Heparin and protamine stimulate the production of nitric oxide.

Heparin has been shown to decrease total vascular resistance while protamine stimulates endothelium-dependent vasodilation. This study was undertaken to determine whether heparin and/or protamine could enhance endothelium-derived relaxing factor (EDRF), as determined by nitric oxide (NO) production. Porcine carotid artery endothelial cells (PAECs) were seeded on multiwell plates, grown to confluence, and exposed to heparin (1-20 U/ml) or protamine (50-200 microg/ml) for 24 hours. With the addition of the NO synthase inhibitor, N(G)-monomethyl-L-arginine (NMMA), to heparin and/or protamine, the medium samples were collected in one hour. In a parallel clinical study, plasma samples were collected from patients undergoing cardiopulmonary bypass (CPB). The NO production was measured as reflected by the formation of nitrite (NO2-) and nitrate (NO3-), the stable end-metabolites of NO. NO production by PAECs was significantly increased by heparin > or = 5 U/ml or protamine > or = 50 microg/ml in a concentration-dependent manner. The increase of NO production was prevented by the addition of NMMA. In CPB patients, plasma NO2-/NO3- concentration was significantly increased after heparin administration compared to the preoperative value, at which time the mean plasma heparin level was 4.9+/-0.5 U/ml. Following slow protamine infusion, there was no significant difference in plasma NO2-/NO3- concentration compared to preoperative value. In conclusion NO production increases following exposure of PAECs to heparin and/or protamine. In patients, NO concentration significantly increased after heparin administration by IV bolus, but not with a slow infusion of protamine after CPB.

Surgical exposure of the left subclavian artery by median sternotomy and left supraclavicular extension.

OBJECTIVE: To evaluate the feasibility of surgical exposure of the full length of the left subclavian artery using a median sternotomy and left supraclavicular extension. DESIGN: Anatomic study of five cadavers, and case review of four patients with blunt trauma to the proximal left subclavian artery. MATERIALS AND METHODS: A median sternotomy with left supraclavicular extension was performed on five cadavers and four patients. The depth of various portions of the subclavian artery was measured. Photographs of the dissections were used to document anatomic relationships and to serve as a basis for pen and ink drawings. The hospital records of four patients in which this exposure was used were reviewed for operative details. MEASUREMENTS AND MAIN RESULTS: The left subclavian artery was readily exposed from its origin on the aortic arch to its termination as the axillary artery in all cadaver dissections, including one who was more than 300% ideal body weight. The first portion of the subclavian artery lay at an average wound depth of 6.0 cm, with a mean length of 4.7 cm. The same surgical approach was used for the care of four patients who sustained blunt trauma to the first portion of the left subclavian artery and permitted expeditious control and excellent exposure for placement of a proximal subclavian interposition graft in two, a proximal subclavian to axillary artery graft in the third, and resection and end-to-end anastomosis in the fourth. CONCLUSIONS: Median sternotomy with left supraclavicular extension provides rapid, safe, and reliable exposure of all portions of the left subclavian artery without the morbidity associated with clavicular resection, thoracotomy, or a "trapdoor" incision. Furthermore, the ability to perform this procedure in the supine position allows access to the abdominal cavity, the neck, and the extremities, which often require concomitant operative intervention in a patient with multiple injuries.

Ultrasound-guided compression of iatrogenic femoral pseudoaneurysm failure, recurrence, and long-term results.

PURPOSE: Iatrogenic femoral pseudoaneurysms (IFP) have traditionally been treated surgically. Recently, this common problem has been successfully treated without operation by use of ultrasound-guided compression (UGC) to induce thrombosis of the false aneurysm cavity, but the risk factors for failure and the long-term outcome have not been defined. METHODS: All patients referred to the vascular laboratory from June 1992 to November 1994 whose femoral pseudoaneurysms were treated by UGC were included in the study. Data were collected prospectively during the last 18 months of the study. Data regarding the location and morphologic characteristics of the pseudoaneurysms and anticoagulation status were documented. Patients who had successful UGC underwent follow-up duplex scanning and ankle-brachial arterial pressure evaluations. RESULTS: Fifty-seven patients with IFP were treated with UGC over a 30-month period; the last 34 were evaluated prospectively. UGC was successful at obliterating the false aneurysm cavity with the initial attempt in 47 (83%). Thrombosis of seven additional pseudoaneurysms was achieved on subsequent UGC attempts for an overall success rate of 95%. Recurrent false aneurysms were noted in two patients 2 and 10 days after initially successful UGC. Both were treated successfully with repeat UGC. Multivariate analysis of 14 variables revealed heparin anticoagulation (chi-square 9.025, p = 0.001) as the only significant risk factor for failure of UGC. There were no episodes of arterial thrombosis, embolization, or femoral nerve injury associated with UGC. Temporary occlusion of femoral artery during UGC and compression intervals of 20 minutes were well tolerated. Long-term follow-up from 30 to 400 days after UGC was available in 36 patients. There was no late recurrence or significant change in ankle-brachial pressures (p > 0.05). CONCLUSION: UGC is a safe and effective treatment for most catheter-induced femoral pseudoaneurysms with a low complication rate and excellent long-term results at a cost substantially lower than operative treatment. Because the natural history of IFP is unpredictable, UGC appears to be the preferred treatment for all IFPs persisting after cessation of heparin anticoagulation.

Acute peritoneal dialysis following ruptured abdominal aortic aneurysms.

BACKGROUND: Acute renal failure is common after repair of ruptured abdominal aortic aneurysm. Early dialysis has recently been advocated to reduce the mortality associated with multiorgan failure, but hemodialysis (HD) is not well-tolerated in critically ill patients because of hemodynamic instability and risk of bleeding from anticoagulation therapy. Peritoneal dialysis (PD) has the advantage in that it causes minimal cardiopulmonary instability and does not require anticoagulation. The presence of a freshly-closed abdominal wound and an aortic graft, however, have previously been considered to be contraindications to PD. METHODS: Peritoneal dialysis catheters were placed in 69 of the 105 patients who underwent grafting for a ruptured abdominal aortic aneurysm between 1982 and 1993. Criteria for placement included shock, perioperative oliguria, and preoperative renal insufficiency. All charts were reviewed retrospectively to evaluate the safety and efficacy of placing PD catheters and initiating early dialysis in patients at risk for developing acute renal failure. RESULTS: Acute tubular necrosis developed in 31 patients, 19 of whom required dialysis. Peritoneal dialysis alone provided effective dialysis in 8 patients, and it was combined with hemofiltration and/or HD in 9 additional patients for an overall efficacy of 58%. The peritoneal catheter also facilitated the early diagnosis of peritonitis due to colon ischemia in 5 patients, and was helpful in diagnosing intra-abdominal hemorrhage in 4 others. Bacterial peritonitis occurred in 3 (17%) patients undergoing PD with no cause noted for the infection diagnosing other than use of the PD catheter. A single aortic graft infection was diagnosed 4.2 years postoperatively with an enteric organism in a patient with recurrent diverticulitis. Two patients with peritoneal catheters developed abdominal wound dehiscence, but neither had undergone PD (P > 0.2). In a multivariate analysis, placement of a PD catheter did not affect survival. CONCLUSIONS: Placement of a PD catheter at the time of resection of a ruptured abdominal aortic aneurysm in patients at risk for development of acute renal failure is without significant complications and can facilitate early and effective dialysis. The peritoneal dialysis catheter may also be useful in making an early diagnosis of intraperitoneal bleeding and infection.

Treatment of metastatic carcinoid tumors using multimodality therapy of octreotide acetate, intra-arterial chemotherapy, and hepatic arterial chemoembolization.

BACKGROUND: Overall survival and quality of life in patients with metastatic carcinoid tumors depend on control of tumor growth and suppression of amine-induced symptoms. METHODS: We report on a series of 10 patients with carcinoid tumors metastatic to the liver who were treated with long-term octreotide acetate therapy (100 to 500 micrograms three times a day), sequential intra-arterial 5-fluorouracil (5-FU) infusions, and hepatic tumor chemoembolization. RESULTS: All 10 patients remained asymptomatic or had extremely mild symptoms after combined modality therapy (mean follow-up duration of 51.5 months). Sixty percent of the patients had a > 50% reduction of their tumor size (mean duration 42 months). An additional 30% experienced stabilization of tumor growth for 6 months or longer. Five of the 10 patients are currently alive. The mean group survival is 58 months since diagnosis (range 33 to 115) and 40 months since starting therapy (range 12 to 65). CONCLUSIONS: Combining octreotide acetate, intra-arterial 5-FU, and tumor chemoembolization effectively retards tumor growth while providing excellent symptom control.

Protective effect of doxorubicin in vitamin C or dimethyl sulfoxide against skin ulceration in the pig.

BACKGROUND: Accidental extravasation of doxorubicin leads to skin necrosis and significant morbidity. Based on our previous work in the rat, we hypothesized that the free radical scavengers dimethyl sulfoxide (DMSO) and vitamin C prevent doxorubicin-induced skin ulcers in white swine. METHODS: Fifteen white swine were anesthetized and injected with 0.5 mg of doxorubicin (1 mg/ml) intradermally delivered in saline, 10% DMSO, 20% DMSO, vitamin C (1 mg/ml), or vitamin C in 20% DMSO. Presence of skin ulceration and ulcer size, in the two greatest dimensions, was determined weekly for 3 weeks. RESULTS: Delivery of doxorubicin in DMSO and/or vitamin C lowered the ulcer incidence from 87% to 27% (p < 0.0001) when compared with delivery in saline. CONCLUSION: We conclude that the free radical scavengers DMSO and vitamin C are capable of lowering the incidence of doxorubicin-induced skin ulcers and could significantly lessen the morbidity associated with doxorubicin extravasation.

Inhibition of angiogenesis by somatostatin and somatostatin-like compounds is structurally dependent.

We have previously demonstrated that somatostatin analogues SMS 201-995 and RC-160 inhibit angiogenesis using the chorioallantoic membrane (CAM) of the developing chicken embryo. In this study, we evaluated the ability of native somatostatin 14 and nine somatostatin analogues to inhibit angiogenesis. Two-millimeter methylcellulose disks containing 50 micrograms of somatostatin or somatostatin analogue were implanted on the CAM of 6- to 7-day-old shell-less chick embryos. Inhibition of blood vessel growth was visually assessed and graded in the region of the disk 24-36 hr following implementation. The analogues SMS 201-995 and RC-160 showed statistically significant inhibition of neovascularization when compared to native somatostatin 14. The amino acid homology comparison of the nine analogues revealed that individual differences in their abilities to inhibit angiogenesis may be structurally dependent.

Effective palliative treatment of metastatic carcinoid tumors with intra-arterial chemotherapy/chemoembolization combined with octreotide acetate.

Survival in patients with metastatic carcinoid tumors is dependent on control of tumor growth and adequate palliation of vasoactive amine-induced symptoms of flushing, diarrhea, wheezing, and valvular heart disease. Eight patients with carcinoid tumors metastatic to the liver were treated with long-term octreotide acetate therapy (100 to 500 micrograms three times a day), intra-arterial 5-fluorouracil infusion (2 g/day x 5 days), and hepatic tumor chemoembolization. All eight patients became asymptomatic and have remained so with a mean follow-up duration of 22 months from the time of first infusion. Following institution of subcutaneous octreotide acetate, intra-arterial infusion, and tumor chemoembolization, all patients are alive with a mean survival of 40 months from the time of diagnosis of carcinoid syndrome (range: 2 to 108 months). Four patients had greater than a 50% decrease in tumor size after therapy (mean follow-up duration: 10.6 months), and the other four patients have had stable disease after institution of therapy. It appears that combinations of long-term subcutaneous administration of octreotide acetate, intra-arterial 5-fluorouracil, and tumor chemoembolization effectively control progressive liver metastasis and provide excellent symptomatic palliation in patients with hepatic metastasis from functional carcinoid tumors.

Phase I-II trial of hyperthermic isolated limb perfusion with cisplatin in the treatment of high risk malignant melanoma of the extremities.

Between 1983 and 1990, 59 patients with malignant melanoma were retrospectively reviewed to assess the safety, efficacy and the maximal tolerated dose of cisplatin used in hyperthermic isolated limb perfusion. The median follow-up was 29 months (range 3-54 months). The local recurrence rate was 12% in Stage I, 33% in Stage II and 30% in Stage III patients. The maximal tolerated dose of cisplatin in hyperthermic isolated limb perfusion was 3.2 mg/kg for forequarter perfusions and 6 mg/kg for hindquarter perfusions based on lean body weight. At these dosages, there is an 8% major complication rate and only one patient experienced long-term sequelae. Hyperthermic isolated limb perfusion using cisplatin in the dosages of 3-6 mg/kg lean body weight is associated with low morbidity and appears to have efficacy comparable to L-phenylalanine mustard for the control of locally recurrent malignant melanoma.