The Scottish-Finnish-Swedish PARTNER study of taprostene versus placebo treatment in patients with critical limb ischemia.

AIM: Atherosclerotic peripheral arterial disease is a major health problem in the western world, often manifested as intermittent claudication, affecting 10-20% males above 60 years. Ischemic complications can lead to rest pain, ulceration and gangrene. The treatment of choice for critical limb ischemia (CLI) is vascular reconstruction or endovascular interventions. Medical management with vasodilator antiplatelet prostaglandins, could be considered in patients unsuitable for surgery. Long term follow-up on previous prostaglandin studies has been insufficient to evaluate amputation rates. Hence this study evaluated safety and longer term efficacy of taprostene sodium, a prostacyclin (PGI2) analogue in CLI. The aim of this study was to determine whether Taprostene sodium, a PGI2 analogue, was a safe and effective treatment for CLI. METHODS: This paper reports the data from the Scottish-Finnish-Swedish PARTNER Study Group which consisted of a double-blind placebo controlled multi-centre study evaluating Taprostene compared to placebo. The primary endpoints were pain relief and early ulcer healing response at the end of the four week infusion phase and amputation at six months follow-up. The patients were randomly allocated to receive taprostene or placebo in a two to one randomization of active versus placebo. A total of 111 patients with CLI were recruited. Taprostene was given twice a day over two 2 hour periods for four weeks. The early response was evaluated at the end of the four week infusion phase. In patients with rest pain without ulceration, a positive response was complete pain relief without any requirement for analgesic therapy. However in patients with ulceration, a positive response was defined as a decrease in the ulcer size by >30%. Amputation scores were compared at the end of the 6 months follow-up period for all participants. RESULTS: Seventy-four patients received taprostene and 37 placebo. Overall, 61 male patients were enrolled in the study along with 50 females with 11% more women in the taprostene (active) group. For both patients with and without ulcers there was no statistically significant difference noted in the early response between those receiving taprostene and those receiving placebo infusion. The percentage of patients without any amputations was 43% in the taprostene group compared to 38% in the control group at the end of six months; however, these results were not statistically significant. CONCLUSION: Although a reasonable number of patients enrolled in the study it has not been possible to demonstrate any statistically significant benefit of taprostene over placebo. This may be due to more patients with risk factors for peripheral artery disease (PAD) such as hypertension, diabetes mellitus and cigarette smoking in the actively treated group and also due the increased number of women in the active group who are known to generally respond less favourably to antiplatelet agents.

A randomized, single-blind, increasing dose safety trial of an oxygen-carrying plasma expander (Hemospan) administered to orthopaedic surgery patients with spinal anaesthesia.

The objective of this study was to further explore the safety of Hemospan (Sangart Inc., San Diego, CA, USA), an oxygen-carrying plasma expander. The aim of this study was to determine if Hemospan is well tolerated in orthopaedic surgery patients with spinal anaesthesia in doses up to 1 L. Hemospan was previously found to be well tolerated in normal volunteers and orthopaedic surgery patients with spinal anaesthesia in doses up to 500 mL. Five cohorts of six orthopaedic surgery patients, American Society of Anesthesiologists (ASA) I and II, were studied. In each cohort, four patients received Hemospan in doses ranging from 200 to 1000 mL, and two received Ringer's lactate immediately prior to induction of spinal anaesthesia. There were no serious adverse events (SAEs). Iohexol clearance measured before and 24 h after dosing was unaffected. There were 14 adverse events (AEs) in the 10 control patients (1.4 per patient) and 30 in the 20 patients receiving Hemospan (1.5 per patient). One patient in the group receiving 200 mL Hemospan had elevated mean arterial pressure after dosing, but there were no elevations in any of the other patients. The peak plasma Hemospan concentration in the 1000 mL group was 1.3 g dL(-1), with a dose-dependent clearance (T(1/2)) ranging from 14.1 to 23.0 h. Plasma methaemoglobin levels were independent of dose, reaching a maximum at 40 h after dosing and never exceeded 0.125 g dL(-1). Troponin T was transiently elevated in two patients receiving Hemospan without symptoms or electrocardiographic abnormalities or elevation of myocardial creatinine kinase isoenzyme. Hemospan was well tolerated in this group of patients at doses up to 1000 mL.

Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.

OBJECTIVE: The present study was undertaken to compare the predictive values of transcutaneous oxygen tension (TcPO2) and toe blood pressure (TBP) measurements for ulcer healing in patients with diabetes and chronic foot ulcers. RESEARCH DESIGN AND METHODS: Investigated prospectively were 50 diabetic patients (37 men) with chronic foot ulcers. The age was 61 +/- 12 (mean +/- SD), and the diabetes duration was 26 +/- 14 years. TBP (mmHg) was measured in dig I and TcPO2 (mmHg) at the dorsum of the foot. Ulcer healing was continuously evaluated by measuring the ulcer area every 4-6 weeks. After a follow-up time of 12 months, the patients were divided into three groups according to clinical outcome: healed with intact skin, improved ulcer healing, or impaired ulcer healing. RESULTS: Of the 13 patients who deteriorated, 11 had TcPO2 < 25 mmHg, while 34 of the 37 patients who improved had TcPO2 > or = 25 mmHg. The sensitivity and specificity for TcPO2 were 85 and 92%, respectively, when a cutoff level of 25 mmHg was used for determination of outcome of ulcer healing (healing or nonhealing). The corresponding values for TBP at 30 mmHg were 15 and 97%. Measurement of TcPO2 provided a higher positive predictive value (79%) than TBP (67%). CONCLUSIONS: The results indicate that TcPO2 is a better predictor for ulcer healing than TBP in diabetic patients with chronic foot ulcers, and that the probability of ulcer healing is low when TcPO2 is < 25 mmHg.

Pronounced skin capillary ischemia in the feet of diabetic patients with bad metabolic control.

Skin capillary circulation is impaired during postocclusive reactive hyperaemia (PRH) in toes of diabetic patients independent of diabetes duration and macrocirculation. The aim of this study was to examine its relation to metabolic control. The skin microcirculation was investigated in 20 patients with insulin-dependent diabetes mellitus: 10 patients with bad [HbA1c > 7.5 (8.7 +/- 0.8) %], and 10 patients with good metabolic control [HbA1c < 7.5 (6.3 +/- 1.0) %]. The diabetes duration was similar in both groups (16 +/- 9 and 16 +/- 6 years, respectively). None had macroangiopathy. Thirteen healthy subjects served as controls. The capillary blood cell velocity (CBV) in the nailfold of the great toe was investigated by videophotometric capillaroscopy, and the total skin microcirculation by laser Doppler fluxmetry (LDF). CBV and LDF were studied during rest and after 1-min arterial occlusion. The vibration perception thresholds (VPT) of the feet were higher (p < 0.05) in the patients with bad (34 +/- 12 V), as compared to patients with good metabolic control (18 +/- 10 V) and to healthy subjects (13 +/- 3 V). Peak CBV during PRH was reduced in both patient groups (p < 0.01), and lowest in the patients with bad metabolic control (p < 0.05). Time to peak CBV was prolonged (p < 0.01) in the patients with bad, while normal in the patients with good metabolic control. LDF was similar in all groups. An inverse correlation was found between HbA1c and peak CBV during PRH (r = 0.60; p = 0.008), while positive correlations were found to time to peak CBV (r = 0.62; p = 0.004) and VPT (r = 0.60; p = 0.01). No associations were seen between VPT and the microcirculatory variables. The results indicate that the metabolic control is of importance for the nutritive capillary circulation and the peripheral nerve function in the diabetic foot.

Microcirculation: its significance in clinical and molecular medicine.

Microcirculation represents the smallest functional unit of the cardiovascular system, where the interaction between blood and tissue creates the environment necessary for cell function. Analysis of physiology and pathophysiology of this system gives a unique perspective to the disease process, and provides the link between clinical and molecular medicine. The present status and future directions of this medical and scientific frontier were assessed and projected by experts in the field at a meeting in Italy in 1995, and the conclusions are presented in this article.

Altered properties of the fibrin gel structure in patients with IDDM.

High plasma fibrinogen levels are associated with vascular complications in the general population. Fibrin, the structural element in a clot, is derived from fibrinogen by activation of thrombin. An abnormal fibrin gel structure has been demonstrated in patients with myocardial infarction and in diabetic patients during poor metabolic control. In the present study the properties of fibrin gel structure were investigated in 20 patients with insulin-dependent diabetes mellitus (IDDM): 10 patients without (age: 30 +/- 8; diabetes duration: 7 +/- 6 years), and 10 patients (age: 44 +/- 7; diabetes duration: 27 +/- 9 years) with microangiopathy. Fifteen healthy subjects served as controls (age: 40 +/- 8 years). The glycosylated haemoglobin level (HbA1c) was elevated (p < 0.001) in the patients: 6.5 +/- 1.5% in diabetic patients without, and 7.1 +/- 1.0% in diabetic patients with microangiopathy. C-reactive protein and plasma fibrinogen were similar as compared to healthy control subjects. The properties of the fibrin gel structure; i.e. the permeability coefficient (Ks) and the fibre mass length ratio (mu) formed in recalcified plasma on addition of thrombin were investigated. Ks was decreased in the diabetic patients, with (6.5 +/- 2.0 cm2; p < 0.01) and without microangiopathy (6.5 +/- 2.7 cm2; p < 0.05), as compared to healthy subjects (10.0 +/- 3.4 cm2), while mu was not significantly (p = 0.14) altered. The results indicate a lower fibrin gel porosity in patients with IDDM, despite normal plasma fibrinogen and irrespective of microangiopathy. The abnormal fibrin gel structure may be due to an increased glycosylation of the fibrin (-ogen) molecule caused by long-term hyperglycaemia and may be of importance for the development of angiopathy in diabetic patients.

Discrepancy in skin capillary circulation between fingers and toes in patients with type 1 diabetes.

The aim of the present study was to investigate skin microcirculation in patients with diabetes to see if any differences in microvascular reactivity could be found between a skin area with low (fingers) or high risk (toes) of complications. Twelve male patients with type 1 diabetes were investigated, the age was 34.7 +/- 8.5 years, and diabetes duration 12.8 +/- 7.7 years (mean +/- SD). Twelve healthy male subjects served as controls. Capillary blood cell velocity (CBV) in the nailfolds of the great toe and left fourth finger was investigated with videophotometric capillaroscopy, and total skin microcirculation with laser Doppler fluxmetry (LDF). CBV and LDF were studied during rest, and following a 1-min arterial occlusion at the proximal phalanx of the digit. Skin temperature was similar in patients and controls. The diabetic patients showed normal CBV and LDF values in skin microcirculation of the fingers, while a reduced (p < 0.01) CBV was found during reactive hyperemia in the toes. The ratio between CBV and LDF was decreased (p < 0.01), indicating a maldistribution of blood between skin capillaries and subpapillary vessels in the toes of diabetic patients. These disturbances may be of importance for the development of foot complications in diabetic patients.

Vital microscopy and the pathophysiology of deep venous insufficiency.

Insufficiency of the deep venous system of the leg may cause severe disturbances of the skin microcirculation. The pressure in the deep venous system increases markedly during walking when the venous valves are destroyed. This pressure increase is transmitted out through the ankle perforators into the superficial veins of the skin, causing a marked pressure increase in the skin microcirculation, interfering with the normal nutritional circulation. In patients with only superficial venous incompetence, the number of capillaries is unchanged, and the configuration mostly normal. When the capillary pressure is markedly increased, blood components are pressed out through the capillary wall and deposited between the wall and the skin cells. By ordinary capillary microscopy this can be seen as light areas around the capillaries. The capillaries themselves become very enlarged and tortuous, and the number is decreased. One of the most striking findings is the appearance of a <> formation around the nutritional skin capillaries. This halo is caused by a specific microedema which can be demonstrated by microscopic techniques. The edema fluid seems to contain high concentrations of fibrin, other proteins and neutral polysaccharides. The development of the halo formation is most probably due not only to incompetence of the venous but also of the lymphatic system of the affected leg. The normal pathway of nutrients from the capillaries out to the skin cells will be blocked by the oedema, and skin ulcers develop. The good effectiveness of compression bandaging in venous leg ulcers can be explained by a marked reduction of the edema, facilitating the transport of nutrients from the capillaries to the skin cells.