Blunted Response to Hypercapnia: Synonymous with Depressed Respiratory Drive?

Editorials

Blunted Response to Hypercapnia: Synonymous With Depressed Respiratory Drive?

The pathophysiology of failure to wean from mechan- pressure at onset of inspiration are unimportant as long as ical ventilation consists of depressed central respiratory the relationship between P0.1 and ventilation remains sta- drive, impaired respiratory mechanics, respiratory muscle ble.3 weakness, increased load, impaired gas exchange, and com- Another consideration is that P0.1 measured at the mouth promised cardiovascular performance. Among patients can be underestimated, in comparison to that measured with weaning failure, depressed central respiratory drive from esophageal pressure. This occurs because the time occurs in only a small portion (approximately 10%),1 constant of the airways, which consists of airways resis- whereas most patients demonstrate augmented drive with tance and mouth-cavity-walls compliance, is prolonged. In the development of progressive ventilatory failure.2 intubated patients this latter consideration is irrelevant because endotracheal-tube placement circumvents the prob- 3 SEE THE ORIGINAL STUDY ON PAGE 1012 lem. Despite its limitations, when interpreted critically, P0.1 remains a reliable index of respiratory-center drive. To- To assess central respiratory controller output, the pres- gether with ventilation, its measurement is incorporated sure generated during the first 0.1 second of an airway with CO rebreathing to assess respiratory-center chemo- occlusion (P ) that coincides with the onset of inspiratory 2 0.1 sensitivity. The original Read rebreathing method requires effort has been widely used. Its measurement is noninva- the subject to rebreathe a mixture of CO and hyperoxic sive, and it has the advantage of being independent of 2 gas to achieve equilibrium of end-tidal, arterial, and mixed respiratory-system resistance, compliance, and Hering- venous CO tension, such that changes in end-tidal CO Breuer inflation reflex,3 and automatic acquisition of P 2 2 0.1 represent those in arterial and mixed venous blood, and, is available on intensive-care-unit ventilators.4 However, most importantly, in brain tissue as a stimulus for changes the interpretation of P as an index of respiratory-center 0.1 5 drive can be challenging, particularly when the connecting in central chemoreceptor output. Under this condition, nerves from the respiratory controller to the respiratory CO2 stimulus is independent of the dependent variable, muscles are disrupted, the respiratory muscles are weak, or ventilation. The slopes of the ventilatory (change in minute ⌬ ˙ ⌬ volume [ VE] divided by PCO ) and P0.1 responses to the P0.1 measurement is not obtained at resting end-expi- 2 3 hypercapnia (⌬P /⌬P ) are calculated as estimates of ratory lung volume. 0.1 CO2 At volumes higher than resting end-expiratory lung vol- central respiratory drive. As with resting P0.1, using CO2 ume (dynamic hyperinflation), a phase lag between pres- rebreathing to assess central respiratory drive has several sure generation and flow occurs, due to a prolonged time limitations: constant and absence of an end-expiratory pause. Under 1. Abnormal respiratory system resistance and compli- this condition the negative pleural-pressure swing occurs ance preclude ventilatory response to hypercapnia, and early, that is, during late exhalation, before flow reverses leaves only P0.1 response to CO2 as a means to estimate central respiratory drive. to inspiration; but P0.1 cannot be measured until flow be- 2. The range of normal values in healthy awake subjects comes zero. The measured P0.1 value can be equal to, is wide, for ⌬V˙ /⌬P it is 0.47–6.23 L/min/mm Hg.6 To higher than, or lower than the rate of pressure generation E CO2 in the beginning of inspiratory effort, depending on the date, no study with a large number of subjects has de- 3 scribed the range of normal values for ⌬P /⌬P . How- shape of the airway pressure waveform. 0.1 CO2 At volumes lower than resting end-expiratory lung vol- ever, in one study in anesthetized healthy subjects, in which ume that are attributable to expiratory muscle activation, the anesthetic agent had no effect on central respiratory drive, the range of ⌬P /⌬P was 0.17–0.62 cm H O/ the P0.1 generated at zero flow can result partly from the 0.1 CO2 2 negative elastic recoil pressure produced by relaxation of mm Hg.7 the expiratory muscles. When lung volume is below its 3. Both ventilatory and P0.1 responses to hypercapnia resting volume, observations of healthy subjects rebreath- exhibit wide variability. In healthy subjects the coeffi- ing carbon dioxide showed that the means of generating cients of variation for ventilatory and P0.1 responses to

1006 RESPIRATORY CARE • AUGUST 2008 VOL 53 NO 8 BLUNTED RESPONSE TO HYPERCAPNIA hypercapnia are 56% and 66%, respectively.8 This vari- ventilatory support. The large sample size in the study by ability is all the more enormous in patients recovering Raurich et al9 is commendable; however, it is interesting from acute respiratory failure, in whom the coefficient of to note that the ratio of respiratory frequency to tidal vol- variation for ⌬V˙ /⌬P is 81%, and that for ⌬P /⌬P ume (f/V ) measured at baseline had an area under the E CO2 0.1 CO2 T is 76%.2 receiver-operating-characteristic curve that was similar to 9 In this issue of the Journal, Raurich et al report on a that of the ratio of hypercapnia-test P0.1 to resting P0.1, large number of patients recovering from acute respiratory which suggests that a test as simple as f/VT provides in- failure of various etiologies (with the exception of chronic formation similar to that obtained with CO2 rebreathing. obstructive pulmonary disease and neuromuscular disease) Among patients who fail to wean it is likely that only a and who were ready to wean. In the patients who failed to small proportion of these failures are caused by a de- wean, both ventilatory and P0.1 responses to hypercapnia pressed respiratory-center drive, whereas the majority are were lower than in the patients who weaned successfully. caused by impaired respiratory system mechanics and di- Do their findings indicate that patients who fail to wean aphragm muscle weakness. had depressed central respiratory drive? Catherine S Sassoon MD Raurich et al9 excluded patients with chronic obstruc- Pulmonary and Critical Care Section tive pulmonary disease and neuromuscular disease. None- Department of Medicine theless, in patients without airflow limitation, intrinsic pos- Veterans Affairs Long Beach Healthcare System itive end-expiratory pressure (PEEPi) increased 5-fold with Long Beach, California CO2 rebreathing during a modest level of pressure-support ventilation.10 During a weaning trial of patients with diverse etiologies, Laghi et al11 found that patients who failed REFERENCES to wean had higher respiratory-system resistance, lower dynamic compliance, and higher PEEPi than patients who 1. Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory weaned successfully. In addition, many of the patients distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 1997;155(3):906-915. who failed to wean had diaphragm muscle weakness, as 2. Pourriat JL, Baud M, Lamberto C, Fosse JP, Cupa M. Effects of assessed via twitch pressure produced by phrenic-nerve doxapram on hypercapnic response during weaning from mechanical stimulation, which is a measure of diaphragm muscle func- ventilation in COPD patients. Chest 1992;10(6):1639-1643. tion uninfluenced by voluntary effort. The absence of in- 3. Whitelaw WA, Derenne JP. Airway occlusion pressure. J Appl Physiol formation on PEEPi or diaphragm muscle function ham- 1993;74(4):1475-1483. 4. Kuhlen R, Hausmann S, Pappert D, Slama K, Rossaint R, Falke K. pers the interpretation of the blunted CO2 response in the A new method for P0.1 measurement using standard respiratory patients who failed to wean. equipment. Intensive Care Med 1995;21(7):554-560. 9 Raurich et al also found that both ventilatory and P0.1 5. Read DJ. A clinical method for assessing the ventilatory response to responses to hypercapnia, and the ratio of hypercapnia-test carbon dioxide. Aust Ann Med 1967;16(1):20-32. P to resting P were not useful as predictors of weaning 6. Irsigler GB. Carbon dioxide response line in young adults: the limits 0.1 0.1 of the normal response. Am Rev Respir Dis 1976;114(3):529-536. outcome. The latter finding contrasts with those of Mont- 7. Derenne JP, Couture J, Iscoe S, Whitelaw A, Milic-Emili J. Occlu- 12 gomery et al, who found, in a small number of patients sion pressures in men rebreathing CO2 under methoxyflurane anes- with diverse etiologies, that the ratio of hypercapnia-test thesia. J Appl Physiol 1976;40(5):805-814. 8. Montes de Oca M, Celli BR. Mouth occlusion pressure, CO re- P0.1 to resting P0.1 separated patients who failed to wean 2 from those who weaned successfully. It is difficult to com- sponse and hypercapnia in severe chronic obstructive pulmonary disease. Eur Respir J 1998;12(3):666-671. pare these 2 studies, because they did not use similar CO2 9. Raurich JM, Rialp G, Iba´n˜ez J, Campillo C, Ayestara´n I, Blanco C. rebreathing methods or conditions. The patients of Raurich Hypercapnia test as a predictor of success in spontaneous breathing 9 et al rebreathed CO2 via added dead space, without initial trials and extubation. Respir Care 2008;53(8):1012-1018. 10. Ranieri VM, Giuliani R, Mascia L, Grasso S, Petruzzelli V, Puntillo CO2 gas mixture, during pressure-support ventilation, whereas those of Montgomery et al12 rebreathed CO via N, et al. Patient-ventilator interaction during acute hypercapnia: pres- 2 sure-support vs. proportional-assist ventilation. J Appl Physiol 1996; a bag filled with a mixture of CO2 and oxygen, without 81(1):426-436. 11. Laghi F, Cattapan SE, Jubran A, Parthasarathy S, Warshawsky P, Choi YS, Tobin MJ. Is weaning failure caused by low-frequency The author reports no conflict of interest in the content of this editorial. fatigue of the diaphragm? Am J Respir Crit Care Med 2003;167(2): 120-127. Correspondence: Catherine S Sassoon MD, Pulmonary and Critical Care 12. Montgomery AB, Holle RHO, Neagle SR, Pierson DJ, Schone RB. Section, Veterans Affairs Long Beach Healthcare System, 5901 East 7th Prediction of successful ventilator weaning using airway occlusion Street, 11/111P, Long Beach CA 90822. E-mail: [email protected]. pressure and hypercapnic challenge. Chest 1987;91(4):497-499.

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