps in treatment of unresponsive SAA should be initiated in consultation with the pediatric intensive care. Reasons for transfer to a pediatric intensive care are imminent exhaustion and/or respiratory insufficiency, need for mechanical ventilation and intravenous salbutamol.

Implementation of standard sedation management in paediatric intensive care: Effective and feasible? (Article)

2009-09-01T00:00:00Z

Objective. To study the effects of the introduction of a sedation treatment protocol for children in intensive care, including nurses' compliance. Background. While several sedation guidelines for adults and children have been developed and implemented, there is little evidence on use of sedation protocols in critically ill infants. Design. Pretest-posttest intervention study. Methods. Administered sedatives and analgesics over the first seven days of admission were documented for convenience samples, before (n = 27) and after (n = 29) implementation of standard sedation assessments and a sedation protocol. Sedation was assessed with the COMFORT behaviour scale, Nurse Interpretation of Sedation Score and the Visual Analogue Scale for three-month periods, both pretest and posttest. Starting 21 months after the posttest, nurses' compliance with the sedation protocol, as well as administered sedatives and analgesics were evaluated for 12 months. Results. Infants in the posttest period received significantly more midazolam and morphine. The proportion of patients adequately sedated on the grounds of COMFORT scores had increased from 63% pretest to 72% posttest and to 75% in the long run. Adequate sedation as judged from the sedation protocol cutoffs was found in 71% of the assessments. In 45% of assessments indicating undersedation, the infusion rate had been increased on the guidance of the protocol. A survey among staff revealed that most considered the sedation protocol comprehensible and useful. Conclusion. This study showed that regular sedation assessment in critically ill children was feasible and had become standard practice two years after the first posttest. There is insufficient evidence to conclude whether implementation of a sedation treatment protocol indeed improves sedation treatment. Relevance to clinical practice. This sedation protocol provides decision trees for increasing or weaning of sedatives in both haemodynamically stable and unstable patients. It standardises sedation management and allows nurses to adapt medication themselves.

Assessment of opioid and benzodiazepine withdrawal symptoms in critically ill children: current state of the art (Article)

2009-09-01T00:00:00Z

Prolonged administration of benzodiazepines and/or opioids to children in a paediatric intensive care unit (PICU) may in- duce physiological dependence and withdrawal symptoms. We reviewed the literature for relevant contributions on the nature of these withdrawal symptoms and on availability of valid scoring systems to assess the extent of symptoms in children. Symptoms of benzodi- azepine and opioid withdrawal can be classified into three groups: central nervous system (CNS) overstimulation, gastrointestinal dys- regulation and autonomic dysfunction. In children, symptoms associated with CNS overstimulation and autonomic dysfunction may overlap after long-term use of benzodiazepines or opioids. Symptoms of gastrointestinal dysfunction in the PICU population have only been described for opioid withdrawal. Four scoring systems for use in children have been described. Two of these provided good reli- ability and validity to determine withdrawal symptoms: the Withdrawal Assessment Tool version 1 (WAT-1) and the Sophia Observation withdrawal Symptoms-scale (SOS).

Therapeutic drug monitoring of aminoglycosides in neonates (Article)

2009-07-16T00:00:00Z

Construction of the Sophia Observation withdrawal Symptoms-scale (SOS) for critically ill children (Article)

2009-06-01T00:00:00Z

Objective: To construct a reliable and clinically practical instrument for monitoring opioids and benzodiazepine withdrawal symptoms in pediatric ICU patients. Design: Instrument development. Setting: Intensive care unit in an academic children's hospital. Patients and participants: 79 patients up to age 16 years on intravenous midazolam and/or opioids for ≥5 days. An expert panel of 85 physicians and nurses rated clinical relevance of withdrawal symptoms. Intervention: During drug weaning repeated observations were performed with a checklist of 24 withdrawal symptoms described in the literature. Measurements and results: For 76 children, 932 observations were obtained within 24 h after decrease and/or discontinuation of midazolam or opioids. Most frequent symptoms were tachypnea, agitation, motor disturbance, diarrhea, fever, anxiety, sleep disturbance and hypertension (14.6-29.6%). Multidimensional scaling (MDS) was performed to detect the underlying empirical structure of co-occurrences of symptoms. An expert panel judged clinical relevance of each withdrawal symptom on a four-point scale ranging from 'definitively so' to 'definitively not'. Agitation, anxiety, inconsolable crying, increased muscle tension, tremors, tachycardia and sweating were considered relevant by 85-95% of the experts. On the basis of the MDS results and the experts' opinions, 15 symptoms were included in the final instrument. Conclusions: We are the first to develop an assessment tool for withdrawal symptoms in pediatric ICU patients on the basis of the underlying empirical structure of co-occurrences of withdrawal symptoms that experts considered relevant. Future studies need to define cut-off points and clarify psychometric issues.

Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: A first evaluation (Article)

2008-08-01T00:00:00Z

OBJECTIVE: To establish frequencies of benzodiazepine and opioid withdrawal symptoms, and correlations with total doses and duration of administration. DESIGN: A prospective, repeated-measures design. SETTING: Two pediatric intensive care units in a university children's hospital. PATIENTS: Seventy-nine children, aged 0 days to 16 yrs, who received intravenous midazolam and/or opioids for >5 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pediatric intensive care unit nurses assessed withdrawal symptoms using the Sophia Benzodiazepine and Opioid Withdrawal Checklist, which includes all withdrawal symptoms (n ≤ 24) described in the pediatric literature. Over 6 months, 2188 observations in 79 children were recorded. Forty-two percent of observations were performed within 24 hrs after tapering off or discontinuation of medication. Symptoms representing overstimulation of the central nervous system, such as anxiety, agitation, grimacing, sleep disturbance, increased muscle tension, and movement disorder, were observed in >10% of observations. Of symptoms reflecting gastrointestinal dysfunction, diarrhea and gastric retention were most frequently observed. Tachypnea, fever, sweating, and hypertension as manifestations of autonomic dysfunction were observed in >13% of observations. The Spearman's rank-correlation coefficient between total doses of midazolam and maximum sum score (of the Sophia Benzodiazepine and Opioid Withdrawal Checklist) was .51 (p < 0.001). The correlation between total doses of opioids and the maximum sum score was .39 (p < 0.01). A significant correlation (.52; p < 0.001) was also found between duration of use and maximum sum score. CONCLUSIONS: This is the first study to report frequencies of all 24 withdrawal symptoms observed in children after decrease or discontinuation of benzodiazepines and/or opioids. Agitation, anxiety, muscle tension, sleeping <1 hr, diarrhea, fever, sweating, and tachypnea were observed most frequently. Longer duration of use and high dosing are risk factors for development of withdrawal symptoms in children.

Continuous noninvasive monitoring of barbiturate coma in critically ill children using the Bispectral™ index monitor (Article)

2007-09-27T00:00:00Z

Introduction: Traumatic brain injury and generalized convulsive status epilepticus (GCSE) are conditions that require aggressive management. Barbiturates are used to lower intracranial pressure or to stop epileptiform activity, with the aim being to improve neurological outcome. Dosing of barbiturates is usually guided by the extent of induced burst-suppression pattern on the electroencephalogram (EEG). Dosing beyond the point of burst suppression may increase the risk for complications without offering further therapeutic benefit. For this reason, careful monitoring of EEG parameters is mandatory. A prospective study was conducted to evaluate the usefulness of the bispectral index suppression ratio for monitoring barbiturate coma. Methods: A prospective observational pilot study was performed at a paediatric (surgical) intensive care unit, including all children with barbiturate-induced coma after traumatic brain injury or GCSE. The BIS™ (Bispectral™ index) monitor expresses a suppression ratio, which represents the percentage of epochs per minute in which the EEG was suppressed. Suppression ratios from the BIS monitor were compared with suppression ratios of full-channel EEG as assessed by quantitative visual analysis. Results: Five patients with GCSE and three patients after traumatic brain injury (median age 11.6 years, range 4 months to 15 years) were included. In four patients the correlation between the suppression ratios of the BIS and EEG could be determined; the average correlation was 0.68. In two patients, suppression ratios were either high or low, with no intermediate values. This precluded determination of correlation values, as did the isoelectric EEG in a further two patients. In the latter patients, the mean ± standard error BIS suppression ratio was 95 ± 1.6. Conclusion: Correlations between suppression ratios of the BIS and EEG were found to be only moderate. In particular, asymmetrical EEGs and EEGs with short bursts (less than 1 second) may result in aberrant BIS suppression ratios. The BIS monitor potentially aids monitoring of barbiturate-induced coma because it provides continuous data on EEG suppression between full EEG registrations, but it should be used with caution.

Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: A literature review. "Assessment remains troublesome" (Article)

2007-08-01T00:00:00Z

Background: Prolonged administration of benzodiazepines and/or opioids to children in a pediatric intensive care unit (PICU) may induce physiological dependence and withdrawal symptoms. Objective: We reviewed the literature for relevant contributions on the nature of these withdrawal symptoms and on availability of valid scoring systems to assess the extent of symptoms. Methods: The databases PubMed, CINAHL, and Psychinfo (1980-June 2006) were searched using relevant key terms. Results: Symptoms of benzodiazepine and opioid withdrawal can be classified in two groups: central nervous system effects and autonomic dysfunction. However, symptoms of the two types show a large overlap for benzodiazepine and opioid withdrawal. Symptoms of gastrointestinal dysfunction in the PICU population have been described for opioid withdrawal only. Six assessment tools for withdrawal symptoms are used in children. Four of these have been validated for neonates only. Two instruments are available to specifically determine withdrawal symptoms in the PICU: the Sedation Withdrawal Score (SWS) and the Opioid Benzodiazepine Withdrawal Scale (OBWS). The OBWS is the only available assessment tool with prospective validation; however, the sensitivity is low. Conclusions: Withdrawal symptoms for benzodiazepines and opioids largely overlap. A sufficiently sensitive instrument for assessing withdrawal symptoms in PICU patients needs to be developed.

Recombinant human deoxyribonuclease in infants with respiratory syncytial virus bronchiolitis (Article)

2007-03-01T00:00:00Z

Background: Treatment of hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis is mainly supportive. Bronchodilators and systemic steroids are often used but do not reduce the length of hospital stay. Because hypoxia and airways obstruction develop secondary to viscous mucus in infants with RSV bronchiolitis, and because free DNA is present in RSV mucus, we tested the efficacy of the mucolytic drug recombinant human deoxyribonuclease (rhDNase). Methods: In a multicenter, randomized, double-blind, controlled clinical trial, 225 oxygen-dependent infants admitted to the hospital for RSV bronchiolitis were randomly assigned to receive 2.5 mg bid of nebulized rhDNase or placebo until discharge. The primary end point was length of hospital stay. Secondary end points were duration of supplemental oxygen, improvement in symptom score, and number of intensive care admissions. Results: There were no significant differences between the groups with regard to the length of hospital stay (p = 0.19) or the duration of supplemental oxygen (p = 0.07). The ratio (rhDNase/placebo) of geometric means of length of stay was 1.12 (95% confidence interval, 0.96 to 1.33); for the duration of supplemental oxygen, the ratio was 1.28 (95% confidence interval, 0.97 to 1.68). There were no significant differences in the rate of improvement of the symptom score or in the number of intensive care admissions. Conclusions: Administration of rhDNase did not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.

Life-threatening asthma in children: treatment with sodium bicarbonate reduces PCO2. (Article)

2005-03-01T00:00:00Z

OBJECTIVES: To assess the effect of administration of sodium bicarbonate on carbon dioxide levels in children with life-threatening asthma (LTA) and to evaluate the clinical effect of this treatment.Study DESIGN: Retrospective study. SETTING: A pediatric ICU (PICU) of a tertiary care university hospital. PATIENTS: Seventeen children with LTA who received sodium bicarbonate. MEASUREMENTS AND RESULTS: In January 1999, a new protocol for the treatment of LTA was initiated in our institution, incorporating the use of IV sodium bicarbonate in acidotic patients (pH < 7.15) with refractory status asthmaticus. Since January 1999, sodium bicarbonate was administered to 17 patients; 5 patients received two or three doses of sodium bicarbonate. In three patients, sodium bicarbonate was administered after intubation. Intubation and mechanical ventilation were performed in five patients before admission to the PICU, and in one patient during admission. There was a significant decrease of Pco(2) after sodium bicarbonate infusion (p = 0.007). An improvement of respiratory distress in all but one patient was seen as well. CONCLUSIONS: Administration of sodium bicarbonate in 17 children with LTA was associated with a significant decrease in Pco(2) and an improvement of respiratory distress. The possible benefits of sodium bicarbonate in LTA deserve further study in a controlled, prospective design.

Assessment of sedation levels in pediatric intensive care patients can be improved by using the COMFORT "behavior" scale (Article)

2005-01-01T00:00:00Z

Objectives: The original COMFORT scale, including both observational and physiologic items, has been validated for measuring distress in children admitted to a pediatric intensive care unit. However, physiologic variables are influenced by drugs given in the pediatric intensive care unit setting. The objectives of this study were to assess the usefulness of physiologic variables in judgment of sedation and to determine new cutoff points for the COMFORT "behavioral" scale (COMFORT-B), using only observational items. Design: Prospective observational study. Setting: Pediatric intensive care unit in a university hospital Patients: Seventy-eight patients admitted to the pediatric intensive care unit. Interventions: None. Measurements and Results: COMFORT scores were obtained in this patient group. Similar to the original COMFORT scale validation, the expert opinion of nurses (Nurse Interpretation Score of Sedation) served to determine optimal cutoff scores for the COMFORT-B scale. A total of 843 combined COMFORT and Nurse Interpretation Score of Sedation scores were obtained in 78 patients. Cronbach's alpha for the COMFORT scale was .78, increasing to .84 when the physiologic items, blood pressure and heart rate, were excluded. COMFORT scores were significantly different for the three Nurse Interpretation Score of Sedation categories (Kruskal-Wallis, p < .001). According to the pediatric intensive care unit nurses, undersedation was present in 11% and oversedation in 3% of all observations. Cutoff points for the COMFORT-B scale were ≤10 for oversedation and ≥=23 for undersedation. The area in the COMFORT-B score between 11 and 22 does not adequately predict under- or oversedation, pointing to a need for supplemental observation. Conclusions: The COMFORT-B scale is a reliable alternative to the original COMFORT scale. The cutoff points of the COMFORT-B scale in conjunction with the Nurse Interpretation Score of Sedation facilitate the use of sedation algorithms on the pediatric intensive care unit. Copyright

Tobramycin and vancomycin use in newborns: pharmacokinetic and pharmacodynamic aspects (Doctoral Thesis)

2001-11-14T00:00:00Z

A survey of the use of off-label and unlicensed drugs in a Dutch children's hospital (Article)

2001-01-01T00:00:00Z

BACKGROUND: The treatment of pediatric patients with drugs in hospitals is being impeded by a shortage in the availability of licensed drugs in an appropriate formulation. We have studied the extent of use of drugs that are not licensed for use in children (unlicensed) and drugs that are used outside the terms of the product license (off-label). We conducted this study in a Dutch academic children's hospital. METHODS: In a prospective study of 5 weeks' duration, we reviewed drug prescriptions in a pediatric ward and 3 intensive care units. We classified the prescribed drugs in 3 main categories-licensed, unlicensed, and off-label-and determined the nature of their unlicensed and off-label use. RESULTS: Two thousand one hundred thirty-nine courses of drugs were administered to 237 patients in 442 patient-days. Of 2139 prescriptions, 725 (34%) were licensed, 1024 (48%) were unlicensed, and 390 (18%) were off-label. In 392 (90%) of 435 patient-days, children received 1 or more courses of an unlicensed or off-label drug prescription in hospital. CONCLUSION: With regard to the availability of drugs of proven quality and adequate license for pediatric patients in hospital, dramatic shortcomings exist. As a result, drug legislation originally designed to protect patients and prescribing physicians against unsafe drug use and unjustified claims has turned into an insurmountable threshold to make proper drugs available for a vulnerable minority of patients.

DNase treatment for atelectasis in infants with severe respiratory syncytial virus bronchiolitis (Article)

2001-01-01T00:00:00Z

Respiratory insufficiency due to respiratory syncytial virus (RSV) bronchiolitis is partly due to the abundance of thickened mucus and the inability to clear it from the airways. Mucus in RSV bronchiolitis contains necrotic inflammatory and epithelial cells. The viscoelastic properties of purulent airway secretions are largely due to the presence of highly polymerized deoxyribonucleic acid (DNA). Recombinant human deoxyribonuclease (rhDNase) is known to liquefy such mucus in patients with cystic fibrosis, whereas case reports described a beneficial effect in other respiratory disorders. The authors hypothesized that rhDNase would diminish atelectasis and mucus plugging in infants with severe RSV bronchiolitis. Two infants with RSV bronchiolitis with massive unilateral atelectasis in whom mechanical ventilation was imminent due to exhaustion, and three mechanically ventilated infants (two neonates, one with bronchopulmonary dysplasia) with RSV bronchiolitis with pneumonia received treatment with 2.5 mg nebulized rhDNase twice daily. Following administration of nebulized recombinant human deoxyribonuclease, clinical and radiological parameters improved quickly. Mechanical ventilation could be avoided in two infants while in three infants on artificial ventilation, clinical recovery started following the first dose of the drug. A therapeutic trial of recombinant human deoxyribonuclease may be an option in the treatment for atelectasis in severe or complicated respiratory syncytial virus bronchiolitis in infancy.

Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors (Article)

2000-01-01T00:00:00Z

To get insight in the endocrine and metabolic responses in children with meningococcal sepsis 26 children were studied the first 48 h after admission. On admission there was a significant difference in cortisol/ACTH levels between nonsurvivors (n = 8) and survivors (n = 18). Nonsurvivors showed an inadequate cortisol stress response in combination to very high ACTH levels, whereas survivors showed a normal stress response with significantly higher cortisol levels (0.62 vs. 0.89 micromol/L) in combination with moderately increased ACTH levels (1234 vs. 231 ng/L). Furthermore, there was a significant difference between nonsurvivors and survivors regarding pediatric risk of mortality score (31 vs. 17), TSH (0.97 vs. 0.29 mE/L), T3 (0.53 vs. 0.38 nmol/L), reverse T3 (rT3) (0.75 vs. 1.44 nmol/L), C-reactive protein (34 vs. 78 mg/L), nonesterified fatty acids (0.32 vs. 0.95 mmol/L), and lactate (7.3 vs. 3.2 mmol/L). In those who survived, the most important changes within 48 h were seen in a normalization of cortisol and ACTH levels, but without a circadian rhythm; a decrease of rT3 and an increase in the T3/rT3 ratio; and a decrease in the levels of the nonesterified free fatty acids and an unaltered high urinary nitrogen excretion. At this moment, it is yet unknown whether the hormonal abnormalities are determining factors in the outcome of acute meningococcal sepsis or merely represent secondary effects. Understanding the metabolic and endocrine alterations is required to design possible therapeutic approaches. The striking difference between nonsurvivors and survivors calls for reconsideration of corticosteroid treatment in children with meningococcal sepsis.