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.

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.