Tag Archive: microcirculation

  1. Evidence-based Links between Sympathetic Vascular Dysfunction and C-fiber Neuropathy

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    Researchers have long suspected a connection between sympathetic vascular dysfunction and small fiber neuropathy in diabetic patients. This is of special significance regarding the plantar skin of the foot where many diabetic complications arise. Several studies have found reduced vasomotor control to this skin in diabetics with diabetic peripheral neuropathy (DPN). Although the underlying mechanisms behind these observations remain to be elucidated, the connection appears consistent across varying patient populations and test protocols. The most prevalent hypothesis is that lack of proper neurological control results in abnormal vasomotor responses in the microcirculation of the skin.

    In particular, the normal vasoconstriction reflex present in healthy skin seen in response to external stimuli such as cold (1, 2), inspiratory gasp (3, 4) and dependent position (5, 6) has been shown to be muted or absent in patients with neuropathy. It has been suggested that small fiber neuropathy explains these findings; specifically, the C-fiber autonomic nerves responsible for controlling skin microcirculation. Studies investigating the vasomotor effects of the external stimuli noted above revealed an approximately 40% transient drop in skin blood flow consistent with vasoconstriction in healthy patients. This contrasts with observations in DPN patients where a muted or absent vasoconstriction reflex was recorded.

    The results of these studies have led researchers to posit various hypothetical explanations for the pathophysiological processes at work. Most of these point to the deep and complementary interplay of microangiopathic and neuropathic changes that occur in diabetes. Among other conclusions, their findings have direct implications for diabetic wound healing. Others studying microcirculatory dysfunction in diabetes have concluded that these difficult to heal wounds are functionally ischemic due to deficits in skin microcirculation (7). Some have also concluded that measurement of the vasoconstriction reflex could be a valid diagnostic method of quantifying small nerve fiber dysfunction. In particular, Bornmyr et al. (1, 2) have proposed a vasoconstriction index (VAC index*) as a test for small fiber nerve function in response to cold challenge. This approach would have the benefit of being non-invasive, objective and quantitative. Such a measurement would be welcome in clinical practice as small fiber neuropathy is notoriously difficult to quantify at point-of-care.

    *Vasoconstriction Index (healthy skin) = Skin blood flow after cold exposure/Skin blood flow before cold exposure = 0.6 average
    VAC Indices approaching 1.0 indicate impaired vasomotor response to cold exposure.


    1. Bornmyr S, Svensson H, Söderström T, Sundkvist G, Wollmer P. Finger skin blood flow in response to indirect cooling in normal subjects and in patients before and after sympathectomy. Clin Physiol. 1998 Mar;18(2):103-7.
    2. Holmlund F, Freccero C, Bornmyr S, Castenfors J, Johansson AM, Nordquist J, Sundkvist G, Svensson H, Wollmer P. Sympathetic skin vasoconstriction–further evaluation using laser Doppler techniques. Clin Physiol. 2001 May;21(3):287-91.
    3. Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care. 2007 Mar;30(3):655-9.
    4. Aso Y, Inukai T, Takemura Y. Evaluation of skin vasomotor reflexes in response to deep inspiration in diabetic patients by laser Doppler flowmetry. A new approach to the diagnosis of diabetic peripheral autonomic neuropathy. Diabetes Care. 1997 Aug;20(8):1324-8.
    5. Midttun M, Snorgaard O. Heat-washout -an objective method for diagnosing neuropathy and atherosclerosis in diabetic patients.Clin Physiol Funct Imaging. 2013 Jul;33(4):302-6.
    6. Midttun M, Azad BB, Broholm R, Jensen LT, Svarer C, Jensen PE. Heat-washout measurements compared to distal blood pressure and perfusion in orthopaedic patients with foot ulcers. Clin Physiol Funct Imaging. 2017 Jan;37(1):79-83.
    7. Hamdy O, Abou-Elenin K, LoGerfo FW, Horton ES, Veves A. Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy. Diabetes Care. 2001 Feb;24(2):344-9.
  2. The “Heat Washout” Method Identifies Pedal Neuropathy

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    Gjerum and Midttun recently published a study validating the utility of the “Heat Washout Method” as an alternative technique for identifying patients with pedal autonomic neuropathy. The study was performed on 15 elderly patients with established neuropathy enrolled in a Fall clinic. The test involves measuring blood flow to the foot in relation to postural changes. In normal patients, lowering the feet from heart level to 50 cm below the heart, will increase toe blood pressures yet paradoxically reduce blood flow rates to the skin. This is thought to occur due to sympathetic-mediated vasoconstriction and is therefore an indirect measurement of sympathetic vasomotor control in the skin. The following quote from the study further clarifies the technique.

    “The probe was attached on the skin in the first toe interstice of the forefoot avoiding visible veins. The foot was placed at heart level during the first measurement, and 50 cm below heart level at the second measurement, resulting in an increase in the toe blood pressure of approximately 40 mm Hg. A reduction in the blood flow rate of more than 30% with the foot placed below heart level indicated that the veno-arteriolar reflex was present. Lack of the veno-arteriolar reflex indicates that the peripheral sympathetic nervous system may be damaged due to neuropathy.”

    Results indicated a good correlation between traditional bedside neurological tests and this technique. All patients had impaired veno-arteriolar reflex results in one or both legs. Of the bedside tests, the 128Hz tuning fork used by the “on-off method” at the medial malleoli had the best correlation with the Heat Washout technique. It should also be noted that all 15 fall patients had abnormal tuning fork tests highlighting the importance of this test in fall risk prevention protocols.

    Could foot position affect wound healing?

    Possible Implications for Wound Healing

    Another related topic not discussed in the paper concerns foot position and wound healing. Clinicians managing foot wounds often employ conventional treatment recommendations and advise patients to stay off their feet and elevate. The results of this study indicate that lowering the feet in patients with established neuropathy does not invoke sympathetic reflex-mediated vasoconstriction of the superficial skin layers. This finding appears to be supported by results of Iwase et al.  They found that…”skin blood flow significantly decreased in the sitting position from the supine position in control subjects but remained stable in diabetic patients.”  

    Although neuropathy was not directly addressed in their study, it still led them to conclude, “…The present study demonstrated the dissociated regulation of skin oxygenation and blood flow in response to leg dependency. Impaired postural vasoconstriction was associated with altered regulation of skin oxygenation probably due to sympathetic vascular dysfunction in diabetic patients.”

    It may be inferred that foot position could be less important with regard to skin microcirculation than previously thought in neuropathic, diabetic patients.  Indeed, the lack of normal reflex vasoconstriction related to foot position may render previous conventional wisdom on pedal elevation to be without evidenced-based support in this patient population. This finding was corroborated in a study by Park et al where they eventually concluded that, “…foot lowering, rather than elevation, significantly augments TcpO(2) and may stimulate healing of diabetic foot ulcers.”

    Another related complicating factor regarding foot position is pedal edema. Many diabetic patients suffer from this problem and are advised to elevate their feet. Interestingly, this issue has recently been addressed by Wu and Crews et al.  They found that mild compression stockings can be used safely in diabetic patients without reducing blood flow. This finding combined with research on foot position and microcirculation should be taken into consideration when making recommendations to wound care patients. Those patients with intact pedal sympathetic nerves (i.e. no signs of small fiber neuropathy) may improve skin blood flow by keeping their feet at heart level. For those patients with demonstrated small fiber neuropathy, dependent foot position probably does not impede blood flow. It is hoped that future research may allow clinicians to make better evidenced-based recommendations on optimal foot position for diabetic wound healing.