Effects of circulatory arrest and cardiopulmonary bypass on cerebral autoregulation in neonatal swine.

BACKGROUND: Cerebral autoregulation mechanisms help maintain adequate cerebral blood flow (CBF) despite changes in cerebral perfusion pressure. Impairment of cerebral autoregulation, during and after cardiopulmonary bypass (CPB), may increase risk of neurologic injury in neonates undergoing surgery. In this study, alterations of cerebral autoregulation were assessed in a neonatal swine model probing four perfusion strategies. METHODS: Neonatal swine (n = 25) were randomized to continuous deep hypothermic cardiopulmonary bypass (DH-CPB, n = 7), deep hypothermic circulatory arrest (DHCA, n = 7), selective cerebral perfusion (SCP, n = 7) at deep hypothermia, or normothermic cardiopulmonary bypass (control, n = 4). The correlation coefficient (LDx) between laser Doppler measurements of CBF and mean arterial blood pressure was computed at initiation and conclusion of CPB. Alterations in cerebral autoregulation were assessed by the change between initial and final LDx measurements. RESULTS: Cerebral autoregulation became more impaired (LDx increased) in piglets that underwent DH-CPB (initial LDx: median 0.15, IQR [0.03, 0.26]; final: 0.45, [0.27, 0.74]; p = 0.02). LDx was not altered in those undergoing DHCA (p > 0.99) or SCP (p = 0.13). These differences were not explained by other risk factors. CONCLUSIONS: In a validated swine model of cardiac surgery, DH-CPB had a significant effect on cerebral autoregulation, whereas DHCA and SCP did not. IMPACT: Approximately half of the patients who survive neonatal heart surgery with cardiopulmonary bypass (CPB) experience neurodevelopmental delays. This preclinical investigation takes steps to elucidate and isolate potential perioperative risk factors of neurologic injury, such as impairment of cerebral autoregulation, associated with cardiac surgical procedures involving CPB. We demonstrate a method to characterize cerebral autoregulation during CPB pump flow changes in a neonatal swine model of cardiac surgery. Cerebral autoregulation was not altered in piglets that underwent deep hypothermic circulatory arrest (DHCA) or selective cerebral perfusion (SCP), but it was altered in piglets that underwent deep hypothermic CBP.

Does supply meet demand? A comparison of perfusion strategies on cerebral metabolism in a neonatal swine model.

OBJECTIVE: We aimed to determine the effects of selective antegrade cerebral perfusion compared with other perfusion strategies on indices of cerebral blood flow, oxygenation, cellular stress, and mitochondrial function. METHODS: One-week-old piglets (n = 41) were assigned to 5 treatment groups. Thirty-eight were placed on cardiopulmonary bypass. Of these, 30 were cooled to 18°C and underwent deep hypothermic circulatory arrest (n = 10), underwent selective antegrade cerebral perfusion at 10 mL/kg/min (n = 10), or remained on continuous cardiopulmonary bypass (deep hypothermic cardiopulmonary bypass, n = 10) for 40 minutes. Other subjects remained on normothermic cardiopulmonary bypass (n = 8) or underwent sham surgery (n = 3). Novel, noninvasive optical measurements recorded cerebral blood flow, cerebral tissue oxyhemoglobin concentration, oxygen extraction fraction, total hemoglobin concentration, and cerebral metabolic rate of oxygen. Invasive measurements of cerebral microdialysis and cerebral blood flow were recorded. Cerebral mitochondrial respiration and reactive oxygen species generation were assessed after the piglets were killed. RESULTS: During hypothermia, deep hypothermic circulatory arrest piglets experienced increases in oxygen extraction fraction (P < .001), indicating inadequate matching of oxygen supply and demand. Deep hypothermic cardiopulmonary bypass had higher cerebral blood flow (P = .046), oxyhemoglobin concentration (P = .019), and total hemoglobin concentration (P = .070) than selective antegrade cerebral perfusion, indicating greater oxygen delivery. Deep hypothermic circulatory arrest demonstrated worse mitochondrial function (P < .05), increased reactive oxygen species generation (P < .01), and increased markers of cellular stress (P < .01). Reactive oxygen species generation was increased in deep hypothermic cardiopulmonary bypass compared with selective antegrade cerebral perfusion (P < .05), but without significant microdialysis evidence of cerebral cellular stress. CONCLUSIONS: Selective antegrade cerebral perfusion meets cerebral metabolic demand and mitigates cerebral mitochondrial reactive oxygen species generation. Excess oxygen delivery during deep hypothermia may have deleterious effects on cerebral mitochondria that may contribute to adverse neurologic outcomes. We describe noninvasive measurements that may help guide perfusion strategies.

Increased cerebral mitochondrial dysfunction and reactive oxygen species with cardiopulmonary bypass.

OBJECTIVES: Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is unclear. This study examines the impact of CPB on cerebral mitochondrial reactive oxygen species (ROS) generation and mitochondrial bioenergetics. METHODS: Twenty-three piglets (mean weight 4.2 ± 0.5 kg) were placed on CPB for either 1, 2, 3 or 4 h (n = 5 per group) or underwent anaesthesia without CPB (sham, n = 3). Microdialysis was used to measure metabolic markers of ischaemia. At the conclusion of CPB or 4 h of sham, brain tissue was harvested. Utilizing high-resolution respirometry, with simultaneous fluorometric analysis, mitochondrial respiration and ROS were measured. RESULTS: There were no significant differences in markers of ischaemia between sham and experimental groups. Sham animals had significantly higher mitochondrial respiration than experimental animals, including maximal oxidative phosphorylation capacity of complex I (OXPHOSCI) (3.25 ± 0.18 vs 4-h CPB: 1.68 ± 0.10, P < 0.001) and maximal phosphorylating respiration capacity via convergent input through complexes I and II (OXPHOSCI+CII) (7.40 ± 0.24 vs 4-h CPB: 3.91 ± 0.20, P < 0.0001). At 4-h, experimental animals had significantly higher ROS related to non-phosphorylating respiration through complexes I and II (ETSCI+CII) than shams (1.08 ± 0.13 vs 0.64 ± 0.04, P = 0.026). CONCLUSIONS: Even in the absence of local markers of ischaemia, CPB is associated with decreased mitochondrial respiration relative to shams irrespective of duration. Exposure to 4 h of CPB resulted in a significant increase in cerebral mitochondrial ROS formation compared to shorter durations. Further study is needed to improve the understanding of cerebral mitochondrial health and its effects on the pathophysiology of neurological injury following exposure to CPB.

Deep hypothermic circulatory arrest in cyanotic piglets is associated with increased neuronal necrosis.

BACKGROUND: The contribution of neonatal cyanosis, inherent to cyanotic congenital heart disease, to the magnitude of neurologic injury during deep hypothermic circulatory arrest has not been fully delineated. This study investigates the impact of cyanosis and deep hypothermic circulatory arrest on brain injury. METHODS: Neonatal piglets were randomised to placement of a pulmonary artery to left atrium shunt to create cyanosis or sham thoracotomy. At day 7, animals were randomised to undergo deep hypothermic circulatory arrest or sham. Arterial oxygen tension and haematocrit were obtained. Neurobehavioural performance was serially assessed. The animals were sacrificed on day 14. Brain tissue was assessed for neuronal necrosis using a 5-point histopathologic score. RESULTS: Four experimental groups were analysed (sham, n = 10; sham + deep hypothermic circulatory arrest, n = 8; shunt, n = 9; shunt + deep hypothermic circulatory arrest, n = 7). Cyanotic piglets had significantly higher haematocrit and lower partial pressure of oxygen at day 14 than non-cyanotic piglets. There were no statistically significant differences in neurobehavioural scores at day 1. However, shunt + deep hypothermic circulatory arrest piglets had evidence of greater neuronal injury than sham animals (median (range): 2 (0-4) versus 0 (0-0), p = 0.02). DISCUSSION: Cyanotic piglets undergoing deep hypothermic circulatory arrest had increased neuronal injury compared to sham animals. Significant injury was not seen for either cyanosis or deep hypothermic circulatory arrest alone relative to shams. These findings suggest an interaction between cyanosis and deep hypothermic circulatory arrest and may partially explain the suboptimal neurologic outcomes seen in children with cyanotic heart disease who undergo deep hypothermic circulatory arrest.

Epinephrine's effects on cerebrovascular and systemic hemodynamics during cardiopulmonary resuscitation.

BACKGROUND: Despite controversies, epinephrine remains a mainstay of cardiopulmonary resuscitation (CPR). Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. The primary objectives of this study were to determine if (1) epinephrine doses have a significant acute effect on CBF and cerebral tissue oxygenation during CPR and (2) if the effect of each subsequent dose of epinephrine differs significantly from that of the first. METHODS: One-month-old piglets (n = 20) underwent asphyxia for 7 min, ventricular fibrillation, and CPR for 10-20 min. Epinephrine (20 mcg/kg) was administered at 2, 6, 10, 14, and 18 min of CPR. Invasive (laser Doppler, brain tissue oxygen tension [PbtO2]) and noninvasive (diffuse correlation spectroscopy and diffuse optical spectroscopy) measurements of CBF and cerebral tissue oxygenation were simultaneously recorded. Effects of subsequent epinephrine doses were compared to the first. RESULTS: With the first epinephrine dose during CPR, CBF and cerebral tissue oxygenation increased by > 10%, as measured by each of the invasive and noninvasive measures (p < 0.001). The effects of epinephrine on CBF and cerebral tissue oxygenation decreased with subsequent doses. By the fifth dose of epinephrine, there were no demonstrable increases in CBF of cerebral tissue oxygenation. Invasive and noninvasive CBF measurements were highly correlated during asphyxia (slope effect 1.3, p < 0.001) and CPR (slope effect 0.20, p < 0.001). CONCLUSIONS: This model suggests that epinephrine increases CBF and cerebral tissue oxygenation, but that effects wane following the third dose. Noninvasive measurements of neurological health parameters hold promise for developing and directing resuscitation strategies.

Placement of a rapid deployment aortic valve in a patient with severely calcified aortic root homograft.

Significant aortic calcification is a known sequelae of homograft aortic root replacement and creates a treatment challenge if these patients require cardiac reintervention. The standard surgical option for patients requiring an aortic valve replacement in the setting of a calcified aortic homograft has been a Bentall procedure, which is high-risk with extended cross-clamp, cardiopulmonary bypass and operative times. We present a patient with a severely calcified aortic homograft who underwent successful valve replacement using a rapid deployment aortic valve leaving the aortic root and arch intact and avoiding the more extensive redo aortic root replacement. Similar cases in the literature are rare.