Effects of lactate and carbon monoxide interactions on neuroprotection and neuropreservation.

Lactate, historically considered a waste product of anerobic metabolism, is a metabolite in whole-body metabolism needed for normal central nervous system (CNS) functions and a potent signaling molecule and hormone in the CNS. Neuronal activity signals normally induce its formation primarily in astrocytes and production is dependent on anerobic and aerobic metabolisms. Functions are dependent on normal dynamic, expansive, and evolving CNS functions. Levels can change under normal physiologic conditions and with CNS pathology. A readily combusted fuel that is sshuttled throughout the body, lactate is used as an energy source and is needed for CNS hemostasis, plasticity, memory, and excitability. Diffusion beyond the neuron active zone impacts activity of neurons and astrocytes in other areas of the brain. Barriergenesis, function of the blood-brain barrier, and buffering between oxidative metabolism and glycolysis and brain metabolism are affected by lactate. Important to neuroprotection, presence or absence is associated with L-lactate and heme oxygenase/carbon monoxide (a gasotransmitter) neuroprotective systems. Effects of carbon monoxide on L-lactate affect neuroprotection - interactions of the gasotransmitter with L-lactate are important to CNS stability, which will be reviewed in this article.

Cardiac function dependence on carbon monoxide.

Nitric oxide, studied to evaluate its role in cardiovascular physiology, has cardioprotective and therapeutic effects in cellular signaling, mitochondrial function, and in regulating inflammatory processes. Heme oxygenase (major role in catabolism of heme into biliverdin, carbon monoxide (CO), and iron) has similar effects as well. CO has been suggested as the molecule that is responsible for many of the above mentioned cytoprotective and therapeutic pathways as CO is a signaling molecule in the control of physiological functions. This is counterintuitive as toxic effects are related to its binding to hemoglobin. However, CO is normally produced in the body. Experimental evidence indicates that this toxic gas, CO, exerts cytoprotective properties related to cellular stress including the heart and is being assessed for its cytoprotective and cytotherapeutic properties. While survival of adult cardiomyocytes depends on oxidative phosphorylation (survival and resulting cardiac function is impaired by mitochondrial damage), mitochondrial biogenesis is modified by the heme oxygenase-1/CO system and can result in promotion of mitochondrial biogenesis by associating mitochondrial redox status to the redox-active transcription factors. It has been suggested that the heme oxygenase-1/CO system is important in differentiation of embryonic stem cells and maturation of cardiomyocytes which is thought to mitigate progression of degenerative cardiovascular diseases. Effects on other cardiac cells are being studied. Acute exposure to air pollution (and, therefore, CO) is associated with cardiovascular mortality, myocardial infarction, and heart failure, but changes in the endogenous heme oxygenase-1 system (and, thereby, CO) positively affect cardiovascular health. We will review the effect of CO on heart health and function in this article.

Neurointegrity and neurophysiology: astrocyte, glutamate, and carbon monoxide interactions.

Astrocyte contributions to brain function and prevention of neuropathologies are as extensive as that of neurons. Astroglial regulation of glutamate, a primary neurotransmitter, is through uptake, release through vesicular and non-vesicular pathways, and catabolism to intermediates. Homeostasis by astrocytes is considered to be of primary importance in determining normal central nervous system health and central nervous system physiology - glutamate is central to dynamic physiologic changes and central nervous system stability. Gasotransmitters may affect diverse glutamate interactions positively or negatively. The effect of carbon monoxide, an intrinsic central nervous system gasotransmitter, in the complex astrocyte homeostasis of glutamate may offer insights to normal brain development, protection, and its use as a neuromodulator and neurotherapeutic. In this article, we will review the effects of carbon monoxide on astrocyte homeostasis of glutamate.

The internal mammary artery as a shunt in a noncyanotic infant with hemitruncus: surgical and anesthetic management.

The internal mammary artery (IMA) has been used as a systemic-to-pulmonary artery shunt in selected patients with congenital heart disease. Growth and development of hypoplastic pulmonary arteries have been described. We discuss the surgical and anesthetic management of an infant with an atretic-thrombosed right pulmonary artery originating from the ascending aorta in whom the IMA was used to create a systemic-to-pulmonary artery shunt after failure of a previous shunt and later successful pulmonary artery reconstruction. The IMA should be considered as an alternative conduit in patients requiring a systemic-to-pulmonary artery shunt for growth of pulmonary arteries.

Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide.

Studies in animal models show that the primary mechanism by which heme-oxygenases impart beneficial effects is due to the gaseous molecule carbon monoxide (CO). Produced in humans mainly by the catabolism of heme by heme-oxygenase, CO is a neurotransmitter important for multiple neurologic functions and affects several intracellular pathways as a regulatory molecule. Exogenous administration of inhaled CO or carbon monoxide releasing molecules (CORM's) impart similar neurophysiological responses as the endogenous gas. Its' involvement in important neuronal functions suggests that regulation of CO synthesis and biochemical properties may be clinically relevant to neuroprotection and the key may be a change in metabolic substrate from glucose to lactate. Currently, the drug is under development as a therapeutic agent and safety studies in humans evaluating the safety and tolerability of inhaled doses of CO show no clinically important abnormalities, effects, or changes over time in laboratory safety variables. As an important therapeutic option, inhaled CO has entered clinical trials and its clinical role as a neuroprotective and neurotherapeutic agent has been suggested. In this article, we review the neuroprotective effects of endogenous CO and discuss exogenous CO as a neuroprotective and neurotherapeutic agent.

Inhaled carbon monoxide provides cerebral cytoprotection in pigs.

Carbon monoxide (CO) at low concentrations imparts protective effects in numerous preclinical small animal models of brain injury. Evidence of protection in large animal models of cerebral injury, however, has not been tested. Neurologic deficits following open heart surgery are likely related in part to ischemia reperfusion injury that occurs during cardiopulmonary bypass surgery. Using a model of deep hypothermic circulatory arrest (DHCA) in piglets, we evaluated the effects of CO to reduce cerebral injury. DHCA and cardiopulmonary bypass (CPB) induced significant alterations in metabolic demands, including a decrease in the oxygen/glucose index (OGI), an increase in lactate/glucose index (LGI) and a rise in cerebral blood pressure that ultimately resulted in increased cell death in the neocortex and hippocampus that was completely abrogated in piglets preconditioned with a low, safe dose of CO. Moreover CO-treated animals maintained normal, pre-CPB OGI and LGI and corresponding cerebral sinus pressures with no change in systemic hemodynamics or metabolic intermediates. Collectively, our data demonstrate that inhaled CO may be beneficial in preventing cerebral injury resulting from DHCA and offer important therapeutic options in newborns undergoing DHCA for open heart surgery.

Ultrasonic biophysical measurements in the normal human fetus for optimal design of the monolithic fetal pacemaker.

Ultrasound measurements, including xiphoid-to-pericardial distance and deployment angle, were made on human fetuses as a function of gestational age for the purpose of assessing the likelihood of 3 failure modes of a monolithic fetal pacemaker, including primary positioning failure due to device length and secondary dislodgement failure due to somatic growth. The small variation of the measurements over the gestational age range relevant to device implantation for the major indications of the device (for complete heart block complicated by hydrops and for bradycardia risk after fetal surgery or intrauterine intervention) predicts a small likelihood of these failure modes.

Does antegrade cerebral perfusion protect the brain during deep hypothermic circulatory arrest?

PURPOSE: This study compares cerebral protection using no cerebroplegia and using antegrade cerebroplegia with variable flow rates during deep hypothermic circulatory arrest (DHCA). METHODS: Twenty healthy neonatal piglets (2.5-3.8 kg) underwent 60 minutes of DHCA. No cerebroplegia was used in group 1 (n = 5). Cold (16 degrees C) antegrade cerebral perfusate was administered through the innominate artery at 10 mL/kg per minute in group 2 (n = 5), at 25 mL/kg per minute in group 3 (n = 5), and at 50 mL/kg per minute in group 4 (n = 5). Venous samples for lactate, pyruvate, S-100B protein, and creatine kinase BB (CKBB) were drawn from the jugular vein before and after discontinuation of cardiopulmonary bypass--lactate at 5 minutes postbypass, pyruvate at 5 minutes postbypass, S-100B protein at 30 minutes postbypass, and CKBB at 6 hours postbypass. Piglets were killed 6 hours postbypass and their brains were harvested for histological/immunologic studies. Extent of damage was assessed using a semiquantitative score of 0 to 4 based on a validated method. RESULTS: Evidence for significant apoptosis and necrosis was apparent in all groups. The mean H&E score was 2.2 for group 1, 2.3 for group 2, 2.5 for group 3, and 2.3 for group 4. The mean terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling score was 1.0 for group 1, 1.2 for group 2, 1.7 for group 3, and 0.8 for group 4. Pathological changes were not greater in the piglets that did not have antegrade cerebral perfusion. Serum lactate, pyruvate, S-100B protein, and CKBB did not distinguish between perfusion strategies. CONCLUSIONS: In neonates, unmodified antegrade cerebral perfusion at flow rates of 10, 25, and 50 mL/kg per minute during DHCA does not provide additional protection of the brain as determined by histology, immunology, serum lactate, pyruvate, S-100B protein, and CKBB.