Lung Injury Is a Predictor of Cerebral Hypoxia and Mortality in Traumatic Brain Injury.

Background: A major contributor to unfavorable outcome after traumatic brain injury (TBI) is secondary brain injury. Low brain tissue oxygen tension (PbtO2) has shown to be an independent predictor of unfavorable outcome. Although PbtO2 provides clinicians with an understanding of the ischemic and non-ischemic derangements of brain physiology, its value does not take into consideration systemic oxygenation that can influence patients' outcomes. This study analyses brain and systemic oxygenation and a number of related indices in TBI patients: PbtO2, partial arterial oxygenation pressure (PaO2), PbtO2/PaO2, ratio of PbtO2 to fraction of inspired oxygen (FiO2), and PaO2/FiO2. The primary aim of this study was to identify independent risk factors for cerebral hypoxia. Secondary goal was to determine whether any of these indices are predictors of mortality outcome in TBI patients. Materials and Methods: A single-centre retrospective cohort study of 70 TBI patients admitted to the Neurocritical Care Unit (NCCU) at Cambridge University Hospital in 2014-2018 and undergoing advanced neuromonitoring including invasive PbtO2 was conducted. Three hundred and three simultaneous measurements of PbtO2, PaO2, PbtO2/PaO2, PbtO2/FiO2, PaO2/FiO2 were collected and mortality at discharge from NCCU was considered as outcome. Generalized estimating equations were used to analyse the longitudinal data. Results: Our results showed PbtO2 of 28 mmHg as threshold to define cerebral hypoxia. PaO2/FiO2 found to be a strong and independent risk factor for cerebral hypoxia when adjusting for confounding factor of intracranial pressure (ICP) with adjusted odds ratio of 1.78, 95% confidence interval of (1.10-2.87) and p-value = 0.019. With respect to TBI outcome, compromised values of PbtO2, PbtO2/PaO2, PbtO2/FiO2, and PaO2/FiO2 were all independent predictors of mortality while considered individually and adjusting for confounding factors of ICP, age, gender, and cerebral perfusion pressure (CPP). However, when considering all the compromised values together, only PaO2/FiO2 became an independent predictor of mortality with adjusted odds ratio of 3.47 (1.20-10.04) and p-value = 0.022. Conclusions: Brain and Lung interaction in TBI patients is a complex interrelationship. PaO2/FiO2 seems to be a major determinant of cerebral hypoxia and mortality. These results confirm the importance of employing ventilator strategies to prevent cerebral hypoxia and improve the outcome in TBI patients

Effects of Prone Position and Positive End-Expiratory Pressure on Noninvasive Estimators of ICP: A Pilot Study.

BACKGROUND: Prone positioning and positive end-expiratory pressure can improve pulmonary gas exchange and respiratory mechanics. However, they may be associated with the development of intracranial hypertension. Intracranial pressure (ICP) can be noninvasively estimated from the sonographic measurement of the optic nerve sheath diameter (ONSD) and from the transcranial Doppler analysis of the pulsatility (ICPPI) and the diastolic component (ICPFVd) of the velocity waveform. METHODS: The effect of the prone positioning and positive end-expiratory pressure on ONSD, ICPFVd, and ICPPI was assessed in a prospective study of 30 patients undergoing spine surgery. One-way repeated measures analysis of variance, fixed-effect multivariate regression models, and receiver operating characteristic analyses were used to analyze numerical data. RESULTS: The mean values of ONSD, ICPFVd, and ICPPI significantly increased after change from supine to prone position. Receiver operating characteristic analyses demonstrated that, among the noninvasive methods, the mean ONSD measure had the greatest area under the curve signifying it is the most effective in distinguishing a hypothetical change in ICP between supine and prone positioning (0.86±0.034 [0.79 to 0.92]). A cutoff of 0.43 cm was found to be a best separator of ONSD value between supine and prone with a specificity of 75.0 and a sensitivity of 86.7. CONCLUSIONS: Noninvasive ICP estimation may be useful in patients at risk of developing intracranial hypertension who require prone positioning.DC and MC are partially supported by NIHR Brain Injury Healthcare Technology Co-operative, Cambridge, UK. JD is supported by a Woolf Fisher Scholarship (NZ)

Cerebrovascular pressure reactivity and brain tissue oxygen monitoring provide complementary information regarding the lower and upper limits of cerebral blood flow control in traumatic brain injury : a CAnadian High Resolution-TBI (CAHR-TBI) cohort study

Background: Brain tissue oxygen tension (PbtO2) and cerebrovascular pressure reac-tivity monitoring have emerged as potential modalities to individualize care in moder-ate and severe traumatic brain injury (TBI). The relationship between these modalities has had limited exploration. The aim of this study was to examine the relationship between PbtO(2) and cerebral perfusion pressure (CPP) and how this relationship is modified by the state of cerebrovascular pressure reactivity.Methods: A retrospective multi-institution cohort study utilizing prospectively collected high-resolution physiologic data from the CAnadian High Resolution-TBI (CAHR-TBI) Research Collaborative database collected between 2011 and 2021 was performed. Included in the study were critically ill TBI patients with intracranial pres-sure (ICP), arterial blood pressure (ABP), and PbtO(2) monitoring treated in any one of three CAHR-TBI affiliated adult intensive care units (ICU). The outcome of interest was how PbtO2 and CPP are related over a cohort of TBI patients and how this relationship is modified by the state of cerebrovascular reactivity, as determined using the pressure reactivity index (PRx).Results: A total of 77 patients met the study inclusion criteria with a total of 377,744 min of physiologic data available for the analysis. PbtO2 produced a triphasic curve when plotted against CPP like previous population-based plots of cerebral blood flow (CBF) versus CPP. The triphasic curve included a plateau region flanked by regions of relative ischemia (hypoxia) and hyperemia (hyperoxia). The plateau region shortened when cerebrovascular pressure reactivity was disrupted compared to when it was intact.Conclusions: In this exploratory analysis of a multi-institution high-resolution physiology TBI database, PbtO(2) seems to have a triphasic relationship with CPP, over the entire cohort. The CPP range over which the plateau exists is modified by the state of cerebrovascular reactivity. This indicates that in critically ill TBI patients admitted to ICU, PbtO2 may be reflective of CBF.Peer reviewe

Increased blood glucose is related to disturbed cerebrovascular pressure reactivity after traumatic brain injury.

BACKGROUND: Increased blood glucose and impaired pressure reactivity (PRx) after traumatic brain injury (TBI) are both known to correlate with unfavorable patient outcome. However, the relationship between these two variables is unknown. METHODS: To test the hypothesis that increased blood glucose leads to increased PRx, we retrospectively analyzed data from 86 traumatic brain injured patients admitted to the Neurocritical Care Unit. Data analyzed included arterial glucose concentration, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and end-tidal CO2. PRx was calculated as the moving correlation coefficient between averaged (10 seconds) arterial blood pressure and ICP. One arterial glucose concentration and one time-aligned PRx value were obtained for each patient, during each day until the fifth day after ictus. RESULTS: Mean arterial glucose concentrations during the first 5 days since ictus were positively correlated with mean PRx (Pearson correlation coefficient = 0.25, p = 0.02). The correlation was strongest on the first day after injury (Pearson correlation coefficient = 0.47, p = 0.008). CONCLUSION: Our preliminary findings indicate that increased blood glucose may impair cerebrovascular reactivity, potentially contributing to a mechanistic link between increased blood glucose and poorer outcome after TBI.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s12028-014-0042-

The Burden of Brain Hypoxia and Optimal Mean Arterial Pressure in Patients With Hypoxic Ischemic Brain Injury After Cardiac Arrest.

OBJECTIVES: In patients at risk of hypoxic ischemic brain injury following cardiac arrest, we sought to: 1) characterize brain oxygenation and determine the prevalence of brain hypoxia, 2) characterize autoregulation using the pressure reactivity index and identify the optimal mean arterial pressure, and 3) assess the relationship between optimal mean arterial pressure and brain tissue oxygenation. DESIGN: Prospective interventional study. SETTING: Quaternary ICU. PATIENTS: Adult patients with return of spontaneous circulation greater than 10 minutes and a postresuscitation Glasgow Coma Scale score under 9 within 72 hours of cardiac arrest. INTERVENTIONS: All patients underwent multimodal neuromonitoring which included: 1) brain tissue oxygenation, 2) intracranial pressure, 3) jugular venous continuous oximetry, 4) regional saturation of oxygen using near-infrared spectroscopy, and 5) pressure reactivity index-based determination of optimal mean arterial pressure, lower and upper limit of autoregulation. We additionally collected mean arterial pressure, end-tidal CO2, and temperature. All data were captured at 300 Hz using ICM+ (Cambridge Enterprise, Cambridge, United Kingdom) brain monitoring software. MEASUREMENTS AND MAIN RESULTS: Ten patients (7 males) were included with a median age 47 (range 20-71) and return to spontaneous circulation 22 minutes (12-36 min). The median duration of monitoring was 47 hours (15-88 hr), and median duration from cardiac arrest to inclusion was 15 hours (6-44 hr). The mean brain tissue oxygenation was 23 mm Hg (SD 8 mm Hg), and the mean percentage of time with a brain tissue oxygenation below 20 mm Hg was 38% (6-100%). The mean pressure reactivity index was 0.23 (0.27), and the percentage of time with a pressure reactivity index greater than 0.3 was 50% (12-91%). The mean optimal mean arterial pressure, lower and upper of autoregulation were 89 mm Hg (11), 82 mm Hg (8), and 96 mm Hg (9), respectively. There was marked between-patient variability in the relationship between mean arterial pressure and indices of brain oxygenation. As the patients' actual mean arterial pressure approached optimal mean arterial pressure, brain tissue oxygenation increased (p < 0.001). This positive relationship did not persist when the actual mean arterial pressure was above optimal mean arterial pressure. CONCLUSIONS: Episodes of brain hypoxia in hypoxic ischemic brain injury are frequent, and perfusion within proximity of optimal mean arterial pressure is associated with increased brain tissue oxygenation. Pressure reactivity index can yield optimal mean arterial pressure, lower and upper limit of autoregulation in patients following cardiac arrest

Using the relationship between brain tissue regional saturation of oxygen and mean arterial pressure to determine the optimal mean arterial pressure in patients following cardiac arrest: A pilot proof-of-concept study.

INTRODUCTION: Prospectively assess cerebral autoregulation and optimal mean arterial pressure (MAPOPT) using the dynamic relationship between MAP and regional saturation of oxygen (rSO2) using near-infrared spectroscopy. METHODS: Feasibility study of twenty patients admitted to the intensive care unit following a cardiac arrest. All patients underwent continuous rSO2 monitoring using the INVOS(®) cerebral oximeter. ICM+(®) brain monitoring software calculates the cerebral oximetry index (COx) in real-time which is a moving Pearson correlation coefficient between 30 consecutive, 10-s averaged values of MAP and correspond rSO2 signals. When rSO2 increases with increasing MAP (COx ≥0.3), cerebral autoregulation is dysfunctional. Conversely, when rSO2 remains constant or decreases with increasing MAP (COx <0.3), autoregulation is preserved. ICM+(®) fits a U-shaped curve through the COx values plotted vs. MAP. The MAPOPT is nadir of this curve. RESULTS: The median age was 59 years (IQR 54-67) and 7 of 20 were female. The cardiac arrest was caused by myocardial infarction in 12 (60%) patients. Nineteen arrests were witnessed and return of spontaneous circulation occurred in a median of 15.5min (IQR 8-33). Patients underwent a median of 30h (IQR 23-46) of monitoring. COx curves and MAPOPT were generated in all patients. The mean overall MAP and MAPOPT were 76mmHg (SD 10) and 76mmHg (SD 7), respectively. MAP was outside of 5mmHg from MAPOPT in 50% (SD 15) of the time. Out of the 7672 5-min averaged COx measurements, 1182 (15%) were at 0.3 or above, indicating absence of autoregulation. Multivariable polynomial fractional regression demonstrated an increase in COx with increasing temperature (P=0.008). CONCLUSIONS: We demonstrated the feasibility to determine a MAPOPT using cerebral oximetry in patients after cardiac arrest

Trans-cerebral HCO3- and PCO2 exchange during acute respiratory acidosis and exercise-induced metabolic acidosis in humans

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO(3)(−)]) and carbon dioxide tension (PCO(2)) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO(2) (PaCO(2)) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO(3)(−)] increased by 0.15 ± 0.05 mmol ⋅ l(−1) per mmHg elevation in PaCO(2) across a wide physiological range (35 to 60 mmHg PaCO(2); P < 0.001). The narrowing of the venous-arterial [HCO(3)(−)] and PCO(2) differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO(3)(−)] exchange (CBF × venous-arterial [HCO(3)(−)] difference) was reduced indicating a shift from net release toward net uptake of [HCO(3)(−)] (P = 0.004). Arterial [HCO(3)(−)] was reduced by −0.48 ± 0.15 mmol ⋅ l(−1) per nmol ⋅ l(−1) increase in arterial [H(+)] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO(3)(−)] difference and arterial [H(+)] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO(3)(−)] exchange was unaltered throughout exercise when indexed against arterial [H(+)] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO(3)(−)] – during acute respiratory/exercise-induced metabolic acidosis, respectively – differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO(3)(−)] exchange)

Hemoglobin and cerebral hypoxic vasodilation in humans:Evidence for nitric oxide-dependent and S-nitrosothiol mediated signal transduction

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite ((Formula presented.)) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and (Formula presented.). Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not (Formula presented.), while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.</p

The pathophysiology of hypoxic ischemic brain injury after cardiac arrest

The pathophysiology of hypoxic ischemic brain injury comprises of an initial primary injury during circulatory arrest followed by the secondary injury following return of spontaneous circulation. Management strategies are aimed at mitigating the negative consequences of secondary injury to improve long term neurological outcome. This thesis aimed to: 1) delineate the underlying cerebrovascular pathophysiology of secondary injury following return of spontaneous circulation; and, 2) establish important physiologic relationships between the physiologic determinants of cerebral oxygen delivery and brain tissue oxygenation in hypoxic ischemic brain injury. Study 1 investigated the burden of brain hypoxia following return of spontaneous circulation and determined the relationships between physiologic determinants of cerebral oxygen delivery with brain tissue oxygenation. Episodes of brain hypoxia were prevalent following resuscitation. Study 2 sought to delineate the state of autoregulation in hypoxic ischemic brain injury patients and identify the optimal within- individual mean arterial pressure. Overall, autoregulation was dysfunctional during ∼50% of the monitoring but with significant heterogeneity. Study 3 investigated the temporal patterns of intracranial pressure and compliance in hypoxic ischemic brain injury patients after return of spontaneous circulation. Overall, hypoxic ischemic brain injury was characterized by low intracranial pressure but abnormal intracranial compliance. Study 4 examined the mechanisms of brain hypoxia after cardiac arrest and determined the presence of diffusion limitation of oxygen delivery physiology in hypoxic ischemic brain injury patients. The results identified distinct physiologic phenotypes in that diffusion limitation of oxygen delivery accounted for the predominant mechanism of brain hypoxia after resuscitation in half of the cohort; the remaining patients in the study exhibited physiologic patterns consistent with dependence upon augmentation of cerebral oxygen delivery. Collectively, the results of this thesis indicate that brain hypoxia is prevalent after return of spontaneous circulation and autoregulation seems to be dysfunctional; however, significant heterogeneity exists with respect to the vasomotor control of cerebral blood flow and optimal perfusion pressures. Finally, there appear to be distinct physiologic phenotypes with respect to oxygen transport in the cerebral microvasculature and the presence of diffusion limitation being a novel mechanism of brain hypoxia after cardiac arrest.Health and Social Development, Faculty of (Okanagan)Health and Exercise Sciences, School of (Okanagan)Graduat