Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia.

VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.

Quantity of residual thrombus after successful catheter-directed thrombolysis for iliofemoral deep venous thrombosis correlates with recurrence.

OBJECTIVES: Iliofemoral deep venous thrombosis (IFDVT) is an independent risk factor for recurrent DVT. It has been observed that recurrent DVT correlates with residual thrombus. This study evaluates whether risk of recurrence is related to the amount of residual thrombus following catheter-directed thrombolysis (CDT) for IFDVT. METHODS: Patients who underwent CDT for IFDVT had their degree of lysis quantified by a reader blind to the patients' long-term clinical outcome. Patients were classified into two groups, ≥50% and <50% residual thrombus. Recurrence was defined as a symptomatic presentation with image verification of new or additional thrombus. RESULTS: A total of 75 patients underwent CDT for IFDVT. Median follow-up was 35.9 months. Sixty-eight patients (91%) had no evidence of recurrence and seven (9%) developed recurrence. Of the patients who had ≥50% (mean 80%) residual thrombus, 50% (4/8) experienced recurrence, but in those with <50% (mean 35%) residual thrombus, only 5% (3/67) had recurrent DVT (P = 0.0014). CONCLUSION: The burden of residual thrombus at completion of CDT correlates with the risk of DVT recurrence. Patients having CDT for IFDVT had a lower risk of recurrence than expected. Successful clearing of acute clot in IFDVT patients significantly reduces the recurrence risk compared to patients with a large residual thrombus burden.

Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients.

BACKGROUND: The American College of Chest Physicians addressed the dilemma of identifying optimal therapy for venous thromboembolism (VTE) prophylaxis and published their Fourth Consensus Conference on Antithrombotic Therapy in 1995, with recommendations for prophylactic therapy. Despite these recommendations, appropriate VTE prophylactic therapy is underused. OBJECTIVES: To examine routine practices in the prevention of VTE in high-risk surgical patients and to determine the extent of adoption of grade A prophylactic therapies as recommended by the American College of Chest Physicians. METHODS: Retrospective medical record review in 10 teaching or community-based hospitals located in the United States. Medical charts of 1907 patients were randomly selected for review from the population of patients who underwent high-risk major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement between January 1, 1996, and February 28, 1997. RESULTS: Of 1907 patients, VTE prophylaxis was used in 89.3%; use was 93.7% in each of the 3 orthopedic surgery groups and 75.2% in the high-risk major abdominal surgery group. The percentage of patients receiving grade A therapy was highest in the hip replacement group (84.3%) vs. the other groups (knee replacement, 75.9%; hip fracture repair, 45.2%; abdominal surgery, 50.3%). CONCLUSIONS: The use of grade A prophylaxis was related to the type of surgery, with the highest use seen in total hip replacement and the lowest in hip fracture repair. One in 4 patients who underwent high-risk major abdominal surgeries failed to receive any form of VTE prophylaxis. Publication of consensus statements alone may be insufficient to ensure the incorporation of important new clinical information into routine practice.

Deep venous thrombosis and postthrombotic syndrome: invasive management.

Invasive management of postthrombotic syndrome encompasses the two ends of the deep vein thrombosis spectrum, patients with acute iliofemoral deep vein thrombosis and those with chronic postthrombotic iliofemoral venous obstruction. Of all patients with acute deep vein thrombosis, those with involvement of the iliofemoral segments have the most severe chronic postthrombotic morbidity. Catheter-based techniques now permit percutaneous treatment to eliminate thrombus, restore patency, potentially maintain valvular function, and improve quality of life. Randomized trial data support an initial treatment strategy of thrombus removal. Failure to eliminate acute thrombus from the iliofemoral system leads to chronic postthrombotic obstruction of venous outflow. Debilitating chronic postthrombotic symptoms of the long-standing obstruction of venous outflow can be reduced by restoring unobstructed venous drainage from the profunda femoris vein to the vena cava.

Medical management of patients with peripheral arterial disease.

Peripheral arterial disease (PAD) is one of the most frequent manifestations of atherosclerosis and is associated with atherosclerosis in the coronary and carotid arteries, leading to a highly increased incidence of cardiovascular events. Major risk factors of PAD are similar to those that lead to atherosclerosis in other vascular beds. However, there are differences in the power of individual risk factors in the different vascular territories. Cigarette smoking and diabetes mellitus represent the greatest risks of PAD. For prevention of the progression of PAD and accompanying cardiovascular events similar preventative measures are used as in coronary artery disease (CAD). However, recent data indicate that there are some differences in the efficacy of drugs used in the prevention of atherothrombotic events in PAD. Antiplatelet treatment is indicated in virtually all patients with PAD. In spite of the absence of hard evidence- based data on the long term efficacy of aspirin, it is still considered as a first line treatment and clopidogrel as an effective alternative. The new antiplatelet drugs ticagrelol and prasugrel also represent promising options for treatment of PAD. Statin therapy is indicated to achieve the target low density lipoprotein cholesterol level of ≤2.5 mmol/L (100 mg/dL) and there is emerging evidence that lower levels are more effective. Statins may also improve walking capacity. Antihypertensive treatment is indicated to achieve the goal blood pressure (<140/90 mmHg). All classes of antihypertensive drugs including beta-blockers are acceptable for treatment of hypertension in patients with PAD. Diabetic patients with PAD should reduce their glycosylated haemoglobin to ≤7%. As PAD patients represent the group with the highest risk of atherothrombotic events, these patients need the most intensive treatment and elimination of risk factors of atherosclerosis. These measures should be as comprehensive as those in patients with established coronary and cerebrovascular disease.

SPECT quantification of cerebral ischemia before and after carotid endarterectomy.

A method to assess changes in cerebral perfusion following carotid endarterectomy was developed using late (2 hr)/early (20 min) single-photon emission computed tomography (SPECT)/[123I]iodoamphetamine count ratios. Using a ratio greater than 1.0 to indicate redistribution and reversible ischemia, pre- and postoperative studies were compared for 20 patients. Regional polar plots based on 30 degrees angular sectors showed improvement greater than 2 standard deviations (s.d.s) ipsilateral to surgery in 15/19 (79%) and contralateral to the side of surgery in 8/19 (42%) patients with significant hemodynamic lesions. Using a hemispheric perfusion index (mean of four 30 degrees sectors) ipsilateral perfusion improved in 11/19 (58%) with bilateral improvement in 6/19 (32%). Visual interpretation was similar to the regional analysis with 14/19 (74%) improving on the operative side; however, it was less sensitive for contralateral changes, 4/19 (21%). We conclude that quantitation of redistribution can provide an objective index of improved perfusion and is especially important to detect contralateral changes.

Endovascular and surgical revascularization for patients with intermittent claudication.

Intermittent claudication (IC), the most common symptom of peripheral arterial disease (PAD), most often results from flow-reducing lesions in the arteries of the lower extremity that cause exercise-induced muscle ischemia. Intermittent claudication has a significant impact on quality of life and calls attention to PAD, which is secondary to systemic atherosclerosis and a major marker for cardiovascular morbidity and mortality. Most IC patients improve with a regimen that includes aggressive risk-factor modification, exercise, platelet inhibition, and pharmacotherapy to improve walking distance. Selected patients may require endovascular or surgical intervention if it can be offered with low risk. Endovascular procedures, most often percutaneous balloon angioplasty with or without stenting, are recommended for short-segment stenotic lesions in the aortoiliac and infrainguinal arterial segments. Combined platelet inhibition and endoluminal radiation are under study and may be useful to improve long-term outcome with these procedures. Percutaneous hemostatic puncture closure devices can also be used to reduce bleeding complications and allow more aggressive and immediate antithrombotic therapy, further improving results. Operative revascularization is recommended for patients with long-segment and multisegment disease, especially if obstruction is present. Aortofemoral reconstruction is associated with a low operative mortality and an 80% to 85% 5-year patency rate. Iliac reconstruction is recommended for isolated unilateral iliac arterial disease. Infrainguinal arterial reconstruction is associated with a 60% to 80% 5-year patency rate, with better outcomes noted for autogenous conduits than for prosthetic devices. Mechanical modification and pharmacotherapy with platelet inhibitors and anticoagulants improve long-term patency.

Intermittent claudication: magnitude of the problem, patient evaluation, and therapeutic strategies.

Intermittent claudication (IC), the symptom of exercise-induced muscle ischemia of peripheral arterial disease (PAD), afflicts and limits the activities of a significant number of patients. Incidence and prevalence of IC depends on the population studied and the diagnostic instruments used. In large studies, prevalence has ranged from 3% to 10%, with a sharp increase in those aged > or =70 years. Over the next 20 years, the total number of patients affected is expected to increase significantly due to anticipated demographic changes. Analysis of the natural history of IC demonstrates that the risk of cardiovascular morbidity and mortality far exceeds that of severe limb ischemia or limb loss. In fact, only 2% to 4% of all patients with IC will require a major amputation in their lifetime. However, life expectancy is approximately 10 years less than that of an age-matched cohort. By now, PAD is well recognized as a marker of systemic atherosclerosis. The cornerstone of patient evaluation is a history and physical examination, including a detailed atherosclerotic risk-factor assessment. In the differential diagnosis of IC, clinicians should consider etiologies such as arthritis, spinal stenosis, radiculopathy, venous claudication, or inflammatory processes. In >80% of all patients, it is possible to locate the responsible arterial segment by combining the location and severity of pain with a pulse examination. Noninvasive diagnostic studies help determine the level of disease, may unmask a hemodynamically significant stenosis, and are useful in follow-up. Arteriography is reserved for patients in whom the decision for revascularization has been made. Knowing the anatomic detail of a lesion allows the clinician to determine whether and what type of intervention is feasible. Standard therapy for all patients should be directed at both peripheral and systemic atherosclerosis, beginning with risk-factor modification in the form of smoking cessation, optimal diabetes control, and lipid normalization. The benefits of supervised exercise rehabilitation include significantly increased walking distance and enhanced quality of life. Platelet inhibition has been shown to reduce the risk of ischemic stroke, myocardial infarction, and vascular death and should be prescribed for all but those in whom it is medically contraindicated. Symptom-specific pharmacotherapy with a broad range of medications has yielded disappointing results in the past. However, recent studies have demonstrated that patients receiving the novel agent cilostazol experienced increases in walking distance and improvements in quality of life.

The use of dihydroergotamine and heparin in the prophylaxis of deep venous thrombosis.

Three factors leading to the development of postoperative deep venous thrombosis (DVT) are the hypercoagulable state, stasis, and vein wall injury, which occur in patients undergoing surgical procedures. Vein wall injury is thought to occur as a smooth muscle response to surgical trauma in veins distant from the operative site. Heparin and dihydroergotamine (DHE) were combined in an attempt to decrease the hypercoagulable factor and minimize stasis. We believe that by maintaining venous smooth muscle tone, the degree of endothelial damage is also diminished. Low-dose heparin acts through its effect of factor Xa and activation of antithrombin III; DHE selectively increases venous smooth muscle tone to accelerate venous blood flow velocity and minimize venous pooling. The European experience with combination DHE-heparin prophylaxis shows that this combination is more effective than either agent alone, and studies on orthopedic patients have shown that DHE/5,000 is effective in preventing postoperative DVT in this high-risk group. In the US, the Multicenter Trial evaluated postoperative DVT in general surgical patients. The combination of DHE/5,000 was statistically more effective in the prophylaxis of postoperative DVT than placebo (p = 0.0011). The interim results of an ongoing Multicenter Trial on the prophylaxis of postoperative DVT in patients undergoing total hip replacement indicate that DHE/5000 has significant prophylactic efficacy compared to placebo. It is proposed that the mechanism of action of the DHE-heparin combination is synergistic, since all 3 limbs of Virchow's triad are potentially affected.

Phleborheography--results of a ten-year experience.

Phleborheography (PRG) is a physiologic volumetric plethysmographic technique that was developed for the diagnosis of lower extremity deep venous thrombosis. During the past 10 years, 21, 626 extremities have been studied with 709 corresponding venograms. Overall data reveal a sensitivity of 92% (247/268) and specificity of 95% (418/441). There were 21 false negative PRG results, and 12 of these were due to isolated calf vein thrombosis. There were 23 false positive results, and 11 of these were considered true errors of the technique. When isolated calf vein thrombosis was disregarded, the sensitivity increased to 95%. PRG detected 45 of 57 (79%) isolated calf vein thrombi. The modified criteria for interpretation included respiratory waves and baseline elevation as the major criteria and prominent arterial pulsation and foot emptying as the minor criteria. PRG has recently been used to monitor the duration of thrombolytic therapy. While data are limited, this appears to be a promising contribution to the quantification of individual response to lytic therapy and may indicate an objective end point for treatment. PRG is a sensitive and specific method of detecting deep vein obstruction. It is a painless, reproducible, repeatable technique that requires minimal patient cooperation. PRG is a versatile laboratory technique that can be used for a variety of applications in addition to the diagnosis of deep vein thrombosis.

Real-time B-mode carotid imaging in diagnosis of cerebrovascular disease.

We studied 1,044 patients by using real-time B-mode ultrasonic carotid imaging (BioSound), oculoplethysmography and carotid phonoangiography (OPG/CPA), and periorbital Doppler ultrasonography. One hundred and fifty of these patients underwent bilateral carotid arteriography; they form the basis of this study. The x-ray films were compared to the scans and other noninvasive studies. The quality of the B-mode scans were graded according to the severity of disease (the degree of diameter reduction of the arterial lumen by stenosis): grade I (0% to 39% stenosis), grade II (40% to 69% stenosis), and grade III (70% stenosis and greater). The overall results showed that the specificity of the scan was 86%, sensitivity for grade II disease was 75%, and sensitivity for grade III disease was 44%. Only 6 of 16 (38%) totally occluded vessels were identified correctly. The data reveal a direct correlation of scan quality with accuracy. Good-quality scans had 90% accuracy, whereas the accuracy of poor-quality scans was 48%. Four of 12 scan/arteriogram "mismatch" patients underwent carotid endarterectomy. In each instance the surgeon thought that the scan more accurately represented the disease process. When the scan was combined with OPG/CPA and the results agreed, there was a 91% accuracy rate. However, when the scan and OPG/CPA disagreed, the scan was more reliable in the grade I and II categories, whereas the OPG/CPA was much more reliable in grade III disease. The accuracy of this technique can be improved with the addition of a high-quality Doppler system. If technologic improvements can be made so that technically good scans can be obtained in all patients, then this may become the most reliable noninvasive cerebrovascular testing method.

Operative venodilation: a previously unsuspected factor in the cause of postoperative deep vein thrombosis.

Intraoperative venodilation in veins distant from the site of operation has been shown to occur in animals and has been directly correlated with focal venous endothelial damage. This exposure of subendothelial collagen could serve as initiation sites for thrombus formation. This study tests the hypothesis that human beings (1) significant operative venodilation occurs and that it correlates with postoperative deep venous thrombosis (DVT); (2) operative venodilation can be pharmacologically controlled; and (3) this control reduces the incidence of postoperative DVT. Twenty-one patients undergoing total hip replacement had their contralateral cephalic vein continuously monitored with modified ultrasonographic instrumentation, with a continuous on-line recorder graphing venous diameter. Patients were randomly assigned to receive 0.5 mg of dihydroergotamine and 5000 U of heparin (DHE/Hep) for prophylaxis or placebo, with investigators "blinded" Postoperatively, all patients underwent ascending phlebography. Patients in whom postoperative DVT developed (11) had a mean operative venodilation of 28.9% +/- 3.93%, and those in whom DVT did not develop (10) had a mean venodilation of 11.6% +/- 1.55% (p = 0.001). Only 17% (2/12) dilating less than 20% baseline diameter had DVT compared with 100% (9/9) dilating greater than 20% of baseline diameter (p = 0.002). Patients receiving venotonic agent DHE had significantly less venodilation and DVT (p less than 0.001) compared with patients receiving the placebo. Patients who had DVT and whose veins dilated greater than 20% were older than patients who did not have DVT and whose veins minimally dilated: p = 0.04 and p = 0.07, respectively. Although there was a trend toward increased venoconstriction in patients receiving DHE/Hep (p = 0.09), there was no correlation of venoconstriction with ultimate thrombotic outcome. Maximal venodilation occurs during handling of soft tissue (muscle), and this occurs significantly sooner than maximal venoconstriction, which occurs during bone manipulation. We conclude that excessive operative venodilation is a new and important etiologic factor that leads to postoperative DVT. Operative venodilation can be pharmacologically controlled with the venotonic agent DHE. The combination DHE/Hep reduces postoperative DVT by the reduction of operative venodilation in the presence of low doses of an anticoagulant. These findings offer a new approach for predicting postoperative DVT and an object rationale for developing effective prophylaxis.

Does bacteremia pose a direct threat to synthetic vascular grafts?

This study was undertaken to determine the significance of graft lumen exposure to blood-borne organisms in the development of graft infection. Three groups of dogs were studied. In group I (n = 20), the infrarenal aorta was dissected from surrounding tissue, divided, and reconstructed with a Dacron tube interposition graft. In group II (n = 9) the aorta was similarly isolated, but Dacron graft material was wrapped around the intact aorta. In group III (n = 13) the infrarenal aorta was isolated, but no graft material was placed. All dogs were given intravenous 1 X 10(7) Staphylococcus aureus at the completion of surgery. Group I grafts were harvested 8 hours, 1 day, or 21 days after bacterial challenge. Group II and III grafts were harvested 1 day or 21 days after infusion. At the time of harvest, selective cultures of the periaortic tissue (PAT), periaortic graft (PAG), and interposition graft lumen (GL) were taken. The overall infection rates were similar, with 17 of 20 (85%) dogs in group I, 6 of 9 (67%) in group II, and 11 of 13 (85%) in group III found to be culture positive. In group I, 3 of 3 dogs at 8 hours, 2 of 2 on day 1, and 12 of 15 on day 21 had positive PAT cultures. Only 4 of 15 on day 21 had positive GL cultures. In group II, 4 of 5 dogs on day 1 and 2 of 4 on day 21 had positive PAT and PAG cultures. In group III, 9 of 9 animals on day 1 and 2 of 4 on day 21 had positive PAT cultures. All aortic lumen cultures were negative in groups II and III. The difference between GL and PAT cultures was statistically significant in all groups (I, p = 0.01; II, p = 0.05; III, p = 0.01). Serial quantitative blood cultures revealed a mean bacterial load of 10.5 +/- 4.5 CFU/ml at 15 minutes postinfusion, which fell steadily until no bacteria were detected at 3.5 hours. Lymphangiography demonstrated periaortic pooling of lymph in the immediate postoperative period. These data suggest that the bacteremia in this model is transient and rapidly clears. Periaortic tissues quickly sequester bacteria, possibly because of lymphatic leakage. The GL appears to be secondarily infected.

Noninvasive flow techniques in the diagnosis of cerebrovascular disease.

The accuracy of oculoplethysmography (OPG) and carotid phonoangiography (CPA) singly and in combination, the Doppler velocity detector, and photoplethysmography (PPG) was checked by measurement of the degree of stenosis as shown on arteriograms in 308 internal carotid arteries. In a second study using arteriographic measurement in 210 internal carotid arteries, the comparative accuracy of the fluid-filled (Kartchner) and the air-filled (Zira) OPG, each with and without CPA, was assessed. In the first study the specificity in arteries with less than 40% diameter reduction varied from 88% for the PPG to 97% for the Doppler examination. The sensitivity in arteries with more than 40% diameter reduction varied from 17% for the Doppler examination to 80% for the combination of OPG plus CPA. For arteries with a reduction in diameter greater than 70%, the sensitivity varied from 67% for the CPA to 87% for the OPG plus CPA. The sensitivity of the OPG plus CPA for total occlusions was 93%. For bilateral carotid artery stenosis over 40%, the sensitivity varied from 50% for the CPA to 82% for the combined OPG plus CPA. In the second study, for arteries with less than 40% stenosis the specificity varied from 86% for the Zira computed readout to 93% for the OPG(K). In the second study, when retrospectively analyzed, the sensitivity for arteries with more than 40% stenosis varied from 74% for the Zira computed readout to 88% for the combined OPG(K) plus CPA. For arteries with greater than 70% diameter reduction the sensitivity varied from 79% for the Zira readout to 100% for OPG plus CPA. For bilateral carotid artery disease with greater than 40% diameter reduction, the sensitivity ranged from 50% for OPG(Z) to 77% for OPG(Z) plus CPA.

Review of the Multicenter Trial Committee report: a prospective, randomized study on the prophylaxis of postoperative deep venous thrombosis.

The etiology of postoperative deep venous thrombosis (DVT) is thought to be due to a combination of factors including stasis, a hypercoagulable state and venous endothelial damage. Methods of prophylaxis are directed toward correcting one or more of these pathologic events. Methods counteracting more than one of these factors can be expected to be even more effective. The combination of dihydroergotamine (DHE) and heparin was anticipated to minimize stasis and the hypercoagulable state respectively. Based upon current experimental evidence and current theory, an additional benefit might include minimizing venous endothelial injury by controlling venomotor tone. A prospective, randomized, double-blind, multicenter trial was designed and performed in the United States evaluating the prophylactic efficacy of DHE 0.5 mg plus heparin 5000 U, DHE 0.5 mg plus heparin 2500 U, heparin 5000 U, and DHE 0.5 mg versus placebo. General surgical patients including those undergoing noncardiac thoracic and pelvic operations who were identified at moderate to high risk for postop DVT were included. Study medications were injected subcutaneously two hours preoperatively and every 12 hours postoperatively for 5-7 days or until the 125I-fibrinogen-uptake test (RFUT) became positive. Eight hundred and eighty eight patients were entered into this trial and 744 (85%) completed the study. Results showed a statistically significant benefit from DHE/Hep 5000 compared to placebo (p less than 0.01) and compared to other active agents (p less than 0.05). None of the other active agents showed a statistically significant prophylactic benefit.(ABSTRACT TRUNCATED AT 250 WORDS)

Reducing morbidity of thoracoabdominal aneurysm repair by preliminary axillofemoral bypass.

BACKGROUND: Thoracoabdominal aneurysm (TAA) repair continues to be associated with appreciable morbidity and mortality. To reduce the substantial cardiac afterload of thoracic aortic clamping, preserve visceral, renal, and lower-extremity perfusion, and reduce spinal cord ischemia, a right axillofemoral bypass was performed before TAA resection. PATIENTS AND METHODS: Fifteen patients undergoing repair of their TAA had a preliminary axillofemoral bypass with an 8- to 10-mm externally supported polytetrafluoroethylene graft. Nine underwent elective repair and 6 were operated on emergently. All but 2 patients (both had type IV aneurysms) had spinal fluid drainage and all had moderate hypothermia induced (31 degrees C to 32 degrees C). All visible intercostal arteries were reimplanted. RESULTS: Requirements for pharmacologic afterload reduction were minimal. Urine output was preserved during proximal aortic and intercostal anastomoses, and acidosis was minimal. Anticoagulation was not necessary unless the aortic bifurcation was replaced, and no patient had thrombotic complications. One (7%) patient died after repair of a ruptured aneurysm, and 1 (7%) developed paraplegia and required temporary dialysis. CONCLUSION: Preliminary axillofemoral bypass avoids the profound hemodynamic and physiologic derangement caused by clamping of the thoracic aorta, and effectively reduces the morbidity of TAA repair.

Combined dihydroergotamine and heparin prophylaxis of postoperative deep vein thrombosis: proposed mechanism of action.

The cause of postoperative DVT is considered to be changes in blood coagulation, stasis of blood within the veins, and injury to the vein wall. The coagulation changes have been investigated and documented and involve platelet activation, stimulation of the coagulation cascade, and blunting of endogenous fibrinolytic activity. Stasis has been objectively identified by retention of contrast material in soleal sinuses and marked changes in venous flow velocity in patients in the supine position and in those under general anesthesia. Vein wall injury is more controversial, but has been shown to be directly related to venodilation. Such dilation of veins occurs in response to operative trauma, hence venous endothelial damage most likely plays a part in the milieu responsible for postoperative DVT. The prophylaxis provided by the combination of dihydroergotamine and heparin appears to affect each of the three limbs of Virchow's triad. Heparin achieves its prophylactic benefit by activating antithrombin III. Activated antithrombin III affects numerous sites in the coagulation cascade. It has been shown that 1 micrograms of antithrombin III inhibits the formation of 1 unit of thrombin; however, in the presence of heparin, 1 micrograms of activated antithrombin III inhibits 750 units of thrombin. Dihydroergotamine increases venous smooth muscle tone without affecting arteriolar smooth muscle. Hence, it has the effect of preventing stasis without increasing blood pressure. It also affects the platelet membrane, prostaglandin synthesis, and blood distribution, although these findings need to be elucidated. The combination of dihydroergotamine and heparin seems to have a synergistic prophylactic effect in preventing postoperative DVT. Heparin modifies the coagulation changes, whereas dihydroergotamine minimizes stasis and potentially prevents the endothelial damage caused by excessive operative venodilation. Such a combination of effects can explain the synergistic prophylactic efficacy found when dihydroergotamine and heparin were employed in combination in the multicenter trial [42].

Diagnostic methods for deep vein thrombosis: venous Doppler examination, phleborheography, iodine-125 fibrinogen uptake, and phlebography.

Since clinical diagnosis of DVT is often inaccurate, it has become accepted that an objective means of diagnosing clot in the deep venous system becomes critically important in the management of these patients. Important to understanding the diagnostic capabilities of any test are the anatomic and physiologic characteristics of the deep venous system. The venous Doppler examination monitors the velocity of blood flowing through a particular vein. Doppler probes in the 5 to 10 mHz range are routinely used. Respiratory variation is a normal finding due to a diminished flow signal during inspiration, followed by a progressive increase in flow signal during expiration. Characteristics of the spontaneous flow signals are the most important part of interpreting the venous Doppler examination. In addition, the response to distal or proximal compression (augmentation) adds important information to the interpretation; however, the response during any augmentation maneuver depends on the rapidity of compression, the force of compression, the quantity of blood in the veins at the time of compression, and the distance between the Doppler probe and the compression point. The literature reports a wide range of sensitivity and specificity for the Doppler examination, but there is uniform agreement and an observable trend that physicians with a large experience and a dedicated interest will obtain much better results than physicians with less experience and less interest. Phleborheography is a six-channel volumetric plethysmographic technique that monitors volume changes in the lower extremities associated with respiration and foot and calf compression. The volumetric tracings obtained are similar to the velocity profiles obtained on the venous Doppler examination. The criteria used in interpreting phleborheographic tracings are respiratory waves and baseline elevation (major criteria), and prominent arterial pulse waves and foot emptying (minor criteria). Previously reported overall sensitivities for detecting DVT are 83 to 93 percent, with sensitivities of detecting proximal vein thrombosis of 92 to 96 percent. Specificities have been reported to be 87 to 97 percent. In a prospective analysis of 126 extremities with phleborheography and phlebography carried out within the same 24 hour period at Temple University Hospital, we found an overall sensitivity of 79 percent (51 of 65 patients); however, the sensitivity for proximal vein thrombosis was 91 percent (49 of 54 patients).(ABSTRACT TRUNCATED AT 400 WORDS)