Inhaled nitric oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease: vasodilator capacity and cellular mechanisms.

BACKGROUND: Inhaled nitric oxide (iNO) has been used to assess the vasodilator capacity of the pulmonary vascular bed in children with congenital heart disease and elevated pulmonary vascular resistance. Inhaled iloprost is a pulmonary vasodilator for the long-term treatment of pulmonary hypertension (PHT). Because these 2 vasodilators act through different pathways (release of cGMP or cAMP, respectively), we compared the pulmonary vasodilator capacity of each. METHODS AND RESULTS: A total of 15 children with congenital heart disease and PHT who had elevated pulmonary vascular resistance (preoperative, n=10; immediately postoperative, n=5) were first given 20 ppm of iNO for 10 minutes; then, after baseline values were reached again, they were given aerosolized iloprost at 25 ng. kg(-1). min(-1) for another 10 minutes. Finally, iNO and iloprost were given simultaneously for 10 minutes. With iNO, the pulmonary vascular resistance and systemic vascular resistance ratio decreased from 0.48+/-0.38 to 0.27+/-0.16 (P:<0.001). Similarly, iloprost decreased the ratio from 0.49+/-0.38 to 0.26+/-0.11 (P:<0.05). The combination had no additional effect on the resistance ratio. Plasma cGMP increased from 17.6+/-11.9 to 34.7+/-21.4 nmol/L during iNO (P:<0.01), and plasma cAMP increased from 55.7+/-22.9 to 65.1+/-21.2 nmol/L during iloprost inhalation (P:<0.05). CONCLUSIONS: In children with PHT and congenital heart disease, both iNO and aerosolized iloprost are equally effective in selectively lowering pulmonary vascular resistance through an increase in cGMP or cAMP, respectively. However, the combination of both vasodilators failed to prove more potent than either substance alone. Aerosolized iloprost might be an alternative to iNO for early testing of vascular reactivity and for the postoperative treatment of acute PHT.

Pharmacokinetics of intravenous ondansetron in healthy children undergoing ear, nose, and throat surgery.

BACKGROUND: To determine the pharmacokinetics of the 5-HT3 antagonist ondansetron in children, informed written consent was obtained from the parents of 21 healthy children aged from 3 to 12 years scheduled for ear, nose, and throat surgery. METHODS: The children were stratified according to age: 3 to 7 years and 7.1 to 12 years, and a single intravenous infusion of 2 or 4 mg ondansetron, respectively, was administered over 5 minutes before induction of anesthesia. After completion of the infusion, anesthesia was induced intravenously and maintained with inhalational anesthesia. Whole blood (3 ml) was obtained before administration of ondansetron, at completion of the infusion, at the beginning and end of surgery, and at 3, 4, 6, 8, 10, and 12 hours after start of the infusion. Pharmacokinetic variables were determined with use of standard noncompartmental techniques. RESULTS: Mean plasma clearance was 0.50 L.hr-1.kg-1 and 0.39 L.hr-1.kg-1, the mean volume of distribution at steady-state was 1.70 L.kg-1 and 1.61 L.kg-1, and the mean plasma terminal half-life was 2.6 hours and 3.1 hours for the 2 mg and 4 mg groups, respectively. On a body surface area basis, mean plasma clearance was 14.0 and 13.7 L.hr-1.m-2 and mean volume of distribution was 47.7 and 55.9 L.m-2 for the 2 and 4 mg groups, respectively. There were no serious adverse events attributable to ondansetron. CONCLUSIONS: These data indicate that the pharmacokinetics of ondansetron in children from 3 to 12 years old are predictable and similar to those in adults. The elimination half-life of ondansetron increases in parallel with age. However, clearance is constant when normalized to body surface area, but the volume of distribution increases over the age range studied.

Inhaled nitric oxide to test the vasodilator capacity of the pulmonary vascular bed in children with long-standing pulmonary hypertension and congenital heart disease.

Nitric oxide-induced vasodilator capacity greatly varies among children with pulmonary hypertension and elevated vascular resistance. The decline of this selective response seems to parallel the progression of established vascular disease and thus may be helpful for the selection of patients for operation.

Capnometry and the paediatric laryngeal mask airway.

The laryngeal mask airway (LMA), an alternative to tracheal intubation in certain situations, has gained popularity in recent years. Initially designed for use in adults it has now become available in suitable sizes for paediatric anaesthesia. The objectives of this study were to identify the preferred site of sampling the end-tidal carbon dioxide (PETCO2) with the LMA and to determine the accuracy of this recording when compared with arterial CO2 (PaCO2). We studied 30 healthy children, age one to five years and weighing between 10 and 25 kg undergoing minor surgery requiring mask anaesthesia. In each case, after induction of anaesthesia, the LMA was inserted under direct vision to eliminate the possibility of epiglottic airway obstruction. The fresh gas flow was provided by a Jackson Rees modification of an Ayre's T-piece and was determined according to the following formula: 3 x (1000 + (100 x body weight)) LPM. Blood pressure, ECG, O2 saturation, temperature and end-tidal gas concentrations were recorded. The measures of peak PETCO2 were taken at pre-determined distances from the elbow connector down the LMA shaft. During the sampling sequence an arterial blood sample was taken for gas analysis. The PaCO2 was 63.5 +/- 9.3 mmHg (mean +/- SD). At any given sampling site, mean PETCO2 values were less than PaCO2 (P < 0.05). However, in eight patients PETCO2 values measured at the distal site were higher than the PaCO2 (negative P(a-ET)CO2 gradients).(ABSTRACT TRUNCATED AT 250 WORDS)

Epidural sufentanil during paediatric cardiac surgery: effects on metabolic response and postoperative outcome.

The metabolic and neuroendocrine effects of caudal epidural analgesia were studied during paediatric cardiac surgery. Combined epidural and general anaesthesia (EPI group; n=12) was compared with deep opioid anaesthesia (DOA group; n=12). During anaesthesia and surgery, haemodynamic stability was similar in the two groups. There was no significant difference between groups concerning the metabolic response to surgery but circulating catecholamines were significantly lower in the EPI group during and after surgery. Perioperative release of IL-6 was higher in the EPI group possibly reflecting a longer aortic clamp time. Incidence of postoperative life-threatening dysrhythmias was very low in the two groups. No significant reduction of postoperative mechanical ventilation, intensive care unit or hospital stays was reported with epidural analgesia. The incidence of postoperative infections was higher than expected in the two groups because of the poor properative clinical status of most of the children included in the study.

Proximate delivery of a large experimental dose from salbutamol MDI induces epithelial airway lesions in intubated rabbits.

The delivery of aerosolized drugs by metered dose inhaler (MDI) to intubated patients can be substantially improved by actuating the MDI through a narrow catheter placed inside the tracheal tube. However, the deposition of increased quantities of drug, surfactant, in particular oleic acid, and chlorofluorocarbon propellants on the lung surface could result in adverse effects not observed after oral MDI administration. To investigate this hypothesis, 42 adult intubated rabbits (six groups, n = 6 to 9/group) received Ventolin MDI, Ventolin placebo, a placebo MDI containing lecithin as surfactant, instilled salbutamol sulfate, instilled oleic acid solution, or no treatment (control). Heart rate, invasive blood pressure, and hemoglobin oxygen saturation, recorded continuously for the 3-h experiment, were unchanged from baseline (awake) values. Sections of trachea and lungs were reviewed blindly and graded using a four-point, nine-variable Ophoven scale. Blood was obtained after either 1 puff or 20 puffs MDI salbutamol to determine the pharmacokinetic profile of salbutamol. Multiple doses of both Ventolin and Ventolin placebo aerosols produced significant lesions to the epithelium of the trachea and main bronchi (p < 0.05). The histologic injury after lecithin placebo or salbutamol solution did not differ significantly from control, and all were significantly less than that observed after Ventolin MDI administration. Instilled oleic acid caused gross airway lesions. Maximum serum concentrations of salbutamol were 4.4 +/- 1.8 ng/ml after 1 puff and 419 +/- 168 ng/ml after 20 puffs. After 20 puffs, the total body clearance of salbutamol was 108 +/- 27 ml/min/kg, volume of distribution was 3.6 +/- 1.8 L/kg, and the elimination half-life was 22 +/- 7 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral midazolam premedication in children: the minimum time interval for separation from parents.

To determine the minimum time interval between oral midazolam (0.5 mg.kg-1) premedication and separation from parents that ensures a smooth separation, 30 children were assigned randomly to one of three groups (ten children per group). The groups differed only in the time interval between administration of midazolam and separation from their parents: 10, 20 or 30 min. Heart rate, systolic blood pressure, and sedation and anxiolysis scores were assessed before midazolam premedication (baseline), at the time of separation from parents, and during the application of a face mask at the induction of anaesthesia. We found that heart rate and systolic blood pressure changes were similar for all three groups throughout the study period. Sedation scores at the time of separation from parents and on application of the mask for all three groups were greater than baseline values. Sedation scores at separation did not differ among the three groups. Anxiolysis values did not differ from baseline values at any time for all three groups. We conclude that children may be separated from their parents as early as ten minutes after receiving oral midazolam, 0.5 mg.kg-1.

Premedication of children with oral midazolam.

In a randomized, double-blind, placebo-controlled study, the safety, efficacy and feasibility of oral midazolam premedication in children were evaluated in an ambulatory surgery unit. Eighty unmedicated children (ASA PS I or II, ages 1-6 yr) were randomly assigned to one of four groups receiving midazolam 0.5, 0.75, or 1.0 mg.kg-1 or a placebo 30 min before separation from parents. Heart rate, systolic blood pressure, arterial oxygen saturation, respiratory rate, sedation and anxiolysis scores were recorded before premedication, every five minutes for 30 min and then during induction of anaesthesia and recovery. We found that heart rate, systolic blood pressure, arterial oxygen saturation and respiratory rate were unchanged during the study. Sedation and anxiolysis scores in the midazolam-treated groups were greater than those in the placebo group and that anxiolysis at the time of separation from the parents was judged excellent in 80-90% of the children who received midazolam. However, sedation and anxiolysis did not differ among the three midazolam groups. Mean times to discharge from hospital were similar for all four groups. The side effects, loss of balance and head control, blurred vision and dysphoric reactions were observed only in the 0.75 and 1.0 mg.kg-1 midazolam groups. We conclude that oral midazolam 0.5 mg.kg-1 is a safe and effective premedication and that 0.75 and 1 mg.kg-1 while offering no additional benefit, may cause more side effects.

Differential neurotoxic effects of propofol on dissociated cortical cells and organotypic hippocampal cultures.

BACKGROUND: Propofol is a widely used anesthetic agent for adults and children. Although extensive clinical use has demonstrated its safety, neurologic dysfunctions have been described after the use of this agent. A recent study on a model of aggregating cell cultures reported that propofol might cause irreversible lesions of gamma-aminobutyric acid-mediated (GABAergic) neurons when administered at a critical phase of brain development. We investigated this issue by comparing the effects of long-term propofol treatment on two models of brain cultures: dissociated neonatal cortical cell cultures and organotypic slice cultures. METHODS: Survival of GABAergic neurons in dissociated cultures of newborn rat cortex (postnatal age, 1 day) treated for 3 days with different concentrations of propofol was assessed using histologic and cytochemical methods. For hippocampal organotypic slice cultures (postnatal age, 1 and 7 days), cell survival was assessed by measuring functional and morphologic parameters: extracellular and intracellular electrophysiology, propidium staining of dying cells, and light and electron microscopy. RESULTS: In dissociated neonatal cell cultures, propofol induced dose-dependent lesions of GABAergic neurons and of glial cells. In contrast, no evidence for neurotoxic effects of propofol were found after long-term treatment of organotypic slice cultures. Excitatory transmission was not affected by propofol, and inhibitory transmission was still functional. Histologic preparations showed no evidence for cell degeneration or death. CONCLUSION: Although long-term applications of propofol to dissociated cortical cell cultures produced degeneration and death of GABAergic neurons and glial cells, no such lesions were found when using a model of postnatal organotypic slice cultures. This conclusion is based on both functional and morphologic tests.

Corrective surgery for idiopathic scoliosis after heart transplantation.

Cardiac transplant surgery is being performed with increasing frequency as a treatment for end-stage heart disease. In addition to the well-known post-surgical problems of rejection and infection, these patients may present at a future date with other medical problems which require surgical treatment, including orthopaedic pathology. Severe idiopathic scoliosis has been described in association with congenital heart disease, and its surgical treatment poses considerable risks because of heart disease. Spinal fusion in heart transplant recipients involves similar risks due to the particular physiology and pharmacological reactions of the denervated heart. Several cases of cholecystectomy performed in heart transplant recipients have been described, but to our knowledge no orthopaedic procedures have been reported in such patients. We report on a 15-year-old patient who underwent successful corrective surgery for idiopathic scoliosis 14 months after heart transplant.

Aerosolized iloprost induces a mild but sustained inhibition of platelet aggregation.

Pathological studies have revealed that one of the main features encountered in the pulmonary vasculature of patients with pulmonary hypertension is the presence of thrombotic lesions. Open pilot studies have indicated that aerosolized iloprost may have beneficial effects in patients with pulmonary hypertension. The effects of aerosolized iloprost on platelet function and plasma cyclic adenosine monophosphate (cAMP) were studied. Platelet aggregation and plasma cAMP were measured at baseline, 30 min, 4 and 6 h after inhalation of 15 microg iloprost in 10 healthy volunteers. Maximal platelet aggregation in response to adenosine diphosphate (ADP) (2 and 6 micromol x L(-1)), collagen (2.5 and 5 microg x mL(-1)), epinephrine (1.25 and 5 micromol x L(-1)) and arachidonic acid (0.5 mg x mL(-1)) was measured. Platelet aggregation was significantly inhibited at 30 min in response to ADP (2 and 6 micromol x L(-1), epinephrine (1.25 and 5 micromol x L(-1)) and collagen (2.5 microg x mL(-1)). It was still inhibited at 4 h in response to the same agents, but normalized at 6 h. cAMP increased at 30 min, from 27.3+/-1.2 to 31.8+/-1.2 nmol x L(-1), remained increased at 4 h (29.2+/-1.3 nmol x L(-1)) and normalized at 6 h (27.4+/-1.1 nmol x L(-1)). Aerosolized iloprost induced a mild but sustained inhibition of platelet aggregation. Platelet aggregation inhibition may be one of the mechanisms which explains the beneficial effect of repeated inhalation of iloprost in pulmonary hypertension.

Successful weaning from cardiopulmonary bypass after cardiac surgery using inhaled nitric oxide.

Two cases of very difficult weaning from cardiopulmonary bypass after cardiac surgery in children with pulmonary hypertension and ventricular dysfunction are reported. Children fail to respond to conventional therapy combining nitrovasodilators and inotropic support and react successfully to combined inhaled nitric oxide (NO) and epinephrine or left atrial infused norepinephrine. Postoperative NO inhalation must be prolonged and no toxicity appears. Pulmonary endothelial function recovers only after several days.

Comparison of remifentanil versus regional anaesthesia in children anaesthetised with isoflurane/nitrous oxide. International Remifentanil Paediatric Anaesthesia Study group.

We compared the efficacy and safety of a remifentanil (0.25 microg x kg(-1) x min(-1)-based balanced anaesthetic technique with a bupivacaine-based regional anaesthetic technique in an open label, multicentre study in 271 ASA physical status 1 or 2 children aged 1-12 years. Subjects requiring major intra-abdominal, urological or orthopaedic surgery were randomly allocated to receive either intravenous remifentanil (group R; n = 185) or epidural bupivacaine (group B; n = 86) with isoflurane/nitrous oxide for their anaesthesia. The majority of children in both groups (85% in group R, 78% in group B) showed no defined response to skin incision, and although the mean increase in systolic blood pressure (+11 mm Hg) was significantly greater in group R than in group B, this change did not represent a serious haemodynamic disturbance. More children in group R (31%) required interventions to treat hypotension and/or bradycardia than those in group B (12%), but these were easily managed by administration of fluids or anticholinergic drugs. Adverse events, mainly nausea and/or vomiting, occurred in 45% of group R and 42% of group B (NS). The adverse event profile of remifentanil in this study was typical of a potent mu-opioid receptor agonist. Remifentanil was as effective as epidural or caudal block in providing analgesia and suppressing physiological responses to surgical stimuli in children aged between 1 and 12 years undergoing major abdominal, urological, or orthopaedic surgery under isoflurane/nitrous oxide anaesthesia.