Diaphragm Muscle Weakness in an Experimental Porcine Intensive Care Unit Model

Abstract

In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator-induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit.

Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model

“…1). These results are in sharp contrast to our previous results in limb (biceps femoris) and respiratory (diaphragm) single muscle fibers in the same animals, showing an average 45% decline in specific force (48,50).…”

Ventilator-induced diaphragm dysfunction: cause and effect

“…Numerous animal studies using a variety of species (mice, rats, rabbits, and pigs) have reported that prolonged MV results in significant atrophy of diaphragm muscle fibers (16,49,73,78,100,107). However, because the rat and human diaphragm are anatomically alike and contain a similar fiber type composition (76,81), the rat has become the most commonly used animal model to study MV-induced changes in diaphragm fiber size and function.…”

“…Moreover, prolonged MV also reduces rodent diaphragmatic-specific force production at submaximal stimulation frequencies (e.g., 10 -40 Hz) (56,73,87). Investigations using both rodent (113) and porcine (78) models indicate that MV-induced contractile dysfunction occurs in all muscle fiber types. This ventilator-induced impairment in diaphragmatic contractile function in animals appears to be directly linked to diaphragm contractile inactivity because ventilator modes that provide partial ventilator support or short periods of intermittent spontaneous breathing during prolonged MV can reduce the magnitude of full ventilator support-induced contractile dysfunction (35,44,49,94).…”

“…In this regard, two investigations reveal that use of the neuromuscular-blocking agent rocuronium increases the magnitude of MV-induced diaphragmatic contractile dysfunction in rats (108,109). In contrast, another recent study using a porcine model of MV concluded that treatment of animals with rocuronium does not have an additive effect on MVinduced diaphragm dysfunction (78). It is unclear if these divergent results are due to species differences or result from the low dose of rocuronium used in the porcine experiments.…”

Skeletal Muscle Dysfunction in Critical Illness

“…The forkhead box O (FOXO) family of transcription factors stimulates the expression of two important regulators of UPS-mediated proteolysis of ubiquitin ligase atrogin-1 and muscle-specific RING finger protein-1 (MuRF1) [63][64][65]. In animal models, both MuRF1 and atrogin-1 recruitment, and UPS activation, mainly contribute to the loss of muscle mass, such as inactivation-induced atrophy, acute illness, chronic disease, and CIM [63,66,67]. In human studies, mRNA expression levels of components of the UPS are increased in septic muscle.…”