Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: a post-hoc analysis of the COMACARE trial.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury. METHODS: A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TOx) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TOx > 0 indicating impaired reactivity and TOx > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TOx was analysed in the 0-12, 12-24, 24-48 h time-periods and integrated over 0-48 h. The primary outcome was the association between TOx and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3-5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury. RESULTS: In 108 patients with sufficient data to calculate TOx, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TOx for 0-48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [- 1.17 to 2.94] vs. - 2.71 95% CI [- 4.16 to - 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15-650] vs 20 IQR [13-199] pg/ml, p = 0.042). CONCLUSION: Impaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .

Tissue oxygenation indices of cerebrovascular autoregulation in healthy volunteers: a comparison of two NIRS devices.

BACKGROUND: Correlation coefficients between blood pressure and cerebral oxygen saturation measured using near-infrared spectrometry may be used to derive the tissue oximetry index of cerebral autoregulation. Cerebral oxygen saturations demonstrate poor agreement between near-infrared spectrometers however it is unclear if measurements of autoregulation are similarly specific to the equipment used. METHODS: Cerebral oxygen saturation was monitored bilaterally in 74 healthy volunteers using both the FORE-SIGHT and EQUANOX monitors in random order. The tissue oximetry index was calculated during changes in blood pressure induced by isometric handgrip manoeuvres and the mean bias and limits of agreement were calculated. RESULTS: Tissue oximetry index measured by FORE-SIGHT was higher than EQUANOX (0.21 ± 0.16 versus 0.15 ± 0.17, P < 0.001) and limits of agreement were -0.24 to 0.36. Baseline cerebral oxygen saturation by FORE-SIGHT was lower than EQUANOX by 1.48% (CI95% 0.63-2.33) and limits of agreement ranged from -11.8% to 8.8%. CONCLUSIONS: The substantial bias and wide limits of agreement for the tissue oximetry index as a measure of cerebral autoregulation indicate that values must be treated as specific to models of near-infrared spectrometers.

Is cerebrovascular autoregulation associated with outcomes after major noncardiac surgery? A prospective observational pilot study.

BACKGROUND: Studies have identified multiple risk factors for development of cognitive decline after surgery. Impaired cerebrovascular autoregulation may be a contributor to postoperative cognitive decline. METHODS: One hundred and forty patients admitted for major elective noncardiac surgery were recruited. Near-infrared spectroscopy was used to calculate the tissue oxygenation index of dynamic autoregulation (TOx). The primary endpoint was Day 3 cognitive recovery as assessed using the Postoperative Quality of Recovery Scale. The secondary endpoint was a combined major adverse event of death, acute myocardial infarction, cardiac arrest, stroke, pulmonary embolism, sepsis, and acute kidney injury at Day 30. RESULTS: Higher optimal TOx values, signifying impaired autoregulation, were associated with worse outcomes. Patients who cognitively recovered at Day 3 (n = 47) had lower optimal TOx values (TOxopt ) than patients who did not recover (n = 22): 0.06 (0.24) vs 0.18 (0.16) (mean [SD]), P = 0.02. Patients who did not suffer a major adverse event (n = 102) had lower TOxopt than patients who did (n = 17): 0.09 (0.21) vs 0.20 (0.27), P = 0.04. When dichotomized as having impaired or intact autoregulation based on TOxopt levels, a value of TOxopt ≥0.1 correctly identified 72.7% of patients who did not cognitively recover, OR 3.3 (1.1-9.9) (Odds ratio, [95% CI]), P = 0.03. TOxopt ≥0.1 correctly identified 82.4% of patients who suffered a major adverse event, OR 4.7 (1.3-17.2), P = 0.02. CONCLUSIONS: In older and higher risk patients having major noncardiac surgery, impaired cerebrovascular autoregulation was associated with failure of cognitive recovery in the early postoperative period and with 1-month mortality and morbidity.

Long-term Aß exposure augments mCa2+-independent mROS-mediated depletion of cardiolipin for the shift of a lethal transient mitochondrial permeability transition to its permanent mode in NARP cybrids: a protective targeting of melatonin.

Mitochondrial dysfunction is a hallmark of amyloid ß-peptide (Aß)-induced neurodegeneration of Alzheimer's disease (AD). This study investigated whether mtDNA T8993G mutation-induced complex V inhibition, clinically associated with neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP), is a potential risk factor for AD and the pathological link for long-term exposure of Aß-induced mitochondrial toxicity and apoptosis in NARP cybrids. Using noninvasive fluorescence probe-coupled laser scanning imaging microscopy and NARP cybrids harboring 98% mutant genes along with its parental 143B osteosarcoma cells, we demonstrated that Aß-augmented mitochondrial Ca(2+) (mCa(2+))-independent mitochondrial reactive oxygen species (mROS) formation for a cardiolipin (CL, a major mitochondrial protective phospholipid)-dependent lethal modulation of the mitochondrial permeability transition (MPT). Aß augmented not only the amount but also the propagation rate of mROS-induced mROS formation to significantly depolarize mitochondrial membrane potential (∆Ψ(m)) and reduce mCa(2+) stress. Aß-augmented mROS oxidized and depleted CL, thereby enhances mitochondrial fission and movement retardation, which promoted the NARP-augmented lethal transient-MPT (t-MPT) to switch to its irreversible mode of permanent-MPT (p-MPT). Interestingly, melatonin, a multiple mitochondrial protector, markedly reduced Aß-augmented mROS formation and therefore significantly reduced mROS-mediated depolarization of ∆Ψ(m), fission of mitochondria and retardation of mitochondrial movement to stabilize CL and hence the MPT. In the presence of melatonin, Aß-promoted p-MPT was reversed to a protective t-MPT, which preserved ∆Ψ(m) and lowered elevated mCa(2+) to sublethal levels for an enhanced mCa(2+)-dependent O(2) consumption. Thus, melatonin may potentially rescue AD patients associated with NARP symptoms.