ABC | Volume 113, Nº2, August 2019

Case Report Pereira et al. Exertional rhabdomyolysis microvascular reactivity Arq Bras Cardiol. 2019; 113(2):294-298 system (PeriCam PSI system, Perimed, Järfälla, Sweden) in combination with skin iontophoresis of acetylcholine (ACh) for noninvasive and continuous measurement of cutaneous microvascular perfusion changes (in arbitrary perfusion units, APU). 7 During the post-occlusive reactive hyperemia (PORH) test, arterial occlusion was performed with supra-systolic pressure using a sphygmomanometer for 3 min. Following the release of pressure, the maximum flux was measured. Measurements of skin blood flow were divided by the mean arterial pressure to yield the cutaneous vascular conductance (CVC) in APU/mmHg. The capillary density, defined as the number of perfused capillaries per mm 2 of skin area, was assessed by high-resolution intra-vital color microscopy (Moritex, Cambridge, UK). The dorsum of the non-dominant middle phalanx was used for image acquisition. Images were acquired and saved for posterior off-line analysis using a semi‑automatic integrated system (Microvision Instruments, Evry, France). The mean capillary density was calculated as the arithmetic mean of the number of visible (i.e., spontaneously perfused) capillaries in three contiguous microscopic fields of 1 mm 2 each, as described previously. 8 Laboratory testing of the subject is shown in table 1. The plasma levels of the enzyme CK were more than 5 times higher than reference laboratory ranges, and together with the symptoms suggested the diagnosis of ER. The creatinine clearance, calculated using the Cockcroft-Gault formula, was markedly reduced. Treatment consisted primarily of intravenous infusion of saline solution (≥ 2,5 L/day) with bicarbonate for pH normalization and myoglobin washout 9 and to maintain adequate urine output. The plasma cytokine analysis is presented in table 2, showing increased levels of IL-1 β , IL-6, IL-10, IL-1Ra even after hospital discharge. Of note, one day after hospital discharge, systemic endothelium-dependent microvascular reactivity was severely impaired. These results can be observed both in the pharmacological (acetylcholine-induced) and physiological (PORH-induced) microvascular vasodilator responses (Figure 1). Finally, cutaneous endothelium-dependent capillary recruitment was also impaired (Figure 1). After six days of hospitalization and two additional weeks of rest at home, the subject had fully recovered and was able to return to his normal activities. Prognosis of ER is generally good if full recovery occurs. 9 Discussion This case report demonstrates that ER after strenuous physical exercise, performed in adverse environmental conditions and with limited water access, can be paralleled by persistent systemic microvascular dysfunction, detectable up to 1 week after the beginning of symptoms and even after normalization of muscle enzymes and complete resolution of renal dysfunction. In fact, a marked reduction of the endothelium-dependent systemic microvascular reactivity induced by both pharmacological (acetylcholine) and physiological (post-occlusive reactive hyperemia, PORH) stimuli was observed one week after the diagnosis of ER. Moreover, skin capillary function, measured as post-ischemic capillary recruitment, was also significantly impaired, suggesting a loss of vasodilatory reserve and autoregulatory capacity and the existence of severe microvascular endothelial dysfunction. Exercise training of moderate intensity is well-known to induce beneficial effects on the occurrence of cardiovascular diseases through the preservation of vascular endothelial function. 10 On the other hand, strenuous exercise increases oxidativemetabolismand produces a pro-oxidant environment, and consequent endothelial dysfunction, 11 while regular and moderate physical activity promotes an antioxidant state and preserves endothelial function. 10 Thus, high-intensity exercise training in previously untrained individuals, such as that of special military training, could be detrimental to the promotion of vascular health. The microvascular alterations described above were simultaneous with alterations of the profile of plasma cytokines. Nevertheless, it is clearly not possible to establish a link between both phenomena in the present case report, since other metabolic changes could also be involved in the initiation of microvascular dysfunction. It is well known that ER is acutely associated with the production of pro‑inflammatory cytokines. 12 Even though we did not obtain cytokine plasma levels on the day of hospital admission, we observed an increase both in pro-inflammatory (IL-1 β , IL-6) and anti-inflammatory (IL-10, IL-1Ra) cytokines after hospital discharge, compared to values obtained immediately before military training. The plasma levels of muscle-derived IL-6, which is considered to be a key mediator released during exhaustive exercise, 13 usually starts to increase within the first hour of prolonged exercise and continues to rise depending on the duration of the exercise. 13 In fact, it is well established that the elevation of pro-inflammatory cytokines at the time of muscle injury influences the synthesis of acute phase proteins and the expression of anti-inflammatory cytokines, as a physiological response to offset the inflammatory response. 13 Moreover, it has been consistently shown that there is a rise in anti-inflammatory cytokines, IL-1ra and IL‑10, following endurance exercise lasting longer than 2 h. 13 Yet, the plasma levels of TNF- α were not increased one week after ER, suggesting that this cytokine has a different kinetics profile, compared with the aforementioned pro‑inflammatory cytokines. Plasma levels of INF- γ did not show important variations in the present case. Actually, most studies in the literature failed to demonstrate a significant rise in plasma IFN- γ after exercise. 13 Strengths and limitations of our experimental approach should be considered. The use of laser-based skinmicrovascular flowmetry, as well as the evaluation of the levels of plasma cytokines, is not yet possible in clinical practice. One major strength of the present case report is the demonstration of persistent systemic endothelial microvascular dysfunction and systemic inflammatory reaction after clinical and laboratory regression of ER. The long-lasting vascular inflammatory process observed in the present clinical case could have implications in the prognosis of patients presenting with ER. Nevertheless, it was impossible to retest these parameters in longer time intervals in the present case. 295