Time course of diaphragm function recovery after controlled mechanical ventilation in rats

Abstract

Controlled mechanical ventilation (CMV) is known to result in rapid and severe diaphragmatic dysfunction, but the recovery response of the diaphragm to normal function after CMV is unknown. Therefore, we examined the time course of diaphragm function recovery in an animal model of CMV. Healthy rats were submitted to CMV for 24–27 h ( n = 16), or to 24-h CMV followed by either 1 h (CMV + 1 h SB, n = 9), 2 h (CMV + 2 h SB, n = 9), 3 h (CMV + 3 h SB, n = 9), or 4–7 h (CMV + 4–7 h SB, n = 9) of spontaneous breathing (SB). At the end of the experiment, the diaphragm muscle was excised for functional and biochemical analysis. The in vitro diaphragm force was significantly improved in the CMV + 3 h SB and CMV + 4–7 h SB groups compared with CMV (maximal tetanic force: +27%, P < 0.05, and +59%, P < 0.001, respectively). This was associated with an increase in the type IIx/b fiber dimensions ( P < 0.05). Neutrophil influx was increased in the CMV + 4–7 h SB group ( P < 0.05), while macrophage numbers remained unchanged. Markers of protein synthesis (phosphorylated Akt and eukaryotic initiation factor 4E binding protein 1) were significantly increased (±40%, P < 0.001, and ±52%, P < 0.01, respectively) in the CMV + 3 h SB and CMV + 4–7 h SB groups and were positively correlated with diaphragm force ( P < 0.05). Finally, also the maximal specific force generation of skinned single diaphragm fibers was increased in the CMV + 4–7 h SB group compared with CMV (+45%, P < 0.05). In rats, reloading the diaphragm for 3 h after CMV is sufficient to improve diaphragm function, while complete recovery occurs after longer periods of reloading. Enhanced muscle fiber dimensions, increased protein synthesis, and improved intrinsic contractile properties of diaphragm muscle fibers may have contributed to diaphragm function recovery.

Recovery of Diaphragm Function following Mechanical Ventilation in a Rodent Model

“…Consistent with our observation of diaphragmatic recovery during reloading, the degradation products of both proteases decreased during recovery and did not differ from control levels following 12/24 hours of spontaneous breathing. Thomas and colleagues could not find a difference between ventilated animals and reloaded animals after breathing in sedated state for 4–7 hours, which might be due to reduced reloading of the diaphragm [11]. However, the decrease of proteolytic action as shown in our study may allow the re-establishment of cellular homeostasis of protein synthesis and breakdown.…”

“…With this reduction in oxidized proteins, we do observe a significant increase in force production after 24 hours of recovery compared to CMV. Importantly, Thomas and colleagues could not detect a decrease in oxidative damage after 4–7 hours of spontaneous breathing although recovery of function occurs [11]. Both studies suggest that oxidative modification of diaphragm proteins is a major, but not solely the explanation for the contractile deficit after MV.…”

Dysfunction of respiratory muscles in critically ill patients on the intensive care unit

“…Data from animal VIDD models demonstrate a quick and complete recovery within hours if spontaneous breathing is resumed early. However, this needs to be interpreted before the background of limited times of mechanical ventilation (12 to 27 h.) . Moreover, the respective kinetics and time course of VIDD are species dependent, and data may therefore not be easily transferrable between species.…”

Influence of weaning methods on the diaphragm after mechanical ventilation in a rat model

“…Thus, full diaphragm reloading after extubation resulted in a complete reversal towards control levels of both proteases calpain and caspase-3 after 12 h of reloading and this was associated with normalization of diaphragm function [11]. By contrast, Thomas and colleagues did not observe any amelioration of protease activity after 4–7 h of diaphragmatic reloading [9], although animals in their study did most likely have less diaphragm reloading due to sedation and diaphragm fully recovered normal function. This suggests that the calpain system restoration is not only time dependent but also requires a certain amount of reloading to normalize.…”