Reduction of aerobic metabolism and increased microvascular perfusion during pressure-adjusted static compression as underlying mechanism with potential of preventing chemotherapy-induced neuropathy

Abstract

Abstract Chemotherapy (CTX)-induced neuropathy [CIPN] limits the maximal applicable dose. Static compression for prevention of CIPN is recommended by guidelines. The postulated underlying effect of reduced microvascular perfusion (MP), however, contradicts current knowledge of elegant in vivo studies. We, thus tested the hypothesis of increased MP combined with reduction of aerobic metabolism in response to pressure-adjusted static compression (PSC) in CTX-induced endothelial damage (CIED). Metabolic oxygen demand (dh), tissue oxygenation (StO2), oxygen supply (O2h) and microvascular perfusion (th) were measured with quantitative time-resolved near infra-red spectroscopy (NIRS) and temperature with thermography on upper extremities following standard procedures in healthy volunteers (n=12, 6 female; age 22±2), peripheral arterial disease patients (n=17, PAD; 75% male, age 68±9 years, 42%, positive controls) and CTX (n=22) with and without clinical CIPN (n=11 each, 46% male; age 64±11 years). Endothelial microvascular function was quantified during post-ischaemic reactive hyperaemia (PIRH). Resting muscle metabolism was quantified by dh during minute 1 of arterial occlusion. Perfusion was quantified by th during venous occlusion. PSC was applied with commercially available compression products and patented palmar pads for up to 90 minutes under standardised and controlled conditions. PSC induces instant and constant fall of temperature (−4.8±0.8°C, p<0.05) and oxygen demand (−3.4±5.2μM, p<0.05). PSC lead to further reduction of tissue metabolism (O2h: −27±38%, dh: −27±38.2%, PIRH-AUC: −20±27%, p<0,05 each compared to without PSC). Oxygen supply increased time-dependently (O2h: 3.0±1.3 μM, p<0.001) as consequence of locally increased perfusion (19±45%, p<0.05) with subsequent rise of tissue oxygenation (StO2: 9.1±4.2, p<0.01) that continued beyond the PSC-duration, indicating a rather metabolic mechanism. This effect is accompanied by a significant similar, albeit lesser reaction on the control hand (p<0.05). PIRH was reduced in controls in response to PSC as a sign for reduced metabolism. In PAD, reaction to PSC was less pronounced and non-significant, reflecting effects of endothelial dysfunction. Patients with CTX with CIPN showed significant endothelial dysfunction compared to controls (StO2 downslope −7±2%, T95 (s) 13±5, PIRH-AUC 9±6, p<0.05 each) and to CTX without CIPN (p<0.05 each), like PAD. For the first time, CIED as result of CTX comparable to atherosclerotic disease is shown. In contrast to previous assumptions of clinicians propagating compression therapy for prevention of CIPN, the results presented prove that not constriction of the products, but rather a combination of increased local perfusion and oxygen delivery in combination with mechanical effects on the low pressure system and reduced metabolism is induced by PSC. These findings open the field for well-designed RCTs to develop novel treatment options for CIPN targeting CIED. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): MEDIACC GmbH