Inhaled Volatiles for Status Asthmaticus, Epilepsy, and Difficult Sedation in Adult ICU and PICU: A Systematic Review.

OBJECTIVES: Inhaled volatile anesthetics support management of status asthmaticus (SA), status epilepticus (SE), and difficult sedation (DS). This study aimed to evaluate the effectiveness, safety, and feasibility of using inhaled anesthetics for SA, SE, and DS in adult ICU and PICU patients. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, and Embase. STUDY SELECTION: Primary literature search that reported the use of inhaled anesthetics in ventilated patients with SA, SE, and DS from 1970 to 2021. DATA EXTRACTION: Study data points were extracted by two authors independently. Quality assessment was performed using the Joanna Briggs Institute appraisal tool for case studies/series, Newcastle criteria for cohort/case-control studies, and risk-of-bias framework for clinical trials. DATA SYNTHESIS: Primary outcome was volatile efficacy in improving predefined clinical or physiologic endpoints. Secondary outcomes were adverse events and delivery logistics. From 4281 screened studies, the number of included studies/patients across diagnoses and patient groups were: SA (adult: 38/121, pediatric: 28/142), SE (adult: 18/37, pediatric: 5/10), and DS (adult: 21/355, pediatric: 10/90). Quality of evidence was low, consisting mainly of case reports and series. Clinical and physiologic improvement was seen within 1-2 hours of initiating volatiles, with variable efficacy across diagnoses and patient groups: SA (adult: 89-95%, pediatric: 80-97%), SE (adults: 54-100%, pediatric: 60-100%), and DS (adults: 60-90%, pediatric: 62-90%). Most common adverse events were cardiovascular, that is, hypotension and arrhythmias. Inhaled sedatives were commonly delivered using anesthesia machines for SA/SE and miniature vaporizers for DS. Few (10%) of studies reported required non-ICU personnel, and only 16% had ICU volatile delivery protocol. CONCLUSIONS: Volatile anesthetics may provide effective treatment in patients with SA, SE, and DS scenarios but the quality of evidence is low. Higher-quality powered prospective studies of the efficacy and safety of using volatile anesthetics to manage SA, SE, and DS patients are required. Education regarding inhaled anesthetics and the protocolization of their use is needed.

Moral Distress and Other Wellness Measures in Canadian Critical Care Physicians.

Rationale: Understanding the magnitude of moral distress and its associations may point to solutions. Objectives: To understand the magnitude of moral distress and other measures of wellness in Canadian critical care physicians, to determine any associations among these measures, and to identify potentially modifiable factors. Methods: This was an online survey of Canadian critical care physicians whose e-mail addresses were registered with either the Canadian Critical Care Society or the Canadian Critical Care Trials Group. We used validated measures of moral distress, burnout, compassion fatigue, compassion satisfaction, and resilience. We also measured selected individual, practice, and workload characteristics. Results: Of the 499 physicians surveyed, 239 (48%) responded and there were 225 usable surveys. Respondents reported moderate scores of moral distress (107 ± 59; mean ± standard deviation, maximum 432), one-third of respondents had considered leaving or had previously left a position because of moral distress, about one-third met criteria for burnout syndrome, and a similar proportion reported medium-high scores of compassion fatigue. In contrast, about one-half of respondents reported a high score of compassion satisfaction, and overall, respondents reported a moderate score of resilience. Each of the "negative" wellness measures (moral distress, burnout, and compassion fatigue) were associated directly with each of the other "negative" wellness measures, and inversely with each of the "positive" wellness measures (compassion satisfaction and resilience), but moral distress was not associated with resilience. Moral distress was lower in respondents who were married or partnered compared with those who were not, and the prevalence of burnout was lower in respondents who had been in practice for longer. There were no differences in any of the wellness measures between adult and pediatric critical care physicians. Conclusions: Canadian critical care physicians report moderate scores of moral distress, burnout, and compassionate fatigue, and moderate-high scores of compassion satisfaction and resilience. We found no modifiable factors associated with any wellness measures. Further quantitative and qualitative studies are needed to identify interventions to reduce moral distress, burnout, and compassion fatigue.

Sedation and neurodevelopmental outcomes in PICU: Identification of study groups.

BACKGROUND/AIMS: As little as 30 minutes of exposure to anesthetic and sedative agents may adversely affect the developing brain. Safe, humane management of critically ill infants requires the use of sedative agents, often for prolonged periods. We sought to identify two comparable groups of critical care patients who did or did not receive sedatives, with the aim of designing a long-term neurodevelopment follow-up study. This feasibility study aimed to determine if two comparable groups could be found. METHODS: Infants with respiratory diagnoses having noninvasive ventilation without sedation (Group C) or intubation and ventilation with sedation (Group S) were identified by chart review. Charts of patients fulfilling the above inclusion criteria were searched for exclusion criteria including neurological disease, extreme prematurity, congenital cardiac disease, and genetic anomalies. Data were extracted to score pediatric severity of illness scores (PRISM and PELOD) for each patient. These scores were then compared using the absolute scores and by risk strata. RESULTS: Group S included 33 patients and Group C had 39. The absolute PRISM and PELOD scores were different between groups. Comparing the groups in three risk strata (PRISM greater or less than 5 or 10), there were no significant differences between groups. CONCLUSION: It is not possible to randomize infants to sedation or no sedation to investigate neurodevelopmental outcomes. This phase of the project aimed to determine the comparability of two groups of PICU patients. These findings indicate that these groups could be enrolled as exposed and control subjects in an outcomes study.

Enrollment challenges in multicenter, international studies: The example of the GAS trial.

INTRODUCTION: Randomized trials are important for generating high-quality evidence, but are perceived as difficult to perform in the pediatric population. Thus far there has been poor characterization of the barriers to conducting trials involving children, and the variation in these barriers between countries remains undescribed. The General Anesthesia compared to Spinal anesthesia (GAS) trial, conducted in seven countries between 2007 and 2013, provides an opportunity to explore these issues. METHODS: We undertook a descriptive analysis to evaluate the reasons for variation in enrollment between countries in the GAS trial, looking specifically at the number of potential subjects screened, and the subsequent application of four exclusion criteria that were applied in a hierarchical order. RESULTS: A total of 4023 patients were screened by 28 centers in seven countries. Australia and the USA screened the most subjects, accounting for 84% of all potential trial participants. The percentage of subjects eliminated from the screened pool by each exclusion criterion varied between countries. Exclusion due to a predefined condition (H1) eliminated only 5% of potential subjects in Italy and the UK, but 37% in Canada. Exclusions due to a contraindication or a physician's refusal most impacted enrollment in Australia and the USA. The patient being "too large for spinal anesthesia" was the most commonly cited by anesthetists who refused to enroll a patient (64% of anesthetist refusals). The majority of surgeon refusals came from the USA, where surgeons preferred the patient to receive a general anesthetic. The percentage of approached parents refusing to consent ranged from a low of 3% in Italy to a high of 70% in the USA and Netherlands. The most frequently cited reason for parent refusal in all countries was a preference for general anesthesia (median: 43%, range: 32%-67%). However, a sizeable proportion of parents in all countries had a contrasting preference for spinal anesthesia (median: 25%, range: 13%-31%), and 23% of U.S. parents expressed concern about randomization. CONCLUSION: The GAS trial highlights enrollment challenges that can occur when conducting multicenter, international, pediatric studies. Investigators planning future trials should be aware of potential differences in screening processes across countries, and that exclusions by anesthetists and surgeons may vary in reason, in frequency, and by country. Furthermore, investigators should be aware that the U.S. centers encountered particularly high surgeon and parental refusal rates and that U.S. parents were uniquely concerned about randomization. Planning trials that address these difficulties should increase the likelihood of successfully recruiting subjects in pediatric trials.

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

BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. 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. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).

Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes.

BACKGROUND: Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. The General Anesthesia compared to Spinal anesthesia study compares neurodevelopmental outcomes after awake RA or GA in otherwise healthy infants. The aim of the study is to describe success and failure rates of RA and report factors associated with failure. METHODS: This was a nested cohort study within a prospective, randomized, controlled, observer-blind, equivalence trial. Seven hundred twenty-two infants 60 weeks or less postmenstrual age scheduled for herniorrhaphy under anesthesia were randomly assigned to receive RA (spinal, caudal epidural, or combined spinal caudal anesthetic) or GA with sevoflurane. The data of 339 infants, where spinal or combined spinal caudal anesthetic was attempted, were analyzed. Possible predictors of failure were assessed including patient factors, technique, experience of site and anesthetist, and type of local anesthetic. RESULTS: RA was sufficient for the completion of surgery in 83.2% of patients. Spinal anesthesia was successful in 86.9% of cases and combined spinal caudal anesthetic in 76.1%. Thirty-four patients required conversion to GA, and an additional 23 patients (6.8%) required brief sedation. Bloody tap on the first attempt at lumbar puncture was the only risk factor significantly associated with block failure (odds ratio = 2.46). CONCLUSIONS: The failure rate of spinal anesthesia was low. Variability in application of combined spinal caudal anesthetic limited attempts to compare the success of this technique to spinal alone.

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.

A comparison of three dose timings of methylprednisolone in infant cardiopulmonary bypass.

Although commonly used in pediatric cardiopulmonary bypass (CPB) optimal dose and timing of steroid administration is unclear. We hypothesized that early administration of a commonly used dose of methylprednisolone given the evening before surgery (ultra-early) would be more effective in decreasing CPB-related inflammatory response than when given at induction of anesthesia (early) or in pump prime (standard). This was a triple-arm, parallel, active control, superiority RCT including 54 infants <2 years old who were randomised to receive 30 mg/kg methylprednisolone at one of the 3 time points. Outcomes included alveolar-arterial oxygen gradient (AaDO2) during, 24, 48 and 72 hours post-CPB, IL-6, IL-8 and reduced (GSH) to oxidized (GSSG) glutathione ratio (pre-ultrafiltration on CPB, end-CPB and 24 hours), PICU length of stay (LOS) and ventilator days. Data were analysed using descriptive statistics and a random effects regression model. The ultra-early group had higher Risk Adjusted Congenital Heart Surgery Score, lower age and longer CPB times than the other groups. No significant differences in AaDO2, IL-8, PICU LOS and ventilator days were observed between groups. Compared to the ultra-early group, the overall rise in IL-6 in the early and standard groups was lower, -27.8 pg/ml (95% CI -52.7,-2.9) and -35.3 pg/ml (95% CI -64.3,-6.34), respectively. GSH:GSSG was significantly lower in the standard group (-35.9; 95% CI -63.31,-8.5) at 24 hours post-CPB. Ultra-early administration of methylprednisolone does not improve AaDO2 post-CPB, nor diminish cytokine release. Lower GSH:GSSG in the standard group suggests less oxidative stress. However despite statistical adjustments conclusions are limited by the unbalanced randomisation of the groups.

Which pressure to believe? A comparison of direct arterial with indirect blood pressure measurement techniques in the pediatric intensive care unit.

OBJECTIVE: To determine the accuracy of arterial blood pressure monitoring using 1) direct arterial; 2) automated oscillometric; and 3) sphygmomanometer/Doppler ultrasound measurements in pediatric intensive care patients comparing methods 1) and 2) with 3), the gold standard used to define normal blood pressure. DESIGN: Prospective observational study. SETTING: Pediatric intensive care unit of a tertiary care pediatric teaching hospital. PATIENTS: Forty children (birth to 17 yrs) admitted to the pediatric intensive care unit with various clinical conditions requiring a radial arterial catheter for continuous arterial blood pressure monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Each subject had measurements taken every 6 hrs over a 24-hr period. Each set of measurements were: direct arterial blood pressure, indirect blood pressure using the Phillips automated oscillometric device, and indirect blood pressure using the sphygmomanometer and Doppler ultrasound. Analysis used the Bland-Altman plot followed by paired t testing to compare the three different methods. One hundred sixty triads of measurements were analyzed. There were no significant differences between the methods of blood pressure measurement when groups were analyzed based on age. When analyzed by age-specific normo-, hypo-, and hypertensive criteria, arterial blood pressure measurements agree closely with Doppler ultrasound readings, whereas systolic arterial blood pressure measurements were lower than indirect blood pressure using the Phillips automated oscillometric device readings in the hypotensive group (p < .001). In the hypertensive group, the systolic arterial blood pressure values were higher and indirect blood pressure using the Phillips automated oscillometric device readings lower (p < .001) than Doppler ultrasound (p = .03). There was no clinically significant difference between methods in the normotensive group. Diastolic blood pressure measurements were higher by arterial blood pressure in normotensive and hypertensive groups but no different in the hypotensive group. CONCLUSION: Outside the normotensive range, the automated readings were higher during hypotension and lower during hypertension compared with the arterial and Doppler ultrasound methods. The arterial blood pressure was closer to the gold standard Doppler ultrasound blood pressure in all three blood pressure groups.

Extensive lower limb injuries in a child complicated by complex pain management and profound anemia.

We describe a case of severe pain associated with extensive lower limb injures in a 5-year old, complicated by profound anemia in a Jehovah's Witness family. The study was carried out in a pediatric intensive care unit of a tertiary level university hospital. The patient was 5-year-old girl, with multiple open fractures and extensive soft tissue loss on her left foot and ankle due to a lawnmower injury leading to severe pain and profound anemia with management of the latter complicated by family beliefs. The interventions given were multi-modal pain management and treatment of severe anemia with avoidance of transfusion. A drop in hemoglobin from 11.6 g.dl(-1) at admission to a nadir of 4.3 g.dl(-1) on day 7 was observed. Effective pain control was achieved with nurse- and then patient-controlled analgesia plus adjuncts. Effective pain management and control of anxiety can be achieved by a multi-modal approach in young children. Profound anemia was treated without transfusion and without compromise of tissue healing.

Minimal exhaled nitric oxide production in the lower respiratory tract of healthy children aged 2 to 7 years.

BACKGROUND: Exhaled nitric oxide (eNO) is elevated in inflammatory airway conditions, e.g. asthma. We measured eNO levels in normal preschool children for whom there is little data available and in whom the prevalence of asthma is high. SUBJECTS AND METHODS: Fifty children, 2-7 years old, undergoing elective surgery, excluding airway procedures, were recruited. Children with known respiratory disease or acute viral infections were excluded. Gas for eNO measurement was collected in a non-diffusion bag via 1) the mask after inhalation induction of anesthesia, 2) endotreacheal tube (ETT) or laryngeal mask airway (LMA), and 3) during emergence. Measurement was off-line by chemiluminescent analyzer. RESULTS: Mean eNO level by mask was 10.23 ppb (mean value+/-SD of 8.8-11.1 ppb) after induction and 8.35 ppb (mean value+/-SD of 5.9-10.8 ppb) on emergence. Mean eNO for the intubated group (n=25) was 0.75 ppb (mean value+/-SD of 0.4-1 ppb) (P<0.0001 vs mask); mean eNO for the LMA group (n=25) was 2.6 ppb (mean value+/-SD of 2-3.2 ppb), which differed from the mask (P<0.0001), and from ETT values (P<0.0001). CONCLUSIONS: Most eNO is produced by the upper airway in healthy pre-school children. The lower airway constitutive eNO production is very low. The LMA does not completely isolate the upper airway and current mask collection techniques allow significant contamination of samples by sino-nasal eNO production in young children.

A case of propofol toxicity: further evidence for a causal mechanism.

A 5-month-old boy required sedation after a cleft lip repair. He was sedated with propofol and intermittent fentanyl, requiring escalating doses over the subsequent 48 h. On the second post-operative day he developed a metabolic acidosis followed by multiple cardiac dysrhythmias, hepatic and renal failure. Propofol was stopped. His multisystem organ failure gradually resolved after initiation of charcoal haemoperfusion. Further investigation demonstrated an abnormality in acylcarnitine metabolism, similar to that found in one previous case report.