Factors Influencing the Control of Breathing

Albert Dahan MD PhD

Department of Anesthesiology

Leiden University Medical Center

2300 RC Leiden, The Netherlands

In order to maintain cellular carbon dioxide (CO₂), oxygen (O₂) and H⁺-homeostasis, the human body makes use of two ventilatory control systems: the chemical control of breathing and the behavioral control of breathing. Chemical control of breathing indicates that ventilation is critically dependent on arterial and brain tissue PO₂, PCO₂ and pH and involves two sets of chemoreceptors: the peripheral chemoreceptors located in the carotid bodies at the bifurcation of the carotid artery, and the central chemoreceptors located in the ventral medulla. The peripheral chemoreceptors cause an increase in afferent input to the respiratory centers in the brainstem when perfused with hypoxic, hypercapnic and/or acidotic arterial blood; the central chemoreceptors are sensitive to brain tissue hypercapnia and acidosis. Pure chemical control of breathing is operable predominantly during non-rapid-eye-movement sleep and anesthesia. Otherwise, behavioral control of breathing is active. This control system receives input from different sites (for example: cortical and subcortical regions, hypothalamus, proprioceptors, nociceptors) and affects respiration either by direct control of respiratory motoneurons (= corticospinal control of respiration) or by modulation of respiratory centers in the brain stem via the reticular system. Behavioral control may inhibit, override or enhance chemical control, optimizing breathing to our needs (allowing respiratory adaptations so we can exercise, sleep and dream, eat, sing, play a musical instrument, dive, et cetera). However, the behavioral control systems is second in command and chemical control will eventually determine the pattern of breathing without any voluntary action able to suppress breathing activity.

How does the ventilatory control system cope with hypoxia? Since the oxygen reserves in the body are limited, the body responds within seconds to hypoxia with an increase in ventilation due to an effect of hypoxia at the chemoreceptors of the carotid bodies. Neonates lack a hyperventilatory response to hypoxia.

When hypoxia persists from more than 3 min, there is a slow decline in ventilation (hypoxic ventilatory decline or HVD). Ventilation reaches a new steady state after 15 to 20 min with ventilation still 25% above normoxic baseline values. In adults, HVD takes away about half of the hypoxic drive of the carotid bodies. Since this mechanism is operable in neonates and they possess no peripheral hypoxic drive, neonates may respond with severe hypoventilation and possibly even apnea to mild hypoxia (as, for example, may occur during transatlantic airplane flights).

How does the ventilatory control system cope with hyperoxia? Inspiration of hyperoxic gas mixtures cause an initial small decrease in ventilation due to depression (but not silencing) of the carotid bodies. The magnitude of this effect is variable and may range from no depression in some persons to 70% depression in others. Subsequently (within seconds) ventilation increases slowly. The magnitude of hyperoxia-induced ventilatory stimulation is dependent on the oxygen concentration and may be as great as 20 to 30 L/min under isocapnic conditions, but significantly less under poikilocapnic conditions (as exists in perioperative patients).

How do anesthetics affect the ability of the ventilatory control system to increase breathing when a patient is hypoxic? Anesthetics and analgesics act at specific receptors in the peripheral and central nervous system and since the integrity of the ventilatory control system is dependent on many of these, it is not surprising that agents commonly used to induce anesthesia and analgesia, may affect ventilation and the ventilatory responses to acute and sustained hypoxia. For example, at sub-anesthetic doses, inhalational anesthetics at1/10^th of a MAC and propofol at blood concentrations of about 1000 ng/ml, reduce the magnitude of the acute response to hypoxia. In humans, opioids affect the hypoxic drive from the carotid bodies through sex-dependent mechanisms. This is not surprising taking into account that opioid receptors and endogenous opioid peptides are found in high concentrations in areas of the central and peripheral nervous system which play a role in the control of breathing, and the observation of sex differences in opioid analgesia.. Recent studies in m-opioid receptor knockout mice indicate the involvement of m-opioid receptors in the modulation of respiratory frequency and the m-opioid receptor as molecular site of morphine respiratory and antinociceptive effects.

Clinical implications. The loss or severe reduction of the hypoxic drive from the carotid bodies is clinically important. Recurrent hypoxic events are common in the perioperative period, especially during the first postoperative nights. This is partly due to a reduced ventilatory drive from analgesic and residual anesthetics and partly to upper airway obstruction. The arousal needed to overcome upper airway obstruction is partly mediated and dependent on effective functioning of the peripheral chemoreceptors at the carotid bodies. In comparison to normal subjects, perioperative patients require much deeper levels of hypoxia to activate the carotid bodies.This may be especially important in patients with a history of nightly upper airway obstructions (e.g., obese patients, obstructive sleep apnea patients, the elderly). Deep hypoxic events may be an important source of postoperative morbidity and mortality.

How dose pain affect breathing? Noxious stimulation modulates the ventilatory control system. Pain and surgical stimulation act as respiratory stimulants in the awake, sedated and anesthetized states, causing a chemoreflex-independent tonic drive. In other words, pain is unable to reverse anesthetic-induced impairment of chemoreflex-related responses. However, from a clinical point of view, all that matters is whether a patient maintains an adequate minute ventilation. Since pain increases ventilatory drive it may be able to offset the anesthetic-induced loss of chemoreceptor drive. The respiratory effects of the pharmacological treatment of patients with acute or chronic pain should therefore always be viewed as the balance between the stimulatory effects of pain and the depressant effects of the agents used to treat pain. For example, the removal of pain by regional anesthesia may be dangerous for patients with acute pain, initially treated with opioids. Indeed, there are several reports showing profound and live-threatening respiratory depression when regional anesthesia causes the relief of pain in patients treated with opioids. In other words, patients in pain tolerate larger doses of opioids than those without pain.