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

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. Bilateral carotid body resection in three individuals led to reduced sensitivity of central chemoreceptors to CO2, followed by a gradual return, providing evidence of central plasticity within the ventilatory control system. Background.: Several complex mechanisms control human breathing (the rhythmic inspiration and expiration of air into and out of the lungs), the most important of which is the metabolic ventilatory (breathing) control system. Regular breathing ensures that enough oxygen (O2) is absorbed into the blood by the lungs to fuel the body's metabolism (the essential chemical processes of life). It also ensures that sufficient carbon dioxide (CO2), a by-product of metabolism, is removed from the blood to prevent its acidity increasing to a dangerous level. The central control area for breathing is in the medulla of the brainstem, which connects the brain to the spinal cord. Nerve cells in the medulla integrate information coming from the body and then send messages back that set the breathing rate. For example, during exercise, when blood CO2 levels are high (hypercapnia) and blood O2 levels are low (hypoxia), these neurons increase the breathing rate to correct these levels. Blood O2 and CO2 levels are detected by groups of cells called chemoreceptors, which transform this information into electrical messages that pass to the medulla. Central chemoreceptors in the brainstem respond to hypercapnia; peripheral chemoreceptors in the carotid bodies (two small organs in the arteries supplying the head and the neck with oxygenated blood) are sensitive to both hypercapnia and hypoxia. Especially the peripheral chemoreceptors play a crucial role in normalizing blood gas values during exercise. Why Was This Study Done?: The human metabolic ventilatory control system is poorly understood. An improved understanding might help physicians treat respiratory conditions, such as sleep apnea (in which patients briefly and repetitively stop breathing while they are asleep). It might also help them care better for patients whose carotid bodies have been removed because of carotid body tumors. These benign tumors, which can be caused by a rare condition called hereditary paraganglioma, have to be removed because they compress and destroy vessels and nerves in the head and neck. In this study, the researchers investigated the effects on the metabolic ventilatory control system of removal of the carotid bodies in three otherwise healthy patients with hereditary paraganglioma. What Did the Researchers Do and Find?: The researchers measured the patients' breathing responses to hypoxia and hypercapnia before removal of their carotid bodies and at regular intervals after surgery for up to 4 years. In one patient, measurements were also made after removal of one carotid body. They then used a mathematical model of the metabolic ventilatory control system to separate the ventilatory responses to CO2 into a peripheral and a central response. The ventilatory responses of all the patients were normal before surgery. Removal of one carotid body reduced the peripheral ventilatory response to CO2 by 50% but did not affect the response to hypoxia. After removal of both carotid bodies, the peripheral ventilatory response to both hypercapnia and hypoxia was rapidly, completely, and permanently lost. In contrast, the central ventilatory response gradually reduced until, by 3–6 months after surgery, it was at a quarter of its presurgery level. It then gradually returned to its preoperative level. What Do These Findings Mean?: Although based on only three patients, these findings suggest that the peripheral chemoreceptors in the carotid bodies normally influence the output of the central chemoreceptors. Thus, ventilatory responses to CO2 are reduced directly by the removal of the carotid bodies and indirectly by the loss of CO2 sensitivity in the central chemoreceptors. In addition, the eventual recovery of the central sensitivity to CO2 indicates plasticity (adaptation) in the central chemoreceptors, an important result that suggests that the CO2 response mechanisms of the human ventilatory control system are not static. However, the finding that the three patients became permanently insensitive to hypoxia indicates that the ventilatory control system cannot adapt to reinstate sensitivity to low blood O2. Obstructive sleep apnea (which is associated with being overweight) in these patients might, therefore, lead to longer periods of breathing cessation than in patients with intact carotid bodies. Because longer apnea increases the risk of heart injury or stroke, physicians need to react quickly if sleep apnea develops in these patients. Additional Information.: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040239.