Nonassociative learning promotes respiratory entrainment to mechanical ventilation

Abstract

Background: Patient-ventilator synchrony is a major concern in critical care and is influenced by phasic lung-volume feedback control of the respiratory rhythm. Routine clinical application of positive end-expiratory pressure (PEEP) introduces a tonic input which, if unopposed, might disrupt respiratory-ventilator entrainment through sustained activation of the vagally-mediated Hering-Breuer reflex. We suggest that this potential adverse effect may be averted by two differentiator forms of nonassociative learning (habituation and desensitization) of the Hering-Breuer reflex via pontomedullary pathways.

Methodology/principal findings: We tested these hypotheses in 17 urethane-anesthetized adult Sprague-Dawley rats under controlled mechanical ventilation. Without PEEP, phrenic discharge was entrained 1:1 to the ventilator rhythm. Application of PEEP momentarily dampened the entrainment to higher ratios but this effect was gradually adapted by nonassociative learning. Bilateral electrolytic lesions of the pneumotaxic center weakened the adaptation to PEEP, whereas sustained stimulation of the pneumotaxic center weakened the entrainment independent of PEEP. In all cases, entrainment was abolished after vagotomy.

Conclusions/significance: Our results demonstrate an important functional role for pneumotaxic desensitization and extra-pontine habituation of the Hering-Breuer reflex elicited by lung inflation: acting as buffers or high-pass filters against tonic vagal volume input, these differentiator forms of nonassociative learning help to restore respiratory-ventilator entrainment in the face of PEEP. Such central sites-specific habituation and desensitization of the Hering-Breuer reflex provide a useful experimental model of nonassociative learning in mammals that is of particular significance in understanding respiratory rhythmogenesis and coupled-oscillator entrainment mechanisms, and in the clinical management of mechanical ventilation in respiratory failure.

Figure 1. Disruption of respiratory-ventilator entrainment by positive end-expiratory pressure (PEEP) and its adaptation via nonassociative learning in a vagi-intact animal (a) before, and (b) after bilateral lesions at the dorsolateral pons.

Phr, phrenic nerve discharge; ∫Phr, integrated phrenic signal; T.P., tracheal pressure (cm H₂O) at 60 cpm; B.P., arterial blood pressure (mm Hg). Insets show expanded views of selected breaths. (c) Photomicrographs showing extent of lesions covering almost the entire Kölliker-Fuse (KF) nucleus at the left side and the ventrolateral part of this nucleus at the right side. scp, superior cerebellar peduncle. Bar: 0.5 mm.

Figure 2. Similar tests as in Fig. 1 (PEEP-1) in five other vagi-intact animals (PEEP-2–PEEP-6) and one vagotomized animal (PEEP-7) before and after bilateral pontine lesions.

Figure 3. Disruption of respiratory-ventilator entrainment by unilateral stimulation at the dorsolateral pons (pontine stim.) in (a) a paralyzed, and (b) an unparalyzed animal both with intact vagi.

Conventions as in Fig. 1. The response in the unparalyzed animal was more variable but the overall effects were similar to those of the paralyzed animal. (c) Absence of respiratory-ventilator entrainment before, during or after pontine stimulation in the same animal shown in (a) after vagotomy.

Figure 4. Mechanisms of respiratory-ventilator entrainment and its buffering by differentiator-type nonassociative learning.

(Possible reciprocal connections for all paths are not shown.) In the absence of PEEP (top panel), phasic volume-related inputs entrain the respiratory rhythm generator (I-E) via the nucleus tractus solitarius (NTS) which also modulates the pneumotaxic center in dorsolateral pons (dl-pons). Immediately upon the application of PEEP (middle panel), tonic activities in the NTS and dl-pons elicit the Hering-Breuer reflex prolongation of expiration and shortening of inspiration, momentarily impairing entrainment. Finally, habituation of the NTS and desensitization of the pneumotaxic center (bottom panel) eventually buffer the effect of PEEP, restoring the respiratory rhythm. Sustained stimulation of dl-pons produces similar Hering-Breuer reflex and desensitization effects as PEEP.