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.

This is the first study, to our knowledge, demonstrating that mechanical ventilation, with low and high positive end-expiratory pressure (PEEP), increases vascular resistance and reduces total and regional diaphragm perfusion. The rapid reduction in diaphragm perfusion and increased vascular resistance may initiate a cascade of events that predispose the diaphragm to vascular and thus contractile dysfunction with prolonged mechanical ventilation.

During mechanical ventilation (MV), supplemental oxygen (O2) is commonly administered to critically ill patients to combat hypoxemia.Previous studies demonstrate that hyperoxia exacerbates MV-induced diaphragm oxidative stress and contractile dysfunction. Whereas normoxic MV (i.e. 21% O2) diminishes diaphragm perfusion and O2 delivery, the effect of MV with 100% O2 is unknown. We hypothesized that MV with 100% O2 would decrease diaphragmatic blood flow and O2 delivery to a greater extent than MV alone. Female Sprague-Dawley rats (~6 mo) were divided into two groups: 1) MV + 100% O2 followed by MV + 21% O2 (n = 9) or 2) MV + 21% O2 followed by MV + 100% O2 (n = 10). Diaphragmatic blood flow and vascular resistance were determined, via fluorescent microspheres, during spontaneous breathing (SB), MV + 100% O2 and MV + 21% O2. Compared to SB, total diaphragm vascular resistance was increased, and blood flow was decreased with both MV + 100% O2 and MV + 21% O2 (P <0.05). Medial costal diaphragmatic blood flow was lower with MV + 100% O2 (26 ± 6 ml/min/100g) versus MV + 21% O2 (51 ± 15 ml/min/100g; P < 0.05). The addition of 100% O2 during normoxic MV exacerbated the MV-induced reductions in medial costal diaphragm perfusion (23 ± 7 versus 51 ± 15 ml/min/100g; P < 0.05) and O2 delivery (3.4 ± 0.2 versus 6.4 ± 0.3 ml O2/min/100g; P < 0.05). These data demonstrate that supplemental 100% O2 during MV increases diaphragm vascular resistance and diminishes perfusion and O2 delivery to a greater degree than normoxic MV, and may accelerate MV-induced vascular dysfunction.

Introduction Prolonged mechanical ventilation (MV; ≥6 h) results in large, time‐dependent reductions in diaphragmatic blood flow and shear stress. We tested the hypothesis that MV would impair the structural and material properties (ie, increased stress/stretch relation and/or circumferential stretch) of first‐order arterioles (1A) from the medial costal diaphragm. Methods Shear stress was estimated from isolated arterioles and prior blood flow data from the diaphragm during spontaneous breathing (SB) and prolonged MV (6 h MV). Thereafter, female Sprague‐Dawley rats (~5 months) were randomly divided into two groups, SB (n = 6) and 6 h MV (n = 6). Following SB and 6 h MV, 1A medial costal diaphragm arterioles were isolated, cannulated, and subjected to stepwise (0–140 cmH2O) increases in intraluminal pressure in calcium‐free Ringer's solution. Inner diameter and wall thickness were measured at each pressure step and used to calculate wall:lumen ratio, Cauchy‐stress, and circumferential stretch. Results Compared to SB, there was a ~90% reduction in arteriolar shear stress with prolonged MV (9 ± 2 vs 78 ± 20 dynes/cm2; p ≤ .05). In the unloaded condition (0 cmH2O), the arteriolar intraluminal diameter was reduced (37 ± 8 vs 79 ± 13 μm) and wall:lumen ratio was increased (120 ± 18 vs 46 ± 10%) compared to SB (p ≤ .05). There were no differences in the passive diameter responses or the circumferential stress/stretch relationship between groups (p > .05), but at each pressure step, circumferential stretch was increased with 6 h MV vs SB (p ≤ .05). Conclusion During prolonged MV, medial costal diaphragm arteriolar shear stress is severely diminished. Despite no change in the material behavior (stress/stretch), prolonged MV resulted in altered structural and mechanical properties (ie, elevated circumferential stretch) of medial costal diaphragm arterioles. This provides important novel mechanistic insights into the impaired diaphragm blood flow capacity and vascular dysfunction following prolonged MV.

Background: Recent studies have suggested that the arterial stiffness gradient between the aorta and cerebrovasculature, versus aortic stiffness alone, better predicts incidence of cerebrovascular disease, due to increased transmission of pulsatile energy to the cerebral microcirculation. Our aim was to evaluate the association of structural and functional alterations in the carotid artery with the aorta-carotid stiffness gradient versus using aortic stiffness alone. Methods: We evaluated vascular measures in 29 subjects (50±2.4 yrs, range 33–75 yrs, 65.5% women). Carotid pulse wave velocity (an index of stiffness, using the Bramwell-Hill equation), intima-media thickness (cIMT), cIMT-lumen ratio, and strain were calculated from Doppler ultrasound images. Carotid-femoral PWV (cfPWV) was calculated using the distance between the carotid and femoral sites and the timing of the velocity upstrokes relative to the R-wave on simultaneous electrocardiography. The aorta-carotid stiffness gradient (cf/c) was estimated as the ratio of cfPWV to carotid PWV. Blood pressures were taken as the average of two resting measurements prior to testing. The cf/c ratio was log-transformed to account for positive skewness. Results: In univariate analysis, both cfPWV and log(cf/c) were associated with carotid strain (β=-0.76 and β=-15.91 respectively; both p<0.05). The cIMT-lumen ratio was associated with cfPWV (β=0.0049, p=0.019) but not with log(cf/c) (p=0.125). After adjustment for age, sex, BMI and SBP, the association between cfPWV and carotid strain was nonsignificant (p>0.05) while log(cf/c) remained independently associated with carotid strain (β=-12.69, p<0.05). In the adjusted model, both cfPWV and log(cf/c) were independently associated with cIMT-lumen ratio (β=0.0059 and β=0.082 respectively, both p<0.05). Conclusion: After adjustment, cfPWV and cf/c were associated with increases in the cIMT-lumen ratio, an indicator of inward remodeling. However, only cf/c was associated with carotid strain, a measure of vessel distension and an index of vessel stiffness. These results suggest that, compared to aortic stiffness alone, the aorta-carotid stiffness gradient may be a more robust indicator of alterations in carotid structure and function.