Patients with sickle cell disease are at increased risk for vascular diseases such as stroke, pulmonary hypertension, and renal dysfunction. In an effort to develop new technologies to assess vascular dysfunction in patients with sickle cell disease, we compared forearm skin temperature measured by infrared imaging against forearm blood flow measured by conventional strain gauge plethysmography. We found that forearm skin temperature was strongly correlated with forearm blood flow not only at baseline, but also in response to the endothelium-dependent and endothelium-independent vasodilators ACh and SNP. Unexpectedly, we found that warm baseline skin temperature was associated with diminished responsiveness to these vasodilators.
The most striking relationship was observed in response to the infusion of an NO donor, SNP, where warm baseline forearm skin temperature (measured by infrared imaging) and high baseline forearm blood flow (measured by strain gauge plethysmography) were both associated with a diminished vasodilatory response. Resistance to NO-mediated vasodilation has been previously observed in both animal models and humans with sickle cell disease (Kaul et al., 2000
; Eberhardt et al., 2003
; Nath et al., 2000
), but never before has it been related to basal skin temperature. Some of the proposed mechanisms of resistance to NO-mediated vasodilation include increased consumption of NO or decreased activity of soluble guanylate cyclase and other downstream messengers in vascular smooth muscle (Gladwin and Kato, 2005
). In this study, we have identified baseline skin temperature as a new preliminary predictor of NO responsiveness.
Interestingly, the endothelium-independent and endothelium-dependent vasodilators (SNP and ACh) both elicited a similar increase in skin temperature (0.9 ± 0.1° and 1.1 ± 0.2°, respectively) despite SNP stimulating a much smaller cross-sectional forearm blood flow response (8.6 ± 1.0 vs 19.9 ± 2.3 mL/min/100mL). Since infrared imaging is most sensitive to surface blood flow, and strain gauge plethysmography measures total blood flow (surface plus conduit vessels), we can speculate that SNP stimulated skin blood flow to a greater extent than conduit blood flow, relative to ACh. This observation would be consistent with a model of microvascular endothelial dysfunction, where small vessels of the skin respond appropriately to the smooth muscle relaxant SNP, but have impaired responses to the endothelium-dependent vasodilator ACh. An alternative interpretation of these data is that the thermal response to both vasodilators was constrained by a skin temperature ceiling of approximately 33°C, and the additional blood flow elicited by ACh was carried by conduit vessels. Evidence for a skin temperature ceiling (or minimum difference between core and surface temperatures) was recently provided by a study involving strenuous exercise in a warm, humid environment. Skin temperature remained more than 4°C cooler than core body temperature, despite significant elevations of core body temperatures induced by exercise. Skin temperature only exceeded 33°C when core body temperature rose above 37° (Maughan et al., 2011
). However, in our study, there was no direct evidence for a skin thermal response ceiling; we observed significant increases in skin temperature after each increase in vasodilator dose over a four-fold range.
We considered whether high baseline forearm skin temperature was associated with any existing risk factors for vascular complications of sickle cell disease. Baseline skin temperature was positively associated with the tricuspid valve regurgitant velocity (TRV). Elevated TRV is a marker of pulmonary vasculopathy and is associated with increased early mortality in adults with sickle cell disease (Gladwin et al., 2004
; Anthi et al., 2007
; Parent et al., 2011
; Fonseca et al., 2012
). We also found warm baseline skin temperature to be associated with the degree of anemia, another established marker of disease severity in sickle cell patients. One interpretation of these findings is that anemia leads to a compensatory increase in cardiac output, which contributes to both higher TRV(Dham et al., 2009
) and greater perfusion of the skin at baseline.
Increased blood flow in vascular beds other than skin has previously been associated with vascular complications of sickle cell disease. For example, increased blood flow in the large intracranial arteries is predictive of stroke among children with sickle cell disease even in the absence of cerebrovascular stenosis (Adams et al., 1997
). This observation has led to the current standard of care clinical practice of measuring blood flow velocity in the intracranial arteries by transcranial Doppler ultrasonography to identify children at high risk for stroke, and to guide e ective prophylactic therapy (Adams et al., 1998
). Increased renal blood flow has been associated with glomerulomegaly and development of renal insu ciency in patients with sickle cell disease (Etteldorf et al., 1952
; Bernstein and Whitten, 1960
; Hatch et al., 1970
). Outside of sickle cell disease, in patients with congenital heart disease, excessive pulmonary blood flow contributes to the development of pulmonary hypertension (Beghetti and Tissot, 2009
). Our results suggest that the skin may be another vascular bed where pathophysiological increases in baseline blood flow can be observed. This preliminary observation might encourage further investigation into the potential of baseline forearm skin temperature to serve as a simple physiological biomarker of vascular risk in sickle cell patients.
Our study has several limitations. We performed these studies exclusively in subjects with sickle cell disease, in an effort to identify individuals with sickle cell disease who have impaired vascular function and may be at risk for adverse events. We used appropriate within-group analyses such as correlation analysis, analysis of variance, and linear regression that do not require comparison with a control group; however, our observations cannot be extrapolated to healthy individuals. In order to carry out a complicated study procedure accurately and reproducibly, we did not randomize the order of the vasoactive infusions. This could induce bias if one drug had an effect on the next; however these drugs have short half-lives, there was a wash-out period between infusions, and the skin temperatures before the start of each infusion did not differ significantly. Finally, we observed blood flow in the forearm and temperature of the skin, but how this relates to blood flow in other organs such as the brain or kidney was not assessed. With twenty-five subjects, we had a statistical power of 80% to detect a correlation of r = 0.5 or greater at the p < 0.05 threshold. Correlations less than r = 0.50 may not have been detected.
We observed significant correlations between forearm blood flow and skin temperature while vasodilators were administered, but not while the vasoconstrictor L-NMMA was administered. This could be explained by different mechanisms of skin warming and skin cooling. Skin temperature can be changed by increasing or decreasing the inflow of warmer blood: when the inflow of warmer blood is increased, temperature rises immediately; however, when the inflow of warmer blood is decreased, temperature only begins to fall once passive mechanisms such as radiation, evaporation, conduction and air convection remove heat from the skin surface. An extreme example of this is the thermal response to brachial artery occlusion and release; the cooling phase that occurs after brachial artery occlusion is gradual even though arterial blood flow has ceased (McQuilkin et al., 2009
). During the re-warming phase after release of the occlusion, both skin temperature and arterial blood flow increase rapidly. This illustrates the discordance between blood flow and skin temperature after a vasoconstrictor is administered and exposes a limitation of infrared imaging to detect sudden decreases in blood flow.
Despite this limitation, infrared imaging does offer several technical advantages for the assessment of blood flow in clinical studies. It is non-invasive and relies on passive radiation of infrared energy; there is no transmission of energy or radiation to the subject. Standard venous-occlusion plethysmography perturbs the vascular bed under observation by indentation of the skin with a silastic strain gauge and intermittent occlusion of venous blood flow return from the upper limb and arterial blood flow to the hand by pneumatic cuff inflations. In contrast, infrared imaging requires no contact of the detector with the skin, minimizing potential disturbances to the microcirculation under observation. Infrared imaging allows for nearly continuous image acquisition over time, a feature that would support the quantitative analysis of responses to a vasoactive drugs, reactive hyperemia, or cutaneous blood vessel recruitment.
In summary, infrared imaging technology provides a useful, non-invasive alternative to conventional gold-standard methodology of strain gauge venous occlusion plethysmography, as seen in this clinical investigation of blood flow in human sickle cell disease. This methodology has provided preliminary evidence that basal skin temperature might predict vasodilatory response to an NO donor in adults with sickle cell disease. These findings illustrate the potential of infrared imaging to advance our understanding of vascular dysfunction in sickle cell disease.