Sequestration of Dexmedetomidine in Ex Vivo Cardiopulmonary Bypass Circuits.

Dexmedetomidine (DEX) is a sedative used in combination with other drugs in neonates and infants undergoing cardiac surgery using cardiopulmonary bypass (CPB). This study aimed to evaluate the disposition of DEX after administration to the ex vivo CPB circuits following different bolus doses and continuous infusion of DEX, including the effect of circuit coating, temperature, and modified ultrafiltration (MUF). Cardiopulmonary bypass circuits were setup ex vivo and primed with reconstituted blood. Dexmedetomidine was administered to the circuit (as a single bolus or single bolus along with continuous infusion). The circuit was allowed to equilibrate during the first 5 minutes, blood samples were collected at multiple time points (5-240 minutes). Blood samples were processed to collect plasma and analyzed for DEX with a validated assay. The majority of DEX sequestration in ex vivo CPB circuits occurred within the first 15 minutes. The percent of DEX remained in plasma pre-MUF (16-71%) and post-MUF (22-92%) varied depending on the dose and dosing scheme. Modified ultrafiltration significantly increased the plasma concentration of DEX in 19 of 23 circuits by an average of 12.1 ± 4.25% (p < 0.05). The percent sequestration of DEX was lower in CPB circuits at lower DEX doses compared to higher doses. A combination of DEX initial loading dose and continuous infusion resulted in steady concentrations of DEX over 4 hours. At therapeutically relevant concentrations of DEX (485-1,013 pg/ml), lower sequestration was observed in ex vivo CPB circuits compared to higher doses. The sequestration of DEX to circuits should be considered to achieve the optimal concentration of DEX during CPB surgery.

Elevated arterial blood pressure after superior cavo-pulmonary anastomosis is associated with elevated pulmonary artery pressure and cerebrovascular dysautoregulation.

BACKGROUND: Elevated arterial blood pressure (ABP) is common after superior bidirectional cavopulmonary anastomosis (BCPA). The effects of elevated ABP after BCPA on cerebrovascular hemodynamics are unknown. We sought to determine the relationship between elevated ABP and cerebrovascular autoregulation after BCPA. METHODS: Prospective, observational study on infants with single-ventricle physiology after BCPA surgery. Continuous recordings of mean ABP, mean cavopulmonary artery pressure (PAP), near-infrared spectroscopy measures of cerebral oximetry (regional cerebral oxygen saturation (rSO2)), and relative cerebral blood volume index were obtained from admission to extubation. Autoregulation was measured as hemoglobin volume index (HVx). Physiologic variables, including the HVx, were tested for variance across ABP. RESULTS: Sixteen subjects were included in the study. Elevated ABP post-BCPA was associated with both, elevated PAP (P<0.0001) and positive HVx (dysautoregulation; P<0.0001). No association was observed between ABP and alterations in rSO2. Using piecewise regression, the relationship of PAP to ABP demonstrated a breakpoint at 68 mm Hg (interquartile range (IQR) 62-70 mm Hg). Curve fit of HVx as a function of ABP identified optimal ABP supporting robust autoregulation at a median ABP of 55 mm Hg (IQR 51-64 mm Hg). CONCLUSIONS: Elevated ABP post-BCPA is associated with cerebrovascular dysautoregulation, and elevated PAP. The effects, of prolonged dysautoregulation within this population, require further study.

Impaired cerebral autoregulation and elevation in plasma glial fibrillary acidic protein level during cardiopulmonary bypass surgery for CHD.

BACKGROUND: Cerebrovascular reactivity monitoring has been used to identify the lower limit of pressure autoregulation in adult patients with brain injury. We hypothesise that impaired cerebrovascular reactivity and time spent below the lower limit of autoregulation during cardiopulmonary bypass will result in hypoperfusion injuries to the brain detectable by elevation in serum glial fibrillary acidic protein level. METHODS: We designed a multicentre observational pilot study combining concurrent cerebrovascular reactivity and biomarker monitoring during cardiopulmonary bypass. All children undergoing bypass for CHD were eligible. Autoregulation was monitored with the haemoglobin volume index, a moving correlation coefficient between the mean arterial blood pressure and the near-infrared spectroscopy-based trend of cerebral blood volume. Both haemoglobin volume index and glial fibrillary acidic protein data were analysed by phases of bypass. Each patient's autoregulation curve was analysed to identify the lower limit of autoregulation and optimal arterial blood pressure. RESULTS: A total of 57 children had autoregulation and biomarker data for all phases of bypass. The mean baseline haemoglobin volume index was 0.084. Haemoglobin volume index increased with lowering of pressure with 82% demonstrating a lower limit of autoregulation (41±9 mmHg), whereas 100% demonstrated optimal blood pressure (48±11 mmHg). There was a significant association between an individual's peak autoregulation and biomarker values (p=0.01). CONCLUSIONS: Individual, dynamic non-invasive cerebrovascular reactivity monitoring demonstrated transient periods of impairment related to possible silent brain injury. The association between an impaired autoregulation burden and elevation in the serum brain biomarker may identify brain perfusion risk that could result in injury.

Static cerebrovascular pressure autoregulation remains intact during deep hypothermia.

BACKGROUND: Clinical studies measuring cerebral blood flow in infants during deep hypothermia have demonstrated diminished cerebrovascular pressure autoregulation. The coexistence of hypotension in these cohorts confounds the conclusion that deep hypothermia impairs cerebrovascular pressure autoregulation. AIM: We sought to compare the lower limit of autoregulation and the static rate of autoregulation between normothermic and hypothermic piglets. METHODS: Twenty anesthetized neonatal piglets (5-7 days old; 10 normothermic and 10 hypothermic to 20°C) had continuous measurements of cortical red cell flux using laser Doppler flowmetry, while hemorrhagic hypotension was induced without cardiopulmonary bypass. Lower limit of autoregulation was determined for each subject using piecewise regression and SRoR was determined above and below each lower limit of autoregulation as (%change cerebrovascular resistance/%change cerebral perfusion pressure). RESULTS: The estimated difference in lower limit of autoregulation was 1.4 mm Hg (lower in the hypothermic piglets; 95% C.I. -10 to 14 mm Hg; P=0.6). The median lower limit of autoregulation in the normothermic group was 39 mm Hg [IQR 38-51] vs 35 mm Hg [31-50] in the hypothermic group. Intact steady-state pressure autoregulation was defined as static rate of autoregulation >0.5 and was demonstrated in all normothermic subjects (static rate of autoregulation=0.72 [0.65-0.87]) and in 9/10 of the hypothermic subjects (static rate of autoregulation=0.65 [0.52-0.87]). This difference in static rate of autoregulation of 0.06 (95% C.I. -0.3 to 0.1) was not significant (P=0.4). CONCLUSION: Intact steady-state cerebrovascular pressure autoregulation is demonstrated in a swine model of profound hypothermia. Lower limit of autoregulation and static rate of autoregulation were similar in hypothermic and normothermic subjects.

Does hypothermia impair cerebrovascular autoregulation in neonates during cardiopulmonary bypass?

BACKGROUND: Autoregulation monitoring has been proposed as a means to identify optimal arterial blood pressure goals during cardiopulmonary bypass, but it has been observed that cerebral blood flow is pressure passive during hypothermic bypass. When neonates cooled during cardiopulmonary bypass are managed with vasodilators and controlled hypotension, it is not clear whether hypothermia or hypotension were the cause of impaired autoregulation. AIM: We sought to measure the effect of both arterial blood pressure and hypothermia on autoregulation in a cohort of infants cooled for bypass, hypothesizing a collinear relationship between hypothermia, hypotension, and dysautoregulation. METHODS: Cardiopulmonary bypass was performed on 72 infants at Texas Children's Hospital during 2015 and 2016 with automated physiologic data capture, including arterial blood pressure, nasopharyngeal temperature, cerebral oximetry, and a cerebral blood volume index derived from near infrared spectroscopy. Cooling to 18°C, 24°C, and 30°C was performed on 33, 12, and 22 subjects, respectively. The hemoglobin volume index was calculated as a moving correlation coefficient between mean arterial blood pressure and the cerebral blood volume index. Positive values of the hemoglobin volume index indicate impaired autoregulation. Relationships between variables were assessed utilizing a generalized estimating equation approach. RESULTS: Hypothermia was associated with hypotension, dysautoregulation, and increased cerebral oximetry. Comparing the baseline temperature of 36°C with 18°C, arterial blood pressure was 44 mm Hg (39-52) vs 25 mm Hg (21-31); the hemoglobin volume index was 0.0 (-0.02 to 0.004) vs 0.5 (0.4-0.7) and cerebral oximetry was 59% (57-61) vs 88% (80-92) (Median, 95% CI of median; P<.0001 for all three associations by linear regression with generalized estimation of equations with data from all temperatures measured). CONCLUSIONS: Arterial blood pressure, temperature, and cerebral autoregulation were collinear in this cohort. The conclusion that hypothermia causes impaired autoregulation is thus confounded. The effect of temperature on autoregulation should be delineated before clinical deployment of autoregulation monitors to prevent erroneous determination of optimal arterial blood pressure. Showing the effect of temperature on autoregulation will require a normotensive hypothermic model.

The Upper Limit of Cerebral Blood Flow Autoregulation Is Decreased with Elevations in Intracranial Pressure.

BACKGROUND: The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. We sought to delineate the ULA in a neonatal swine model. METHODS: Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF; n = 10), controlled cortical impact (CCI; n = 10), or impact + infusion (CCI + INF; n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flux recordings during arterial hypertension until lethality. An increase in red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression and static rates of autoregulation (SRoRs) were determined above and below this inflection. RESULTS: When identified, the ULA (median [interquartile range]) was as follows: sham group: 102 mmHg (97-109), INF group: 75 mmHg (52-84), CCI group: 81 mmHg (69-101), and CCI + INF group: 61 mmHg (52-57; p = 0.01). Both groups with interventricular infusion had significantly lower ULA compared with the sham group. CONCLUSION: Neonatal piglets without intracranial pathological conditions tolerated acute hypertension, with minimal perturbation of cerebral blood flow. Piglets with acutely elevated intracranial pressure, with or without trauma, demonstrated loss of autoregulation when subjected to arterial hypertension.

Clostridium novyi-NT can cause regression of orthotopically implanted glioblastomas in rats.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that is especially difficult to treat. The tumor's ability to withstand hypoxia leads to enhanced cancer cell survival and therapy resistance, but also yields a microenvironment that is in many aspects unique within the human body, thus offering potential therapeutic opportunities. The spore-forming anaerobic bacterium Clostridium novyi-NT(C. novyi-NT) has the ability to propagate in tumor-generated hypoxia, leading to oncolysis. Here, we show that intravenously injected spores of C. novyi-NT led to dramatic tumor destructions and significant survival increases in implanted, intracranial syngeneic F98 and human xenograft 060919 rat GBM models. C. novyi-NT germination was specific and confined to the neoplasm, with sparing of the normal brain parenchyma. All animals tolerated the bacteriolytic treatment, but edema and increased intracranial pressure could quickly be lethal if not monitored and medically managed with hydration and antibiotics. These results provide pre-clinical data supporting the development of this therapeutic approach for the treatment of patients with GBM.

The upper limit of cerebral blood flow autoregulation is decreased with elevations in intracranial pressure.

BACKGROUND: The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. OBJECTIVE: To delineate the ULA in an infant swine model. METHODS: Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF) (n = 10), controlled cortical impact (CCI) (n = 10), or CCI + INF (n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flowmetry recordings during arterial hypertension to lethality using an aortic balloon catheter. An increase of red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression, and static rates of autoregulation were determined above and below this inflection. The ULA was rendered as the first instance of an upward deflection of Doppler flux causing a static rate of autoregulation decrease greater than 0.5. RESULTS: ULA was identified in 55% of piglets after sham surgery, 70% after INF, 70% after CCI, and 91% after CCI with INF (P = .36). When identified, the median (interquartile range) ULA was as follows: sham group, 102 mm Hg (97-109 mm Hg); INF group, 75 mm Hg (52-84 mm Hg); CCI group, 81 mm Hg (69-101 mm Hg); and CCI + INF group, 61 mm Hg (52-57 mm Hg) (P = .01). In post hoc analysis, both groups with interventricular INF had significantly lower ULA than that observed in the sham group. CONCLUSION: Neonatal piglets without intracranial pathology tolerated acute hypertension with minimal perturbation of cerebral blood flow. Piglets with acutely increased intracranial pressure with or without trauma demonstrated loss of autoregulation when subjected to arterial hypertension.

Continuous cerebrovascular reactivity monitoring and autoregulation monitoring identify similar lower limits of autoregulation in patients undergoing cardiopulmonary bypass.

OBJECTIVES: Cerebrovascular autoregulation can be monitored with a moving linear correlation of blood pressure to cerebral blood flow velocity (mean velocity index, Mx) during cardiopulmonary bypass (CPB). Vascular reactivity can be monitored with a moving linear correlation of blood pressure to cerebral blood volume trended with near-infrared spectroscopy (hemoglobin volume index, HVx). We hypothesized that the lower limits of autoregulation (LLA) and the optimal blood pressure (ABPopt) associated with the most active autoregulation could be determined by HVx in patients undergoing CPB. METHODS: Adult patients (n = 109) who underwent CPB for cardiac surgery had monitoring of both autoregulation (Mx) and vascular reactivity (HVx). Individual curves of Mx and HVx were constructed by placing each in 5 mmHg bins. The LLA and ABPopt for each subject were then identified by both methods and compared for agreement by correlation analysis and Bland-Altman. RESULTS: The average LLA defined by Mx compared to HVx were comparable (66±13 and 66±12 mmHg). Correlation between the LLA defined by Mx and HVx was significant (Pearson r = 0.2867; P = 0.0068). The average ABPopt with the most robust autoregulation by Mx was comparable to HVx (75±11 and 74±13 mmHg) with significant correlation (Pearson r = 0.5915; P < or =0.0001). DISCUSSION: Autoregulation and vascular reactivity monitoring are expected to be distinct, as flow and volume have different phasic relationships to pressure when cerebrovascular autoregulation is active. However, the two metrics have good agreement when identifying the LLA and optimal blood pressure in patients during CPB.

Noninvasive autoregulation monitoring in a swine model of pediatric cardiac arrest.

BACKGROUND: Cerebrovascular autoregulation after resuscitation has not been well studied in an experimental model of pediatric cardiac arrest. Furthermore, developing noninvasive methods of monitoring autoregulation using near-infrared spectroscopy (NIRS) would be clinically useful in guiding neuroprotective hemodynamic management after pediatric cardiac arrest. We tested the hypotheses that the lower limit of autoregulation (LLA) would shift to a higher arterial blood pressure between 1 and 2 days of recovery after cardiac arrest and that the LLA would be detected by NIRS-derived indices of autoregulation in a swine model of pediatric cardiac arrest. We also tested the hypothesis that autoregulation with hypertension would be impaired after cardiac arrest. METHODS: Data on LLA were obtained from neonatal piglets that had undergone hypoxic-asphyxic cardiac arrest and recovery for 1 day (n = 8) or 2 days (n = 8), or that had undergone sham surgery with 2 days of recovery (n = 8). Autoregulation with hypertension was examined in a separate cohort of piglets that underwent hypoxic-asphyxic cardiac arrest (n = 5) or sham surgery (n = 5) with 2 days of recovery. After the recovery period, piglets were reanesthetized, and autoregulation was monitored by standard laser-Doppler flowmetry and autoregulation indices derived from NIRS (the cerebral oximetry [COx] and hemoglobin volume [HVx] indices). The LLA was determined by decreasing blood pressure through inflation of a balloon catheter in the inferior vena cava. Autoregulation during hypertension was evaluated by inflation of an aortic balloon catheter. RESULTS: The LLAs were similar between sham-operated piglets and piglets that recovered for 1 or 2 days after arrest. The NIRS-derived indices accurately detected the LLA determined by laser-Doppler flowmetry. The area under the curve of the receiver operator characteristic curve for cerebral oximetry index was 0.91 at 1 day and 0.92 at 2 days after arrest. The area under the curve for hemoglobin volume index was 0.92 and 0.89 at the respective time points. During induced hypertension, the static rate of autoregulation, defined as the percentage change in cerebrovascular resistance divided by the percentage change in cerebral perfusion pressure, was not different between postarrest and sham-operated piglets. At 2 days recovery from arrest, piglets exhibited neurobehavioral deficits and histologic neuronal injury. CONCLUSIONS: In a swine model of pediatric hypoxic-asphyxic cardiac arrest with confirmed brain damage, the LLA did not differ 1 and 2 days after resuscitation. The NIRS-derived indices accurately detected the LLA in comparison with laser-Doppler flow measurements at those time points. Autoregulation remained functional during hypertension.

Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia.

OBJECTIVE: Knowledge remains limited regarding cerebral blood flow autoregulation after cardiac arrest and during postresuscitation hypothermia. We determined the relationship of cerebral blood flow to cerebral perfusion pressure in a swine model of pediatric hypoxic-asphyxic cardiac arrest during normothermia and hypothermia and tested novel measures of autoregulation derived from near-infrared spectroscopy. DESIGN: Prospective, balanced animal study. SETTING: Basic physiology laboratory at an academic institution. SUBJECTS: Eighty-four neonatal swine. INTERVENTIONS: Piglets underwent hypoxic-asphyxic cardiac arrest or sham surgery and recovered for 2 hrs with normothermia followed by 4 hrs of either moderate hypothermia or normothermia. In half of the groups, blood pressure was slowly decreased through inflation of a balloon catheter in the inferior vena cava to identify the lower limit of cerebral autoregulation at 6 hrs postresuscitation. In the remaining groups, blood pressure was gradually increased by inflation of a balloon catheter in the aorta to determine the autoregulatory response to hypertension. Measures of autoregulation obtained from standard laser-Doppler flowmetry and indices derived from near-infrared spectroscopy were compared. MEASUREMENTS AND MAIN RESULTS: Laser-Doppler flux was lower in postarrest animals compared to sham-operated controls during the 2-hr normothermic period after resuscitation. During the subsequent 4-hr recovery, hypothermia decreased laser-Doppler flux in both the sham surgery and postarrest groups. Autoregulation was intact during hypertension in all groups. With arterial hypotension, postarrest, hypothermic piglets had a significant decrease in the perfusion pressure lower limit of autoregulation compared to postarrest, normothermic piglets. The near-infrared spectroscopy-derived measures of autoregulation accurately detected loss of autoregulation during hypotension. CONCLUSIONS: In a pediatric model of cardiac arrest and resuscitation, delayed induction of hypothermia decreased cerebral perfusion and decreased the lower limit of autoregulation. Metrics derived from noninvasive near-infrared spectroscopy accurately identified the lower limit of autoregulation during normothermia and hypothermia in piglets resuscitated from arrest.

Neuroprotective effect of acid-sensing ion channel inhibitor psalmotoxin-1 after hypoxia-ischemia in newborn piglet striatum.

Na+,Ca2+-permeable acid-sensing ion channel 1a (ASIC1a) is involved in the pathophysiologic process of adult focal brain ischemia. However, little is known about its role in the pathogenesis of global cerebral ischemia or newborn hypoxia-ischemia (H-I). Here, using a newborn piglet model of asphyxia-induced cardiac arrest, we investigated the effect of ASIC1a-specific blocker psalmotoxin-1 on neuronal injury. During asphyxia and the first 30min of recovery, brain tissue pH fell below 7.0, the approximate activation pH of ASIC1a. Psalmotoxin-1 injection at 20min before hypoxia, but not at 20min of recovery, partially protected the striatonigral and striatopallidal neurons in putamen. Psalmotoxin-1 pretreatment largely attenuated the increased protein kinase A-dependent phosphorylation of DARPP-32 and N-methyl-d-aspartate (NMDA) receptor NR1 subunit and decreased nitrative and oxidative damage to proteins at 3h of recovery. Pretreatment with NMDA receptor antagonist MK-801 also provided partial neuroprotection in putamen, and combined pretreatment with psalmotoxin-1 and MK-801 yielded additive neuroprotection. These results indicate that ASIC1a activation contributes to neuronal death in newborn putamen after H-I through mechanisms that may involve protein kinase A-dependent phosphorylation of NMDA receptor and nitrative and oxidative stress.

The role of natriuretic peptide receptor-A signaling in unilateral lung ischemia-reperfusion injury in the intact mouse.

Ischemia-reperfusion (IR) causes human lung injury in association with the release of atrial and brain natriuretic peptides (ANP and BNP), but the role of ANP/BNP in IR lung injury is unknown. ANP and BNP bind to natriuretic peptide receptor-A (NPR-A) generating cGMP and to NPR-C, a clearance receptor that can decrease intracellular cAMP. To determine the role of NPR-A signaling in IR lung injury, we administered the NPR-A blocker anantin in an in vivo SWR mouse preparation of unilateral lung IR. With uninterrupted ventilation, the left pulmonary artery was occluded for 30 min and then reperfused for 60 or 150 min. Anantin administration decreased IR-induced Evans blue dye extravasation and wet weight in the reperfused left lung, suggesting an injurious role for NPR-A signaling in lung IR. In isolated mouse lungs, exogenous ANP (2.5 nM) added to the perfusate significantly increased the filtration coefficient sevenfold only if lungs were subjected to IR. This effect of ANP was also blocked by anantin. Unilateral in vivo IR increased endogenous plasma ANP, lung cGMP concentration, and lung protein kinase G (PKG(I)) activation. Anantin enhanced plasma ANP concentrations and attenuated the increase in cGMP and PKG(I) activation but had no effect on lung cAMP. These data suggest that lung IR triggered ANP release and altered endothelial signaling so that NPR-A activation caused increased pulmonary endothelial permeability.