Detrimental effect of high-dose prostaglandin E1 in the treatment of ischemic ulcers

Eight patients with ischemic lower extremity ulcers were entered into a randomized, controlled trial of intravenous prostaglandin E1 (PGE1) versus placebo. All ulcers had been stable or increasing in size for at least 3 weeks prior to the study. Each patient had rest pain assessment, Doppler pressure measurements, and ulcer measurements before and after infusion. Four patients received PGE1 and four received placebo. There were no significant preinfusion differences between groups. Rest pain remained stable or improved in all patients. In the placebo group the mean absolute ankle pressure decreased 5 +/- 14 mm Hg, but the mean ankle/arm pressure ratio increased 0.03 +/- 0.06. In the PGE1 group the mean absolute ankle pressure decreased 16 +/- 16 mm Hg and the mean ankle/arm pressure ratio decreased 0.05 +/- 0.06. Neither difference is statistically significant. Patients who received placebo had no change or decrease in ulcer size, but all patients who received PGE1 had an increase in ulcer size (P = 0.05, Wilcoxon rank sum test). One of the four placebo patients required extremity amputation during follow-up of 10.5 +/- 3.5 months. All four patients in the PGE1 group required amputation within 3.3 +/- 2.6 months. Despite theoretic benefits, intravenous PGE1 may be detrimental in the treatment of ischemic ulcers.     

Amputations at the middle level of the foot. A retrospective and prospective review

Recent trends in amputation surgery favor amputation at the most distal level to preserve the patient's ability to walk. This paper reports the results of sixty-four amputations performed at the level of the middle of the foot in fifty-eight patients. All were performed in patients with peripheral vascular disease who had a diagnosis of either gangrene or resistant, nonhealing ulcers. Forty-three patients (74 per cent) had diabetes. Nutritional evaluation of the patient was used to improve the potential for healing. In the initial forty-six patients, a retrospective review of the serum albumin level, the blood total-lymphocyte count, and the Doppler ischemic index was performed. A prospective study was performed in the final twelve patients, in whom a minimum level in each of these three factors was required before the distal amputation was done. The healing rate for all sixty-four amputations was 81 per cent. When all three factors were above the minimum level, the healing rate was increased to 92.2 per cent. When one or two of the factors was below the minimum level, the rate of healing decreased to 38.5 per cent. Aggressive distal amputation can be performed with a high rate of success when the factors influencing the decision on the amputation level include non-invasive vascular testing and nutritional evaluation.     

Osteosarcoma: A Multifactorial Clinical and Histopathological Study with Special Regard to Therapy and Survival

A multifactorial analysis was performed on all 153 unequivocal cases of genuine osteosarcoma recorded in the Swedish Cancer Registry for the years 1958 through 1968. Cases of so-called parosteal osteosarcoma, soft-tissue osteosarcoma and osteosarcoma secondary to Paget's disease of bone were not included. The osteosarcomas were subclassifiecl as follows: osteoblastic (69 per cent), chondroblastic (19 per cent) and fibroblastic (12 per cent). The overall 5-year survival rate was 22 per cent; 55 per cent for those who had undergone amputation above the joint proximal to the involved skeletal part, 22 per cent for those amputated on the involved skeletal part, 11 per cent for those treated with local extirpation of the tumor, and 1 per cent in cases in which the lesion was not radically removed. Tumors of the femur, humerus and scapula were as malignant as axial tumors. The former carried a 5-year survival rate of 13 per cent, regardless of whether the patients had been treated with exarticulation or amputation on the involved skeletal part. Patients with axial tumors showed a 5-year survival rate of 15 per cent. These survival data suggest that proximal amputation alone might suffice for lesions situated distally to the knee and elbow joints, while tumors in the humerus and femur should be treated with amputation combined with multicytostatic treatment or immunotherapy and axial tumors with local resection and multicytostatic or immunologic treatment.     

Osteosarcoma. A multifactorial clinical and histopathological study with special regard to therapy and survival.

A multifactorial analysis was performed on all 153 unequivocal cases of genuine osteosarcoma recorded in the Swedish Cancer Registry for the years 1958 through 1968. Cases of so-called parosteal osteosarcoma, soft-tissue osteosarcoma and osteosarcoma secondary to Paget's disease of bone were not included. The osteosarcomas were subclassified as follows: osteoblastic (69 per cent), chondroblastic (19 per cent) and fibroblastic (12 per cent). The overall 5-year survival rate was 22 per cent; 55 per cent for those who had undergone amputation above the joint proximal to the involved skeletal part, 22 per cent for those amputated on the involved skeletal part, 11 per cent for those treated with local extirpation of the tumor, and 1 per cent in cases in which the lesion was not radically removed. Tumors of the femur, humerus and scapula were as malignant as axial tumors. The former carried a 5-year survival rate of 13 per cent, regardless of whether the patients had been treated with exarticulation or amputation on the involved skeletal part. Patients with axial tumors showed a 5-year survival rate of 15 per cent. These survival data suggest that proximal amputation alone might suffice for lesions situated distally to the knee and elbow joints, while tumors in the humerus and femur should be treated with amputation combined with multicytostatic treatment or immunotherapy and axial tumors with local resection and multicytostatic or immunologic treatment.     

Ultimate salvage for the patient with limb-threatening ischemia. Realistic goals and surgical considerations

Ultimate salvage for the patient with a severely ischemic lower limb should be the preservation of bipedal gait. Arterial reconstructions which will sustain the limb by restoring circulation will accomplish this objective if the limb is functional. However, major amputations of the leg performed for ischemia are increasing yearly despite the proliferation of “salvage” bypass procedures. Evaluation of large experiences in revascularizations performed to popliteal or distal arteries for limb salvage reveal: (1) mortality 4 per cent; (2) early graft failure 20 to 35 per cent, late failure (2 years) 30 to 50 per cent; (3) amputation despite patent graft 7 to 10 per cent; and (4) factual palliation (2 years) less than 50 per cent. To these must be added the number of patients who required an above-knee amputation after their revascularization attempt failed, in whom a primary below-knee amputation would have healed.Primary healing has been achieved at the below-knee level in 80 per cent of such patients, most of whom are successfully returned to ambulatory status. Since the rehabilitation time is doubled and the attainment of independent bipedal gait halved with an above-knee amputation, the importance of the knee joint for ambulation cannot be overemphasized. In view of these observations, the wisdom of proceeding with a tenuous arterial reconstruction for treatment of patients with advanced limb ischemia is questioned. Primary below-knee amputations should be used more often in this setting. Appropriate therapy should not interfere with the dysvascular patient attaining the ultimate goal: social and economic independence through the preservation of bipedal gait.     

Increased limb salvage. Distal tibial/peroneal artery thrombectomy/embolectomy in acute lower extremity ischemia

Fifty-five acutely ischemic lower extremities, in 35 patients, which remained ischemic after standard thrombectomy/embolectomy techniques were further treated with distal tibial/peroneal thrombectomy/embolectomy by ankle level arteriotomy to increase limb salvage. A total of 84 infrapopliteal arteries were explored and thromboembolectomy performed in 79. The precipitating ischemic event was arterial embolus in 38 per cent, arterial thrombus in 60 per cent, and trauma in 2 per cent of the cases. There were 16 female and 19 male patients. Additional bypass grafting was used in 18 per cent of extremities. The limb salvage rate was 91 per cent in this select "tibial/peroneal" group. This technique salvaged 50 limbs that otherwise would have required major amputation. The addition of this technique changed the potential limb salvage rate from 76 per cent of the entire 199 lower extremities treated during this period to an actual limb salvage rate of 97 per cent. Operative mortality was 16 per cent in this selected group with an overall mortality of 6 per cent for all patients with acutely ischemic lower limbs. A mean patient follow-up of 32 months (range 12 to 72 months) identified only three late amputations, demonstrating that distal tibial/peroneal thrombectomy/embolectomy is a durable procedure. It is a technically easy means of promoting limb salvage in the acutely ischemic limb which either 1) remains ischemic after standard transinguinal iliofemoral thromboembolectomy, or 2) is secondary to infrapopliteal artery occlusion. It allows successful thromboembolectomy of acutely occluded infrapopliteal arteries without distal popliteal arteriotomy. These techniques should be within the armamentarium of all surgeons dealing with acute lower extremity ischemia.     

A protocol for the safe treatment of acute lower limb ischaemia with intra-arterial streptokinase and surgery

Over a 5-year period 70 patients, presenting with subacute ischaemia of the lower limb (more than 12 h), were treated with low-dose intra-arterial streptokinase. There were 72 infusions and effective lysis was achieved in 52 (72 per cent), with an average infusion time of 25 h. A total of 23 (32 per cent) also underwent percutaneous transluminal angioplasty when lysis showed an underlying stenosis, and a further 19 (26 per cent) required surgery to remove persistent stenosis, organized thrombus or atheromatous debris. Significant bleeding occurred in 4 patients (6 per cent) and 13 (18 per cent) underwent amputation. There were five deaths (7 per cent), one of which was directly related to the infusion, while three were due to myocardial infarction. All of the major complications occurred in the early part of the study and both the selection of patients and the technique of infusion were modified to improve safety. Complementary treatment by percutaneous transluminal angioplasty and surgery was used more frequently in the later part of the study. The technique is not recommended for the white leg of acute ischaemia (less than 12 h), or for lysis of clot in a retroperitoneal Dacron graft, but may be uniquely valuable to demonstrate the cause of subacute ischaemia.     

Major amputation in a defined population: incidence, mortality and results of treatment

Medical records of all patients, from a defined population of 88,000 inhabitants, who underwent major lower limb amputation during 1980-82 were retrospectively scrutinized. The records showed 131 amputations were performed in 106 patients at the district hospital and 22 amputations on 17 patients at the local university hospital, referral centre, altogether 57 men and 66 women. This gave an amputation incidence of 46 per 10(5) inhabitants per year. Of the amputees 47 per cent were older than 80 years. Only two patients underwent reconstructive vascular surgery (at the university hospital) before surgery. Final amputation level was above-knee in 61 per cent of the patients treated at the district hospital. Mortality rates at 30 days and 2 years after the amputation were 23 and 56 per cent, respectively, and the age-corrected survival after 2 years was 55 per cent. For patients who came from and eventually returned to their own homes the mean hospital stay amounted to 184 days (postoperative deaths excluded). After amputation 26 patients were trained to wear a prosthesis and 16 of these used the prosthesis 2 years after amputation. The present study underlines the need for prospective and parallel studies of vascular surgery and amputation as well as analyses of the risk factors involved in lower limb ischaemia in defined populations.     

Haemodynamic effects of intra-arterial and intravenous administration of prostaglandin E1 in patients with peripheral arterial disease

The purpose of this study was to compare the haemodynamic effects of intra-arterial and intravenous prostaglandin E1 (PGE1) both injected and infused into ischaemic legs. Continuous intra-arterial infusion of PGE1 induced a significantly greater increase in skin temperature and blood flow than did intravenous drip infusion. Furthermore, intra-arterial infusion caused no steal phenomenon in the toe as indicated by skin temperature. On the other hand, toe skin temperature decreased during intravenous drip in 33 per cent of the legs tested. Continuous intravenous infusion also produced a significantly greater increase in toe skin temperature than did brief intravenous drip. In three of ten ulcers healed by continuous intra-arterial infusion, no definitive effect was obtained from continuous intravenous infusion even when it was repeated up to three times before continuous intra-arterial infusion. Intra-arterial injection of PGE1 caused no significant increase in toe skin temperature.     

Osteogenic sarcoma. A study of one hundred and thirty cases.

One hundred and thirty patients with osteogenic sarcoma were studied clinically, roentgenographically, and pathologically. Prognosis by each of ten factors was analyzed with the Wilcoxon test. The test yielded p smaller than 0.05 in a comparison between the survival curves of patients fifteen years old or younger and that of patients over fifteen, but other comparisons did not yield p smaller than 0.05. The actual five-year survival rate was 25.5 per cent (twenty-six of 102 patients who had radical surgery). Our therapeutic regimen for osteogenic sarcoma at the present time consists of regional perfusion, amputation, bronchial artery infusion, and systemic administration of anticancer agents.     

Natural history of the leg amputee

For 173 patients undergoing major leg amputations, the operative mortality was 13 per cent. The ratio of below-knee (BK) to above-knee (AK) amputations was approximately unity. Of the 150 patients who survived amputation, 93 were given prostheses. Among the latter group, 76 per cent of the unilateral AK amputees and 90 per cent of the unilateral BK amputees had a successful rehabilitation. For those patients who had to be converted from BK to AK unilateral amputations, 40 per cent experienced successful rehabilitation, and for those who had either bilateral BK or bilateral mixed amputations, 45 per cent were successful. The most common contraindications to granting prostheses were debility and dementia. The mean time interval from first amputation to latest observation was 3.5 years (range, 5 weeks to 13.5 years). At three years 49 per cent of the patients survived and at five years 31 per cent survived. Despite major impediments, satisfactory rehabilitation is accomplished frequently enough to justify optimism for a considerable number of geriatric amputees.     

Early and late results following implantation of an aortic bifurcation prosthesis

Aorto-iliacal or aortofemoral bifurcation grafts were implanted to 351 patients for stenotic or occlusive diseases of pelvic and femoral arteries, between 1974 and 1986. The average age of patients was 62.7 years, and perioperative lethality amounted to 7.4 per cent. The average age of patients who died was 68.2 years. Intraoperative complications occurred in 18 cases, early postoperative problems in 103, and complications over more extended periods of time in 37 instances. Postoperative amputation was necessary for eight patients (2.3 per cent) with pre-existence of gangrene. Another 30 patients (9.2 per cent) had to undergo amputation later on. Second, third and more interventions were required in 75 patients. Postoperative follow-up periods were between three months and 13 years during which 51 patients died of cardiovascular diseases, 21 of malignoma, and 14 of other diseases. Adequate surgical results were established by follow-up checks in 80 per cent of the above cases. Twenty-four per cent complained about continued or recurrent claudication. Forty-six per cent of all survivors have continued to be smokers.     

Early results of low dose intra-arterial streptokinase therapy in acute and subacute lower limb arterial ischaemia

Thirty-two patients with acute and subacute limb-threatening peripheral arterial ischaemia were treated with low dose intra-arterial streptokinase infusions. The mean duration of infusion was 38 h. Six patients developed pericatheter thrombosis and two had distal embolization of fragments of thrombus but in all cases these responded to repositioning the catheter and continuing the infusion. Five patients developed groin haematomata and in three of these there was evidence of a systemic fibrinolytic effect from the streptokinase with plasma fibrinogen reduced below 1 g/l. The most serious complication was perforation of the popliteal and tibial arteries which occurred on two occasions and required cessation of the infusion. Twenty-two patients (69 per cent) achieved limb salvage, eight (25 per cent) suffered a major amputation and two (6 per cent) died. The outcome was not related to the site, nature or duration of the arterial occlusion but patients with loss of sensation or paralysis of the affected limb were significantly less likely to obtain limb salvage (P = 0.001). For occlusions greater than 30 cm in length a new technique was used where the thrombus was lysed from distal to proximal in short lengths by gradual catheter withdrawal. This was successful in five out of six cases. Low dose intra-arterial streptokinase has been confirmed as an effective, relatively safe method of treatment in recent arterial ischaemia and can be recommended in situations where the results of surgery may not be favourable. In particular, patients with arterial thromboses and no distal run-off, distal and late arterial emboli, thrombosed popliteal aneurysms and patients after a failed embolectomy, have all been shown to respond to thrombolytic therapy with intra-arterial streptokinase.     

Peripheral thrombolysis for acute-onset claudication. Thrombolysis Study Group.

BACKGROUND: The aim of this study was to determine the outcome of patients who presented with sudden onset of incapacitating claudication of less than 2 weeks' duration and who were treated with peripheral arterial thrombolysis. METHODS: The database of the Thrombolysis Study Group was searched retrospectively for patients who received thrombolysis for acute-onset claudication. Some 108 patients (65 men, median age 69 (range 29-94) years) were treated with intra-arterial tissue plasminogen activator at 14 hospitals. The median duration of symptoms was 72 h (range from 2 h to 2 weeks). There were 52 graft and 56 native vessel arterial occlusions. RESULTS: The immediate outcome of thrombolysis for native vessel arterial occlusion was thrombus clearance in 50 patients (89 per cent) and failed lysis in six (11 per cent). Thirty-six patients (64 per cent) had a secondary radiological or surgical procedure carried out after lysis. After 30 days four patients (7 per cent) had a major amputation, eight (14 per cent) had died, 38 (68 per cent) were symptom free and seven (12 per cent) continued to have claudication. Three patients (5 per cent) suffered a major haemorrhage. The immediate outcome of thrombolysis for graft occlusion was thrombus clearance in 48 patients (92 per cent) and failed lysis in four (8 per cent); 27 patients (52 per cent) had a secondary procedure. After 30 days four patients (8 per cent) had a major amputation, seven (13 per cent) had died, 32 (62 per cent) were symptom free and nine (17 per cent) had persistent claudication. Three patients (6 per cent) suffered a major haemorrhage. CONCLUSION: Patients who presented with acute onset of incapacitating claudication had an outcome similar to that after thrombolysis for critical ischaemia. It is recommended that patients who present in this way should be observed and treated with thrombolysis only if they progress to critical ischaemia. Presented to the Association of Surgeons of Great Britain and Ireland, Edinburgh, UK, May 1998, and published in abstract form as Br J Surg 1998; 85(Suppl 1): 24     

The role of non-invasive vascular studies in determining levels of amputation

Various non-invasive vascular studies have been reported to provide valuable data for selection of the optimum level of amputation in limbs in patients who have vascular disease. We evaluated three such methods: (1) measurement of the change in the transcutaneous PO2 after inhalation of oxygen; (2) determination, by the Doppler method, of segmental blood pressure; and (3) measurement of the temperature of the skin. The records of eighty patients (ninety amputations) were retrospectively reviewed for correlations between the results of the vascular studies and the outcome of the amputation. Measurement of transcutaneous PO2 was found to be the most accurate predictor of successful healing of an amputation; the other two measurements were less reliable. The values for transcutaneous PO2 both at rest and after inhalation of oxygen were significantly different (p less than 0.001) for the patients who had a healed amputation compared with those who had a failed amputation. Regardless of the initial value, if, after inhalation of oxygen, the transcutaneous PO2 reached ten millimeters of mercury or more, it predicted healing of the amputation stump with a sensitivity of 98 per cent. When the level of amputation was selected on the basis of clinical judgment at the time of operation, the sensitivity was only 90 per cent.     

Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease. Results of a prospective randomized, double-blind, multicenter clinical trial

Most previous reports suggesting beneficial effects of prostaglandin E1 (PGE1) have been retrospective and uncontrolled. Therefore, this study was undertaken to assess the efficacy of PGE1 in the treatment of ischemic ulcers in patients with peripheral vascular occlusive disease (PVOD). One hundred twenty patients with one to three ischemic ulcers not healing for 3 weeks with standard care were randomized to receive either PGE1 (20 ng/kg/min) or a placebo for 72 hours through a central venous catheter. Ulcers were measured and photographed, and the rest pain was evaluated before and after infusion and at 1- and 2-month follow-up intervals. Fifty-seven patients with 95 ulcers received PGE1. Seventeen ulcers healed (18%); 22 ulcers decreased in size (23%); 37 ulcers remained unchanged or increased in size (39%); five new ulcers developed during the study (5%); and 14 ulcers had inadequate follow-up (15%). Sixty-three patients with 115 ulcers received a placebo. Nineteen ulcers healed (16%); 38 ulcers decreased in size (33%); 45 ulcers remained unchanged or increased in size (39%); three new ulcers developed during the study (3%); and 10 ulcers had inadequate follow-up (9%). None of the above differences between the drug-treated group and the placebo-treated group was statistically significant. This study did not demonstrate efficacy for intravenously administered PGE1 in the healing of ischemic ulcers in patients with PVOD.     

Mortality After Major Amputation Following Gangrene of the Lower Limb

Major amputations were performed on 310 patients because of gangrene of the lower limb. The mean age was 70 years and 58 per cent of the patients were males. Females were on average 5 years older.

The primary levels of amputation were above-knee (AK) in 33 per cent (103/310), through-knee (TK) in 21 per cent (66/310) and below-knee (BK) in 46 per cent (141/310).

Mortality during hospitalization was 18 per cent and the average hospitalization time 68 days. Mortality during hospital stay was primarily dependent on the occurrence of somatic complications, secondarily on the level of the amputation (as an expression of the extent of the gangrene) and finally on the age of the patient. The long-term survival rate was correlated primarily to the level of the amputation and secondarily to age. A high excess mortality was noted during the first few postoperative years, especially among AK amputees, but after this period the survival curve ran parallel to the expected survival rate. Mortality after 1 year was 34 per cent, comprising 17 per cent after BK amputation, 39 per cent after TK and 54 per cent after AK amputation.     

Penicillin G versus cefuroxime for prophylaxis in lower limb amputation

Out of 457 patients amputated below or above the knee, we randomized 288 to receive penicillin G and 229 cefuroxime as prophylaxis against infection. We also stratified the patients into two groups: Group A (313 patients) who did not receive antibiotic treatment within 48 hours prior to the operation and Group B (88 patients) who did. There were 56 dropouts according to protocol regulations. The patients were evaluated for efficacy on the 21st postoperative day. In Group A, 20 of 158 (13 per cent) penicillin G-treated and 27 of 155 (17 per cent) cefuroxime-treated had wound sepsis; 5 (3 per cent) penicillin G-treated and 4 (3 per cent) cefuroxime-treated patients had been reamputated by Day 21 (P greater than 0.05). We concluded that prophylactic penicillin G prevents infection as effectively as cefuroxime after lower limb amputation.     

Mortality After Major Amputation Following Gangrene of the Lower Limb

Major amputations were performed on 310 patients because of gangrene of the lower limb. The mean age was 70 years and 58 per cent of the patients were males. Females were on average 5 years older.

The primary levels of amputation were above-knee (AK) in 33 per cent (103/310), through-knee (TK) in 21 per cent (66/310) and below-knee (BK) in 46 per cent (141/310).

Mortality during hospitalization was 18 per cent and the average hospitalization time 68 days. Mortality during hospital stay was primarily dependent on the occurrence of somatic complications, secondarily on the level of the amputation (as an expression of the extent of the gangrene) and finally on the age of the patient. The long-term survival rate was correlated primarily to the level of the amputation and secondarily to age. A high excess mortality was noted during the first few postoperative years, especially among AK amputees, but after this period the survival curve ran parallel to the expected survival rate. Mortality after 1 year was 34 per cent, comprising 17 per cent after BK amputation, 39 per cent after TK and 54 per cent after AK amputation.     

Experimental study of the effect of intraportal prostaglandin E1 on hepatic blood flow during reperfusion after ischaemia and hepatectomy.

BACKGROUND: Prostaglandin E1 (PGE1) has protective effects experimentally and clinically in individual models of hepatic ischaemia-reperfusion injury and of partial hepatectomy. The present study investigated the effects of intraportal administration of PGE1 on hepatic blood flow, systemic arterial pressure and long-term animal survival after 60 min of total liver ischaemia followed by 70 per cent partial hepatectomy in rats. METHODS: Total liver ischaemia was induced by occluding the hepatoduodenal ligament for 60 min. PGE1 0.5 microg per kg per min was infused intraportally for 15 min before inducing ischaemia and for 120 min after ischaemia in the treatment group. Normal saline was infused in the control group. During ischaemia 70 per cent partial hepatectomy was performed. Portal venous flow (PVF), peripheral tissue blood flow (PTBF) and hepatic artery flow were measured before and after ischaemia. Serum biochemical analysis was carried out at 1, 3 and 24 h, and 7 and 14 days; and liver histology at 1 and 24 h, and 7 days after reperfusion. Survival was followed for 1 year. RESULTS: Intraportal infusion of PGE1 significantly improved PVF and PTBF without affecting the systemic arterial pressure. Long-term survival was significantly higher in the PGE1 group. Serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels decreased significantly, and 2-h bile flow was significantly improved, in the PGE1 group. Histological examination revealed significant portal venous congestion, sinusoidal congestion, fatty degeneration and tissue necrosis 24 h and 7 days after reperfusion in the control group. CONCLUSION: PGE1 has a protective effect against liver damage when the liver is injured by warm ischaemia and reperfusion followed by partial resection.