Daijiro Hori

Arterial pressure above the upper cerebral autoregulation limit during cardiopulmonary bypass is associated with postoperative delirium

BACKGROUND Mean arterial pressure (MAP) below the lower limit of cerebral autoregulation during cardiopulmonary bypass (CPB) is associated with complications after cardiac surgery. However, simply raising empiric MAP targets during CPB might result in MAP above the upper limit of autoregulation (ULA), causing cerebral hyperperfusion in some patients and predisposing them to cerebral dysfunction after surgery. We hypothesized that MAP above an ULA during CPB is associated with postoperative delirium. METHODS Autoregulation during CPB was monitored continuously in 491 patients with the cerebral oximetry index (COx) in this prospective observational study. COx represents Pearsons correlation coefficient between low-frequency changes in regional cerebral oxygen saturation (measured with near-infrared spectroscopy) and MAP. Delirium was defined throughout the postoperative hospitalization based on clinical detection with prospectively defined methods. RESULTS Delirium was observed in 45 (9.2%) patients. Mechanical ventilation for >48 h [odds ratio (OR), 3.94; 95% confidence interval (CI), 1.72-9.03], preoperative antidepressant use (OR, 3.0; 95% CI, 1.29-6.96), prior stroke (OR, 2.79; 95% CI, 1.12-6.96), congestive heart failure (OR, 2.68; 95% CI, 1.28-5.62), the product of the magnitude and duration of MAP above an ULA (mm Hg h; OR, 1.09; 95% CI, 1.03-1.15), and age (per year of age; OR, 1.01; 95% CI, 1.01-1.07) were independently associated with postoperative delirium. CONCLUSIONS Excursions of MAP above the upper limit of cerebral autoregulation during CPB are associated with risk for delirium. Optimizing MAP during CPB to remain within the cerebral autoregulation range might reduce risk of delirium. CLINICAL TRIAL REGISTRATION clinicaltrials.gov NCT00769691 and NCT00981474.

Melanopsin mediates light-dependent relaxation in blood vessels.

Significance Non–image-forming opsins such as Opn4 regulate important physiological functions such as circadian photo-entrainment and affect. The recent discovery that melanopsin (Opn4) functions outside the central nervous system prompted us to explore a potential role for this receptor in blood vessel regulation. We hypothesized that Opn4-mediated signaling might explain the phenomenon of photorelaxation, for which a mechanism has remained elusive. We report the presence in blood vessels of Opn4 and demonstrate that it mediates wavelength-specific, light-dependent vascular relaxation. This photorelaxation signal transduction involves cGMP and phosphodiesterase 6, but not protein kinase G. Furthermore it is regulated by G protein-coupled receptor kinase 2 and involves vascular hyperpolarization. This receptor pathway can be harnessed for wavelength-specific light-based therapy in the treatment of diseases that involve altered vasoreactivity. Melanopsin (opsin4; Opn4), a non-image-forming opsin, has been linked to a number of behavioral responses to light, including circadian photo-entrainment, light suppression of activity in nocturnal animals, and alertness in diurnal animals. We report a physiological role for Opn4 in regulating blood vessel function, particularly in the context of photorelaxation. Using PCR, we demonstrate that Opn4 (a classic G protein-coupled receptor) is expressed in blood vessels. Force-tension myography demonstrates that vessels from Opn4−/− mice fail to display photorelaxation, which is also inhibited by an Opn4-specific small-molecule inhibitor. The vasorelaxation is wavelength-specific, with a maximal response at ∼430–460 nm. Photorelaxation does not involve endothelial-, nitric oxide-, carbon monoxide-, or cytochrome p450-derived vasoactive prostanoid signaling but is associated with vascular hyperpolarization, as shown by intracellular membrane potential measurements. Signaling is both soluble guanylyl cyclase- and phosphodiesterase 6-dependent but protein kinase G-independent. β-Adrenergic receptor kinase 1 (βARK 1 or GRK2) mediates desensitization of photorelaxation, which is greatly reduced by GRK2 inhibitors. Blue light (455 nM) regulates tail artery vasoreactivity ex vivo and tail blood blood flow in vivo, supporting a potential physiological role for this signaling system. This endogenous opsin-mediated, light-activated molecular switch for vasorelaxation might be harnessed for therapy in diseases in which altered vasoreactivity is a significant pathophysiologic contributor.

Soluble Guanylate Cyclase Is Required for Systemic Vasodilation But Not Positive Inotropy Induced by Nitroxyl in the Mouse

Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO·), confers unique physiological effects including vasorelaxation and enhanced cardiac contractility. These features have spawned current pharmaceutical development of HNO donors as heart failure therapeutics. HNO interacts with selective redox sensitive cysteines to effect signaling but is also proposed to activate soluble guanylate cyclase (sGC) in vitro to induce vasodilation and potentially enhance contractility. Here, we tested whether sGC stimulation is required for these HNO effects in vivo and if HNO also modifies a redox-sensitive cysteine (C42) in protein kinase G-1&agr; to control vasorelaxation. Intact mice and isolated arteries lacking the sGC-&bgr; subunit (sGCKO, results in full sGC deficiency) or expressing solely a redox-dead C42S mutant protein kinase G-1&agr; were exposed to the pure HNO donor, CXL-1020. CXL-1020 induced dose-dependent systemic vasodilation while increasing contractility in controls; however, vasodilator effects were absent in sGCKO mice whereas contractility response remained. The CXL-1020 dose reversing 50% of preconstricted force in aortic rings was ≈400-fold greater in sGCKO than controls. Cyclic-GMP and cAMP levels were unaltered in myocardium exposed to CXL-1020, despite its inotropic-vasodilator activity. In protein kinase G-1&agr;C42S mice, CXL-1020 induced identical vasorelaxation in vivo and in isolated aortic and mesenteric vessels as in littermate controls. In both groups, dilation was near fully blocked by pharmacologically inhibiting sGC. Thus, sGC and cGMP-dependent signaling are necessary and sufficient for HNO-induced vasodilation in vivo but are not required for positive inotropic action. Redox modulation of protein kinase G-1&agr; is not a mechanism for HNO-mediated vasodilation.

Cerebral Autoregulation Monitoring with Ultrasound-Tagged Near-Infrared Spectroscopy in Cardiac Surgery Patients.

BACKGROUND:Individualizing mean arterial blood pressure (MAP) based on cerebral blood flow (CBF) autoregulation monitoring during cardiopulmonary bypass (CPB) holds promise as a strategy to optimize organ perfusion. The purpose of this study was to evaluate the accuracy of cerebral autoregulation monitoring using microcirculatory flow measured with innovative ultrasound-tagged near-infrared spectroscopy (UT-NIRS) noninvasive technology compared with transcranial Doppler (TCD). METHODS:Sixty-four patients undergoing CPB were monitored with TCD and UT-NIRS (CerOx™). The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of TCD-measured CBF velocity and MAP. The cerebral flow velocity index (CFVx) was calculated as a similar coefficient between slow waves of cerebral flow index measured using UT-NIRS and MAP. When MAP is outside the autoregulation range, Mx is progressively more positive. Optimal blood pressure was defined as the MAP with the lowest Mx and CFVx. The right- and left-sided optimal MAP values were averaged to define the individual optimal MAP and were the variables used for analysis. RESULTS:The Mx for the left side was 0.31 ± 0.17 and for the right side was 0.32 ± 0.17. The mean CFVx for the left side was 0.33 ± 0.19 and for the right side was 0.35 ± 0.19. Time-averaged Mx and CFVx during CPB had a statistically significant “among-subject” correlation (r = 0.39; 95% confidence interval [CI], 0.22–0.53; P < 0.001) but had only a modest agreement within subjects (bias 0.03 ± 0.20; 95% prediction interval for the difference between Mx and CFVx, −0.37 to 0.42). The MAP with the lowest Mx and CFVx (“optimal blood pressure”) was correlated (r = 0.71; 95% CI, 0.56–0.81; P < 0.0001) and was in modest within-subject agreement (bias −2.85 ± 8.54; 95% limits of agreement for MAP predicted by Mx and CFVx, −19.60 to 13.89). Coherence between ipsilateral middle CBF velocity and cerebral flow index values averaged 0.61 ± 0.07 (95% CI, 0.59–0.63). CONCLUSIONS:There was a statistically significant correlation and agreement between CBF autoregulation monitored by CerOx compared with TCD-based Mx.

Evidence of an association between brain cellular injury and cognitive decline after non-cardiac surgery

BACKGROUND Postoperative cognitive dysfunction (POCD) is common after non-cardiac surgery, but the mechanism is unclear. We hypothesized that decrements in cognition 1 month after non-cardiac surgery would be associated with evidence of brain injury detected by elevation of plasma concentrations of S100β, neuron-specific enolase (NSE), and/or the brain-specific protein glial fibrillary acid protein (GFAP). METHODS One hundred and forty-nine patients undergoing shoulder surgery underwent neuropsychological testing before and then 1 month after surgery. Plasma was collected before and after anaesthesia. We determined the relationship between plasma biomarker concentrations and individual neuropsychological test results and a composite cognitive functioning score (mean Z-score). RESULTS POCD (≥-1.5 sd decrement in Z-score from baseline) was present in 10.1% of patients 1 month after surgery. There was a negative relationship between higher plasma GFAP concentrations and lower postoperative composite Z-scores {estimated slope=-0.14 [95% confidence interval (CI) -0.24 to -0.04], P=0.005} and change from baseline in postoperative scores on the Rey Complex Figure Test copy trial (P=0.021), delayed recall trial (P=0.010), and the Symbol Digit Modalities Test (P=0.004) after adjustment for age, sex, history of hypertension and diabetes. A similar relationship was not observed with S100β or NSE concentrations. CONCLUSIONS Decline in cognition 1 month after shoulder surgery is associated with brain cellular injury as demonstrated by elevated plasma GFAP concentrations.

Blood Pressure Deviations From Optimal Mean Arterial Pressure During Cardiac Surgery Measured With a Novel Monitor of Cerebral Blood Flow and Risk for Perioperative Delirium: A Pilot Study

OBJECTIVE The aim of this study was to evaluate whether excursions of blood pressure from the optimal mean arterial pressure during and after cardiac surgery are associated with postoperative delirium identified using a structured examination. DESIGN Prospective, observational study. SETTING University hospital. PARTICIPANTS The study included 110 patients undergoing cardiac surgery. INTERVENTIONS Patients were monitored using ultrasound-tagged near-infrared spectroscopy to assess optimal mean arterial pressure by cerebral blood flow autoregulation monitoring during cardiopulmonary bypass and the first 3 hours in the intensive care unit. MEASUREMENTS AND MAIN RESULTS The patients were tested preoperatively and on postoperative days 1 to 3 with the Confusion Assessment Method or Confusion Assessment Method for the Intensive Care Unit, the Delirium Rating Scale-Revised-98, and the Mini Mental State Examination. Summative presence of delirium on postoperative days 1 through 3, as defined by the consensus panel following Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria, was the primary outcome. Delirium occurred in 47 (42.7%) patients. There were no differences in blood pressure excursions above and below optimal mean arterial pressure between patients with and without summative presence of delirium. Secondary analysis showed blood pressure excursions above the optimal mean arterial pressure to be higher in patients with delirium (mean±SD, 33.2±26.51 mmHgxh v 23.4±16.13 mmHgxh; p = 0.031) and positively correlated with the Delirium Rating Scale score on postoperative day 2 (r = 0.27, p = 0.011). CONCLUSIONS Summative presence of delirium was not associated with perioperative blood pressure excursions; but on secondary exploratory analysis, excursions above the optimal mean arterial pressure were associated with the incidence and severity of delirium on postoperative day 2.

Perioperative optimal blood pressure as determined by ultrasound tagged near infrared spectroscopy and its association with postoperative acute kidney injury in cardiac surgery patients

OBJECTIVES Perioperative blood pressure management by targeting individualized optimal blood pressure, determined by cerebral blood flow autoregulation monitoring, may ensure sufficient renal perfusion. The purpose of this study was to evaluate changes in the optimal blood pressure for individual patients, determined during cardiopulmonary bypass (CPB) and during early postoperative period in intensive care unit (ICU). A secondary aim was to examine if excursions below optimal blood pressure in the ICU are associated with risk of cardiac surgery-associated acute kidney injury (CSA-AKI). METHODS One hundred and ten patients undergoing cardiac surgery had cerebral blood flow monitored with a novel technology using ultrasound tagged near infrared spectroscopy (UT-NIRS) during CPB and in the first 3 h after surgery in the ICU. The correlation flow index (CFx) was calculated as a moving, linear correlation coefficient between cerebral flow index measured using UT-NIRS and mean arterial pressure (MAP). Optimal blood pressure was defined as the MAP with the lowest CFx. Changes in optimal blood pressure in the perioperative period were observed and the association of blood pressure excursions (magnitude and duration) below the optimal blood pressure [area under the curve (AUC) < OptMAP mmHgxh] with incidence of CSA-AKI (defined using Kidney Disease: Improving Global Outcomes criteria) was examined. RESULTS Optimal blood pressure during early ICU stay and CPB was correlated (r = 0.46, P < 0.0001), but was significantly higher in the ICU compared with during CPB (75 ± 8.7 vs 71 ± 10.3 mmHg, P = 0.0002). Thirty patients (27.3%) developed CSA-AKI within 48 h after the surgery. AUC < OptMAP was associated with CSA-AKI during CPB [median, 13.27 mmHgxh, interquartile range (IQR), 4.63-20.14 vs median, 6.05 mmHgxh, IQR 3.03-12.40, P = 0.008], and in the ICU (13.72 mmHgxh, IQR 5.09-25.54 vs 5.65 mmHgxh, IQR 1.71-13.07, P = 0.022). CONCLUSIONS Optimal blood pressure during CPB and in the ICU was correlated. Excursions below optimal blood pressure (AUC < OptMAP mmHgXh) during perioperative period are associated with CSA-AKI. Individualized blood pressure management based on cerebral autoregulation monitoring during the perioperative period may help improve CSA-AKI-related outcomes.

Usefulness of fenestrated stent grafts for thoracic aortic aneurysms

OBJECTIVES Endovascular stent grafts (SGs) comprise a novel therapeutic approach to repairing aortic aneurysms. However, endovascular repair of the aortic arch remains challenging. Generally, the repair of sites with SGs requires an extra-anatomical bypass. We introduced SG repair of the aortic arch with strategically positioned fenestrations for each arch branch in 2006. An extra-anatomical bypass is not required for this procedure. This study evaluates the early and mid-term outcomes of fenestrated SG treatment. METHODS We retrospectively analysed the early and mid-term outcomes of 24 of 80 repairs with fenestrated SG among 383 single thoracic aortic aneurysm repairs that were undertaken at our department between January 2006 and March 2012. RESULTS Technical success was obtained in 100% of the patients. However, there was a 30-day perioperative mortality rate of 4.1% (1 of 24) due to a shower embolism. One patient developed a Type 2 endoleak without aneurysm enlargement within a median follow-up time is 25.1 months. However, migrations or device-related complications requiring additional procedures did not arise. CONCLUSIONS Treatment with fenestrated SGs does not require surgical transposition of the arch branches. The procedure is widely applicable and less invasive and outcomes are excellent.

Successful usage of extracorporeal membrane oxygenation as a bridge therapy for acute pulmonary embolism between hospitals

A 50-year-old man presented to a nearby hospital with loss of consciousness. Investigation revealed thrombus formation at the tricuspid valve. Due to suspected pulmonary embolism, the patient underwent contrast-enhanced computed tomography during which he went into a shock with sudden drop in functional oxygen saturation (SpO2). Extracorporeal membrane oxygenation (ECMO) was introduced for cardiovascular and respiratory support, and he was transferred to our hospital for further treatment. The patient was treated by surgical thromboembolectomy and was dismissed from the hospital without major complications. We have experienced a case where ECMO was successfully used for cardiovascular and respiratory support, serving as a bridge therapy between hospitals.

Rewarming Rate During Cardiopulmonary Bypass Is Associated With Release of Glial Fibrillary Acidic Protein.

BACKGROUND Rewarming from hypothermia during cardiopulmonary bypass (CPB) may compromise cerebral oxygen balance, potentially resulting in cerebral ischemia. The purpose of this study was to evaluate whether CPB rewarming rate is associated with cerebral ischemia assessed by the release of the brain injury biomarker glial fibrillary acidic protein (GFAP). METHODS Blood samples were collected from 152 patients after anesthesia induction and after CPB for the measurement of plasma GFAP levels. Nasal temperatures were recorded every 15 min. A multivariate estimation model for postoperative plasma GFAP level was determined that included the baseline GFAP levels, rewarming rate, CPB duration, and patient age. RESULTS The mean rewarming rate during CPB was 0.21° ± 0.11°C/min; the maximal temperature was 36.5° ± 1.0°C (range, 33.1°C to 38.0°C). Plasma GFAP levels increased after compared with before CPB (median, 0.022 ng/mL versus 0.035 ng/mL; p < 0.001). Rewarming rate (p = 0.001), but not maximal temperature (p = 0.77), was associated with higher plasma GFAP levels after CPB. In the adjusted estimation model, rewarming rate was positively associated with postoperative plasma log GFAP levels (coefficient, 0.261; 95% confidence intervals, 0.132 to 0.390; p < 0.001). Six patients (3.9%) experienced a postoperative stroke. Rewarming rate was higher (0.3° ± 0.09°C/min versus 0.2° ± 0.11°C/min; p = 0.049) in the patients with stroke compared with those without a stroke. CONCLUSIONS Rewarming rate during CPB was correlated with evidence of brain cellular injury documented with plasma GFAP levels. Modifying current practices of patient rewarming might provide a strategy to reduce the frequency of neurologic complications after cardiac surgery.