Neurocardiovascular coupling in congenital diaphragmatic hernia patients undergoing different types of surgical treatment.

BACKGROUND: The effect of peri-operative management on the neonatal brain is largely unknown. Triggers for perioperative brain injury might be revealed by studying changes in neonatal physiology peri-operatively. OBJECTIVE: To study neonatal pathophysiology and cerebral blood flow regulation peri-operatively using the neuro-cardiovascular graph. DESIGN: Observational, prospective cohort study on perioperative neuromonitoring. Neonates were included between July 2018 and April 2020. SETTING: Multicentre study in two high-volume tertiary university hospitals. PATIENTS: Neonates with congenital diaphragmatic hernia were eligible if they received surgical treatment within the first 28 days of life. Exclusion criteria were major cardiac or chromosomal anomalies, or syndromes associated with altered cerebral perfusion or major neurodevelopmental impairment. The neonates were stratified into different groups by type of peri-operative management. INTERVENTION: Each patient was monitored using near-infrared spectroscopy and EEG in addition to the routine peri-operative monitoring. Neurocardiovascular graphs were computed off-line. MAIN OUTCOME MEASURES: The primary endpoint was the difference in neurocardiovascular graph connectivity in the groups over time. RESULTS: Thirty-six patients were included. The intraoperative graph connectivity decreased in all patients operated upon in the operation room (OR) with sevoflurane-based anaesthesia ( P  < 0.001) but remained stable in all patients operated upon in the neonatal intensive care unit (NICU) with midazolam-based anaesthesia. Thoracoscopic surgery in the OR was associated with the largest median connectivity reduction (0.33 to 0.12, P  < 0.001) and a loss of baroreflex and neurovascular coupling. During open surgery in the OR, all regulation mechanisms remained intact. Open surgery in the NICU was associated with the highest neurovascular coupling values. CONCLUSION: Neurocardiovascular graphs provided more insight into the effect of the peri-operative management on the pathophysiology of neonates undergoing surgery. The neonate's clinical condition as well as the surgical and the anaesthesiological approach affected the neonatal physiology and CBF regulation mechanisms at different levels. TRIAL REGISTRATION: NL6972, URL: https://www.trialre-gister.nl/trial/6972 .

Towards integrative neuromonitoring of the surgical newborn: A systematic review.

BACKGROUND: The altered neurodevelopment of children operated on during the neonatal period might be due to peri-operative changes in the homeostasis of brain perfusion. Monitoring of vital signs is a standard of care, but it does not usually include monitoring of the brain. OBJECTIVES: To evaluate methods of monitoring the brain that might be of value. We also wanted to clarify if there are specific risk factors that result in peri-operative changes and how this might be evaluated. DESIGN: Systematic review. DATA SOURCES: A structured literature search was performed in MEDLINE in Ovid, Embase, Cochrane CENTRAL, Web of Science and Google Scholar. ELIGIBILITY CRITERIA: Studies in neonates who received peri-operative neuromonitoring were eligible for inclusion; studies on neurosurgical procedures or cardiac surgery with cardiopulmonary bypass and/or deep hypothermia cardiac arrest were excluded. RESULTS: Nineteen of the 24 included studies, totalling 374 infants, reported the use of near-infrared spectroscopy. Baseline values of cerebral oxygenation greatly varied (mean 53 to 91%) and consequently, no coherent results were found. Two studies found a correlation between cerebral oxygenation and mean arterial blood pressure. Five studies, with in total 388 infants, used (amplitude-integrated) electro-encephalography to study peri-operative brain activity. Overall, the brain activity decreased during anaesthesia and epileptic activity was more frequent in the peri-operative phase. The association between intra-operative cerebral saturation or activity and neuro-imaging abnormalities and/or neurodevelopmental outcome was investigated in six studies, but no association was found. CONCLUSION: Neuromonitoring with the techniques currently used will neither help our understanding of the altered neonatal pathophysiology, nor enable early detection of deviation from the norm. The modalities lack specificity and are not related to clinical (long-term) outcome or prognosis. Accordingly, we were unable to draw up a monitoring guideline.

Perioperative management of esophageal atresia/tracheo-esophageal fistula: An analysis of data of 101 consecutive patients.

BACKGROUND: The perioperative management of esophageal atresia/tracheo-esophageal fistula by open or thoracoscopic approach can be complicated by metabolic derangements. Little is known, however, about the severity of derangements of vital and metabolic parameters in the perioperative period. AIM: The aim of this study is to describe the perioperative courses of vital and metabolic parameters in 101 consecutive neonates undergoing surgical repair of esophageal atresia type C. METHOD: In a retrospective cohort study, we extracted all data from the electronic anesthetic and medical charts of patients who underwent esophageal atresia type C repair within 30 days of life (2007-2017). We distinguished three types of surgery: primary open, primary thoracoscopic, and primary thoracoscopic surgery converted to open surgery. Descriptive analysis was applied. RESULTS: The charts of 117 patients were reviewed: data of 101 were included. The perioperative anesthetic management was not standardized; various methods and medications were used for anesthesia induction and maintenance. Intraoperative blood gas analysis data of 72 patients were available and showed derangements regardless of type of surgery. The median pH-value decreased to 7.21 [IQR 7.14-7.30] and a pH-value below 7.20 was found in 29 patients; in four cases below 7.0, with the lowest value 6.83. The median PaCO2 reached an upper level of 7.5kPa [IQR 5.8-9.2]; in 13 cases above 10.0kPa, with a peak value of 25.8kPa. These high PaCO2 levels fluctuated with lowest measured PaCO2 of median 5.6 [IQR 4.5-6.6], with the lowest value 2.8kPa. The median PaO2 level reached an upper level of 16.9kPa [IQR 11.8-25.7], in 22 cases above 20.0kPa, with a peak value of 50.0kPa. These high levels fluctuated with lowest measured PaO2 levels of median 8.3kPa [IQR 6.73-10.5]; the lowest PaO2 value was 4.7 kPa. CONCLUSION: Open and thoracoscopic correction of esophageal atresia were associated with periods of severe metabolic derangements. These events need to be taken into account for the evaluation of esophageal atresia (surgical) care and in evaluations of short- and long-term outcomes.

Thoracoscopic versus open repair of CDH in cardiovascular stable neonates.

BACKGROUND: Thoracoscopic surgery is an increasingly popular surgical technique to repair congenital diaphragmatic hernia (CDH). However, acidosis during surgery and the higher recurrence rate are considerable risk factors. The aim of this retrospective study is to compare the outcome of open versus thoracoscopic repair of the diaphragm in neonates with CDH with the same degree of cardiovascular and pulmonary illness who meet the criteria for thoracoscopic repair. METHODS: Retrospective analysis of all patients of two large national reference centers for CDH born in the years 2008 through 2012, and meeting the criteria for surgical repair on cardiopulmonary and physiological criteria according to the CDH EURO consortium consensus and meeting the criteria for thoracoscopic repair according to the review by Vijfhuize et al. The surgical technical aspects were comparable in both centers. RESULTS: 108 patients were included, of whom 75 underwent thoracoscopic repair and 34 underwent open repair. The gestational age and lung-to-head ratio were significantly lower and stay on the ICU significantly longer in the open-repair group. The operation time was longer (178 vs. 150 min, p = .012) and the recurrence rate higher (18.9 vs. 5.9 %, p = .036) in the thoracoscopic-repair group. The arterial pH, pO2, pCO2 and base excess before and after thoracoscopic repair were all significantly different. CONCLUSION: After critical selection for thoracoscopic repair of left-sided CDH based on the patient's preoperative condition, the outcomes of open repair were almost identical to those of thoracoscopic repair. A notable exception is the recurrence rate, which was significantly higher in the thoracoscopic-repair group. For the time being, thoracoscopic primary closure seems a safe and effective procedure, but efficacy of thoracoscopic patch repair has not been established.

Automatic Max-Likelihood Envelope Detection Algorithm for Quantitative High-Frame-Rate Ultrasound for Neonatal Brain Monitoring.

OBJECTIVE: Post-operative brain injury in neonates may result from disturbed cerebral perfusion, but accurate peri-operative monitoring is lacking. High-frame-rate (HFR) cerebral ultrasound could visualize and quantify flow in all detectable vessels using spectral Doppler; however, automated quantification in small vessels is challenging because of low signal amplitude. We have developed an automatic envelope detection algorithm for HFR pulsed wave spectral Doppler signals, enabling neonatal brain quantitative parameter maps during and after surgery. METHODS: HFR ultrasound data from high-risk neonatal surgeries were recorded with a custom HFR mode (frame rate = 1000 Hz) on a Zonare ZS3 system. A pulsed wave Doppler spectrogram was calculated for each pixel containing blood flow in the image, and spectral peak velocity was tracked using a max-likelihood estimation algorithm of signal and noise regions in the spectrogram, where the most likely cross-over point marks the blood flow velocity. The resulting peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistivity index (RI) were compared with other detection schemes, manual tracking and RIs from regular pulsed wave Doppler measurements in 10 neonates. RESULTS: Envelope detection was successful in both high- and low-quality arterial and venous flow spectrograms. Our technique had the lowest root mean square error for EDV, PSV and RI (0.46 cm/s, 0.53 cm/s and 0.15, respectively) when compared with manual tracking. There was good agreement between the clinical pulsed wave Doppler RI and HFR measurement with a mean difference of 0.07. CONCLUSION: The max-likelihood algorithm is a promising approach to accurate, automated cerebral blood flow monitoring with HFR imaging in neonates.

Feasibility of Doppler Ultrasound for Cortical Cerebral Blood Flow Velocity Monitoring During Major Non-cardiac Surgery of Newborns.

Background and Aim: Newborns needing major surgical intervention are at risk of brain injury and impaired neurodevelopment later in life. Disturbance of cerebral perfusion might be an underlying factor. This study investigates the feasibility of serial transfontanellar ultrasound measurements of the pial arteries during neonatal surgery, and whether perioperative changes in cerebral perfusion can be observed and related to changes in the perioperative management. Methods: In this prospective, observational feasibility study, neonates with congenital diaphragmatic hernia and esophageal atresia scheduled for surgical treatment within the first 28 days of life were eligible for inclusion. We performed transfontanellar directional power Doppler and pulsed wave Doppler ultrasound during major high-risk non-cardiac neonatal surgery. Pial arteries were of interest for the measurements. Extracted Doppler ultrasound parameters were: peak systolic velocity, end diastolic velocity, the resistivity index and pulsatility index. Results: In 10 out of 14 patients it was possible to perform perioperative measurements; the others failed for logistic and technical reasons. In 6 out of 10 patients, it was feasible to perform serial intraoperative transfontanellar ultrasound measurements with directional power Doppler and pulsed wave Doppler of the same pial artery during neonatal surgery. Median peak systolic velocity was ranging between 5.7 and 7.0 cm s-1 and end diastolic velocity between 1.9 and 3.2 cm s-1. In patients with a vasoactive-inotropic score below 12 the trend of peak systolic velocity and end diastolic velocity corresponded with the mean arterial blood pressure trend. Conclusion: Perioperative transfontanellar ultrasound Doppler measurements of the pial arteries are feasible and provide new longitudinal data about perioperative cortical cerebral blood flow velocity. Trial Registration: https://www.trialregister.nl/trial/6972, identifier: NL6972.

Cerebral Oxygenation and Activity During Surgical Repair of Neonates With Congenital Diaphragmatic Hernia: A Center Comparison Analysis.

Background and aim: Neonatal brain monitoring is increasingly used due to reports of brain injury perioperatively. Little is known about the effect of sedatives (midazolam) and anesthetics (sevoflurane) on cerebral oxygenation (rScO2) and cerebral activity. This study aims to determine these effects in the perioperative period. Methods: This is an observational, prospective study in two tertiary pediatric surgical centers. All neonates with a congenital diaphragmatic hernia received perioperative cerebral oxygenation and activity measurements. Patients were stratified based on intraoperatively administrated medication: the sevoflurane group (continuous sevoflurane, bolus fentanyl, bolus rocuronium) and the midazolam group (continuous midazolam, continuous fentanyl, and continuous vecuronium). Results: Intraoperatively, rScO2 was higher in the sevoflurane compared to the midazolam group (84%, IQR 77-95 vs. 65%, IQR 59-76, p = < 0.001), fractional tissue oxygen extraction was lower (14%, IQR 5-21 vs. 31%, IQR 29-40, p = < 0.001), the duration of hypoxia was shorter (2%, IQR 0.4-9.6 vs. 38.6%, IQR 4.9-70, p = 0.023), and cerebral activity decreased more: slow delta: 2.16 vs. 4.35 µV 2 (p = 0.0049), fast delta: 0.73 vs. 1.37 µV 2 (p = < 0.001). In the first 30 min of the surgical procedure, a 3-fold increase in fast delta (10.48-31.22 µV 2) and a 5-fold increase in gamma (1.42-7.58 µV 2) were observed in the midazolam group. Conclusion: Sevoflurane-based anesthesia resulted in increased cerebral oxygenation and decreased cerebral activity, suggesting adequate anesthesia. Midazolam-based anesthesia in neonates with a more severe CDH led to alarmingly low rScO2 values, below hypoxia threshold, and increased values of EEG power during the first 30 min of surgery. This might indicate conscious experience of pain. Integrating population-pharmacokinetic models and multimodal neuromonitoring are needed for personalized pharmacotherapy in these vulnerable patients. Trial Registration: https://www.trialregister.nl/trial/6972, identifier: NL6972.

Mitochondrial Oxygen Monitoring During Surgical Repair of Congenital Diaphragmatic Hernia or Esophageal Atresia: A Feasibility Study.

Current monitoring techniques in neonates lack sensitivity for hypoxia at cellular level. The recent introduction of the non-invasive Cellular Oxygen METabolism (COMET) monitor enables measuring in vivo mitochondrial oxygen tension (mitoPO2), based on oxygen-dependent quenching of delayed fluorescence of 5-aminolevulinic acid (ALA)-enhanced protoporphyrin IX. The aim is to determine the feasibility and safety of non-invasive mitoPO2 monitoring in surgical newborns. MitoPO2 measurements were conducted in a tertiary pediatric center during surgical repair of congenital diaphragmatic hernia or esophageal atresia. Intraoperative mitoPO2 monitoring was performed with a COMET monitor in 11 congenital diaphragmatic hernia and four esophageal atresia neonates with the median age at surgery being 2 days (IQR 1.25-5.75). Measurements were done at the skin and oxygen-dependent delayed fluorescence was measurable after at least 4 h application of an ALA plaster. Pathophysiological disturbances led to perturbations in mitoPO2 and were not observed with standard monitoring modalities. The technique did not cause damage to the skin, and seemed safe in this respect in all patients, and in 12 cases intraoperative monitoring was successfully completed. Some external and potentially preventable factors-the measurement site being exposed to the disinfectant chlorohexidine, purple skin marker, or infrared light-seemed responsible for the inability to detect an adequate delayed fluorescence signal. In conclusion, this is the first study showing it is possible to measure mitoPO2 in neonates and that the cutaneous administration of ALA to neonates in the described situation can be safely applied. Preliminary data suggests that mitoPO2 in neonates responds to perturbations in physiological status.

Effects of Neonatal Thoracoscopic Surgery on Tissue Oxygenation: A Pilot Study on (Neuro-) Monitoring and Outcomes.

INTRODUCTION: Multiple reports have questioned the feasibility of neonatal thoracoscopic repair of congenital diaphragmatic hernia (CDH) and esophageal atresia (EA). The aim of this study is to examine the effects of CO2 pneumothorax on cerebral and renal rSO2 and to assess the potential predictive value of these data on neurodevelopmental outcome after neonatal thoracoscopic surgery for CDH or EA. MATERIALS AND METHODS: A prospective observational pilot study. Cerebral and renal regional tissue oxyhemoglobine saturation (rSO2) rSO2 were assessed using near-infrared spectroscopy (NIRS) during thoracoscopic surgery in neonates with CDH and with EA, in addition to routine anesthesia monitoring. Cerebral and renal rSO2, linked to repeated arterial blood gas analyses, heart rate, blood pressure, and to structured longitudinal neurodevelopmental follow-up. RESULTS: Baseline estimated marginal means of cerebral rSO2 values (CDH: 82%, EA: 91%) did not change significantly during pneumothorax (CDH: 81%, EA 79% [n.s. versus baseline]) despite severe acidosis (lowest pH, CDH: 6.99, EA: 7.1). Neurodevelopmental outcomes at 24 months were normal in all 7 patients who were available for evaluation. CONCLUSION: Neonatal thoracoscopic repair of CDH and EA using CO2-pneumothorax leads to severe acidosis. Cerebral rSO2 remained within clinical acceptable limits during intraoperative periods of acidosis. Neurodevelopmental outcome was favorable within the first 24 months. The potential of NIRS to further improve perioperative care and long-term outcome in this specific patient group deserves further investigation.