Impaired diaphragm resistance vessel vasodilation with prolonged mechanical ventilation

Abstract

Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an impaired hyperemic response of unknown origin. Female Sprague-Dawley rats (4–8 mo, n = 118) were randomized into two groups; spontaneous breathing (SB) and 6-h (prolonged) MV. After MV or SB, vasodilation (flow-induced, endothelium-dependent and -independent agonists) and constriction (myogenic and α-adrenergic) responses were measured in first-order (1A) diaphragm resistance arterioles in vitro, and endothelial nitric oxide synthase (eNOS) mRNA expression was quantified. Following prolonged MV, there was a significant reduction in diaphragm arteriolar flow-induced (SB, 34.7 ± 3.8% vs. MV, 22.6 ± 2.0%; P ≤ 0.05), endothelium-dependent (via acetylcholine; SB, 64.3 ± 2.1% vs. MV, 36.4 ± 2.3%; P ≤ 0.05) and -independent (via sodium nitroprusside; SB, 65.0 ± 3.1% vs. MV, 46.0 ± 4.6%; P ≤ 0.05) vasodilation. Compared with SB, there was reduced eNOS mRNA expression ( P ≤ 0.05). Prolonged MV diminished phenylephrine-induced vasoconstriction (SB, 37.3 ± 6.7% vs. MV, 19.0 ± 1.9%; P ≤ 0.05) but did not alter myogenic or passive pressure responses. The severe reductions in diaphragmatic blood flow at rest and during contractions, with prolonged MV, are associated with diaphragm vascular dysfunction which occurs through both endothelium-dependent and endothelium-independent mechanisms. NEW & NOTEWORTHY Following prolonged mechanical ventilation, vascular alterations occur through both endothelium-dependent and -independent pathways. This is the first study, to our knowledge, demonstrating that diaphragm arteriolar dysfunction occurs consequent to prolonged mechanical ventilation and likely contributes to the severe reductions in diaphragmatic blood flow and weaning difficulties.

Effects of elevated positive end-expiratory pressure on diaphragmatic blood flow and vascular resistance during mechanical ventilation

“…Importantly, a prolonged enhanced constriction, or compression, could lead to vascular entrenchment ( 22 , 23 ) and accelerate the development of vascular dysfunction. This may explain mechanistically the inability to augment diaphragm blood flow after prolonged MV ( 7 ) and the associated microvascular dysfunction ( 13 ), which may be more pronounced with elevated PEEP. The rapid reductions in diaphragm perfusion, most apparent within the medial costal portion, may result in areas of local tissue hypoxia, supported by previously demonstrated elevations in HIF-1α in the diaphragm with MV ( 4 ).…”

“…However, after prolonged MV (i.e., 6 h), there is an inability of the diaphragm to augment blood flow in response to contractions ( 7 ). Therefore, the reductions in diaphragmatic blood flow and vascular impairments with prolonged MV ( 13 ) cannot be solely attributed to the pressures in the thoracic cavity. The data presented here suggest that the MV-induced reductions in diaphragmatic blood flow are due to increased vascular resistance in the quiescent diaphragm.…”

“…If the diaphragm vasculature is exposed to increased levels of circulating catecholamines in vivo during prolonged MV, it is possible to have increased vascular resistance and α-AR desensitization simultaneously. Interestingly, prolonged MV can result in α-AR desensitization and reduced α 1 -AR mediated vascular control in the diaphragm ( 13 ). During weaning, a reduced α-AR sensitivity will decrease the vasoconstrictive impact of increased circulating catecholamines in vivo.…”

“…The precise mechanism(s) for the time-dependent reductions in diaphragm perfusion with inactivity, which is not present in other highly oxidative muscles ( 7 ), is currently unknown. Importantly, prolonged MV induces diaphragm resistance vessel dysfunction ( 13 ) and elevated levels of hypoxia-inducible factor 1α (HIF-1α) ( 4 ), indicating rapid deficits in vasomotor control and tissue hypoxia, respectively.…”

“…These studies are clinically relevant to understanding the impact of PEEP on diaphragmatic blood flow during MV. Specifically, these studies may provide mechanistic insights into the bases for vasomotor dysfunction with prolonged MV ( 13 ). It is hoped these insights will help provide a foundation for designing targeted therapeutic strategies to augment diaphragmatic blood flow, manage critically ill patients, and facilitate successful weaning.…”