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Original Article
Volume 330:1329-1334 May 12, 1994 Number 19
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Chemosensitivity and Perception of Dyspnea in Patients with a History of Near-Fatal Asthma
Yoshihiro Kikuchi, Shinichi Okabe, Gen Tamura, Wataru Hida, Masaaki Homma, Kunio Shirato, and Tamotsu Takishima

 

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ABSTRACT

Background Many deaths from attacks of asthma may be preventable. However, the difficulty in preventing fatal attacks is that not all the pathophysiologic risk factors have been identified.

Methods To examine whether dyspnea and chemosensitivity to hypoxia and hypercapnia are factors in fatal asthma attacks, we studied 11 patients with asthma who had had near-fatal attacks, 11 patients with asthma who had not had near-fatal attacks, and 16 normal subjects. Their respiratory responses to hypoxia and hypercapnia, determined by the standard rebreathing technique while the patients were in remission, were assessed in terms of the slopes of ventilation and airway occlusion pressure as a function of the percentage of arterial oxygen saturation and end-tidal carbon dioxide tension, respectively. The perception of dyspnea was scored on the Borg scale during breathing through inspiratory resistances ranging from 0 to 30.9 cm of water per liter per second.

Results The mean (±SD) hypoxic ventilatory response (0.14 ±0.12 liter per minute per percent of arterial oxygen saturation) and airway occlusion pressure (0.05 ±0.05 cm of water per percent of arterial oxygen saturation) were significantly lower in the patients with near-fatal asthma than in the normal subjects (0.60 ±0.35, P<0.001, and 0.16 ±0.08, P<0.001, respectively) and the patients with asthma who had not had near-fatal attacks (0.46 ±0.29, P = 0.003, and 0.15 ±0.09, P = 0.004). The Borg score was also significantly lower in the patients with near-fatal asthma than in the normal subjects, and their lower hypoxic response was coupled with a blunted perception of dyspnea.

Conclusions Reduced chemosensitivity to hypoxia and blunted perception of dyspnea may predispose patients to fatal asthma attacks.

Concern about deaths from asthma is increasing1,2,3. Most of the deaths are avoidable if patients are adequately treated3,4. However, adequate treatment requires clarification of the mechanisms by which fatal or near-fatal attacks develop and identification of the risk factors for these attacks.

Although there have been many epidemiologic studies of fatal or near-fatal asthma,4,5,6,7 there have been few studies of the mechanisms underlying life-threatening attacks1. One report8 suggested that respiratory arrest, not cardiac arrest, may be the principal cause of death during an attack. The precise mechanisms of life-threatening attacks, however, were not elucidated in this study, and one is left with the impression that the patients were suffocating as a result of a narrowing of the airway. Although this may have been the case, other explanations are possible, such as rapidly progressive airflow obstruction, reduced chemosensitivity to hypercapnia and hypoxia, or a decreased perception of dyspnea1.

The purpose of this study was to examine two of these possible underlying causes of life-threatening attacks in patients with asthma. We examined the perception of dyspnea during resistive loading and chemosensitivity to hypercapnia and hypoxia in patients with a history of near-fatal attacks.

Methods

Subjects

We studied 11 patients who had had near-fatal attacks of asthma, 11 patients with asthma but no near-fatal attacks, and 16 normal subjects (Table 1). All patients with asthma met the American Thoracic Society's diagnostic criteria12. Near-fatal attacks were defined as attacks of asthma requiring treatment with mechanical ventilation (in eight patients) or resulting in unconsciousness and severe respiratory failure (in three patients). All the patients with near-fatal attacks had had severe respiratory failure with retention of carbon dioxide during their most recent near-fatal attack (Table 2). Three patients had recovered from unconsciousness without mechanical ventilation after initial intensive therapy; the duration of unconsciousness was estimated to have been from 20 to 60 minutes. Eight patients had been treated with mechanical ventilation for two to eight days. Five of the 11 patients had had more than one near-fatal attack.

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  		Table 1. Demographic and Clinical Characteristics of the Patients with Near-Fatal Asthma, Patients with Asthma but No Near-Fatal Attacks, and Normal Subjects.

 
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  		Table 2. Values of Arterial-Blood Gases during Spontaneous Breathing at the Time of the Most Recent Near-Fatal Asthma Attack and the Outcome of the Attack.

 
To exclude the effect of airway obstruction on chemosensitivity and the perception of dyspnea, the patients were enrolled in the study when their disease was in clinical remission and the forced expiratory volume in one second (FEV1) was greater than 80 percent of the predicted value9. None of the patients with asthma and only five of the normal subjects had had measurements of chemosensitivity or perception of dyspnea before this study; dyspnea was not measured in four of these five normal subjects because they were familiar with the purpose of the study. The study protocol was approved by the instititutional ethics committee, and informed consent was obtained from all the subjects.

Protocols and Measurements

The patients did not use any medications after their regular treatment in the morning; the measurements were obtained in the afternoon. After spirometric and plethysmographic measurements of airway resistance and thoracic gas volume had been obtained, the perception of dyspnea during inspiratory resistive loading and then chemosensitivity to hypoxia and hypercapnia were measured with the use of a previously described apparatus consisting of a unidirectional Hans-Rudolph valve and a rebreathing circuit13,14. Mouth pressure was measured with a Validyne pressure transducer (Northridge, Calif.), which was used with a device to measure airway occlusion pressure (P0.1, mouth pressure 0.1 second after the start of inspiration against an occluded airway)15,16. Minute ventilation was measured by electrically integrating the expiratory flow signal obtained with a heated (37 °C) pneumotachygraph. End-tidal carbon dioxide tension (PETCO2) and end-tidal oxygen tension (PETO2) were monitored at the Hans-Rudolph valve with a mass spectrometer. Arterial oxygen saturation (SaO2) was measured continuously with a finger-pulse oximeter.

The sensation of dyspnea was measured while the subject breathed through the Hans-Rudolph valve with linear inspiratory resistances of 0 (control), 2.3, 5.0, 10.1, 20.0, and 30.9 cm of water per liter per second. Neither ventilation nor breathing pattern was controlled during the test. After breathing for one minute at each level of resistance, the subject rated the sensation of difficulty in breathing (dyspnea) using a modified Borg scale17. This is a linear scale of numbers ranking the magnitude of difficulty in breathing, ranging from 0 (none) to 10 (maximal). The phrase "difficulty in breathing" was not defined,18 but the subjects were instructed to avoid rating nonrespiratory sensations, such as headache or irritation of the pharynx.

Respiratory responses to progressive isocapnic hypoxia and progressive hyperoxic hypercapnia were measured with standard rebreathing methods19,20 and assessed in terms of the slopes of minute ventilation and P0.1 as a function of PETCO2 and SaO2. After an equilibration period during which the subjects breathed room air, they rebreathed through a bag containing the initial gas mixture: 21 percent oxygen in nitrogen for the hypoxic response and 7 percent carbon dioxide in oxygen for the hypercapnic response. In the hypoxic test, a bypass circuit consisting of a carbon dioxide absorber and a variable fan was connected between the inspiratory and expiratory lines, and PETCO2 was held constant (within 1 mm Hg) at the level of each subject's resting PETCO2 during the procedure by varying the flow of the carbon dioxide absorber. The trials of hypoxic and hypercapnic responses were terminated when the subjects reached 70 percent SaO2 and 64 mm Hg PETCO2, respectively.

Statistical Analysis

The results are expressed as means ±SD, unless otherwise indicated. The slopes of the minute ventilation and P0.1 responses to hypercapnia and hypoxia were calculated by a least-squares regression analysis with PETCO2 and SaO2, respectively14,21,22. Differences were tested for significance with a two-tailed Student's t-test in a one-way analysis of variance and a post hoc Scheffe's test in a two-way analysis of variance. Correlations were assessed by calculating Spearman correlation coefficients (rs). P values less than 0.05 were considered to indicate statistical significance.

Results

The mean age of the subjects did not differ significantly among the three groups (Table 1). The mean height and body weight of the patients with near-fatal asthma did not differ significantly from those of the patients without near-fatal attacks but were significantly lower than the mean height and weight of the normal subjects. Pulmonary function was similar in the three groups of subjects except for vital capacity and FEV1. The mean vital capacity was slightly but significantly larger in the patients with near-fatal asthma than in the other two groups, and FEV1 was significantly larger in the patients with near-fatal asthma than in the patients without near-fatal attacks. The duration and severity of asthma, airway hyperreactivity as measured by methacholine provocation testing,10 and use of medications at the time of the study did not differ significantly between the two groups of patients with asthma.

Figure 1 shows the hypoxic responses, expressed in terms of the minute ventilation slope (change in minute ventilation/change in SaO2) and the P0.1 slope (change in P0.1/change in SaO2), in all the subjects. There were no significant differences in the minute ventilation or P0.1 slope between the normal subjects and the patients without near-fatal attacks. However, the mean values of the minute ventilation and P0.1 slopes were significantly lower in the patients with near-fatal asthma than in the normal subjects or the patients with asthma but no near-fatal attacks. Figure 2 shows the hypercapnic responses in all the subjects. The mean value of the minute ventilation slope (change in minute ventilation/change in PETCO2) in the patients with near-fatal asthma was significantly lower than that in the normal subjects but was not significantly lower than that in the patients without near-fatal attacks. There were no significant differences in the mean value of the P0.1 slope (change in P0.1/change in PETCO2) among the three groups.


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  		Figure 1. Hypoxic Responses Expressed in Terms of the Minute Ventilation Slope (Change in Minute Ventilation/Change in SaO2) and P0.1 Slope (Change in P0.1/Change in SaO2) in 16 Normal Subjects, 11 Patients with Asthma but No Near-Fatal Attacks, and 11 Patients with Near-Fatal Asthma.

The horizontal bars indicate mean values, and the vertical lines ±1 SD. For convenience, the value of the slope of the hypoxic response was expressed as positive when minute ventilation or P0.1 increased with a decrease in SaO2.

 

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  		Figure 2. Hyperoxic Hypercapnic Responses Expressed in Terms of the Minute Ventilation Slope (Change in Minute Ventilation/Change in PETCO2) and the P0.1 Slope (Change in P0.1/Change in PETCO2) in All Subjects.

The horizontal bars indicate mean values, and the vertical lines ±1 SD.

 
The mean Borg score during resistive loaded breathing was significantly lower in the patients with near-fatal asthma than in the normal subjects (Figure 3). There were no significant differences in breathing pattern or P0.1 during quiet breathing at any level of resistance among the three groups. The Borg scores of individual patients during breathing with a resistance of 20.0 cm of water per liter per second are shown in Figure 4. The mean score for the patients with near-fatal asthma was significantly lower than that for the normal subjects but was not significantly lower than the mean score for the patients without near-fatal attacks.


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  		Figure 3. Mean (±SE) Perception of Dyspnea (Borg Score) during Breathing at Six Levels of Resistance in 12 Normal Subjects, 11 Patients with Asthma but No Near-Fatal Attacks, and 11 Patients with Near-Fatal Asthma.

 

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  		Figure 4. Perception of Dyspnea (Borg Score) during Breathing with a Resistance of 20.0 cm of Water per Liter per Second in Individual Subjects.

The horizontal bars indicate mean values, and the vertical lines ±1 SD.

 
Figure 5 shows the relation between the perception of dyspnea and hypoxic chemosensitivity. There was a significant relation between the Borg score with a resistance of 20.0 cm of water per liter per second and both the minute ventilation slope (rs = 0.61, P<0.001) and the P0.1 slope (rs = 0.70, P<0.001) of the hypoxic response in all the subjects. There was also a significant relation among these values when calculated separately in the normal subjects (rs = 0.69, P = 0.013 for the minute ventilation slope; rs = 0.89, P<0.001 for the P0.1 slope). The Borg score with a resistance of 30.9 cm of water per liter per second was also significantly related to the minute ventilation slope (rs =0.57, P<0.001) and the P0.1 slope (rs = 0.65, P<0.001). Most of the subjects with a decreased sensitivity to hypoxia, whether they were patients with asthma or normal subjects, had a blunted perception of dyspnea as well (Figure 5). The Borg score was not correlated with the hypercapnic response.


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  		Figure 5. Relation between the Perception of Dyspnea (Borg Score) during Breathing with a Resistance of 20.0 cm of Water per Liter per Second and the Hypoxic Response (Minute Ventialtion and P0.1 Slopes).

 
Discussion

Most of the patients with near-fatal asthma had a decreased chemosensitivity to hypoxia as well as a blunted perception of dyspnea during resistive loading, and there was a significant positive relation between hypoxic chemosensitivity and the perception of dyspnea during resistive loading.

Several methodologic issues should be considered. Because ventilatory responses are affected by the degree of airway obstruction,23 we chose patients whose predicted values of FEV1 were more than 80 percent. Furthermore, we measured not only minute ventilation but also P0.1, which is known to reflect respiratory neuromuscular function more directly than minute ventilation does16,24. Therefore, the decreased minute ventilation during hypercapnia in the patients with near-fatal asthma, as compared with minute ventilation in normal subjects, may have been attributable to mild residual airway obstruction rather than to decreased chemosensitivity to hypercapnia. The decreased sensation of dyspnea in the patients with near-fatal asthma is unlikely to have been caused by their acclimation to dyspnea or chronic airway obstruction, because dyspnea during the hypercapnic response did not differ significantly among the three groups (data not shown).

Our finding that most of the patients with near-fatal asthma had a decreased hypoxic response accompanied by a blunted perception of dyspnea during resistive loading suggests that, in addition to severe bronchoconstriction, a dysfunction of the defense mechanisms against profound hypoxemia and airway narrowing may play an important part in causing life-threatening attacks of asthma. If chemosensitivity is blunted in patients with asthma, severe respiratory failure may develop, leading to death1,25. However, this speculation has not been systematically examined. In one report, a patient with profound hypercapnia and hypoxia during asthma attacks had a markedly decreased ventilatory response to hypoxia but a normal response to hypercapnia26. The same investigators27 also reported that the hypoxic response was severely decreased in some patients with asthma and a history of severe respiratory failure. These observations are consistent with our finding that hypoxic chemosensitivity was decreased in patients with near-fatal asthma.

The perception of airway obstruction is blunted in some patients with asthma28. Although such a decreased perception is potentially dangerous because the severity of an exacerbation of asthma may be underestimated,1,25,28,29 this possibility has not been thoroughly examined. Most of our patients with near-fatal asthma had a markedly depressed perception of dyspnea during resistive loading, suggesting that when they did experience dyspnea, the degree of airway obstruction may already have been severe.

We were surprised that hypoxic chemosensitivity was related to dyspnea during resistive loading and that a decreased hypoxic response was coupled with a blunted perception of dyspnea in both groups of patients with asthma as well as in the normal subjects. The mechanisms responsible for the relation between these two factors are not known. In patients with asthma who had had both carotid bodies removed, no discomfort or increase in ventilation was reported, even when the patients were anoxic30. The hypoxic response was greatly impaired and there was no perception of dyspnea in a boy with asthma who had repeated episodes of severe respiratory failure with loss of consciousness after carotid-body resection31. These two reports suggest that a decreased hypoxic response and a blunted sensation of dyspnea may coexist if the function of the carotid chemoreceptors is impaired. Most of our patients with near-fatal asthma were quite similar to the patients described above. Therefore, a dysfunction of the carotid chemoreceptors may account for the coexistence of decreased hypoxic chemosensitivity and blunted dyspnea in patients with near-fatal asthma.

The ability to respond to hypoxia may be influenced by a hereditary factor, presumably genetic,26,32,33,34 and even some normal subjects have a very low hypoxic response. Because the role of the hypoxic stimulus in the control of ventilation is limited,35 it is not surprising that patients with near-fatal asthma usually have a normal response to hypoxia between attacks of asthma. However, in unusual conditions in which hypoxemia is progressive -- for example, at high altitude36 -- hypoxic chemosensitivity may have a critical role in maintaining breathing. We speculate that this may be the case during life-threatening asthma attacks when hypoxemia worsens rapidly.

Our results have several clinical implications for preventing death from asthma. First, measurements of chemosensitivity and perception of dyspnea are needed to identify patients at high risk for a fatal attack of asthma. Second, because some patients have a blunted perception of dyspnea, measurements of airway narrowing, such as peak-flow monitoring, are required to assess a patient's actual condition. Finally, education of physicians is important to prevent death from asthma. Physicians should know that reliance on a patient's own assessment of his or her condition without an objective determination of airway narrowing carries a risk of undertreatment, which may lead to death.

We are indebted to Dr. James P. Butler for his helpful suggestions; to Drs. Jun Midorikawa, Akiko Mizusawa, and Hiromasa Ogawa for their expert technical assistance; and to Mr. Brent Bell for reading the manuscript.


Source Information

From the First Department of Internal Medicine, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980, Japan, where reprint requests should be addressed to Dr. Shirato.

References

  1. McFadden ER Jr. Fatal and near-fatal asthma. N Engl J Med 1991;324:409-411. [Medline]
  2. Drazen JM, Boushey HA, Holgate ST, et al. The pathogenesis of severe asthma: a consensus report from the Workshop on Pathogenesis. J Allergy Clin Immunol 1987;80:428-437. [Medline]
  3. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423-429. [Medline]
  4. British Thoracic Association. Death from asthma in two regions of England. BMJ 1982;285:1251-1255.
  5. Sears MR, Rea HH. Patients at risk for dying of asthma: New Zealand experience. J Allergy Clin Immunol 1987;80:477-481. [CrossRef][Medline]
  6. Spitzer WO, Suissa S, Ernst P, et al. The use of {beta}-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-506. [Abstract]
  7. Rea HH, Scragg R, Jackson R, Beaglehole R, Fenwick J, Sutherland DC. A case-control study of deaths from asthma. Thorax 1986;41:833-839. [Free Full Text]
  8. Molfino NA, Nannini LJ, Martelli AN, Slutsky AS. Respiratory arrest in near-fatal asthma. N Engl J Med 1991;324:285-288. [Abstract]
  9. Cotes JE. Lung function: assessment and application in medicine. 4th ed. Oxford, England: Blackwell Scientific, 1979:365-87.
  10. Takishima T, Hida W, Sasaki H, Suzuki S, Sasaki T. Direct-writing recorder of the dose-response curves of the airway to methacholine: clinical application. Chest 1981;80:600-606. [Free Full Text]
  11. Guidelines for the diagnosis and management of asthma: National Heart, Lung, and Blood Institute: National Asthma Education Program: expert panel report. J Allergy Clin Immunol 1991;88:Suppl:427-438. [CrossRef]
  12. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225-244. [Medline]
  13. Taguchi O, Kikuchi Y, Hida W, et al. Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea. J Appl Physiol 1991;71:2183-2190. [Free Full Text]
  14. Okabe S, Chonan T, Hida W, Satoh M, Kikuchi Y, Takishima T. Role of chemical drive in recruiting upper airway and inspiratory intercostal muscles in patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:190-195. [Medline]
  15. Hida W, Susuki R, Kikuchi Y, et al. Effect of local vibration on ventilatory response to hypercapnia in normal subjects. Bull Eur Physiopathol Respir 1987;23:227-232. [Medline]
  16. Whitelaw WA, Derenne JP, Milic-Emili J. Occlusion pressure as a measure of respiratory center output in conscious man. Respir Physiol 1975;23:181-199. [CrossRef][Medline]
  17. el-Manshawi A, Killian KJ, Summers E, Jones NL. Breathlessness during exercise with and without resistive loading. J Appl Physiol 1986;61:896-905. [Free Full Text]
  18. Chonan T, Mulholland MB, Altose MD, Cherniack NS. Effects of changes in level and pattern of breathing on the sensation of dyspnea. J Appl Physiol 1990;69:1290-1295. [Free Full Text]
  19. Read DJC. A clinical method for assessing the ventilatory response to carbon dioxide. Australas Ann Med 1967;16:20-32. [Medline]
  20. Rebuck AS, Campbell EJM. A clinical method for assessing the ventilatory response to hypoxia. Am Rev Respir Dis 1974;109:345-350. [Medline]
  21. Onal E, Lopata M, O'Connor TD. Diaphragmatic and genioglossal electromyogram responses to isocapnic hypoxia in humans. Am Rev Respir Dis 1981;124:215-217. [Medline]
  22. Onal E, Lopata M, O'Connor TD. Diaphragmatic and genioglossal electromyogram responses to CO2 rebreathing in humans. J Appl Physiol 1981;50:1052-1055. [Free Full Text]
  23. Kelsen SG, Fleegler B, Altose MD. The respiratory neuromuscular response to hypoxia, hypercapnia, and obstruction to airflow in asthma. Am Rev Respir Dis 1979;120:517-527. [Medline]
  24. Altose MD, Kelsen SG, Stanley NN, Levinson RS, Cherniack NS, Fishman AP. Effects of hypercapnia on mouth pressure during airway occlusion in conscious man. J Appl Physiol 1976;40:338-344. [Free Full Text]
  25. Hudgel DW. Control of breathing in asthma. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma: mechanisms and therapeutics. 2nd ed. Boston: Little, Brown, 1985:193-8.
  26. Hudgel DW, Weil JV. Asthma associated with decreased hypoxic ventilatory drive: a family study. Ann Intern Med 1974;80:623-625.
  27. Hudgel DW, Weil JV. Depression of hypoxic and hypercapnic ventilatory drives in severe asthma. Chest 1975;68:493-497. [Free Full Text]
  28. Rubinfeld AR, Pain MC. Perception of asthma. Lancet 1976;1:882-884. [Medline]
  29. Barnes PJ. Poorly perceived asthma. Thorax 1992;47:408-409. [Free Full Text]
  30. Nakayama K. The surgical significance of the carotid body in relation to bronchial asthma. J Int Coll Surg 1963;39:374-389. 
  31. Chang KC, Morrill CG, Chai H. Impaired response to hypoxia after bilateral carotid body resection for treatment of bronchial asthma. Chest 1978;73:667-669. [Free Full Text]
  32. Collins DD, Scoggin CH, Zwillich CW, Weil JV. Hereditary aspects of decreased hypoxic response. J Clin Invest 1978;62:105-110.
  33. Moore GC, Zwillich CW, Battaglia JD, Cotton EK, Weil JV. Respiratory failure associated with familial depression of ventilatory response to hypoxia and hypercapnia. N Engl J Med 1976;295:861-865. [Abstract]
  34. Kawakami Y, Yoshikawa T, Shida A, Asanuma Y, Murao M. Control of breathing in young twins. J Appl Physiol 1982;52:537-542. [Free Full Text]
  35. West JB. Respiratory physiology -- the essentials. 3rd ed. Baltimore: Williams & Wilkins, 1985:113-27.
  36. Lakshminarayan S, Pierson DJ. Recurrent high altitude pulmonary edema with blunted chemosensitivity. Am Rev Respir Dis 1975;111:869-872. [Medline]

 

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