Peter Satter

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.

Reperfusion injury in skeletal muscle: controlled limb reperfusion reduces local and systemic complications after prolonged ischaemia

Previous studies in isolated limbs using crystalloid perfusion solutions have shown that control of the initial reperfusion reduces postischaemic complications. However, no experimental study has been undertaken to evaluate the concept of controlled limb reperfusion experimentally in an in vivo blood-perfused model and to assess the local as well as systemic effects of normal blood reperfusion and controlled limb reperfusion. Of 20 pigs undergoing preparation of the infrarenal aorta and iliac arteries, six were observed for 7.5 h and served as controls; 14 others underwent 6 h of complete infrarenal occlusion. Thereafter, embolectomy was simulated in eight pigs by removing the aortic clamp and establishing normal blood reperfusion at systemic pressure. In six other pigs, the composition of the reperfusate and the conditions of reperfusion were controlled during the first 30 min, followed by normal blood reperfusion. Some 6 h of infrarenal aortic occlusion leads to a severe decrease in high-energy phosphates and muscle temperature, together with a slight increase in creatine kinase and potassium in the systemic circulation. Normal blood reperfusion resulted in severe reperfusion injury: massive oedema developed, the tissue showed a marked decrease in oxygen consumption, glucose consumption. tissue ATP. total adenine nucleotides, muscle pH and total calcium in the femoral vein. Furthermore, a massive increase was seen in plasma creatine kinase concentration and potassium, together with the development of muscle rigidity. In sharp contrast, initial treatment of the ischaemic skeletal muscle by controlled limb reperfusion resulted in normal water content, oxygen consumption, glucose consumption, flow and muscle rigidity. Furthermore, controlled limb reperfusion resulted in higher total adenine nucleotides content. less tissue acidosis, markedly reduced creatine kinase release, and potassium release as compared with that of normal blood reperfusion. This study shows that 6 h of acute infrarenal aortic occlusion will result in severe reperfusion injury (postischaemic syndrome) if normal blood at systemic pressure is given in the initial reperfusion phase. In contrast, initial treatment of the ischaemic skeletal muscle by controlled limb reperfusion reduces the metabolic, functional and biochemical alterations.

Studies of the Tissue Reaction Induced by Transvenous Pacemaker Electrodes. I. Microscopic Examination of the Extent of Connective Tissue Around the Electrode Tip in the Human Right Ventricle

The purpose of this study was to investigate the extent of connective tissue of the human right ventricle induced by cardiac pacing electrodes. Between January 1984 and July 1987, 34 consecutive patients with VVI‐pacing systems were autopsied in the Department of Pathology at the University of Frankfurt/M. The surrounding tissue of these 34 electrodes (17 Siemens Elema 412 S, five Medtronic 6957, one Medtronic 6959, one Medtronic 4011, three Biotronik D2K, three Biotronik K10, two Osypka FY 62, one Biotronik N, and one Siemens Elema 588) in the right ventricle were investigated histologically. The tissue was stained with Giemsa and the thickness of the connective tissue layer was measured. Stimulation threshold data at various times were known in four of eight screw‐in electrodes, in seven of 17 vitreous carbon electrodes and in two of seven smooth surface electrodes. Electrode surface area, implantation time, age of the patient and cause of death were comparable for all three electrode groups. However, a significant difference was found in the extent of connective tissue between the porous surface and screw‐in electrodes (128 ± 55 VS 397 ± 269 μm, P 0.01) and porous surface and smooth surface electrodes (128 ± 55 vs 307 ± 117 μm, P 0.01). No relation (r = 0.106) was found between the duration of implantation and the extent of connective tissue for the vitreous carbon electrodes (Siemens Elema 412 S). The lowest chronic stimulation thresholds were measured in the latter type of electrodes (0.5 ± 0.3 V) as compared to the screw‐in (0.75 ± 0.30 V) and smooth surface electrodes. We conclude from this study, that vitreous carbon electrodes induce only a small amount of connective tissue around the insertion site in the human right ventricle, as compared to other smooth surface or screw‐in electrodes. Chronic stimulation threshold data parallel those morphological results.

Endothelium-dependent and endothelium-independent flow regulation in coronary vascular regions supplied by arterial and venous bypass grafts

The endothelium-dependent and endothelium-independent vasodilation of arterial and venous coronary bypass grafts and of epicardial conduit vessels and microcirculatory coronary vessels supplied by these grafts was investigated. Vasodilatory response and flow regulation were tested with cumulative intracoronary doses of acetylcholme (25 and 50 µg i.e.), nitroglycerin (0.3 mg i.e.), and papaverine (10 mg i.e.) in 10 patients (age 60 ± 2.3 years) with arterial grafts and in 16 patients (age 57.7 ± 1.5 years) with venous grafts. The effect of acetylcholme on arterial and venous bypass grafts and on large conduit arteries was evaluated by quantitative coronary angiography. Coronary blood flow velocity changes as a parameter of microcirculatory function were measured by intraluminal Doppler ultrasound. Indices for coronary flow and coronary resistance were calculated from the mean Doppler flow velocity and the computed cross-sectional vascular area. The coronary resistance decreased endothelium dependent after 25 and 50 µg of acetylcholme by 16 ± 30% (p

New Surgical Treatment for Severe Limb Ischemia

Revascularization after prolonged complete limb ischemia may result in severe damage to skeletal muscle and systemic alterations (postischemic syndrome). Our previous experimental studies have shown that this injury can be reduced substantially by treating the jeopardized extremity by controlling the conditions of reperfusion and composition of the initial reperfusate. In the present study this concept of controlled limb reperfusion was applied in patients with prolonged severe limb ischemia. Controlled limb reperfusion was used in 14 patients after prolonged complete uni- or bilateral ischemia. The ischemic interval ranged from 5 to 21 h. Two patients were in cardiogenic shock, 11 had associated cardiac disease, and seven coexistent peripheral vascular disease. After systemic heparinization, standard thromboembolectomy was done using a Fogarty catheter. Cannulas were placed into the iliac, profunda, and superficial femoral arteries and were connected to a reperfusion set. Oxygenated blood was drawn from the iliac artery and mixed with an asanguineous solution (ratio 6:1). This controlled reperfusate was delivered into the profunda and superficial femoral arteries using a single rollerpump. The system allows control of the composition of the reperfusate (calcium, pH, osmolarity, glucose, substrate, pO2, free radical scavengers) and the conditions of reperfusion (pressure, flow, temperature). After 30 min of controlled limb reperfusion, the cannulas were removed and normal blood reperfusion started. All 12 patients who were stable hemodynamically before the operation survived the revascularization. Eleven patients, including one with acute aortic occlusion for several hours, were discharged with functional recovery of their extremities. Despite the severe ischemic insult, controlled limb reperfusion avoided amputation and profound systemic complications. Two patients who were in cardiogenic shock preoperatively died from progressive cardiac failure. We conclude that controlled arterioarterial limb reperfusion may reduce the local manifestations of the postischemic syndrome after prolonged periods of ischemia, may salvage limbs thought previously to be damaged irreversibly by prolonged ischemia, and can be done easily in the operating room.

Examination of Explanted Polyurethane Pacemaker Leads Using the Scanning Electron Microscope

Since 1978, 2,365 polyurethane (PV) insulated cardiac pacing leads were implanted transvenously at our institution. To date, there have been no insulation failures in those leads. Thirtyseven PU leads were explanted, mainly for exit block, and 28 of these were investigated using the scanning electron microscope. We found a homogeneous distribution of surface changes in all lead segments in 56% of the 28 examined. These changes were more pronounced at the ligature site; severe surface cracking was noticed in 21%, with the deepest crack being 40 μm (average range of 10–15 μm). There appeared to be no time‐dependency of the surface changes as indicated by regression analysis (r = 0.32. p > 0.05). The ultimate severity and outcome of this degradation process in the leads reported in this study will only be known in the future after longer use. We conclude that excess stress must be avoided during the implantation procedure and that careful surveillance is necessary.

Time course of endothelial function in epicardial conduit coronary arteries and in the microcirculation in the long-term follow-up after cardiac transplantation

BACKGROUND Endothelial dysfunction has been reported in epicardial conduit coronary arteries and in the microcirculation after cardiac transplantation. It has been assumed that endothelial dysfunction may precede hemodynamically relevant transplant vasculopathy. In this study the long-term course of endothelial function was investigated in conduit coronary arteries and in the microcirculation after cardiac transplantation. METHODS Patients were stratified according to time after transplantation (group I, up to 2 years after transplantation; group II, 2 to 4 years after transplantation; group III, more than 4 years after transplantation). Changes of the diameter of proximal, mid and distal segments of the left anterior descending coronary artery and the circumflex branch of the left coronary artery were investigated after endothelium-dependent and endothelium-independent stimulation with acetylcholine (ACh, 50 and 100 micrograms i.c.) and nitroglycerin 0.3 mg i.c. Coronary flow changes were assessed endothelium-dependently (ACh 50 and 100 micrograms i.c.) and endothelium-independently (dipyridamole 0.56 mg/kg i.v.) utilizing an 8 F Judkins-style Doppler catheter. RESULTS Application of 50 micrograms/100 micrograms ACh resulted in a reduction of coronary artery diameter in proximal, mid and distal vascular segments of the left anterior descending coronary artery and the circumflex branch of the left coronary artery. The vasoconstrictive effect did not differ significantly between groups I,II and III. Nitroglycerin 0.3 mg i.c. increased coronary artery diameters in groups I, II and III. ACh (50 micrograms/100 micrograms) increased coronary flow index by 217 +/- 70%/236 +/- 110% (P < 0.05 vs. baseline) in group I, 113 +/- 26%/77 +/- 22% (P < 0.05 vs. baseline) in group II and 108 +/- 26%/109 +/- 21% (P < 0.05 vs. baseline) in group III. Dipyridamole increased coronary flow index by 296 +/- 78% (P < 0.05 vs. baseline) in group I, by 63 +/- 16% (P < 0.05 vs. baseline and vs. group I) in group II and by 113 +/- 30% (P < 0.05 vs. baseline and vs. group I) in group III. CONCLUSION A constant vasosonstrictor response to ACh was observed in epicardial coronary arteries after cardiac transplantation indicating endothelial dysfunction independent of the time course. Endothelial dysfunction in these vessels may not be an early indicator of hemodynamically relevant transplant vasculopathy. Endothelium-dependent and endothelium-independent flow reserves decreased 2 years after transplantation and remained constant thereafter.

Right ventricular volumes and hemodynamics after successful orthotopic heart transplantation. A comparison to coronary artery disease using thermodilution

Only few data exist concerning right ventricular function in the chronic stage after cardiac transplantation. Therefore, we investigated hemodynamic and right ventricular volumetric data by a computerized thermodilution Swan-Ganz catheter in 17 patients (median age: 53, range: 18-63 yr) at a median of 24 (4 to 44) months after cardiac transplantation during rest and supine bicycle exercise. Myocardial biopsy showed grade one or less according to the classifications of Billingham. Sixteen patients with coronary artery disease, but without prior myocardial infarction, served for comparison. While angiographic left ventricular ejection fraction was nearly identical in transplant recipients [77 (60-92)%, median (range)] and in patients with coronary artery disease [78 (64-94)%], right ventricular ejection fraction was lower (p < 0.001) in patients after cardiac transplantation [37 (16-58)%] as compared to patients with coronary artery disease [56 (46-62)%]. In transplant recipients right atrial pressure was significantly higher both at rest [10 (2-18) mmHg] and exercise [18 (8-30) mmHg] than in patients with coronary artery disease [5 (1-11) and 8 (3-18) mmHg]. Pulmonary capillary wedge pressure behaved similar in both groups. To further evaluate reasons for right ventricular impairment, a correlation analysis was performed. This showed a negative correlation between right ventricular ejection fraction and the time interval after transplantation (p < 0.0002). However, there was no correlation between right ventricular ejection fraction and acute rejection or a rejection score. In conclusion, right ventricular function may be severely altered in transplant recipients, in contrast to an only slight impairment of left ventricular function.

Endothelium-dependent and endothelum-independent flow regulation in coronary vascular regions supplied by arterial and venous bypass grafts

The endothelium-dependent and endothelium-independent vasodilation of arterial and venous coronary bypass grafts and of epicardial conduit vessels and microcirculatory coronary vessels supplied by these grafts was investigated. Vasodilatory response and flow regulation were tested with cumulative intracoronary doses of acetylcholine (25 and 50 micrograms i.c.), nitroglycerin (0.3 mg i.c.), and papaverine (10 mg i.c.) in 10 patients (age 60 +/- 2.3 years) with arterial grafts and in 16 patients (age 57.7 +/- 1.5 years) with venous grafts. The effect of acetylcholine on arterial and venous bypass grafts and on large conduit arteries was evaluated by quantitative coronary angiography. Coronary blood flow velocity changes as a parameter of microcirculatory function were measured by intraluminal Doppler ultrasound. Indices for coronary flow and coronary resistance were calculated from the mean Doppler flow velocity and the computed cross-sectional vascular area. The coronary resistance decreased endothelium dependent after 25 and 50 micrograms of acetylcholine by 16 +/- 30% (p < 0.05 vs. control) and 22 +/- 25% (p < 0.05 vs. control), respectively, in regions supplied by venous grafts and by 48 +/- 20% (p < 0.05 vs. control and vs. venous graft) and 41 +/- 32% (p < 0.05 vs. control), respectively, in regions supplied by arterial grafts. The coronary resistance decreased endothelium independent after 0.3 mg nitroglycerin and 10 mg papaverine by 18 +/- 56% (p < 0.05 vs. control) and 39 +/- 29% (p < 0.05 vs. control), respectively in regions supplied by venous grafts and by 45 +/- 45% (p < 0.05 vs. control) and 70 +/- 12% (p < 0.05 vs. control and vs. venous graft), respectively in regions supplied by arterial grafts. In conclusion, during the long-term course after coronary artery bypass grafting, vascular regions supplied by arterial grafts have a better preserved endothelium-dependent and endothelium-independent flow reserve as compared with vascular regions supplied by venous grafts.

Extrakorporale, kontrollierte Extremitäten-Reperfusion

Revaskularisationen nach akuter, kompletter, mehrstundiger Extremitatenischamie sind haufig mit der Entwicklung eines schweren Postischamie-Syn-droms verbunden. Durch extrakorporale, kontrollierte Extremitaten-Reperfusion ist eine Verminderung der Schaden zu erzielen. Voraussetzung ist jedoch die Moglichkeit zur kompletten Revaskularisation.