Control of ventilation and hypercapnic studies.
Ventilation is controlled through a series of sensors found in the lung, the carotid and aortic bodies of the arterial system, and lining the medulla in the brain's fourth ventricle. In the lung, stretch receptors in the airway smooth muscle and irritant receptors found adjacent to bronchial epithelial cells stimulate increases in minute ventilation when the lung is in need of a stretch for muscle tenor.
Muscle and joint receptors initiate increases in breathing in response to limb movement as in the beginning of exercise. Juxtacapillary (J) receptors, which are found in the alveolar walls, sense the filling of the pulmonary capillaries and simulate rapid shallow breathing.
The most important or dominant sensors for the control of breathing or respiratory drive are the central chemoreceptors in the medulla of the brain, and peripheral chemoreceptors in the carotid and aortic bodies in the arterial blood system. The central chemoreceptors respond to changes in cerebral spinal fluid of the hydrogen ion concentration (minus the log of the hydrogen ion concentration or pH). This results in hyperventilation from a decrease in pH and in hypoventilation from an increase. Increases or decreases in pH taking place in the systemic circulation from metabolic or respiratory processes or imbalances can take hours to cross the blood brain barrier.
Changes in the arterial carbon dioxide partial pressure (PaCO2) and the resultant changes in pH cause ventilatory changes in both the central and peripheral cheomorecoptors. But the peripheral chemoreceptors respond more rapidly to decreased or increased arterial oxygen partial pressure (PaO2), decreased or increased PaC[O.sub.2], and increased or decreased arterial pH because there are no barriers at all to pass. Although all gases readily diffuse, or more accurately transfer, though the blood brain barrier onto the central chemoreceptors, the resultant changes in ventilation may take up to a one minute.
The peripheral chemoreceptors only respond to partial pressure of gas and not to gas content. Experiments show that when carboxyhemoglobin (hemoglobin bound to carbon monoxide) is increased or total hemoglobin levels are decreased, the peripheral chemoreceptors do not respond. The carotid bodies are close to the carotid bifurcation on both sides of the neck and the aortic bodies are located near the aortic arch. They both are located in areas of maximum blood flow and, therefore, are in the best position to monitor blood gas partial pressure and pH.
An acute rise in PaC[O.sub.2] causes a ventilatory response primarily through the central chemoreceptors (approximately 80 percent) with the remainder attributable to the peripheral chemoreceptors. As indicated above, carbon dioxide readily crosses the blood brain barrier so that the CSF PaCO2 is similar to that of blood.
Both central and peripheral chemoreceptors do not respond to partial pressures of oxygen above 200 mmHg. But significant hyperventilation occurs when the PaC[O.sub.2] goes below 60 mmHg. Although hypoxic (low levels of oxygen) drive is minimal or non existent with PaC[O.sub.2] levels above 60 mmHg, even at rest at sea level in normal subjects the hypoxic drive can be detectable in some patients so that it is advisable to eliminate any possible hypoxic drive by maintaining the PaC[O.sub.2] above 160 mmHg with high levels of oxygen in the gas mixture.
The hypercapnic (high level of carbon dioxide) drive can be affected by a number of factors such as long-term residence at altitude, disease, drugs, athleticism, and age. CO2 retention as found in emphysema or muscular-spinal conditions such as kyphoscoliosis can cause significant blunting of CO2 response. Neurological diseases and brain malformation can also result in decreased CO2 responses. In general, impaired respiratory mechanics decrease the sensitivity of any study designed to measure respiratory drive.
The first step in any respiratory drive study is to rule out any possible contributing factor by the use of other tests. A flow volume loop could indicate obstruction that would involve a delay in ventilation and would hide or delay a hypercapnic response. Arterial blood gases would indicate if the patient is a C[O.sub.2] retainer and therefore a blunted response to C[O.sub.2] would be expected.
High physiologic levels of C[O.sub.2] and significantly decreased single breath diffusion capacity with carbon monoxide (DLCO) values have been shown to cause blunting of respiratory drive in response to C[O.sub.2]. Finally, increased dead space to tidal volume ratio (VD/VT), increased shunt, and high residual volume to total lung capacity ratio (RV/TLC) or distribution of ventilation all have a negative effect on the respiratory drive.
The most effective and commonly used method for measuring the respiratory drive in response to C[O.sub.2] is based on progressive increases in C[O.sub.2] in a re-breathing or Douglas bag. The method is simple, fast, takes a minimum of equipment and is particularly suited for clinical investigations. The measurement of C[O.sub.2], or capnography, has become very reliable, and the devices can be purchased for between $2,000 and $3,000.
The technique involves placing a percentage of C[O.sub.2] in a re-breathing bag. The subject is connected to the bag by a mouthpiece and re-breaths. As additional C[O.sub.2] is produced by metabolism, the C[O.sub.2] in the bag accumulates, and the partial pressure of carbon dioxide (PC[O.sub.2]) of all body fluids rises progressively. As the PC[O.sub.2] in the region of the peripheral chemoreceptors rises, a progressive carbon dioxide stimulus to ventilation develops immediately. An initial high concentration of oxygen in the bag provides oxygen for metabolism and prevents the development of hypoxic stimulus to ventilation.
The beauty of this method is that a linear relationship has been shown to exist between the minute ventilation (VE) and PCO2 changes of arterial blood and medillary chemoreceptor tissue. This linear relationship between the PCO2 of arterial blood and chemoreceptor tissue negates the need for successive arterial blood gas analysis to demonstrate the correlation PaC[O.sub.2] with end tidal carbon dioxide (ETCO2). It has been shown by direct measurement that the partial pressure of expired carbon dioxide equals the partial pressure of arterial carbon dioxide (PEC[O.sub.2] = PaC[O.sub.2]) and in normal individuals the VE increases in a linear fashion in response.
People with a familial history of stroke or cerebral vascular aneurisms or weakness must be excluded from testing. Also people with high blood pressure may be excluded at the discretion of the physician. With myself having served as a standard subject for this procedure, I can attest to the fact that when the test is allowed to advance to maximum levels of CO2, a significant acute and chronic headache often results. I would suggest that one refer to published normal responses, instead of developing one's own.
The method begins with filling a re-breathing or Douglas bag to a constant volume in the range of 4 L to 6 L. Many investigators use the rule of thumb that the volume should be the patient's forced expiratory volume in the first second (FEV1) plus 1 L. The gas should contain 7 percent C[O.sub.2], 50 percent oxygen (O2), and 43 percent nitrogen ([N.sub.2]). In case of poor distribution of ventilation, five minutes prior to the test the patient is given 50 percent 02 and balance N2 to exclude complications from an increased residual volume and possible hidden hypoxic drive.
The patient sits in a comfortable chair and rests for one-half hour before the study. The patient is turned into the re-breathing bag at the end of an exhaled maximum breath or at residual volume, and the re-breathing continues for four minutes. All studies should be performed at least four hours after any intake of bronchodilators, coffee, tea or food. A repeat of the study after 30 minutes is an option but not necessary.
During the study the minute ventilation, VE is graphed on the Y axis and PC[O.sub.2] or carbon dioxide concentration recorded on the X axis. At 15 seconds into the study, PC[O.sub.2] equilibrium has been established between the alveolar gas and the mixed venous blood. As a result of this PCO2 equilibrium, ETC[O.sub.2] will reflect the change in PaC[O.sub.2] even in the presence of pulmonary disease and this has been confirmed by direct measurement. End tidal oxygen (ETO2), although falling, continually remains in all patients above normal through the re-breathing.
When the VE is graphed against PC[O.sub.2], the results are linear for normal patients. This finding in itself is good evidence for the validity of end-tidal PCO2 as an index of the carbon dioxide stimulus. When patients with abnormal or blunted response are graphed, the slopes are decreased or may even be flat or nearly flat. The slopes of the data are calculated as the change in minute ventilation over the change in partial pressure of carbon dioxide ([DELTA]VE/[DELTA]PC[O.sub.2]).
Researchers who have published normal values have presented slopes of between 2.40 and 2.65 millimeter per minute per millimeter of mercury (ml/min/mmHg). A normal slope of 2.60 [+ or -] 1.2 is a reasonable choice for laboratory normals.
The ventilatory response to two or three breaths using C[O.sub.2] concentrations of up to 20 percent has been used by some investigators to determine the relative contribution of the peripheral chemoreceptors to total respiratory drive. These studies are based on the premise that the transient response to the elevated PC[O.sub.2] is initially sensed by the peripheral chemoreceptors, while the total response over the usual four or five minutes is produced by the central chemoreceptors.
A simple variant bedside method has been used, which is to fill the re-breathing bag with 100 percent [O.sub.2] and have the patient re-breath while measuring the PC[O.sub.2] and minute ventilation. The PC[O.sub.2] will rise to a higher level through metabolism alone, and the test run will take eight or nine minutes.
A study related to the hypercapnic response is a test referred to as occlusion pressure (PI00). In this study, the patient breaths through a mouthpiece attached to a tube with a shutter valve and pressure transducer catheter attached proximal to the shutter valve. The shutter valve is usually a balloon device which can be closed very quietly. The patient is brought to a relaxed state and presented with white noise or natural sounds through ear phones so that he or she is distracted from the shutter valve closing at the end of an occasional normal breath and the pressure measured automatically at 100 milliseconds after the shutter valve closes.
The inspiratory pressure measured at this point of a normal inhalation indicates the respiratory drive. The measurement is often done with the patient breathing both room air and hypercapnic mixtures. The occlusion pressure is graphed against different CO2 mixtures, producing both normal slopes as well as slopes indicating reduced drive of breathing.
In a similar vain, diaphragm muscle electromyographic (EMG) measurements have been measured in relation to increasing C[O.sub.2] levels as an indication of respiratory drive. As mentioned above, patients with indication of cerebral aneurism or high blood pressure, or patients who may be susceptible to headaches should not be tested.
In summary, any method used to test the control of ventilation or respiratory drive is fraught with difficulties because these test methods and their interpretations have never been standardized within the pulmonary testing community. At present these tests, especially hypercapnic studies, can not be considered suitable for routine testing in the pulmonary function laboratory. They should only be used as tools to answer specific physiologic queries concerning a specific group or sub group of patients.
Jim Harvey RRT, RPFT
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|Title Annotation:||PULMONARY FUNCTION|
|Publication:||FOCUS: Journal for Respiratory Care & Sleep Medicine|
|Date:||Jun 22, 2015|
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