Toxicodynetics in nordiazepam and oxazepam overdoses.

OBJECTIVES: Toxicodynetics aims at defining the time-course of major clinical events in drug overdose. We report the toxicodynetics in mono-intoxications with oxazepam and nordiazepam. METHODS: Cases of oxazepam or nordiazepam overdoses collected at the Paris poison control centre from 1999 to 2014 on the basis of self-report. A particular attention was paid to eliminate the concomitant alcohol or psychotropic co-ingestions. The toxicodynetic parameters were assessed as previously described. Results are expressed using 10-90 percentiles. In adults, the dose was normalized (TI, toxic Index) by dividing the supposed ingested dose by the maximal recommended dose. RESULTS: Two hundred and fifty-one and 74 cases of oxazepam and nordiazepam poisonings were included, respectively. The Emax for oxazepam and nordiazepam were sleepiness or obtundation in 106 and 36 cases, respectively. Coma was used to qualify only one oxazepam overdose. The median delay in onset of the Emax was 1.5h (0.33-15) in nordiazepam and 4h (0.5-15) in oxazepam overdose. In both overdoses, the onset of Emax occurred on an "on-off" mode. In adults, the greatest TIs in nordiazepam and oxazepam overdoses were 45 and 26.7, respectively. The TI in the oxazepam-induced coma was 26.7, the largest dose. CONCLUSION: Data collected in PCC allow determining a number of toxicodynetic parameters. Toxicodynetics showed that nordiazepam is not a cause of coma even in large overdose while oxazepam causes coma only at a very high dose. Deep coma in nordiazepam overdose whatever the dose and deep coma in overdose with oxazepam involving TI less than 20 result from unrecognized drug-drug interaction.

Availability of digital dermoscopy in daily practice dramatically reduces the number of excised melanocytic lesions: results from an observational study.

BACKGROUND: Digital dermoscopy has been shown to permit an earlier detection of melanoma. However, few studies have investigated its added value in reducing unnecessary excisions in everyday clinical practice. OBJECTIVES: To compare, in daily practice, the efficiency of three dermoscopy methods: dermoscopy alone with little training, dermoscopy alone with adequate training and dermoscopy with adequate training and access to digital dermoscopy, and to confirm the safety of this latter approach. METHODS: Thirty-six dermatologists working without digital dermoscopy were divided into two groups according to their training in dermoscopy. The third group constituted of two dermatologists working in a pigmented lesion clinic with access to the digital dermoscopy technique and eight additional dermatologists working in the same dermatology department. These 46 dermatologists included all presumed melanocytic lesions excised over a period of 1 year. The primary endpoint was the melanoma/nonmelanoma ratio (M/NM-R); secondary endpoints were the ratio of 'problem' naevi to common naevi (PN/CN-R), specificity and sensitivity for the diagnosis of melanoma, in situ/invasive melanoma ratio, and the mean Breslow thickness. RESULTS: In total, 1865 excised lesions, including 231 melanomas, were included. In the digital dermoscopy availability group (DD-G) the M/NM-R was significantly better (1/2.43), as was the PN/CN-R (1/1.48) (P < 0.001 in both cases). The specificity was significantly higher in the DD-G and significantly higher for trained examiners as compared with examiners with little training. More that one-third of all melanomas discovered by digital dermoscopy were in situ, and the mean Breslow thickness was 0.32 mm for the invasive ones. CONCLUSIONS: The reduction of unnecessary excisions when using digital dermoscopy compared with dermoscopy alone in our study suggests that access to digital dermoscopy offers a better management of pigmented lesions in daily practice. The high number of early lesions diagnosed by this technique confirms that its use is safe.

Influence of xanthines on gastroesophageal reflux in infants at risk for sudden infant death syndrome.

Theophylline and caffeine are two drugs frequently administered to infants at risk for sudden infant death syndrome, because of their stimulatory effects on the respiratory system. These drugs are known to increase gastric acid secretion and to decrease lower esophageal sphincter pressure that, in turn, possibly increases gastroesophageal reflux (GER). Thirty babies were tested for GER before and during caffeine treatment. Eighteen were studied under the same conditions while undergoing theophylline treatment. All results of pH monitoring before treatment were within normal ranges. Episodes of GER increased significantly (P less than .001) in about 50% of the group treated with caffeine and in 66% of the group treated with theophylline. These results were independent of plasma xanthine concentrations (within or below therapeutic ranges) and of the efficacy of the drug. In addition, an increase was noted for the number of episodes of GER in 24 hours (from 5.3 to 17.1 in the caffeine group and from 5.3 to 24.3 in the theophylline group) and for the time pH was less than 4 (from 0.87% to 6% in the caffeine group and up to 13% in the theophylline group). Because GER is another known risk factor for sudden infant death syndrome, the administration of xanthine derivatives in babies at risk for sudden infant death syndrome should be carefully considered in each case.

Gastroesophageal reflux, as measured by 24-hour pH monitoring, in 509 healthy infants screened for risk of sudden infant death syndrome.

Continuous long-term esophageal pH monitoring has become the preferred test to quantify acid gastroesophageal reflux. Because reflux to a limited extent is physiologic, the determination of optimal thresholds to separate normal from abnormal reflux is mandatory. Esophageal pH was measured during 24 hours in 509 healthy thriving infants, aged 3 days to 1 year, using a glass microelectrode with an external reference electrode connected to a portable recorder. Percentiles of the four parameters studied (reflux index or percent of the investigation time with a pH less than 4, number of episodes with a pH less than 4 during 24 hours, number of episodes lasting greater than 5 minutes, the duration of the longest episode (in minutes) are presented. A percentile curve of the reflux index regarding the age distribution shows that the normal range for the reflux index during the first 12 months of life is about 10% (95 percentile), decreasing from 13% at birth to 8% at 12 months. Application of an age-related percentile curve offers a close-to-reality possibility of data interpretation and illustrates that there is inevitably an overlap of data between normal and abnormal populations, because reflux is a phenomenon occurring to some extent in every human being.

Neonatal diagnosis of the immotile cilia syndrome.

The immotile cilia syndrome is an inherited disorder characterized by inappropriate motility of the cilia. The clinical symptoms include recurrent sinopulmonary infections and reduced fertility. In about half of the cases, situs inversus is encountered. The case presented is of a two-day-old boy in whom diagnosis was based on ultrastructural abnormalities. Early diagnosis permitted immediate symptomatic treatment and an absence of infections during a 37-month period of observation. Nasal biopsies performed in six newborns with various degrees of respiratory distress secondary to classic neonatal respiratory problems and in a healthy one-day-old newborn demonstrated the presence of normal ciliary structures at birth. In cases without situs inversus, diagnosis of the immotile cilia syndrome may be difficult. The importance of early diagnosis and management is stressed; the ultrastructural abnormalities are present at birth in newborns with the immotile cilia syndrome.

Neonatal myotubular myopathy with a probable X-linked inheritance: observations on a new family with a review of the literature.

During the 3 weeks of his life, an infant born at term presented pronounced hypotonia, areflexia and generalized paresis with severe respiratory and feeding problems. He was the fourth male in two generations to die in the perinatal period, therefore suggesting an X-linked inheritance. Post-mortem examination revealed a centronuclear or myotubular myopathy. The difficulty in distinguishing the signs due to muscle disorder from those due to hypoxaemic encephalopathy is stressed. Infants with centronuclear myopathy have in any case a high risk for hypoxaemic encephalopathy. The literature concerning neonatal centronuclear myopathy with X-linked inheritance is reviewed.

Unexpected diagnosis of Candida albicans meningitis in a premature neonate.

Candida albicans meningitis was found in an otherwise healthy 44-day-old premature infant whose birth weight was 1,860 gm. Almost no abnormal clinical or neurologic findings were present. The electroencephalogram, however, was abnormal. All previous body fluid cultures were negative. The combined use of amphotericin B and 5-fluorocytosine resulted in negative cerebrospinal fluid cultures after 3 weeks of therapy. Physical and psychomotor development remained normal on subsequent examination.

PH monitoring in children.

Long-term oesophageal pH monitoring has become the preferred technique for detection and quantification of gastro-oesophageal reflux (GOR). The most obvious advantages of pH monitoring are the duration of the investigation, the possibility of being able to relate "events" (emesis, heartburn, apnoea) to pH changes (and to study "occult GOR"), the physiological conditions in which the data are recorded (sleep, work), and the possibility of repeating the investigation in treatment conditions. However, it has been reported that the accuracy of pH monitoring is no higher than 90%, because the intermittent presence of acid in the oesophagus is only one of the various abnormalities in the syndrome of GOR. A tremendous number of technique- (pH monitoring system, type of electrode, location of the electrode) and patient-related factors influence pH data. Age, position (both for adults and for infants), duration of the investigation (day/night), feeding and drugs are patient-related factors. Finally, the question arises (which is still unanswered) whether the indication for pH monitoring should be considered in the interpretation of the data: are the same criteria valid for GOR in children presenting with emesis and oesophagitis as for children with GOR resulting in chronic respiratory disease or "near-miss sudden infant death syndrome".

Milk-thickening agents as a treatment for gastroesophageal reflux.

Milk thickening agents are believed to reduce episodes of gastroesophageal reflux, but their use has not been evaluated thoroughly. We studied the effect of these agents in 30 bottle-fed babies, 6-8 weeks old, with clinical gastroesophageal reflux pathology. Continuous 24-hour esophageal pH monitoring revealed gastroesophageal reflux pathology for all parameters studied: reflux index (18.4%), duration of the longest reflux episode (23.3 min), number of reflux episodes in 24 h (34.5), number of reflux episodes greater than 5 min (6.8). All investigations were performed in prone-anti-Trendelenburg position. The infants were treated with milk thickening agents (1 g to 115 ml, as recommended by Carre). Most (n = 25) showed clinical improvement of their symptoms. A second pH monitoring was performed under treatment conditions after 7-14 days, and showed in 24 infants a decrease of the number of reflux episodes (15.1 in 24 h) (p less than 0.001), but a comparable reflux index (17.8%) (NS) and number of long lasting (greater than 5 min) reflux episodes (7.8) (NS). The duration of the longest reflux episode, however, increased significantly (56.6 min) (p less than 0.001). In six infants all parameters were within normal ranges at follow-up. Milk thickening agents seem clinically effective as a treatment for gastroesophageal reflux in individual cases, but can lead to occult gastroesophageal reflux episodes of long duration, possibly increasing the risk for esophagitis or respiratory dysfunction.

Computerized prescription of total parenteral nutrition in pediatrics.

Total parenteral nutrition is often administered in pediatrics, especially to newborn infants and (very)-low-birth-weight infants. The use of a personal computer virtually eliminates errors, and removes the problem of tedious mathematical and time-absorbing calculations. The authors describe and discuss the TPN-program they developed.

The use of cimetidine in newborns.

Cimetidine, a specific H2 antagonist and a potent inhibitor of gastric secretion, was administered in newborns who failed to tolerate oral feeding and presented with abnormal gastric residues accompanied by microscopic or macroscopic high gastrointestinal bleeding. This group of 18 infants was compared to a control group of 15 in similar clinical conditions. After 4 days of treatment with cimetidine (24 mg/kg/day), adapted oral alimentation generally was well tolerated with normal gastric residues. No side effects of the therapy were observed.

[Xanthines in apnea of premature infants. Influence on gastroesophageal reflux]. / Les xanthines dans les apnées du prématuré. Influence sur le reflux gastro-oesophagien.

Theophylline and caffeine are two xanthine-derivated drugs frequently administered for their stimulating effects on the respiratory center in premature babies presenting with "idiopathic apnea". These drugs are known to increase the gastric acid secretion and to decrease the lower esophageal sphincter pressure, that in turn possibly increase gastroesophageal reflux. We studied 14 premature babies presenting with "idiopathic apnea", treated with caffeine at recommended dose (2.5 mg/kg/day). At 24 hour continuous esophageal pH monitoring was performed 3 to 5 days after starting the treatment. In 6 babies total reflux time (5.6% of the investigation time with ph less than 4) and the number of refluxes in 24 hours (15.3) were significantly increased compared to the other 8 babies (pH less than 4: 0.92%; number of refluxes 6.1). These results were also compared to the results obtained ina symptomatic full term neonates (5-10 days old) (pH less than 4: 0.87; number 5.3/24 hours). The results we obtained in the caffeine treated group were independent of the plasma xanthine levels (all within or below therapeutic ranges). A second pH monitoring 2 weeks after stopping caffeine administration was always within normal ranges. The increase of gastroesophageal reflux seems individual for each patient. Gastroesophageal reflux can lead to pulmonary aspiration, and, in this way, it can be the origin of obstructive apnea or aspiration pneumonia.

Influences of neonatal serum IgE concentration, family history and diet on the incidence of cow's milk allergy.

Serum IgE concentration was measured on the 5th day of life in 943 infants. All infants were included in a 3 month follow-up study. The frequency of cow's milk allergy was studied according to either family history, IgE level, or both. Feeding (mother's milk or formula feeding) was taken into account. Manifestations suggestive of food allergy were hardly observed in breast-fed babies. In the formula-fed group a positive family history correlated with a 40% incidence of allergic manifestations, compared to a 13% incidence (P less than 0.001) in the group with negative family history. A high IgE level (IgE greater than 1.3 U/ml) indicated a 43% risk of developing allergic manifestations in formula-fed babies as compared to 15% (P less than 0.001) in the group with normal results of a screening test. Frequency of allergic manifestations in a subgroup with a negative family history and a high IgE level (38%) was equal to the frequency in the subgroup with a positive family history and negative screening test results (IgE less than 1.3 U/ml)(36%). The incidence in the subgroup with both positive screening test results and a positive family history was 49%. None of these differences were significant. The frequency in the subgroup with both parameters negative was 8% (P less than 0.001 to 3 other subgroups). Our results indicate that the family history seems to correlate as well with the incidence of allergic manifestations as the neonatal serum IgE concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastroesophageal reflux associated with respiratory abnormalities during sleep.

To determine whether gastroesophageal reflux (GER) might be a factor in the pathogenesis of apnea in certain infants, we analyzed the frequency of prolonged central apnea (greater than 15 s) and of numerous irregularly repeated short apneas (5-15 s) ("respiratory dysfunction") in infants with an apparent life-threatening event (ALTE) (group 1, n = 62), in control infants (group 2, n = 387), and in infants with GER pathologic findings (group 3, n = 60). Finally, the incidence of GER was analyzed in 76 infants with a respiratory dysfunction during sleep (group 4). Gastroesophageal reflux was investigated using 24-h esophageal pH monitoring; respiration during sleep was investigated by polysomnography. The pH monitoring data and results of sleep investigation were analyzed in a double-blind study. A great number of infants who had an ALTE appeared to suffer from GER (42%, 26 of 62 infants), especially if the ALTE occurred while the infant was awake (52%, 14 of 27 infants). In the control infants, pH monitoring data were abnormal in 8.5%; respiratory dysfunction was observed in 5%. In those with a respiratory dysfunction, GER was detected in 75% (15 of 20 infants). In those with GER, respiratory dysfunction was observed in 45% (15 of 33 infants). In groups 3 and 4, respiratory dysfunction was associated with abnormal pH data in 40-43%. If, in the infants with a respiratory dysfunction, the GER pathologic symptoms were treated efficiently (normalization of pH data), respiratory dysfunction disappeared in 92%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of formula feeding on gastric acidity time and oesophageal pH monitoring data.

Gastro-oesophageal reflux (GOR) occurs mainly during postcibal (PC) periods. The duration of PC gastric acidity and the incidence of GOR were analysed in 11 asymptomatic premature infants. GOR was studied during PC periods of 120 min and also during the following 120 min defined as fasting (FT) periods. These infants were subjected to simultaneous continuous gastric and oesophageal pH monitoring using a double-blind crossover technique. Two formulae with different fat contents (2.6 vs 3.6 g/100 ml) and different carbohydrate concentrations (8.1 vs 7.3 g/100 ml; malto-dextrin 2.8 vs 1.9 g/100 ml) were given. Gastric acidity (pH less than 4) in the PC periods lasted significantly (P less than 0.001) longer (68 min +/- 10) with the low fat/high malto-dextrin formula versus 43 min +/- 11 with the high fat/low malto-dextrin formula. Oesophageal pH monitoring data were within normal limits for the total investigation time in all infants. During PC periods acid GOR was detected more frequently in the group with a low fat formula. More PC GOR was recorded when the gastric acidity time was longer.

Congenital toxoplasmosis after maternal infection before or slightly after conception.

We report a newborn with typical lesions of congenital toxoplasmosis. Retrospectively, the time of infection could be located to or even before conception. A diagnostic work-up should be performed in every newborn whose mother presents persistent high antibody titers against toxoplasma during pregnancy.

Preliminary data on a field study with a new hypo-allergic formula.

The incidence of atopic manifestations due to cow's milk proteins was analysed in five groups of 15 newborns considered to be at risk for atopy because of a positive family history. All infants were studied over a 4-month period. The infants received either an adapted formula (AdFo), breast milk or a new hypo-allergic formula (HAF). Atopic manifestations appeared in 1 out of 15 breast-fed infants compared with 18 out of 45 infants fed with an AdFo. None of the infants receiving the HAF (exclusively from birth for 2-4 months) developed symptoms of atopy. Symptoms in each infant receiving an AdFo (n = 18) disappeared with the HAF. Although the results of this study are promising, data on a larger population and double-blind investigations are needed before firm conclusions can be drawn.

Incidence of gastroesophageal reflux in sleep, awake, fasted, and postcibal periods in asymptomatic and symptomatic infants.

The incidence of gastroesophageal reflux (GER) in infants has been shown to be dependent on different factors, e.g., position, feeding, age. Using continuous esophageal pH monitoring, we examined 30 asymptomatic (15 were 1.5-2.5 months old; 15 were 2.5-4.5 months old) and 20 symptomatic infants (1.5-4.5 months old) for GER. The occurrence of GER was analyzed in different periods of interest: awake, asleep, fasted, and postcibal periods. The increasing incidence of GER we reported previously in asymptomatic infants according to their age appeared to be due to an increased occurrence in the awake (and postcibal) periods. In symptomatic infants, however, the increase was noticed mostly during the sleep (fasted) periods as far as the reflux index, the duration of the longest reflux episode, and the number of reflux episodes of greater than 5 min are concerned.

Reproducibility of continuous 24 hour oesophageal pH monitoring in infants and children.

The reproducibility of 24 hour oesophageal pH monitoring was studied in 30 infants and children including the proportions of the investigation time with a pH less than 4 (reflux index), the number of episodes with a pH less than 4 or lasting longer than five minutes, and the duration of the longest episodes with a pH less than 4. Twenty four hour pH monitoring was performed using identical equipment on two consecutive days under similar conditions. Pearson correlation coefficients range from 0.88 to 0.98. The results obtained on two consecutive days were similar. The reflux index and the number of reflux episodes greater than five minutes were the most reproducible parameters. Despite the many patient related factors influencing pH data, the reproducibility of 24 hour pH monitoring data are satisfactory for routine clinical application.

Cisapride decreases prolonged episodes of reflux in infants.

Twenty-nine infants (2-4 months old), with pathological gastroesophageal reflux assessed by 24-h esophageal pH monitoring, were studied. Cisapride or placebo was randomly added to positional treatment, prone-antiTrendelenburg position, which was applied to all infants. The pH monitoring was repeated after 13-16 days of treatment and revealed a significant improvement in both groups for most parameters. But the number of reflux episodes lasting longer than 5 min and the total number of reflux episodes had not decreased significantly in the placebo group. Only in the number of reflux episodes lasting longer than 5 min was improvement during treatment significantly greater in the cisapride group. This suggests cisapride both prevented reflux and improved esophageal clearance. These results suggest that in addition to other therapeutic measurements, such as positional treatment (which was previously demonstrated to be effective in this age group), cisapride might be of benefit in the treatment of gastroesophageal reflux disease.