Gun Jörneskog

Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up

BACKGROUND The cause of diabetic foot ulcers is multifactorial, e.g., neuropathy and angiopathy, leading to functional disturbances in the macrocirculation and skin microcirculation. Adequate tissue oxygen tension is an essential factor in infection control and wound healing. Hyperbaric oxygen (HBO) therapy, daily sessions of oxygen breathing at 2.5-bar increased pressure in a hyperbaric chamber, has beneficial actions on wound healing including antimicrobial action, prevention of edema and stimulation of fibroblasts. The aim of the present study was to investigate the long-term effect of HBO in treatment of diabetic foot ulcers. METHODS Thirty-eight diabetic patients (30 males) with chronic foot ulcers were investigated in a prospective study. The mean age was 60+/-13 years and the mean diabetes duration 27+/-14 years. All patients were evaluated with measurements of transcutaneous oxygen tension (tcPO(2)), peripheral blood pressure, and HbA(1c). All patients had a basal tcPO(2) value lower than 40 mmHg, which increased to >/=100 mmHg, or at least three times the basic value, during inhalation of pure oxygen. Seventeen patients underwent 40-60 sessions of HBO therapy, while 21 patients were treated conventionally. The follow-up time was 3 years. RESULTS 76% of the patients treated with HBO (Group A) had healed with intact skin at a follow-up time of 3 years. The corresponding value for patients treated conventionally (Group B) was 48%. Seven patients (33%) in Group B compared to two patients (12%) in Group A went to amputation. Peripheral blood pressure, HbA(1c), diabetes duration, and basal values of tcPO(2) were similar in both groups. CONCLUSIONS Adjunctive HBO therapy can be valuable for treating selected cases of hypoxic diabetic foot ulcers. It seems to accelerate the rate of healing, reduce the need for amputation, and increase the number of wounds that are completely healed on long-term follow-up. Additional studies are needed to further define the role of HBO, as part of a multidisciplinary program, to preserve a functional extremity, and reduce the short- and long-term costs of amputation and disability.

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

Summary 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 (μ) 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 μ 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. [Diabetologia (1996) 39: 1519–1523]

Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications

SummaryWe have recently shown that the skin microcirculation of toes is significantly impaired in patients with diabetes and peripheral vascular disease, and this may be one major reason why these patients are highly susceptible to developing skin ulcers. The aim of the present study was to investigate whether the skin microcirculation is impaired also in diabetic patients free from macroangiopathy. One foot in each of 20 patients with insulin-dependent diabetes was investigated: 10 patients with and 10 patients without late complications. All patients had normal arterial circulation of their lower extremities. Two groups of age- and sex-matched healthy subjects served as controls. The capillary blood cell velocity in the nailfold of the great toe was investigated by computerised videophotometric capillaroscopy, and the total microcirculation within the same area evaluated by laser Doppler fluxmetry. The capillary blood cell velocity and the total skin microcirculation were studied during rest, and during postocclusive reactive hyperaemia. The total microcirculation was similar in patients and control subjects, whereas the capillary circulation was markedly reduced (p<0.01) in the patients. The ratio between the capillary and total microcirculation was significantly decreased (p<0.05–0.01) in the patients as compared to the control subjects, indicating a local maldistribution of blood in the skin microcirculation of the diabetic patients. The results of the present study show that in spite of a normal total skin microcirculation in the toes of insulin-dependent diabetic patients, both with and without late complications, the nutritional capillary circulation is severely impaired. These findings indicate that a chronic ischaemia is present in the skin capillaries of diabetic feet, and is related to the diabetic disease per se and not to late diabetic complications, and may be a cause for these complications.

Skin Capillary Circulation is More Impaired in the Toes of Diabetic Than Non‐diabetic Patients with Peripheral Vascular Disease

The aim of the present study was to investigate if diabetes negatively influences the skin microvascular reactivity in the toes of patients with peripheral vascular disease (PVD). Twenty healthy subjects, 20 diabetic, and 20 non‐diabetic patients with PVD participated. One foot in each subject was investigated. The patient groups were matched for age, sex, and toe pressure. The capillary blood cell velocity in the nailfold of the great toe was investigated by videophotometric capillaroscopy, and the total skin microcirculation within the same area by laser Doppler fluxmetry. Capillary blood cell velocity and laser Doppler flux were studied during rest, and following a 1 min arterial occlusion at the toe base. The skin microvascular reactivity was impaired in both diabetic and non‐diabetic patients. In the diabetic patients the disturbances were mainly seen in the capillaries, and the capillary blood flow was severely reduced during reactive hyperaemia (p<0.01). In contrast, the total skin microcirculation was normal, indicating that sufficient blood reaches the area, but does not come out into the capillaries. The ratio between capillary blood cell velocity and laser Doppler flux, representing the distribution of blood between nutritional and non‐nutritional blood compartments, was reduced in the diabetic patients (p<0.05). These findings may contribute to the higher risk for development of chronic foot ulcers in diabetic patients with PVD.

Atorvastatin reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease

We investigated the effects of statin treatment on platelet-derived microparticles (PMPs) and thrombin generation in atherothrombotic disease. Nineteen patients with peripheral arterial occlusive disease were randomised to eight weeks of treatment with atorvastatin or placebo in a cross-over fashion. Expression of GPIIIa (CD61), P-selectin (CD62P), tissue factor (TF, CD142) and phosphatidylserine (PS; annexin-V or lactadherin binding) was assessed on PMPs. Thrombin generation in vivo was assessed by measurement of prothrombin fragment 1+2 in plasma (F1+2) and ex vivo by using the calibrated automated thrombogram (CAT). During atorvastatin treatment, expression of TF, P-selectin and GPIIIa was significantly reduced vs. placebo (p<0.001 for all). No effect on annexin-V or lactadherin binding was seen. Thrombin generation was significantly reduced during atorvastatin as assessed by both the CAT assay (p<0.001) and by measurements of F1+2 (p<0.01). Subsequent in vitro experiments showed that when TF on microparticles (MPs) was blocked by antibodies, the initiation of thrombin generation was slightly but significantly delayed. Blocking PS on MPs using annexin-V or lactadherin resulted in almost complete inhibition of thrombin generation. In conclusion, atorvastatin reduces thrombin generation and expression of TF, GPIIIa and P-selectin on PMPs in patients with peripheral vascular disease. Microparticle-bound TF slightly enhances initiation of thrombin generation whereas negatively charged surfaces provided by MPs or lipoproteins could reinforce thrombin generation. Statins may inhibit initiation of thrombin generation partly through a microparticle dependent mechanism but the main effect is probably through reduction of lipoprotein levels.

Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia.

INTRODUCTION Diabetes is a prothrombotic state involving a more thrombogenic fibrin network. In the present study we investigated the effects of lipid-lowering therapy with atorvastatin on fibrin network structure and platelet-derived microparticles in patients with type 1 diabetes and dyslipidemia. MATERIALS AND METHODS Twenty patients were treated with atorvastatin (80 mg daily) or placebo during 2 months in a randomized, double-blind, cross-over study. Fibrin network permeability, expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles, plasma endogenous thrombin potential, plasminogen activator inhibitor-1 and tissue plasminogen activator antigen levels were assessed. Additionally, levels of plasma fibrinogen, high-sensitivity C-reactive protein and glycated haemoglobin were measured. RESULTS During treatment with atorvastatin, fibrin network permeability increased (p=0.01), while endogenous thrombin potential and expression of glycoprotein IIIa, P-selectin and tissue factor decreased (p<0.01). In vitro experiments indicated that platelet-derived microparticles influence the fibrin network formation as fibrin network permeability decreased significantly when platelet-derived microparticles were added to normal plasma. Baseline levels of plasminogen activator inhibitor-1 and tissue plasminogen activator antigen as well as plasma fibrinogen and high-sensitivity C-reactive protein were within reference values and not significantly changed during atorvastatin treatment, while glycated haemoglobin increased 0.3% (p<0.001). CONCLUSIONS Novel treatment effects were found in patients with type 1 diabetes and dyslipidemia during atorvastatin therapy, i.e. a more porous fibrin network, to which reduced expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles may contribute. The observed impairment of glycemic control during long-term statin treatment deserves attention.

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

Summary 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. [Diabetologia (1998) 41: 410–415]

Influence of perioperative blood glucose levels on outcome after infrainguinal bypass surgery in patients with diabetes.

High glucose levels are associated with increased morbidity and mortality after coronary surgery and in intensive care. The influence of perioperative hyperglycaemia on the outcome after infrainguinal bypass surgery among diabetic patients is largely unknown. The aim was to determine whether high perioperative glucose levels were associated with increased morbidity after infrainguinal bypass surgery.

Disturbed microvascular reactivity and shunting - a major cause for diabetic complications

In diabetic patients, hypoxia and capillary ischemia have been demonstrated in several organs while local blood flow is normal or even increased. 1–4 A similar situation is present in the skin of patients with venous insufficiency where blood flow is often increased while tissue nutrition is severely impaired. 5 Causes of this clinical paradox are not fully understood, but there is mounting evidence that they are linked to the malfunction of microvascular regulation. 6–8

Endothelin-A receptor blockade increases nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy.

Aims: Endothelin-1 levels are elevated in patients with type 2 diabetes mellitus and may contribute to impaired microvascular function. We investigated the effect of selective endothelin-A (ETA) receptor blockade (BQ123) on skin microcirculation in patients with type 2 diabetes and albuminuria. Methods: Ten type 2 diabetes patients and 8 non-diabetic controls were investigated. Nutritive skin capillary circulation, investigated by videophotometric capillaroscopy, and total skin microcirculation, assessed by laser Doppler fluxmetry (LDF), were studied during intra-arterial infusion of saline for 15 min, followed by BQ123 infusion for 60 min. Results: Following BQ123 infusion there was a significant increase in resting capillary blood cell velocity (CBV) in patients with type 2 diabetes from 0.24 (0.20–0.34) mm/s at baseline to 0.61 (0.46–0.88) mm/s at 60 min, but no significant change in the control subjects [0.55 (0.10–0.68) vs. 0.38 (0.13–0.88) mm/s; p < 0.005 for difference between groups]. Peak CBV following arterial occlusion and skin temperature increased significantly in the type 2 diabetes group but not in the control group during BQ123 infusion. There were no significant changes in LDF parameters during infusion of BQ123 in either group. Conclusion: ETA receptor blockade improves nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy.