Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age.

BACKGROUND: Information has been very limited on the pharmacokinetics of the selective alpha(2)-adrenoceptor agonist dexmedetomidine in children, particularly in children <2 yr of age. METHODS: Eight children aged between 28 days and 23 months and eight children aged between 2 and 11 yr undergoing either elective bronchoscopy or nuclear magnetic resonance imaging were included in the study. Dexmedetomidine 1 microg kg(-1) was infused i.v. over 5 min. Blood samples for the measurement of plasma concentrations of dexmedetomidine were collected for 5 h after starting the infusion. Pharmacokinetic calculations were based on non-compartmental methods. RESULTS: In the two groups of paediatric patients, the median (range) values for total plasma clearance of dexmedetomidine were 17.4 (14.1-27.6) and 17.3 (9.3-22.5) ml kg(-1) min(-1), for volume of distribution at steady state 3.8 (1.9-4.6) and 2.2 (1.3-2.8) litre kg(-1) (P<0.05), and for elimination half-life 139 (90-198) and 96 (69-140) min (P<0.05), respectively. The volume of distribution at steady state was negatively associated with subject age (r=-0.69, P<0.05). CONCLUSIONS: To reach a certain plasma concentration, children younger than 2 yr of age evidently need larger initial doses of dexmedetomidine than the older children, as young children have a larger volume of distribution of the drug than older children and adults. Since the total plasma clearance of dexmedetomidine is independent of age, similar rates of infusion can be used in younger and older children to maintain a steady-state concentration of dexmedetomidine in plasma.

Elevated levels of trypsinogen-2 and trypsin-2-alpha1-antitrypsin in sera of infants and children after cardiac surgery.

Acute pancreatitis is a known complication of cardiac surgery with cardiopulmonary bypass but amylase is not a reliable marker in infants. We evaluated whether the serum concentrations of trypsinogen-2 and trypsin-2-alpha1-antitrypsin (AAT) can be used to study disturbances in pancreatic function in children and infants undergoing cardiac surgery. The study comprised 21 infants < 1 year and 25 children aged 1-16 years undergoing cardiopulmonary bypass at the Children's Hospital, Helsinki University Central Hospital. Consecutive serum samples were taken before surgery, at 12 h, 1, 2 and 3 days after surgery, and before discharge from the hospital. A moderate increase in trypsinogen-2 and trypsin-2-AAT in serum was found in more than two-thirds of the patients. On day 3, there was a 4.3-fold mean increase (CI 95% 2.8-6.5) in trypsinogen-2 and a 2.4-fold mean increase (CI 95% 1.8-3.1) in trypsin-2-AAT. In 4 patients trypsinogen-2 was elevated by more than 20-fold. One patient had clinical pancreatitis, but there were no clinical signs of pancreatitis in the other three patients. The changes in trypsinogen-2 and trypsin-2-AAT were similar in infants and children. The moderate increase in the serum concentrations of trypsinogen-2 and trypsin-2-AAT after cardiac surgery in the absence of signs of pancreatitis may be due to a subclinical pancreatic disturbance, but it could also be caused by an inflammatory response and expression of extrapancreatic trypsin. Contrary to amylase, trypsinogen-2 is expressed in the pancreas of infants.

Development of anti-bovine TNF-alpha mAb and ELISA for quantitating TNF-alpha in milk after intramammary injection of endotoxin.

Murine mAb reactive with recombinant bovine tumor necrosis factor-alpha (r-boTNF-alpha) were produced. An ELISA using murine mAb and rabbit polyclonal antibodies, each reactive with r-boTNF-alpha to sandwich bovine TNF-alpha was developed. Secretion of TNF-alpha in quarter milk increased 1 h after injection of 0.1 mg (four cows) or 0.5 mg (four cows) Escherichia coli lipopolysaccharide (LPS) into a mammary quarter, peaked 1 to 5 h later, and returned to control levels in 24 h. There were no differences in body temperature, SCC, TNF-alpha, and blood leukocyte responses between 0.1 and 0.5 mg of LPS. To determine effects of repeated injections of LPS into the same udder, a second injection of 0.1 mg of LPS into the same quarter (two cows) 24 h after the first injection produced a strongly attenuated TNF-alpha response. However, a normal TNF-alpha response was observed when LPS was injected into a contralateral quarter (two cows) 24 h after the first LPS injection. Leukocyte counts in blood decreased and body temperature increased substantially after each injection of LPS. Quarter milk SCC increased 200-fold 8 to 12 h after the LPS injections. It would appear that these changes were not regulated by TNF-alpha secretion because the changes were also similar after the second injection of LPS into the same mammary quarter.

Pharmacokinetics of amrinone in neonates and infants.

OBJECTIVE: To evaluate the pharmacokinetics of amrinone and its metabolites in neonates and infants after reconstructive surgery for congenital heart disease. DESIGN: Prospective study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Fifteen neonates aged less than 1 month with transposition of the great arteries and 14 infants aged 2 to 6 months with complete atrioventricular septal defect. INTERVENTIONS: Amrinone, loading dose of 2 mg/kg, was administered before weaning from cardiopulmonary bypass, followed by a maintenance infusion of 7.5 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: Blood samples to determine plasma concentrations of amrinone, N-acetylamrinone, and N-glycolylamrinone were drawn before amrinone administration, frequently after the loading dose, every 6 hours during the maintenance infusion, and until 48 hours after the end of the infusion. Amrinone clearance was 2.4 +/- 0.9 mL/kg/min in neonates and 3.2 +/- 1.2 mL/kg/min in infants (p < 0.05). The volume of distribution at steady-state was smaller (p < 0.05) in neonates than in infants. The elimination half-life of amrinone was 10.7 +/- 6.7 hours in neonates and 6.1 +/- 1.4 hours in infants (p < 0.05). There was a linear correlation between the clearance of amrinone and the body surface area (r = 0.67; p < 0.05). The ratio of the plasma concentration of N-acetylamrinone to that of amrinone did not differ between neonates and infants. CONCLUSIONS: Amrinone is eliminated at a slower rate in neonates than in infants. The rate of acetylation of amrinone appears to be similar; the differences in the elimination capacity of amrinone are mainly due to the immature renal function in neonates.

In situ hybridization detection of human herpesvirus 6 in brain tissue from fatal encephalitis.

A 23-month-old girl died after 2 days' illness with rash, fever, and convulsions. Neuropathologic findings were consistent with viral hemorrhagic encephalitis in pontine tegmentum and medial thalamic areas. Human herpesvirus 6 (HHV-6) DNA was detected in pontine nuclei by in situ hybridization. In addition, polymerase chain reaction for HHV-6 of serum and paraffin-embedded pontine tissue was positive, and serology indicated an acute primary infection. This is the first case showing HHV-6 DNA in the brain cells of an immunocompetent patient with acute encephalitis.

Amrinone versus dopamine and nitroglycerin in neonates after arterial switch operation for transposition of the great arteries.

OBJECTIVE: To compare the efficacy and safety of amrinone and a combination of dopamine and nitroglycerin in neonates after reconstructive surgery for transposition of the great arteries. DESIGN: A prospective, randomized, double-blind study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Thirty-five neonates with transposition of the great arteries. INTERVENTIONS: A loading dose of amrinone, 2 mg/kg, followed by a maintenance infusion of 7.5 microg/kg/min, were administered to 16 neonates before separation from cardiopulmonary bypass. The remaining 19 patients were administered a combination of dopamine, 5 microg/kg/min, and nitroglycerin, 1 microg/kg/min. An open-label epinephrine infusion was administered in both groups as required. MEASUREMENTS AND MAIN RESULTS: The circulatory state of the patients was evaluated from 4 to 18 hours after cardiopulmonary bypass. The systemic blood flow index, calculated using the Fick principle, was higher in the amrinone group (1.7+/-0.5 L/min/m2 [mean +/- SD]) compared with the dopamine-nitroglycerin group (1.4+/-0.4 L/min/m2; p < 0.04). The systemic vascular resistance in the amrinone group was lower (26+/-8 Wood units x m2) than in the dopamine-nitroglycerin group (35+/-12 Wood units x m2; p < 0.02). The oxygen extraction ratio was higher in the dopamine-nitroglycerin group (0.34+/-0.08) compared with the amrinone group (0.28+/-0.06; p < 0.02). Lower platelet counts were observed in the amrinone group, but no difference in hemorrhagic complications was seen between the groups. CONCLUSION: With the dosage regimen used, supplemented with epinephrine, amrinone provides a higher cardiac output and more favorable oxygen dynamics than a combination of dopamine and nitroglycerin.

Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect.

OBJECTIVES: To compare the effectiveness and safety of amrinone and a combination of dopamine and nitroglycerin in infants after reconstructive surgery for congenital heart disease. DESIGN: A prospective, randomized, double-blind study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Thirty-two infants with complete atrioventricular septal defect. INTERVENTIONS: Amrinone loading dose, 2 mg/kg, followed by a maintenance infusion, 7.5 micrograms/kg/min, was given to 17 infants before separation from cardiopulmonary bypass. The remaining 15 patients received a combination of dopamine, 5 micrograms/kg/min, and nitroglycerin, 1 microgram/kg/min. MEASUREMENTS AND MAIN RESULTS: The circulatory state of the patients was evaluated from 4 to 18 hours after cardiopulmonary bypass. The systemic blood flow index, calculated using the Fick principle, was higher in the amrinone group (2.5 +/- 0.7 L/min/m2) compared with the dopamine-nitroglycerin group (2.0 +/- 0.6 L/min/m2, mean +/- SD). The pulmonary blood flow index in the amrinone group was higher (2.9 +/- 0.6 L/min/m2) than in the dopamine-nitroglycerin group (2.2 +/- 0.6 L/min/m2); no significant difference was noted in the mean pulmonary artery pressure. The oxygen extraction ratio was higher in the dopamine-nitroglycerin group (0.41 +/- 0.07) compared with the amrinone group (0.34 +/- 0.08). Despite lower platelet counts in the amrinone group, no hemorrhagic complications were seen in any patient. CONCLUSIONS: With this dosage regimen, amrinone provides a higher cardiac output, more favorable oxygen dynamics, and lower pulmonary vascular resistance than dopamine and nitroglycerin.

Hyperamylasemia after cardiac surgery in infants and children.

OBJECTIVE: This study was conducted to clarify the incidence of hyperamylasemia after cardiac surgery in infants and children. DESIGN AND PATIENTS: 186 infants and children operated on at Children's Hospital. Helsinki, during an 11-month period were enrolled in the study. Serum samples were taken before and on 3 consecutive days after cardiac surgery at the intensive care unit and before discharge from the hospital. MEASUREMENTS: We measured serum total amylase and serum pancreatic amylase with two different assays (1) reduction of salivary amylase from total amylase activity and (2) measurement of mass concentration with monoclonal antibodies. RESULTS: Preoperative values for both total amylase and pancreatic isoenzymes were strongly age-related. At least one of the three tests showed postoperative hyperamylasemia (> +/- 2 SD above starting values of the age group and maximal value > 3 times the individual starting value) in 64/186 (34%) patients. 22/186 (12%) patients had abnormal results in all assays. A more than tenfold rise in pancreatic amylase, suggesting pancreatitis, was found in 14 patients (8%). Mortality was 21% in this subgroup, but 5% in the rest of the patients. Hyperamylasemia was more common after 1 year of age, and after open-heart surgery, especially homograft implantation or cardiac transplantation. CONCLUSIONS: Hyperamylasemia is a common finding after cardiac surgery in pediatric patients. Amylase isoenzyme measurements are needed for clinical decision making. Age-group-related reference values are mandatory for the right interpretation of amylase values.

Prenatal muscle relaxation in congenital diaphragmatic hernia.

An infant with congenital diaphragmatic hernia was given 2 mg vecuronium bromide intramuscularly in utero 40 min before vaginal delivery at 40 weeks gestation. At birth the infant had complete muscle relaxation, which facilitated decompression of the bowel and surgical correction. Prenatal muscle relaxation may improve the care of infants with congenital diaphragmatic hernia.

Successful treatment of ARDS with two doses of synthetic surfactant.

A 50-year-old man with adult respiratory distress syndrome (ARDS) was successfully treated with synthetic surfactant. The therapy rapidly improved the respiratory function; it also increased the release of endogenous surfactant. Synthetic surfactant may thus be of value in the treatment of ARDS.

Alfentanil sedation for cardiac catheterization of children with Fontan shunts.

After Fontan operation, prolonged invasive cardiac assessment is often needed. This study is a clinical evaluation of the effectiveness of flunitrazepam premedication, EMLA cream, and alfentanil continuous infusion for management of children undergoing such catheterization. Fourteen consecutive subjects aged 5-20 yr with Fontan shunts (right atrium to pulmonary artery) undergoing elective haemodynamic and electrophysiological catheterization were sedated with an individually titrated alfentanil infusion. After oral premedication with flunitrazepam 2 mg, the mean induction dose and mean maintenance requirement of alfentanil were 4.4 +/- 2.7 micrograms.kg-1 and 10.3 +/- 8.6 micrograms.kg-1 x hr-1, respectively. Mean oxygen consumption during haemodynamic catheterization was 4.1 +/- 0.4 ml.kg-1 x min-1 with an average individual variation of 10%. For every patient, tranquil and stable conditions during catheterization could be produced. It is concluded that alfentanil infusion is a method of sedation of children and adolescents with Fontan shunts during haemodynamic and electrophysiologic catheterization. However, continuous monitoring of ventilation and an understanding of the slow circulation time after Fontan operation are essential with such sedation in these patients.

Sudden and unexpected death of a 6-month-old baby with silent heart failure due to anomalous origin of the left coronary artery from the pulmonary artery.

A 6-month-old girl died suddenly without any previous symptoms of heart failure. Autopsy examination showed cardiomegaly (97 g) with a severely fibrotized myocardium. The left coronary artery was originating from the pulmonary artery. Histologically, the myocardium showed myocardial infarcts of different ages, as well as grossly thickened arterial branches due to increased flow in left-right shunt. We suggest that rare anomalies of the coronary arteries should be considered in the autopsies of suspected sudden infant death syndrome cases.

Alfentanil infusion for sedation in infants and small children during cardiac catheterization.

We have analyzed several sedation techniques for paediatric cardiac catheterization which offer stable conditions for a few hours investigation, and maintain spontaneous breathing. In the present study, after premedication with oral flunitrazepam 0.1 mg.kg-1, 14 children aged 1-17 mo were sedated with an individually titrated alfentanil infusion. Every patient was sedated to a level which produced no reaction to pain or any discomfort. The induction dose and the maintenance requirement of alfentanil were 24 +/- 8 micrograms.kg-1 and 32 +/- 8 micrograms.kg-1.hr-1 (mean +/- SD), respectively. These doses were less in cyanotic than in acyanotic patients: 21 +/- 6 vs 28 +/- 8 micrograms.kg-1 and 29 +/- 10 vs 34 +/- 3 micrograms.kg-1.hr-1, respectively (P less than 0.05). The mean plasma concentration of alfentanil during maintenance of sedation was 79 +/- 23 ng.ml-1. Ventilation of two children was assisted for a short time after an incremental bolus of alfentanil. It is concluded that an alfentanil infusion technique with close monitoring of breathing is a practical sedation method for paediatric cardiac catheterization.

Haemodynamic responses and prolongation of QT interval of ECG after suxamethonium-facilitated intubation during anaesthetic induction in children: a dose-related attenuation by alfentanil.

The haemodynamic response to endotracheal intubation and changes in the QT interval of ECG during anaesthetic induction were studied in 68 healthy children (5.5 years). The children were pretreated double-blindly with either alfentanil 10 micrograms/kg (A10), 25 micrograms/kg (A25), 50 micrograms/kg (A50) or saline (control) (17 children in each group) i.v. 1 min before thiopentone 5 mg/kg. The trachea was intubated after suxamethonium 1.5 mg/kg. Central nervous system excitation was seen in four of 17 and in one of 17 children after alfentanil 50 and 25 micrograms/kg, respectively. After intubation, heart rate increased significantly in the control group, remained at initial levels in the A10 and A25 groups and decreased in the A50 group. A pressor response to intubation was seen in the control and A10 groups. The QT interval was significantly prolonged after suxamethonium in the control and A10 groups, but remained at baseline levels in the A25 and A50 groups. Ventricular ectopic beats were only seen in 2/17 children in the control group. In conclusion, alfentanil 25 microgram/kg is ideal for preventing the haemodynamic response to endotracheal intubation and prolongation of the QT interval, a sign of sympathoadrenal activation, before induction of intravenous anaesthesia in children.

Alfentanil and fentanyl sedation in infants and small children during cardiac catheterization.

Thirty patients aged 1-23 mth received either alfentanil or fentanyl for the induction and maintenance of IV sedation during cardiac catheterization following oral flunitrazepam premedication (0.1 mg.kg-1). Patients breathed spontaneously 30 per cent oxygen in air. Both alfentanil and fentanyl abolished all reaction to pain and discomfort with minimal haemodynamic and respiratory changes. Induction doses of alfentanil and fentanyl were 20 +/- 6 and 2.5 +/- 1.1 (mean +/- SD) micrograms.kg-1, respectively, and maintenance requirements 30 +/- 12 and 1.5 +/- 0.6 micrograms.kg-1.h-1, respectively. These requirements were comparable among younger and older as well as cyanotic and acyanotic patients. The IV sedation described adds an effective method to the armamentarium of an anaesthetist working in the cardiac laboratory.

QT interval of the ECG, heart rate and arterial pressure using propofol, methohexital or midazolam for induction of anaesthesia.

The effects of propofol 2 mg/kg, methohexital 2 mg/kg or midazolam 0.3 mg/kg were studied on the QT interval of the ECG corrected by the heart rate (QTc), heart rate and arterial pressure during induction of anaesthesia in 87 ASA class I-(II)-patients. The patients were randomly allocated to one of the three anaesthetic groups. The incidence of the patients with a prolonged QTc interval (= more than 440 ms) ranged from 29 to 41% between the groups. In each group these patients were treated separately. After all anaesthetics, the QTc interval was significantly prolonged in the patients with a normal control QTc interval, whereas in the patients with a prolonged control QTc interval, it tended to be shortened both after propofol and methohexital and it was significantly shortened after midazolam. After injection of suxamethonium, no significant QTc interval changes occurred in the patients with a normal control QTc interval in either the propofol or the methohexital groups, whereas in the patients with a prolonged control QTc interval treated with propofol the QTc interval decreased significantly 60 s after suxamethonium when compared with the corresponding preceding values. The mean values in the propofol group in the patients with a normal control QTc interval were always below the upper limit of the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)