Apnea Following Mechanical Ventilation May Not Be Caused by Neuromechanical Influences

Magdy Younes

Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

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Dempsey and associates (Madison) advocate a response that produces apnea during mechanical ventilation (MV) even when isocapnia is maintained (1). Hence, it is attributed to mechanoreceptors in lungs or chest wall (neuromechanical inhibition, NMI). The clinical implication is that central apnea, observed during MV or upon switching to a spontaneous mode, can be "normal" and need not indicate "sinister" possibilities.

NMI is not new. The classic Hering-Breuer inspiratory terminating, expiratory prolonging reflexes, described 140 yr ago, are examples. What is new about Madison's response is that inhibition evolves gradually (4) and displays substantial memory (apnea outlasting MV by up to 30 s [2]), whereas conventional NMI operates on a breath-by-breath basis and shows little cumulative/memory characteristics. I do not believe this response exists because it does not make sense and can be artifactual.

Why doesn't it make sense? According to Madison, an isocapnic increase in ventilation (E) as little as 2-3 L/min is enough to wipe out resting drive (3). During exercise and chemical stimulation, VE may increase > 100 L/min (40 × threshold for Madison's response). Why don't people become apneic with exercise or CO₂ stimulation? Perhaps respiratory drive under these conditions is greater than NMI with the observed respiratory muscle output being the balance between two opposing influences. Or, perhaps, this response works only when E is artificially increased. We addressed these two possibilities by studying the response to rebreathing with and without proportional assist ventilation (PAV) (5). During rebreathing, the time course of chemical drive is independent of ventilation and breathing pattern; at comparable end-tidal (partial) carbon dioxide pressure (PET_CO2) chemical drive is the same. We saw no difference in respiratory muscle output even though VE was 20 L/min (10× threshold) higher with PAV.

Perhaps this reflex works only when drive is low. However, in the assist mode, resting awake (6) or sleeping (4) subjects get no apnea despite doubling VT, provided isocapnia is maintained during sleep.

This, then, is inhibition that does not work when E increases naturally, or when artificial inflations are synchronized with effort. It works only when inflations are made nonsynchronous. This sort of discrimination cannot reside in the rather simple receptors of the thorax. Specialized brain circuits must exist that, even while we sleep, can tell when we get connected to a ventilator, specifically in the "control" mode. If so, our Creator has anticipated CMV, and provided circuits to inhibit breathing when on it, thereby making the manufacturer look good. Furthermore, these circuits survived eons of evolution despite never being used. Does this make sense?

There are possible artifactual explanations. Evidence supporting Madison's response came from awake and sleeping humans and from dogs.

Intelligent awake humans are not likely to keep making efforts when ventilator pumps are out of synch, particularly if instructed to "relax" and "let the ventilator do the work." When the ventilator is, then, suddenly turned off, subjects may wait a while before giving up on the ventilator. Voila, central apnea!

Dogs are inappropriate for studying this phenomenon. They are very "vagal." Sustained inflations at one or two times eupneic VT produce protracted apneas (7). Even brief inflations during expiration lengthen TE a few seconds (8), indicating a trailing aftereffect with particularly long decay characteristics. If brief inflations are repeated 15-20 times/min, the aftereffect cannot decay completely and would increase with time. After several breaths, there could well be sufficient aftereffect to prolong TE by 10 s, as was observed (8). By contrast, sustained inflations, twice eupneic VT, in sleeping humans do not prolong TE (9, 10); there is no "ON" response. Clearly, aftereffects of brief inflations cannot be expected to produce 20-s apneas when an "ON" response is nonexistent.

What about sleeping humans? First, the response was not consistent in Madison's laboratory. Early reports emphasized absence of apnea with isocapnic MV, even though one study included observations where VT was 140-260% of control (11) and in another study VT was an average of 180% of control (12). Later, Madison found that only a 40% increase in VT is enough (3). Second, in sleeping subjects, reducing (PET_CO2) by only 2-3 mm Hg produces apnea (12) even when NMI is not a factor (13). Thus, inhibitory artifacts that, singly or collectively, are equivalent to 3 mm Hg reduction in PCO₂ can entirely explain Madison's findings. There is no shortage of these. A partial list follows:

1. Madison did not decrease fraction of inspired oxygen (FI_O2) when they increased E. PA_O2 was, necessarily, higher, reducing O₂ drive.

2. Increasing flow through the upper airway (UA), without heating and humidification, evokes an inhibitory response (15).

3. UA is rich in inhibitory mechanoreceptors. They are powerful; stimulation of the superior laryngeal nerve produces apnea that, importantly, outlasts the stimulus by as much as 30 s (16). With noninvasive CMV, the ventilator forces air through vocal cords that are not ready (they widen during spontaneous inspiration). Published airway pressure (Paw) records reveal a pattern that indicates very high resistance; most of the increase in Paw occurs at triggering (e.g., Figure 1 [2]). This is not just nasal resistance; a similar pattern occurs when CMV is delivered via mouth (17, personal observations). Substantial turbulence must exist at the cords. Laryngeal mechanoreceptors may well become stimulated.

Madison increased FI_CO2 to maintain isocapnia. This potentially generates three inhibitory artifacts:

1. Increasing UA PCO₂ evokes an inhibitory response (18).

2. The amplitude of Pa_CO2 oscillations decreases when FI_CO2 increases (19). Pa_CO2 oscillations are believed to contribute to respiratory drive. A particularly relevant study is that by Phillipson and coworkers (20) who found that venous CO₂ unloading in awake sheep decreased _E, down to apnea, whereas Pa_CO2 remained the same. The only credible explanation for these findings is reduction in Pa_CO2 oscillations (20).

3. Madison invariably relied on (PET_CO2) to infer isocapnia. There is evidence that (a-ET)PCO₂ decreases as FI_CO2 increases (21); at the same (PET_CO2), Pa_CO2 may be lower. Madison never assessed (a-ET)PCO₂ during the relevant studies (steady-state isocapnic CMV during sleep).

It must be emphasized that we are not looking for one artifact that can, single-handedly, offset the effect of 3.0 mm Hg of Pa_CO2. A combination of minor contributions is enough to explain the response. Madison may point to persistence of the response when one or another of these artifacts was neutralized. However, there is considerable redundancy of possible artifacts, so that persistence of the response in the absence of one means little.

Madison may consider designing experiments that circumvent most or all artifacts simultaneously. I wager my best 10 papers that such experiments will not show the response. If I lose, the papers would be transferred to Dempsey's C.V. (Dempsey may consider this unfair; he loses either way!). Meanwhile, my advice to intensivists is this: If your patient stops triggering during A/C, or develops apneas upon switching to a spontaneous mode, do not discount this as "normal" NMI. Consider overassist, oversedation, or central nervous system disease.

Acknowledgments: Supported by the Medical research Council of Canada.

	References

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