Apnea Following Mechanical Ventilation May Be Caused by Nonchemical Neuromechanical Influences

Jerome A. Dempsey and James B. Skatrud

Department of Preventive Medicine and Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin

	INTRODUCTION

TOP INTRODUCTION MECHANICAL VENTILATION REFERENCES

Our contention is that mechanical ventilation (MV) will markedly inhibit or even eliminate respiratory motor output both during and following periods of MV solely by virtue of the mechanical changes imposed on the lung and chest wall. Two types of mechanical ventilation during which Pa_CO2 is maintained at or above normocapnia (via increased fraction of inspired CO₂ [FI_CO2]) will affect amplitude and/or timing of respiratory motor output. These effects are most likely to be manifested during non-rapid eye movement (NREM) sleep where behavioral influences are obviated and feedback regulatory mechanisms are dominant.

	MECHANICAL VENTILATION

TOP INTRODUCTION MECHANICAL VENTILATION REFERENCES

Reduced Amplitude Effects

If tidal volume (VT) is increased using assist control or pressure support mechanical ventilation in normocapnia without a mandatory ventilator frequency (1) or controlled mechanical ventilation (CMV) at eupneic frequency (6), then the amplitude of respiratory motor outputas measured by transdiaphragm electromyogram (EMGdi), rate of change of mouth pressure or transdiaphragm pressureis reduced by 20% to 60%. The reduction in amplitude of respiratory motor output is time dependent over the first several ventilator cycles (5). Expiratory time is not significantly affected by the increased VT unless the increased volume is maintained into the early portion of neural expiration (5, 9, 10). Upon termination of MV, VT and EMGdi amplitude in the initial few spontaneous breaths are reduced and gradually rise back to control eupneic levels (5).

Timing EffectsSingle Breaths

If single normocapnic ventilator breaths are introduced during the initial half of expiration, then expiratory time (TE) is prolonged and this prolongation is enhanced with increasing VT (11, 12). These single breaths have no aftereffect on the timing or amplitude of subsequent spontaneous breaths.

Resetting to Cause Sustained Passive Mechanical Ventilation, Then Apnea, and Then Hypopnea

Now, if normocapnic CMV is continued at a rate 1 to 3 breaths per minute (bpm) greater than the normal spontaneous frequency and at a raised VT, phasic inspiratory motor output is silenced within five ventilator cycles and remains off for the duration of the CMV (4, 12). An apnea ensues at the cessation of mechanical ventilation, followed by resumption of spontaneous respiratory efforts whose amplitude is markedly reduced. Expiratory muscle EMG activity occurs throughout the period of silent EMGdi; it is briefly interrupted with each ventilator cycle and is tonic during the postventilator apneic period (12, 15).

Several factors influence the duration of apnea following the cessation of normocapnic CMV:

• Once the high ventilator frequency has silenced inspiratory motor output, the greater the ventilator VT, the longer the postventilator apnea (4, 12).
• The length of the postventilator apnea varies positively with the duration of the passive CMV, at least up to about 1 min of CMV (12). Similarly, TE prolonging aftereffects of repeated electrical stimulation of vagal or superior laryngeal nerves vary in proportion to the duration of the phasic sensory input (16).
• If Pa_CO2 is raised up to 5 mm Hg greater than normocapnia, the EMGdi is still eliminated during CMV at raised frequency (12). Significant, but shorter, postventilator apneas still occur in the presence of this hypercapnia but only when the ventilator VT is raised much more than eupnea. In turn, postapnea hypopnea also occurs. Of course, if Pa_CO2 is allowed to fall during CMV, postventilator apneas are prolonged.

Why Does Resetting Occur?

For a constant ventilator frequency to cause sustained passive ventilation, each ventilator breath must be delivered during the "inflation sensitive" phase of neural expiration (see TIMING EFFECTSSINGLE BREATHS, above). If it is not, then suppression of inspiratory motor output would not be sustained (13). It seems unlikely that each ventilator cycle would be delivered as precisely as required throughout a CMV trial unless the inflation-sensitive phase is prolonged. This prolongation could be realized by a cumulative carryover of an inhibitory influence, which in effect widens the inflation-sensitive phase as CMV continues beyond the initial cycle of mechanical ventilation. The evidence for the cumulative effect is found in the postventilator apneas whose duration was dependent upon the total number of ventilator cycles and the amplitude of their VT (4, 12).

Mechanisms?

It is clear that the decision to reduce or to eliminate the inspiratory motor output during MV is activated when ventilatory supply exceeds demand. Without question, carotid and especially medullary chemoreceptors are the principal sources of feedback when Pa_CO2 is allowed to fall (5); but when PCO₂ is controlled, the means of informing the respiratory controller of the adequacy of ventilation must require neurally mediated sensory information (concerning pressure, volume and/or muscle tension) from one or more sites of mechanoreception (4, 11, 13, 19). In making the case against chemical mediators, we emphasize that arterial as well as end-tidal PCO₂ is maintained greater or equal to normocapnia in the MV trials and that carotid chemoreceptor denervation does not prevent inhibition of respiratory motor output during normocapnic MV; furthermore, systemic blood pressure is not changed via normocapnic MV (5, 12).

The mechanisms involved in the continued inhibitory aftereffects on respiratory motor output following assist-control normocapnic or hypercapnic MV or passive CMV are unknown. Recordings from the nucleus of the solitary tract show that potentiation of the synaptic input to these cells will enhance inhibitory outflow and reduce their response to subsequent afferent chemoreceptor inputs (20). Thus, these postventilator apneas probably reflect the imbalance between a dominant continued short-term suppression of inspiratory motor output and a rising chemoreceptor input, as asphyxia intensifies during the postventilator apneic period. The resumption of normal rhythm following the apneas must represent the eventual dominance of the excitatory chemoreceptor input over the continued "inertia" of central respiratory motor neurons; but even at these high levels of Pa_CO2 (and reduced PO₂) the central inhibitory effect is still present, as evidenced by the reduced amplitude and gradual recovery of successive spontaneous breaths.

In summary, we believe the conclusion is inescapable that nonchemical mechanisms are responsible for inhibition and/or elimination of respiratory motor output during and following mechanical ventilation. Certainly, hypocapnia is important when it is presentbut it is not required!

Acknowledgments: The authors are grateful to colleagues who were essential to the conduct of these studies, including P. Eastwood, H. Havèrkamp, K. Henke, A. Leevers, S. Manchanda, H. Nakayama, T. Rice, M. Satoh, P. Simon, C. Smith, E. Vidruk, and C. Wilson.

Supported by NHLBI and the VA Merit Review.

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