BORSTEL, GERMANY—Although mechanical ventilation can save lives, it also can worsen or even cause lung injury. This adverse effect has long been attributed to overstretching of the lungs when a high tidal volume (Vt) is delivered. However, a new study provides strong support for the hypothesis that high Vt can produce damage in ways other than by physical force.[1]

“The new concept in mechanical ventilation is that it can activate immunologic forces that damage the lung,” Stefan Uhlig, PhD, one of the study’s authors, told PULMONARY REVIEWS. This effect has become known as biotrauma, he added.

Biotrauma occurs, the study revealed, when ventilation is delivered with a high Vt (Figure 1). The resulting overventilation causes activation of nuclear factor kappaB (NF-kappaB), followed by the release of proinflammatory mediators, particularly chemokines and cytokines. (The term overventilation was coined by the authors to differentiate the problems that arise in the lung as a result of increased volume and pressure from those that are caused by hyperventilation, which may be produced by either increased volume or frequency.)

FIGURE 1 PATHWAY TO BIOTRAUMA

LPS = lipopolysaccharide; NF-kappaB = nuclear factor kappaB Courtesy of Stephen Uhlig, PhD.

In fact, overventilation was just as potent a trigger of proinflammatory mediator release in this study as was bacterial lipopolysaccharide (LPS), which is one of the most powerful immune system stimulators known. Ventilator-induced biotrauma may therefore be as harmful to patients as bacterial infections, the authors suggested.

ENROLLING A SPECIAL KIND OF MOUSE

Dr. Uhlig and colleagues compared the proinflammatory effects of mechanical ventilation and LPS administration in the lungs of mice, some of which were resistant to LPS. These resistant mice were included in the study to help discern the effects of LPS from those of overventilation.

During a 60-minute baseline period, the lungs were perfused and ventilated at a normal Vt. Negative pressure ventilation was used because its low perfusion pressures minimize hydrostatic edema. After the baseline period, the mice were randomly divided into three groups. Two of the groups continued to receive the same level of perfusion and ventilation, but one of them also received 50 µg/mL of LPS. In the third group, Vt was more than tripled.

Perfusate samples were obtained from all lungs every 10 minutes for the next hour and later analyzed for proinflammatory mediators, including macrophage inflammatory protein (MIP)-1a, MIP-2, tumor necrosis factor-a (TNFalpha), and interleukin 6. At the end of the experiments, tissue samples were analyzed for NF-kappaB.

Vt remained stable in the control and LPS groups throughout the study. However, noted the authors, it gradually fell in the overventilated group, possibly because of surfactant depletion, small areas of atelectasis, or mild edema.

IMPLICATIONS FOR FUTURE THERAPY

In the mice that were not resistant to LPS, both LPS administration and overventilation caused NF-kB activation; no such activation was observed in the control group. Similarly, proinflammatory mediator release occurred in both the LPS-challenged and overventilated mice (usually, in comparable amounts and with similar timing), but not in the controls. The only notable difference was in the onset of TNF-a release, which occurred earlier in the LPS group.

Among the LPS-resistant mice, overventilation caused NF-kappaB activation, whereas LPS administration did not. This difference also appeared to be true for mediator release, as indicated by increased perfusate MIP-2 levels in the overventilated group but not in the LPS group.

“The lungs we ventilated remained intact,” said Dr. Uhlig, head of the Division of Pulmonary Pharmacology at the Research Center Borstel in Germany. “So the effects we observed from overventilation did not occur because we destroyed the lungs.”

In both the LPS-challenged and overventilated mice, pretreatment with dexamethasone attenuated NF-kB activation and release of virtually all of the proinflammatory mediators. The only exception was the LPS-induced rise in MIP-2 release, which was unaffected by dexamethasone administration.

This finding suggests that the damage induced by overventilation and LPS administration may arise from separate pathways. Further, it raises the possibility that ventilator-induced biotrauma could be reduced in the clinical setting through corticosteroid administration, although it is far too soon to recommend a specific regimen, Dr. Uhlig remarked.

Other ways of avoiding ventilator-induced biotrauma could also be sought based on this study’s results, wrote Arthur S. Slutsky, MD, in an accompanying editorial.[2] He called the results exciting because they offer the possibility of attenuating ventilator-induced biotrauma without affecting other host defense mechanisms. In contrast, corticosteroids “represent a sledgehammer approach … and block many pathways we don’t want blocked,” stressed Dr. Slutsky, Vice President of Research in the Respiratory Therapy Unit at St. Michael’s Hospital in Toronto, Canada.

—Timothy Begany

References
1. Held HD, Boettcher S, Hamann L, Uhlig S. Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kB and is blocked by steroids. Am J Respir Crit Care Med. 2001;163:711-716.

2. Slutsky AS. Basic science in ventilator-induced lung injury: implications for the bedside. Am J Respir Crit Care Med. 2001;163:599-600.

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