Thiopentone elimination in newborn infants: exploring Michaelis-Menten kinetics.

BACKGROUND: Thiopentone elimination has been described using Michaelis-Menten pharmacokinetics in adults after prolonged infusion or overdose, but there are few reports of elimination in neonates. METHODS: Time-concentration profiles for neonates (n=37) given single-dose thiopentone were examined using both first-order (constant clearance) and mixed-order (Michaelis-Menten) elimination processes using nonlinear mixed effects models. These profiles included a 33-week post-menstrual age (PMA) neonate given an overdose. A two-compartment mamillary model was used to fit data. Parameter estimates were standardized to a 70 kg person using allometric models. RESULTS: There were 197 observations available for analysis from neonates with a mean post-menstrual age of 35 (SD 4.5) weeks and a mean weight of 2.5 (SD 0.9) kg. They were given a mean thiopentone dose of 3 (SD 0.4) mg/kg as a rapid bolus. Clearance at 26 weeks PMA was 0.015 l/min/70 kg and increased to 0.119 l/min/70 kg by 42 weeks PMA. The maximum rate of elimination (V(max)) at 26 weeks PMA was 0.22 mg/min/70 kg and increased to 4.13 mg/min/70 kg by 42 weeks PMA. These parameter estimates are approximately 40% adult values at term gestation. The Michaelis constant (K(m)) was 28.3 [between subject variability (BSV) 46.4%, 95% confidence interval (CI) 4.49-99.2] mg/l; intercompartment clearance was 0.44 (BSV 97.5%, 95% CI 0.27-0.63) l/min/70 kg; central volume of distribution was 46.4 (BSV 29.2%, 95% CI 41.7-59.8) l/70 kg; peripheral volume of distribution was 95.7 (BSV 70.3%, 95% CI 61.3-128) l/70 kg. CONCLUSIONS: Both first-order and mixed-order processes satisfactorily described elimination. First-order elimination adequately described the time-concentration profile in the premature neonate given an overdose. Clearance is immature in the pre-term neonate although there is rapid maturation around 40 weeks PMA, irrespective of post-natal age.

Ropivacaine pharmacokinetics after caudal block in 1-8 year old children.

We studied the pharmacokinetics after caudal block of ropivacaine (2 mg ml-1, 1 ml kg-1) performed in 20 children aged 1-8 yr undergoing subumbilical surgery, in this open, non-comparative, multicentre study. Venous blood samples were collected up to 12-36 h. The mean (SD) peak plasma concentration, 0.47 (0.16) mg litre-1, was achieved after 12-249 min. The free fraction was 5% and the highest individual peak plasma concentration of free ropivacaine was 0.04 mg litre-1. Clearance was 7.4 (1.9) ml min-1 kg-1 and the terminal half-life 3.2 (0.8) h. Thus, the free plasma concentrations of ropivacaine were well below those associated with toxic symptoms in adults and the capacity to eliminate ropivacaine seems to be well developed in this age group. In this open study of 20 patients, ropivacaine was well tolerated and provided satisfactory postoperative pain relief without observable motor block.

Sevoflurane causes more postoperative agitation in children than does halothane.

BACKGROUND: An agitated recovery may occur after inhalation anesthesia. The aim of the present study was to assess the recovery quality after mask anesthesia with either halothane or sevoflurane in children. METHODS: Sixty-two children, 8 months to 18 years of age, scheduled for minor surgery, were randomly assigned to receive either halothane or sevoflurane. The patients were premedicated with midazolam and anesthesia was induced i.v. with propofol or by inhalation and maintained with halothane or sevoflurane in N2O/O2 via face mask. Recovery was assessed by a "blinded" observer using a postanesthetic recovery score. Agitation and pain were judged using a visual analog scale. The incidence of vomiting was noted. The day after anesthesia older children and parents of younger children were interviewed about their experience of the anesthesia and recovery period. RESULTS: There were no differences between groups in respect of age, weight, length, or duration of surgery or inhalational gas exposure. Median time from end of administration of inhalational agent to spontaneous eye opening was less after sevoflurane (25 min) than after halothane (48 min), (P < 0.01). Likewise, recovery was faster after sevoflurane anesthesia (P < 0.05). Agitation, but not pain, occurred more frequently after sevoflurane than after halothane (P < 0.05) and agitation was significantly more common in younger children. There was no difference in duration of hospital stay between day-care patients in the two groups. CONCLUSION: Early postanesthetic agitation and recovery was faster after mask anesthesia with sevoflurane than after halothane. There was a higher incidence of agitation in younger children, without correlation to pain.

Jaw lift--a simple and effective method to open the airway in children.

Assessment of breathing during resuscitation of children is important. Misjudgement due to failure to open the airway may lead to mouth-to-mouth ventilation in unconscious children who have retained spontaneous breathing efforts, and might lead to completely ineffective ventilation with gastric distension. The efficiency of the standard head tilt-chin lift manoeuvre (HT-CL) and the jaw lift manoeuvre (JL) for opening of the airway in children was investigated. Fifty children between 1 and 9 years of age breathing spontaneously during deep anaesthesia were studied. Both manoeuvres were randomly performed in all children by nurse anaesthetists. The time for opening and the quality of the airway was determined by a blind folded anaesthesiologist listening to the breathing sounds. The standard HT-CL manoeuvre was insufficient in 12% of the children. JL was more effective than HT-CL in opening the airway in unconscious children who had retained attempts at spontaneous breathing. The JL manoeuvre may, therefore, be recommended in situations when the HT-CL manoeuvre is insufficient.

Intravenous induction of general anaesthesia with eltanolone in children 6-15 years of age.

BACKGROUND: Eltanolone is a short-acting intravenous anaesthetic, formulated as an oil-water emulsion. The aim of the present study was to estimate the anaesthetic dose (ED50) for induction in children 6-10 and 11-15 years of age and to collect safety data. METHODS: Forty-nine unpremedicated children, all ASA I or II, divided in one pilot-study group, with 5 children 6-15 years and two main study groups, 6-10 and 11-15 years of age, were studied. The first patient in each study group was given 0.86 mg/kg of eltanolone iv over 20 s. Fifty s after injection the chin was gently lifted to "the sniffing position' and the anaesthesia mask was placed over the face. Induction was considered satisfactory if there was no gross movement, coughing or response to verbal command during the following 15 s. The dose selected for the next patient was based on the observed response: if induction was not classified as satisfactory the dose was increased by a factor of 20%, otherwise it was decreased by the same factor. ED50 was estimated as described by Dixon and Massey. RESULTS: In children 6-10 years of age ED50 was 0.68 (0.49-0.92; 95% confidence limits) mg/kg and in children 11-15 years of age 0.53 (0.41-0.68) mg/kg. No child showed sign of pain on injection. One patient developed urticaria and 15 patients had transient rash after induction. Two patients (both responders receiving 0.86 and 0.40 mg/kg respectively) had apnoea lasting more than 15 s. Involuntary movements occurred in one patient. CONCLUSION: The ED50 of eltanolone for induction of anaesthesia in unpremedicated children 6-10 years of age was 0.68 mg/kg and in children 11-15 years of age 0.53 mg/kg. The findings suggest that an induction dose for children 6-15 years of age of about 1 mg/kg would be adequate in most cases. No serious adverse events were recorded. However, the drug has subsequently been withdrawn from further investigation due to an unacceptable incidence of rash and urticaria.

Thiopentone requirements in adults after varying pre-induction doses of fentanyl.

The thiopentone dose needed for satisfactory induction of anaesthesia was determined in 60 adult patients using a double-blinded study design. No premedication was given. The effect of pretreatment with four different doses of fentanyl on ED50 for thiopentone was determined and compared with a control group not receiving fentanyl. The cardiovascular effects of the combinations were also studied. ED50 for thiopentone was reduced from 4.0 mg.kg-1 in the control group to 2.2 mg.kg-1 in patients receiving fentanyl 5.0 micrograms.kg-1. Only in the group of patients receiving fentanyl 5.0 micrograms.kg-1 was there no significant change in systolic arterial blood pressure. An increased heart rate was noted in patients induced with thiopentone in combination with fentanyl 0.625 micrograms.kg-1. No adverse effects of thiopentone, fentanyl or the combinations were noted.

Faster recovery after anesthesia in infants after intravenous induction with methohexital instead of thiopental.

BACKGROUND: To determine possible delays in recovery after intravenous anesthesia induction with thiopental, the drug was compared with methohexital in infants 1-12 months of age who were scheduled for hernia repair or circumcision. METHODS: The infants were given equipotent doses of methohexital (3.0 mg/kg, n = 21) or thiopental (7.3 mg/kg, n = 20), in random and blind fashion. After tracheal intubation, anesthesia was maintained with isoflurane in nitrous oxide/oxygen. All children received 0.75 ml/kg caudal bupivacaine (2.5 mg/ml). Isoflurane was discontinued at the beginning of skin closure, and nitrous oxide was terminated immediately after the last suture (end of surgery). RESULTS: There were no differences between the two groups with respect to age, weight, or duration of surgery, which lasted 19 min (14-23 min) in the methohexital group and 16 min (15-19 min) in the thiopental group (median and inner quartile range). Time from termination of nitrous oxide to extubation did not differ significantly between the groups. Time to spontaneous eye opening after end of surgery was 23 min (5-44 min) after methohexital induction and 55 min (25-74 min) after thiopental induction (P < 0.05). Recovery, assessed as postanesthetic recovery scores by a blinded observer, was significantly more rapid in the methohexital group at arrival in the recovery room and 5, 15, and 45 min after arrival. After 120 min, almost all infants of both groups were awake. CONCLUSIONS: Recovery after short surgical procedures in infants is faster after intravenous induction with methohexital than with thiopental.

Methohexital dissolved in lipid emulsion for intravenous induction of anesthesia in infants and children.

The induction dose of thiopental and propofol has been shown previously to vary during childhood. The methohexital dose needed for satisfactory induction of anesthesia in 50% of patients (ED50) was determined in 75 infants and children, 1 month to 16 yr of age. An intravenous bolus of methohexital, dissolved in a lipid emulsion to decrease pain on injection, was given over 10 s. After 30 s the anesthesia mask was applied. The patient was considered to be asleep if there were no gross movements when the head was placed in the sniffing position and the anesthesia mask applied, and no response to verbal command (tested in children more than 4 yr of age) during the next 30 s while the patient breathed O2. ED50 (+/- SE) was 2.6 +/- 0.2 mg/kg in infants 1-6 months of age, 1.9 +/- 0.1 mg/kg in infants 7-11 months of age, 1.4 +/- 0.1 mg/kg in children 1-3 yr of age, 1.1 +/- 0.1 mg/kg in children 4-7 yr of age, and 1.3 +/- 0.1 mg/kg in children 8-16 yr of age. ED50 in each of the two groups of infants was significantly greater than ED50 in each of the three other groups (P less than 0.05). Pain or discomfort on injection was observed in 1 infant and 3 children (5%). Eight patients (11%) had apnea longer than 15 s, and excitatory phenomena occurred in 9 (12%). It is concluded that the dose of methohexital needed for induction of anesthesia varies with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissolving methohexital in a lipid emulsion reduces pain associated with intravenous injection.

Pain often accompanies intravenous injection of 1% methohexital. The aim of the present study was to test whether pain on injection could be reduced by dissolving methohexital in a lipid emulsion (study A) and whether this would affect anesthetic potency (study B). In study A, 24 healthy volunteers, 36 +/- 1 yr (mean +/- SE), were given 1 ml 1% methohexital in saline, 1 ml 1% methohexital in lipid emulsion, and 5 ml 0.1% methohexital in saline in random order. The injections were given in a small vein in the forearm at 5-min intervals. One minute after each injection, the subject was asked to assess the injection pain on a visual analog scale (0-100 mm). The pain score (median [range]) was 44.5 (0-77) after 1% methohexital in saline, 0.5 (0-26) after 1% methohexital in a lipid emulsion, and 1.0 (0-26) after 0.1% methohexital in saline. The pain score for 1% methohexital in saline was significantly greater than those for the other two solutions (P less than 0.001 for each comparison). In study B, 42 patients, 41 +/- 3 yr, were given 1% methohexital in lipid emulsion (n = 22) or 1% methohexital in saline (n = 20). A bolus of either solution was administered over 10 s, and the patient was considered asleep if there was no gross movement or response to verbal command 40-70 s after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

The induction dose of propofol in infants 1-6 months of age and in children 10-16 years of age.

The propofol dose needed for satisfactory induction of anesthesia was determined in 22 infants 1-6 months of age and 22 children 10-16 yr of age. A single bolus of propofol was given over 10 s. Thirty seconds after injection the lid reflex was tested and the anesthesia mask was applied. The patient was considered to be asleep if there were no gross movements during the next 30 s while the patient breathed O2. The dose required for satisfactory induction in 50% of patients (ED50) (+/- SE) was 3.0 +/- 0.2 mg/kg in infants and 2.4 +/- 0.1 mg/kg in older children (P less than 0.02). Pain on injection occurred in 50% of the infants and 18% of the children.

Thiopental requirements for induction of anesthesia in neonates and in infants one to six months of age.

The authors determined the thiopental dose needed for satisfactory induction in ten neonates, 0-14 days of age, and 20 infants, 1-6 months of age. A single iv bolus of thiopental was given. Thirty seconds after injection the anesthesia mask was applied and the response was observed during the following 30 s while the patient breathed oxygen. Induction was considered satisfactory if there were no gross movements or coughing. The dose required for satisfactory induction in 50% of patients, ED50 (+/- SE), was 3.4 +/- 0.2 mg/kg in neonates and 6.3 +/- 0.7 mg/kg in infants (P less than 0.001). It is concluded that the thiopental dose needed for satisfactory induction is less in neonates than in infants.

Effects of portacaval shunt on the rat stomach.

In portacaval-shunted rats, basal but not pentagastrin-stimulated acid secretion was higher than in sham-operated controls. The basal serum gastrin concentration was unchanged and the postprandial serum gastrin concentration lowered following portacaval shunt. Thus, gastrin is not responsible for the elevated basal acid secretion. The present study provides evidence that there is no trophic effect on the oxyntic mucosa as a whole and that there is no change in parietal cell-associated gastrin receptors after portacaval shunting. Interestingly, however, endocrine cells in the oxyntic mucosa (the histamine-containing ECL cells) proliferated greatly and the pentagastrin- and cholecystokinin octapeptide-induced activation of the histamine-forming enzyme, histidine decarboxylase, in these cells was much greater than in control rats. Analysis of the dose-response curves for the enzyme-activating effect of pentagastrin and cholecystokinin-octapeptide indicated that the D50 values for these two stimulants were not altered by shunting but that the maximal enzyme activation was greatly elevated. The enhanced enzyme activation can be partly, but not fully, explained by the fact that the ECL cells were increased in number. The enhanced response following portacaval shunt probably reflects also an increased number of gastrin receptors per ECL cell. The effect of portacaval shunting on gastric ECL cells can perhaps be explained by impaired degradation in the liver of intestinal substance(s) exerting a highly specific trophic effect on the ECL cells or, alternatively, causing an enrichment of gastrin receptors on these cells, thereby making them more sensitive to the trophic effect of gastrin. The ECL cell hyperplasia is manifest about 4 weeks after the shunting. A modified procedure for portacaval shunting which left the gastroduodenal vein (otherwise ligated) drained to the liver produced the same trophic effect as conventional portacaval shunt, suggesting an intestinal rather than gastroduodenal origin of the agent(s) responsible for the trophic action.