Plasticity of central chemoreceptors: effect of bilateral carotid body resection on central CO2 sensitivity

Abstract

Background: Human 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 findings: The 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.

Conclusions: The 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. The Multifrequency Binary Sequence in PET co 2

In this study we applied two of the shown (approximately 23.5 min) sequences in succession.

Figure 2. An Example of the Steady-State Ventilatory Response to an Increase in PET co2 from 44 to 50 mm Hg

The response is linear (continuous red line) over the given trajectory; the extrapolated PET co2 (red circles) at which ventilation is zero is given (in this example it is 41.3 mm Hg, open symbol). Resting ventilation and resting PET co2 are also shown (blue circle).

Figure 3. Separation of the Dynamic Ventilatory Response to PET co2

PET co2 is depicted in blue. Shown is separation of measured ventilation (dark yellow) into a fast component with a short delay (ΔTP) originating at the peripheral chemoreceptors (red, time constant of response 3 s), and a slow component with a long delay (ΔTC) originating at the central chemoreceptors (green, time constant of response 120 s).

Figure 4. Resting PET co2 Values Observed on Days 1–5 after Bilateral Resection of the Carotid Bodies and Subsequent Days of Testing in Patient 1

The lower PET co2 values on postoperative day 1 may reflect anesthesia- or analgesia-induced lowering of metabolism. The subsequent rise in resting PET co2 is related to the loss of the peripheral chemoreceptors and the effect of this loss on the central chemoreceptors.

Figure 5. The Dynamic Ventilatory Response to CO2 in Patient 2

Response was monitored before resection of the carotid bodies (A), 6 mo after bilateral carotid body resection (B), and 1 y after bCBR (C). The applied multifrequency binary sequence is shown on the top of each graph (green; units mm Hg; the dashed lines represent resting PET co2 values). The breath-to-breath ventilation is depicted by the grey dots. The ventilatory response is separated into a slow component originating at the central chemoreceptors (red) and a fast component originating at the peripheral chemoreceptors (blue). The sum of these two components plus a trend term (not shown) and the (parallel) noise corrupting the data, is the yellow line through the measured data points. The analysis shows that 6 mo after resection of the two carotid bodies the peripheral component was not present and the central component initially reduced to about 40% of preoperative values. Six months later, the central component had increased to about 70% of preoperative values. Parameter values are given in Table 2.

Figure 6. Central and Peripheral Chemoreceptor Activity in Response to Stimulation with CO2 in the Three Patients during the Whole Testing Period

In all three patients bCBR caused the loss of the peripheral component or reduction to a value of less than 10% of preoperative values combined with an initial sharp reduction in the magnitude of the central component to about 30% of preoperative values, which was followed by a slow increase to values 85%–95% of the preoperative values. In patient 3 we also obtained data after unilateral carotid body resection.