Drug safety in paediatric anaesthesia.

Life-threatening drug errors are more common in children than in adults. This is likely to be because of their variations in age and weight, combined with the occasional exposure of most anaesthetists to paediatric patients. Drug administration in anaesthesia is mostly undertaken by a single operator and thus represents a potentially greater risk compared with other areas of medicine. This increased risk is believed to be offset by anaesthetists working with only a limited number of drugs on a very frequent and repetitive basis. However, high rates of errors continue to be reported. Paediatric anaesthesia practice requires individual age- and weight-specific drug dose calculations and is therefore without a 'familiar' or 'usual' dose. The aim of this narrative systematic review of existing recommendations and current evidence of preventive strategies is to identify measures to enhance the safety and quality of drug administration in paediatric anaesthesia. This review collates and grades the evidence of such interventions and recommendations and assesses their feasibility. Most highly effective available measures require low or limited costs and labour. The presented solutions should, therefore, achieve a high level of acceptance and contribute significantly to safety and quality of care in paediatric anaesthesia.

Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery.

BACKGROUND: Sedation of critically ill children requiring artificial ventilation remains a therapeutic challenge due to large individual variation in drug effects and a paucity of knowledge of pharmacokinetics in this population. This study aimed to determine the pharmacokinetics of remifentanil in children requiring ventilation after cardiac surgery. METHODS: Twenty-six ventilated children aged 1 month to 9.25 yr (median 1.77 yr) who had undergone cardiac surgery were sedated with a fixed rate infusion of midazolam 50 microg kg(-1) h(-1) and a remifentanil infusion that was commenced at 0.8 microg kg(-1) min(-1) for a minimum of 60 min and subsequently decreased by 0.1 microg kg(-1) min(-1)every 20 min until the patient awoke. Arterial blood concentrations of remifentanil and midazolam were measured using high-performance liquid chromatography. Mixed-effects population models were fitted to the remifentanil concentration-time data. RESULTS: Satisfactory sedation was achieved in all patients as assessed by Comfort score during the initial maintenance and reduction phase of the remifentanil infusion. One patient was withdrawn from the study due to hypotension. Remifentanil pharmacokinetics were best described using a two-compartment allometric model. For a typical child with a body weight of 10.5 kg, clearance was 68.3 ml kg(-1) min(-1), intercompartmental clearance was 80 ml kg(-1) min(-1), the central compartment volume was 91.7 ml kg(-1), and the peripheral compartment volume was 141 ml kg(-1). CONCLUSIONS: A combination of remifentanil and midazolam provided satisfactory sedation for these patients. Owing to enhanced clearance rates, smaller (younger) children will require higher remifentanil infusion rates than larger (older) children and adults to achieve equivalent blood concentrations.

Emergence and recovery in children after desflurane and isoflurane anaesthesia: effect of anaesthetic duration.

BACKGROUND: We hypothesized that increasing duration of inhalation anaesthesia is associated with slower emergence and recovery in children, and that this effect would be less marked with desflurane in comparison with isoflurane. METHODS: Fifty-four infants and children assigned in groups according to age and expected length of operation were prospectively randomized to receive either isoflurane (I) or desflurane (D) for anaesthesia. After standard induction, the anaesthesia was maintained using an age-related 1.0 minimum alveolar concentration (MAC) equivalent for either agent in air and oxygen. Local analgesia was used as appropriate. End-tidal volatile agent concentration was recorded until extubation. Clinical evaluation of recovery was made by observers, blinded to group allocation. RESULTS: For patients <4 yr of age, the median (95% CI) times in minutes to first movement [5.27 (D), 9.22 (I)], eye opening [9.42(D), 13.3(I)] and extubation [7.18 (D), 12.5 (I)] were significantly shorter (P<0.05) for desflurane. In the group >4 yr of age, the median (95% CI) times in minutes to first movement [4.42 (D), 11.6 (I)], eye opening [8.55(D), 18.0(I)] and extubation [7.08 (D), 16.7 (I)] were significantly shorter (P<0.001) for desflurane. Times to leave recovery were not significantly different for the group <4 yr of age, but were significantly shorter for desflurane in the group >4 yr of age (P<0.01). The isoflurane, but not desflurane, had a time-dependent effect on arousal. There were no significant differences in incidence of airway irritation or emergence delirium between the two agents. CONCLUSIONS: The rate of recovery in children after exposure to desflurane was faster than those patients receiving isoflurane; recovery from desflurane, but not isoflurane, was relatively unaffected by the duration of anaesthesia.

Prospective comparison of sevoflurane and desflurane in formerly premature infants undergoing inguinal herniotomy.

BACKGROUND: Formerly premature infants having inguinal herniotomy have been at a high risk of postoperative apnoea, newer less soluble anaesthetic agents may reduce this risk. METHODS: Thirty infants, under 37 weeks gestation and under 47 weeks post-conceptional age, undergoing inguinal herniotomy had an inhalational induction with sevoflurane and were randomly allocated to sevoflurane (group S) or desflurane (group D) for maintenance. All infants received i.v. atracurium 0.5 mg kg(-1), rectal acetaminophen 20 mg kg(-1) and caudal bupivacaine 0.25% 1 ml kg(-1). Infants were monitored for apnoeas (using nasal thermistry and impedance), haemoglobin oxygen desaturations and bradycardias for 12 h before and after operation with an Alice 4 polysomnograph. Emergence timings were recorded. RESULTS: There was no difference between pre- and postoperative incidence of apnoeas in either group, and no group difference between desflurane and sevoflurane in terms of pre- and postoperative ventilatory events or in the number of apnoeas in the postoperative period (nine patients in group D and five patients in group S had apnoeas). Median times to first movement, tracheal extubation, eye opening and first cry were all faster with group D (group D: 3.0, 10.0, 9.0 and 11.0 min and group S: 7.0, 15.1, 13.5 and 16.1 min, respectively). No infant had problems with airway irritation on emergence and no infant required airway intervention for apnoea. CONCLUSIONS: Infants wake faster from general anaesthesia when maintained with desflurane as compared with sevoflurane, but no difference in postoperative respiratory events was demonstrated between the groups.

Pain, nociception and the developing infant.

The study of paediatric pain and the provision of safe but reliable analgesia for all age groups has become a central issue in paediatric anaesthesia. For the practising paediatric anaesthetist, this represents a major challenge: the developing infant is not a single discrete entity but one that changes constantly with increasing maturity of individual organs. Recent developments in both basic and clinical sciences has given valuable insights into this process, giving the clinician a firm basis to provide analgesia at all ages. This review looks at some of the most interesting recent developments in this field.

A modified Pitot tube for the accurate measurement of tidal volume in children.

A device using modification of a Pitot tube has been designed for measurement of tidal volume in infants and small children. Its accuracy was compared both n vitro and n vivo to that of a calibrated pneumotachograph (Fleish #1) designed for a similar flow range. In vitro measurement of air flow with the modified Pitot tube (MPT) was within 5% of the pneumotachograph readings over a range of 1-60 l/min. Similar accuracy was found with measurement of tidal volumes from 20 ml to 1 l, delivered by a calibrated volume-cycled ventilator using a variety of inspiratory flow rates. Tidal volume measurements with the MPT were compared to the pneumotachograph using helium, oxygen, carbon dioxide, and a range of nitrous oxide/oxygen mixtures. A manual control was incorporated into the MPT electronics to allow direct measurements of tidal volume with different nitrous oxide/oxygen concentrations. In vivo, the insertion of the MPT into the patient circuit caused no apparent changes in ventilatory parameters in children under 20 kg. Measurement of tidal volumes with the MPT agreed to within 8% of pneumotachograph readings. The low dead space (1.5 cc) and light weight (12 gm) of the MPT confer advantages over the pneumotachograph (15 ml dead space and a weight of 90 gm) for routine use in pediatric anesthesia.

Pain relief for infants undergoing abdominal surgery: comparison of infusions of i.v. morphine and extradural bupivacaine.

We have undertaken a prospective, randomized double-blind study to compare extradural bupivacaine infusions with i.v. morphine infusions for postoperative analgesia in 32 infants younger than 4 yr undergoing abdominal surgery. "Sham" extradural or i.v. catheters were used to maintain the blinded nature of the study. Both techniques provided adequate analgesia for most of the 36-h postoperative period; differences in the pattern or quality of the analgesia were not detected. Patients in the i.v. morphine group were significantly more sedated; this was accompanied by slower ventilatory frequencies (26.7 (SD 1.8) b.p.m.) compared with the extradural group (33.6 (1.3) b.p.m.). Similarly, oxygen saturation was significantly less (P < 0.01) in patients receiving morphine (medians and quartiles of 94.0 (93-96)% compared with 96.0 (93-96)%). Mean systolic arterial pressure was similar in the two groups and there were no life-threatening complications. The lack of sedation was troublesome in three patients in the extradural group.

Pain in children.

Children, and particularly neonates, often receive inadequate pain relief after surgery. In this review we describe the important physiological and pharmacological differences between babies and children, and discuss practical aspects of pain assessment and relief.

Ventilatory arrest after a fluid challenge in a neonate receiving s.c. morphine.

S.c. infusions of morphine have been advocated for postoperative analgesia in children, but experience with this technique is limited. We report a case in which an s.c. infusion of morphine given after operation to a neonate failed to provide acceptable analgesia until the child had been adequately rehydrated. However, restoration of peripheral perfusion with a fluid challenge was followed by sudden ventilatory arrest which required resuscitation and naloxone infusion. This report emphasizes the dangers of giving morphine by a peripheral route in the dehydrated or hypovolaemic infant.

Propofol and alfentanil in children: infusion technique and dose requirement for total i.v. anaesthesia.

We estimated the dose of propofol (initial dose followed by a stepped infusion) when given with two different infusion rates of alfentanil for total i.v. anaesthesia in 59 children aged 3-12 yr. Patients in series 1 (four groups) received an alfentanil loading dose of 85 micrograms kg-1 and an infusion of 65 micrograms kg-1 h-1. Patients in series 2 (groups 5 and 6) received an alfentanil loading dose of 65 micrograms kg-1 and infusion of 50 micrograms kg-1 h-1. Parents gave their informed consent. Premedication comprised temazepam 0.3 mg kg-1. Glycopyrronium 5 micrograms kg-1 was administered and anaesthesia induced and maintained with alfentanil (loading dose and infusion) followed by propofol (loading dose and three-stage manual infusion scheme). Suxamethonium 1 mg kg-1 was used to facilitate tracheal intubation and the lungs were ventilated artificially to normocapnia with 30% oxygen in air. Probit analysis was used to determine the dose requirement of propofol. In series 1, the ED50 was 6.0 mg kg-1 h-1 (95% confidence limits 5.5-6.2 mg kg-1 h-1) and ED95 8.6 (6.8-7.8) mg kg-1 h-1. Corresponding values for series 2 were ED50 7.5 (8.0-9.8) mg kg-1 h-1 and ED95 10.5 (9.6-13.1) mg kg-1 h-1.

Modifying infant stress responses to major surgery: spinal vs extradural vs opioid analgesia.

Twenty-six infants due to undergo major abdominal or thoracic surgery under general anaesthesia were randomized to receive additional analgesia with group A) spinal/epidural analgesia; B) epidural analgesia or C) opioid analgesia with fentanyl. We wished to determine if spinal analgesia followed by epidural analgesia might result in more complete control of cardiovascular or stress responses than the other two treatment groups. Heart rate and blood pressure were recorded at five min intervals throughout surgery. Blood samples were taken for measurement of catecholamines and whole blood sugar on induction, 45 min after skin incision and at the end of surgery. Heart rate rose significantly at the start of surgery in groups B and C but not group A. Systolic blood pressures were higher in group C compared to A and B. The rise in plasma glucose concentrations was significantly different between the groups in the order C > B > A (P < 0.05). A similar trend was seen in the plasma adrenaline and noradrenaline concentrations but this failed to achieve significance due to the limited sample size.

Changes in blood-gas tensions during apnoeic oxygenation in paediatric patients.

We report changes in arterial blood-gas tensions for up to 5 min of apnoeic oxygenation in 26 anaesthetized paediatric patients (21 children, five infants). Changes in oxygen and carbon dioxide tension were greatest in the first minute of apnoeic oxygenation. In subsequent minutes, rates of change in gas tension were approximately constant. The rate of decline in oxygen tension (31 (95% confidence interval (CI) 20.1-42.2) mm Hg min-1) was more than three times that reported in studies in adults. The rate of increase in carbon dioxide tension (4.2 (95% CI 3.7-4.7) mm Hg min-1) was similar to that reported in adults. After successful preoxygenation, oxygen tension remained greater than 290 mm Hg in all children (age > 1 yr) throughout the study. This was not the case in infants. We found no correlation between changes in blood-gas tensions and age or weight of patients. The small number of infants studied showed rapid decreases in oxygen tension which if sustained would be expected to limit the safe duration of apnoeic oxygenation, unlike adults where apnoeic oxygenation is limited by hypercapnia. Extrapolation of our results suggests that when preoxygenation has been successful, apnoeic oxygenation could continue safely in children for at least 10 min. Infants may become hypoxic after only 2 min.

Combined morphine-bupivacaine caudals for reconstructive penile surgery in children: systemic absorption of morphine and postoperative analgesia.

We wished to determine if the addition of a small dose of morphine (0.05 mg.kg-1) to a caudal solution of 0.25% bupivacaine could extend the duration of analgesia after major reconstructive penile surgery and also to measure the systemic absorption of morphine after caudal injection. Thirty children undergoing reconstructive penile surgery received a caudal injection of 0.25% bupivacaine 0.75 ml.kg-1 with or without morphine 0.05 mg.kg-1. All patients awoke pain-free, but eight of the fifteen patients receiving bupivacaine alone required supplementary injections of opioid postoperatively, whereas none of the patients receiving the bupivacaine-morphine mixture required additional opioids. The incidence of side-effects was similar for the two groups. Morphine was absorbed rapidly after caudal injection to reach a peak plasma level of 21.2 (+/- 4.8) ng.ml-1 at ten minutes and then fell to 10.1 (+/- 3.8) ng.ml-1 at one hour and 4.1 (+/- 2.6) ng.ml-1 at three hours. These levels are low compared with plasma levels associated with systemic analgesia. We conclude that the extended duration of analgesia from morphine 0.05 mg/kg given caudally is due at least in part to specific spinal analgesia.

Effect of remifentanil infusion rate on stress response to the pre-bypass phase of paediatric cardiac surgery.

BACKGROUND: Opioids are used routinely to eliminate the stress response in the pre-bypass phase of paediatric cardiac surgery. Remifentanil is a unique opioid allowing a rapidly titratable effect. No data are available regarding a suitable remifentanil dose regimen for obtunding stress and cardiovascular responses to such surgery. METHODS: We recruited 49 infants and children under 5 yr old who were randomized to receive one of four remifentanil infusion rates (0.25, 1.0, 2.5, or 5.0 micro g kg(-1) min(-1)). Blood samples were obtained at induction, pre-surgery, 5 min after opening the chest, and immediately pre-bypass. Whole blood glucose was measured at all time points while cortisol and neuropeptide Y (NPY) were measured in the first and last samples. Heart rate and arterial pressure were also recorded. RESULTS: There was a significant increase in whole blood glucose 5 min after opening the chest and pre-bypass (P=0.009, P=0.002) in patients receiving remifentanil 0.25 micro g kg(-1) min(-1), but not in those receiving higher doses. Increased remifentanil dosage was associated with reduced plasma cortisol during surgery (P<0.001). Baseline NPY showed considerable variation and there was no association between pre-bypass NPY and remifentanil dose. There was a significantly higher heart rate at the pre-bypass stage of surgery in the remifentanil 0.25 micro g kg(-1) min(-1) group compared with higher doses (P=0.0006). Four out of five neonates with complex cardiac conditions showed severe bradycardia associated with remifentanil. CONCLUSIONS: In infants and children under 5 yr, remifentanil infusions of 1.0 micro g kg(-1) min(-1) and greater can suppress the glucose increase and tachycardia associated with the pre-bypass phase of cardiac surgery, while 0.25 micro g kg(-1) min(-1) does not. Remifentanil should be used with caution in neonates with complex congenital heart disease.

Fresh gas formulae do not accurately predict end-tidal PCO2 in paediatric patients.

To determine the fresh gas flow (FGF) requirements in paediatric patients, we measured the FGFs needed to maintain distal end-tidal PCO2 (PETCO2) values at 30 and 38 mmHg in patients weighing between 3.8 and 20 kg ventilated with either a Sechrist Infant Ventilator IV-100B or an Air-Shields Ventimeter and a Mapleson D circuit. The FGF requirement was 500 ml.kg-1.min-1 to maintain a PETCO2 of 30 mmHg and 250 ml.kg-1.min-1 to maintain a PETCO2 of 38 mmHg when minute ventilation greater than or equal to FGF. When these formulae were used in a subsequent group of similar patients, a wide variation in PETCO2 measurements were obtained. We conclude that the safest and most accurate approach to determine the FGF requirement of paediatric patients is to continuously monitor the PETCO2 in each patient and to adjust the FGF accordingly.

Recovery after desflurane anaesthesia in the infant: comparison with isoflurane.

We have studied 20 infants, aged 2.5-8 weeks, undergoing general anaesthesia for pyloromyotomy with either desflurane or isoflurane. Patients were anaesthetized with equivalent 1 MAC values for age and agent. A blinded observer recorded times to breathing, swallowing, movement, extubation and side effects after discontinuation of the agent. Recovery times in the desflurane group were significantly shorter than in the isoflurane group. The times to swallowing, movement and extubation in the desflurane group were 3.89 (SD 2.4) min, 5.33 (4.95) min, 7.5 (4.53) min, respectively, and 8.82 (2.40) min, 10.73 (3.93) min, 13.45 (4.20) in the isoflurane group. In addition, postoperative apnoea was documented in the isoflurane group but not in those infants receiving desflurane. There was no laryngospasm after extubation in either group. We conclude that desflurane possesses useful characteristics for recovery conditions in the infant and may be particularly useful in the ex-premature infant prone to apnoea and ventilatory depression.