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Introduction: Protective ventilation by using limited airway pressures and ventilation may result in moderate and prolonged hypercapnic acidosis, as often observed in critically ill patients. Because allowing moderate and prolonged hypercapnia may be considered protective measure for the lungs, we hypothesized that moderate and prolonged hypercapnic acidosis may protect the diaphragm against ventilator-induced diaphragmatic dysfunction (VIDD). The aim of our study was to evaluate the effects of moderate and prolonged (72 hours of mechanical ventilation) hypercapnic acidosis on in vivo diaphragmatic function., Methods: Two groups of anesthetized piglets were ventilated during a 72-hour period. Piglets were assigned to the Normocapnia group (n = 6), ventilated in normocapnia, or to the Hypercapnia group (n = 6), ventilated with moderate hypercapnic acidosis (PaCO₂ from 55 to 70 mm Hg) during the 72-hour period of the study. Every 12 hours, we measured transdiaphragmatic pressure (Pdi) after bilateral, supramaximal transjugular stimulation of the two phrenic nerves to assess in vivo diaphragmatic contractile force. Pressure/frequency curves were drawn after stimulation from 20 to 120 Hz of the phrenic nerves. The protocol was approved by our institutional animal-care committee., Results: Moderate and prolonged hypercapnic acidosis was well tolerated during the study period. The baseline pressure/frequency curves of the two groups were not significantly different (Pdi at 20 Hz, 32.7 ± 8.7 cm H₂O, versus 34.4 ± 8.4 cm H₂O; and at 120 Hz, 56.8 ± 8.7 cm H₂O versus 60.8 ± 5.7 cm H₂O, for Normocapnia and Hypercapnia groups, respectively). After 72 hours of ventilation, Pdi decreased by 25% of its baseline value in the Normocapnia group, whereas Pdi did not decrease in the Hypercapnia group., Conclusions: Moderate and prolonged hypercapnic acidosis limited the occurrence of VIDD during controlled mechanical ventilation in a healthy piglet model. Consequences of moderate and prolonged hypercapnic acidosis should be better explored with further studies before being tested on patients.

Rationale: Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation (MV). Paradoxically, MV itself results in a rapid loss of diaphragmatic strength in animals. However, very little is known about the time course or mechanistic basis for such a phenomenon in humans., Objectives: To determine in a prospective fashion the time course for development of diaphragmatic weakness during MV; and the relationship between MV duration and diaphragmatic injury or atrophy, and the status of candidate cellular pathways implicated in these phenomena., Methods: Airway occlusion pressure (TwPtr) generated by the diaphragm during phrenic nerve stimulation was measured in short-term (0.5 h; n = 6) and long-term (>5 d; n = 6) MV groups. Diaphragmatic biopsies obtained during thoracic surgery (MV for 2-3 h; n = 10) and from brain-dead organ donors (MV for 24-249 h; n = 15) were analyzed for ultrastructural injury, atrophy, and expression of proteolysis-related proteins (ubiquitin, nuclear factor-κB, and calpains)., Measurements and Main Results: TwPtr decreased progressively during MV, with a mean reduction of 32 ± 6% after 6 days. Longer periods of MV were associated with significantly greater ultrastructural fiber injury (26.2 ± 4.8 vs. 4.7 ± 0.6% area), decreased cross-sectional area of muscle fibers (1,904 ± 220 vs. 3,100 ± 329 μm²), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-κB (+77%), and greater levels of the calcium-activated proteases calpain-1, -2, and -3 (+104%, +432%, and +266%, respectively) in the diaphragm., Conclusions: Diaphragmatic weakness, injury, and atrophy occur rapidly in critically ill patients during MV, and are significantly correlated with the duration of ventilator support.

Background: Contrary to adaptive support ventilation (ASV), prolonged totally controlled mechanical ventilation (CMV) results in the absence of diaphragm activity and causes ventilator-induced diaphragmatic dysfunction. Because maintaining respiratory muscles at rest is likely a major cause of ventilator-induced diaphragmatic dysfunction, ASV may prevent its occurrence in comparison with CMV. The aim of our study was to compare the effects of ASV with those of CMV on both in vivo and in vitro diaphragmatic properties., Methods: Two groups of six anesthetized piglets were ventilated during a 72-h period. Piglets in the CMV group (n = 6) were ventilated without spontaneous ventilation, and piglets in the ASV group (n = 6) were ventilated with spontaneous breaths. Transdiaphragmatic pressure was measured after bilateral, supramaximal transjugular stimulation of the two phrenic nerves. A pressure-frequency curve was drawn after stimulation from 20 to 120 Hz of the phrenic nerves. Diaphragm fiber proportions and mean sectional area were evaluated., Results: After 72 h of ventilation, transdiaphragmatic pressure decreased by 30% of its baseline value in the CMV group, whereas it did not decrease in the ASV group. Although CMV was associated with an atrophy of the diaphragm (evaluated by mean cross-sectional area of both the slow and fast myosin chains), atrophy was not detected in the ASV group., Conclusion: Maintaining diaphragmatic contractile activity by using the ASV mode may protect the diaphragm against the deleterious effect of prolonged CMV, as demonstrated both in vitro and in vivo, in healthy piglets.

Background: The effects of hypercapnic acidosis on the diaphragm and its recovery to normocapnia have been poorly evaluated. The authors studied diaphragmatic contractility facing acute variations of arterial carbon dioxide tension (Paco2) and evaluated the contractile function at 60 min after normocapnia recovery., Methods: Thirteen piglets weighing 15-20 kg were anesthetized, ventilated, and separated into two groups: a control group (n = 5) evaluated in normocapnia (time-control experiments) and a hypercapnia group (n = 8) in which animals were acutely and shortly exposed to five consecutive ranges of Paco2 (40, 50, 70, 90, and 110 mmHg). Then carbon dioxide insufflation was stopped. Diaphragmatic contractility was assessed by measuring transdiaphragmatic pressure variations obtained after bilateral transjugular phrenic nerve pacing at increased frequencies (20-120 Hz). For each level of arterial pressure of carbon dioxide, pressure-frequency curves were obtained in vivo by phrenic nerve pacing., Results: In the hypercapnia group, mean +/- SD transdiaphragmatic pressure significantly decreased from 41 +/- 3 to 29 +/- 3 cm H2O (P < 0.05) between the first (40 mmHg) and fifth (116 mmHg) stages of capnia at the frequency of 100 Hz stimulation. The observed alteration of the contractile force was proportional to the level of Paco2 (r = 0.61, P < 0.01). Normocapnia recuperation allowed a partial recovery of the diaphragmatic contractile force (80% of the baseline value) at 60 min after carbon dioxide insufflation interruption., Conclusion: A short exposure to respiratory acidosis decreased diaphragmatic contractility proportionally to the degree of hypercapnia, and this alteration was only partially reversed at 60 min after exposure.

Objective: Prolonged controlled mechanical ventilation (MV) is known to induce diaphragmatic oxidative stress that seems to be an important factor reducing force-generating capacity. To better understand the cellular mechanisms involved, this work examined the effect of short vs. prolonged MV on antioxidant defense in the diaphragm., Design and Setting: Prospective, randomized, controlled animal study in a university laboratory., Methods: Eleven piglets (15-20 kg) were assigned to one of two groups: a long-MV group (n=6) ventilated for 3 days or a short-MV group (n=5) ventilated for 3 h. Force frequency curves of the transdiaphragmatic pressure (Pdi) were obtained in vivo by phrenic nerve pacing. Oxidative stress was evaluated by thiobarbituric reactive substance (TBARs) content and the enzymatic antioxidant activity of both superoxide dismutase (SOD) and glutathione peroxidase (GPx) in samples of diaphragm., Results: Pdi decreased in the long-MV group by 30-35% over the 3 days at all frequencies compared to the short-MV group. Diaphragm TBARs content was significantly higher and SOD activity lower in long-MV animals than in short-MV animals after 72 h. GPx activity tended to be lower in diaphragms from long-MV animals, but this difference was not significant., Conclusions: This study shows that 3 days of MV in piglets is associated with a decrease in antioxidant activity which could emphasize oxidative stress and both contribute to the diaphragm dysfunction caused by MV.