Insights Into Ventilator-induced Diaphragm Dysfunction


Vol. 20 • Issue 8 • Page 10

Ventilation today

Mechanical ventilation is a necessary life-saving intervention in critical care medicine, although its implementation carries with it significant collateral consequences.

Convincing evidence in animal models and a growing body of human data suggest that disuse and “rest” of the diaphragm in controlled mechanical ventilation leads to significant decline in contractile muscle properties and atrophy of the diaphragm. If indeed present, this ventilator-induced diaphragm dysfunction (VIDD) may lead to prolonged ventilation and ineffective liberation from mechanical ventilation, producing much greater morbidity than once thought.

First formally described in 2004, the concept of VIDD is in direct opposition to a still widely held belief that patients with respiratory failure on mechanical ventilation need a period of total “diaphragmatic rest” with controlled ventilation.1,2 The objective of this review is to provide the background evidence for VIDD, its pathophysiology, and insights into recent literature regarding possible prevention and treatment strategies.

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Functional decline of the diaphragm

In order to perform its inspiratory duties effectively and efficiently, the diaphragm is reliant on its highly evolved contractile force-generating capabilities. Over the last two decades, many animal and human studies have shown that the institution of controlled mechanical ventilation (CMV) leads to diaphragm weakness and loss of force-generation capacity. Beginning in the mid-1990s, several animal studies emerged examining the effects of CMV on diaphragm function.

In rats, it was shown that after only 48 hours there was a significant force-generation reduction in the diaphragm of animals on CMV vs. controls. Interestingly, this reduction was selective to the diaphragm, as no force reduction was seen in other skeletal muscle groups.3 In healthy baboons on CMV for 11 days, there was a significant decline in both maximum transdiaphragmatic pressure (25 percent) and diaphragmatic endurance (36 percent).4

To dispel criticism over limitations and several design flaws in the above studies, multiple studies in animals followed that have shown consistent dose-dependent decreased diaphragm contractile properties with the use of standard mechanical ventilation paradigms. Pathophysiologic evaluation of these animals uniformly show increased muscle fatigue and atrophy of diaphragm muscle fibers.5-7

In humans, similar evidence of diaphragm weakness in patients placed on CMV has been reported. In an observational study of 10 critically ill, ventilated patients, measurements of transdiaphragmatic pressure were obtained following magnetic phrenic nerve stimulation (TwPdi) over a period ranging from 24 to 120 hours on mechanical ventilation. There was a severe decline in TwPdi with mechanical ventilation (compared to control values). The duration of ventilator use was strongly associated with a logarithmic decline in diaphragmatic force.8

More recently, it was reported that airway occlusion pressures measured after magnetic phrenic nerve stimulation (TwPtr) significantly declined in a time-dependent fashion on CMV, and those on long-term ventilation had approximately half the TwPtr than short-term ventilated patients by day five and six on CMV.2

From these preliminary studies, it appears that the duration of mechanical ventilation has an effect on both effort-dependent and effort-independent force-generating characteristics of the diaphragm. Further study is needed to determine the etiology of this decline in muscle function as it did not appear to be a problem of central nervous system output.

Effects on diaphragm muscle

In accord with the functional decline of the diaphragm seen with CMV, investigators sought to elucidate the structural and biochemical processes leading to the disturbed physiology. It is straightforward to associate the loss of function with induced muscle atrophy, but the loss of muscle fibers alone is likely only part of this functional disruption. This is because the diaphragm muscle has such a large reserve, and it has been suggested that up to 70 percent loss of muscle function is required for there to be meaningful clinical impact on diaphragm force generation.

From a muscle ultrastructure standpoint, the organization and normal alignment of muscle fibers within the diaphragm have been shown to be quickly disrupted while being ventilated in control mode. In two rabbit studies following 48 hours of CMV, there was evidence of myofibril disruption and damage – that in one study accounted for approximately two-thirds of force-generation loss.5,9

As with any atrophic muscle, in general the loss of diaphragm muscle fibers will occur by increased destruction and/or impaired production/healing. These processes can occur via various biochemical mechanisms and have been assessed in studying VIDD. In a seminal paper comparing diaphragm biopsy specimens from brain-dead organ donors vs. elective thoracic surgery patients (longer vs. short-term CMV), it was shown that even short-term CMV (18 to 69 hours) elicited marked atrophy of the diaphragm. Furthermore, there were significant elevations in protein markers of diaphragm muscle breakdown, signs of oxidative stress, and associated genetic (mRNA) transcripts.10

Two subsequent studies looking at diaphragm biopsy specimens from brain-dead organ donors vs. elective surgical controls have confirmed previous work and further defined the metabolic processes at work in diaphragm muscle protein degradation pathways associated with CMV, including the appearance of degraded muscle removal vesicles (autophagosomes).11,12

Prevention and treatment

It remains unclear how best to identify, treat, and prevent VIDD, but the avoidance of ventilator modes that eliminate participation of the diaphragm seems paramount. Several studies have been performed in animals looking at various modes of mechanical ventilation in attempts to mitigate VIDD.

In rats, the use of pressure-support ventilation (PSV) compared to CMV elicited a significant reduction in the amount of diaphragm muscle breakdown and damage.13 Two other studies in rats and rabbits examined both the biochemical and mechanical effects of alternative ventilator modes on VIDD when compared to CMV. Markers of diaphragm muscle breakdown and loss of mechanical force-generation were significantly reduced with intermittent spontaneous breathing and assist-control modes, respectively.14,15

A recent study in piglets compared adaptive support ventilation with CMV. Following a 72-hour ventilation period, piglets ventilated on ASV showed no decrease in contractile force or histologic signs of muscle atrophy, while those on CMV showed a 30 percent drop in transdiaphragmatic pressure and decreased cross-sectional area of both the slow and fast muscle fibers.16 It remains unclear if an ASV mode is superior to other forms of partially supported ventilation (e.g. PSV or CPAP). Yet, it is intriguing to think that by using mechanical ventilation modes that aim to stabilize (and regularize) minute ventilation, but are not controlled settings, we may impact VIDD.

An additional approach in the prevention and treatment of VIDD is targeting the biochemical processes at work leading to muscle breakdown and loss. As discussed above, it is clear that VIDD is defined by an upramping of muscle protein breakdown mechanisms and signs of oxidative stress. In response to this, it was recently shown that a mitochondria-targeted antioxidant given to rats on CMV prevented the increases in reactive oxygen species normally seen in VIDD. Furthermore, these supplemented rats also were protected against functional loss of force-generation capacity.17

Well controlled human clinical studies are needed to better characterize patients most at risk of VIDD, to define contributing comorbidities, and to determine how best to diagnose and implement therapeutic strategies.

Visit www.advanceweb.com/respiratory for a list of references.

Eric Gartman, MD, is a pulmonologist in the department of pulmonary, critical care, and sleep medicine at Alpert Medical School of Brown University, Providence, R.I. Michael Stanchina, MD, is clinical assistant professor of medicine at the same facility.