Occult risk factor for the development of cerebral edema in children with diabetic ketoacidosis: possible role for stomach emptying.

The incidence of cerebral edema during therapy of diabetic ketoacidosis (DKA) in children remains unacceptably high-this suggests that current treatment may not be ideal and that important risk factors for the development of cerebral edema have not been recognized. We suggest that there are two major sources for an occult generation of osmole-free water in these patients: first, fluid with a low concentration of electrolytes that was retained in the lumen of the stomach when the patient arrived in hospital; second, infusion of glucose in water at a time when this solution can be converted into water with little glucose. In a retrospective chart review of 30 patients who were admitted with a diagnosis of DKA and a blood sugar > 900 mg/dL (50 mmol/L), there were clues to suggest that some of the retained fluid in the stomach was absorbed. To minimize the likelihood of creating a dangerous degree of cerebral edema in patients with DKA, it is important to define the likely composition of fluid retained in the stomach on admission, to look for signs of absorption of some of this fluid during therapy, and to be especially vigilant once fat-derived brain fuels have disappeared, because this is the time when glucose oxidation in the brain should increase markedly, generating osmole-free water.

Naloxone for shock.

BACKGROUND: There is pre-clinical evidence, involving several animal species, suggesting that opioid peptides play a role in the physiopathology of shock (endotoxic, hypovolemic, cardiogenic, spinal, anaphylactic). Many case reports have suggested that naloxone (an opiate antagonist) might be an effective treatment for shock in humans, but others have not supported such a point of view. This controversy led us to undertake a meta-analysis of the available evidence on the efficacy of naloxone as a treatment measure of shock in humans. OBJECTIVES: To evaluate the effectiveness and safety of naloxone in human shock and to estimate the methodological quality of the clinical trials. SEARCH STRATEGY: Computerized bibliographic search up to December 2002, review of references of all papers found on the subject and contact with primary investigators of eligible studies. SELECTION CRITERIA: Randomized controlled trials evaluating naloxone in human shock, regardless of the patient's age (adult, child or neonate). DATA COLLECTION AND ANALYSIS: Three independent reviewers extracted data on study design, intervention, outcome and methodological quality. MAIN RESULTS: Three independent readers reviewed 80 human publications and selected six clinical trials. Overall agreement on study selection was perfect (concordance: 100%). This meta-analysis includes six studies involving 126 patients with septic, cardiogenic, hemorrhagic or spinal shock. Naloxone therapy was associated with statistically significant hemodynamic improvement (odds ratio 0.24; 95% confidence interval [95%CI] 0.09-0.68). The mean arterial pressure was significantly higher in the naloxone groups than in the placebo groups (weighted mean difference: +9.33 mmHg; 95%CI 7.07-11.59). No heterogeneity was found for this outcome. The death rate was lower in the naloxone group (odds ratio 0.59; 95%CI 0.21-1.67) but this was consistent with the play of chance. A significant heterogeneity for the latter outcome was detected (p<0.05). REVIEWER'S CONCLUSIONS: Naloxone improves blood pressure, especially mean arterial blood pressure. However, the clinical usefulness of naloxone to treat shock remains to be determined, and additional randomized controlled trials are needed to assess its usefulness.

Characterization of PGE2 receptors in fetal and newborn ductus arteriosus in the pig.

We compared the total density and the relative expression of EP receptor (EP) subtypes in ductus arteriosus (DA) of the newborn with that of the fetal piglet. Saturation binding experiments showed 3-fold less PGE2 receptors in the newborn than in the fetus because of loss of EP3 and EP4 receptors thus explaining, at least partly, the reduced responsiveness to PGE2 of the newborn DA. Displacement experiments showed that the relative proportions of EP2, EP3, and EP4 were similar in the fetal DA but only EP2 was detected in the DA of the newborn pig. Hence, PGE2 effects in the newborn DA seem to be exclusively mediated by EP2 receptors both in vitro and in vivo. These findings may help to propose more specific therapies for regulation of DA's tone in certain newborns for whom conventional therapy is contraindicated.

Pulmonary injury after intravenous hydrocarbon injection.

This report describes the case of a young man in whom an intravenous injection of a hydrocarbon led to reversible pulmonary edema. An 18-year-old male presented with chest pain, a cough and progressive dyspnea at a multidisciplinary paediatric intensive care unit in a tertiary care university hospital. Six hours after oxygen was given, blood gases were pH 7.16, partial pressure of carbon dioxide 43 torr (5.7 kPa), partial pressure of arterial oxygen 149 torr (19.9 kPa) and bicarbonate concentration 15 mEq/L. A chest radiograph suggested pulmonary edema. On day 3, the patient stated that he had injected himself with Varsol (Imperial Oil, Canada) - a mixture of straight and branched-chain hydrocarbons, naphthenes and alkyl derivatives of benzene - several hours before his admission. On day 5, the patient's respiratory rate returned to 20 breaths/min, and his chest radiograph was normal by day 7. The present case report suggests that the intravenous injection of hydrocarbons may lead to reversible pulmonary injury.

Developmental changes in prostaglandin E(2) receptor subtypes in porcine ductus arteriosus. Possible contribution in altered responsiveness to prostaglandin E(2).

BACKGROUND: Prostaglandin E(2) (PGE(2)) is important in ductus arteriosus (DA) patency, but the types of functional PGE(2) receptors (EP) in the developing DA are not known. We postulated that age-dependent alterations in EP and/or their subtypes may possibly contribute to the reduced responsiveness of the newborn DA to PGE(2). METHODS AND RESULTS: We determined PGE(2) receptor subtypes by competition binding and immunoblot studies on the DA of fetal ( approximately 75% and 90% gestation) and newborn (<45 minutes old) pigs. We studied the effects of EP receptor stimulation on cAMP signaling in vitro and on term newborn (<3 hours old) DA patency in vivo. Fetal pig DA expressed EP(2), EP(3), and EP(4) receptors equivalently, but not EP(1). In neonatal DA, EP(1), EP(3), and EP(4) were undetectable, whereas EP(2) density was similar in fetus and newborn. Prostaglandin-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE(2) and 11-deoxy PGE(1) (EP(2)/EP(3)/EP(4) agonist) produced more cAMP in fetus than newborn, but butaprost (selective EP(2) agonist) caused similar cAMP increases in both; EP(3) and EP(4) ligands (M&B28767 and AH23848B, respectively) affected cAMP production only in fetus. After birth, administration of butaprost alone was as effective as 11-deoxy PGE(1) and 16,16-dimethyl PGE(2) in dilating DA in vivo. CONCLUSIONS: The data reveal fewer PGE(2) receptors in the DA of the newborn than in that of the fetus; this may contribute to the decreased responsiveness of the DA to PGE(2) in newborn. Because EP(2) receptors seem to mediate the effects of PGE(2) on the newborn DA, one may propose that a selective EP(2) agonist may be preferred as a pharmacological agent to maintain DA patency in infants with certain congenital heart diseases.

Ribavirin in ventilated respiratory syncytial virus bronchiolitis. A randomized, placebo-controlled trial.

We undertook a prospective, double-blind, placebo-controlled trial to resolve the question of the clinical effectiveness of ribavirin in previously well infants who require ventilation for respiratory distress secondary to respiratory syncytial virus (RSV) bronchiolitis. Aerosol ribavirin or NaCl 0.9% was administered within 24 h of initiation of ventilation, 18 h/d, for a maximum of 7 d or until extubation. From March 1994 to March 1997, 42 children were randomized and 41 patients were retained for analysis. Baseline characteristics of each group-ribavirin and placebo (20:21)-were not significantly different with respect to age (62.5 +/- 35.9 versus 62.7 +/- 30.9 d), sex, weight, and length of ventilation pre-aerosol. "Intent to treat" outcome analysis found no significant differences in the length of the following: ventilation (102.16 +/- 65.26 versus 126.28 +/- 78.72 h; p = 0.29), aerosol therapy, stay in the intensive care unit, total oxygen therapy, and hospitalization. The aerosols were well tolerated and no deaths occurred. This trial demonstrates the lack of effectiveness of aerosolized ribavirin in reducing the length of ventilation and course of illness in infants with no underlying illness ventilated for respiratory distress secondary to RSV bronchiolitis.

Expression of cyclooxygenases in ductus arteriosus of fetal and newborn pigs.

OBJECTIVE: We studied the ontogeny of the expression of cyclooxygenase-1 and cyclooxygenase-2 in the ductus arteriosus and evaluated their functional significance. STUDY DESIGN: The expression of cyclooxygenase-1 and cyclooxygenase-2 was studied in ductus arteriosus of fetal (at approximately 75% gestation) and term newborn pig. Effects of selective inhibitors of cyclooxygenase-1 and cyclooxygenase-2 on ductal patency were evaluated by Doppler ultrasonography. RESULTS: Ductus arteriosus of the fetus expressed virtually only cyclooxygenase-1 immunoreactive protein and activity. In contrast, the ductus of the term newborn pig (<45 minutes old) contained proteins of both cyclooxygenase-1 and cyclooxygenase-2, but the latter contributed to >90% of prostaglandin E2 formation. The selective cyclooxygenase-2 inhibitor DuP697 reduced prostaglandin E2 levels in the ductus arteriosus, albeit not in plasma, but did not affect ductal patency in the newborn pig (<1(1/2) hours old); in contrast, the cyclooxygenase-1 inhibitor valeryl salicylate, like indomethacin, markedly reduced levels of prostaglandin E2 in the plasma and ductus arteriosus and caused significant constriction of the ductus arteriosus. CONCLUSION: The ductus arteriosus of the term newborn pig, in contrast to that of the fetus, expresses cyclooxygenase-2, but circulating prostaglandins, arising mostly from cyclooxygenase-1, seem to exert the major control on ductal patency in vivo. Our data suggest that cyclooxygenase-2 inhibitors might be better alternatives for the fetus than nonselective cyclooxygenase blockers if indicated for maternal conditions such as inflammation or for tocolysis.

Therapy of shock with naloxone: a meta-analysis.

OBJECTIVES: To evaluate the effectiveness of naloxone in human shock; and to estimate the methodologic quality of the clinical trials. DATA SOURCES: Computerized bibliographic search on MEDLINE covering the period from January 1979 to July 1996, review of references of all papers found on the subject, and contact with primary investigators of eligible studies. STUDY SELECTION: To be included in this study, a paper should be a randomized, clinical trial published in a peer-reviewed journal evaluating naloxone in human shock, regardless of the patient's age (adult, child, neonate). Three independent readers reviewed 61 human publications and selected five clinical trials. Overall agreement on study selection was perfect (concordance: 100%). We excluded a posteriori two studies whose authors were unable to provide us with the raw data to complete contingency tables. This meta-analysis deals with three studies including 61 patients with septic shock. DATA EXTRACTION: Three independent reviewers extracted data on study design, intervention, outcome, and methodologic quality. The intraclass correlation coefficient was 0.7. The quality score of each study was 48, 60, and 61, on a scale of 104. DATA SYNTHESIS: Naloxone therapy was associated with statistically significant hemodynamic improvement (typical odds ratio: 0.241; 95% confidence interval: 0.08 to 0.68). The overall effect size was 0.89. However, a publication bias was possible. The case fatality rate was not decreased by naloxone (typical odds ratio: 0.60; 95% confidence interval: 0.21 to 1.67); a chi-square analysis detected significant heterogeneity for the latter outcome (p < .05). CONCLUSIONS: Naloxone improves blood pressure. However, the clinical usefulness of naloxone to treat shock remains to be determined and additional randomized clinical trials are needed to assess its usefulness.

Key role for cyclooxygenase-2 in PGE2 and PGF2alpha receptor regulation and cerebral blood flow of the newborn.

Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E2 (PGE2) and PGF2alpha receptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evidence that COX-2-generated prostaglandins govern PGE2 and PGF2alpha receptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE2 and PGF2alpha receptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE2 and PGF2alpha concentrations were significantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS-398, and ibuprofen, PGE2 and PGF2alpha receptor densities in brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE2 (EP1 receptor agonist), M&B-28767 (EP3 receptor agonist), PGF2alpha, and fenprostalene (PGF2alpha analog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure limit of cerebral cortex and periventricular blood flow autoregulation from 85 to > or = 125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE2 and PGF2alpha receptors, IP3 production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE2 and PGF2alpha receptors and their functions in the newborn cerebral vasculature.