A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.

BACKGROUND: Effective medication is limited for the relief of intermittent claudication, a common manifestation of arterial occlusive disease. Cilostazol is a potent inhibitor of platelet aggregation with vasodilation effects. OBJECTIVE: To evaluate the safety and efficacy of cilostazol for the treatment of intermittent claudication. METHODS: Thirty-seven outpatient vascular medicine clinics at regional tertiary and university hospitals in the United States participated in this multicenter, randomized, double-blind, placebo-controlled, parallel trial. Of the 663 screened volunteer patients with leg discomfort, a total of 516 men and women 40 years or older with a diagnosis of moderately severe chronic, stable, symptomatic intermittent claudication were randomized to receive cilostazol, 100 mg, cilostazol, 50 mg, or placebo twice a day orally for 24 weeks. Outcome measures included pain-free and maximal walking distances via treadmill testing, patient-based quality-of-life measures, global assessments by patient and physician, and cardiovascular morbidity and all-cause mortality survival analysis. RESULTS: The clinical and statistical superiority of active treatment over placebo was evident as early as week 4, with continued improvement at all subsequent time points. After 24 weeks, patients who received cilostazol, 100 mg, twice a day had a 51% geometric mean improvement in maximal walking distance (P<.001 vs placebo); those who received cilostazol, 50 mg, twice a day had a 38% geometric mean improvement in maximal walking distance (P<.001 vs placebo). These percentages translate into an arithmetic mean increase in distance walked, from 129.7 m at baseline to 258.8 m at week 24 for the cilostazol, 100 mg, group, and from 131.5 to 198.8 m for the cilostazol, 50 mg, group. Geometric mean change for pain-free walking distance increased by 59% (P<.001) and 48% (P<.001), respectively, in the cilostazol, 100 mg, and cilostazol, 50 mg, groups. These results were corroborated by the results of subjective quality-of-life assessments, functional status, and global evaluations. Headache, abnormal stool samples or diarrhea, dizziness, and palpitations were the most commonly reported potentially drug-related adverse events and were self-limited. A total of 75 patients (14.5%) withdrew because of any adverse event, which was equally distributed between all 3 treatment groups. Similarly, there were no differences between groups in the incidence of combined cardiovascular morbidity or all-cause mortality. CONCLUSION: Compared with placebo, long-term use of cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent claudication.

A comparison of cilostazol and pentoxifylline for treating intermittent claudication.

PURPOSE: We performed a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the relative efficacy and safety of cilostazol and pentoxifylline. PATIENTS AND METHODS: We enrolled patients with moderate-to-severe claudication from 54 outpatient vascular clinics, including sites at Air Force, Veterans Affairs, tertiary care, and university medical centers in the United States. Of 922 consenting patients, 698 met the inclusion criteria and were randomly assigned to blinded treatment with either cilostazol (100 mg orally twice a day), pentoxifylline (400 mg orally 3 times a day), or placebo. We measured maximal walking distance with constant-speed, variable-grade treadmill testing at baseline and at 4, 8, 12, 16, 20, and 24 weeks. RESULTS: Mean maximal walking distance of cilostazol-treated patients (n = 227) was significantly greater at every postbaseline visit compared with patients who received pentoxifylline (n = 232) or placebo (n = 239). After 24 weeks of treatment, mean maximal walking distance increased by a mean of 107 m (a mean percent increase of 54% from baseline) in the cilostazol group, significantly more than the 64-m improvement (a 30% mean percent increase) with pentoxifylline (P <0.001). The improvement with pentoxifylline was similar (P = 0.82) to that in the placebo group (65 m, a 34% mean percent increase). Deaths and serious adverse event rates were similar in each group. Side effects (including headache, palpitations, and diarrhea) were more common in the cilostazol-treated patients, but withdrawal rates were similar in the cilostazol (16%) and pentoxifylline (19%) groups. CONCLUSION: Cilostazol was significantly better than pentoxifylline or placebo for increasing walking distances in patients with intermittent claudication, but was associated with a greater frequency of minor side effects. Pentoxifylline and placebo had similar effects.

Comparative effects of cilostazol and other therapies for intermittent claudication.

Many patients with peripheral arterial disease (PAD) have intermittent claudication or problems with ambulation and mobility. Exercise and smoking cessation are primary therapies for claudication, but drug treatment may provide additional benefit. The data supporting use of pentoxifylline for claudication are weak, and pentoxifylline is not generally accepted as efficacious. Cilostazol is a new drug for the treatment of claudication. It appears to modestly benefit walking ability and it has other potentially useful effects, including inhibition of platelet aggregation and beneficial effects on serum lipids. In a randomized, prospective, double-blind trial examining walking ability in patients with PAD with moderate-to-severe claudication, cilostazol was superior to both placebo and pentoxifylline.

Injuries to the portal triad.

We reviewed the management and clinical course of 21 patients with extrahepatic injuries to the portal triad seen over the past 11 years at a Level I trauma center. These represented only 0.21% of patients with multiple trauma admitted during this time. Portal triad injury was never specifically diagnosed preoperatively. Extrahepatic bile duct injury occurred in 4 patients, portal vein injury in 14, and hepatic artery injury in 7; 3 patients had combined injuries. Eleven patients (52%) died, all due to uncontrolled hemorrhage from either an injured portal vein or associated intra-abdominal injuries. Management of the bile duct injuries included drainage alone, bile duct ligation, and Roux-Y hepaticojejunostomy. Survivors of portal vein injury were managed with lateral venorrhaphy. Ligation of the hepatic artery appeared to be optimal for injuries incurred by this vessel. Complications necessitating reoperation or percutaneous drainage procedures were encountered in 8 of 10 surviving patients (80%). Injuries to the portal triad are uncommon, difficult to diagnose, and technically challenging. Mortality is most directly related to uncontrolled intraabdominal hemorrhage, and salvage requires rapid control of bleeding as the first treatment priority.

Role of arteriography in the preoperative evaluation of carotid artery disease.

This retrospective study was undertaken to determine the role of arteriography in the treatment of patients being considered for carotid endarterectomy. The results of preoperative classification of disease severity by duplex ultrasound and arteriography were compared, and the impact of arteriography on patient management was ascertained. We reviewed the records of 83 patients who had carotid surgery planned on the basis of their clinical history and duplex scan results and who then underwent arteriography. Duplex scan results agreed with the classification of stenosis by arteriography in 87% of evaluated sides and were within one category in 98%. In 87% of the cases reviewed, the clinical presentation and duplex scan findings were sufficient for appropriate patient management. In the instances that arteriography was useful (13%), the need for arteriography was evident when the duplex scan (1) was technically inadequate or equivocal; (2) showed an unusual distribution of disease, atypical anatomy, or a recurrent lesion; or (3) demonstrated an internal carotid artery with diameter-reducing stenosis of less than 50% in a patient with hemispheric neurologic symptoms despite antiplatelet therapy.

Does infrapopliteal arterial runoff predict success for popliteal artery aneurysmorrhaphy?

BACKGROUND: A 6-year experience with surgical management of popliteal artery aneurysms (PAAs) was examined to determine the influence of infrapopliteal outflow vessel patency on the long-term success of popliteal artery aneurysmorrhaphy. METHODS: Arteriograms were reviewed to characterize the anatomy of the infrapopliteal arterial runoff. Regular clinical evaluation and prospective serial duplex scan surveillance assessed graft patency. RESULTS: A total of 28 patients underwent 45 popliteal aneurysmorrhaphies. Elective repair was performed in 32 limbs (71%); emergency treatment was needed for 13 limbs (29%) because of acute limb-threatening ischemia. All patients were managed with PAA exclusion and reversed saphenous vein grafting. Only 20 limbs (44%) had a patent trifurcation with three continuous vessels to the ankle, 13 (29%) had two continuous tibial vessels, 10 (22%) had one patent runoff artery, and 2 (4%) had no vessel continuous to the foot. With a mean follow-up of 19.1 months, the 5-year primary graft patency by life-table analysis was 95 +/- 12.3%, with a 5-year assisted primary patency of 97 +/- 10.0%. One vein graft underwent elective secondary revision. Another graft thrombosed, requiring a secondary bypass. Outcome did not correlate with the status of the runoff anatomy. Limb salvage was 100%. CONCLUSION: The use of autologous reversed vein grafting and attention to technical details yielded normal graft hemodynamics and excellent long-term patency and limb salvage despite the suboptimal runoff anatomy associated with PAAs.

The effect of withdrawal of drugs treating intermittent claudication.

BACKGROUND: Pharmacologic treatment for intermittent claudication is a management option. This study evaluated the effect of withdrawal of drug therapies, cilostazol and pentoxifylline, on the walking ability of peripheral artery disease patients. METHODS: Single-blind placebo crossover from a randomized, double-blind trial; 45 claudication patients received either cilostazol 100 mg orally twice daily (n = 16), pentoxifylline 400 mg orally three times daily (n = 13), or placebo (n = 16) for 24 weeks. After 24 weeks of double-blind therapy, treatment for all groups was placebo only, and follow-up continued through week 30. Treatment efficacy was established with treadmill testing. RESULTS: Profile analysis demonstrated a highly significant loss of treatment benefit after crossover (P = 0.001) for cilostazol-treated patients, but no significant change after crossover was observed with pentoxifylline. CONCLUSIONS: Drug withdrawal worsened the walking of claudicants who had benefited from cilostazol therapy. This decline with crossover to placebo suggests that the initial improvement with cilostazol treatment was due to the drug's action. Withdrawal of pentoxifylline did not adversely affect walking.

Noninvasive assessment of renal artery stenosis.

Noninvasive diagnostic methods for evaluation of renal arteries continue to improve. Contrast arteriography is the reference standard to which other techniques are compared, and preoperative arteriography before operative or endovascular therapy remains the practice standard. However, noninvasive examination methods have supplanted arteriography as a screening test for renal artery occlusive disease, and they allow more selective use of the invasive technique. ACE inhibitor-enhanced renal scintigraphy has improved on the sensitivity of standard renal scintigraphy, but several investigators found it still lacks when significant renal dysfunction is present. A positive scan implies the renal artery lesion is functionally significant and is predictive of a response to therapy. Although ACE inhibitor-enhanced renal scintigraphy can detect significant renal artery disease, it can neither localize the arterial lesion nor can it characterize the severity of the stenosis. Renal scintigraphy therefore lacks utility as a method to follow progression of the arterial disease. Magnetic resonance and helical CT imaging are advanced technologies that acquire axial imaging data, but with advanced software and powerful image processing hardware, the anatomic information can be represented in multiple planes or with three-dimensional reconstructions. The anatomic information provided is not limited to the renal arteries, but can define relationships to the surrounding anatomy. Validation studies from several institutions suggest that although these methods for renal artery assessment may be sufficiently accurate for screening use, they remain relatively expensive and are just now becoming more widely available. Not all patients can be studied. Helical CT scanning requires a relatively large intravenous contrast dose, which is undesirable in patients with renal insufficiency, and it seems to underestimate severity of some renal artery stenoses. MRA is impractical or unsafe for patients with claustrophobia, cardiac dysrhythmias, pacemakers, certain types of metallic implants or clips, or for seriously ill patients requiring monitoring. Duplex scanning is both sensitive and specific. It is the least expensive of the available diagnostic modalities, and it is completely safe and noninvasive. Not only is the presence of a renal artery lesion detectable, the severity of the stenosis can be categorized and its hemodynamic significance or renal blood flow can be evaluated. Renal artery duplex scanning is the optimal method for renal artery assessment when it is available from a validated vascular laboratory. However, this last point is the key. The utility of the study is entirely dependent on the skill and experience of the examining technologist. Other drawbacks to duplex scanning include the fact that to yield the "whole picture" of the anatomy and pathology requires a mental synthesis. Real-time scanning generates a series of images and flow data that must be interpreted with a understanding of how the scan was performed. Clinical circumstances, local expertise, equipment availability, costs, and other important considerations will factor into the decision-making process of planning a work-up for suspected renal artery stenosis. The noninvasive diagnostic technologies continue to advance, and as new methods are validated, the need for arteriography may be further lessened.

Neovascularization of canine sutured and stapled small intestinal anastomoses.

New blood vessels develop as a gastrointestinal anastomosis heals. The morphologic aspects of this neovascularization were studied in 22 dogs, each of which underwent one sutured and one stapled small bowel anastomosis. At intervals ranging from three to 24 days after surgery, the dogs were killed, and the bowel was injected with Batson's compound or india ink. The pattern of vascular growth across the anastomotic site was studied. Both stapled and sutured anastomoses caused an increase in submucosal capillary density at day three compared with control specimens taken from bowel remote from the anastomotic site. This increase was maintained consistently through day 24 in sutured anastomoses but had decreased by day five in stapled anastomoses. Growth of submucosal vessel across the anastomotic site could be demonstrated by day three in sutured and day four in stapled anastomoses. The more vigorous inflammatory response associated with sutured anastomoses may be responsible for more rapid and prominent neovascularization.

Venous segmentation of the human spleen. A corrosion cast study.

Partial splenectomy is possible because of vascular segmentation of this organ. Although interest has focused upon arterial supply, this study shows similar venous segmentation. Emerging splenic veins in excess of 1.7 mm at the hilum of ten unembalmed spleens were injected with different colors of modified Batson's compound, and corrosion casts were made. In four additional spleens, alternate veins and arteries were injected. Ten spleens had two primary segments (lobes); four had three lobes. Half of these lobes were further subdivided into two segments. Lobes and segments extended through the full thickness of the spleen. Relatively avascular interlobar planes were always approximately perpendicular to the longitudinal axis of the spleen, whereas intersegmental planes were more variable. Both interlobar and intersegmental planes frequently corresponded to marginal notches. When arteries and veins were both injected, similar segmentation was noted. Venous drainage did not overlap arterial segments, indicating that veins are intrasegmental. These results indicate that the surgical unit of the spleen can be based upon surgically accessible vessels at the hilum of the spleen. Identification of segmental vessels could permit salvage of a larger amount of splenic tissue than would be possible if only lobar vessels were identified.

The fate of the left kidney after division of its vein.

The effect of dividing the left renal vein was studied in Sprague-Dawley rats. Immediately after the left renal vein is divided near the renal hilum, the left kidney becomes markedly edematous and dusky. Twenty-four hours later, the kidney remains edematous and boggy. In contrast, the edema that immediately follows division of the left renal vein adjacent to the inferior vena cava is much less dramatic and virtually resolves within 24 hours. When the left renal vein was divided near the hilum simultaneously with right nephrectomy, all animals died within 48 hours. When the vein was divided adjacent to the vena cava with simultaneous nephrectomy, all animals survived. The effect of dividing the renal vein on perfusion of the left kidney was studied in Sprague-Dawley rats using intra-arterial injection of copper pigment. Division of the left renal vein reduced perfusion of that kidney to 68.9 per cent of control levels. This reduction was demonstrated to be totally reversible within 10 days.

Vascular grafts in head and neck reconstructive surgery.

The best management of advanced head and neck tumors invading the carotid artery utilizes a collaborative, anticipatory approach. Preoperative characterization of the anatomy and extent of tumor involvement, coupled with the physiologic assessment of the cerebrovascular circulation through the variety of adjunctive studies, facilitates operative planning. Careful preoperative evaluation allows the surgeon to make the most informed decision regarding extracranial carotid artery reconstruction, should carotid artery resection be required for adequate tumor removal. When the preoperative evaluation indicates that adequate cerebral perfusion or collateral reserve will not be maintained with carotid artery occlusion, carotid artery reconstruction needs to accompany any resection of this vessel. Autogenous saphenous vein remains the graft conduit of choice, but prosthetic materials may be used. Graft patency and healing require appropriate concomitant soft-tissue coverage of any overlying mucosal or cutaneous defects.

Preoperative intraincisional cefamandole reduces wound infection and postoperative inpatient stay in upper abdominal surgery.

The use of preoperative intraincisional (POII) single dose antibiotic prophylaxis has the advantage of providing extremely high concentrations of antibiotic along all layers of the wound, whilst achieving adequate systemic concentrations throughout the operation. In a single blind controlled trial, 250 patients undergoing upper abdominal surgery were randomised to receive POII cefamandole (2g) or to act as control. There was one wound infection in the POII group compared with 18 in the control group (P less than 0.001). Hospital stay was reduced by an average of one day (P less than 0.02) in the antibiotic treated group.

Surgical instrument restraint in weightlessness.

BACKGROUND: Performing a surgical procedure during spaceflight will become more likely in the future as the duration of missions becomes longer. Only minimal surgical capability was available on previous missions since the definitive medical care time was short and the likelihood of a surgical event too low to justify carrying surgical hardware onboard. Early demonstrations of surgical procedures in the microgravity environment of parabolic flight indicated the need for careful logistical planning and restraint of surgical hardware. Human ergonomics also has more effect in microgravity than in the conventional 1-G environment. METHODS: Three methods of surgical instrument restraint--a Minor Surgical Kit (MSK), a Surgical Restraint Scrub Suit (SRSS), and a Surgical Tray (ST)--were evaluated in parabolic flight surgical procedures. RESULTS: The MSK was easily stored, easily deployed, and demonstrated the best ability to facilitate a surgical procedure in microgravity. CONCLUSION: Important factors in a surgical restraint system for microgravity include excellent organization of supplies, ability to maintain sterility, accessibility while providing secure restraint, ability to dispose of sharp items and biological trash, and ergonomic efficiency.

Percutaneous aspiration of fluid for management of peritonitis in space.

BACKGROUND: As a medical emergency that can affect even well-screened, healthy individuals, peritonitis developing during a long-duration space exploration mission may dictate deviation from traditional clinical practice due to the absence of otherwise indicated surgical capabilities. Medical management can treat many intra-abdominal processes, but treatment failures are inevitable. In these circumstances, percutaneous aspiration under sonographic guidance could provide a "rescue" strategy. HYPOTHESIS: Sonographically guided percutaneous aspiration of intra-peritoneal fluid can be performed in microgravity. METHODS: Investigations were conducted in the microgravity environment of NASA's KC-135 research aircraft (0 G). The subjects were anesthetized female Yorkshire pigs weighing 50 kg. The procedures were rehearsed in a terrestrial animal lab (1 G). Colored saline (500 mL) was introduced through an intra-peritoneal catheter during flight. A high-definition ultrasound system (HDI-5000, ATL, Bothell, WA) was used to guide a 16-gauge needle into the peritoneal cavity to aspirate fluid. RESULTS: Intra-peritoneal fluid collections were easily identified, distinct from surrounding viscera, and on occasion became more obvious during weightless conditions. Subjectively, with adequate restraint of the subject and operators, the procedure was no more demanding than during the 1-G rehearsals. CONCLUSIONS: Sonographically guided percutaneous aspiration of intra-peritoneal fluid collections is feasible in weightlessness. Treatment of intra-abdominal inflammatory conditions in spaceflight might rely on pharmacological options, backed by sonographically guided percutaneous aspiration for the "rescue" of treatment failures. While this risk mitigation strategy cannot guarantee success, it may be the most practical option given severe resource limitations.

Modeling and simulation for space medicine operations: preliminary requirements considered.

The NASA Space Medicine program is now developing plans for more extensive use of high-fidelity medical simulation systems. The use of simulation is seen as means to more effectively use the limited time available for astronaut medical training. Training systems should be adaptable for use in a variety of training environments, including classrooms or laboratories, space vehicle mockups, analog environments, and in microgravity. Modeling and simulation can also provide the space medicine development program a mechanism for evaluation of other medical technologies under operationally realistic conditions. Systems and procedures need preflight verification with ground-based testing. Traditionally, component testing has been accomplished, but practical means for "human in the loop" verification of patient care systems have been lacking. Medical modeling and simulation technology offer potential means to accomplish such validation work. Initial considerations in the development of functional requirements and design standards for simulation systems for space medicine are discussed.

Functional interpretations of the radiographic anatomy of the femora of Myotis lucifugus, Pipistrellus subflavus, and Blarina brevicauda.

Radiographs of right femora from 29 shrews (Blarina brevicauda) and 51 bats (27 Myotis lucifugus, 14 Pipistrellus subflavus) were analyzed to determine if bone in these small mammals conformed to Bassett's ('68) revision of Wolff's Law. Five external and four cortical dimensions were made on enlargements of radiographs of each femur. Comparative descriptions of the spongiosa are given. External dimensions appear to be determined genetically, and, in bats, are closely related to functional demands. Shrew femora retain a primitive mammalian morphology. No apparent relationship exists between animal weight and mid-diaphyseal cortical thickness. Although differences in cortical thickness in bats suggest a possible relation between bone and pressure, no relationship is apparent in shrews; further, the comparative magnitude of these dimensions is similar in all three species, indicating genetic control mechanisms. Computation of maximal loading suggest that loading is so slight, that the inherent strength of bone tissue is adequate to resist mechanical deformation. However, there is evidence or cortical bone response to physiological demands. Inspection of the spongiosa also fails to provide evidence of conformity to Wolff's Law. Instead, the trabeculae appear to be related to pysiologic factors, animal age, and inherited disposition patterns. Thus, there is no evidence that bone in these diminutive mammals responds to mechanical forces, and the applicability of Wolff's Law is not indicated. It is hypothesized that, as the mechanical forces are so minimal, intrinsic tissue strength is sufficient to resist mechanical deformation, and femoral anatomy in these species is dictated by genetic and inherent physiologic conditions.

Hepatic duct disruption from blunt abdominal trauma: case report and literature review.

A laceration-avulsion injury of the hepatic duct from blunt trauma is described. Operative findings rather than preoperative studies led to the correct diagnosis. A combination of suture repair, left hepatic duct ligation, and hepaticojejunostomy were used to primarily manage this complex injury. Postoperative hepatobiliary scintigraphy and clinical follow-up over 1 year demonstrate satisfactory biliary drainage. Principles of the management of hepatic duct injury are reviewed.

Technical considerations in distal pancreatectomy with splenic preservation.

Splenic preservation may be attempted when distal pancreatectomy is performed for nonmalignant disease. The splenic artery and vein can be preserved with meticulous control of the multiple small, thin-walled branches that tether these vessels to the pancreas, allowing splenic salvage. Mobilization of the spleen into the operative field, ligation of the short gastric vessels and splenectomy are not performed. Thus, the operative procedure may be accomplished in carefully selected patients with little increase in operative time or blood loss over conventional distal pancreatectomy with splenectomy.