D. A. Shields

Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease

PURPOSE It has been suggested that leukocyte trapping and activation in the microcirculation of the leg skin causes lipodermatosclerosis and ulceration in patients with chronic venous disease. Ambulatory venous hypertension is accepted as the physiologic factor that leads to ulceration. We investigated leukocyte endothelial adhesion in patients who were subjected to short-term venous hypertension. METHODS Two groups of patients with venous disease were studied: group 1, varicose veins with skin changes (n = 15); and group 2, varicose veins without skin changes (n = 15). Blood samples were taken from a foot vein before and after standing for 30 minutes to raise the venous pressure in the lower limb, and after lying supine again for 10 minutes. The samples were analyzed for leukocyte surface CD11b and L-selectin (CD62L) expression using a flow cytometer. Plasma-soluble L-selectin was also measured using an enzyme-linked immunosorbent assay. RESULTS In patients with skin changes, median neutrophil CD11b levels fell from 4.66 to 3.83 arbitrary units (p = 0.005, Wilcoxon) after 30 minutes of venous hypertension, Median monocyte CD11b levels fell from 7.65 to 5.8 arbitrary units (p = NS, Wilcoxon) after venous hypertension and then fell further to 5.43 arbitrary units (p = 0.02 vs baseline; Wilcoxon) when the venous hypertension was removed. Neutrophil and monocyte L-selectin levels also fell in response to venous hypertension, remaining low even after venous hypertension was removed. A similar pattern was seen in patients with uncomplicated varicose veins. There was a rise in soluble L-selectin in the plasma of both groups of patients after venous hypertension, reflecting leukocyte adhesion to endothelium. In the group of patients with skin changes the level of soluble L-selectin rose from 695 ng/ml to 836 ng/ml (p = 0.02, Wilcoxon), and in the group without skin changes the rise was from 700 ng/ml to 801 ng/ml (p = 0.02, Wilcoxon). CONCLUSION Venous hypertension results in sequestration of the more activated population of neutrophils and monocytes in the microcirculation of the leg in patients with venous disease. These cells bind to the endothelium, releasing L-selectin, and do not emerge from the limb when venous hypertension is reversed. These findings do not differ between patients with varicose veins and those with skin changes.

Endothelial Activation in Patients With Chronic Venous Disease

OBJECTIVES Leukocyte trapping due to leukocyte-endothelial activation has been implicated as the cause of lipodermatosclerosis and ulceration in patients with chronic venous disease. We investigated endothelial activity in normal controls and patients subjected to short-term venous hypertension. METHODS Twenty-five normal volunteers and 30 patients with chronic venous disease divided into two groups: varicose veins with skin changes (LDS, n = 15); and varicose veins without skin changes (VVs, n = 15) were studied. Blood samples were taken from a foot vein before and after experimental venous hypertension. Plasma levels of ELAM-1 (endothelial leukocyte adhesion molecule-1), ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and von Willebrand factor (vWf) was measured by an ELISA. RESULTS There was a significant rise in the plasma concentration of ELAM-1, ICAM-1 and VCAM-1 in patients and normal controls in response to venous hypertension. Basal levels of plasma VCAM-1 and vWf were higher in patients with LDS compared to patients with VVs. The magnitude of rise of VCAM-1 was greater in patients with LDS compared to patients with VVs (p = 0.01, Mann-Whitney U-test). There was no difference in the basal levels or in the magnitude of change in plasma ICAM-1 and ELAM-1 between the two patient groups. CONCLUSION Venous hypertension results in endothelial activation which may aid endothelial-leukocyte adhesion. Patients with LDS exhibit increased VCAM-1, which is a counterligand for receptors expressed by monocytes and lymphocytes signifying that these cells may be more important in the development of skin changes.

Photoplethysmography: A valuable noninvasive tool in the assessment of venous dysfunction?

We have investigated the photoplethysmography findings in 152 patients admitted to the Middlesex Hospital Vascular Laboratory with suspected lower limb venous disease, and we compared the results obtained with patient grouping using clinical criteria and the presence of reflux on color duplex scanning. All photoplethysmography traces were normalized with use of computer software to enable direct comparison between the traces. The parameters investigated were the 95% and 50% refilling times and the initial gradient of the refilling curve. Receiver operating characteristic curves were constructed to determine which parameter was the most useful predictor of disease and to identify which value within each observation gave the greatest sensitivity and specificity. We found a large overlap between interquartile values for all three parameters, with limbs grouped both clinically and by duplex scanning, making differentiation between normal and abnormal limbs difficult on the basis of photoplethysmography traces alone. We found that a 95% refilling time of less than 15 seconds indicated venous dysfunction with the greatest sensitivity and specificity and suggest that this value is most useful. Photoplethysmography readings are reproducible, noninvasive, and correlate well with the presence of clinical disease, and photoplethysmography remains useful in the assessment of venous dysfunction.

Selection of amputation level: A review

Preservation of the knee joint in a patient undergoing lower limb amputation for critical ischaemia is associated with improved postoperative rehabilitation and mobility. Yet, for most surgeons the below-knee to above-knee amputation ratio remains less than one. Poor wound healing and a high reamputation rate for below knee stumps are important factors mitigating against below-knee amputations. Many tests (Doppler indices, segmental pressures, skin blood flow, skin perfusion pressure, TcpO2, thermography) have been described to predict the likelihood of successful healing of an amputation stump but none appears to have gained widespread acceptance. Clinical judgement alone is insufficient to predict the success or failure of an amputation stump. In this review, we have looked at the evidence in support of these tests, particularly those routinely available to most surgeons.

Plasma Lactoferrin as a Marker of White Cell Degranulation in Venous Disease

Objective: To measure plasma lactoferrin as a marker of neutrophil degranulation in groups of patients with varying severity of venous disease and compare with age- and sex-matched control subjects. Design: Prospective study of patients with varicose veins compared with a group of control subjects with no history or clinical findings of varicose veins. Setting: The Middlesex Hospital Vascular Laboratory, Mortimer Street, London WIN 8AA, UK. Patients: Patients referred to the Middlesex Hospital Vascular Laboratory for investigation of venous disease. Control subjects were obtained from within the laboratory and hospital staff, and from a group of Patients attending the London Foot Hospital for routine chiropody. Neither group had arterial disease nor any other illness or medication known to alter white cell activity. Interventions: 10 ml of blood taken from an arm vein into EDTA for a neutrophil count and measurement of Plasma lactoferrin using an ELISA. Results: Significantly raised plasma lactoferrin was found in all four groups of patients compared with their controls (p = 0.0156 for uncomplicated varicose veins, P = 0.01 for lipodermatosclerosis, p = 0.0413 for active venous ulceration, and p = 0.0005 for healed ulcers, Mann-Whitney U-test). Differences between medians (95% confidence interval) for the four groups were 269 (62–603), 199 (60–314), 133 (44–218) and 215 (98–349) ng/ml respectively. There was no difference in the neutrophil count between the patient and control groups, and correcting plasma lactoferrin for the neutrophil count did not remove significance in any group. Conclusions: This study shows evidence of increased neutrophil activation as shown by increased degranulation in patients with venous disease.

Neutrophil Activation in Experimental Venous Hypertension

Objective: To investigate the white cell trapping hypothesis of venous ulceration by measuring plasma lactoferrin as a marker of neutrophil degranulation in normal volunteers in two experimental models of venous hypertension. Design: A prospective study of volunteers with no history or clinical evidence of venous disease. Setting: The Middlesex Hospital Vascular Laboratory, Mortimer Street, London WIN 8AA, UK. Patients: Volunteers within the Middlesex Hospital Vascular Laboratory with no history or clinical findings of venous or arterial disease, no other systemic disease, on no medication known to alter white cell activity, and with no recent infection. Interventions: Venous blood was taken from cannulae in both feet and the right arm for a neutrophil count and Plasma lactoferrin, measured using an ELISA, during application of a tourniquet to 80 mmHG for 30 min to the right leg while supine, 5 min after release of tourniquet, and then during a 30 min period of standing. Results: During application of a tourniquet to the right leg there was a significant rise in plasma lactoferrin and in lactoferrin corrected for the neutrophil count (p < 0.05, Wilcoxon). In the unoccluded leg, although Plasma lactoferrin rose, this was not significant when corrected for the rise in neutrophil count. After standing for 30 min, the lactoferrin and neutrophil count increased in all three limbs; corrected lactoferrin showed a significant increase in the legs (p < 0.02), though not in the arm. Conclusion: Increased neutrolphil degranulation occurs during periods of short-term venous hypertension in normal volunteers, in keeping with the white cell trapping hypothesis.

Peripheral Nerve Function in Chronic Venous Insufficiency

Abnormalities of vasomotion, impairment of the venoarteriolar reflex and increased skin blood flow reported in the liposclerotic skin of patients with chronic venous insufficiency (CVI) suggest altered nervous control of the skin microcirculation. The aim of this study was to determine whether patients with CVI have a peripheral neuropathy. Forty patients with CVI and lipodermatosclerosis (LDS) and 35 age and sex-matched controls were examined for neuropathy using three modalities of testing. Threshold to warming was used to assess unmyelinated fibres, and threshold to cooling and vibration to assess myelinated fibres. Warming and cooling thresholds were measured on the sole of the foot by a purpose built, computer controlled instrument. The threshold to vibration was measured on the big toe using the Ohio Bio-thesiometer. A significantly raised threshold to warming and vibration was found in the CVI group compared to the normal controls [median threshold to warming (interquartile range) in CVI group = 5.3 (0.1-9.1) median threshold to warming (interquartile range) in controls = 1.21 (0.17-3.5), p = 0.005 and median threshold to vibration (interquartile range) in CVI group = 22 (13-31) median threshold to vibration (interquartile range) in controls = 12 (8.5-27.5), p = 0.024]. The thresholds to cooling was not statistically different in the two groups. This study demonstrates the presence of a peripheral neuropathy in patients with chronic venous insufficiency, and this may be important in the pathogenesis of venous ulceration.

Medicolegal claims following laparoscopic cholecystectomy in the UK and Ireland

INTRODUCTION The causes and outcomes of medicolegal claims following laparoscopic cholecystectomy were evaluated. SUBJECTS AND METHODS A retrospective analysis of the experience of a consultant surgeon acting as an expert witness within the UK and Ireland (1990-2007). RESULTS A total of 151 claims were referred for an opinion. Sixty-three related to bile duct injuries and four followed major vascular injury. Bowel injury resulted in 17 claims. A postoperative biliary leak not associated with a bile duct injury was responsible for 25 claims. Other reasons for claims included spilled gallstones, port-site herniae, haemorrhage and other recognised complications associated with laparoscopic cholecystectomy. Twelve of the claims are on-going, two went to trial, 79 (52%) were settled out of court and 58 (38%) were discontinued after the claimants were advised that they were unlikely to win their case. Disclosed settlement amounts are reported. CONCLUSIONS Bile duct and major vascular injuries are almost indefensible. The delay in diagnosis and (mis)management of other recognised complications following laparoscopic cholecystectomy have also led to a significant number of successful medicolegal claims.

Thrombolysis in Acute Lower Limb Ischaemia

For the past three decades balloon embolectomy has been the treatment of choice for acute lower limb occlusion. However, although usually successful in emboli, results are often disappointing in thrombotic atherosclerotic vessels. Attempted dissolution of the clot is accordingly attractive, and has theoretically been possible since the introduction of streptokinase in 1933. This was initially used intravenously, with variable success rates, although intraarterial administration is currently the method of choice. Later thrombolytic drugs such as tissue plasminogen activator, urokinase and anistreplase have been introduced. Lysis time has also been increased by using pharmaco-mechanical methods of administration such as pulsed spray catheters, which could increase the usefulness of thrombolysis in patients with rapidly progressive neurological signs where currently surgical embolectomy would be advocated. Several newer drugs with theoretical advantages over older drugs such as single-chain urokinase-type plasminogen activator or K1K2PU are currently undergoing trials. The role of thrombolysis as an adjunct to surgical embolectomy is also promising, though again requires further trials. There is still no consensus as to which patients are best suited to thrombolysis, nor an optimum drug or method of administration. However, there seems no doubt that thrombolysis will be increasingly used in the management of peripheral limb ischaemia, though requiring a team approach between surgeons, radiologists and haematologists.

Neutrophil CD11b Expression in Patients with Venous Disease

The white cell trapping hypothesis suggests that raised venous pressure causes white cell margination and activation, with the release of proteolytic enzymes and Superoxide radicals, believed responsible for the tissue destruction seen in chronic venous insufficiency [1]. We have demonstrated raised levels of plasma lactoferrin [2] and elastase [3] as markers of neutrophil degranulation in patients with venous disease previously.