Intravenous Phenylephrine Preconditioning of Cardiac Grafts From Non–Heart-Beating Donors

Background. Hypoxia and warm ischemia produce severe injury to cardiac grafts harvested from non–heart-beating donors. To potentially improve recovery of such grafts, we studied the effects of intravenous phenylephrine preconditioning.Methods. Thirty-seven blood-perfused rabbit hearts were studied. Three groups of non–heart-beating donors underwent intravenous treatment with phenylephrine at 12.5 (n = 8), 25 (n = 7), or 50 μg/kg (n = 7) before initiation of apnea. Non–heart-beating controls (n = 8) received saline vehicle. Hypoxic cardiac arrest occurred after 6 to 12 minutes of apnea, followed by 20 minutes of warm in vivo ischemia. A 45-minute period of ex vivo reperfusion ensued. Nonischemic controls (n = 7) were perfused without antecedent hypoxia or ischemia.Results. Phenylephrine 25 μg/kg significantly delayed the onset of hypoxic cardiac arrest compared with saline controls (9.6 ± 0.5 versus 7.7 ± 0.4 minutes; p = 0.00001), yet improved recovery of left ventricular developed pressure compared with saline controls (57.1 ± 5.3 versus 41.0 ± 3.4 mm Hg; p = 0.04). Phenylephrine 25 μg/kg also yielded a trend toward less myocardial edema than saline vehicle (p = 0.09).Conclusions. Functional recovery of nonbeating cardiac grafts is improved by preconditioning. We provide evidence that the myocardium can be preconditioned with phenylephrine against hypoxic cardiac arrest.(Ann Thorac Surg 1997;63:1664–8)     

Preconditioning: myocardial function and energetics during coronary hypoperfusion and reperfusion

Background. Ischemic preconditioning (IP) is gaining more acceptance as a protective method in beating heart surgery. Yet it remains controversial whether preconditioning can attenuate myocardial dysfunction during reperfusion after severe coronary hypoperfusion. We examined this issue and also the issue of whether this protection is mediated by adenosine A₁ receptors.

Methods. In isolated, blood-perfused rabbit hearts, the effects of IP (3 minutes of no flow ischemia and 8 minutes of reperfusion) during 30 minutes of coronary hypoperfusion and 60 minutes of reperfusion were investigated. In two groups (n = 8 each) with and without (control group) preconditioning, ventricular function was assessed by load-insensitive measures: slope of the end-systolic pressure–volume relation (E_max), slope of the stroke work/end-diastolic volume relation (M_w), and end-diastolic pressure–volume relation. External efficiency was calculated, and contractile efficiency was assessed using the reciprocal of the myocardial oxygen consumption–pressure–volume area relationship. To investigate the possible role of adenosine, the adenosine A₁ receptor antagonist DPCPX (2.5 μmol/L) was administered before preconditioning in a third group (n = 7).

Results. The effects of hypoperfusion on systolic function, diastolic function (dP/dt_min, end-diastolic pressure–volume relation), external efficiency, and contractile efficiency were similar in both the IP and control groups. Lactate efflux was significantly reduced after preconditioning (p = 0.02). During reperfusion, recovery of systolic function and coronary flow were significantly improved in the IP group compared with controls: aortic flow, 85% versus 63% (p = 0.01); dP/dt_max, 91% versus 67% (p = 0.001); pressure–volume area, 97% versus 68% (p = 0.01); E_max, 74% versus 62% (p = 0.03); and M_w, 94% versus 84% (p = 0.04). Release of creatine kinase was reduced in the IP group, 9.6 ± 1.3 U · 5 min⁻¹ · 100 g⁻¹ wet weight, versus controls, 12.7 ± 2.7 U · 5 min⁻¹ · 100 g⁻¹ wet weight (p = 0.04). During reperfusion, contractile efficiency (p = 0.03) and external efficiency (p = 0.02) recovered better in preconditioned than in untreated hearts. Recovery was less pronounced in the DPCPX group compared with the IP group (p, not significant).

Conclusions. The results, derived from load-insensitive measures, confirm that IP provides protection after episodes of severe hypoperfusion by attenuating systolic dysfunction without improving diastolic dysfunction and reduces the severity of anaerobic metabolism as well as ischemic injury. Contractile efficiency and external efficiency both indicate improved energetics after IP (oxygen utilization by the contractile apparatus). The protective effect, at least in part, is mediated by adenosine A₁ receptors.     

Adenosine-enhanced ischemic preconditioning provides enhanced cardioprotection in the aged heart

Background. Recently we have reported a novel myoprotective protocol “adenosine-enhanced ischemic preconditioning” (APC), which extends and amends the protection afforded by ischemic preconditioning (IPC) by both reducing myocardial infarct size and enhancing postischemic functional recovery in the mature rabbit heart. However, the efficacy of APC in the senescent myocardium was unknown.

Methods. The efficacy of APC was investigated in senescent rabbit hearts and compared with magnesium-supplemented potassium cardioplegia (K/Mg) and IPC. Global ischemia (GI) hearts were subjected to 30 minutes of global ischemia and 120 minutes of reperfusion. Ischemic preconditioning hearts received 5 minutes of global ischemia and 5 minutes of reperfusion before global ischemia. Magnesium-supplemented potassium cardioplegia hearts received cardioplegia just before global ischemia. Adenosine-enhanced ischemic preconditioning hearts received a bolus injection of adenosine in concert with IPC. To separate the effects of adenosine from that of APC, a control group (ADO) received a bolus injection of adenosine 10 minutes before global ischemia.

Results. Infarct size was significantly decreased to 18.9% ± 2.7% with IPC (p < 0.05 versus GI); 17.0% ± 1.0% with ADO (p < 0.05 versus GI); 7.7% ± 1.3% with K/Mg (p < 0.05 versus GI, IPC, and ADO); and 2.1% ± 0.6% with APC (p < 0.05 versus GI, IPC, ADO, and K/Mg; not significant versus control). Only APC and K/Mg significantly enhanced postischemic functional recovery (not significant versus control).

Conclusions. Adenosine-enhanced ischemic preconditioning provides similar protection to K/Mg cardioplegia, significantly enhancing postischemic functional recovery and decreasing infarct size in the senescent myocardium.     

Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways

Background. Depressed myocardial performance is an important clinical problem after open heart surgery. We hypothesized pretreating with bradykinin would pharmacologically precondition the heart and improve postischemic performance, and induce myocardial preconditioning by activating nitric oxide synthase.

Methods. Thirty-three rabbit hearts underwent retrograde perfusion with Krebs-Henseleit buffer (KHB) followed by 50 minutes of 37°C cardioplegic ischemia with St. Thomas’ cardioplegia solution (StTCP). Ten control hearts received no pretreatment. Ten bradykinin-pretreated hearts received a 10-minute infusion of 0.1 μMol/L bradykinin-enriched KHB and cardioplegic arrest with 0.1 μMol/L bradykinin-enriched StTCP. Six other hearts received 0.1 μMol/L HOE 140, a selective B2 receptor antagonist, added to both the 0.1 μMol/L bradykinin-enriched KHB and 0.1 μMol/L bradykinin-enriched StTCP solutions. Finally, six other hearts received 100 μMol/L of N-Ω-nitro- -arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, added to both the 0.1 μMol/L bradykinin-enriched KHB and 0.1 μMol/L bradykinin-enriched StTCP solutions.

Results. Bradykinin pretreatment significantly improved postischemic performance and coronary flow (CF) compared with control (LVDP: 53 ± 5* vs 27 ± 4 mm Hg; +dP/dt_max: 1,025 ± 93* vs 507 ± 85 mm Hg/s; CF: 31 ± 3* vs 22 ± 2 mL/min; *p < 0.05). Both HOE 140 and L-NAME abolished bradykinin-induced protection, resulting in recovery equivalent to untreated controls.

Conclusions. Bradykinin pretreatment improves recovery of ventricular and coronary vascular function via nitric oxide-dependent mechanisms. Pharmacologic preconditioning by bradykinin pretreatment may be an important new strategy for improving myocardial protection during heart surgery.     

Calcitonin Gene-Related Peptide-Induced Preconditioning Improves Preservation With Cardioplegia

Background. Our recent work has shown that calcitonin gene-related peptide (CGRP) may play an important role in mediation of ischemic preconditioning. Therefore, we tested the hypothesis that CGRP-induced preconditioning protects against myocardial damage after prolonged cardioplegic arrest in isolated rat hearts.

Methods. Six groups were studied: the control, ischemic preconditioning, and CGRP-pretreated groups for both 4- and 8-hour hypothermic ischemia. All hearts were arrested using St. Thomas Hospital cardioplegia, and then reperfused with normothermic Krebs-Henseleit solution for 60 minutes after the 4- or 8-hour hypothermic ischemic period. Hearts were subjected to two cycles of 5-minute ischemia and 10-minute reperfusion in the ischemic preconditioning group. In the CGRP-pretreated group, Krebs-Henseleit solution containing CGRP (5 × 10⁻⁹ mol/L) was substituted for the ischemic period.

Results. At 30 minutes of reperfusion after 4-hour storage, left ventricular pressure (mm Hg) and its first derivative (dp/dt_max, mm Hg/s) in the control, ischemic preconditioning, and CGRP groups were 65.2 ± 5.93 and 1,170 ± 119, 94.13 ± 4.93 and 1,825 ± 145.83, and 85.47 ± 4.17 and 1,900 ± 123.13, respectively (p < 0.01). After 8-hour storage, left ventricular pressure (mm Hg) and dp/dt_max (mm Hg/s) in the same groups were 51.07 ± 5.83 and 815 ± 107.17, 83.47 ± 6.54 and 1,480 ± 120.91, and 84.8 ± 8.49 and 1,396 ± 126.16 (p < 0.01). Ischemic preconditioning and CGRP-induced preconditioning also significantly reduced the release of myocardial enzymes.

Conclusions. The present studies suggest that ischemic preconditioning protects against ischemia-reperfusion injury even after 8 hours of hypothermic preservation in isolated rat hearts, and that CGRP exerts preconditioning-like cardioprotection.     

Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection

Background. Ischemic preconditioning is an endogenous mechanism whereby brief periods of ischemia render neurons resistant to subsequent lethal insults. This protection appears to alter cellular apoptosis and can be induced by potassium channel openers acting on the inner membrane of the mitochondria (mitoK_ATP). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoK_ATP opener diazoxide was used in a canine model of brain injury induced by hypothermic circulatory arrest (HCA).

Methods. Seventeen dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18°C. After 2 hours of HCA, animals were rewarmed and weaned from CPB. Six dogs received intravenous diazoxide (2.5 mg/kg bolus 15 minutes prior to CPB, then 0.5 mg/min until circulatory arrest, then restarted for the first hour of rewarming). Six animals received vehicle only. Five received diazoxide and the mitoK_ATP blocker 5-hydroxydecanoate (5-HD). Using a modified Pittsburgh Canine Neurological Scoring System (0 = normal, 500 = brain death), animals were evaluated every 24 hours for 3 days. The brains were removed and histologic sections of four regions characteristically injured in this model were scored (0 = no injury, 4 = infarction) by a neuropathologist in a blinded fashion.

Results. Clinical scoring showed marked improvement in the diazoxide group at 48 hours (101 ± 10.5 vs 165 ± 14.8, p < 0.01) and 72 hours (54 ± 9.3 vs 137 ± 12.1, p < 0.01). This neuroprotection was attenuated when 5-HD was concomitantly administered. Three of four brain regions typically injured in this model (cortex, hippocampus, and entorhinal cortex) had significant neuron preservation in the diazoxide group. Likewise, combined region scores were significantly improved in the treatment group (1.18 ± 0.2 vs 2.46 ± 0.2, p < 0.01).

Conclusions. Pretreatment with diazoxide resulted in significant improvement in both clinical neurologic scores and histopathology in our model of HCA. This suggests that pharmacologic preconditioning with the mitoK_ATP channel opener diazoxide may offer effective neuroprotection during HCA.     

Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis

Background. This study tested the hypothesis that ischemic preconditioning (IP) inhibits myocardial apoptosis after a short period of ischemia and reperfusion.

Methods. In 9 anesthetized dogs, the left anterior descending (LAD) coronary artery was occluded for 30 min and reperfused for 3 h (control), while in 9 others, LAD occlusion was preceded by 5 min of occlusion and 5 min of reperfusion (IP). DNA from frozen myocardial tissue samples was extracted, and apoptosis were identified as “ladders” by agarose gel electrophoresis or confirmed histologically using the terminal transferase UTP nick end-labeling (TUNEL) assay. Neutrophil accumulation was detected by measuring cardiac myeloperoxidase activity.

Results. Thirty minutes of LAD occlusion caused a significant decrease in blood flow (colored microspheres), which was comparable between groups. In the control group, DNA ladders occurred in the area at risk (AAR) in six out nine experiments. In contrast, DNA laddering in the AAR was not observed in any of the IP group. AAR in the control group showed a greater percentage of apoptotic cells than IP (6.7 ± 0.9% vs 1.2 ± 0.2%; p < 0.01). Cardiac myeloperoxidase activity (U/g tissue) was significantly reduced from 0.07 ± 0.004 in control to 0.04 ± 0.01 in IP group (p < 0.05).

Conclusions. We conclude that ischemic preconditioning attenuates apoptosis and neutrophil accumulation in the AAR in a model of nonlethal acute ischemia and reperfusion.     

Leukocyte Depletion of Blood Cardioplegia Attenuates Reperfusion Injury

Background. Leukocytes are associated with myocardial injury during reperfusion after ischemia. Short periods of leukocyte depletion during reperfusion result in persistent attenuation of postischemic myocardial dysfunction.

Methods. Leukocyte depletion was examined in a canine model of regional myocardial ischemia and reperfusion. The extracorporeal circuit and cardioplegia circuits underwent leukocyte depletion by mechanical filtration. Animals were instrumented for baseline global function before 90-minute occlusion of the left anterior descending coronary artery. Global function during ischemia and at 5, 30, 60, and 90 minutes after a 60-minute cardioplegic arrest using continuous blood cardioplegia was assessed in leukocyte-depleted (n = 9) and control (n = 10) groups.

Results. No significant difference between groups was seen for systemic leukocyte counts, global function, or water content. Endothelial function was significantly protected as assessed by response to both calcium ionophore (endothelial-dependent, receptor-independent relaxation: leukocyte-depleted, 72% ± 19% of endothelin-induced constriction versus control, 46% ± 14%; p < 0.05) and acetylcholine (endothelial-dependent, receptor-dependent relaxation: leukocyte-depleted, 83% ± 11% versus control, 44% ± 15%; p < 0.05).

Conclusions. Leukocyte-mediated endothelial reperfusion injury can be attenuated by leukocyte depletion during reperfusion.     

Heparin-Bonded Circuits Decrease Myocardial Ischemic Damage: An Experimental Study

Background. Heparin-bonded cardiopulmonary bypass circuits reduce complement activation, but their effect on myocardial function is unknown. This study was undertaken to determine whether heparin-bonded circuits reduce myocardial damage during acute surgical revascularization.

Methods. In 16 pigs, the second and third diagonal vessels were occluded with snares for 90 minutes followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion with the snares released. During the period of coronary occlusion, all animals were placed on percutaneous bypass followed by standard cardiopulmonary bypass during the periods of cardioplegic arrest and reperfusion. In 8 pigs, heparin-bonded circuits were used, whereas 8 other pigs received nonbonded circuits.

Results. Animals treated with heparin-bonded circuits had the best preservation of wall motion scores (3.5 ± 0.3 versus 2.3 ± 0.2; 4 = normal to −1 = dyskinesis; p < 0.05), least tissue acidosis (change in pH = −0.31 ± 0.02 versus −0.64 ± 0.08; p < 0.05), smallest increase in lung H₂O (1.7% ± 0.7% versus 6.1% ± .5%; p < 0.05), and the lowest area of necrosis/area of risk (20.3% ± 2.2% versus 40.4% ± 1.6%; p < 0.05).

Conclusions. We conclude that heparin-bonded circuits significantly decrease myocardial ischemic damage during acute surgical revascularization.     

Heat shock improves recovery and provides protection against global ischemia after hypothermic storage

Background. Improved methods of donor heart preparation before preservation could allow for prolonged storage and permit remote procurement of these organs. Previous studies have shown that overexpression of heat-shock protein 72 provides protection against ischemic cardiac damage. We sought to determine whether rats subjected to heat stress with only 6-hour recovery could acquire protection to a subsequent heart storage for 12 hours at 4°C.

Methods. Three groups of animals (n = 10 each) were studied: control, sham-treated, and heat-shocked rats (whole-body hyperthermia 42°C for 15 minutes). After 12-hour cold ischemia hearts were reperfused on a Langendorff column. To confirm any differences in functional recovery, hearts were then subjected to an additional 15-minute period of warm global ischemia after which function and lactate dehydrogenase enzyme leakage were measured.

Results. Heat-shocked animals showed marked improvements compared with controls in left ventricular developed pressure (63 ± 4 mm Hg versus 44 ± 4 mm Hg, p < 0.05) heart rate × developed pressure (13,883 ± 1,174 beats per minute × mm Hg versus 8,492 ± 1,564 beats per minute × mm Hg, p < 0.05), rate of ventricular pressure increase (1,912 ± 112 mm Hg/second versus 1,215 ± 162 mm Hg/second, p < 0.005), rate of ventricular pressure decrease (1,258 ± 89 mm Hg/second versus 774 ± 106 mm Hg/second, p < 0.005). Diastolic compliance and lactate dehydrogenase release were improved in heat-shocked animals compared with controls and sham-treated animals. Differences between heat-shocked animals and control or sham-treated animals were further increased after the additional 15-minute period of warm ischemia. Western blot experiments confirmed increased heat-shock protein 72 levels in heat-shocked animals (> threefold) compared with sham-treated animals and controls.

Conclusions. Heat shock 6 hours before heart removal resulted in marked expression of heat-shock protein 72 and protected isolated rat hearts by increased functional recovery and decreased cellular necrosis after 12-hour cold ischemia in a protocol mimicking that of heart preservation for transplantation. Protection was further confirmed after an additional 15-minute period of warm ischemia.     

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.     

Effects of diltiazem on renin-aldosterone and ACTH-adrenocortical function during upper abdominal surgery

Study Objective: To observe the effects of continuous intravenous infusion of diltiazem on the renin-aldosterone system and ACTH-adrenocortical axis responses during surgical stimulation.

Design: Randomized study of intravenous diltiazem.

Setting: Operating room at the Hyogo Medical College Hospital.

Patients: Twenty-three patients undergoing upper abdominal surgery were divided into two groups: the control group (n = 10) and the diltiazem group (n = 13). All the patients were without any complications and classified as ASA physical status I.

Interventions: Patients in the diltiazem group received an infusion of 10 μg/kg/ min for 90 to 120 minutes following skin incision.

Measurements and Main Results: Plasma adrenocorticotropic hormone, plasma aldosterone and cortisol concentrations, and plasma renin activity were determined with radioimmunoassay before the induction of anesthesia at 10, 30, 60, and 90 minutes after skin incision and at the end of anesthesia. Renin activity did not change significantly. Maximal increases in plasma adrenocorticotropic hormone, aldosterone, and cortisol observed 90 minutes after skin incision were 355 ± 95 pg/ml, 118 ± 30 pg/ml, and 14.2 ± 2.3 μg/dl in the control group versus 246 ± 41 pg/ml, 119 ± 25 pg/ml, and 15.0 ± 1.8 μg/dl in the diltiazem group, respectively, and there were no significant differences between these groups. Adrenocorticotropic hormone was significantly lower in the diltiazem group compared with that in the control group 60 minutes after the start of surgery (p < 0.05). There was marked natriuresis (40 ± 25 μEq/min vs 470 ± 147 μEq/min at the 90-minute mark) and diuresis (0.16 ± 0.13 ml/min vs. 2.53 ± 0.88 ml/min) in the diltiazen group.     

Prevention of Reperfusion Injury by Inhaled Nitric Oxide in Lungs Harvested From Non-Heart-Beating Donors

Background. In lung transplantation using non-heart-beating donors (NHBD), the postmortem period of warm ischemia exacerbates lung ischemia-reperfusion injury. We hypothesized that inhaled nitric oxide (NO) would reduce ischemia-reperfusion injury, and thus ameliorate the viability of the lung graft.

Methods. A blood-perfused, isolated rat lung model was used. Lungs were flushed and harvested from non-heart-beating donors after 30 minutes of in situ warm ischemia. The lung was then stored for 2 hours at 4°C. Inhaled NO at 30 ppm was given either during the period of warm ischemia, during reperfusion, or during both periods. Lung ischemia-reperfusion injury was assessed after 1 hour of reperfusion by measuring pulmonary vascular resistance, coefficient of filtration, wet-to-dry lung weight ratio, and myeloperoxidase activity.

Results. A severe IR injury occurred in lungs undergoing ischemia and reperfusion without NO as evidenced by high values of pulmonary vascular resistance (6.83 ± 0.36 mm Hg · mL⁻¹ · min⁻¹), coefficient of filtration (3.02 ± 0.35 mL · min⁻¹ · cm H₂O⁻¹ · 100 g⁻¹), and wet-to-dry lung weight ratio (8.07 ± 0.45). Lower values (respectively, 3.31 ± 0.44 mm Hg · mL⁻¹ · min⁻¹, 1.49 ± 0.34 mL · min⁻¹ · cm H₂O⁻¹ · 100 g⁻¹, and 7.44 ± 0.43) were observed when lungs were ventilated with NO during ischemia. Lung function was further improved when NO was given during reperfusion only. All measured variables, including myeloperoxidase activity were significantly improved when NO was given during both ischemia and reperfusion. Myeloperoxidase activity was significantly correlated with coefficient of filtration (r = 0.465; p < 0.05).

Conclusions. These data suggest that inhaled NO significantly reduces ischemia-reperfusion injury in lungs harvested from non-heart-beating donors. This effect might be mediated by inhibition of neutrophil sequestration in the reperfused lung.     

Excimer versus carbon dioxide transmyocardial laser revascularization: effects on regional left ventricular function and perfusion

Background. Transmyocardial laser revascularization (TMR) has been established with the carbon dioxide (CO₂) laser. The largely unstudied excimer laser creates channels through chemical bond dissociation instead of thermal ablation, thereby avoiding thermal injury. We sought to compare the effects of CO₂ and excimer TMR in a porcine model of chronic ischemia.

Methods. Pigs underwent ameroid constrictor placement on the circumflex artery to create chronic ischemia. TMR was performed with CO₂ (n = 8) or excimer (n = 8) laser 6 weeks later; controls (n = 7) had ameroid placement only. Regional myocardial blood flow (RMBF), determined by radioactive microspheres, and regional myocardial function, determined by percent segmental shortening (%SS), were assessed 18 weeks after ameroid placement.

Results. Values are mean ± SD. In the ischemic zone, RMBF (mL/min/g) was improved in the CO₂ (0.73 ± 0.19) and excimer (0.78 ± 0.22) groups when compared with controls (0.55% ± 0.12%, p < 0.05). %SS was also improved in the CO₂ (15.2% ± 5.5%) and excimer (15.3% ± 5.1%) groups when compared with controls (8.0% ± 4.2%, p < 0.05).

Conclusions. Excimer and CO₂ TMR significantly improve RMBF and regional function in this porcine model of chronic myocardial ischemia despite fundamentally different tissue interactions.     

Delayed impairment of cerebral oxygenation after deep hypothermic circulatory arrest in children

Background. Clinical studies of deep hypothermic circulatory arrest (DHCA) have focused only on the immediate postoperative period. However, experimental findings suggest impairment of cerebral oxygenation at 2 to 8 hours after reperfusion.

Methods. In 10 children who had DHCA for heart operations, transcerebral differences of hemoglobin oxygen saturation and plasma hypoxanthine, xanthine, and lactoferrin concentrations were measured in concurrently obtained cerebral venous, arterial, and mixed venous samples up to 10 hours postoperatively.

Results. Compared with preoperative levels (57% ± 7%), cerebral venous oxygen saturation was not significantly reduced until 2 hours (44% ± 6%) and 6 hours (42% ± 5%) after DHCA (p < 0.05). A statistically significant transcerebral (ie, cerebral vein versus artery) concentration difference of hypoxanthine was observed at 30 minutes (3.6 ± 0.9 μmol/L), 1 hour (3.4 ± 1.1 μmol/L), and 2 hours (3.1 ± 0.8 μmol/L) after DHCA but not preoperatively (0.4 ± 0.2 μmol/L). A transcerebral concentration difference of lactoferrin occurred 30 minutes after DHCA (196 ± 70 μg/mL) but not preoperatively (16 ± 20 μg/mL).

Conclusions. Cerebral venous oxygen saturation of hemoglobin decreased as late as 2 to 6 hours after DHCA, in association with impaired cerebral energy status. Neutrophil activation in the cerebral circulation occurred 30 minutes after reperfusion.     

Sodium Nitroprusside Exacerbates Myocardial Ischemia–Reperfusion Injury

Background. The role of nitric oxide in myocardial ischemia–reperfusion is controversial. Although many studies claim that nitric oxide ameliorates reperfusion injury, others suggest that it exacerbates such injury, possibly through peroxynitrite production. These discordant results may be attributable to a dose-dependent phenomenon.

Methods. Isolated rabbit hearts sustained sequential periods of blood perfusion (20 minutes), warm ischemia (30 minutes), and reperfusion (20 minutes). During reperfusion, four groups underwent intracoronary infusion of saline solution (n = 6), or the nitric oxide donor sodium nitroprusside (100 nm/min [SNP100, n = 6], 1 nmol · L⁻¹/min⁻¹ [SNP1, n = 6], or 0.01 nmol · L⁻¹ · min⁻¹ [SNP0.01]). Left ventricular-developed pressure and oxygen consumption were measured after preischemic perfusion and reperfusion. Levels of myocardial nitrotyrosine, a marker for peroxynitrite, were measured after reperfusion with an immunoradiochemical assay.

Results. Postischemic-developed pressure and myocardial oxygen consumption were significantly higher in the saline group than all nitroprusside-reperfused groups (p < 0.01 for both parameters). However, there were no differences in either parameter between SNP100, SNP1, or SNP0.01. Nitrotyrosine levels were similar among the four groups (p = 0.43).

Conclusions. Nitroprusside exacerbates myocardial ischemia–reperfusion injury over a wide range of doses, although the mechanism does not appear to be mediated by peroxynitrite.     

Intraaortic Balloon Counterpulsation Improves Right Ventricular Failure Resulting From Pressure Overload

Background. Right ventricular (RV) dysfunction is common after heart transplantation, and myocardial ischemia is considered to be a significant contributor. We studied whether intraaortic balloon counterpulsation would improve cardiac function using a model of acute RV pressure overload.

Methods. In 10 anesthetized sheep, RV failure was induced using a pulmonary artery constrictor. Baseline measurements included mean systemic blood pressure, RV peak systolic pressure, cardiac index, and RV ejection fraction. Myocardial and organ perfusion were measured using radioactive microspheres.

Results. After pulmonary artery constriction, there was an increase in RV peak systolic pressure (32 ± 2 to 60 ± 3 mm Hg; p < 0.01) and a decrease in mean systemic blood pressure (68 ± 4 to 49 ± 2 mm Hg; p < 0.01), RV ejection fraction (0.51 ± 0.04 to 0.16 ± 0.02; p < 0.01), and cardiac index (2.48 ± 0.04 to 1.02 ± 0.11; p < 0.01). Blood flow to the RV did not change significantly, but there was a significant reduction in blood flow to the left ventricle. The initiation of intraaortic balloon counterpulsation (1:1) using a 40-mL intraaortic balloon inserted through the left femoral artery resulted in an increase in mean systemic blood pressure (49 ± 2 to 61 ± 3 mm Hg; p < 0.01), cardiac index (1.02 ± 0.11 to 1.45 ± 0.14; p < 0.05), RV ejection fraction (0.16 ± 0.02 to 0.23 ± 0.02; p < 0.01), and blood flow to the left ventricle.

Conclusions. In a model of right heart failure, the institution of intraaortic balloon counterpulsation caused a significant improvement in cardiac function. Although RV ischemia was not demonstrated, the augmentation of left coronary artery blood flow by intraaortic balloon counterpulsation and subsequent improvement in left ventricular function suggest that left ventricular ischemia contributes to RV dysfunction, presumably through a ventricular interdependence mechanism. Therefore, study of the safety and efficacy of intraaortic balloon counterpulsation in the management of patients with acute right heart dysfunction is warranted.     

Time to peak effect of neostigmine at antagonism of atracurium- or vecuronium-induced neuromuscular block

Study Objective: (1) To determine the time to peak effect of neostigmine (time to peak antagonism) during atracurium- or vecuronium-induced neuromuscular block; and (2) to determine the effect on time to peak effect of neostigmine during atracurium-induced neuromuscular block, when the dose of neostigmine is increased from 35 μg/kg to 70 μg/kg.

Design: Prospective, randomized clinical study.

Setting: Gynecologic operating room suite at a university hospital.

Patients: 45 ASA I and II women admitted for gynecologic laparotomy.

Interventions: Anesthesia was performed with thiopental sodium, fentanyl, halothane, nitrous oxide, and atracurium or vecuronium. Train-of-four (TOF) stimulation and mechanomyography were used to monitor neuromuscular transmission. Neostigmine was administered while a constant degree of neuromuscular block was maintained at a twitch height at a point between 4% and 11% of the control twitch height, using a continuous infusion of atracurium or vecuronium. The patients were randomized to three groups, with 15 patients in each group. Group 1 received atracurium block antagonized with neostigmine 35 μg/kg; group 2 received vecuronium block antagonized with neostigmine 35 μg/kg; and group 3 received atracurium block antagonized with neostigmine 70 μg/kg.

Measurements and Main Results: The degree of neuromuscular block at antagonism was similar in the three groups. Time to peak effect (mean ± SD) on TOF ratio was significantly longer in Group 1 (9.7 ± 3.0 minutes) versus Group 2 (6.6 ± 1.4 minutes; (p < 0.05). The time to peak effect on TOF ratio during atracurium-induced block was reduced from 9.7 ± 3.0 minutes to 6.3 ± 2.0 minutes when the dose of neostigmine was increased from 35 μg/kg to 70 μg/kg (p < 0.05). The peak effect on TOF ratio was significantly greater in Group 3 compared with Group 1 (p < 0.05), while it was similar in groups 1 and 2.

Conclusion: The time to peak effect of neostigmine 35 μg/kg is about 6 to 10 minutes when antagonizing a constant degree of atracurium- or vecuronium-induced neuromuscular block at a twitch height at a point between 4% and 11%. Even though the time to peak effect was longer with atracurium than with vecuronium, clinically significant differences between the antagonizing effect of atracurium versus vecuronium block were not demonstrated. The time to peak effect during atracurium-induced block decreased when the dose of neostigmine was increased from 35 μg/kg to 70 μg/kg.     

Brief pretreatment of radial artery conduits with phenoxybenzamine prevents vasoconstriction long term

Background. Radial artery bypass conduits are prone to early vasospasm or “string sign” with use of vasopressor therapy intraoperatively and postoperatively, causing increased resistance in coronary artery grafts. Current intraoperative treatment with papaverine fails to provide sustained inhibition of vasoconstriction. We tested the hypothesis that a 30-minute pretreatment of radial artery segments with the -adrenergic antagonist phenoxybenzamine (PB) or the putative protein phosphatase 2,3-butadione monoxime (BDM) attenuates vasoconstriction induced by the vasopressors phenylephrine or norepinephrine for as long as 48 hours compared with papaverine.

Methods. Canine radial arteries were harvested, incubated in control buffer or solutions of papaverine 10⁻⁶ M, BDM 10⁻⁶ M or phenoxybenzamine 10⁻⁶ M for 30 minutes, washed, and stored in drug-free culture medium for 2, 24, or 48 hours. After storage, constriction was induced by norepinephrine at incremental concentrations ranging from 0.7 to 3.5 μmol/L or by phenylephrine (0.300 to 1.5 μmol/L) with or without the inhibitors, and the degree of vasoconstriction was quantified in organ chambers. Responses to norepinephrine or phenylephrine were compared to constriction with receptor-independent potassium chloride KC1 (30 mmol/L).

Results. Maximum responses to phenylephrine and norepinephrine were comparable at 2, 24, and 48 hours after harvest in the control group (phenylephrine: 67% ± 4%, 62% ± 6%, 65% ± 6% of KC1 response; norepinephrine: 75% ± 4%, 62% ± 1%, 58% ± 7%, respectively). Papaverine failed to attenuate constriction to phenylephrine and norepinephrine 2, 24, or 48 hours posttreatment. Pretreatment with BDM did not reduce vasoconstriction responses to phenylephrine or norepinephrine 2 hours after incubation but did reduce constriction responses thereafter. In contrast, phenoxybenzamine completely attenuated constriction to both phenylephrine (19% ± 8%, 1% ± 4%, −12% ± 4%) and norepinephrine (7.1% ± 1%, −5% ± 5%, −20% ± 5%) at 2, 24, and 48 hours posttreatment, respectively. Phenoxybenzamine did not alter endothelial function relative to controls at any time point.

Conclusions. Thirty-minute pretreatment of RA conduits with 10⁻⁶ M phenoxybenzamine completely inhibits vasoconstriction to phenylephrine and norepinephrine for as long as 48 hours. Soaking radial artery grafts briefly in phenoxybenzamine solution before implantation may be effective in preventing postoperative vasospasm caused by two common -adrenergic agonists used in postoperative hemodynamic management.     

Cardiotomy Suction: A Major Source of Brain Lipid Emboli During Cardiopulmonary Bypass

Background. Brain injury remains a significant problem in patients undergoing cardiac surgery assisted by cardiopulmonary bypass (CPB). Autopsy brain specimens of patients after cardiac operations with CPB reveal numerous acellular lipid deposits (10 to 70 μm) in the microvasculature. We hypothesize that these small capillary and arterial dilatations result from a diffuse inflammatory response to CPB or from emboli delivered by the bypass circuit. This study was undertaken to determine which aspect of CPB is most clearly associated with these dilatations.

Methods. Thirteen dogs were studied in four groups: group I (n = 3), right-heart CPB; group II (n = 2), lower-extremity CPB; group III (n = 3), hypothermic CPB; and group IV (n = 5), hypothermic CPB with cardiotomy suction. All dogs in all groups were maintained on CPB for 60 minutes and then euthanized. Brain specimens were harvested, fixed in ethanol, embedded in celloidin, and stained with the alkaline phosphate histochemical technique so that dilatations could be counted.

Results. All dogs completed the protocol. The mean density of dilatations per square centimeter for each group was as follows: group I, 1.77 ± 0.77; group II, 4.17 ± 1.65; group III, 4.54 ± 1.69; and group IV, 46.5 ± 14.5. In group IV (cardiotomy suction), dilatation density was significantly higher than in group III (hypothermic cardiopulmonary bypass) (p = 0.04) and all other groups (p = 0.04).

Conclusions. Blood aspirated from the surgical field and subsequently reinfused into dogs undergoing CPB produces a greater density of small capillary and arterial dilatations than CPB without cardiotomy suction, presumably because of lipid microembolization.