Surgical Ischemia Research Articles

Acute Traumatic Aortic Injuries: Posttherapy Multidetector CT Findings

Acute traumatic aortic injury is a life-threatening entity that requires emergent treatment. Treatment was once performed with left thoracotomy, resection of the damaged aortic segment, and placement of an interposition graft. Within the past decade, endovascular therapy has gained increased acceptance, primarily because of a significant decrease in mortality and morbidity compared with those of surgery. The authors reviewed the experience with management of acute traumatic aortic injuries at their institution, as well as that reported in the literature. Complications after endovascular repair include endoleak, endograft collapse, stroke, upper extremity ischemia, paraplegia, graft infection, endograft structural failure, missed injury or stent migration, and access site complications. After surgical repair, paraplegia and ischemia to other organs, graft dehiscence, graft infection, and graft stenosis may occur. With the growing use of endovascular management of acute traumatic aortic injuries and the increased likelihood of patient survival, the radiologist will be expected to be familiar with the findings in these patients and is positioned to play a critical role in early recognition of potential complications. Early diagnosis of the complications of therapy for aortic injury is imperative for reduction of mortality and morbidity.

Embryonic stem cells attenuate myocardial dysfunction and inflammation after surgical global ischemia via paracrine actions

Stem cell treatment may positively influence recovery and inflammation after shock by multiple mechanisms, including the paracrine release of protective growth factors. Embryonic stem cells (ESCs) are understudied and may have greater protective power than adult bone marrow stem cells (BMSCs). We hypothesized that ESC paracrine protective mechanisms in the heart (decreased injury by enhanced growth factor-mediated reduction of proinflammatory cytokines) would be superior to the paracrine protective mechanisms of the adult stem cell population in a model of surgically induced global ischemia. Adult Sprague-Dawley rat hearts were isolated and perfused via Langendorff model. Hearts were subjected to 25 min of warm global ischemia and 40 min of reperfusion and were randomly assigned into one of four groups: 1) vehicle treated; 2) BMSC or ESC preischemic treatment; 3) BMSC or ESC postischemic treatment; and 4) BMSC- or ESC-conditioned media treatment. Myocardial function was recorded, and hearts were analyzed for expression of tissue cytokines and growth factors (ELISA). Additionally, ESCs and BMSCs in culture were assessed for growth factor production (ELISA). ESC-treated hearts demonstrated significantly greater postischemic recovery of function (left ventricular developed pressure, end-diastolic pressure, and maximal positive and negative values of the first derivative of pressure) than BMSC-treated hearts or controls at end reperfusion. ESC-conditioned media (without cells) also conferred cardioprotection at end reperfusion. ESC-infused hearts demonstrated increased VEGF and IL-10 production compared with BMSC hearts. ESC hearts also exhibited decreased proinflammatory cytokine expression compared with MSC hearts. Moreover, ESCs in cell culture demonstrated greater pluripotency than MSCs. ESC paracrine protective mechanisms in surgical ischemia are superior to those of adult stem cells.

Oxidative stress injury during cardiac surgery: How important is it?

See article by Milei et al. [11] (pages 710–719) in this issue. The concept that the reintroduction of oxygen to the ischaemic myocardium causes significant injury has long been known [1], and it is now well-established [2] that oxidative stress is one of the major initiators of myocardial injury during ischaemia and reperfusion. Cardiac surgery for coronary artery bypass generally involves cardiopulmonary bypass with cardioplegic arrest and elective global ischaemia of the heart. It would appear to represent the ideal situation to evaluate the potential injury induced by oxidative stress during ischaemia and subsequent reperfusion, since in this clinical situation (and unusually for most ischaemic conditions) the time of onset and the duration of ischaemia are known as is the time and conditions of reperfusion, and all are under the control of the operating surgeon. This means that studies in patients undergoing surgery are able to be controlled in a similar manner to that of experimental studies involving animal models. In experimental studies on isolated rat hearts, ischaemia and reperfusion are known to generate oxygen-derived free radicals; the use of electron-spin-resonance techniques has allowed the direct detection of reactive oxygen species produced when ischaemic myocardium is reperfused [3] and has also shown that this production can be prevented by various antioxidant or scavenger agents [4]. A large number of experimental studies that simulate this surgical ischaemia and reperfusion have shown that various antioxidant agents can ameliorate the detrimental effects of oxidative stress … *Tel.: +44 20 7188 0958; fax: +44 20 7188 3902. Email address: david.chambers{at}kcl.ac.uk david.chambers{at}gstt.nhs.uk

Cyclosporin A Has a Protective Effect with Induced Upregulation of Hsp70 and nNOS on Severe Spinal Cord Ischemic Injury in Rabbits

The purpose of this study is to ascertain the neuroprotective effect of cyclosporin A on the 25-min surgical ischemia model in the spinal cords of rabbits with neuropathological correlation and histoimmunochemical analyses measuring HSP70 and neuronal NOS (nNOS). New Zealand white rabbits were randomly divided into four groups (each n = 8): the C2, C7, Cs2, and Cs7 groups. The C2 and C7 groups underwent a 25-min surgical aortic cross-clamp without intervention and were sacrificed respectively on day 2 and on day 7 postoperatively. The Cs2 and Cs7 groups received cyclosporin A (25 mg/kg) intravenously 15 min after the 25-min cross-clamp and were sacrificed respectively on day 2 and day 7 postoperatively. Neurologic functions were evaluated on postoperative days 2 and 7 using the Tarlov scoring system. Then the rabbits were sacrificed for histopathologic observation. HSP 70 and nNOS stains with TUNEL assay were done for the C2 and Cs2 groups. All rabbits survived the experimental procedure. Tarlov's score for the Cs7 group (2.75 ± 0.89) was significantly higher than that of the C7 group (1.25 ± 1.39) (p <. 05). Tarlov's score of the Cs7 group was also statistically higher on day 7 than on day 2 (p <. 05). Strong correlation between the neurological and histological scorings was found. The TUNEL assay showed that the mean number of positive cells in the C2 group was 17.5 ± 22.6 and in the Cs2 group was 12.5 ± 11.1, but there was no statistically significant difference between the groups. There was more expression of HSP70 and nNOS in the cyclosporin groups than in the ischemia groups. In conclusion, this study demonstrates that cyclosporin A reduces neurological injury in the rabbit model of 25-min spinal cord ischemia. The neuroprotective effect of cyclosporin A against ischemia seems to be related to overexpressions of nNOS and HSP70.

Value of Triple H Therapy in a Patient with an Ischemic Penumbra Following Subarachnoid Hemorrhage

We report the case of a 43-year-old patient with delayed ischemic neurological deficit and an ischemic penumbra, reversed with triple H therapy (hypertension, hypervolemia, and hemodilution). The patient presented with subarachnoid hemorrhage caused by an aneurysm of the anterior communicating artery. He underwent surgical clipping and developed cerebral ischemia due to vasospasm. Permanent damage to the area of ischemic brain was prevented by institution of the triple H therapy. He recovered and was discharged with no subsequent neurological deficits.

Vitamin C prophylaxis promotes oxidative lipid damage during surgical ischemia–reperfusion

Reactive oxygen species (ROS) have been implicated in the cellular membrane damage and postoperative morbidity associated with obligatory ischemia–reperfusion (I-R) during vascular surgery. Thus, a clinical study was undertaken to evaluate the effects of ascorbate prophylaxis on ROS exchange kinetics in 22 patients scheduled for elective abdominal aortic aneurysm (AAA) or infra-inguinal bypass (IIB) repair. Patients were assigned double-blind to receive intravenous sodium ascorbate (2 g vitamin C, n = 10) or placebo (0.9% saline, n = 12) administered 2 h prior to surgery. Blood samples were obtained from the arterial and venous circulation proximal to the respective sites of surgical repair (local) and from an antecubital vein (peripheral) during cross-clamping (ischemia) and within 60 s of clamp release (reperfusion). Ascorbate supplementation increased the venoarterial concentration difference ( v– a diff) of lipid hydroperoxides (LH), interleukin (IL)-6 and vascular endothelial growth factor (VEGF) protein during ischemia. This increased the peripheral concentration of LH, total creatine phosphokinase (CPK), and VEGF protein during reperfusion ( P < 0.05 vs placebo). Electron paramagnetic resonance (EPR) spectroscopy confirmed that free iron was available for oxidative catalysis in the local ischemic venous blood of supplemented patients. An increased concentration of the ascorbate radical (A − ) and α-phenyl- tert-butylnitrone (PBN) adducts assigned as lipid-derived alkoxyl (LO ) and alkyl (LC ) species were also detected in the peripheral blood of supplemented patients during reperfusion ( P < 0.05 vs ischemia). In conclusion, these findings suggest that ascorbate prophylaxis may have promoted iron-induced oxidative lipid damage via a Fenton-type reaction initiated during the ischemic phase of surgery. The subsequent release of LH into the systemic circulation may have catalyzed formation of second-generation radicals implicated in the regulation of vascular permeability and angiogenesis.

Dolor miofascial tras la artroscopia de rodilla: estudio de la prevalencia y de los posibles factores de activación

Objective To find out the prevalence of Myofascial Trigger Points (MTPs) in a sample of patients who have undergone arthroscopic knee surgery and to make a study of the possible activating factors of this activation. Materials and methods The study has been undertaken with a sample of 46 patients (28 male and 18 female) with an age range of 18-74 years old (average age 39,95 years old). The patients’ knees were given a general examination and localised examination of the muscles relationated with myofascial pain of the region searching MTPs. Only the post-operative MTPs were taken into consideration as the pain identified prior to surgery was not related to the post-operative state of the patient. The exploration was repeated periodically until the patient was discharged or in the case of the results of the MTPs search were stable during four consecutive evaluations. The statistical analysis was undertaken using the 11.5 SPSS programme version for Windows. Results The data show a prevalence of 58,7 % of MTPs activation. The majority of patients have between 2 and 5 active MTPs over the recuperation period (77,7 %). A total of 91 MTPs have been found. The muscles, which have activated their MTPs more frequently, were vastus medialis, popliteus, vastus lateralis, internal gastrocnemius and internal ischiotibialis. With regard to the study of the activating factors, the activations caused by surgical ischemia are prominent, although the possibility of multiple activating factors in the activations is also quite possible. Of the patients who were not subjected to surgical ischemia, only 11,1 % had active MTPs. Conclusions The appearance of the Myofascial Pain Syndrome after knee arthroscopies occurs in 58,7 % of patients. The majority have between 2 and 5 MTPs during their recuperation period. With regard to the factors of activation, the surgical ischemia is prominent. The knee flexum and the pain and/or adherences in the entry points have more importance when they are combined, above all with ischemia.

Pretreatment with an adenosine A1 receptor agonist and lidocaine: A possible alternative to myocardial ischemic preconditioning

The heart possesses an extraordinary ability to remember short episodes of sublethal ischemia and reperfusion (angina), which protects the myocardium and coronary vasculature from a subsequent lethal insult, a phenomenon known as ischemic preconditioning. A therapeutic goal for more than 2 decades has been to develop a pharmacologic mimetic comparable with ischemic preconditioning. Our aim was to investigate the preconditioning effect of a new combinatorial therapy targeting adenosine A1 receptors and voltage-dependent sodium fast channels in the in vivo rat model of regional ischemia. Ischemia-reperfusion was achieved by placing a reversible tie around the left coronary artery in anesthetized and ventilated Sprague-Dawley rats (n = 37). Rats were randomly assigned to 1 of 5 groups: (1) saline control (n = 13); (2) ischemic preconditioning (n = 6); (3) lidocaine only (608 microg . kg -1 . min -1 , n = 5); (4) adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 5 microg/kg, n = 7); and (5) CCPA plus lidocaine (n = 6). Ischemic preconditioning was achieved by using 3 cycles of ischemia and reperfusion lasting 3 minutes each. Lidocaine was infused continuously 5 minutes before and throughout 30 minutes of ischemia and ceased at reperfusion. A bolus of CCPA was infused 5 minutes before ligation along with a constant infusion of lidocaine (as above). All animals were reperfused for 120 minutes for infarct size measurement. Fifty-four percent of saline control rats, 17% of ischemic preconditioning-treated rats, and 29% of CCPA-treated rats died during ischemia from ventricular fibrillation. Infarct size of saline control animals was 61% +/- 5%. Pretreating with CCPA and lidocaine infusion resulted in no deaths, no severe arrhythmias, and significant infarct size reduction compared with that seen in saline control animals (P < .05). Remarkably, infarct size reduction in CCPA plus lidocaine-treated rats (12% +/- 4%) was equivalent to that achieved with ischemic preconditioning (11% +/- 3%), whereas infarct size in rats undergoing CCPA-only and lidocaine-only treatments was 42% +/- 7% and 60% +/- 6%, respectively. Although CCPA plus lidocaine treatment reduced heart rate, mean arterial pressure, and systolic pressure during ischemia, no correlation was found between these variables and infarct size reduction. We conclude that activating adenosine A1 receptor subtype with CCPA and concomitantly modulating sodium fast channels with lidocaine was comparable with ischemic preconditioning and might offer a new therapeutic window to minimize myocardial damage during surgical ischemia and reperfusion.

Protein kinase C and myocardial calcium handling during ischemia and reperfusion: lessons learned using Rhod-2 spectrofluorometry.

We sought to assess myocardial Ca (2+) handling and excitation-contraction coupling in surgically relevant models of ischemia-reperfusion injury and to clarify the importance of protein kinase C (PKC) for cardioprotection. Experimentally, surgical ischemia and reperfusion can only be mimicked in intact perfused heart models. We introduced the long-wavelength fluorescent Ca (2+) indicator Rhod-2 for real-time recording of cytosolic Ca (2+) transients in Langendorff-perfused rabbit, rat, and mouse hearts, and utilized it to study the impact of PKC on myocardial Ca (2+) handling during ischemia and reperfusion. We first established that the dissociation constant for Rhod-2 and Ca (2+) must be adjusted to account for changes in pH and temperature during ischemia and reperfusion. Based on this method, we determined the time-course and extent of cytosolic Ca (2+) accumulation during myocardial ischemia, which is associated with translocation of the PKC isoforms alpha and epsilon between the cytosolic and particulate compartments in cardiomyocytes. The PKC translocation is mediated by activation of phosphatidyl-inositol-specific phospholipase C (PI-PLC), and represents a cardioprotective mechanism. Finally, we studied the mechanism of action of PKC and found that it both limits the accumulation of cytosolic Ca (2+) during reperfusion and attenuates contractile protein Ca (2+) sensitivity via phosphorylation of troponin I. Rhod-2 spectrofluorometry is a valuable tool for assessment of cytosolic Ca (2+) in surgically relevant experimental models and can aid the development of more effective methods for myocardial protection.

Relación entre la cirugía artroscópica de rodilla y la activación de puntos gatillo miofasciales: presentación de una hipótesis

AbstractSince Dr. Severin Nodertoft performed the first interior exploration of the knee using arthroscopy, this procedure has made huge progress throughout the twentieth century and is now used in many pathological processes.Although this technique has greatly reduced postoperative complications, physiotherapists find, in the treatment of patients who have undergone knee arthroscopy, the activation of different Myofascial Trigger Points (MTPs) that explain various painful symptoms present. The possible causes of the appearance of these MTPs are:–The adherences and pain at entry points.– The surgical ischemia.– Knee flexion caused by secondary hydrarthrosis due to surgery.It appears that each cause can activate a specific group of MTPs in the flexor and extensor muscles of the knee.This study puts forward a hypothesis to explain the specific relationship between the origin of activation and MTPs activated and attempts to verify this by clinical investigation.

Activation of protein kinases in chronically hypoxic infant human and rabbit hearts: role in cardioprotection.

Many infants who undergo heart surgery have a congenital cyanotic defect in which the heart is chronically perfused with hypoxic blood. However, the signaling pathways by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia is unknown. We determined the activation and translocation of protein kinase C (PKC) isoforms and mitogen activated protein kinases (MAP kinases) in 15 infants with cyanotic (SaO2<85%) or acyanotic (SaO2>95%) heart defects undergoing surgical repair and in 80 rabbits raised from birth in a hypoxic (SaO2<85%) or normoxic (SaO2>95%) environment. Tissues from infant human and rabbit hearts were processed for Western and in vitro kinase analysis. In human infants with cyanotic heart defects, PKCepsilon, p38 MAP kinase, and JUN kinase but not p42/44 MAP kinase were activated and translocated from the cytosolic to the particulate fraction compared with acyanotic heart defects. In rabbit infants there was a parallel response for PKCepsilon, p38 MAP kinase, and JUN kinase similar to humans. In infant rabbit hearts inhibition of PKCepsilon with chelerythrine, p38 MAP kinase, with SB203580 and JUN kinase with curcumin abolished the cardioprotective effects of chronic hypoxia but had no effects on normoxic hearts. Infant human and rabbit hearts adapt to chronic hypoxia through activation of PKCepsilon, p38 MAP kinase, and JUN kinase signal transduction pathways. These pathways may be responsible for cardioprotection in the chronically hypoxic infant rabbit heart.

Vascular endothelial growth factor gene therapy in ischaemic rat skin flaps

Gene therapy with the complementary DNA (cDNA) of the angiogenic cytokine vascular endothelial growth factor (VEGF) has emerged as a promising strategy in the treatment of myocardial and lower-limb ischaemia. The objective of this study was to determine whether these principles could be applied to a recognised model of skin-flap ischaemia. Plasmid vectors including the cDNA of green fluorescent protein (GFP) and one of three VEGF isoforms (A165, B167 or B186) were constructed, and their base sequences confirmed. GFP expression was used as a marker of successful in vitro transfection of human endothelial cells with each plasmid. The plasmids were then administered subcutaneously to rat abdominal skin flaps surgically rendered ischaemic, and the percentage of viable tissue was assessed at 1 week. Angiograms of the flaps and histological preparations of flap tissue were assessed for evidence of angiogenesis. The survival of flaps treated with VEGF A165 or B167 cDNA was significantly greater than that of controls (P < 0.05). The survival of flaps treated with VEGF B186 cDNA was greater than that of controls, but statistical significance was not reached. Angiograms and microvessel density counts failed to produce evidence of angiogenesis. With improved delivery strategies, VEGF may have a role in the management of surgical ischaemia.

Diazoxide protects mitochondria from anoxic injury: Implications for myopreservation

Background: Heart muscle primarily relies on adenosine triphosphate produced by oxidative phosphorylation and is highly vulnerable to anoxic insult. Although a number of strategies aimed at improving myopreservation are available, no effective means of preserving mitochondrial energetics under conditions of anoxic injury have been developed. Openers of mitochondrial adenosine triphosphate–sensitive potassium channels have emerged as powerful cardioprotective agents presumably capable of maintaining mitochondrial function under metabolic stress. Here, we evaluated the ability of a prototype mitochondrial adenosine triphosphate–sensitive potassium channel opener, diazoxide, to preserve oxidative phosphorylation in mitochondria subjected to anoxia and reoxygenation. Methods: Mitochondria were isolated from rat hearts and subjected to 20 minutes of anoxia, followed by reoxygenation. Mitochondrial respiration and oxidative phosphorylation, as well as mitochondrial integrity, were assessed by means of ion-selective minielectrodes, high-performance liquid chromatography, fluorometry, and electron microscopy. Results: Anoxia-reoxygenation decreased the rate of adenosine diphosphate–stimulated oxygen consumption, inhibited adenosine triphosphate production, and disrupted mitochondrial integrity. On average, anoxic stress reduced adenosine diphosphate–stimulated respiration from 291 ± 14 to 141 ± 15 ng-atoms O2 · min–1 · mg–1 protein and decreased the rate of adenosine triphosphate production from 752 ± 14 to 414 ± 34 nmol adenosine triphosphate · min–1 · mg–1 protein. After anoxia, the majority (88%) of mitochondria was damaged or swollen and released adenylate kinase, a marker of mitochondrial integrity. Diazoxide (100 μmol/L), present throughout anoxia, preserved adenosine diphosphate–stimulated respiration at 255 ± 7 ng-atoms O2 · min–1 · mg–1 protein and adenosine triphosphate production at 640 ± 39 nmol adenosine triphosphate · min–1 · mg–1 protein. Diazoxide also protected mitochondrial structure from anoxia-mediated damage, so that after anoxic stress, 67% of mitochondria remained intact and adenylate kinase was confined to the mitochondria. Conclusions: The present study demonstrates that diazoxide diminishes anoxia-induced functional and structural deterioration of cardiac mitochondria. By protecting mitochondria and preserving myocardial energetics, diazoxide may be useful under conditions of reduced oxygen availability, including global surgical ischemia or storage of donor heart. (J Thorac Cardiovasc Surg 2001;121:298-306)

Does the degree of cyanosis affect myocardial adenosine triphosphate levels and function in children undergoing surgical procedures for congenital heart disease?

Objective: The outcome of children with cyanosis after cardiac surgical procedures is inferior to that of children who are acyanotic. Animal studies indicated detrimental effects of chronic hypoxia on myocardial metabolism and function. We studied whether the presence or the degree of cyanosis adversely affected myocardial adenosine triphosphate, ventricular function, and clinical outcome in children. Methods: Forty-eight children who underwent repair of tetralogy of Fallot were divided according to their preoperative saturation: group I, 90% to 100% (n = 14 patients); group II, 80% to 89% (n = 16 patients); and group III, 65% to 79% (n = 18 patients). Adenosine triphosphate was measured from right ventricular biopsy specimens taken before ischemia, at 15 minutes of ischemia, at end-ischemia, and at 15 minutes of reperfusion. Ejection fraction was measured by echocardiography. Results: Even before surgical ischemia, compared with groups I and II, group III had lower preoperative ejection fraction (59% ± 2.9% vs 67% ± 1.7% and 68% ± 1.0%; P < .01) and lower preischemic adenosine triphosphate levels (15.1 ± 2.1 vs 19.1 ± 1.9 and 21.4 ± 1.5 μmol/g dry weight; P < .01). After 15 minutes of ischemia, group III had lower adenosine triphosphate levels (11.2 ± 1.8 vs 14.77 ± 2.3 and 17.6 ± 3.1 μmol/g dry weight; P < .01). With reperfusion, both cyanotic groups lost further adenosine triphosphate compared with partial recovery in the acyanotic group (–22% ± 3.8%, –20% ± 3.1% vs +18% ± 1.8%; P < .01). Children in group III had a more complicated postoperative course as evidenced by longer ventilatory support (85 ± 25 hours vs 31 ± 15 and 40 ± 21 hours; P = .07), inotropic support (86 ± 23 hours vs 38 ± 12 and 36 ± 4 hours; P < .01), and intensive care unit stay (160 ± 35 hours vs 60 ± 10 and 82 ± 18 hours; P = .02). Conclusions: The degree of cyanosis adversely affects myocardial adenosine triphosphate, function, and clinical outcome of children who undergo cardiac operation. Children with cyanosis should be identified as a higher risk group that could be targeted for supportive interventions. (J Thorac Cardiovasc Surg 2000;119:515-24)

Introduction

The first symposium on “Myocardial Protection From Surgical Ischemia and Reperfusion Injury” was held in Asheville, North Carolina in September 1994, and the second was held in 1997. During the intervening years, much occurred in the field of research and clinical applications of myocardial protective strategies for surgical ischemic and reperfusion injury. In a unique collaboration between basic science and clinical medicine, greater knowledge about the pathophysiology of myocardial injury, both in the ischemic and reperfusion phases, has been brought forth due to intense and innovative research into the molecular aspects of the responses and adaptations to injury. In addition, the interaction between the vascular endothelium and inflammatory cells has emerged as an important mediator of the pathophysiology of the ischemic-reperfusion injury pattern with particular relevance to cardiopulmonary bypass, representing a potential therapeutic target. Autacoids such as adenosine and nitric oxide have been studied extensively in relation to their protective effects, both during ischemia and reperfusion, through actions on a broad spectrum of targets including, neutrophils, endothelial cells, and the generation of oxygen radicals. Molecular mechanisms relating not only to the pathophysiology of ischemia, but also to myocardial protection, are being intensively investigated and are reported in this symposium. The first attempts at gene therapy to modify myocardial responses to stress and ischemia are just now being evaluated in experimental situations for possible assimilation into the surgical armamentarium.

Spinal cord protection during aortic cross-clamping using retrograde venous perfusion

Background. Paraplegia remains a devastating complication following thoracic aortic operation. We hypothesized that retrograde perfusion of the spinal cord with a hypothermic, adenosine-enhanced solution would provide protection during periods of ischemia due to temporary aortic occlusion. Methods. In a rabbit model, a 45-minute period of spinal cord ischemia was produced by clamping the abdominal aorta and vena cava just below the left renal vessels and at their bifurcations. Four groups (n = 8/group) were studied: control, warm saline, cold saline, and cold saline with adenosine infusion. In the experimental groups, saline or saline plus adenosine was infused into the isolated cavae throughout the ischemic period. Clamps were removed and the animals to recovered for 24 hours before blinded neurological evaluation. Results. Tarlov scores (0 = paraplegia, 1 = slight movement, 2 = sits with assistance, 3 = sits alone, 4 = weak hop, 5 = normal hop) were (mean ± standard error of the mean): control, 0.50 ± 0.50; warm saline, 1.63 ± 0.56; cold saline, 3.38 ± 0.26; and cold saline plus adenosine, 4.25 ± 0.16 (analysis of variance for all four groups, p < 0.00001). Post-hoc contrast analysis showed that cold saline plus adenosine was superior to the other three groups ( p < 0.0001). Conclusion. Retrograde venous perfusion of the spinal cord with hypothermic saline and adenosine provides functional protection against surgical ischemia and reperfusion.

Protective action of 17β-estradiol in cardiac cells: implications for hyperkalemic cardioplegia

Background. Hyperkalemic cardioplegic solutions effectively arrest the heart, but may also induce intracellular Ca 2+ loading and cellular hypercontracture, which could contribute to ventricular dysfunction associated with global surgical ischemia. Recently, it has been proposed that 17β-estradiol may possess protective properties in the ischemic myocardium. The purpose of the present study was to examine the action of 17β-estradiol on cardiac cells exposed to hyperkalemic stress. Methods. Single ventricular cardiomyocytes, a preparation devoid of vascular and neuronal elements, were isolated from guinea pig hearts, loaded with a Ca 2+-sensitive fluorescent probe, and imaged by digital epifluorescent microscopy. The emitted fluorescence of the probe, a measure of intracellular Ca 2+ concentration, and cell length were simultaneously recorded during hyperkalemic challenge, in the absence or presence of 17β-estradiol. Results. In control cardiomyocytes, the cytosolic concentration of Ca 2+ was 138 ± 11 nmol/L and cell length 93 ± 11 μm. Exposure to high K + (+16 mmol/L KCl) significantly increased cytosolic Ca 2+ to 2,191 ± 187 nmol/L ( p < 0.001), and produced cell shortening (length at 39 ± 5 μm; p < 0.001). 17β-Estradiol (10 μmol/L) acutely prevented high K + to induce either intracellular Ca 2+ loading (144 ± 13 nmol/L, p < 0.001) or hypercontracture (91 ± 10 μm, p < 0.001). Tamoxifen (10 μmol/L), an antiestrogen, abolished the protective effect of 17β-estradiol. Conclusions. We conclude that 17β-estradiol prevents hyperkalemia-induced Ca 2+ loading and hypercontracture through a direct and tamoxifen-sensitive action in cardiomyocytes. This study raises the possibility that 17β-estradiol should be considered as a cardioprotective adjunct toward a safer hyperkalemic cardioplegia.

Studies of hypoxemic/reoxygenation injury:: I. Linkage between cardiac function and oxidant damage

Surgical correction of cardiac defects causing cyanosis is done with the use of cardiopulmonary bypass (CPB) in early infancy with increasing frequency. Postoperative cardiac dysfunction is the major cause of morbidity and mortality despite successful anatomic correction and is more severe than after repair of acquired defects in adults with normoxic conditions. 1 Intraoperative management differs principally in that reversal of hypoxemia occurs with initiation of extracorporeal circulation and precedes the surgical ischemia used for operative repair in children with cyanotic disease. The conventional method of starting CPB in infants and children with hypoxemia is to raise oxygen tension (P02) to approximately 400 mm Hg by priming the extracorporeal circuit with hyperoxic fluid. We have speculated that this causes an unintended reoxygenation that adds to subsequent intraoperative stress when surgical ischemia is needed to provide a bloodless field. 2 The role of reoxygenation injury as a contributory factor has yet to be established, despite experimental evidence that functional, biochemical, and structural alterations that follow reoxygenation are similar to changes that follow reperfusion after ischemia: these include stunned myocardium, 3' 4 lipid peroxidation, 5 enzyme release, 6 and necrosis. 7 Several clinical observations support this hypothesis including (1) myocardial lipid peroxidation in preischemic right ventricular biopsy samples from children with cyanotic Conditions supported by CPB, 8 (2) reduced myocardial endogenous antioxidants in cyanotic versus normoxic patients, 9 (3) strong correlation between Po 2 and endogenous antioxidant enzymes, a°

Electrophysiologic Consequences of Hyperkalemic Cardioplegia during Surgical Ischemia

Abstract Myocardial protection strategics use cardioplegic solutions to reduce the injury induced by surgical ischemia and reperfusion. However, there is a high incidence of electrophysiotogic abnormalities after cardioplegic arrest. A computerized epicardial mapping system in a porcine cardiopulmonary bypass model was used to measure the electrophysiologic consequences of different myocardial protection techniques. Both warm and cold, crystalloid and blood cardioplegic solutions were compared. The effects of hypothermia and prolonged cardiopulmonary bypass were examined in a control group that underwent a 2-hour period of hypothermia without cardioplegia or aortic cross-clamping, followed by 2 hours of normothermic reperfusion. Isochronous activation maps, unipolar electrograms, ventricular refractory periods, and pacing thresholds were measured before cardioplegic arrest and during reperfusion. Compared with the control group, crystalloid cardioplegia, but not blood cardioplegia, was accompanied by large changes in the pattern of ventricular activation and by persistent (> 2 hours) and significant slowing of the time required for complete ventricular activation. This was not the result of hypoxia. Moreover, the effective refractory period and the pacing threshold were unchanged by any cardioplegia. Our data suggest that crystalloid cardioplegia increases myocardial resistance to current flow leading to a derangement of electrical impulse propagation that may underlie arrhythmogenesis.

Role of controlled cardiac reoxygenation in reducing nitric oxide production and cardiac oxidant damage in cyanotic infantile hearts.

Cardiopulmonary bypass (CPB) is used increasingly to correct cyanotic heart defects during early infancy, but myocardial dysfunction is often seen after surgical repair. This study evaluates whether starting CPB at a conventional, hyperoxic pO2 causes an "unintentional" reoxygenation (ReO2) injury. We subjected 2-wk-old piglets to ventilator hypoxemia (FIO2 approximately 0.06, pO2 approximately 25 mmHg) followed by 5 min of ReO2 on CPB before instituting cardioplegia. CPB was begun in hypoxemic piglets by either abrupt ReO2 at a pO2 of 400 mmHg (standard clinical practice) or by maintaining pO2 approximately 25 mmHg on CPB until controlling ReO2 with blood cardioplegic arrest. The effects of abrupt vs. gradual ReO2 without surgical ischemia (blood cardioplegia) were also compared. Myocardial nitric oxide (NO) production (chemiluminescence measurements of NO2- + NO3-) and conjugated diene (CD) generation (spectrophotometric A233 measurements of lipid extracts) using aortic and coronary sinus blood samples were assessed during cardioplegic induction. 30 min after CPB, left ventricular end-systolic elastance (Ees, catheter conductance method) was used to determine cardiac function. CPB and blood cardioplegic arrest caused no functional or biochemical change in normoxic (control) hearts. Abrupt ReO2 caused a depression of myocardial function (Ees = 25 +/- 5% of control). Functional depression was relatively unaffected by gradual ReO2 without blood cardioplegia (34% recovery of Ees), and abrupt ReO2 immediately before blood cardioplegia caused a 10-fold rise in cardiac NO and CD production, with subsequent depression of myocardial function (Ees 21 +/- 2% of control). In contrast, controlled cardiac ReO2 reduced NO production 94%, CD did not rise, and Ees was 83 +/- 8% of normal. We conclude ReO2 injury is related to increased NO production during abrupt ReO2, nullifies the cardioprotective effects of blood cardioplegia, and that controlled cardiac ReO2 when starting CPB to correct cyanotic heart defects may reduce NO production and improve myocardial status postoperatively.