[Attitudes and experiences of off-label prescribing among paediatricians in a French university teaching hospital]. / Attitudes et expériences des médecins face à la prescription hors autorisation de mise sur le marché dans un hôpital pédiatrique français.

PURPOSE: The lack of drugs specifically assessed for paediatric use results in a widespread off-label drug use. The aim of this work is to identify experiences and attitudes towards paediatrics off-label prescribing in a university teaching paediatric hospital. METHODS: A questionnaire of 24 items was sent by email to 409 paediatricians in February 2013. DATA COLLECTED: frequency of off-label prescribing, sources of information, concern about safety and adverse events with off-label drug use, proportion of parents informed and order with "off-label" mention. RESULTS: Eighty questionnaires were returned. Over 81% of responders were familiar with the concept of off-label drugs prescribing. The most common reason given for off-label prescribing was for a younger age (74%) and for another indication (28%). They (79%) used a colleague's opinion and the most important sources of information used were the literature (72%), international guidelines (62%), the French National Formulary Vidal (56%) and national guidelines (46%). Although 54% of responders expressed concerns about safety about off-label prescription, only 29% had observed adverse event with off-label drug use. Two third of respondents informed the parents but off-label prescribing cannot be always explained to family. Many respondents (81%) did not write "off-label" mention on prescription. However, 52% stated that they would be willing to undertake off-label prescription monitoring with a local observatory. CONCLUSION: Our study describes the perceptions and attitudes of paediatrician's regarding off-label prescribing for children. Patient information and documentation in the patient file remain incomplete. The prospective collection of off-label prescription will locally be performed.

Reflux in esophageal atresia, tracheoesophageal cleft, and esophagocoloplasty: Bianchi's procedure as an alternative approach.

PURPOSE: Fundoplication has been used successfully to treat gastroesophageal reflux (GER) in the pediatric population. Although successful in many patients, there is a significant risk of complications and failure, especially in high-risk patients such as those with certain types of associated anomalies, diffuse motility disorders, chronic pulmonary disease, neurological impairment, and young infants. However, the results are poorer with children with severe pathologic lesion associated to reflux: tracheoesophageal cleft, esophagocoloplasty, and esophageal atresia (EA) with severe dysmotricity. In neurologically impaired children with neuromuscular incoordination and GER, Bianchi has proposed total esophagogastric dissociation (TED). The authors report the use of esophagogastric or esocologastric dissociation to control reflux in children with severe GER in other situations, such as EA, burn esophageal lesions having led to coloplasty and severe esotracheal cleft. METHODS: The authors reviewed the patients operated on for an esogastric or cologastric disconnection between 1997 and 2002. It is a single center retrospective study. The initial diagnosis, previous surgical procedure, postoperative course, and follow-up results were studied. RESULTS: Between September 1999 and June 2003, 13 TEDs were performed in 6 boys and 7 girls. The mean age for TED procedure was 35 months (range 14 days to 218 months). Indication for TED was severe persistent reflux in, respectively, 9 cases of EA (7 with coloplasty and 2 with preservation of the native esophagus after atresia repair, associated in 1 case with an esotracheal cleft), 2 cases of esotracheal cleft type III, and 2 cases of esophagocoloplasty for caustic burns. Six patients had undergone previous fundoplications (1-4 procedures) that failed, whereas the remaining patients underwent TED as the primary antireflux procedure. The average follow-up was 26 months (range 1 month to 4 years). There were no complication during the immediate postoperative course. Three children died at 3, 4, and 12 months after the procedure from acute respiratory failure. Respiratory status was improved in 8 children, and recurrent bronchitis was noted in 1 child. Regarding the digestive status, gastrostomy was closed at 18 and 24 months in 2 children, and partial nocturnal enteral nutrition (200 to 900 mL/d) through the gastrostomy remains necessary in the other children. CONCLUSION: Total esophagogastric dissociation procedure improves the respiratory consequences of severe GER, particularly in children for whom other surgical treatments have failed. The long-term safety of this operation remains to be determined especially regarding the consequences of a gastrointestinal Roux-en-Y loop procedure.

Bisphosphonate-ciprofloxacin bound to Skelite is a prototype for enhancing experimental local antibiotic delivery to injured bone.

BACKGROUND: The risk of osteomyelitis after open bone fracture may be reduced by locally applied antibiotics. ENC-41-HP (E41), which comprises ciprofloxacin linked to a 'bone seeking' bisphosphonate, loaded on to carrier Skelite calcium phosphate granules (E41-Skelite) has favourable in vitro characteristics for application to wounded bone. This study assessed E41-Skelite in a rat model of acute tibial osteomyelitis. METHODS: Mechanically induced tibial troughs were contaminated with approximately log10 4 colony forming units (c.f.u.) of Staphylococcus aureus (Cowan 1 strain) 'resistant' to E41 (minimum inhibitory concentration 8-16 microg/ml), lavaged and packed with Skelite alone, or with E41-Skelite slurry. Animals were killed at 24 h (n = 62), 72 h (n = 46) or 14 days (n = 12), and each tibia was assessed for S. aureus load (c.f.u./g tibia) and histological appearance (14 days only). RESULTS: At 24 and 72 h, the tibias of rats treated with E41-Skelite (n = 54) had a significantly lower mean (s.e.m.) load of S. aureus than animals that received Skelite alone (n = 54): log10 3.6(0.2) versus 6.4(0.1) c.f.u./g respectively at 24 h (P < 0.001, Mann-Whitney rank sum test) and log10 4.4(0.2) versus 6.6(0.1) c.f.u./g at 72 h (P < 0.001). At 14 days, E41-Skelite-treated tibias had fewer bacteria, no signs of osteomyelitis and histological signs of healing. CONCLUSION: E41-Skelite, a prototype granulated topical antibiotic delivery system, reduced the development of infection in experimental bone wounds.

[Prolonged length of stays in pediatric intensive care. Retrospective study of 100 stays]. / Les séjours prolongés en réanimation pédiatrique. Analyse rétrospective de 100 séjours.

UNLABELLED: New issues have arisen in pediatric intensive care units, especially concerning long-stay patients. The aims of the present study were to describe the etiologic factors of these long-stay patients and to recognize the comorbidities. MATERIAL AND METHODS: Ninety-five patients who had a total of 100 hospitalizations of more than 30 days were admitted to the pediatric intensive care unit at Robert-Debre Hospital during a 3-year period (1993-1995); this accounted for 9.1% of total admissions. We retrospectively reviewed these 100 long-stay hospitalizations. RESULTS: Most of these patients were newborns (65%). Patients with severe congenital anomalies (44 patients) and very premature infants (26 patients) constituted the majority of long-stay patients. The mean duration of mechanical ventilation for the 95 patients was 110 days (ranges 17-789 days). Two factors of comorbidity were found: gastroesophageal reflux (41% of cases) and nosocomial infections (89% of cases). CONCLUSION: In order to prevent long stays, pediatric intensive care units must be directed toward these factors.

Beta-lactam antibiotics functionalized with gem-bisphosphonates.

Acylation of amoxycillin and cephalexin with acids III, V and VII, and with isocyanate VIII furnished the corresponding beta-lactam antibiotics (X and XIII-XV, respectively). The antibacterial activity of these new antibiotic analogues against Helicobacter pylori was found to be identical with those of amoxycillin, Augmentin, erythromycin and ciprofloxacin.

Can blood gas values predict pulmonary hypoplasia in antenatally diagnosed congenital diaphragmatic hernia?

The prognosis of antenatally diagnosed congenital diaphragmatic hernias (CDH) is clearly related to the degree of pulmonary hypoplasia (PH). After birth, controversies remain regarding the implementation of various therapies, especially the use of extracorporeal membrane oxygenation (ECMO). In the literature, the persistence of a Pao2 below 100 mm Hg and of Paco2 above 40 mm Hg despite optimal conventional therapy indicates poor prognosis. Therefore, since 1992, published and personal experiences led the authors to exclude CDH patients from ECMO when conventional therapy (including high-frequency oscillatory ventilation and nitric oxide) did not obtain Pao2 of above 80 mm Hg and Paco2 of below 60 mm Hg. The aim of this retrospective study is to determine whether blood gas results correlate with postmortem findings. Between July 1990 and July 1994, 32 cases of CDH were monitored antenatally and managed postnatally at the authors' institution. Six patients survived; 26 died, including one immediately at birth. Thirteen were treated by ECMO. Seventeen had a best Pao2 of above 80 mm Hg, including the six survivors. Fourteen did not reach this level, and none of them survived. Twenty-three infants underwent postmortem examination. PH was assessed using two criteria: (1) lung weight to body weight ratio (LW/BW) and (2) radial alveolar count (RAC). Two patients did not have hypoplasia (LW/BW > 0.018). Twenty-one patients had PH; 12 of them had an LW/BW ratio of less than .009; for 9, the LW/BW ratio was between .009 and .018, and the RAC (< 3.1) confirmed PH. All infants with a best Pao2 of less than 80 mm Hg had PH. Patients with a best Pao2 of greater than 80 mm Hg included two infants who died from complications without PH, eight infants with demonstrated PH, and the six survivors. In conclusion. (1) No infant with nonhypoplastic lungs has been deprived of ECMO by the authors' criteria. (2) Adequate values of blood gases may not eliminate PH. Therefore, this probably justifies starting ECMO when conventional therapy fails. (3) Conversely, permanent poor values of Pao2 allowed the prediction of PH in all cases. Such patients probably can be excluded from ECMO treatment.

Thrombosis of the arterial cannula during extracorporeal membrane oxygenation in a full-term newborn infant.

The authors report a rare case of cannula thrombosis during extracorporeal membrane oxygenation (ECMO). A full-term newborn infant was successively placed on single-cannula veno-venous extracorporeal lung support and then on veno-arterial ECMO, because of persistent pulmonary hypertension. At 140 hours of ECMO, the infant displayed general cyanosis except in the right arm. Since asymmetric hypoxemia during ECMO may be related either to cannula malposition or to a tip thrombosis, a chest x-ray after contrast injection into the arterial line of the circuit was performed. It showed an opacification of the whole cannula but for the last distal centimeter, and of the vascular bed extending from the right subclavian artery. Cannula thrombosis was suspected and confirmed by removal of the arterial cannula. Demonstration of cannula thrombosis by opacification of the arterial line of the circuit indicates catheter removal.

Cerebral blood flow during cardiopulmonary bypass: influence of temperature and pH management strategy.

Because disordered autoregulation of cerebral blood flow may underlie neurologic injury associated with cardiopulmonary bypass (CPB), we studied the effects of normothermic (37 degrees C) and hypothermic (18 degrees C) CPB on cerebral vascular reactivity in 6 to 8-week-old piglets. Hypothermic CPB animals were subdivided into alpha-stat and pH-stat groups (n = 6 animals each group) according to acid-base management protocol. Cerebral blood flow (CBF), cerebral oxygen consumption (CMRO2), cerebral vascular resistance (CVR), and CBF response to hypercapnia were examined before, during, and 1 hour after CPB and used to calculate CVR per millimeter of mercury change in arterial partial pressure of CO2: (CVRnormocapnia - CVRhypercapnia)/(PaCO2 hypercapnia - PaCO2 normocapnia). Before CPB, CBF, CMRO2, and vascular reactivity to elevated CO2 were similar in the three groups; these parameters remained unchanged by normothermic CPB. However, during hypothermic CPB, CBF and CMRO2 decreased in both alpha-stat and pH-stat groups; in the alpha-stat group, CBF decreased from 27 +/- 5 mL.min-1.100 g-1 (normothermic CPB) to 5 +/- 1 mL.min-1.100 g-1 (hypothermic CPB) (p < 0.05) and CMRO2 decreased from 1.8 +/- 0.21 to 0.24 +/- 0.04 mL.min-1.100 g-1 (p < 0.05), whereas in the pH-stat group CBF decreased from 28 +/- 2 to 9 +/- 1 mL.min-1. 100 g-1 (p < 0.05) and CMRO2 decreased from 1.63 +/- 0.07 to 0.31 +/- 0.09 mL.min-1.100 g-1 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Is there a role for inhaled nitric oxide in pediatric ARDS?

Despite advances in ventilator management and use of extracorporeal lung support, mortality related to ARDS in pediatric patients has not been reduced over the past 20 years. Progressive respiratory failure, due to evolution of the primary illness or to complications of ventilator therapy, significantly contributes to poor outcome. ARDS is characterized by severe ventilation-perfusion mismatch and by pulmonary hypertension. Because of their side effects which affect systemic hemodynamic status or worsen intrapulmonary shunting, intravenous vasodilator trials have been of limited interest. Nitric oxide (NO) has been recognized as a gas with vasodilator properties. In neonates studies have shown that inhaled NO may have an important role in the therapy of persistent pulmonary hypertension. Inhaled NO in adults with severe ARDS has been shown to reduce pulmonary hypertension without producing systemic vasodilation. This reduction of pulmonary vascular resistances may reduce pulmonary edema formation, decrease vasoconstrictor response to cardiotonic agents, and improve biventricular function. In addition, arterial oxygenation seems to be increased by improved matching of ventilation with perfusion. Improvement of oxygenation with inhaled NO suggests that use of lower tidal volumes and FIO2 may be more successful. Until now, there are no published studies regarding NO administration in ARDS affecting nonneonatal pediatric patients. However, the results obtained in adults and newborns suggest that inhaled NO may be a useful adjuvant therapy of ARDS in children, possibly in association with other therapies. Even in adults it remains unclear whether therapy with inhaled NO can reduce morbidity and mortality. Prospectives and randomized studies are essential to assess the real utility of inhaled NO in ARDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Doppler echocardiographic assessment of pulmonary circulation in severe respiratory failure of the neonate: an aid for extracorporeal lung support indications.

Extracorporeal lung support (ECLS) for newborns with acute respiratory failure has achieved increased popularity over the last decade. However, precise criteria for its implementation remain controversial. The aim of this study was to assess the value of Doppler echocardiography (DE) in 31 neonates with PaO2 of < or = 50 mmHg, FIO2 of 1, and optimal ventilation. Treatment included mechanical ventilation, paralysis, volume loading, vasopressors, and tolazoline. Markers indicative of ECLS (failure of maximal medical therapy, assessed by AaDO2 of more than 610 mm Hg beyond 8 hours and/or an oxygenation index (OI = mean airway pressure x FIO2%/postductal PaO2) of more than 40 beyond 4 to 6 hours) were present in 23 (group 1) and absent in eight (group 2). Shunt direction and systolic pulmonary arterial pressure (sPAP) calculated from tricuspid insufficiency velocity were assessed using DE. At the time of admission, sPAP was significantly higher in group 1 (62.1 v 43.7 mm Hg). On day 1, group 1 differed from group 2 in maximum sPAP value (73.2 v 44.4 mm Hg), PaCO2 (56.1 v 40 mm Hg), right-to-left shunting (85% v 25% of the patients), and pulmonary-to-systemic-pressure systolic ratio (sPAP:sSAP) (1.29 v 0.75). Patients with an sPAP:sSAP ratio of more than 1 and patients with high sPAP associated with high PaCO2 on day 1, all later (average, 10 hours later) fulfilled ECLS criteria; this suggests that DE assessment of pulmonary circulation may yield early and predictive markers of impending ECLS indication. Further confirmation of these results would help avoid unnecessary delays in ECLS implementation in newborns with severe respiratory failure.

[Maternal and neonatal effects of indomethacin administrated during pregnancy. Apropos of 18 cases]. / Effets maternels et néonatals de l'indométacine administrée pendant la grossesse. A propos de 18 observations.

BACKGROUND: There have been several reports that prolonged exposure of pregnant women to indomethacin for tocolysis may have significant pharmacological effects on the fetus or newborn. PATIENTS: Eighteen pregnant women were given indomethacin during the year 1989 for treatment of premature labor (n = 16) or polyhydramnios (n = 2). Treatment was started at gestational week 28.1 +/- 2.5 and was discontinued at gestational week 30.7 +/- 1.8. The mean age of the women at the onset of pregnancy was 30.6 +/- 5.3 years. The daily dose of indomethacin was initially 200 mg (2-3 mg/kg), then 107 +/- 59 mg. The cumulative dose was 1,820 +/- 2,370 mg. The duration of treatment was 18.1 +/- 16.4 days (less than 7 days in 8 women). RESULTS: The term at delivery was 33.4 +/- 3.3 weeks (11 after 32 weeks). The mean interval between discontinuation of treatment and delivery was 19.0 +/- 18.7 days. Indomethacin was effective in 10 cases of premature labor, and gestation was prolonged by 52.6 +/- 19.2 days. Among the 23 live-born neonates, 5 developed renal insufficiency attributed to indomethacin (4 premature labor, 1 hydramnios). The kidney failure with early hyperkalemia was cured within about 7 days in 4 cases. The remaining neonate also suffered from severe prolonged hypoxia and died on day 4. CONCLUSIONS: Administration of indomethacin for premature labor places the fetus at risk because of the short drug-free interval before birth. High daily or cumulative doses of indomethacin dit not result in adverse effects.

Tunica layers of the carotid artery of the rat: isolation and macromolecular synthetic abilities.

The tunicas media and adventitia can be isolated, intact, from the rat carotid artery by simple mechanical extrusion. While morphologically normal, when incubated for 24 hr in vitro in appropriate radioactive precursor the isolated layers synthesized DNA, RNA and protein at very low levels which was only a fraction (5-15%) of that synthesized by the intact vessel.

[Continuous arteriovenous hemofiltration. Management in case of neonatal leucinosis]. / Hémofiltration artérioveineuse continue. Prise en charge en cas d'une leucinose néonatale.

BACKGROUND: Neonates with classic maple syrup urine disease (MSUD) undergo rapid neurological deterioration by the end of the first week of life. Exchange transfusion and peritoneal dialysis are the usual emergency treatment. Continuous arteriovenous hemofiltration (CAVHF) appears to be safe and more rapidly effective. CASE REPORT: Martin was born at the 37th week from a normal pregnancy. Abnormal movements of legs and lethargy appeared on the 7th day of life. Progressive brain dysfunction with coma led to intubation on the 13th day. A diagnosis of MSUD was immediately made and CAVHF was initiated and continued for 19 hours. The plasma leucine, valine and isoleucine levels fell from 2,248 to 275, 640 to 91 and 298 to 13 mumol/l, respectively. Neurologic improvement was dramatic, except for moderate hypertonia which lasted for the 2 following days. CONCLUSION: CAVHF is an appropriate treatment for very young patients with inborn errors of metabolism. It appears safer and more rapidly effective for eliminating branched-chain amino acids than other techniques, such as peritoneal dialysis with or without exchange transfusions. It also permits more rapid introduction of the specific diet.

[Congenital diaphragmatic hernia. Value of preoperative stabilization]. / Hernie diaphragmatique congénitale. Intérêt d'une stabilisation préopératoire.

Seventy-two patients with congenital diaphragmatic hernia (CDH) diagnosed in the first 12 hours of live have been reviewed retrospectively. Forty-eight patients born before 1985 (group I) were compared to 24 patients born between 1985 and 1989 (group II). The management was different for the 2 groups. Group I was operated on immediately. For group II, delayed surgery after stabilization was preferred. For this group, stability was sought before, during and after surgery. Therapy was first aimed at optimizing ventilation and oxygenation by way mechanical ventilation. Pharmacologic agents were used in an attempt to decrease pulmonary vascular resistance and improve cardiac output. The survival rate was 37.5% before 1985, 62.5% after 1985 (P less than 0.01). Main prognostic factors were Apgar score, paCO2, pH, ventilation index, alveolar-arterial difference in oxygen and oxygenation index. The stabilization before surgery improved the survival rate.

Influence of age on the synthesis of macromolecules in the smooth muscle cells of the isolated myointimal mass in vitro.

The influence of growth and aging on the synthesis of DNA, RNA and protein in the myointima in vivo was explored by incubating isolated myointima of different ages in labelled precursors. As myointima grew and aged in vivo, the rates of DNA and protein synthesis declined, while the quantity of DNA increased more than two-fold in seven days. The rate of RNA synthesis remained constant and was unaffected by growth. Like that of DNA and protein synthesis, fetal bovine serum was not required by the isolated myointima to synthesize RNA in vitro. Taken together, these findings confirm and extend our previous results which showed the synthetic autonomy of the isolated myointima, and demonstrate further that during growth the synthesis of RNA is affected in a manner that differs from that which controls DNA and protein.

Macromolecular synthesis in the isolated rat myointima in vitro.

The myointima, which forms within the lumen of the carotid artery of the rat in response to the removal of the endothelium by a balloon catheter, could be extruded from the vessel as early as 6 days after denudation. The mean concentration of DNA in the isolated myointima increased as the myointima grew in vivo until 12 to 14 days after denudation, when the arterial lumen was filled with the myointima; thereafter the mean concentration of DNA declined. DNA and protein synthesis, incorporation of 3H-glucosamine and 3H-fucose into macromolecules, occurred in the myointima during incubation in vitro in the absence of fetal bovine serum, and with the exception of 3H-glucosamine, failed to be stimulated by it. These data indicate that the cells of the intact myointima do not require exogenous macromolecular growth factors for the synthesis of macromolecules in vitro.

Effect of insulin pump therapy on blood pressure and the renin-angiotensin system of diabetic rats.

Insulin therapy, administered by continuous subcutaneous infusion with osmotic pumps over a 28 day period at doses of 2.5 and 5.0 units/day, resulted in a statistically significant increase in body weight of diabetic rats. The concentration of blood glucose was reduced by 68% to 109 mg/dl blood sugar by the higher dose of insulin and only partial control of diabetes was achieved by the lower dose (185 mg/dl blood sugar, -39%). Blood pressure was normalized by both doses of insulin. Elevated serum angiotensin converting enzyme activity and plasma renin activity, expressed as generated angiotensin I, were unaffected by the lower dose of insulin, but were reduced by 26% and 40%, respectively at the higher dose. These data suggest that elevated serum ACE and plasma renin activity, commonly found in the streptozotocin-diabetic rat, may not be primarily responsible for hypertension in this model.

Noninvasive determination of hemoglobin saturation in dogs by derivative near-infrared spectroscopy.

An in vivo method utilizing derivative near-infrared spectroscopy was developed to noninvasively determine cerebral venous hemoglobin O2 saturation (SVO2). The method was tested on eight pentobarbital-anesthetized dogs ventilated with differing inspired O2 mixtures to force changes in SVO2 over a wide range. Spectral data obtained by transilluminating the tissues surrounding the superior sagittal sinus (SS) were transformed into first derivative units for correlation with SVO2 data measured from the SS. Linear regression analysis was applied to data obtained from five dogs and used to build a three-wavelength algorithm for predicting brain SVO2. In three dogs, SVO2 was varied to test this equation ability to predict SVO2. The standard deviation of differences between measured SVO2 and SVO2 predicted from 31 separate spectra was 3.2%. These predicted values, when regressed against the sampled SVO2, yielded an r value of 0.97. The results demonstrate that during hypoxic hypoxia (HH) it is possible to noninvasively quantify SVO2 with the use of infrared spectroscopy.

Determination of cerebral venous hemoglobin saturation by derivative near infrared spectroscopy.

An "in vivo" method for non-invasive determination of cerebral venous hemoglobin O2 saturation (SvO2) was developed. A specially designed spectrophotometer recorded the Td near IR spectra of transilluminated brain tissue surrounding the SS. The accuracy of the method, based on the principle of DNIRS was tested on eight pentobarbital anesthetized dogs during hypoxic hypoxia (inspired O2 6-21%). Spectral data were transformed into first derivative for correlation with SvO2 data measured from the SS. Linear regression analyses were applied using data from 5 dogs, with SvO2 ranging from 1.5%-70%, to build a 3 wavelength algorithm for predicting brain SvO2. In three dogs, this regression equation was employed to predict SvO2 in 31 separate spectra of varying HH intensity. The standard deviation of differences between SvO2 and predicted values was 3.2%. The predicted values, when regressed against the sampled SvO2, yielded an r value of 0.97. The results demonstrate that it is possible to noninvasively quantify SvO2 utilizing IR spectroscopy.