Animal experiments have shown that inhalational anaesthetics used in daily clinical practice have adverse consequences on the developing brain in young animals.1–3 This anaesthetic-induced brain injury causes an increase in apoptosis, impaired neurogenesis and neuroinflammation.1–3 Infants with cardiac and noncardiac congenital anomalies requiring surgery have a higher risk of adverse neurodevelopmental outcomes.4,5 It is not yet certain what the influence of inhalational anaesthetics is on neurodevelopmental outcome in young children. The clinical studies are inconclusive and mainly based on retrospective cohort database analyses.1–3,6–8 Therefore, three ongoing clinical trials [the Pediatric Anesthesia & Neurodevelopment Assessment (PANDA) project, the Mayo Anesthesia Safety in Kids study and the General Anaesthesia compared to Spinal anaesthesia (GAS) study] are trying to gain more insight into the risks of inhalational anaesthetics in infants.1,3,8,9 Results of the PANDA study, a sibling-matched cohort study investigating cognitive function after a single exposure to anaesthesia before the age of 36 months, showed no differences in intelligence quotient scores in later childhood.10 The recently published secondary outcomes of the GAS study showed strong evidence that general anaesthesia does not increase the risk of adverse neurodevelopmental outcome in infants at the age of 2 years.11 However, the primary outcome results in terms of neurodevelopmental assessments at age 5 years will not be available until 2018. Whilst awaiting these results, it has been suggested that it would be good practice to keep anaesthesia and surgery as short as possible to reduce the overall anaesthetic drug exposure.1,12,13
Anaesthetic requirements are usually expressed as a proportion of the minimal alveolar concentration (MAC)14,15 which is defined as the alveolar (or end-expiratory) concentration at which 50% of patients will not show a motor response to a standardised surgical incision. Age, opioids and local anaesthetics may influence MAC. The range of doses of inhalational anaesthetics currently used in clinical practice in infants is virtually unknown, and this impairs our ability to quantify the potential effect of anaesthetic neurotoxicity. Therefore, the aim of this study is to document the range of doses of inhalational anaesthetics used in clinical practice for maintenance of anaesthesia in infants.
In this two-centre prospective [Great Ormond Street Hospital (GOSH), London, United Kingdom] and retrospective [Wilhelmina Children's Hospital, University Medical Center Utrecht (UMCU), The Netherlands] observational cohort study, patients younger than 1 year undergoing anaesthesia for noncardiac surgery and diagnostic procedures in March and November 2013 were studied. The institutional Review Board of the UMCU, The Netherlands, and GOSH, United Kingdom, approved the use of the clinically acquired data for the purpose of the study and waived written parental informed consent. The manuscript was reported in accordance with the reporting of observational studies in epidemiology statement checklist.16 The study started with a prospective cohort study in GOSH. All infants undergoing inhalational anaesthesia involving mechanical ventilation for at least 15 min were investigated for practical reasons in two study periods of 1 month, March and November 2013. Subsequently, to validate the results, we matched patients from the GOSH retrospectively with patients from the UMCU who were anaesthetised during the same period. Patients from GOSH were individually matched by procedure, age and weight to patients selected from the database of the Anaesthesia Information Management System (AIMS), Anstat (Carepoint, Ede, The Netherlands) from the UMCU in a 1 : 1 fashion who were operated in the same period (March and November 2013).
The primary endpoint was the mean end-tidal concentration of the inhalational anaesthetic used during the maintenance phase of anaesthesia corrected for the age-specific MAC. We calculated the mean end-tidal concentration during the maintenance phase and divided this by the associated MAC from Table 1 (expressed as %MAC).17–19 This enabled us to compare different anaesthetic agents at different ages. The end-tidal anaesthetic concentration in GOSH was measured by Philips IntelliVue patient monitors (IntelliVue G1 Anesthetic Gas Module, Eindhoven, The Netherlands) and registered by a researcher present in the operating room (LJS or PP). Manual recording by a researcher was required as the automatic recording system was not available in GOSH. Inspired and end-tidal concentrations were assessed every 5 min. The end-tidal anaesthetic concentration in the UMCU was measured by the ventilator (Aestiva 7900 Ventilator, GE Healthcare, Wauwatosa, Wisconsin, USA) and automatically registered every minute in AIMS. In GOSH and in the UMCU, the end-tidal anaesthetic concentrations were sampled at the bacterial filter and/or moisturiser. In both centres, the mean of the end-tidal concentration of the maintenance phase was defined from start to end of surgery or diagnostic intervention. Demographic characteristics of the patients were collected from the anaesthetic article (GOSH) and electronic (UMCU: EZIS, Chipsoft, Amsterdam, The Netherlands) charts.
The differences in the dose ranges used in the maintenance phase of standard anaesthesia between the two specialised paediatric centres were evaluated. Differences in patient characteristics from GOSH and the UMCU were evaluated with the two-sample t test, Mann–Whitney U test and chi-square test. The relation between anaesthetic concentration and age was analysed through linear regression. The effect of the use of local anaesthetics (e.g. caudal or epidural block) and opioids on the %MAC was evaluated by the two-sample t test. One-way analysis of variance (ANOVA) was used to compare the anaesthetic end-tidal concentration in the four different subgroups of analgesia; no analgesia, opioids, local anaesthetics and opioids combined with local anaesthetics. A P value less than 0.05 was considered statistically significant; all tests were two-sided. The data were analysed using IBM SPSS statistics software package (IBM SPSS Statistics version 21, IBM Corp., Armonk, New York, USA), except for the determination of 95% confidence intervals (95% CIs) for percentages that were calculated according to the method of Agresti–Coull (http://epitools.ausvet.com.au/content.php?page=CIProportion).
In total, 56 infants were included in the GOSH database and matched with 180 infants from the retrospectively collected UMCU database. In total, 38 infants enrolled from the UMCU database were useful matches with 38 infants from the GOSH database (Fig. 1). During the study period, 38 different anaesthesiologists participated, 22 from GOSH and 16 from the UMCU.
Patient characteristics were similar in both centres, except for the different types of inhalation anaesthetics used (P < 0.0001), types of airway management employed (P < 0.0001) and the American Society of Anesthesiologists physical status classification system (ASA) class (P < 0.0001, Table 2). There were no significant differences in the use of local anaesthetics or opioids between the centres. Abdominal surgery was the main procedure in both centres.
The relation between the mean of the end-tidal concentration during the maintenance phase and age irrespective of the MAC is shown in Fig. 2. The mean %MAC in GOSH (%MAC, 0.87) was not significantly different from the UMCU (%MAC, 0.82) (P = 0.329). When both groups were combined, the mean %MAC in the total group was 0.85. There was a significant increase in the %MAC in relation to age in the total group (slope = 0.036 MAC month−1, P = 0.0001, Fig. 3). In 57 of the 76 infants [75% (95% CI, 64 to 83%)], the anaesthetic end-tidal concentration was below 1 MAC. There were no significant differences in %MAC between the groups with and without tracheal intubation [mean difference, −0.057 (95% CI, −0.179 to 0.66); P = 0.357]. Furthermore, there were no significant differences in %MAC between the groups receiving local anaesthesia or not [mean difference, −0.088 (95% CI, −0.20 to 0.019); P = 0.105] nor between the groups receiving opioids or none [mean difference, 0.056 (95% CI, −0.67 to 0.179); P = 0.367]. There was no significant effect of the use of analgesia on the end-tidal concentration (P
The results of our study demonstrate that anaesthetic end-tidal concentrations administered for maintenance of anaesthesia increase with age and that 75% of infants were given an anaesthetic end-tidal concentration below 1 MAC. Furthermore, this study also shows that there were no significant differences in the dose of inhalational anaesthetics used for maintenance of anaesthesia in two distinct institutions from different countries. Contrary to expectations, the use of opioids and the use of local anaesthetics had no significant effect on the dose of inhalational anaesthesia administered.
The Food and Drug Administration, SmartTots and the American Academy of Pediatrics published a consensus statement12,13 recommending a reduction in the exposure to general anaesthesia drugs in infants.1,12,13 Furthermore, most of the anaesthetic agents used in daily clinical practice have not been tested thoroughly for their safety in infants.13
MAC is a reference value at which 50% of patients do not move in response to a painful stimulus.14,15,20 This study showed that the youngest infants received the lowest anaesthetic concentrations and that 75% of the infants received an anaesthetic concentration below 1 MAC, which might imply that anaesthesiologists are already being cautious with dosing of anaesthetic drugs to infants. It could be argued that the MAC value of sevoflurane, desflurane and isoflurane in infants is not employed as a useful dosage guide in clinical practice. This study shows for the first time that anaesthesiologists titrate inhalational anaesthetics to a lower concentration target when based on clinical parameters (e.g. heart rate).17–19 The differences in anaesthetic agents used in this study were based on experience and normal clinical practice, the choice of the anaesthetic being entirely at the discretion of the anaesthesiologist. To correct for the differences in practice, the end-tidal concentrations were corrected for age-specific MAC. Therefore, the present variation clearly illustrates the differences in clinical practice. In any future study, it would be interesting to investigate which physiological parameters are used to target and titrate the dose of anaesthetic drug delivered.
It is possible that most of the infants in our study received too little anaesthesia with the risk of inadequate sedation and awareness during surgery.21 Animal studies have shown that exposure to painful stimuli causes an increased rate of neuronal cell death.8,22 Previous studies have proven that premature infants experiencing painful procedures encountered stress that can affect outcome.1 If the dose of anaesthesia is minimised, one should be aware of the risks of inadequate anaesthesia as well.23
Almost all infants in this study received analgesia. Infants who received no analgesia still had a mean end-tidal concentration of inhalational anaesthetics below 1 MAC. Previous studies have observed that the use of opioids and the use of local anaesthetics reduced the required dose of inhaled anaesthetics,8,14 but we did not find this in our study. This rather contradictory result may be due to the fact that we did not take into account the dose of opioids and local anaesthetics due to the small sample size, and so pain medication was studied as a dichotomous measure instead of a continuous variable. Therefore, infants who received one dose of opioids were in the same group as infants who received multiple doses of opioids. Morphine was only given at the end of surgery as pain medication and did not influence the administered dose of anaesthesia.
Although the present study showed comparable results in two centres in two countries, we studied a relatively small group of infants, and so the generalisability of the present results is limited. It might be valuable to perform a similar study in a larger multicentre and multinational population. Furthermore, there were differences in patient characteristics between the two groups, especially for ASA class. However, patients were matched for age, weight and type of procedure, as these factors are more relevant for the primary outcome of the study. There may have been observer bias in the prospective cohort study in GOSH as the researchers were present during surgery that may have influenced the anaesthesiologists in reducing the anaesthetic dosage. This study investigated only the maintenance phase of standard anaesthesia during surgery to try to minimise the number of confounding factors in the anaesthetic technique.
In conclusion, the results of the present study suggest that most young infants received inhalational anaesthetics at a concentration below 1 MAC, which accords with current guidance to minimise anaesthetic drug exposure but may have unintended consequences. Human experience is perhaps a better surrogate of the “true” anaesthetic needs, and MAC might needs to be re-evaluated. However, this would require a larger multicentre study. Multiple reviews and agencies recommend the reduction of the dose of anaesthesia in infants, nevertheless this study might indicate that the dose used by anaesthesiologists is already in decline.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: an abstract of this study is presented at the Pediatric Academic Society (PAS), 25 to 28 April 2015, San Diego, United States and at the seventh ESPA European Congress on Paediatric Anaesthesia, 17 to 19 September 2015, Istanbul, Turkey.
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