Jurgen C. de Graaff

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial

__Background__ In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. __Methods__ In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. __Findings__ Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI –2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. __Interpretation__ Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial

Background:Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia. Methods:Infants aged 60 weeks or younger, postmenstrual age scheduled for inguinal herniorrhaphy, were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born less than 26 weeks gestation. The primary outcome of this analysis was any observed apnea up to 12 h postoperatively. Apnea assessment was unblinded. Results:Three hundred sixty-three patients were assigned to RA and 359 to GA. Overall, the incidence of apnea (0 to 12 h) was similar between arms (3% in RA and 4% in GA arms; odds ratio [OR], 0.63; 95% CI, 0.31 to 1.30, P = 0.2133); however, the incidence of early apnea (0 to 30 min) was lower in the RA arm (1 vs. 3%; OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367). The incidence of late apnea (30 min to 12 h) was 2% in both RA and GA arms (OR, 1.17; 95% CI, 0.41 to 3.33; P = 0.7688). The strongest predictor of apnea was prematurity (OR, 21.87; 95% CI, 4.38 to 109.24), and 96% of infants with apnea were premature. Conclusions:RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Cardiorespiratory monitoring should be used for all ex-premature infants.

Predictive factors for difficult intravenous cannulation in pediatric patients at a tertiary pediatric hospital

Background:  It is generally believed that certain patient characteristics (e.g., Body Mass Index and age) predict difficulty of intravenous cannulation in children, but there is not much literature evaluating these risk factors. In this study, we investigated predictive factors for success rate at first attempt and time needed for intravenous cannulation.

The use of near-infrared light for safe and effective visualization of subsurface blood vessels to facilitate blood withdrawal in children

Obtaining access to blood vessels can be difficult, especially in children. Visualization of subsurface blood vessels might be a solution. Ultrasound and visible light have been used to this purpose, but have some drawbacks. Near-infrared light might be a better option since subsurface blood vessels can be visualized in high contrast due to less absorption and scattering in tissue as compared to visible light. Our findings with a multispectral imaging system support this theory. A device, the VascuLuminator, was developed, based on transillumination of the puncture site with near-infrared light. The VascuLuminator was designed to meet the requirements of compact and safe use. A phantom study showed that the maximum depth of visibility (5.5mm for a 3.6mm blood vessel) is sufficient to visualize blood vessels in typical locations for peripheral venous and arterial access. A quantitative comparison of the VascuLuminator and to two other vessel imaging devices, using reflection of near-infrared light instead of transillumination, was conducted. The VascuLuminator is able to decrease failure at first attempt in blood withdrawal in pediatric patients from 10/80 (13%) to 1/45 (2%; P=.05).

Incidence of intraoperative hypoxemia in children in relation to age.

BACKGROUND:Although respiratory problems are by far the most frequent complications of pediatric anesthesia, there are currently no reliable data on the incidence of perioperative hypoxemia in children. Most studies investigating the incidence of pediatric respiratory complications were based on self-report. METHODS:We studied the incidence of intraoperative hypoxemia as well as that of pulse oximeter artifacts prospectively in 575 pediatric noncardiac surgery patients aged between 0 and 16 years operated in a tertiary pediatric university hospital. Subsequently, the incidence of intraoperative hypoxemia was determined retrospectively in 8277 patients registered in an anesthesia information management system (AIMS) of the same hospital. RESULTS:In the prospective cohort, at least 1 episode of oxygen saturation (SpO2) ⩽ 90% for at least 1 minute occurred in 69 of 575 cases (12%; 95% confidence interval [CI], 9%–15%). Furthermore, in 35 of 575 (6%; 95% CI, 4%–8%) cases at least 1 true hypoxemic event was observed. In total, 117 episodes of SpO2 ⩽ 90% were observed in the prospective study, of which 3 of 117 could not be specified and 67 of 114 (54%; 95% CI, 42%–65%) episodes were classified as true hypoxemia. False-positive low SpO2 values were mainly caused by dislodgment of the pulse oximeter. In the retrospective analysis, SpO2 ⩽ 90% and SpO2 ⩽ 80% for at least 1 minute were documented in the AIMS in 18% (95% CI, 17%–19%) and 7.5% (95% CI, 7%–8%) of the cases, respectively; 31 and 10 episodes per 100 cases, respectively. The incidence of hypoxemia increased in younger age groups: SpO2 ⩽ 90% for at least 1 minute occurred in 56% (95% CI, 49%–63%) of neonates (170 episodes per 100 cases). CONCLUSIONS:The incidence of intraoperative hypoxemia increased with younger age, with the highest incidence in neonates. Because of the high artifact rate, unvalidated pulse oximeter data in AIMS should be interpreted with caution because only up to 65% of all hypoxemic episodes recorded during pediatric anesthesia were caused by true hypoxia.

Anesthesia and the developing brain: a way forward for clinical research.

It is now well established that many general anesthetics have a variety of effects on the developing brain in animal models. In contrast, human cohort studies show mixed evidence for any association between neurobehavioural outcome and anesthesia exposure in early childhood. In spite of large volumes of research, it remains very unclear if the animal studies have any clinical relevance; or indeed how, or if, clinical practice needs to be altered. Answering these questions is of great importance given the huge numbers of young children exposed to general anesthetics. A recent meeting in Genoa brought together researchers and clinicians to map a path forward for future clinical studies. This paper describes these discussions and conclusions. It was agreed that there is a need for large, detailed, prospective, observational studies, and for carefully designed trials. It may be impossible to design or conduct a single study to completely exclude the possibility that anesthetics can, under certain circumstances, produce long‐term neurobehavioural changes in humans; however , observational studies will improve our understanding of which children are at greatest risk, and may also suggest potential underlying etiologies, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome.

Visualizing Veins With Near-Infrared Light to Facilitate Blood Withdrawal in Children

Introduction. This study aims to evaluate for the first time the value of visualizing veins by a prototype of a near-infrared (NIR) vascular imaging system for venipuncture in children. Methods. An observational feasibility study of venipunctures in children (0-6 years) attending the clinical laboratory of a pediatric university hospital during a period of 2 months without (n = 80) and subsequently during a period of 1 month with a prototype of an NIR vascular imaging system (n = 45) was conducted. Failure rate (ie, more than 1 puncture) and time of needle manipulation were determined. Results. With the NIR vascular imaging system, failure rate decreased from 10/80 to 1/45 (P = .05) and time decreased from 2 seconds (1-10) to 1 second (1-4, P = .07). Conclusion . This study showed promising results on the value of an NIR vascular imaging system in facilitating venipunctures.

The effectiveness of a near-infrared vascular imaging device to support intravenous cannulation in children with dark skin color : a cluster randomized clinical trial

BACKGROUND:Poor vein visibility can make IV cannulation challenging in children with dark skin color. In the operating room, we studied the effectiveness of a near-infrared vascular imaging device (VascuLuminator) to facilitate IV cannulation in children with dark skin color. METHODS:In the operating room of a general hospital in Curacao, all consecutive children (0–15 years of age) requiring IV cannulation were included in a pragmatic cluster randomized clinical trial. The VascuLuminator was made available to anesthesiologists at the operating complex in randomized clusters of 1 week. RESULTS:Success at first attempt was 63% (27/43, 95% confidence interval [CI], 47%–77%) in the VascuLuminator group vs 51% (23 of 45 patients, 95% CI, 36%–66%) in the control group (P = 0.27). Median time to successful cannulation was 53 seconds (interquartile range: 34–154) in the VascuLuminator group and 68 seconds (interquartile range: 40–159) in the control group (P = 0.54), and hazard ratio was 1.12 (95% CI, 0.73–1.71). CONCLUSION:The VascuLuminator has limited value in improving success at first attempt of facilitating IV cannulation in children with dark skin color.

One-Year Mortality, Causes of Death, and Cardiac Interventions in Patients with Postoperative Myocardial Injury

BACKGROUND:To evaluate the role of routine troponin surveillance in patients undergoing major noncardiac surgery, unblinded screening with cardiac consultation per protocol was implemented at a tertiary care center. In this study, we evaluated 1-year mortality, causes of death, and consequences of cardiac consultation of this protocol. METHODS:This observational cohort included 3224 patients ≥60 years old undergoing major noncardiac surgery. Troponin I was measured routinely on the first 3 postoperative days. Myocardial injury was defined as troponin I >0.06 &mgr;g/L. Regression analysis was used to determine the association between myocardial injury and 1-year mortality. The causes of death, the diagnoses of the cardiologists, and interventions were determined for different levels of troponin elevation. RESULTS:Postoperative myocardial injury was detected in 715 patients (22%) and was associated with 1-year all-cause mortality (relative risk [RR] 1.4, P = 0.004; RR 1.6, P < 0.001; and RR 2.2, P < 0.001 for minor, moderate, and major troponin elevation, respectively). Cardiac death within 1 year occurred in 3%, 5%, and 11% of patients, respectively, in comparison with 3% of the patients without myocardial injury (P = 0.059). A cardiac consultation was obtained in 290 of the 715 patients (41%). In 119 (41%) of these patients, the myocardial injury was considered to be attributable to a predisposing cardiac condition, and in 111 patients (38%), an intervention was initiated. CONCLUSIONS:Postoperative myocardial injury was associated with an increased risk of 1-year all-cause but not cardiac mortality. A cardiac consultation with intervention was performed in less than half of these patients. The small number of interventions may be explained by a low suspicion of a cardiac etiology in most patients and lack of consensus for standardized treatment in these patients.

Near-Infrared Imaging in Intravenous Cannulation in Children: A Cluster Randomized Clinical Trial

OBJECTIVE: Intravenous cannulation is a widespread medical procedure that can be difficult in children. Visualization of veins with near-infrared (NIR) light might support intravenous cannulation. Therefore, we investigated the effectiveness of an NIR vascular imaging system (VascuLuminator) in facilitating intravenous cannulation in children in the operating room. METHODS: This was a pragmatic, cluster randomized clinical trial in all consecutive children (0–18 years) scheduled for elective surgery and in need of intravenous cannulation at a tertiary pediatric referral hospital. Daily operating rooms (770 patients) were randomized for allocation of the VascuLuminator or control group. The primary outcome was success at first attempt; the secondary outcome was time to successful cannulation. RESULTS: Success at first attempt was 70% (171/246) with and 71% (175/245) without the use of the VascuLuminator (P = .69). Time to successful cannulation was 162 (±14) seconds and 143 (±15) seconds respectively (P = .26). In 83.3%, the vein of first choice was visible with the VascuLuminator. CONCLUSIONS: Although it was possible to visualize veins with NIR in most patients, the VascuLuminator did not improve success rate or time to obtain intravenous cannulation. There are 3 possible explanations for this result: first, it could be that localization of the vein is not the main problem, and therefore visualization is not a solution; second, the type of system used in this study could be less than optimal; and, third, the choice of the patient population in this study could be inappropriate.