Infrainguinal revascularizations in octogenarians and septuagenarians.

OBJECTIVE: Severe atherosclerosis is a major contributor for death in octogenarians and a cause of multiple vascular-related ailments, including claudication and limb loss. Advanced age and health may limit the success of limb-salvaging procedures. Mortality, morbidity, and outcome of infrainguinal grafts have been examined in octogenarians and septuagenarians. METHODS: After 128 femoropopliteal and 99 femorotibial bypass grafts in 209 octogenarians and 242 femoropopliteal and 166 femorotibial bypass grafts in 383 septuagenarians, survival, primary patency, limb salvage, myocardial infarction and stroke rates were determined. The survival, myocardial infarction, and stroke rates of controls, 1514 octogenarians and 2011 septuagenarians, were compared. RESULTS: After a bypass graft, 5-year survival of octogenarians (54%) and septuagenarians (64%) was similar (P >.2) and was 89% and 89% for controls. The 5-year primary patency rates were 74% for octogenarians and 68% for septuagenarians (P >.2). Five-year limb salvage rates were 86% for octogenarians and 86% for septuagenarians. After a bypass graft, the respective rates of myocardial infarction were 4.1% and 3.9% per year and of a stroke 3.2% and 3.2% per year for octogenarians and septuagenarians, which occurred more frequently (P <.05) than in controls. CONCLUSIONS: Death and cardiovascular events are higher after revascularization in octogenarians and septuagenarians, compared with controls, and are related to the severity of atherosclerosis and not age. Patency rates are excellent and similar. Limb salvage procedures should be considered for most octogenarians.

Risk factors associated with rapid growth of small abdominal aortic aneurysms.

BACKGROUND: Approximately 50% of patients who have a ruptured abdominal aortic aneurysm will die. To identify those patients who may be at high risk for rupture, we determined the risk factors for the rapid expansion of the aorta. METHODS: The growth of 514 aneurysmal aortas was followed in this study. The size of each was measured by ultrasonography at 6- to 12-month intervals until a critical size was reached or a rapid expansion of the aorta occurred. Possible risk factors for rapid expansion were determined from both initial evaluation and clinical laboratory results. RESULTS: The initial size varied from 2.5 cm to 6.0 cm. The expansion rate of the aorta was 0.5 cm/yr or less in 401 patients (78%), between 0.5 and 1.0 cm/year in 50 patients (10%), and 1.0 cm/year or more (rapid expansion) in 63 patients (12%). Elective repair of aneurysms was done before rupture. Multivariate analysis indicated that the risk factors associated (p < 0.03) with rapid expansion were advanced age, severe cardiac disease, previous stroke, and history of cigarette smoking. The incidence for rapid expansion increased (p < 0.01) in older patients with aneurysms larger than 3 cm and in younger patients with aneurysms larger than 4 cm. CONCLUSIONS: Risk factors associated with rapid expansion of the aorta have been determined and may help identify the patient at high risk for rupture. Ultrasonographic surveillance should be performed more frequently in these patients to help prevent rupture.

Long-term results with axillo-axillary bypass grafts for symptomatic subclavian artery insufficiency.

PURPOSE: The surgical treatment for patients with a subclavian steal is controversial, especially for patients with coexisting severe carotid stenosis. This study determines the long-term efficacy of axillo-axillary bypass grafts in patients with and without a simultaneous carotid endarterectomy. METHODS: The axillo-axillary bypass was done in 39 patients who were monitored for 5.8 +/- 3.9 years. Fifteen of these patients with severe carotid artery disease had a carotid endarterectomy done simultaneously. Twenty-four patients had an axillo-axillary bypass alone; four of these patients later had a carotid endarterectomy at 0.5 to 10 years. Graft patency was evaluated at intervals of 6 to 12 months by clinical evaluation and noninvasive vascular studies. RESULTS: Ten-year primary and secondary patency rates for all axillo-axillary bypass grafts were 88% and 91%, respectively. When carotid endarterectomy was done with axillo-axillary bypass, these patency rates were 86% and 93%, respectively. Patients with only axillo-axillary grafts had 10-year primary and secondary patency rates of 89% and 89%, respectively. Most patients had complete relief from symptoms of arm ischemia (90%) and vertebrobasilar insufficiency (85%). No perioperative mortality or permanent neurologic deficit occurred. CONCLUSIONS: Axillo-axillary bypass is a safe and effective method for revascularization of the subclavian artery and should be considered for patients at high risk.

Late stroke in patients after carotid endarterectomy.

BACKGROUND: Some patients may be more predisposed to develop an ulceration of atherosclerotic plaque in the carotid artery, and emboli. These patients should be more at risk for a late stroke even after carotid endarterectomy than patients who are not. MATERIALS AND METHODS: Six-hundred thirty-eight patients had 750 carotid endarterectomies. Excised plaque specimens were examined for gross ulceration. The degree of stenosis was determined by duplex scan and/or angiography, and at operation. The median follow-up time was 3.6 years. The risk of a stroke occurring >30 days after carotid endarterectomy was calculated. Within 1 year, an endarterectomy of the contralateral artery was done in 77 patients (Subgroup) at a median time of 60 days. RESULTS: Late stroke occurred in 48 patients. Patients who had had ulcerated plaque had a stroke at a median time of 2.0 years, and patients who had had no ulcers had a stroke at a median time of 5.2 years (P < 0.025). The 14-year stroke-free curve was lower (P < 0.05) if there was plaque ulceration. In the Subgroup, plaque ulcers were found in 55 patients (71%) at the first endarterectomy and later in 46 of the 55 patients (84%) in the contralateral artery. No ulcers were found in 22 patients (29%) initially, but later 50% had ulcers in the contralateral artery. The risk of an ulcer in the contralateral artery was increased (P < 0. 005) in those patients who had ipsilateral carotid ulcers. CONCLUSIONS: Some patients appear to be predisposed for plaque ulceration and late stroke.

The long-term value of composite grafts for limb salvage.

PURPOSE: We determined the long-term efficacy of composite grafts for limb salvage when autogenous vein grafts were not available. METHODS: After arterial bypass, the 8-year primary and secondary patency, limb salvage, and mortality rates were compared by life-table analysis. One hundred twenty-five patients had 130 composite grafts for 27 femoropopliteal bypasses, 48 femorotibial bypasses, and 55 sequential femoropopliteotibial bypasses. Three hundred forty patients had autogenous vein grafts for 247 femoropopliteal bypasses and 114 femorotibial bypasses. Seventy-two patients had 82 femoropopliteal prosthetic grafts. RESULTS: Eight-year primary and secondary patency rates were 56% and 62% for femoropopliteal procedures with composite grafts, respectively, and 53% and 59% for autogenous vein grafts, respectively. The secondary patency rate for polytetrafluoroethylene grafts was 35% and was less (p < 0.05) than the rate for the vein grafts. Secondary patency rates for femorotibial procedures were 66% for the vein grafts, 56% for single outflow composite grafts, and 52% for dual outflow composite grafts. Limb salvage rates for femoropopliteal procedures were 73% for composite grafts, 63% for polytetrafluoroethylene, and 82% for vein grafts, and for femorotibial procedures were 53% for single outflow composite grafts, 65% for dual outflow composite grafts, and 86% for vein grafts. CONCLUSIONS: Composite grafts achieve long-term preservation of ischemic limbs in patients who are facing limb loss because of poor run-off and have insufficient autogenous vein for a graft.

Cytokines in Crohn's colitis.

BACKGROUND: Increasing evidence points to a pathologic role for cytokines in Crohn's colitis. Levels of cytokines are increased in diseased segments of colon in Crohn's colitis, but no one has studied the concentration of cytokines in clinically and histologically nondiseased segments. METHODS: Mucosal biopsies were obtained from 7 patients with active segmental Crohn's colitis and from 7 controls without inflammatory bowel disease. The concentration of Interleukin (IL)-1 beta, IL-2, IL-6, and IL-8 in patients and controls were determined using enzyme linked immunosorbent assay and compared. Histologic sections were also performed to confirm diseased and nondiseased segments of colon. RESULTS: The concentrations of IL-1 beta, IL-6, and IL-8 were significantly higher in the involved segments of colon (10.3 +/- 4.1, 3.7 +/- 1.0, 34.4 +/- 6.9 picograms [pg] per mg) when compared to controls (1.8 +/- 0.5, 1.1 +/- 0.5, 5.3 +/- 1.0 pg/mg). The concentrations of IL-1 beta, IL-2, and IL-8 (8.5 +/- 2.9, 5.3 +/- 1.2, 26.3 +/- 8.8 pg/mg) in normal appearing segments of colon of patients with Crohn's colitis were also significantly higher than in controls, whose IL-2 level was 2.0 +/- 0.5 pg/mg. IL-1 beta and IL-8 were significantly more concentrated in both the involved and uninvolved colonic segments of patients with Crohn's colitis compared to controls. IL-2 and IL-6 were also more concentrated in Crohn's patients than in controls, but not significantly. The differences in interleukin concentrations between involved and uninvolved segments of colon in patients with segmental Crohn's colitis were not significant. CONCLUSIONS: Although Crohn's colitis is often a segmental disease, concentrations of IL-1 beta and IL-8 are increased throughout the entire colon. These observations reinforce the hypothesis that Crohn's colitis involves the whole colon even when this is not apparent clinically or histologically.

Comparison of 5-fluorouracil anabolite levels after intravenous bolus and continuous infusion.

The levels of 5-fluorouracil (5FU) and its anabolites in the serum, bile, pancreatic juice, liver, pancreas, and skeletal muscle of dogs were compared after single bolus administration and after continuous infusion. Six dogs had a bolus of 5FU (15 mg/kg) and were studied for 120 min. Five dogs had a continuous infusion of 5FU (30 mg/kg) and were studied for 24 h. After the bolus infusion, serum 5FU levels were initially high and then declined, whereas anabolite levels gradually increased over 45 min. Within 2 h, anabolite levels exceeded 5FU levels in tissues but were undetectable in bile and pancreatic juice. During the continuous infusion, anabolite levels in serum increased more rapidly than 5FU levels and remained significantly higher for 24 h. Anabolite levels also exceeded 5FU levels in bile, pancreatic juice, pancreas, and muscle but not in the liver. Continuous infusion of 5FU produced higher levels of the anabolites than did bolus infusion and maintained constant levels throughout the infusion period.

5-Fluorouracil pharmacokinetics in patients with metastatic colorectal carcinoma after high-dose leucovorin.

The effect of high-dose leucovorin on 5-fluorouracil (5-FU) pharmacokinetics was studied in 5 patients with metastatic colorectal carcinoma. Patients received leucovorin, 500 mg/m2, and 5-FU, 600 mg/m2, on 1 day and 5-FU alone 1 week later. Plasma concentrations of 5-FU and 5-FU anabolites were determined over 2 hr. Levels of 5-FU were highest initially and then fell rapidly. Plasma concentration-time curves suggested a two-compartment kinetic model. Anabolite levels exceeded 5-FU levels after 15 min. When leucovorin was administered, the time of distribution (t1/2 alpha for 5-FU increased from 8.9 +/- 2.4 to 12.8 +/- 2.5 min (p < 0.0005) and the volume of distribution (Vd) increased from 0.129 +/- 0.039 to 0.237 +/- 0.033 L/kg (p < 0.03). Elimination and plasma clearance of 5-FU were unchanged. Anabolite levels were initially lower (p < 0.05) with leucovorin, suggesting increased tissue extraction of 5-FU.

Hepatopancreatic uptake and elimination of 5-fluorouracil after intravenous injection.

The efficacy of 5-fluorouracil (5FU) chemotherapy depends, in part, upon maintaining adequate intracellular levels of active metabolites. The uptake, distribution and elimination of 5FU and 5FU-anabolites were determined after an intravenous bolus infusion of 5FU, 15 mg kg-1, and the relationship between serum and tissue levels were evaluated. In six dogs samples of liver, pancreas, rectus abdominus muscle, blood, bile and pancreatic juice were collected at 0, 15, 45, 90 and 120 min. Bile and pancreatic juice levels of 5FU followed the same pattern as the serum, rising rapidly and falling exponentially, suggesting elimination by simple diffusion. Elimination of anabolites was more complex. Tissue levels of anabolites were highest in the liver and peaked later than in the pancreas and muscle. They were unrelated to serum levels of 5FU. The higher and more sustained levels of 5FU-anabolites in the liver may be responsible for some of the beneficial effects of 5FU chemotherapy on hepatic tumours.

Stress induced experimental colitis.

Stress induces chemical changes in the central nervous system which alters the biochemistry and physiology of the digestive tract. The present study determines arachidonic acid oxidation and damage in the colon following stress. Ten rats were stressed by the cold-restraint method; ten were controls. Stress induced 0.5 +/- 0.7 (S.D.) mucosal erosions whereas controls had none. Subepithelial hemorrhage and erosions occurred only in the proximal two-thirds of the colon. Prostaglandin E(2) synthesis was increased after stress compared to the control (381 +/- 130 vs. 1610 +/- 372 ng/g/min). Leukotriene C(4) synthesis also increased after stress (4217 +/- 994 vs. 11300 +/- 1662 ng/g/min). Synthesis of prostaglandin E(2) increased (r = 0.9381) with leukotriene C(4). The response of the colon to stress is less severe than that in the stomach and may be related to regional regulation of prostaglandin and leukotriene synthesis.

The effect of cocaine on gastric mucosal PGE(2), LTC(4) and ulcerations.

The association between cocaine use and acute gastroduodenal perforation is known. The effect of cocaine and stress on gastric mucosal ulceration and the levels of prostaglandin E(2) (PGE(2)) and leukotriene C(4) (LTC(4)) was studied in 40 Sprague-Dawley rats. Controls received intraperitoneal (i.p.) saline, ten received i.p. cocaine (35 mg/kg), ten were stressed by the cold restraint method, and ten had i.p. cocaine and stress. Cocaine alone did not induce ulceration, but decreased PGE(2) levels. Stress alone caused ulceration, but was not associated with a change in either PGE(2) or LTC(4) levels. When combined with stress, however, cocaine caused a three-fold increase in ulceration and a significant increase in PGE(2) and LTC(4) levels. Stress may predispose the cocaine addict to loss of gastroduodenal mucosal integrity, which is related to an imbalance of PGE(2) and LTC(4) synthesis.

Inhibition of glycerol-3-phosphate acyltransferase by analogs of glycerol-3-phosphate.

Analogs of glycerol-3-phosphate were tested as substrates or inhibitors of the glycerol-3-phosphate acyltransferases of mitochondria and microsomes. (rac)-3,4-Dihydroxybutyl-1-phosphonate, (rac)-glyceraldehyde 3-phosphate, (rac)-3-hydroxy-4-oxobutyl-1-phosphonate, (1S,3S)-1,3,4-trihydroxybutyl-1-phosphonate, and (1R,3S)-1,3,4 trihydroxybutyl-1-phosphonate were competitive inhibitors of both mitochondrial and microsomal sn-glycerol-3-phosphate acyltransferase activity. An isosteric analog of dihydroxyacetone phosphate, 4-hydroxy-3-oxobutyl-1-phosphonate, was a much stronger competitive inhibitor of the microsomal than the mitochondrial enzyme. Phenethyl alcohol was a noncompetitive inhibitor of both the microsomal and the mitochondrial acyltransferases. The product of the mitochondrial acyltransferase reaction with (rac)-3,4-dihydroxybutyl-1- phosphonate was almost exclusively (rac)-4-palmitoyloxy-3-hydroxybutyl-1-phosphonate. The microsomal acylation reaction generated both the monoacyl product and (S)-3,4-dipalmitoyloxybutyl-1-phosphonate. The apparent Km for (S)-3,4-dihydroxybutyl-1-phosphonate was 2.50 and 1.38 mM for the mitochondrial and microsomal enzymes, respectively.

Is colonoscopy safe in the early postcolectomy period?

Colonoscopy was performed preoperatively and 1, 2, 3 and 7 days following a left hemicolectomy with a primary anastomosis in 11 dogs. The remaining colon and anastomosis were adequately visualized. Maximal intraluminal pressures achieved were from 15 to 35 mmHg. No leakage of air or intra-abdominal abscesses were present. In ten patients undergoing colonoscopy for lower gastrointestinal symptoms, the pressures were similarly measured. Although pressures were slightly higher in patients, averaging 30 mmHg, the results suggest that colonoscopy can be safely performed during the early postcolectomy period.

Stress-induced gastric lesions and the synthesis of prostaglandins and leukotrienes.

Prostaglandin E2 renders the mucosa of the GI tract more resistant to acute injury by aspirin, acid, bile salts, and stress, whereas leukotrienes promote inflammation and retard healing of ulcers. The relationship of stress ulcer formation to changes in the activities of prostaglandin synthetase and lipoxygenase was evaluated in this study. After a 24 hr fast, 10 rats were stressed by the cold-restraint method for 4 hr and 10 rats were not stressed. Rats were terminated, stomachs were excised, the number of lesions were counted, and the nonulcerated mucosa was assayed for prostaglandin E2 and leukotriene synthesis. The mucosa was minced, washed in buffered saline, and then incubated for 10 min in a 1.3 mM sodium arachidonate solution containing a nonionic detergent (poloxamer 188), NaCl, KCl, KPO4, glutathione, hemin, MgSO4 and Hepes at pH 8.0. An ANOVA was used to compare the groups. Following stress the number of gastric lesions increased from 0.7 +/- 0.6 to 13.5 +/- 2.6, while leukotriene synthesis increased from 173 +/- 20 to 2170 +/- 187 pg/mg/min. A shift in synthesis from prostaglandins to leukotrienes in the mucosa appears to be detrimental to cytoprotection.

Measurement of prostaglandin G/H synthase and lipoxygenase activity in the stomach wall by HPLC.

A method for the determination of prostaglandin G/H synthase and lipoxygenase activities in tissues was developed and employed with rat gastric mucosa samples. Tissues and microsomes were incubated in a buffer containing nonionic detergent and 1.32 mM arachidonic acid for 10 min. Following extraction with ethyl acetate, the oxidation products of arachidonic acid were derivatized with panacyl bromide. A reversed-phase column and a quaternary mobile phase were used to separate and quantitate the panacyl bromide esters of prostaglandin E2 and leukotriene C4/D4. Prostaglandin G/H synthase and lipoxygenase activities were determined in gastric mucosa and were 371 +/- 66 and 173 +/- pg/mg/min, respectively.

Prevention of stress-induced erosive gastritis by parenteral administration of arachidonic acid.

Stress-induced mucosal ulcerations are associated with a decreased synthesis of mucosal prostaglandin (PG) E2. This phenomenon is poorly understood. To investigate whether it is due to a decreased availability of the necessary substrates to the mucosa, four groups of 10 Holtzman rats were studied: group 1 received normal saline by intraperitoneal (ip) injection; group 2 also received ip normal saline, then were submitted to stress, by the cold restraint method; group 3 received a solution of arachidonic acid (AA) ip; and group 4 also received ip AA, then were submitted to stress. After sacrifice, the number of gastric ulcerations were counted and specimens of nonulcerated mucosa were assayed for PGE2 by high-performance liquid chromatography; the mean numbers of ulcers were 0, 5.8, 0.8, and 3 and the mean levels of PGE2 were 55, 41, 125, and 62 pg/mg of wet tissue for groups 1, 2, 3, and 4, respectively. It is concluded that parenteral administration of AA reduces but does not completely eliminate stress-induced gastric ulcerations and that the stressed animals synthesized half as much PGE2 as the nonstressed ones after ip administration of equal amounts of AA, suggesting that stress reduces the availability of AA to the gastric mucosa, possibly by vascular spasm.

Effect of verapamil on the gastric mucosal level of PGE2 during stress.

Prostaglandin E2 is one of the factors in the maintenance of gastric mucosal integrity and verapamil, a calcium channel blocker, has been shown to reduce gastric mucosal ulcerations during stress. To investigate whether this protective effect of verapamil is mediated via PGE2, four groups of 20 Holtzman rats were given either 1 ml of normal saline (NS) intraperitoneally (ip): 1 mg/kg of indomethacin (I) ip; 2 mg/kg of verapamil (V) ip or I followed by V. Then 10 animals from each group were submitted to stress by the cold-restraint method. After sacrifice, gastric mucosal ulcerations were counted and specimens of nonulcerated mucosa were assayed for PGE2 by HPLC. Stress-induced mucosal ulcerations were associated with a significant decrease in the gastric mucosal levels of PGE2 (from 64.2 to 32.7 pg; P less than 0.05). This effect was magnified by the administration of indomethacin (down to 21.0 pg). Verapamil significantly increased PGE2 levels both in the stressed (48.0 pg) and unstressed (99.9 pg) animals and significantly reduced ulcerogenesis when compared to either NS- or I-treated groups. This effect of verapamil was completely blocked by the administration of indomethacin. In conclusion, verapamil stimulates PGE2 synthesis and its protective effect against stress-induced mucosal damage seems to be mediated by PGE2.

Measurement of 5-fluorouracil and its active metabolites in tissue.

The 5-fluorouracil content of serum, bile, pancreatic juice, liver, pancreas and muscle was measured by reversed-phase high-performance liquid chromatography using a mobile phase of 5 mM 1-heptanesulfonic acid in 5 mM acetic acid. Free or unmetabolized 5-fluorouracil was extracted from samples with a mixture of light petroleum-n-propanol (40:60). The active metabolites of 5-fluorouracil were hydrolyzed with hot perchloric acid to free 5-fluorouracil and the combined 5-fluorouracil content was extracted. The active metabolite fraction was calculated from the difference between the combined and the free fractions. A straight line plot of the peak areas against concentration was achieved and the detection limit was 50 ng/ml. Five minutes after stopping an intravenous infusion of 15 mg/kg of 5-fluorouracil in a dog, the serum contained only the free form, but other body fluids and tissues contained both free and metabolite fractions. The method may be useful to determine the amount of total drug in patient samples.