Oxygen fluctuations in the brain and periphery induced by intravenous fentanyl: effects of dose and drug experience.

Fentanyl is the leading contributor to drug overdose deaths in the US. Its potency, rapid onset of action, and lack of effective reversal treatment make the drug more lethal than other opioids. Although it is understood that fentanyl is dangerous at higher doses, literature surrounding fentanyl's physiological effects remains contradictory at lower doses. To explore this discrepancy, we designed a study incorporating electrochemical assessment of oxygen in the brain (nucleus accumbens; NAc) and subcutaneous (SC) space, multi-site thermorecording (brain, skin, muscle), and locomotor activity at varying doses of fentanyl (1.0, 3.0, 10, 30, 90 µg/kg) in rats. In the NAc, lower doses of fentanyl (3.0, 10 µg/kg) led to an increase in oxygen levels while higher doses (30, 90 µg/kg) led to a biphasic pattern, with initial dose-dependent decrease followed by increase. In the SC space, oxygen decreases started to appear at relatively lower doses (>3 µg/kg), had shorter onset latencies, and were stronger and prolonged. In the temperature experiment, lower doses of fentanyl (1.0, 3.0, 10 µg/kg) led to an increase in brain, skin, and muscle temperatures, while higher doses (30 and 90 µg/kg) resulted in a dose-dependent biphasic temperature change, with an increase followed by a prolonged decrease. We also compared oxygen and temperature responses induced by fentanyl over six consecutive days and found no evidence of tolerance in both parameters. In conclusion, we report that fentanyl's effects are highly dose-dependent, drawing attention to the importance of better characterization to adequately respond in emergent cases of fentanyl misuse.

Neuroinflammation and the immune system in hypoxic ischaemic brain injury pathophysiology after cardiac arrest.

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules.

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal azithromycin administration in near-term lambs following global ischemic injury to support earlier treatment approaches. METHODS: Ewes and their lambs of both sexes (n=34, 141-143 days) were randomly assigned to receive azithromycin or placebo before delivery as well as postnatally. Lambs were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Outcomes were assessed over a 6-day period. RESULTS: While maternal azithromycin exhibited relatively low placental transfer, azithromycin-treated lambs recovered spontaneous circulation faster following the initiation of cardiopulmonary resuscitation and were extubated sooner. Additionally, peri- and postnatal azithromycin administration was well tolerated, demonstrating a 77-hour plasma elimination half-life, as well as significant accumulation in the brain and other tissues. Azithromycin administration resulted in a systemic immunomodulatory effect, demonstrated by reductions in proinflammatory IL-6 (interleukin-6) levels. Treated lambs exhibited a trend toward improved neurodevelopmental outcomes while histological analysis revealed that azithromycin supported white matter preservation and attenuated inflammation in the cingulate and parasagittal cortex. CONCLUSIONS: Perinatal azithromycin administration enhances neonatal resuscitation, attenuates neuroinflammation, and supports limited improvement of select histological outcomes in an ovine model of hypoxic-ischemic brain injury/encephalopathy.

"THE MANTLE" bundle for minimizing cerebral hypoxia in severe traumatic brain injury.

To ensure neuronal survival after severe traumatic brain injury, oxygen supply is essential. Cerebral tissue oxygenation represents the balance between oxygen supply and consumption, largely reflecting the adequacy of cerebral perfusion. Multiple physiological parameters determine the oxygen delivered to the brain, including blood pressure, hemoglobin level, systemic oxygenation, microcirculation and many factors are involved in the delivery of oxygen to its final recipient, through the respiratory chain. Brain tissue hypoxia occurs when the supply of oxygen is not adequate or when for some reasons it cannot be used at the cellular level. The causes of hypoxia are variable and can be analyzed pathophysiologically following "the oxygen route." The current trend is precision medicine, individualized and therapeutically directed to the pathophysiology of specific brain damage; however, this requires the availability of multimodal monitoring. For this purpose, we developed the acronym "THE MANTLE," a bundle of therapeutical interventions, which covers and protects the brain, optimizing the components of the oxygen transport system from ambient air to the mitochondria.

Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest-a substudy of the XeHypotheca trial.

PURPOSE: We compared the predictive accuracy of early-phase brain diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and serum neuron-specific enolase (NSE) against the motor score and epileptic seizures (ES) for poor neurological outcome after out-of-hospital cardiac arrest (OHCA). METHODS: The predictive accuracy of DTI, 1H-MRS, and NSE along with motor score at 72 h and ES for the poor neurological outcome (modified Rankin Scale, mRS, 3 - 6) in 92 comatose OHCA patients at 6 months was assessed by area under the receiver operating characteristic curve (AUROC). Combined models of the variables were included as exploratory. RESULTS: The predictive accuracy of fractional anisotropy (FA) of DTI (AUROC 0.73, 95% CI 0.62-0.84), total N-acetyl aspartate/total creatine (tNAA/tCr) of 1H-MRS (0.78 (0.68 - 0.88)), or NSE at 72 h (0.85 (0.76 - 0.93)) was not significantly better than motor score at 72 h (0.88 (95% CI 0.80-0.96)). The addition of FA and tNAA/tCr to a combination of NSE, motor score, and ES provided a small but statistically significant improvement in predictive accuracy (AUROC 0.92 (0.85-0.98) vs 0.98 (0.96-1.00), p = 0.037). CONCLUSION: None of the variables (FA, tNAA/tCr, ES, NSE at 72 h, and motor score at 72 h) differed significantly in predicting poor outcomes in this patient group. Early-phase quantitative neuroimaging provided a statistically significant improvement for the predictive value when combined with ES and motor score with or without NSE. However, in clinical practice, the additional value is small, and considering the costs and challenges of imaging in this patient group, early-phase DTI/MRS cannot be recommended for routine use. TRIAL REGISTRATION: ClinicalTrials.gov NCT00879892, April 13, 2009.

Effects of riboflavin in the treatment of brain damage caused by oxygen deprivation: an integrative systematic review.

Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods for post-hypoxia/anoxia injuries are limited and still have deficiencies in terms of safety and efficacy. Recently, clinical studies of stroke have reported the use of drugs containing riboflavin for post-injury clinical rehabilitation, however, the effects of vitamin B2 on exposure to cerebral oxygen deprivation are not completely elucidated. This review aimed to investigate the potential antioxidant, anti-inflammatory and neuroprotective effects of riboflavin in cerebral hypoxia/anoxia. After a systematic search, 21 articles were selected, 8 preclinical and 12 clinical studies, and 1 translational study. Most preclinical studies used B2 alone in models of hypoxia in rodents, with doses of 1-20 mg/kg (in vivo) and 0.5-5 µM (in vitro). Together, these works suggested greater regulation of lipid peroxidation and apoptosis and an increase in neurotrophins, locomotion, and cognition after treatment. In contrast, several human studies have administered riboflavin (5 mg) in combination with other Krebs cycle metabolites, except one study, which used only B2 (20 mg). A reduction in lactic acidosis and recovery of sensorimotor functions was observed in children after treatment with B2, while adults and the elderly showed a reduction in infarct volume and cognitive rehabilitation. Based on findings from preclinical and clinical studies, we conclude that the use of riboflavin alone or in combination acts beneficially in correcting the underlying brain damage caused by hypoxia/anoxia and its inflammatory, oxidative, and behavioral impairments.

Perfusion Computed Tomography as a Screening Tool for Pending Delayed Cerebral Ischemia in Comatose Patients After Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently complicated by delayed cerebral ischemia (DCI), leading to poor outcomes. Early diagnosis of DCI is crucial for improving survival and outcomes but remains challenging in comatose patients. In this study, we aimed to evaluate computed tomography with angiography and perfusion (P-CT) as a screening modality on postictal days four and eight for impending DCI after aSAH in comatose patients using vasospasm with hypoperfusion (hVS) as a surrogate and DCI-related infarction as an outcome measure. Two objectives were set: (1) to evaluate the screening's ability to accurately risk stratify patients and (2) to assess the validity of P-CT screening. METHODS: We conducted a retrospective review of the records of comatose patients with aSAH from January 2019 to December 2021 who were monitored with P-CT scans on days four and eight. The event rates of DCI-related infarction, hVS, and endovascular rescue therapy (ERT) were analyzed, and the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for DCI were calculated. DCI-related infarction was defined as new secondary cerebral infarction > 48 h < 6 weeks post aSAH not attributable to other causes, and hVS was defined as arterial narrowing with corresponding hypoperfusion on P-CT. RESULTS: Fifty-six comatose patients were included, and 98 P-CT scans were performed. The incidence of DCI-related infarction was 40%. Screening P-CT on days four and eight found vasospasm in 23% of all patients, including 11% with hVS. A positive hVS on day four or eight revealed a relative risk of 2.4 [95% confidence interval (CI) 1.13-5.11, p = 0.03], sensitivity of 23% (95% CI 8-45, p = 0.03), specificity of 95% (95% CI 36-100, p = 0.03), PPV of 0.83 (95% CI 0.36-1.00, p = 0.03), and NPV of 0.65 (95% CI 0.50-0.78). Six positive P-CT scans led to digital subtraction angiography in five patients, three of whom received ERT. All ERT-intervened patients developed DCI-related infarction. CONCLUSIONS: P-CT resulted in few interventions and often resulted in late detection of DCI at an irreversible stage. Although a positive P-CT result accurately predicts impending DCI-related infarction, screening on days four and eight alone in comatose patients with aSAH often fails to timely detect impending DCI. Based on our analysis, we cannot recommend P-CT as a screening modality. P-CT is likely best used as a confirmatory test prior to invasive interventions when guided by continuous multimodal monitoring; however, prospective studies with comparison groups are warranted. The need for a reliable continuous screening modality is evident because of the high rate of deterioration and narrow treatment window.

Defining Longer-Term Outcomes in an Ovine Model of Moderate Perinatal Hypoxia-Ischemia.

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

Relationship Between Brain Tissue Oxygen and Near-Infrared Spectroscopy in Patients with Nontraumatic Subarachnoid Hemorrhage.

BACKGROUND: Continuous monitoring of cerebral oxygenation is one of the diagnostic tools used in patients with brain injury. Direct and invasive measurement of cerebral oxygenation with a partial brain oxygen pressure (PbtO2) probe is promising but invasive. Noninvasive assessment of regional transcranial oxygen saturation using near-infrared spectroscopy (NIRS) may be feasible. The aim of this study was to evaluate the interchangeability between PbtO2 and NIRS over time in patients with nontraumatic subarachnoid hemorrhage. METHODS: This retrospective study was performed in a neurocritical care unit. Study participants underwent hourly PbtO2 and NIRS measurements over 72 h. Temporal agreement between markers was described by their pointwise correlation. A secondary analysis assessed the structure of covariation between marker trajectories using a bivariate linear mixed model. RESULTS: Fifty-one patients with subarachnoid hemorrhage were included. A total of 3362 simultaneous NIRS and PbtO2 measurements were obtained. The correlation at each measurement time ranged from - 0.25 to 0.25. The global correlation over time was - 0.026 (p = 0.130). The bivariate linear mixed model confirmed the lack of significant correlation between the PbtO2 and NIRS measurements at follow-up. NIRS was unable to detect PbtO2 values below 20 mm Hg (area under the receiver operating characteristic curve 0.539 [95% confidence interval 0.536-0.542]; p = 0.928), and percentage changes in NIRS were unable to detect a decrease in PbtO2 ≥ 10% (area under the receiver operating characteristic curve 0.615 [95% confidence interval 0.614-0.616]; p < 0.001). CONCLUSIONS: PbtO2 and NIRS measurements were not correlated. There is no evidence that NIRS could be a substitute for PbtO2 monitoring in patients with nontraumatic subarachnoid hemorrhage.

Outcome Prediction of Postanoxic Coma: A Comparison of Automated Electroencephalography Analysis Methods.

BACKGROUND: To compare three computer-assisted quantitative electroencephalography (EEG) prediction models for the outcome prediction of comatose patients after cardiac arrest regarding predictive performance and robustness to artifacts. METHODS: A total of 871 continuous EEGs recorded up to 3 days after cardiac arrest in intensive care units of five teaching hospitals in the Netherlands were retrospectively analyzed. Outcome at 6 months was dichotomized as "good" (Cerebral Performance Category 1-2) or "poor" (Cerebral Performance Category 3-5). Three prediction models were implemented: a logistic regression model using two quantitative features, a random forest model with nine features, and a deep learning model based on a convolutional neural network. Data from two centers were used for training and fivefold cross-validation (n = 663), and data from three other centers were used for external validation (n = 208). Model output was the probability of good outcome. Predictive performances were evaluated by using receiver operating characteristic analysis and the calculation of predictive values. Robustness to artifacts was evaluated by using an artifact rejection algorithm, manually added noise, and randomly flattened channels in the EEG. RESULTS: The deep learning network showed the best overall predictive performance. On the external test set, poor outcome could be predicted by the deep learning network at 24 h with a sensitivity of 54% (95% confidence interval [CI] 44-64%) at a false positive rate (FPR) of 0% (95% CI 0-2%), significantly higher than the logistic regression (sensitivity 33%, FPR 0%) and random forest models (sensitivity 13%, FPR, 0%) (p < 0.05). Good outcome at 12 h could be predicted by the deep learning network with a sensitivity of 78% (95% CI 52-100%) at a FPR of 12% (95% CI 0-24%) and by the logistic regression model with a sensitivity of 83% (95% CI 83-83%) at a FPR of 3% (95% CI 3-3%), both significantly higher than the random forest model (sensitivity 1%, FPR 0%) (p < 0.05). The results of the deep learning network were the least affected by the presence of artifacts, added white noise, and flat EEG channels. CONCLUSIONS: A deep learning model outperformed logistic regression and random forest models for reliable, robust, EEG-based outcome prediction of comatose patients after cardiac arrest.

Efficacy of Citicoline as a Neuroprotector in children with post cardiac arrest: a randomized controlled clinical trial.

Brain hypoxia after cardiac arrest leads to damage of the neuronal cell membrane. Citicoline is necessary for the synthesis of cell membrane. We planned to assess the neuroprotective effect of citicoline in children after cardiac arrest. This randomized controlled trial was carried out at pediatric intensive care units (PICU) and surgical ICU at Tanta university hospital on 80 consecutive children surviving in-hospital cardiac arrest who were subdivided into two groups. Group I (citicoline group) included 40 children with post-cardiac arrest who received citicoline 10 mg /kg /12 h IV for 6 weeks plus other supportive measures and group II (control group) included 40 children with post-cardiac arrest who were managed with only supportive measures. All patients were evaluated for Glasgow coma score (GCS), modified Rankin scale (mRS) for children, seizures frequency, type and duration, and serum neuron-specific enolase (NSE) before and 3 months after the treatment. GCS and mRS significantly improved in citicholine group compared to the control group. Seizure frequency and duration, mortality, PICU and hospital stay significantly decreased in citicholine group compared to the control group. Serum NSE levels significantly decreased in citicholine group only. No side effects were recorded.Conclusion: Citicoline is a promising neuroprotective drug in children with post-cardiac arrest.Trial Registration: The study was registered at Pan African Clinical Trials Registry (PACTR) www.pactr.samrc.ac.za with trial number PACTR201907742119058. What is known? • Post-resuscitation brain injury is one of the major complications that can lead to death or disability. • CDP-choline has been studied for acute ischemic stroke in several adult studies because of its reparative effect. What is new? • Our study was the first in pediatrics that assessed the neuroprotective effect of CDP-choline on the brain in children after cardiac arrest. • We found that Citicoline is a promising neuroprotective drug in children with post-cardiac arrest.

Quantitative contrast-enhanced ultrasound of the brain on twin fetal lambs maintained by the extrauterine environment for neonatal development (EXTEND): initial experience.

BACKGROUND: With the development of an artificial environment to support the extremely premature infant, advanced imaging techniques tested in this extrauterine system might be beneficial to evaluate the fetal brain. OBJECTIVE: We evaluated the feasibility of (a) performing contrast-enhanced ultrasound (CEUS) and (b) quantifying normal and decreased brain perfusion in fetal lambs maintained on the extrauterine environment for neonatal development (EXTEND) system. MATERIALS AND METHODS: Twin premature fetal lambs (102 days of gestational age) were transferred to the EXTEND system. Twin B was subjected to sub-physiological flows (152 mL/kg/min) and oxygen delivery (15.9 mL/kg/min), while Twin A was maintained at physiological levels. We administered Lumason contrast agent into the oxygenator circuit and performed serial CEUS examinations. We quantified perfusion parameters and generated parametric maps. We also recorded hemodynamic parameters, serum blood analysis, and measurements across the oxygenator. Postmortem MRIs were performed. RESULTS: No significant changes in hemodynamic variables were attributable to CEUS examinations. On gray-scale images, Twin B demonstrated ventriculomegaly and progressive parenchymal volume loss culminating in hydranencephaly. By CEUS, Twin B demonstrated decreased peak enhancement and decreased overall parenchymal perfusion when compared to Twin A by perfusion parameters and parametric maps. Changes in perfusion parameters were detected immediately following blood transfusion. Postmortem MRI confirmed ultrasonographic findings in Twin B. CONCLUSION: In this preliminary experience, we show that CEUS of the brain is feasible in fetal lambs maintained on the EXTEND system and that changes in perfusion can be quantified, which is promising for the application of CEUS in this extrauterine system supporting the premature infant.

Electrocerebral Signature of Cardiac Death.

BACKGROUND: Electroencephalography (EEG) findings following cardiovascular collapse in death are uncertain. We aimed to characterize EEG changes immediately preceding and following cardiac death. METHODS: We retrospectively analyzed EEGs of patients who died from cardiac arrest while undergoing standard EEG monitoring in an intensive care unit. Patients with brain death preceding cardiac death were excluded. Three events during fatal cardiovascular failure were investigated: (1) last recorded QRS complex on electrocardiogram (QRS0), (2) cessation of cerebral blood flow (CBF0) estimated as the time that blood pressure and heart rate dropped below set thresholds, and (3) electrocerebral silence on EEG (EEG0). We evaluated EEG spectral power, coherence, and permutation entropy at these time points. RESULTS: Among 19 patients who died while undergoing EEG monitoring, seven (37%) had a comfort-measures-only status and 18 (95%) had a do-not-resuscitate status in place at the time of death. EEG0 occurred at the time of QRS0 in five patients and after QRS0 in two patients (cohort median - 2.0, interquartile range - 8.0 to 0.0), whereas EEG0 was seen at the time of CBF0 in six patients and following CBF0 in 11 patients (cohort median 2.0 min, interquartile range - 1.5 to 6.0). After CBF0, full-spectrum log power (p < 0.001) and coherence (p < 0.001) decreased on EEG, whereas delta (p = 0.007) and theta (p < 0.001) permutation entropy increased. CONCLUSIONS: Rarely may patients have transient electrocerebral activity following the last recorded QRS (less than 5 min) and estimated cessation of cerebral blood flow. These results may have implications for discussions around cardiopulmonary resuscitation and organ donation.

Individualized Brain Tissue Oxygen-Monitoring Probe Placement Helps to Guide Therapy and Optimizes Outcome in Neurocritical Care.

BACKGROUND/OBJECTIVE: In order to monitor tissue oxygenation in patients with acute neurological disorders, probes for measurement of brain tissue oxygen tension (ptO2) are often placed non-specifically in a right frontal lobe location. To improve the value of ptO2 monitoring, placement of the probe into a specific area of interest is desirable. We present a technique using CT-guidance to place the ptO2 probe in a particular area of interest based on the individual patient's pathology. METHODS: In this retrospective cohort study, we analyzed imaging and clinical data from all patients who underwent CT-guided ptO2 probe placement at our institution between October 2017 and April 2019. Primary endpoint was successful placement of the probe in a particular area of interest rated by two independent reviewers. Secondary outcomes were complications from probe insertion, clinical consequences from ptO2 measurements, clinical outcome according to the modified Rankin Scale (mRS) as well as development of ischemia on follow-up imaging. A historical control group was selected from patients who underwent conventional ptO2 probe placement between January 2010 and October 2017. RESULTS: Eleven patients had 16 CT-guided probes inserted. In 15 (93.75%) probes, both raters agreed on the correct placement in the area of interest. Each probe triggered on average 0.48 diagnostic or therapeutic adjustments per day. Only one infarction within the vascular territory of a probe was found on follow-up imaging. Eight out of eleven patients (72.73%) reached a good outcome (mRS ≤ 3). In comparison, conventionally placed probes triggered less diagnostic and therapeutic adjustment per day (p = 0.007). Outcome was worse in the control group (p = 0.024). CONCLUSION: CT-guided probe insertion is a reliable and easy technique to place a ptO2 probe in a particular area of interest in patients with potentially reduced cerebral oxygen supply. By adjusting treatment aggressively according to this individualized monitoring data, clinical outcome may improve.

Is jugular bulb oximetry monitoring associated with outcome in out of hospital cardiac arrest patients?

Cerebral protection against secondary hypoxic-ischemic brain injury is a key priority area in post-resuscitation intensive care management in survivors of cardiac arrest. Nevertheless, the current understanding of the incidence, diagnosis and its' impact on neurological outcome remains undetermined. The aim of this study was to evaluate jugular bulb oximetry as a potential monitoring modality to detect the incidences of desaturation episodes during post-cardiac arrest intensive care management and to evaluate their subsequent impact on neurological outcome. We conducted a prospective, observational study in unconscious adult patients admitted to the intensive care unit who had successful resuscitation following out of hospital cardiac arrest of presumed cardiac causes. All the patients were treated as per European Resuscitation Council 2015 guidelines and they received jugular bulb catheter. Jugular bulb oximetry measurements were performed at six hourly intervals. The neurological outcomes were evaluated on 90th day after the cardiac arrest by cerebral performance categories scale. Forty patients met the eligibility criteria. Measurements of jugular venous oxygen saturation were performed for 438 times. Altogether, we found 2 incidences of jugular bulb oxygen saturation less than 50% (2/438; 0.46%), and 4 incidences when it was less than 55% (4/438; 0.91%). The study detected an association between SjVO2 and CO2 (r = 0.26), each 1 kPa increase in CO2 led to an increase in SjvO2 by 3.4% + / - 0.67 (p < 0.0001). There was no association between SjvO2 and PaO2 or SjvO2 and MAP. We observed a statistically significant higher mean SjvO2 (8.82% + / - 2.05, p < 0.0001) in unfavorable outcome group. The episodes of brain hypoxia detected by jugular bulb oxygen saturation were rare during post-resuscitation intensive care management in out of hospital cardiac arrest patients. Therefore, this modality of monitoring may not yield any additional information towards prevention of secondary hypoxic ischemic brain injury in post cardiac arrest survivors. Other factors contributing towards high jugular venous saturation needs to be considered.

Comparison of Frequency- and Time-Domain Autoregulation and Vasoreactivity Indices in a Piglet Model of Hypoxia-Ischemia and Hypothermia.

INTRODUCTION: The optimal method to detect impairments in cerebrovascular pressure autoregulation in neonates with hypoxic-ischemic encephalopathy (HIE) is unclear. Improving autoregulation monitoring methods would significantly advance neonatal neurocritical care. METHODS: We tested several mathematical algorithms from the frequency and time domains in a piglet model of HIE, hypothermia, and hypotension. We used laser Doppler flowmetry and induced hypotension to delineate the gold standard lower limit of autoregulation (LLA). Receiver operating characteristics curve analyses were used to determine which indices could distinguish blood pressure above the LLA from that below the LLA in each piglet. RESULTS: Phase calculation in the frequency band with maximum coherence, as well as the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy relative total tissue hemoglobin (HbT) or regional oxygen saturation (rSO2), accurately discriminated functional from dysfunctional autoregulation. Neither hypoxia-ischemia nor hypothermia affected the accuracy of these indices. Coherence alone and gain had low diagnostic value relative to phase and correlation. CONCLUSION: Our findings indicate that phase shift is the most accurate component of autoregulation monitoring in the developing brain, and it can be measured using correlation or by calculating phase when coherence is maximal. Phase and correlation autoregulation indices from MAP and rSO2 and vasoreactivity indices from MAP and HbT are accurate metrics that are suitable for clinical HIE studies.

Unrecognized maternal heart rate artefact in cases of perinatal mortality reported to the United States Food and Drug Administration from 2009 to 2019: a critical patient safety issue.

BACKGROUND: Maternal heart rate artefact is a signal processing error whereby the fetal heart rate is masked by the maternal pulse, potentially leading to danger by failure to recognize an abnormal fetal heart rate or a pre-existing fetal death. Maternal heart rate artefact may be exacerbated by autocorrelation algorithms in modern fetal monitors due to smooth transitions between maternal and fetal heart rates rather than breaks in the tracing. In response, manufacturers of cardiotocography monitors recommend verifying fetal life prior to monitoring and have developed safeguards including signal ambiguity detection technologies to simultaneously and continuously monitor the maternal and fetal heart rates. However, these safeguards are not emphasized in current cardiotocography clinical practice guidelines, potentially leading to a patient safety gap. METHODS: The United States Food and Drug Administration Manufacturer and User Facility Device Experience database was reviewed for records with event type "Death" for the time period March 31, 2009 to March 31, 2019, in combination with search terms selected to capture all cases reported involving cardiotocography devices. Records were reviewed to determine whether maternal heart rate artefact was probable and/or whether the report contained a recommendation from the device manufacturer regarding maternal heart rate artefact. RESULTS: Forty-seven cases of perinatal mortality were identified with probable maternal heart rate artefact including 14 with antepartum fetal death prior to initiation of cardiotocography, 14 with intrapartum fetal death or neonatal death after initiation of cardiotocography, and 19 where the temporal relationship between initiation of cardiotocography and death cannot be definitively established from the report. In 29 cases, there was a recommendation from the manufacturer regarding diagnosis and/or management of maternal heart rate artefact. CONCLUSIONS: This case series indicates a recurring problem with undetected maternal heart rate artefact leading to perinatal mortality and, in cases of pre-existing fetal death, healthcare provider confusion. In response, manufacturers frequently recommend safeguards which are found in their device's instructions for use but not in major intrapartum cardiotocography guidelines. Cardiotocography guidelines should be updated to include the latest safeguards against the risks of maternal heart rate artefact. An additional file summarizing key points for clinicians is included.

The multifunctional role of phospho-calmodulin in pathophysiological processes.

Calmodulin (CaM) is a versatile Ca2+-sensor/transducer protein that modulates hundreds of enzymes, channels, transport systems, transcription factors, adaptors and other structural proteins, controlling in this manner multiple cellular functions. In addition to its capacity to regulate target proteins in a Ca2+-dependent and Ca2+-independent manner, the posttranslational phosphorylation of CaM by diverse Ser/Thr- and Tyr-protein kinases has been recognized as an important additional manner to regulate this protein by fine-tuning its functionality. In this review, we shall cover developments done in recent years in which phospho-CaM has been implicated in signalling pathways that are relevant for the onset and progression of diverse pathophysiological processes. These include diverse systems playing a major role in carcinogenesis and tumour development, prion-induced encephalopathies and brain hypoxia, melatonin-regulated neuroendocrine disorders, hypertension, and heavy metal-induced cell toxicity.

Neurodevelopmental effect of intracranial hemorrhage observed in hypoxic ischemic brain injury in hypothermia-treated asphyxiated neonates - an MRI study.

BACKGROUND: Identification of early signs of hypoxic ischemic encephalopathy (HIE) with magnetic resonance imaging (MRI) has proven of prognostic significance. Yet, the importance of intracranial hemorrhage (ICH), being present concomitantly had not been investigated yet, despite the known influence of hypothermia on hemostasis. We aimed to determine whether presence of ICH on MRI alongside the signs of HIE have an impact on prognosis in neonates with the clinical diagnosis of HIE. METHODS: A retrospective study of consecutively sampled 108 asphyxiated term infants admitted to a tertiary neonatal intensive care unit (between 2007 and 2016), treated with whole body hypothermia and having brain MRI within 1 week of life was conducted. Presence or absence of HIE signs on MRI (basal ganglia-thalamus, watershed pattern and total brain injury) and on MR spectroscopy (lactate peak with decreased normal metabolites measured by Lac/NAA ratio) and/or of the five major types of ICH were recorded. Neurodevelopmental outcome was measured with Bayley Scales of Infant Development-II (BSID-II) test. Death or abnormal neurodevelopment (BSID-II score < 85) was defined as poor outcome in Chi-square test. Multivariate logistic regression analysis was performed on survivors. RESULTS: MRI and MR-spectroscopy (MRS) signs of HIE were present in 72% (n = 78). 36% (n = 39) of neonates had ICH, being mainly small in size. Chi-square test showed a relationship between neurodevelopmental outcome and initial MRI. Unadjusted logistic regression showed that neonates presenting MRI and MRS signs of HIE have 6.23 times higher odds for delayed mental development (OR = 6.2292; CI95% = [1.2642; 30.6934], p = 0.0246), than infants without imaging alterations; with no ICH effect on outcome. Adjustment for clinical and imaging parameters did not change the pattern of results, i.e. HIE remained an independent risk factor for delayed neurodevelopment (OR = 6.2496; CI95% = [1.2018; 32.4983], p = 0.0294), while ICH remained to have no significant effect. CONCLUSION: HIE related MRI abnormalities proved to be important prognostic factors of poor outcome in cooled asphyxiated infants when present, suggesting that early MRI with MRS is beneficial for prognostication. Interestingly, ICHs present in about one third of all cases had no significant effect on neurodevelopmental outcome, despite the known hemostasis altering effects of hypothermia.

Effects of spinal immobilization at a 20° angle on cerebral oxygen saturations measured by INVOS™.

BACKGROUND AND AIM OF THE STUDY: In this study, we aimed to investigate whether performing the immobilization at 20° instead of 0° changes cerebral oxygenation. MATERIALS AND METHODS: 33 volunteers were put in a hard cervical collar and backboard at 0° and immobilized for 30min. The cerebral oxygen saturations of the volunteers were measured at 1, 5, and 30min after the start of the procedure (Group 1). The volunteers were asked to return the day after the Group 1 procedure but at the same time. Serial cerebral oxygen saturations were obtained at the same time intervals as in Group 1, but for Group 2, the backboard was set to 20°. RESULTS: When the cerebral oxygen saturations of the two groups were compared, there was a slight decrease when the backboard position was changed from 0° to 20°, but it was not statistically significant (P=0.220 and P=0.768, respectively). The results revealed that immobilizing the patients with a spinal backboard at 20° instead of 0° did not alter the cerebral oxygen saturations. CONCLUSION: Our study results revealed that spinal immobilization at 20°, which was a new suggestion for spinal immobilization following a report that this position reduced the decrease in pulmonary function secondary to spinal immobilization, did not alter the cerebral oxygenation, so this suggestion is safe at least from the standpoint of cerebral oxygenation.