D. J. Newton

Skin blood flow changes in response to intradermal injection of bupivacaine and levobupivacaine, assessed by laser Doppler imaging.

Background and Objectives The vascular effects of local anesthetics are important determinants of their therapeutic activity. Drugs that vasoconstrict have the potential clinical advantages of limited systemic uptake and prolonged duration of effect. The aim of this study was to assess quantitatively the cutaneous vasoactivity of racemic bupivacaine and one of its enantiomers, levobupivacaine. Methods Four concentrations of each drug (0.1 mL each of 0.125%, 0.25%, 0.5%, and 0.75%), as well as normal saline, were injected intradermally into randomly assigned sites on the forearms of 10 volunteers. We measured skin blood perfusion using laser Doppler imaging before injection and at 2.5, 10, 20, 40, 60, and 90 minutes thereafter. Results Both drugs produced a rapid, dose-dependent increase in skin perfusion (P < .001). Saline also caused an increase in perfusion, although less sustained. By 40 minutes, most responses had returned to baseline levels. However, after this time, perfusion continued to decrease, below baseline, for both bupivacaine and levobupivacaine. The exception to this was 0.75% bupivacaine, the response to which was significantly higher than the same concentration of levobupivacaine over this later period (P < .05). Conclusions Bupivacaine and levobupivacaine both have a biphasic effect on skin microvessels. The vasoconstriction observed after 40 minutes may occur when the quantity of drug remaining at the administration site has decreased to a lower level. The continued vasodilatation caused by bupivacaine is more difficult to interpret. The results suggest that these local anesthetics cause vasodilatation at high doses and vasoconstriction at lower, subclinical doses. This hypothesis and the clinical relevance of these effects warrant further investigation.

Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy

The study investigated whether the effects of dermal replacement therapy on wound healing are associated with an increase in blood flow at the base of diabetic foot ulcers treated with Dermagraft. Seven full-thickness ulcers were assessed in five patients with type 2 diabetes mellitus and peripheral neuropathy. All lesions had been present for at least 3 months with no recent change in size, despite routine foot care and protective dressings. Dermal replacement therapy was applied weekly to the base of each wound for 8 weeks, after which regular dressing was resumed. Microvascular blood flow was assessed using laser Doppler imaging immediately before and after 2, 5, and 8 weeks of treatment. Blood flow increased by an average of 72% in the base of five out of the seven ulcers studied. Five of the lesions healed by 12 weeks and the other two reduced in size by approximately 25%. The changes in blood flow observed in this pilot study might reflect angiogenesis in the newly formed granulation tissue and/or vasodilatation of existing vessels, processes that are possibly enhanced by the intervention.

Mechanisms influencing the vasoactive effects of lidocaine in human skin

The vasodilator properties of lidocaine are believed to be due mainly to the inhibition of action potentials via sodium channel blocking in vasoconstrictor sympathetic nerves. However, mechanisms involving the vascular endothelium may also play a role, and in this study we investigated the potential influences of nitric oxide release, the cyclo‐oxygenase pathway and the β‐adrenoceptors of vascular smooth muscle. Laser Doppler imaging was used to measure microvascular blood flow responses to intradermal injection of lidocaine 2%, with or without the addition of preservatives, in eight healthy, male volunteers. Co‐injection of the nitric‐oxide–synthase inhibitor Nω‐nitro‐l‐arginine methyl ester caused a 60% reduction in the response after about 20 min, and this reduction was enhanced with the lidocaine solution containing the preservatives methylhydroxybenzoate and propylhydroxybenzoate. No reduction in response was seen after blocking the cyclo‐oxygenase or β‐adrenoceptor pathways. Nitric oxide release contributes to the vasoactivity of lidocaine in human skin.

Amputation level assessment using lightguide spectrophotometry

The aim of this experimental study was to investigate whether lightguide spectrophotometry in the visible wavelength range in skin could be used to predict stump healing viability in patients with critical lower limb ischaemia. Remission spectra recorded at two sites (medial and lateral) on the line of a proposed trans-tibial amputation (TTA) and at 10mm intervals along the leg were analysed to give haemoglobin oxygenation (SO2). Degree of tissue hypoxia (DTH) along the leg was defined as the percentage of values along the leg less than 10% SO2. DTH and mean SO2 values were compared with skin blood flow values ((I125) 4-Iodoantipyrine clearance technique) and clinical outcome of trans-tibial amputation, (TTA) or trans-femoral amputation (TFA), in 41 patients. SO2 histograms were also measured in 12 normal subjects for comparison. The results of the study allowed the establishment of criteria for the accurate prediction of flap healing potential. Successful TTAs all displayed a minimum mean SO2 at the medial and lateral measurement sites of 30%, together with a maximum degree of tissue hypoxia of 15% along the limb. The combination of these criteria gave a sensitivity and selectivity of 1.0 for prediction of a successful outcome of TTA.

Laser Doppler Imaging in the Investigation of Lower Limb Wounds

Good blood supply is a primary determinant for the healing of acute and chronic wounds alike. Chronic wounds commonly occur in the lower extremity in man. Scientists are forever looking for objective techniques with which tissue perfusion may be measured with accuracy. Laser Doppler imaging is a very useful technique for measuring microvascular perfusion in wounds because it involves no contact and produces a color image representing flow distribution over an area of tissue. In this article, the authors discuss its application to the assessment of lower limb wounds, and they review published studies in which it has been used to investigate a range of wound types. This review examines the study of healing mechanisms, treatment effects, risk prediction, healing potential, and underlying pathology. It also considers areas in which laser Doppler imaging is still to be exploited fully.

The effect of adjuvant epinephrine concentration on the vasoactivity of the local anesthetics bupivacaine and levobupivacaine in human skin.

Background and Objectives The recommended optimal concentration of adjuvant epinephrine for use with local infiltration anesthesia is usually 5 μg/mL. However, a lower dose might be as effective at prolonging the anesthetic effects, while limiting the risk of hazards associated with unintentional intravascular injection. The aim of our study was to determine the lowest effective vasoconstrictor concentration of epinephrine in human skin for a range of doses of bupivacaine and its less-vasodilatory S(−) isomer, levobupivacaine. Methods We injected combinations of 0.125%, 0.25%, and 0.75% bupivacaine and levobupivacaine with 1.25, 2.5, and 5 μg/mL epinephrine into the forearm skin of 10 healthy volunteers and measured the resulting blood flow changes over 1 hour using laser Doppler imaging. Results All 3 concentrations of epinephrine produced marked vasoconstriction, both alone and in combination with all 3 doses of the anesthetics (P < .001 in all cases). There was almost no difference in effect between the 3 epinephrine concentrations. Conclusions We conclude that 1.25 μg/mL epinephrine produces a comparable vasoconstrictor effect in human skin to that of higher concentrations when coinjected with clinical doses of bupivacaine and levobupivacaine and may be equally effective for infiltration anesthesia.

Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure

In the present study, we have investigated whether the peripheral cholinergic abnormalities that we have reported previously [Spence, Khan and Belch (2000) Am. J. Med. 108, 736-739] in patients with chronic fatigue syndrome (CFS) are also present in those with Gulf War syndrome (GWS) and agricultural workers exposed to organophosphate pesticides, where cholinesterase inhibition is specifically implicated. We also looked at whether these abnormalities might be due to a reduction in the activity of cholinesterase expressed on the vascular endothelium. We used laser Doppler imaging to measure the forearm skin blood flow responses to iontophoresis of acetylcholine and of methacholine (which is resistant to breakdown by cholinesterase) in patients with CFS, GWS and those with a history of ill health after definite organophosphate exposure, as well as in matched healthy controls. The response to acetylcholine was significantly higher in patients with CFS than in controls ( P =0.029, repeated-measures ANOVA), but was normal in those with GWS and those exposed to organophosphates. The methacholine response was higher than the acetylcholine response in all patient groups except for those with CFS, where there was no difference between the responses. Although there are many clinical similarities between these three illnesses, our results indicate peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase.

The beneficial effects of breastfeeding on microvascular function in 11- to 14-year-old children:

Abstract Infant feeding practices have an impact on health in later life, although the evidence for its effects on cardiovascular health is not so clear. The aim of this study was to investigate the relationship between breastfeeding in infancy and vascular function in later childhood. Infant feeding data, together with demographic and clinical information, were obtained prospectively from a cohort of children from birth until 2 years of age. Vascular function was assessed in 159 children, now aged 11–14 years, by measuring their skin microvascular responses to iontophoretic administration of the endothelium-dependent vasodilator acetylcholine. Endothelial function was significantly better in children who had been breastfed than in those who had received infant milk formula (p = 0.001), after adjustment for potential confounding factors. Linear regression showed that acetylcholine responses were significantly related to the duration of breastfeeding (r = 0.30, p = 0.006). The risk of later cardiovascular disease may be reduced by exclusively breastfeeding during infancy. These findings have potential public health implications, and support policies aimed at promoting breastfeeding.

The inhibitory effects of local anaesthetics on the vascular flare responses to bradykinin and substance P in human skin

Bradykinin and substance P are involved in inflammation and act through Gq‐protein‐coupled receptors. Local anaesthetics inhibit the signalling of these receptors and have potent anti‐inflammatory actions. The aim of this study was to investigate the effects of local anaesthetics on the cutaneous flare responses to bradykinin and substance P. Skin blood flow responses to intradermal injections of bradykinin and substance P were assessed in the absence and presence of anaesthetic and analgesic concentrations of lidocaine, levobupivacaine and ropivacaine. All local anaesthetics significantly attenuated the vascular responses to bradykinin (p = 0.001) and substance P (p < 0.001). There were no differences in this effect between the different agents, but anaesthetic concentrations had a greater attenuating effect than analgesic concentrations on the substance P response (p < 0.001). Local anaesthetics may therefore be useful in the suppression of inflammation and the prevention of postoperative hyperalgesia.

Chemical synthesis and microvascular effects of new nitric oxide donors in humans

Nitric oxide (NO) is produced continuously from the endothelium and plays a pivotal role in the control of vascular tone. Many of the current therapeutic agents that increase blood flow through production of NO have to be taken orally and can produce significant adverse side effects. We now report on some novel NO-donor drugs, based on thiosugars that generate NO spontaneously. From the range of compounds synthesized, D-SNAG ( S -nitroso-1-thio-2,3,4,6-tetra- O -acetyl-beta-D-glucopyranose) was as effective a vasodilator as any other and, as it was the easiest to synthesize, we undertook a more detailed evaluation to understand the chemistry and mode of action of its vasodilator effect. From the chemical kinetic data, we found that NO release occurred predominantly by thermal decomposition, with a 20-fold increase in decomposition rate between 19 and 37 degrees C. In the forearm of eight normal male subjects, we found that D-SNAG produced a significant dose-dependent vasodilator effect ( P =0.001) with good reproducibility (19%) on repeated testing. We propose that delivery of NO from D-SNAG to the forearm skin microvessels most probably occurs by diffusion across the epidermis. Since such compounds release NO in a non-enzymic manner following topical application, they might produce an attractive therapeutic source of localized NO delivery without inducing systemic side effects.