Abstract
In five patients who suffered from chronic venous insufficiency clinical stage C4 (n = 3) and C6 (n = 2) the capillary blood pressure was measured twice by means of invasive direct cannulation of nailfold capillaries of the toe. During one measurement course the patients wore below knee medical compression stockings (40 mmHg) during the other they did not have compression therapy. With the patient in supine position, the CP was investigated by the servo-nulling technique under resting conditions and under dynamic conditions: the calf-muscle/ankle joint venous pump was simulated by means of inflating a blood pressure cuff, which surrounded the mid lower leg, to 60 mmHg for 60 s. Results: The simulated calf-muscle contraction induced a steep increase of CP with 5.65 mmHg/s (Q1 5.27 mmHg/s, Q3 5.92 mmHg/s), which was significantly (p = 0.013) reduced by MCS to 2.47 mmHg/s (Q1 1.65 mmHg/s, Q3 3.0 mmHg/s). Time needed to reach the max. CP was 11.35 s, which was lengthened by MCS to 23.4 s (p = 0.134). Conclusion: Compression therapy prevents capillary hypertension, the major hemodynamic reason for the development of advanced stages of chronic venous insufficiency which are defined by skin disease like hyperpigmentation, lipodermatosclerosis and ulcer.
Keywords
Introduction
Chronic venous insufficiency (CVI) is characterized by abnormal hemodynamics of sub-, intra-, trans- and epifascial leg veins. In clinically advanced stages of CVI valvular insufficiency renders possible venous reflux which causes elevated pressure in the peripheral venous system during walking – ambulatory venous hypertension defined H. Partsch [1]. If venous blood flows backwards from proximal to distal parts of the body without being blocked by venous valves blood pressure and volume waves reach the cutaneous capillaries of the gaiter area of the lower leg and the foot. Particularly with activated calf-muscle/ankle-joint venous pump blood pressure is drastically increased in patients’ nailfold capillaries of the toe [2]. As consequence trophic skin changes like hyperpigmentation, dermatolipofasciosclerosis, atrophy blanche or ulceration are likely to occur [3].
CVI-induced cutaneous microangiopathy like capillary dilatation, rarefaction and microthrombosis recede by medical compression therapy, which prevents venous reflux [4]. From this observation the hypothesis is drawn, that increased capillary blood pressure will be reduced or normalized by effective medical compression therapy.
Methods
In this experimental study the influence of a medical compression stocking on the blood pressure in nailfold capillaries (CP) of the toe was investigated.
Subjects
We examined 5 patients who suffered from Chronic Venous Insufficiency (CVI). Venous hemodynamics of the sub-, intra-, trans- and epifascial veins of the leg were examined in all patients by Duplex-Scanning, venous disturbance was objectified in each patient. Reflux in the long saphenous vein, from the sapheno-femoral junction down to the distal lower limb, defined as stage Hach 4 or Hach 3, was mandatory for the patients included into this study.
Excluded were peripheral arterial occlusive disease (ABI <0.9), diabetes mellitus, use of vasoactive drugs and consumption of nicotine.
The study was approved by the local ethics committee and all subjects gave informed consent.
Experimental protocol
All experiments were performed in a temperature-controlled environment (23,5°C±0,5°C) after a period of 30 minutes of acclimatization with the patient in reclining position. The patients lay in a supine position at an adjustable bed with the leg bent in the knee joint to an angle of 90°. The foot being examined was placed on a special microscope table (Fig. 1). CP was measured in the nailfold capillaries of the toe during “resting” conditions and during “dynamic” conditions which means, that during the CP-measurement the patient’s calf-muscle venous pump was activated. In order to simulate one single action of the calf-muscle pump, a blood pressure cuff (width 15 cm) positioned at the midth of the lower limb was inflated to 60 mmHg within 2 s, in order to squeeze the lower leg veins similar to the contracting calf muscles when the patient is walking. The desired pressure in the cuff of 60 mmHg lasted for 60 s.
The examination situation is shown: The patient was lying in a supine position on an adjustable bed while the leg was bent in the knee-joint at an angle of 90°; the foot being examined was placed on a special microscope table. The capillaries in the nailfold were visualised by video microscopy and cannulated with micropipettes using a micromanipulator.
The described course of examination with measurement of CP under resting conditions and under dynamic conditions was performed twice: during one course the patient wore a below-knee medical compression stocking (MCS, Venotrain® ulcertec, Bauerfeind, Zeulenroda, Germany, interface pressure at ankle height 40 mmHg), during the other experimental course no compression stocking was worn.
An electrocardiogram (Hewlett Packard, 78354C, Böblingen, Germany) and toe skin temperature (Mammendorfer Institut für Physik und Medizin, Temperaturmeßmodul, Hattenhofen, Germany) were recorded simultaneously.
Capillaries were visualized by video microscopy, which made it possible to record the procedure. A video camera (BC-5, AVT-Horn, Aalen, Germany) was attached to an incident light microscope (lens: L25/022 PUT) with a built-in zoom (Leica, Wetzlar, Germany), and lighting was provided by a mercury vapor lamp. The microscopical image was transmitted via the video recorder (U-matic, Sony, Tokyo, Japan) to a black and white monitor (Ikegami Tsushinki, Tokyo, Japan). This system gave an on-screen magnification of between 1 pixel per 1.16μm and 1 pixel per 0.46μm.
The nailfold capillaries were cannulated (Fig. 2) at the top of the capillary loop under a microscope, using micropipettes (borosilicate tube with glass filament 1403531, Hilgenberg, Germany) held in a micromanipulator (Leitz, Type 114140, Wetzlar, Germany). Readings were accepted if the signal was insensitive to an increase in gain, and if capillary blood flow and the shape of the capillary remained unaltered by the procedure [5].
For cannulation, a micromanipulator with fine and coarse vertical, horizontal and axial travel is required. An entry angle of about 50° of the pipette to the plane examination field is optimal. Before cannulation, the tip of the pipette is immersed in a pool of normal saline above the examination field for measuring zero pressure. The tip is then aligned vertically until the blood in the capillary is expelled. The pipette is then advanced toward the capillary and slowly pulled up vertically until blood comes back into the capillary and flow can be observed. Subsequent micromanipulation of the pipette tip is necessary to achieve unimpeded capillary flow.
To record pressure, we used a servo nulling pressure system (Model 5A, IPM, San Diego, CA) [6]. The pressure transducer (P23XL, Statham, CA), amplifier (Mammendorfer Institut, München, Germany), and computer were calibrated against a digital manometer (Digitron Instruments, Hertford, Hertfordshire, U.K.). The signal of the pressure transducer was amplified and low-pass filtered (frequency 20 Hz, Mammendorfer Institut, München, Germany) [7]. Data digitalisation with a digital analog converter (DT 2826, Data-Translation, Marlboro, MA) was followed by computerized data acquisition (DAGP-PC, Gesellschaft für Strukturanalyse, Aachen, Germany). The data were stored on a hard disk for later off-line analysis [8].
Data analysis
Computer based recordings enabled us to use computerized data analysis. The data sampling frequency was 100 Hz for CP and ECG. In addition, the skin temperature of the examined toe and blood pressure were continuously recorded.
Statistical methods
Data are presented as median, 25% and 75% quartile. Statistical analysis was performed using the Wilcoxon sign rank test (open source data analysis software R, RStudio, RStudio Inc, 250 Northern Ave, Boston, MA 02210, USA).
Results
Five patients, four women and one man, who met the inclusion and exclusion criteria were included into the study, mean age amounted to 53.5 year (range 36–72 y). Venous reflux objectified by Duplex scanning concerned the long saphenous vein in all patients down to the lower leg (stage Hach IV n = 4; stage Hach III n = 1), venous reflux was additionally present in the short saphenous vein (n = 1), in the femoral and popliteal vein (n = 2), in tibial veins (n = 1) and in transfascial veins (n = 3). Clinically [9] an ulcer (C6) was present in 2 patients and lipodermatosclerosis (C4) in 3 patients.
The capillary pressure was recorded continuously (Fig. 3) for at least 120 s. Within this time interval the 60 s long lasting dynamic phase of capillary pressure measurement, in which calf muscle contraction was simulated occurred. Under resting conditions, the mean capillary pressure in the nailfold capillaries of the toe was 31.6 mmHg (Q1 25.6 mmHg; Q3 36.02 mmHg). MCS reduced the resting capillary pressure slightly to 25.9 mmHg (Q1 18.6 mmHg; Q3 33.4 mmHg).
Original reading of a CP measurement which was performed in a morphologically normal, hair-pin-shaped nailfold capillary of the first row at patient’s toe. During the CP measurement the calf-muscle venous pump, which means the squeezing of veins by contracting calf muscles, was simulated by inflating a blood pressure cuff at the midth of the lower leg to 60 mmHg for 60 s, shown here in the figure by the horizontal line in between the two X-markers. The simulated calf-muscle contraction induced in this example an increase of CP from 11 mmHg to 81 mmHg.
The CP measurement with the dynamic test, the simulated calf-muscle contraction, did not succeed completely in one experimental course (CP measurement without MCS) of one patient, therefore the following calculations are based on the data of four patients. During the simulated calf muscle contraction test the capillary blood pressure increased fast by 5.65 mmHg/s (Q1 5.27 mmHg/s; Q3 5.92 mmHg/s). By contrast the steep increase of capillary pressure was significantly (p = 0.013) reduced by MCS to 2.47 mmHg/s (Q1 1.65 mmHg/s; Q3 3.0 mmHg/s) (Fig. 4). The time needed to reach the maximum CP of 11.35 s (Q1 7.55 s; Q3 15.27 s) was lengthened by MCS to 23.40 s (Q1 18.03 s; Q3 48.52 s) (p = 0.134). Other measured values like maximum CP and Delta CP during the simulated calf muscle contraction test did not differ from each other substantially (Table 1).
In the nailfold capillaries of the toe the blood pressure increase (mmHg/sec) was measured via glass pipettes and the servo nulling technique during one simulated calf-muscle contraction in patients with chronic venous insufficiency: a blood pressure cuff was fitted round the mid lower leg and inflated to 60 mmHg within 2 s. In CVI-patients 5.65 mmHg/s increase of capillary pressure was measured. When the patients wore a below knee compression stocking (40 mm Hg), the speed of increase was significantly reduced to 2.47 mmHg/s (p = 0.013): the venous reflux due to the “activated “calf-muscle pump into the direction of the foot was efficiently prevented by the compression stocking.
Median, Q1 and Q3 of the CP variables CP under resting conditions, CP increase during simulated calf-muscle contraction, time to maximum CP and the difference (delta) of CP during the simulation of the calf-muscle contraction are given. MCS significantly (p = 0.013) reduced the CP increase during the activated calf-muscle pump
Ambulatory capillary hypertension was shown here in vivo by dynamic capillary pressure measurement using the servo nulling technique in patients with CVI. It contributes to the damage and ultimately the destruction of the nutritive capillaries in the skin which is described as typical cutaneous microangiopathy at the distal part of the lower leg [3]. Compression therapy prevents the pathologically steep pressure increase in the nutritive capillaries of the lower limb during walking which was shown here by the simulation of the active calf-muscle pump in CVI patients during the CP measurement in the nailfold capillaries of the toe. Because increase of blood pressure in the nutritive compartment of skin circulation is significantly lowered by adequate (interface pressure of 40 mmHg) compression therapy as shown here, the capillaries regain their normal diameter and capillary density increases in the inner ankle area [4]. From these data it can be concluded that the healing of venous ulcers achieved by compression therapy [10] is essentially based on the improvement of nutritive blood flow in the skin [11].
Footnotes
Acknowledgments
This study was supported in part by the Deutsche Forschungsgemeinschaft (DFG), grants Ju 178/5-1 and HA 1841/1-1, the Daimler-Chrysler-Fond of the Stifterverband für die Deutsche Wissenschaft and the fortüne program of the University Hospital of Tübingen. We thank Prof. Dr. Friedrich Jung, Institute of Biomaterial Science, Helmholtz Zentrum Geesthacht, Teltow, Germany for valuable hints and Prof. Dr. J.E. Tooke School of Life & Medical Science, and Medical School at UCL London and Prof. Dr. Angela C. Shore, Diabetes and Vascular Research Centre, NIHR Exeter Clinical Research Facility for Experimental Medicine, University of Exeter Medical School, England for their support.