CONTENTS  •  Volume 9  Number 3 1994

In my previous editorial I discussed general aspects of pharmacological treatment for venous disease. In this issue we publish another paper which uses a pharmacological treatment applied topically to the wound to achieve healing. Many topical treatments have been reported over the years, some used with more success than others. Both antibiotics and antiseptics have been applied, hut it has been established that skin sensitisation from the former and toxicity of some of the latter preparations to healing tissue make both inappropriate in the management of venous ulceration, except for specific indications. New types of dressing held the hope of more rapid ulcer healing, including both alginate and hydrocolloid dressings. These fulfil the criterion of maintaining a moist environment that research suggests is beneficial to wound healing and permit dressings to he left in place for longer intervals, facilitating ulcer management. Unfortunately controlled trials have not shown an overwhelming increase in ulcer healing rate following the use of these dressings.

An alternative strategy based on an understanding of wound healing processes is the topical application of growth factors to healing ulcers. Many growth factors are believed to be expressed during the wound healing process and there is the potential that the appropriate administration of one or more of these may facilitate would healing. At present little data is available to suggest which factors would be the most appropriate to use. It seems attractive to apply a growth factor that is deficient for some reason, but it is unclear which these might be. The appropriate frequency of application or mode of administration is also unclear. Should such growth factors be included in the dressing themselves? Do topically applied growth factors reach the healing tissues in sufficient quantity to be effective?

In a paper in this issue Rasmussen et al. report an investigation of the effect of a topically applied human growth hormone analogue to improve healing. Although low doses of this showed some benefit, higher doses seemed to impede healing. Clearly a better understanding of what such treatment may achieve is desirable before full scale clinical studies are undertaken.

To my mind it would seem better to use a drug that addresses the underlying destructive mechanisms of venous ulceration than to use something to resolve the consequences. This may be a naive hope and in practice a full understanding of the healing mechanisms at work in a venous ulcer may permit application of growth factors and other drugs to bring about more rapid healing. The results of recently published studies suggest that we at present understand too little of the detailed mechanisms of wound healing to permit effective use of these treatments.

Design: Double-blind, placebo-controlled study.

Setting: Multicentre study, University Hospitals of Copenhagen, Denmark.

Patients: Eighty-seven patients with chronic venous ulcers.

Interventions: Solutions of growth hormone (Norditropin), 0.17 IU/ml, 1 IU/ml and 11.2 IU/ml, 0.1 ml/cm²/day, or placebo (groups 1-4) was administered daily except weekends for 6 weeks.

Main outcome measures: Healing rates evaluated as weekly ulcer area reduction and complete healing. Local collagen synthesis was evaluated by measurement of the propeptides of collagen types I and III (PICP and PIIINP) in wound washings twice weekly during the first 3 weeks.

Results: No significant difference in ulcer area reduction between the groups was seen, although patients treated with 0.17 IU/ml healed faster than the other groups (p = 0.14). Nine (45%), five (29%), seven (31%) and six (3 1%) ulcers in groups 1-4 respectively were healed at follow-up (p = 0.06-0.1, log rank test). PICP and PIINP increased by 21.4% per week, (14.5-28% per week) and 20.2% per week, (12.2-28.2% per week) respectively compared with placebo, p <0.05. Both PIIINP and PICP at 3 weeks correlated significantly with the healing rates, r = 0.44, p <0.001 and r = 0.34, p <0.005.

Conclusion: The study failed to demonstrate a significant influence on healing, whereas collagen synthesis was stimulated dose-dependently by growth hormone. Procollagen propeptides are sensitive markers of growth hormone action and may be useful markers of healing in clinical investigations in chronic venous ulcers. Lower doses of growth hormone should he considered in future studies.

Keywords: Collagen synthesis; Growth hormone; Venous ulcers; Wound healing

Design: One group of patients with venous hypertension and a group of normal, comparable subjects were treated with intermittent sequential pneumatic compression applied for 30 mm. Skin blood flow was measured by laser Doppler flowmetry at the penmalleolar region at rest (horizontal position) and on standing. The measurements were repeated at 0, 30 and 60 mm after cessation of the compression. As criteria of inclusion, only limbs with high perimalleolar skin flux and decreased venoarteriolar response were included.

Setting: St Mary’s Hospital, London (teaching hospital).

Patients, participants: Sixteen limbs in 16 patients with chronic venous hypertension and 12 limbs of comparable healthy volunteers were studied.

Results: At rest, in the normal controls, the mean (SD) flux was 0.56(0.3) units: it decreased on average by 35% on standing (venoarteriolar response). There was normal vasomotor activity. In patients, the mean flux was 1.45 (0.8) (p<0.025) and the median venoarticular response only 7%. There was very limited vasomotor activity. Vasomotor activity started 10 mm after the commencement of compression. At the end of the compression period there was a marked change towards normality. Resting flux was 0.90 (0.5) (significantly decreased) and the venoarteriolar response had increased to 23% (p<O.O²⁵) with an improvement in vasomotor activity. These changes persisted at 30 and 60 mm.

Conclusions: The findings offer an explanation of the effect of sequential compression on the healing of leg ulcers in chronic venous insufficiency.

Keywords: Intermittent sequential pneumatic compression; Laser Doppler flowmetry; Microcirculation; Venous hypertension

Design: Prospective randomized trial with follow-up to 1 year after surgery.

Patients: Sixty-nine patients presenting for varicose vein surgery.

Interventions: Interview for stocking compliance postoperatively with clinical and Doppler assessment of recurrence at 3, 6, 9 and 12 months postoperatively.

Main outcome measures: Recurrence of varicosities and patient compliance.

Results: 39% of patients allocated stockings were either lost to follow-up or abandoned their use after 3 months; 11% declined the stockings on presentation. By I year postoperatively, only 6%. in the stocking group had recurrent varicose veins compared with 71% in the control group (no stockings).

Conclusion: Despite an early, relatively high noncompliance rate, external compression hosiery significantly reduced postoperative recurrence of varicose veins.

Keywords: Compression stockings; Surgical treatment; Varicose veins; Varicose vein recurrence

Design: Prospective scanning of patients referred for evaluation of possible chronic deep venous insufficiency.

Setting: A non-invasive vascular diagnostic laboratory in Melbourne, Australia.

Patients: A study of 1340 legs in 917 consecutive patients referred with primary or recurrent varicose veins, or for evaluation of possible deep venous disease causing aching or swelling in the legs.

Interventions: Examination of the crural veins by duplex ultrasound scanning.

Main outcome measure: Identification of all three sets of crural veins.

Results: Rates for detecting the posterior tibial, anterior tibial and peroneal veins were 97%, 92% and 91% respectively and all three were observed in 91%. If the last 1227 legs studied by colour-Doppler duplex ultrasound are considered, the rates for detection were 98%, 96% and 96% respectively.

Conclusion: Examination of the crural veins can be a part of routine duplex ultrasound scanning in patients referred with suspected venous disease.

Keywords: Chronic venous insufficiency; Duplex scanning; Ultrasound

Design: Prospective blinded series.

Setting: University teaching hospital.

Patients: Fifty-nine symptomatic legs in 45 consecutive patients presenting with varicose veins.

Interventions: Patients were evaluated by physical examination, quantitative photoplethysmography (QPG) and colour flow duplex examination.

Main outcome measure: Colour flow duplex as the standard of comparison.

Results: Of the limbs studied, 29% had isolated TD. The sensitivity of physical examination for GSV incompetence was 43%, hut specificity was 100%. QPG yielded a similar sensitivity of 24% and specificity of 100%.

Conclusions: Twenty-nine per cent of limbs were optimal candidates for sparing of the GSV with excision of branch varicosities alone. Duplex examination was necessary only when the GSV was clinically normal, and QPG was not helpful.

Keywords: Algorithm; Duplex; Photoplethysmography; Ultrasound; Varicose veins

Design: A prospective study of volunteers with no history or clinical evidence of venous disease.

Setting: The Middlesex Hospital Vascular Laboratory, Mortimer Street, London W1N 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 mm to the right leg while supine, 5 mm after release of tourniquet, and then during a 30 mm 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 un-occluded leg, although plasma lactoferrin rose, this was not significant when corrected for the rise in neutrophil count. After standing for 30 mm, the lactoferrin and neutrophil count increased in all three limbs: corrected lactoferrin showed a significant increase in the legs (p <(1.112), 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.

Keywords: Lactoferrin; Neutrophil activation; Neutrophil degranulation; Venous disease; Venous hypertension