Resuscitation of injured myocardium with adenosine and biventricular assist

Recovery of energy metabolism and contractility in stunned myocardium requires several days, even when mechanical circulatory support is employed. This double-blind study was undertaken to determine if myocardial recovery could be accelerated by intracoronary infusion of adenosine during reperfusion. Ten mongrel dogs were subjected to 45 minutes of global normothermic ischemia while on biventricular support with centrifugal pumps. During initial reperfusion, 20 minutes later, and at hourly intervals for 4 hours, dogs received 100 mL/min of unaltered blood or blood enriched with adenosine (0.2 mmol/L) into the coronary arteries for 5 minutes. Circulatory support was discontinued after 4 hours or sooner if the first time derivative of left ventricular pressure exceeded 2,000 mm Hg/s. Animals that received adenosine were weaned sooner (72 +/- 27 versus 216 +/- 54 minutes) and had higher systolic pressure (110 +/- 21 versus 57 +/- 36 mm Hg), lower left ventricular end-diastolic pressure (23.8 +/- 4.8 versus 34.0 +/- 7.2 mm Hg), and higher first time derivative of left ventricular pressure (3,407 +/- 812 versus 1,510 +/- 1376 mm Hg/s) than controls at the completion of the experiment (p less than 0.05). Final myocardium adenosine triphosphate levels were higher in the adenosine group (20.0 +/- 3.6 versus 14.2 +/- 4.0 mumol/g protein; p less than 0.05). Determination of infusion and coronary sinus blood concentrations demonstrated a 90% uptake of adenosine. All adenosine animals survived, but 2 of 5 control animals died within 1 hour of weaning. Reperfusion with adenosine-enriched blood accelerated recovery of ischemic myocardium and should be considered for patients requiring mechanical circulatory support after a heart operation.     

Pathophysiology of chronic cyanosis in a canine model. Functional and metabolic response to global ischemia

To investigate the pathophysiology of chronic cyanosis, we subjected 14 adult mongrel dogs to diversion of the inferior vena cava to the right inferior pulmonary vein. This produced a mean oxygen tension of 42 +/- 2 mm Hg and a calculated right-to-left shunt of 52.0% +/- 3.9%. These animals (Group C) and 15 normal dogs (Group N) were subjected to cardiopulmonary bypass with 20 minutes of normothermic global ischemia. Functional indices studied were rate of rise of left ventricular pressure and the end-systolic pressure/volume ratio. Metabolic status was assessed by obtaining transmural myocardial biopsy specimens for measurement of adenosine triphosphate content. Myocardial blood flow was measured with radiolabeled microspheres. There were no significant differences between Group C and Group N in either functional index or blood flow measurement prior to global ischemia. At 45 minutes after ischemia, Group N animals had a significantly greater rate of rise of left ventricular pressure (at a left ventricular end-diastolic pressure of 0, 5, 10, and 15 mm Hg, p less than 0.025 to 0.05) and subendocarial perfusion (endocardial/epicardial flow ratio 0.961 +/- 0.037 versus 0.815 +/- 0.021, p less than 0.01). At 90 minutes after ischemia, Group N animals exhibited a significantly higher end-systolic pressure/volume ratio (4.9 +/- 0.7 versus 3.0 +/- 0.4 mm Hg/ml, p less than 0.05), rate of rise of left ventricular pressure (at an end-diastolic pressure of 0 to 20 mm Hg, p less than 0.005 to 0.05), and endocardial/epicardial flow ratio (1.065 +/- 0.046 versus 0.829 +/- 0.059, p less than 0.01). No differences in adenosine triphosphate content were found at any sampling period. The Group C left ventricles exhibited no hypertrophy but were significantly dilated compared to Group N (38.8 +/- 0.3 versus 30.1 +/- 0.2 mm, p less than 0.05). Inferior vena cava to pulmonary vein diversion produces cyanosis with left ventricular dilatation but without hypertrophy. It is proposed that abnormal loading characteristics of the left ventricle are responsible for the functional derangements that result from global ischemia.     

Preventive effect of Fluosol-DA for paraplegia encountered after surgical treatment of the thoracic aorta. Preliminary results in a dog model

The effectiveness of Fluosol-DA (Green Cross Corporation, Osaka, Japan) on circulatory dynamics and neurologic outcome in dogs with ischemic spinal cord injury produced by aortic crossclamping was tested. The control group (receiving saline solution) had an elevated mean aortic proximal pressure (112.9 +/- 30.2 mm Hg versus 175.3 +/- 20.5 mm Hg, p greater than 0.05) and a drastic drop in mean distal aortic pressure (112.9 +/- 30.2 mm Hg versus 29.8 +/- 11.2 mm Hg, p less than 0.05). Although the same trend occurred in dogs treated prophylactically with Fluosol-DA, these changes were not statistically significant. However, there was a significant difference in mean distal aortic pressure during the ischemic phase between the two groups (58.9 +/- 16.0 mm Hg versus 29.8 +/- 11.2 mm Hg, p less than 0.05). Postoperatively all animals had mean arterial pressures within the normal range. All dogs in the control group were paraplegic (partial or complete); the treatment group had one dog with partial paraplegia. The difference between the mean neurologic scores of the two groups was of high statistical significance (3.7 +/- 0.5 versus 1.6 +/- 1.0, p less than 0.05). Our preliminary results show that prophylactic use of Fluosol-DA has favorable effects on hemodynamics and neurologic outcome in dogs with spinal cord ischemia produced by aortic crossclamping. The high propensity of the drug to carry oxygen and carbon dioxide and to provide nutritional support to the ischemic area with resultant improvement in local microcirculation and blood rheology are some speculative mechanisms advocated for these changes.     

Use of a counterpulsation balloon as a substitute for the pulmonic valve: a new application

An inflatable, 3-ml balloon positioned within the distal right ventricular outflow tract was used to restore pulmonic valve function in 8 dogs that had undergone open-chest valvectomy. Balloon inflation and deflation were accomplished with a counterpulsation console. Valvectomy produced loss of the pulmonic incisura, a decrease in pulmonary artery diastolic pressure (PADP; mean +/- standard error) (9.5 +/- 1.3 versus 4.4 +/- 0.6 mm Hg, p less than 0.01), and an increase in pulmonary artery pulse pressure (PAPP) (8.6 +/- 0.7 versus 19.1 +/- 1.9 mm Hg, p less than 0.01) without significantly affecting forward cardiac output (CO) (1,750 +/- 110 versus 1,880 +/- 230 ml/min, p is not significant). Properly timed counterpulsation restored the pulmonic incisura, raised the PADP from 6.1 +/- 0.8 to 9.5 +/- 0.8 mm Hg (p less than 0.01), lowered the PAPP from 15.1 +/- 1.4 to 10.6 +/- 1.0 mm Hg (p less than 0.01), and raised the forward CO from 1,850 +/- 260 to 1,920 +/- 260 ml/min (p less than 0.01). The injection of glass beads, 40 to 150 microns in diameter, into the right ventricular outflow tract increased pulmonary vascular resistance from 383 +/- 87 to 730 +/- 150 dyne . sec cm-5 (p less than 0.05) and decreased forward CO from 1,850 +/- 260 to 1,570 +/- 230 ml/min (p less than 0.05). Following this injection, counterpulsation again restored the pulmonic incisura, raised the PADP from 9.3 +/- 1.4 to 16.0 +/- 1.8 mm Hg (p less than 0.01), lowered the PAPP from 25.0 +/- 2.5 to 18.2 +/- 2.5 mm Hg (p less than 0.01), and raised the forward CO from 1,570 +/- 230 to 1,720 +/- 220 ml/min (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Avoiding reperfusion injury after limb revascularization: experimental observations and recommendations for clinical application

This study tests the hypothesis that reperfusion injury is the principal cause of limb loss after acute arterial occlusion and that this injury is avoidable. Of 61 isolated hindlimbs amputated at the level of the hip joint, 17 were controls (group I), 5 were perfused without ischemia to establish the validity of the model (group II), and 15 underwent 4 hours of ischemia at room temperature without reperfusion (group III). Acute embolectomy was simulated in 24 limbs after 4 hours of ischemia; 12 were reperfused with standard Krebs-Henseleit solution at 100 mm Hg (group IV), and 12 were reperfused under controlled conditions (i.e., 37 degrees C, 50 mm Hg) with substrate-enriched modified reperfusate (group V). Leg volume, water content, contractile function, and high-energy phosphate content were assessed and data were expressed as mean +/- SD. Four hours of ischemia caused a profound fall in adenosine triphosphate content (4.0 vs 26.0 mmol/L/gm of protein, p less than or equal to 0.001). Uncontrolled reperfusion resulted in severe reperfusion injury; massive edema developed (83% vs 75%, p less than or equal to 0.01), leg volume increased markedly (21.5% above control, p less than or equal to 0.001), and no contractile function followed electrical stimulation. In contrast, controlled reperfusion resulted in normal water content (76.9% vs 75.0%, NS) and minimal change of leg volume (5.5% +/- 5% of control, NS), replenished adenosine triphosphate completely (24.2 vs 26.4 mmol/L/gm of protein, NS), and restored immediate contractile function in all limbs (24.3% +/- 14% of control). This study shows that 4 hours of room-temperature ischemia (18 degrees C) does not produce irreversible damage of the rat hindlimb because the reperfusion injury that follows uncontrolled reperfusion can be avoided. Immediate recovery of contractile function can be restored if the conditions of reperfusion are controlled by gentle reperfusion pressure (50 mm Hg) at 37 degrees C and if a modified substrate-enriched, hyperosmotic, alkalotic, low-Ca++ reperfusate is administered.     

Controlled reperfusion of the regionally ischemic myocardium with leukocyte-depleted blood reduces stunning, the no-reflow phenomenon, and infarct size.

Open-chest sheep underwent 90 minutes' occlusion of the diagonal branch of the left anterior descending coronary artery, followed by vented cardiopulmonary bypass. After 30 minutes of cardioplegic arrest, simulating distal anastomoses, the occlusion on the coronary artery branch was released. Controlled reperfusion (40 to 50 mm Hg, 135 to 150 ml/min) for the first 20 minutes was delivered at the aortic root with either unmodified whole blood (control, n = 7) or blood passed through leukocyte filters (filters, n = 7). Serial measurements were made during 3 additional hours reperfusion off cardiopulmonary bypass. During ischemia, the major determinants of infarct size, which include area at risk, collateral myocardial blood flow, and rate-pressure product were not significantly different between groups. Overall, during reperfusion, mean left ventricular stroke work index in the filter group was greater than in the control group (28.7 +/- 5.8 versus 12.6 +/- 6.4 x 10(3) erg/gm, p less than 0.05), as was mean rate of rise of left ventricular pressure (1900 +/- 260 versus 1348 +/- 279 mm Hg/sec, p less than 0.05). Myocardial blood flow to the area at risk at 3 1/2 hours of reperfusion in the filter group was also significantly better than in the control group (0.57 +/- 0.15 versus 0.27 +/- 0.05 ml/min/gm, p less than 0.05), as was necrotic area as a percentage of area at risk (40% +/- 6% versus 70% +/- 5%, p less than 0.05). These results demonstrate amelioration of myocardial stunning and the no-reflow phenomenon, as well as decreased infarct size. We conclude that controlled reperfusion with leukocyte-depleted blood is superior to whole-blood reperfusion for the surgical treatment of acute regional ischemia.     

In a canine model, lung preservation at 10 degrees C is superior to that at 4 degrees C. A comparison of two preservation temperatures on lung function and on adenosine triphosphate level measured by phosphorus 31-nuclear magnetic resonance.

Techniques for organ preservation generally use hypothermia to retard metabolic requirements. However, excessive hypothermia may also produce injury. Using a canine left lung allotransplantation procedure, we compared two preservation temperatures (4 degrees and 10 degrees C) in terms of subsequent lung function measured by temporary occlusion of the right pulmonary artery after implantation of the preserved left donor lung. The lungs were flushed with low-potassium dextran electrolyte solution, inflated with 100% oxygen, and preserved for 18 hours. To investigate possible changes of energy stores at different temperatures, we performed phosphorus 31-nuclear magnetic resonance analyses of lung samples. Sequential determinations of adenosine triphosphate levels in lung tissue preserved at 4 degrees, 10 degrees, and 22 degrees C were studied. After transplantation, lungs preserved at 10 degrees C (n = 6) provided significantly better arterial oxygen tension than those preserved at 4 degrees C (n = 6), 451 +/- 46 mm Hg versus 243 +/- 86 mm Hg (p less than 0.05), and lower pulmonary vascular resistance, 581 +/- 68 dynes.sec.cm-5 versus 1006 +/- 157 dynes.sec.cm-5 (p less than 0.05). Adenosine triphosphate levels at 4 degrees and 10 degrees C were stable and did not differ from each other at the end of the 18-hour preservation period: 0.86 +/- 0.04 mumol/gm wet weight for control versus 0.86 +/- 0.07 mumol/gm wet weight for 4 degrees C and 0.93 +/- 0.06 mumol/gm wet weight for 10 degrees C after 18 hours of preservation. Preservation at 22 degrees C caused a 28% depression of adenosine triphosphate after 18 hours of preservation. These results lead us to conclude the following: (1) Optimal temperature for lung preservation is in the vicinity of 10 degrees C, and (2) lung dysfunction caused by excessive hypothermia is not due to a failure to maintain adenosine triphosphate levels. We suspect that adenosine triphosphate is generated by oxidative phosphorylation during lung preservation.     

Protection of the immature heart. Temperature-dependent beneficial or detrimental effects of multidose crystalloid cardioplegia in the neonatal rabbit heart

There are conflicting reports of the detrimental or beneficial effects of hypothermic cardioplegia in the immature heart. We therefore investigated the temperature-dependence of myocardial protection and the ability of single-dose and multidose infusions of cardioplegic solution to protect the immature heart during hypothermic ischemia. Isolated, working hearts (n = 6 per group) from neonatal rabbits (aged 7 to 10 days) were perfused aerobically (37.0 degrees C) for 20 minutes before infusion (2 minutes) with either perfusion fluid (noncardioplegia control) or St. Thomas' Hospital cardioplegic solution and ischemic arrest (for 4, 6, and 18 hours) at various temperatures between 10.0 degrees and 30.0 degrees C. Hearts arrested with cardioplegic solution received either one preischemic infusion only (single-dose cardioplegia) or repeated infusions at intervals of 60 or 180 minutes (multidose cardioplegia). Ischemic arrest with single-dose cardioplegia for 4 hours at 10.0 degrees, 20.0 degrees, 22.5 degrees, 25.0 degrees, 27.5 degrees, and 30.0 degrees C resulted in 96.0% +/- 4.3%, 96.6 +/- 2.5%, 87.0% +/- 3.8%, 71.8% +/- 10.0% (p less than 0.05 versus 10.0 degrees C group), 35.1% +/- 10.3% (p less than 0.01 versus 10.0 degrees C group), and 3.0% +/- 1.9% (p less than 0.04 versus 10.0 degrees C group) recovery of preischemic cardiac output, respectively. With 6 hours of ischemia at 20.0 degrees C, single-dose cardioplegia significantly (p less than 0.01) increased the recovery of cardiac output from 20.9% +/- 13.1% (control) to 76.4% +/- 4.4%, whereas multidose cardioplegia (infusion every 60 minutes) further increased recovery to 97.8% +/- 3.8% (p less than 0.01 versus control and single-dose cardioplegia). In contrast, after 6 hours of ischemia at 10.0 degrees C, cardiac output recovered to 93.4% +/- 1.2% (control) and 92.3% +/- 3.1% (single-dose cardioplegia), whereas multidose cardioplegia reduced recovery to 76.9% +/- 2.2% (p less than 0.01 versus both groups). This effect was confirmed after 18 hours of ischemia at 10.0 degrees C; single-dose cardioplegia significantly increased the recovery of cardiac output from 24.5% +/- 10.9% (control) to 62.9% +/- 13.3% (p less than 0.05), whereas multidose cardioplegia reduced recovery to 0.8% +/- 0.4% (p less than 0.01 versus single-dose cardioplegia) and elevated coronary vascular resistance from 8.90 +/- 0.56 mm Hg.min/ml (control) to 47.83 +/- 9.85 mm Hg.min/ml (p less than 0.01). This effect was not reduced by lowering the infusion frequency (from every 60 to every 180 minutes).(ABSTRACT TRUNCATED AT 400 WORDS)     

Skeletal muscle ventricles in the pulmonary circulation: up to 16 weeks' experience.

Skeletal muscle ventricles (SMVs) were constructed from the right latissimus dorsi muscle of 8 mongrel dogs. After a 3-week vascular delay period, each SMV was electrically preconditioned with 2-Hz continuous stimulation of the thoracodorsal nerve for 6 weeks. A porcine-valved conduit was then anastomosed between the right ventricle and the SMV, with a second valved conduit connecting the SMV to the main pulmonary artery. The pulmonary artery was then ligated proximal to the conduit. The SMVs were stimulated to contract in 1:2 diastolic mode with a 33-Hz burst frequency. Effective right ventricular assist was achieved in all dogs. Cardiac output increased by 22.6% (1,799 +/- 97 versus 1,467 +/- 84 mL/min; p less than 0.001), systemic systolic arterial pressure by 9.3% (90.1 +/- 3.5 versus 82.4 +/- 3.9 mm Hg; p less than 0.005), and peak pulmonary artery pressure by 31.8% (27.8 +/- 2.0 versus 21.1 +/- 1.7 mm Hg; p less than 0.001) at the initiation of this study. In 6 dogs, effective right heart assist was sustained for periods of between 1 week and 12 weeks. Two dogs survived for longer than 3 months, though with evidence of deteriorating SMV function. These results demonstrate the feasibility of providing sustained right ventricular assist using this modified "Rastelli-SMV" configuration, which obviates the limitations imposed by low right atrial preload.     

Exogenous adenosine accelerates recovery of cardiac function and improves coronary flow after long-term hypothermic storage and transplantation.

Impaired coronary flow during postischemic reperfusion may limit functional recovery. In the present studies we used the heterotopically transplanted rat heart and the isolated working rat heart to assess whether adenosine, given during reperfusion, could improve either the rate or the extent of postischemic recovery. Hearts were arrested (2 minutes at 4 degrees C) with the St. Thomas' Hospital cardioplegic solution and stored by immersion in the same solution for 8 hours at 4 degrees C. Hearts were then transplanted into the abdomen of homozygous recipients. Immediately before reperfusion, adenosine (0.5 ml of a 1 mumol/L solution, equivalent to 0.13 micrograms) was injected into the left ventricle (control rats received an equivalent amount of saline). Hearts were reperfused in vivo for 30 minutes or 24 hours, after which they were excised and perfused (Langendorff) for 20 minutes for the assessment of function. They were then freeze clamped and taken for metabolic analysis. After 50 minutes of reperfusion, left ventricular developed pressure was 75 +/- 5 mm Hg (4 mm Hg end-diastolic pressure) in the adenosine group versus 61 +/- 4 mm Hg in the control group (p less than 0.05); however, after 24 hours function was identical in the two groups (52 +/- 4 versus 52 +/- 3 mm Hg). After 50 minutes of reperfusion coronary flow was greater in the adenosine group (11.0 +/- 0.4 versus 9.7 +/- 0.4 ml/min in control rats; p less than 0.05), a difference that was sustained for 24 hours (12.8 +/- 0.3 versus 11.4 +/- 0.4 ml/min in control rats; p less than 0.05). Adenosine triphosphate and creatine phosphate contents recovered to similar extents in control and adenosine groups after both 50 minutes and 24 hours of reperfusion. In further studies with an identical storage protocol (8 hours at 4 degrees C), hearts were not transplanted but were reperfused with crystalloid medium in the Langendorff mode for 15 minutes (creatine kinase leakage measured) and in the working mode for 180 minutes. In an attempt to mimic the heterotopic transplant protocol, adenosine (1 mumol/L) was included in the perfusion fluid for the first 2 minutes of reperfusion. Similar results to those of the transplant studies were obtained, with coronary flow being consistently improved in the adenosine group; however, this benefit was lost after only 2 hours of reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Improvement in thoracic aortic pressure after proximal aortic cross-clamping by balloon occlusion of the distal aorta

Spinal cord hypoperfusion injury is a devastating complication of cross-clamping the proximal thoracic aorta. The collateral circulation around the cross-clamp is generally poorly developed, and the run-off is immense, resulting in extremely low thoracic aortic and spinal cord perfusion pressures. The authors postulated that balloon occlusion of the abdominal aorta might confine this reduced collateral flow around the cross-clamp to the thoracic aorta. In 8 of 16 dogs subjected to aortic cross-clamping of the aorta just beyond the arch vessels, the abdominal aorta was also occluded by a balloon. Thoracic aortic pressure and spinal cord perfusion pressure were significantly higher in the animals with aortic balloon occlusion than in those without balloon occlusion (77 +/- 8 mm Hg versus 26 +/- 1 mm Hg, p less than 0.01, and 67 +/- 8 mm Hg versus 18 +/- 2 mm Hg, p less than 0.01, at 10 minutes after cross-clamping). Abdominal aortic balloon occlusion increases thoracic aortic pressure after the aorta is cross-clamped proximally. Further studies are necessary in primates to assess the effect of this procedure in spinal cord perfusion and the rate of paraplegia.     

Noncardiogenic pulmonary edema after abdominal aortic aneurysm surgery.

Limb ischemia in experimental animals leads to white blood cell (WBC) and thromboxane (Tx)A2 dependent pulmonary dysfunction. This study examines the pulmonary sequelae of lower torso ischemia in 20 consecutive patients aged 63 +/- 5 years (mean +/- SEM) who underwent elective abdominal aortic aneurysm surgery. After 30 minutes of aortic cross-clamping, plasma TxB2 levels had risen from 77 +/- 26 pg/ml to 359 +/- 165 pg/ml (p less than 0.01) and was temporally related to increases in mean pulmonary artery pressure (MPAP) from 18 +/- 1 to 23 +/- 3 mmHg (p less than 0.01), as well as to increases in pulmonary vascular resistance (PVR) from 0.07 +/- 0.02 to 0.12 +/- 0.02 mmHg sec/ml (p less than 0.01). Each time that the aortic clamp was repositioned and with final declamping, after 83 +/- 10 minutes, there were further increases in MPAP to a peak of 32 +/- 2 mmHg (p less than 0.01) and in PVR to 0.26 +/- 0.030 mmHg sec/ml (p less than 0.01), corresponding to a plasma TxB2 level of 406 +/- 177 pg/ml (p less than 0.01). MPAP and PVR returned to baseline values within 30 minutes of declamping. Ten minutes after removal of the aortic clamp, platelet levels had fallen from 180 +/- 41 to 97 +/- 17 X 10(3)/mm3 (p less than 0.01) and WBC levels from 8900 +/- 1100 to 4700 +/- 400/mm3 (p less than 0.01). Both platelets and WBC returned towards normal levels, but at 24 hours, while WBC was elevated at 13000 +/- 900/mm3 (p less than 0.01), platelets were 44% of baseline at 135 +/- 14 X 10(3)/mm3 (p less than 0.01). Four to 8 hours after surgery, pulmonary dysfunction was manifest by increases in physiologic shunt from 9 +/- 2% to 16 +/- 2% (p less than 0.01), and peak inspiratory pressure (PIP) from 23 +/- 2 to 33 +/- 2 cmH2O (p less than 0.01). Chest radiography demonstrated interstitial pulmonary edema in all patients, whereas pulmonary artery wedge pressure was 12 +/- 2 mmHg, excluding the possibility of left ventricular failure. After 24 hours, pulmonary edema had resolved, and the PIP and PaO2 had both returned to baseline. These data indicate that reperfusion of the ischemic lower torso leads to the synthesis of TxA2, an event temporally related to pulmonary hypertension and transient leukopenia with subsequent pulmonary microvascular injury manifest by interstitial edema.     

Optimal hypothermic preservation of arrested myocardium in isolated perfused rabbit hearts: a 31P NMR study

The purpose of this study was to (1) relate myocardial high-energy phosphate stores to functional recovery after ischemia and reperfusion, (2) assess the bioenergetics and functional influence of clinically relevant myocardial hypothermia, and (3) examine tissue pH as an independent indicator of postischemic recovery of function. Rabbit hearts were perfused via a modified Langendorff technique, monitored for developed pressure (DP) and left ventricular end-diastolic pressure (LVEDP) via an isovolumic left ventricular balloon catheter, and placed in a Brucker NMR magnet (4.7 tesla) to measure phosphocreatine (PCr), adenosine triphosphate (ATP), and pH. Hearts underwent 1 hour of global ischemia at 7 degrees, 17 degrees, 27 degrees and 37 degrees C initiated by one dose of K+ cardioplegia followed by 30 minutes of reperfusion. After reperfusion, DP (expressed as a percentage of preischemic control) and LVEDP (mm Hg) in 7 degrees and 17 degrees C hearts were no different (96 + 5% vs 97 +/- 3%; 5 +/- 2 mm Hg vs 6 +/- 2 mm Hg; p = NS), but were better (p less than 0.01) than 27 degree hearts (72 +/- 6%, 17 +/- 6 mm Hg) and 37 degree hearts (31 +/- 7%, 60 +/- 6 mm Hg). PCr was severely depleted in all groups. ATP was 90 +/- 7% and 87 +/- 5% of preischemic control in the 7 degree and 17 degree hearts, which was significantly better than the 68 +/- 3% and 21 +/- 3% in the 27 degree and 37 degree groups (p less than 0.01). The pH at end ischemia was 6.83, 6.89, 6.54, and 5.86 for the 7 degree, 17 degree, 27 degree, and 37 degree hearts, respectively (7 degrees vs 27 degrees or 37 degrees, p less than 0.01; 17 degrees vs 27 degrees or 37 degrees, p less than 0.01). Linear regression of DP on end-ischemic ATP (EIATP) and end-ischemic pH revealed: DP = 0.96 (EIATP) + 20 (r = 0.92) and DP = 60 (pH) -317 (r = 0.86). We conclude that (1) end-ischemic ATP predicts recovery of ventricular function, and, furthermore, there appears a threshold ATP concentration (80% of control) below which full recovery of function will not occur; (2) end-ischemic pH predicts recovery of ventricular function; (3) 7 degrees C hypothermic ischemia does not cause a clinically significant cold injury; and (4) in a single-dose crystalloid cardioplegia model, end-ischemic pH is linearly related to recovery of function (r = 0.86).     

Studies of controlled reperfusion after ischemia. XVII. Reperfusion conditions: controlled reperfusion through an internal mammary artery graft--a new technique emphasizing fixed pressure versus fixed flow

This study tests the usefulness of delivering a controlled reperfusate through an internal mammary graft after acute ischemia by applying a percutaneous technique of mammary artery cannulation and compares reperfusion at fixed pressure versus fixed flow. Methods: Twenty-one dogs underwent 2 hours of ligation of the left anterior descending coronary artery followed by regional controlled revascularization on total vented bypass. A reperfusion catheter was introduced percutaneously from the brachial artery into the internal mammary artery. Five dogs received normal blood reperfusion at 50 mm Hg pressure, and eight dogs received a regional blood cardioplegic reperfusate at 50 mm Hg before reperfusion with normal blood. Eight additional dogs received regional cardioplegia at 30 ml/min for 20 minutes. Coronary vascular resistance, segmental shortening (ultrasonic crystals), tissue water content, and histochemical damage (triphenyltetrazolium chloride stain) were assessed. Results: Reperfusion with normal blood increased coronary vascular resistance progressively to 62% above initial values (p less than 0.05) and failed to restore regional contractility (9% +/- 6% systolic shortening, p less than 0.05). In contrast, coronary resistance remained low throughout blood cardioplegic reperfusion at fixed pressure and the reperfused muscle recovered immediate contractility (73% systolic shortening, p less than 0.05). Controlled reperfusion at a fixed flow rate resulted in pressure that ranged from 30 to 80 mm Hg, slightly less recovery of systolic shortening (57%), and less return of contractile reserve (81% versus 114%, p less than 0.05). Regional blood cardioplegic reperfusion limited edema formation (79.5 versus 82% water content, p less than 0.05) and histochemical damage (11% versus 50% area of necrosis/area at risk, p less than 0.05). Conclusion: An internal mammary artery graft can be used effectively in the setting of acute ischemia if a controlled blood cardioplegic reperfusate is delivered through it to ensure limitation of histochemical damage, low reflow phenomenon, and restoration of immediate segmental contractility. Controlled-pressure reperfusion seems superior to fixed-flow reperfusion. A technique is described that may allow preoperative insertion of the reperfusion catheter in the internal mammary artery in the catheterization laboratory.     

University of Wisconsin solution for pulmonary preservation in a rat transplant model.

University of Wisconsin and modified Euro-Collins solutions for pulmonary preservation were compared in a rat orthotopic left lung isotransplant model. Heart-lung blocks of donor rats were flushed with and preserved in one of the preservation solutions at 0 degrees C. After 6 or 12 hours of cold ischemia, the left lungs were transplanted into recipient rats and reperfused for 1 hour. Pulmonary function was assessed by measuring oxygen and carbon dioxide tensions in arterial blood after removal of the right lung. Lipid peroxide concentrations were measured as thiobarbiturate acid-reactive substances. The ratios of wet to dry weight of grafts after ischemia and after reperfusion were calculated. Histologic changes of ischemia-reperfusion injury of the lung tissue were evaluated using a graded scale. Oxygen tension after 6 hours of preservation followed by reperfusion was significantly higher with University of Wisconsin solution (308.8 +/- 81.1 mm Hg) than with Euro-Collins solution (50.8 +/- 17.8 mm Hg; p less than 0.001). Carbon dioxide tension in the University of Wisconsin solution group was also significantly lower than in the Euro-Collins solution group (28.2 +/- 2.3 versus 46.0 +/- 4.5 mm Hg; p less than 0.05). Lipid peroxide concentration after 6 hours' preservation in University of Wisconsin solution was significantly lower (0.88 +/- 0.07 mumol/g) than that in Euro-Collins solution (1.26 +/- 0.12 mumol/g; p less than 0.05). After 12 hours of preservation only lipid peroxide concentration with University of Wisconsin solution was significantly lower (1.30 +/- 0.09 mumol/g) than with Euro-Collins solution (1.71 +/- 0.15 mumol/g; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Circulatory support for right ventricular dysfunction

New modes of circulatory support for right ventricular dysfunction have recently been described. The present study compared the effectiveness of pulmonary artery balloon counterpulsation with a right ventricular assist device for support of surgically induced right ventricular dysfunction. Right ventricular hypertrophy was created in 16 neonatal lambs by pulmonary artery banding. Right ventricular dysfunction was produced in all animals by performing a right ventriculotomy and maintaining the pulmonary artery band. Four unassisted animals developed severe acute right heart failure and died. Six sheep had pulmonary artery balloon counterpulsation with a Dacron graft anastomosed to the proximal pulmonary artery as a reservoir for a 40 ml intra-aortic balloon after the onset of heart failure. The remaining six sheep had a pneumatically activated ventricular assist device inserted between the proximal pulmonary artery and the right ventricular apex. Periods of circulatory support with the balloon pump and the assist device on and off were compared. Decreases in right atrial pressure were observed with both balloon counterpulsation and right ventricular assistance: 14 +/- 1 to 11 +/- 1 mm Hg, p less than 0.0001, versus 19 +/- 2 to 12 +/- 2 mm Hg, p less than 0.0002, respectively. Cardiac output increased with both balloon counterpulsation and ventricular assistance: 1.45 +/- 0.16 to 2.03 +/- 0.13 L/min, p less than 0.001, versus 0.72 +/- 0.15 to 2.24 +/- 0.23 L/min, p less than 0.0002, respectively. Aortic systolic pressure increased in both support groups: 78 +/- 7 to 99 +/- 6 mm Hg, p less than 0.0004, versus 53 +/- 9 to 85 +/- 9 mm Hg, p less than 0.0001, respectively. Ventricular assistance produced greater changes in the right atrial pressure (39% +/- 6% versus 17% +/- 3%, p less than 0.01), cardiac output (153% +/- 39% versus 54% +/- 11%, p less than 0.05), and aortic systolic pressure (85% +/- 13% versus 39% +/- 9%, p less than 0.01). The insertion of a right ventricular assist device caused a significant increment in right ventricular dysfunction. These data, obtained with the devices in place but not operating, showed significantly increased right atrial and right ventricular end-diastolic pressures and approximately 50% less cardiac output than with the pulmonary artery balloon counterpulsation system. The results demonstrate that both modes of circulatory support were effective in reversing surgically induced right ventricular failure.(ABSTRACT TRUNCATED AT 400 WORDS)     

Reduction of the extent of ischemic skeletal muscle necrosis by perfusion with oxygenated perfluorocarbon.

Oxygenated perfluorocarbon emulsion has been shown to preserve feline cerebral function after ischemia. The postulated protective effects of perfluorocarbons include improvement of blood rheology and prevention of neutrophil adherence by nonchemical inhibition of surface receptors. In this study, we used a well-described gracilis muscle model to investigate whether oxygenated perfluorocarbon can minimize skeletal muscle necrosis by mitigating the degree of leuko-sequestration. In eight adult mongrel dogs, both gracilis muscles were weighed and then subjected to 6 hours of normothermic ischemia followed by 48 hours of normothermic reperfusion. However, one randomly selected side (experimental side) was infused with oxygen (O2) Fluosol-DA 20% (4.4 +/- 0.2 mL O2/100 mL) intra-arterially at 12 mL/min for 40 minutes immediately after ischemia. Muscle biopsy specimens were obtained before ischemia and after 1 hour and 48 hours of reperfusion to estimate myeloperoxidase (MPO) activity, a marker of neutrophil infiltration. After 48 hours, both gracilis muscles were harvested and weighed in all animals. Muscle necrosis was measured by serial transections, nitroblue tetrazolium staining, and computerized planimetry. The transmuscular oxygen tension (pO2) of the gracilis muscle on the experimental side increased from 2 to 4 mm Hg during ischemia to 315 +/- 50 mm Hg during O2 Fluosol-DA 20% infusion. The percentage of muscle necrosis on the control side was 48.08% +/- 8.46%, compared with 27.62% +/- 6.96% on the experimental side (p less than 0.001). MPO activity was significantly higher at 48 hours of reperfusion compared with pre-ischemic and 1-hour reperfusion values (5.46 +/- 1.52 U/mg tissue protein versus 0.06 +/- 0.01 U/mg tissue protein and 0.16 +/- 0.06 U/mg tissue protein, respectively, in the control group; 1.78 +/- 0.60 U/mg tissue protein versus 0.16 +/- 0.08 U/mg tissue protein and 0.27 +/- 0.10 U/mg tissue protein, respectively, in the experimental group, p less than 0.05). However, MPO activity at 48 hours of reperfusion in the experimental group was significantly lower than in the control group (p less than 0.05). There was no difference in the percentage of weight gain between the control and the experimental groups (38.31% +/- 9.36% and 28.34% +/- 7.35%, respectively, p greater than 0.05). These data show that perfluorocarbons minimize the extent of skeletal muscle necrosis in this canine model. Based on our data on MPO activity, we believe t hat the protective effect of perfluorocarbons is in part due to th e decreased leuko-sequestration in the muscle during the the periods of ischemia and reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Melatonin attenuates posttransplant lung ischemia-reperfusion injury

BACKGROUND: Melatonin, a pineal hormone, is a free radical scavenger and an antioxidant. The purpose of this study was to assess the protective effect of melatonin on posttransplant lung ischemia-reperfusion injury. METHODS: Rat single-lung transplantation was performed in two (n = 10) experimental groups after 18 hours of cold (4 degrees C) ischemia. Group I animals consisted of the ischemic control group. In group II, donor and recipient animals were treated with intraperitoneal injection of 10 mg/kg melatonin 10 minutes before harvest and reperfusion, respectively. After 2 hours of reperfusion, oxygenation, plasma, and bronchoalveolar lavage nitrite levels were measured. Lung tissue was assessed for thiobarbituric acid reactive substances and myeloperoxidase activity. Peak airway pressure was recorded throughout the reperfusion period. RESULTS: The melatonin-treated group showed significantly better oxygenation (321.8+/-33.8 mm Hg versus 86.1+/-17.4 mm Hg; p < 0.001), reduced lipid peroxidation (0.65+/-0.3 nmol/g versus 1.63+/-0.8 nmol/g; p = 0.032), and reduced myeloperoxidase activity (0.56+/-0.1 deltaOD x mg(-1) x min(-1) versus 1.01+/-0.2 deltaOD x mg(-1) x min(-1); p = 0.032). Bronchoalveolar lavage nitrite levels in the transplanted lungs were significantly lower in group II than in group I (0.34+/-0.06 micromol/L versus 1.65+/-0.6 micromol/L; p = 0.016). In group II significant reduction in peak airway pressure was noted compared with group I (p = 0.002). CONCLUSIONS: In this model, exogenously administered melatonin effectively protected lungs from reperfusion injury after prolonged ischemia.     

Iron chelation therapy and lung transplantation. Effects of deferoxamine on lung preservation in canine single lung transplantation

Reperfusion injury is a limiting factor in lung transplantation. Deferoxamine is an iron chelator that inhibits the formation of oxygen-derived free radicals. We investigated the effects of deferoxamine on posttransplantation lung function in a canine model of single lung transplantation. Twelve dogs underwent left lung transplantation after 20- to 24-hour hypothermic storage in a modified Euro-Collins solution. In six experiments donor and recipient received a 10 mg/kg dose of deferoxamine before harvest and transplantation, and 10 mg/kg was added to the preservation solution. Arterial oxygen tension, alveolar-arterial oxygen difference, pulmonary vascular resistance, and dynamic lung compliance were measured. Data were recorded for 6 hours after ligation of the native pulmonary artery. At the end of the study the mean arterial oxygen tension was 175.1 mm Hg for the deferoxamine treated group versus 71.1 mm Hg for the control group (p less than 0.001), and the alveolar-arterial oxygen difference was less in the deferoxamine-treated group: 502.3 versus 606.0 mm Hg (p less than 0.001). The mean pulmonary vascular resistance was lower throughout the study, and after 6 hours it was 455.1 dynes/sec/cm(-5) in the deferoxamine-treated group versus 663.7 dynes/sec/cm(-5) in the control group (p less than 0.035). Compliance was similar in both groups. We conclude that deferoxamine improves lung preservation and early posttransplantation function in canine single lung transplantation.     

Effects of dynamic cardiomyoplasty on indices of left ventricular systolic and diastolic function in a canine model of chronic heart failure.

The effects of cardiomyoplasty were evaluated with multiple-gated equilibrium radionuclide angiocardiography and catheterization in a canine model of chronic heart failure. Doxorubicin was administered to 12 dogs at a dose of 1 mg/kg/wk intravenously for 10 weeks. Left ventricular ejection fraction was reduced from a mean of 53.6% +/- 3.4% to 33.5% +/- 2.3% preoperatively. Two dogs died of presumed arrhythmia during this period. Cardiomyoplasty with the left latissimus dorsi muscle was performed on 10 dogs. The muscle was wrapped around both the left and right ventricles. Five dogs died of infection or arrhythmia after the operation. Postoperatively the muscle remained unstimulated for 2 weeks to allow adhesion to the heart. After this period, the latissimus dorsi muscle was conditioned by a progressive stimulation protocol. After the muscle was conditioned, multiple-gated equilibrium radionuclide angiocardiography studies showed that left ventricular global ejection fraction was 18.4% +/- 7.2% at 0 volts (nonstimulation), 26.2% +/- 3.7% at 5-volt stimulation (p less than 0.05), and 31.0% +/- 5.4% at 10-volt stimulation (p less than 0.05). Regional ejection fractions in low lateral, apical, and low septal regions at 5 volts and 10 volts were higher than those at 0 volts (p less than 0.05). Regional wall motion (percent radial shortening) of the low lateral region was higher than that during nonstimulation (p less than 0.05). Peak emptying rate was 2.07 +/- 0.95 end-diastolic counts per second at 0-volt, 3.10 +/- 0.67 at 5-volt, and 3.34 +/- 0.89 at 10-volt stimulation (p less than 0.05). Peak filling rate was 1.81 +/- 0.52 end-diastolic counts per second at 0-volt, 2.67 +/- 1.18 at 5-volt, and 3.11 +/- 0.65 at 10-volt stimulation (p less than 0.05). Cardiac catheterization data showed a nonsignificant increase in left ventricular rate of pressure rise with increasing voltage (1302 +/- 355 mm Hg/sec at 0 volts, 1450 +/- 413 mm Hg/sec at 5 volts, and 1568 +/- 455 mm Hg/sec at 10 volts). Left ventricular systolic pressures were unchanged. End-diastolic pressures decreased (11.2 +/- 1.48 mm Hg at 0 volts, 10.4 +/- 2.30 mm Hg at 5 volts, and 9.6 +/- 1.52 at 10 volts; p less than 0.05). These data show that cardiomyoplasty can improve indices of systolic and diastolic function in a canine model of chronic heart failure.