Research Article: Plasticity of Central Chemoreceptors: Effect of Bilateral Carotid Body Resection on Central CO2 Sensitivity

Date Published: July 24, 2007

Publisher: Public Library of Science

Author(s): Albert Dahan, Diederik Nieuwenhuijs, Luc Teppema, Ronald M Harper

Abstract: BackgroundHuman breathing is regulated by feedback and feed-forward control mechanisms, allowing a strict matching between metabolic needs and the uptake of oxygen in the lungs. The most important control mechanism, the metabolic ventilatory control system, is fine-tuned by two sets of chemoreceptors, the peripheral chemoreceptors in the carotid bodies (located in the bifurcation of the common carotid arteries) and the central CO2 chemoreceptors in the ventral medulla. Animal data indicate that resection of the carotid bodies results, apart from the loss of the peripheral chemoreceptors, in reduced activity of the central CO2 sensors. We assessed the acute and chronic effect of carotid body resection in three humans who underwent bilateral carotid body resection (bCBR) after developing carotid body tumors.Methods and FindingsThe three patients (two men, one woman) were suffering from a hereditary form of carotid body tumors. They were studied prior to surgery and at regular intervals for 2–4 y following bCBR. We obtained inspired minute ventilation (Vi) responses to hypoxia and CO2. The Vi-CO2 responses were separated into a peripheral (fast) response and a central (slow) response with a two-compartment model of the ventilatory control system. Following surgery the ventilatory CO2 sensitivity of the peripheral chemoreceptors and the hypoxic responses were not different from zero or below 10% of preoperative values. The ventilatory CO2 sensitivity of the central chemoreceptors decreased by about 75% after surgery, with peak reduction occurring between 3 and 6 mo postoperatively. This was followed by a slow return to values close to preoperative values within 2 y. During this slow return, the Vi-CO2 response shifted slowly to the right by about 8 mm Hg.ConclusionsThe reduction in central Vi-CO2 sensitivity after the loss of the carotid bodies suggests that the carotid bodies exert a tonic drive or tonic facilitation on the output of the central chemoreceptors that is lost upon their resection. The observed return of the central CO2 sensitivity is clear evidence for central plasticity within the ventilatory control system. Our data, although of limited sample size, indicate that the response mechanisms of the ventilatory control system are not static but depend on afferent input and exhibit a large degree of restoration or plasticity. In addition, the permanent absence of the breathing response to hypoxia after bCBR may aggravate the pathological consequences of sleep-disordered breathing.

Partial Text: Human breathing is regulated by two control systems, behavioral control and metabolic control. They both make use of complex feed-forward and feedback control mechanisms allowing the strict matching between our metabolic and nonmetabolic needs and oxygen uptake in the lungs [1]. For example, behavioral control enables our breathing to adapt to various activities, such as speaking, singing, or eating. The metabolic ventilatory control system drives our breathing at rest and ensures optimal cellular homeostasis with respect to pH, partial pressure of carbon dioxide (Pco2), and partial pressure of oxygen (Po2). Metabolic control consists primarily of some yet-to-be-identified mechanism by which breathing is grossly matched to metabolic rate. It uses two sets of chemoreceptors that provide a fine-tuning function: the central chemoreceptors located in the ventral medulla and the peripheral chemoreceptors in the carotid body, a small (10 mm3, 15 mg) and highly vascularized organ situated in the bifurcation of the common carotid artery. The central chemoreceptors are sensitive to hypercapnia (high blood CO2 levels), and the peripheral chemoreceptors are sensitive to hypercapnia and hypoxia (low blood oxygen levels). Activation of the sensors by their respective stimuli results in brisk ventilatory responses aimed at the restoration of cellular homeostasis [1]. The carotid bodies are strategically situated in the carotid arteries and are sometimes referred to as the “watchdogs” of the brain [2].

In all three patients, control ventilatory responses to carbon dioxide were in the mid-range of “normal” study populations (normal value approximately 1.5 l·min−1·mm Hg−1 [20,22]). The values of the contribution of the peripheral chemoreceptors to total ventilation were at the low end of what is normally observed in healthy volunteers. In our three participants, we observed that the contribution of the peripheral response to the total response to CO2 was on average 22% (range 16%–31%). In healthy volunteers this value ranges from 20% to 40% [20,28]. Similarly, the preoperative values of the ventilatory responses to the 3-min hypoxic pulses were at low end of “normal” with a mean response of 0.3 l·min−1·%−1. In normal volunteers the hypoxic ventilatory response ranges from 0.2–2.0 l·min−1·%−1 [22,30].

To our knowledge for the first time, the effects of bCBR on respiration were followed over time in healthy humans. Loss of the carotid bodies, which contain the peripheral chemoreceptors, results in loss of the ability to respond to hypoxia. Indeed, none of our three patients displayed a significant response to lowered inspired oxygen concentrations after bCBR (Tables 1–3). Apart from their involvement in the ventilatory response to hypoxia, the peripheral chemoreceptors of the carotid bodies play an appreciable role in the ventilatory response to carbon dioxide and as such determine an important part of the level of Pco2 in blood and body tissues. In humans with intact carotid bodies, the peripheral chemoreceptors contribute 20%–40% to the total ventilatory response to CO2 with the central chemoreceptors providing the remaining 60%–80% of ventilatory CO2 drive [1,20,22]. In agreement with the loss of the hypoxic ventilatory response, all of our three patients lost the fast component of the ventilatory response to CO2 and increased their PETco2 (which is a good reflection of arterial Pco2 in persons with normal lung and heart function) by 6–8 mm Hg. This pinpoints the origin of the acute isocapnic hypoxic ventilatory response (AHR) and the fast component in the CO2 response to the carotid bodies. It also adds proof to the validity of the two-compartment model we used in the data analysis.



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