David M. Polaner

Inhaled nitric oxide in persistent pulmonary hypertension of the newborn

Nitric oxide (NO) has vasodilatory effects on the pulmonary vasculature in adults and animals. We examined the effects on systemic oxygenation and blood pressure of inhaling up to 80 parts per million by volume of NO at FiO2 0.9 for up to 30 minutes by 6 infants with persistent pulmonary hypertension of the newborn (PPHN). In all infants this treatment rapidly and significantly increased preductal oxygen saturation (SpO2); in 5 infants postductal SpO2 and oxygen tensions also increased. Inhalation of NO did not cause systemic hypotension or raise methaemoglobin. These data suggest that low levels of inhaled NO have an important role in the reversal of hypoxaemia due to PPHN.

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.

Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.

We determined whether inhaling low levels of nitric oxide (NO) gas could selectively reverse hypoxic pulmonary vasoconstriction in the near-term newborn lamb and whether vasodilation would be attenuated by respiratory acidosis. To examine the mechanism of air and NO-induced pulmonary vasodilation soon after birth, we measured plasma and lung cGMP levels in the newly ventilated fetal lamb. Breathing at FIO2 0.10 nearly doubled the pulmonary vascular resistance index in newborn lambs and decreased pulmonary blood flow primarily by reducing left-to-right blood flow through the ductus arteriosus. Inhaling 20 ppm NO at FIO2 0.10 completely reversed hypoxic pulmonary vasoconstriction within minutes. Maximum pulmonary vasodilation occurred during inhalation of > or = 80 ppm NO. Breathing 8% CO2 at FIO2 0.10 elevated the pulmonary vascular resistance index to a level similar to breathing at FIO2 0.10 without added CO2. Respiratory acidosis did not attenuate pulmonary vasodilation by inhaled NO. In none of our studies did inhaling NO produce systemic hypotension or elevate methemoglobin levels. Four minutes after initiating ventilation with air in the fetal lamb lung, cGMP concentration nearly doubled without changing preductal plasma cGMP concentration. Ventilation with 80 ppm NO at FIO2 0.21 increased both lung and preductal plasma cGMP concentration threefold. Our data suggest that inhaled NO gas is a rapid and potent selective vasodilator of the newborn pulmonary circulation with an elevated vascular tone due to hypoxia and respiratory acidosis that acts by increasing lung cGMP concentration.

Pediatric Regional Anesthesia Network (PRAN): a multi-institutional study of the use and incidence of complications of pediatric regional anesthesia.

BACKGROUND: Regional anesthesia is increasingly used in pediatric patients to provide postoperative analgesia and to supplement intraoperative anesthesia. The Pediatric Regional Anesthesia Network was formed to obtain highly audited data on practice patterns and complications and to facilitate collaborative research in regional anesthetic techniques in infants and children. METHODS: We constructed a centralized database to collect detailed prospective data on all regional anesthetics performed by anesthesiologists at the participating centers. Data were uploaded via a secure Internet connection to a central server. Data were rigorously audited for accuracy and errors were corrected. All anesthetic records were scrutinized to ensure that every block that was performed was captured in the database. Intraoperative and postoperative complications were tracked until their resolution. Blocks were categorized by type and as single-injection or catheter (continuous) blocks. RESULTS: A total of 14,917 regional blocks, performed on 13,725 patients, were accrued from April 1, 2007 through March 31, 2010. There were no deaths or complications with sequelae lasting >3 months (95% CI 0–2:10,000). Single-injection blocks had fewer adverse events than continuous blocks, although the most frequent events (33% of all events) in the latter group were catheter-related problems. Ninety-five percent of blocks were placed while patients were under general anesthesia. Single-injection caudal blocks were the most frequently performed (40%), but peripheral nerve blocks were also frequently used (35%), possibly driven by the widespread use of ultrasound (83% of upper extremity and 69% of lower extremity blocks). CONCLUSIONS: Regional anesthesia in children as commonly performed in the United States has a very low rate of complications, comparable to that seen in the large multicenter European studies. Ultrasound may be increasing the use of peripheral nerve blocks. Multicenter collaborative networks such as the Pediatric Regional Anesthesia Network can facilitate the collection of detailed prospective data for research and quality improvement.

Diaphragmatic shortening after thoracic surgery in humans. Effects of mechanical ventilation and thoracic epidural anesthesia.

BackgroundDiaphragmatic function is believed to be inhibited after thoracic surgery and may be improved by thoracic epidural anesthesia. MethodsDiaphragmatic function after a thoracotomy was monitored by implanting one pair of sonomicrometry crystals and two electromyogram (EMG) electrodes on the costal diaphragm of six patients undergoing an elective pulmonary resection. Crystals and EMG electrodes remained in place for 12–24 h. ResultsDuring mechanical ventilation, costal diaphragmatic length (as a percent of rest length; %LFRC)decreased passively as tidal volume (VT) Increased (%LFRC = 2.81 + 1.12 × 10-2 VT (ml), r = 0.99). During spontaneous ventilation, the costal shortening (2.1 ± 2.3 %LFRC) was less than during mechanical ventilation (7.9 ± 3.0 %LFRC, P < 0.05) at the same VT. Comparing spontaneous ventilation before and 30 min after thoracic epidural anesthesia, there were Increases of VT (390 ± 78 to 555 ± 75 ml), vital capacity (1.37 ± 0.16 to 1.68 ± 0.21 1), and esophageal (-8.5 ± 1.5 to −10.6 ± 1.7 cmH2O), gastric (-0.7 ± 0.8 to ±0.8 ± 0.8 cmH2O), and transdiaphragmatic (7.7 ± 1.5 to 11.5 ± 1.9 cmH2O) pressures, but diaphragmatic EMG and shortening fraction remained constant. In three of six patients, epidural anesthesia produced paradoxical segment lengthening upon inspiration. ConclusionsThoracotomy and pulmonary resection produce a marked reduction of active diaphragmatic shortening, which is not reversed by thoracic epidural anesthesia despite improvement of other indices of respiratory function.

Massive subcutaneous emphysema and sudden airway compromise after postoperative vomiting.

Postoperative nausea and vomiting is common, but rarely produces life-threatening symptoms. We describe a case of massive mediastinal and subcutaneous emphysema, which developed immediately after postoperative vomiting in the postanesthesia recovery unit and caused imminent airway compromise, requiring emergent fiberoptic endotracheal intubation.

Does cerebral oxygen delivery limit incremental exercise performance

Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxic conditions, where oxygen transport is impaired. We hypothesized that raising end-tidal Pco(2) (Pet(CO(2))) during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W(peak)). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which Pet(CO(2)) was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure = 630 mmHg, 1,650 m) and hypoxia (barometric pressure = 425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower Pet(CO(2)) (40 Torr) from ∼75 to 100% W(peak) to reduce potential influences of respiratory acidosis and muscle fatigue imposed by clamping Pet(CO(2)) at 50 Torr. Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping Pet(CO(2)) at 50 Torr in both normoxia (n = 9) and hypoxia (n = 11) elevated CBF velocity (∼40%) and improved cerebral hemoglobin oxygenation (∼15%), but decreased W(peak) (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n = 6) also improved cerebral oxygenation (∼15%), but again limited W(peak) (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO(2)-mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis.

Airway management complications in children with difficult tracheal intubation from the Pediatric Difficult Intubation (PeDI) registry: a prospective cohort analysis

BACKGROUND Despite the established vulnerability of children during airway management, remarkably little is known about complications in children with difficult tracheal intubation. To address this concern, we developed a multicentre registry (Pediatric Difficult Intubation [PeDI]) to characterise risk factors for difficult tracheal intubation, establish the success rates of various tracheal intubation techniques, catalogue the complications of children with difficult tracheal intubation, and establish the effect of more than two tracheal intubation attempts on complications. METHODS The PeDI registry consists of prospectively collected tracheal intubation data from 13 childrens hospitals in the USA. We established standard data collection methods before implementing the secure web-based registry. After establishing standard definitions, we collected and analysed patient, clinician, and practice data and tracheal intubation outcomes. We categorised complications as severe or non-severe. FINDINGS Between August, 2012, and January, 2015, 1018 difficult paediatric tracheal intubation encounters were done. The most frequently attempted first tracheal intubation techniques were direct laryngoscopy (n=461, 46%), fibre-optic bronchoscopy (n=284 [28%]), and indirect video laryngoscopy (n=183 [18%]) with first attempt success rates of 16 (3%) of 461 with direct laryngoscopy, 153 (54%) of 284 with fibre-optic bronchoscopy, and 101 (55%) of 183 with indirect video laryngoscopy. Tracheal intubation failed in 19 (2%) of cases. 204 (20%) children had at least one complication; 30 (3%) of these were severe and 192 (19%) were non-severe. The most common severe complication was cardiac arrest, which occurred in 15 (2%) patients. The occurrence of complications was associated with more than two tracheal intubation attempts, a weight of less than 10 kg, short thyromental distance, and three direct laryngoscopy attempts before an indirect technique. Temporary hypoxaemia was the most frequent non-severe complication. INTERPRETATION More than two direct laryngoscopy attempts in children with difficult tracheal intubation are associated with a high failure rate and an increased incidence of severe complications. These results suggest that limiting the number of direct laryngoscopy attempts and quickly transitioning to an indirect technique when direct laryngoscopy fails would enhance patient safety. FUNDING None.

Asleep versus awake: does it matter?: Pediatric regional block complications by patient state: a report from the Pediatric Regional Anesthesia Network.

Background and Objectives The impact of the patient state at time of placement of regional blocks on the risk of complications is unknown. Current opinion is based almost entirely on case reports, despite considerable interest in the question. Analyzing more than 50,000 pediatric regional anesthesia blocks from an observational prospective database, we determined the rate of adverse events in relation to the patient’s state at the time of block placement. Primary outcomes considered were postoperative neurologic symptoms (PONSs) and local anesthetic systemic toxicity (LAST). Secondary outcome was extended hospital stay due to a block complication. Methods The Pediatric Regional Anesthesia Network is a multi-institutional research consortium that was created with an emphasis on rigorous, prospective, and complete data collection including a data validation and audit process. For the purpose of the analysis, blocks were divided in major groups by single injection versus continuous and by block location. Rates were determined in aggregate for these groups and classified further based on the patient’s state (general anesthesia [GA] without neuromuscular blockade [NMB], GA with NMB, sedated, and awake) at the time of block placement. Results Postoperative neurological symptoms occurred at a rate of 0.93/1000 (confidence interval [CI], 0.7–1.2) under GA and 6.82/1000 (CI, 4.2–10.5) in sedated and awake patients. The only occurrence of PONSs lasting longer than 6 months (PONSs-L) was a small sensory deficit in a sedated patient (0.019/1000 [CI, 0–0.1] for all, 0.48/1000 [CI, 0.1–2.7] for sedated patients). There were no cases of paralysis. There were 5 cases of LAST or 0.09/1000 (CI, 0.03–0.21). The incidence of LAST in patients under GA (both with and without NMB) was 0.08/1000 (CI, 0.02–0.2) and 0.34/1000 (CI, 0–1.9) in awake/sedated patients. Extended hospital stays were described 18 times (0.33/1000 [CI, 0.2–0.53]). The rate for patients under GA without NMB was 0.29/1000 (CI, 0.13–0.48); GA with NMB, 0.29/1000 (CI, 0.06–0.84); sedated, 1.47/1000 (CI, 0.3–4.3); and awake, 1.15/1000 (CI, 0.02–6.4). Conclusions The placement of regional anesthetic blocks in pediatric patients under GA is as safe as placement in sedated and awake children. Our results provide the first prospective evidence for the pediatric anesthesia community that the practice of placing blocks in anesthetized patients should be considered safe and should remain the prevailing standard of care. Prohibitive recommendations based on anecdote and case reports cannot be supported.

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.