Physiology, Carbon Dioxide Response Curve

Article Author:
Andrew Benner
Article Editor:
Sandeep Sharma
Updated:
2/11/2019 9:37:49 PM
PubMed Link:
Physiology, Carbon Dioxide Response Curve

Introduction

Through oxygen transport, carbon dioxide excretion, and the maintenance of acid/base status; properly functioning lungs play an essential role in stabilizing the biochemical environment necessary to preserve vital metabolic processes. Numerous driving forces influence the stimulation and suppression of respiratory drive. The lungs operate within a predetermined set range (baseline respiratory drive) that is influenced by a controller (medullary centers). This controller achieves balance by activating or inhibiting factors (signal amplification, gene upregulation, metabolic derangements) to produce a controlled process (contraction of respiratory muscles) and output (ventilation). This controlled process is vulnerable to transient or prolonged external loads (toxins, medications, obstructive or restrictive processes) that may disturb or amplify its effectiveness. This regulatory control system is maintained via a sensor-feedback transducer loop (chemoreceptor reflex) to fine-tune the controller response based on the current environment as determined by a summation of all inputs and outputs within the system. In summary, the lungs operate within a system of numerous checks and balances to achieve the appropriate level of respiratory drive necessary to maintain life. The carbon dioxide response curve represents an essential portion of this chemoreceptor negative feedback loop, relying on both central and peripheral chemoreceptors to detect alterations in the acid/base balance, ultimately altering our respiratory drive to maintain homeostasis.

Cellular

Carbon dioxide (CO2) is produced in the peripheral tissues and transported to the lungs primarily in the form of bicarbonate (HCO3-), but also as dissolved gas and as carbaminohemoglobin (HbCO2). Carbon dioxide is produced via aerobic metabolism, dissolving from peripheral tissues into nearby capillaries before being transported back to the lung for excretion via alveolar ventilation. During this process of transportation, dissolved CO2 must be converted (CO2 + H2O -> H2CO3 -> H+ + HCO3-) by carbonic anhydrase to form carbonic acid before dissociating into hydrogen and bicarbonate, with the HCO3- shifted into red blood cells in exchange for chloride anions via the bicarbonate/chloride exchanger.[1] In doing so, CO2 can be transported within the red blood cells in the form of bicarbonate, before ultimately utilizing carbonic anhydrase and the HCO3-/Cl- exchanger in the reverse chemical reaction direction to reform CO2 for diffusion into alveolar capillaries. The resulting hydrogen ions (H+) from the reaction bind to hemoglobin (Haldane effect), with any remaining unbuffered hydrogen ions acidifying venous blood.[2] Ideally, massive changes in CO2 content and subsequent pH alterations are minimized through the hydrogen ion buffering capabilities of hemoglobin and plasma proteins. Without these buffering systems, minutes of apnea would result in fatal hypercapnia secondary to lethal shifts towards acidic pH. However, it is this hypercapnic acidification that drives the central and peripheral chemoreceptors to reflexively stimulate respiratory drive in the form of induced bronchodilation and hypoxic vasoconstriction to increase CO2 clearance and improve ventilation/perfusion matching.[3] Although alveolar pressure of CO2 shares a direct relationship to CO2 production, it is inversely proportional to alveolar ventilation.

Function

The carbon dioxide response curve or VE/PaCO2, functions as a graphical depiction of the nearly linear relationship between increases in PaCO2 and the resulting stimulated alveolar ventilation. These response curves vary immensely for each person within a population, with roughly 1 to 4 L/min increase in minute ventilation for each 1 mm Hg increase in PaCO2 (Miller’s anesthesia). These ventilatory responses get blunted when the carbon dioxide narcosis and apneic thresholds are reached, at extremely high and low PaCo2, respectively. However, this blunted response in the setting of extreme CO2 is dissimilar to the changes observed at extremes of O2. In the setting of hyperoxia and hypoxia, the carbon dioxide response curve slope (sensitivity) decreases and increases, respectively.[4] Thus, the body is less sensitive to hypercapnic challenges in the setting of hyperoxia, as a result of only central chemoreceptors driving ventilation increases.[5] In the setting of hypoxia, the body is more sensitive to changes in PaCO2, as both central and peripheral chemoreceptors cause an additive increase respiratory drive.[4] This increased carbon dioxide response curve slope (sensitivity) in the setting of hypoxia is only prevalent if the central chemoreceptor reflex is intact, as it has not been observed with peripheral response alone.[4]

Mechanism

To monitor changes in [H+] and influence respiratory response, the body possesses two groups of chemoreceptors: 1) central, H+ receptors in the ventrolateral medulla and 2) peripheral, PaO2 and H+ receptors located in the carotid and aortic bodies.[6] The central chemoreceptors respond to alterations in [H+] as a result of CO2 diffusing across the blood-brain barrier, decreasing the pH of the cerebrospinal fluid (CSF). While, peripheral receptors are most sensitive to changes in PaO2, with some influence from [H+]. In the event of hypoxia, the carotid body response dominates, serving as the primary oxygen sensor.[7] The aortic bodies also function to detect changes in oxygen, but this response has since been determined to be vestigial in comparison to the carotid bodies; aortic bodies play a more relevant role in the detection of alterations in blood pressure.[7] In scenarios in which the receptors disagree, such as hypoxic hypocapnia, the peripheral chemoreceptor hypoxic response dominates, stimulating the respiratory drive to improve oxygenation despite further decreases in CO2.[6] In the setting of hypercapnia and acutely increased [H+], the peripheral and central chemoreceptors will simultaneously respond by significantly stimulating alveolar ventilation, inducing respiratory alkalosis to shift acid/base status towards neutral. These respiratory changes occur rapidly, while the renal system takes hours to days to adequately respond to metabolic acid/base disturbances through bicarbonate reabsorption and excretion of titratable acids. The kidneys and lungs function in unity, with their abilities to correct derangements strongest when compensating against the other system. For example, in the setting of metabolic acidemia, the kidneys are unable to properly restore acid/base status, and thus rely on the lungs for compensatory respiratory alkalosis through stimulation of the peripheral and central chemoreceptors in response to hydrogen ion increases.

Clinical Significance

In the setting of clinical anesthesia, the carbon dioxide response curve is subject to drastic changes ranging from changes in threshold (left/right shifts) or sensitivity (slope amplification/depression) pending the agents utilized throughout the procedure, ventilation settings, and current health status of the patient, among others (See Figure). In the event of hypoxemia with PaO2 less than 60 mmHg, the CO2 response curve left-shifts, amplifying respiratory drive.[4] Volatile anesthetics such as des/iso/sevoflurane cause a dose-dependent reduction in the slope of the carbon dioxide response curve, limiting hypercapnic drive.[8] Commonly utilized analgesic medications such as opioids, specifically fentanyl, further dampen the CO2 response curve, causing a right-shift (decreased threshold).[9] Suspicions are that propofol and benzodiazepines suppress the carbon dioxide response curve by decreasing the slope (sensitivity). Unfortunately, most of the substances/gases utilized to achieve the depth of sedation necessary for proper amnesia and analgesia concomitantly dampen the carbon dioxide response curve, and thus respiratory drive. Under these influences, mechanical ventilation serves as a necessary intervention to artificially maintain a desirable physiological environment. By allowing medications to fall out of their therapeutic window, reversing neuromuscular blockade, and decreasing mechanical ventilation to allow permissive hypercapnia; the anesthesia provider may directly alter the patient's carbon dioxide response curve to increase respiratory drive at the end of the procedure with the intention of extubating the patient upon returning to spontaneous ventilation. But in procedures like bronchoscopy, upper GI endoscopy, and colonoscopy where conscious sedation is used pulse oximetry along with capnography is a must. Good oxygen saturation can is easily maintainable by giving more fio2 but if the patient is not maintaining proper alveolar ventilation CO2 levels can rise to dangerous levels leading to bradycardia and potential cardiac arrest. That's why monitoring capnography in these procedures is a must. The alveolar gas equation can easily explain this concept.[10]



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      Contributed by Andrew Benner

References

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