The Arterial to End-Expiratory Carbon Dioxide Tension Gradient in Acute Pulmonary Embolism and Other Cardiopulmonary Diseases

The Arterial to End-Expiratory Carbon Dioxide Tens ion Gradient in Acute Pulmonary Embolism and Other Cardiopulmonary Diseases* L. Hatle, M.D., •• and R. Rokseth, M.D.t The arterial to end-tidal Pco2 gradient was measured in normal subjects and in the following patient groups: acute puhnonary embolism, acute myocardial infarction, left ventricular failure, pneumonia, obstmctive long diseases, primary pulmonary hypertension and shock from various causes. Increased gradients were observed in 24 of 25 patients with moderate or massive embolism, in 7 of 17 with small emboH, in 20 of 34 with chronic long

diseaes, in 6 of 14 with shock and in 3 of 24 with left ventricular failure. By measuring in maximal expiration, high gradients in lung embolism were only slightly reduced, but approached zero in obstmctive hmg diseaes or left ventricular failure. The patients with large emboH were thus clearly separated from other groups with acute or chronic ventilation-perfusion disturbances. No conclusive results were obtained in patients in shock.

Robin et aP pointed out that the difference between carbon dioxide tension in arterial blood and end-tidal air was increased in acute pulmonary embolism because of continued ventilation of nonperfused parts of the lung. The clinical value of this gradient has not been clearly established, among other reasons because it may also be increased in other acute or chronic lung diseases.2.3 The gradient should not diminish substantially in pulmonary embolism by measuring at the end of maximal expiration, but should decrease in conditions with uneven ventilation or low ventilation-perfusion ratio. The purpose of the present study was to test this hypothesis and its clinical value in separating pulmonary embolism from other diseases with similar clinical pictures.

monary disease, and previous right-heart catheterization had demonstrated elevated pulmonary arterial pressure and normal wedge pressure. The term "chronic cor pulmonale" in this study does not include patients with primary pulmonary hypertension or patients with a history of embolism. The carbon dioxide tension ( P002) gradients were usually measured one to four days after admission and on the same day as angiography or within one to four days before autopsy in those who died.

PATIENTS

The subjects were classified according to the following conditions:

Healthy Lung-Circulatory System This control group comprised 19 subjects, including 4 with hyperventilation syndrome.

Pulmonary Embolism This group comprised 46 nonselected patients. The diagnosis was confirmed by angiography in 28 and autopsy in the remaining 18. Four had chronic cor pulmonale and were considered separately. They had chronic obstructive pui0From the Department of Cardiology, Central Hospital, Trondheim, Norway. ••Registrar, Department of Cardiology. tChief, Department of Cardiology. Supported by the Norwegian Council on Cardiovascular Diseases and the Oldtime Dancing Club, Tempo 1964, Trondheim, Norway. Manuscript received August 13, 1973; revision accepted April 3. Reprint requests: Dr. Rokseth, Central Hospital, Tr~m, Norway.

352 HATLE, ROKSETH

Acute Myocardial Infarction Thirty-three patients were examined one to three days after onset of myocardial infarction. Some still had retrosternal pain, but none had left ventricular failure as judged by clinical methods, ie, absence of dyspnea, apical diastolic sound, pulmonary rales OJI roentgenologic signs of congestion.

Left Ventricular Faaure and Pneumonia These diseases were considered together, as the Pco2 gradient behaved similarly. The group comprised 24 patients with acute or chronic left ventricular failure due to coronary heart disease or aortic stenosis/insufficiency and five patients with bronchopneumonia. The diagnosis of ventricular failure was made clinically, ie, from the presence of orthopnea, pulmonary rales and roentgenologic signs of congestion. None of the 24 patients had signs of obstructive pulmonary disease as judged by clinical history or physical, ventilatory or roentgenologic examination.

Chronic Bronchitis/ Emphysema This group comprised 34 patients with or without exacerbation of the disease. Clinical and ventilatory examination revealed obstructive pulmonary disease.

Primary Pulmonary Hypertension This group comprised five patients. The diagnosis had previously been confirmed by right heart catheterization, shunts being excluded by analyses of oxygen saturation and angiography. The systolic pulmonary artery pressure was above 65 mm Hg in all.

CHEST, 66: 4, OCTOBER, 1974

Patients in Shock Patients in this group comprlsed 14 fn shock due to various causes except pulmonary embolism: eight had acute myocardial infarction, four septic shock, one hemorrhagic shock and one Addison crisis. Shock was defined as "a systolic blood pressure below 90 mm Hg and oliguria in addition to clinical signs, pallor, moist, clammy or cyanotic skin and mental confusion." The duration of shock before testing was 20 minutes in one patient and one hour or more in the others. METIIODS

The patients were examined in the supine or half-sitting position in bed. The procedure was explained to them, a noseclip was then applied, and they became accustomed to breathing through a mouthpiece for three to four minutes, while a thin needle was inserted into the brachial or femoral artery, nearly always without pain. If the patient's breathing was rapid and shallow, he was told to try breathing calmly and evenly, which in most cases was successful. The mouthpiece was connected to an infrared rapid C02·analyzer (ListonBeeker, model LB 1 ) , allowing continuous recording. Endtidal Pco2 was taken as an average of five to ten plateau readings at the same time as the collection of arterial blood. The patient was then instructed to exhale maximally from level respiration. The infrared analyzer was frequently calibrated with gas from cylinders containing various amounts of C02, the gas contents being checked with a Micro-Scholander apparatus. All blood samples were analyzed immediately, with arterial P002 and pH measured by an Astrup machine. Oxygen saturation was measured by an oximeter. Lung ventilation was measured by collecting exhaled air in a Douglas bag for a period of three minutes. The results were usually available within 15 to 20 minutes after start of the procedure. Right-heart catheterization was performed in the department of roentgenology, angiography usually being performed from the right ventricle. The size of the embolized area was estimated as a percentage area, without visible perfusion in the frontal plane.

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fu:sULTS

The Pcxn Gradient During Normal Respiration, Control Subjects The results are seen in Figure 1. The Pcxn gradient was within +3.5 mm Hg in all subjects. The arterial Pcxn varied from 34 to 46 mm Hg in 15 and from 22 to 33 in the 4 subjects with hyperventilation syndrome. Mean pH was 7.42 (range 7.39-7.46) in 15 subjects and 7.49 (range 7.41-7.56) in those who hyperventilated. Arterial oxygen saturation varied from 96 to 100 percent.

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25 40 45 30 35 FIGURE 1. Relationship between end-tidal and arterial P002 in subjects with no circulatory or lung diseases. Four had hyperventilation syndrome. Lines of identity and normal range are shown.

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CHEST, 66: 4, OCTOBER, 1974

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FIGURE 2. Relationship between.end-tidal and arterial Pc02 in patients with pulmonary embolism. Closed circles show less than 25 percent occlusion of pulmonary vascular bed; open circles: between 25 and 50 percent occlusion; crosses: more than 50 percent occlusion.

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ARTERIAL TO END-EXPIRATORY Pco 2 IN ACUTE PULMONARY EMBOLISM 353

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Figure 3 shows the results. The P<::02 gradient ranged from 6 to -3.5 mm Hg, mean arterial P<::02 was 37 (range 28-43), pH 7.42 (7.35-7.50) and oxygen saturation 93 ( 87-98) percent.

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The P<::02 gradient was within normal range in all except three patients (Fig 4). The mean arteria] P<::02 was 37 (23-50), pH 7.43 (7.27-7.52) and arterial oxygen saturation 88 ( 70-95) percent.

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mean oxygen saturation of 82 percent (range 5994), a mean pH of 7.46 (range 7.39-7.58) and a mean lung ventilation of 13.2 L (range 8.9-19.5 L).

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classified according to percentage of occlusion of the pulmonary vascular bed as judged by angiography. In 10 of 17 patients with small emboli, the P<::02 gradient was within generally accepted norma] range (less than ±5 nun Hg).u In this group the mean arterial P<::02 was 36 mm (range 30-44). Mean pH was 7.45 (range 7.38-7.55) and mean arteria] oxygen saturation 90 percent (range 83-96). The lung ventilation per minute varied from 7.5 to 13.2 L (mean 10.5 L ). All except one patient with moderate or m~ive embolism showed gradients above 5 mm Hg. Most patients with massive embolism had low arterial Pco2 (mean 30, range 23-42 mm Hg). They had a Chronic bronchitis- enphyaema 34 patients end-tidal

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Figure 5 shows that arterial P002 ranged from 35 to 83 mm Hg, being normal ie, less than 45 mm Hg in 14 patients, while it was 47 or more in 20. The PCO:! gradient was elevated above normal in 20 of the 34 patients, especially those with high arteria] P<::02, but also in some with low values. Mean pH was 7.41 (7.31-7.52) and oxygen saturation 80 (5698) percent. Primary Pulmonary Hypertension

All patients had clinical hyperpnea. The mean lung ventilation was 13.1 L ( 10.1-16.8). The PCO:! gradient ranged from 6.5 to-4 mm Hg, mean arteria] PCO:! was 31 (23.5-37.5), pH 7.47 (7.37-7.51) and oxygen saturation 87 ( 62-97) percent.

Shock Figure 6 shows the results. The PCl02 gradient was within normal range in seven patients, between 5.5 and 8 mm Hg in six and 24 in one. Mean arterial Shock - 14 patients end-tidal

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354 HATLE, ROKSETH

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CHEST, 66: 4, OCTOBER, 1974

P002 was 33 (25.5-47), mean pH 7.31 (6.97-7.43) and mean oxygen saturation 88 ( 82-94) percent. All except one patient had low P002 and most had metabolic acidosis. There was no relationship between the P002 gradient, arterial oxygen saturation and the degree of acidosis.

The P002 Gradient During Maximal Expiration In patients with embolism, an enlarged arterial to end-tidal Pco2 gradient was reduced little on maximal expiration. The test was carried out in 11 patients, with a mean gradient of 10.5 mm Hg. During maximal expiration the mean gradient was 9 (Fig 7). This contrasted with the response in patients with chronic bronchitis/emphysema (Fig 5, 7) in which the gradient on maximal expiration was normalized in all but two patients. The gradient was reduced on an average from 8.5 to -0.5 in 21 patients. Three of the four patients with previous chronic cor pulmonale had been examined prior to the embolic episode. The results are seen in Figure 8. The P002 gradient on maximal expiration which in these three patients was normal beforehand, increased significantly after embolism had occurred. The arterial blood gas levels changed as they do with increasing respiratory failure, ie, P002 increased and arterial oxygen saturation decreased. The fourth patient was examined while on artificial ventilation. In four other patients, not included in the present study, with respiratory failure but without embolism, the arterial end-expiratory P002 gradient was measured during artificial respiration and was always below 5 mm Hg. In patients with left ventricular failure or pneumonia the P002 gradient was measured during maximal expiration in four, two of whom demonstrated increased gradients. The gradient was significantly reduced in all. This is exemplified in Figure 7 in a patient in whom the gradient was reduced from 11 to l mm Hg. In the severely ill patients with shock, it was only possible to measure the gradient during maximal expiration in one. He was in hemorrhagic shock, which had lasted 20 minutes. The systolic blood pressure was 70 mm Hg. The gradient was reduced from 24 mm Hg to 18 during maximal expiration. Repeated Recordings df P002 Gradient Figure 9 shows the results of repeated recordings of arterial to end-tidal P002 gradient in 14 patients with pulmonary embolism and without congestive heart failure. The gradient often decreased during the first days or weeks after onset of symptoms, but might be high after one to two weeks or more. Occasionally it even rose, probably due to recurrent emboli, which was clinically likely in three of the four patients showing this pattern.

CHEST, 66: 4, OCTOBER, 1974

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CoMMENT

Previous studies on arterial to end-tidal P002 in acute pulmonary embolism either report conflicting results or do not include a comparison with other well defined groups of circulatory or lung disorders. Our results support those of Robin et al:' They observed no gradient higher than 5 mm Hg in 24 normal subjects, a gradient of 6 to 15 in 3 patients, with pulmonary embolism verified later at autopsy and 4 to 32 in 9 others with probable embolism. Another report6 showed gradients above 6 mm Hg in only three of seven patients with embolism, but these patients were examined as late as 7 to 30 days after onset of symptoms. One study8 of a mixed group of 43 patients including acute or chronic heart/lung diseases showed gradients. varying from 0.5 to 4.5, and from 5.5 to 17.5 in 16 patients with probable or verified pulmonary embolism. By balloon occlusion of the right pulmonary artery a gradual increase in the gradient from 2 to 14 mm Hg was noted. Nutter and Massumi 3 found mean arterial to end-tidal gradients of 4, 11 and 14 mm Hg, respectively, in 29 subjects with no disease, 20 patients with pulmonary embolism and 14 patients with chronic lung diseases. They recorded variable changes after balloon occlusion of one pulmonary artery. Their results did not allow a clear separation of pulmonary embolism from chronic lung disease. The elevated arterial end-tidal P002 gradient in patients with pulmonary embolism rests on sound physiologic bases, ie, normal or high ventilation of an underperfused lung or lung segment. But an elevated gradient is also logical in patients with other ventilation-perfusion disturbances, such as chronic bronchitis/ emphysema. All except one of our patients with large emboli as well as many with chronic lung diseases had increased gradients. By maximal expiration the patients with pulmonary embolism were clearly separated from those with

ARTERIAL TO END-EXPIRATORY Pco2 IN ACUTE PULMONARY EMBOLISM 355

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chronic lung diseases, the former showing little gradient reduction, while the latter showed reduction to normal or near normal. This was also expected as deep expiration should wash out some hypoventilated but well perfused areas in ventilatory disorders. The expiratory tracings from the infrared analyzer in patients with pulmonary embolism ended in a fiat or nearly Bat plateau, but in patients with chronic lung diseases there was a rule of steady slope upwards. Similar values of P002 in arterial blood and in deep expiratory air in patients with chronic lung disease were also found by others.7 The importance of deep expiration has previously been stressed, 5 but has to our knowledge not been studied systematically with the aim of ACUTI IMIOLISM

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356 HAllE, ROKSETH

comparing different disorders such as the present material. Pulmonary embolism in the four patients with previous chronic cor pulmonale resulted in worsening of the respiratory failure and increased gradients during maximal expiration. The method of such gradient measurements has been criticized3 because it may be difficult to ensure sufficient expiration in these severely ill patients. To test if this was a likely explanation, three other patients with chronic cor pulmonale and similar severity of clinical condition and degree of respiratory failure were tested before and after breathing 100 percent oxygen. Breathing oxygen decreased ventilation further, with increasing arterial P002 (Fig 8) and worsening of the clinical condition. The gradients during maximal expiration, however, changed little in sharp contrast to those in pulmonary embolism. With a little patience, it was nearly always possible to ensure maximal expiration, even in patients with pain. But falsepositive gradients may certainly be found if this factor is not taken into account. ( Fig 7) . Our study showed, in accordance with others, 8 that some patients in shock due to acute myocardial infarction for example also may display an enlarged arterial to end-tidal P002 gradient. The patients with uncomplicated myocardial infarction showed normal gradients. An occasional patient with left ventricular failure displayed an elevated gradient which, however, was normalized during maximal expiration. Hyperpnea is a well known clinical sign in acute pulmonary embolism. Elevated P002 gradients were not found in our patients with hyperventilation syndrome or primary pulmonary hypertension, both groups having similar hyperventilation to patients with pulmonary embolism. Few studies have been made on the change of gradiant with time after onset of embolism. According to the experience of some clinicians,9 the gradient is significantly elevated only during the first few days. Petersen, 10 however, reported a patient whose gradient was elevated for two to three weeks. In experiments with dogs, 11 •12 a return to pre-embolic values has been observed after four to ten days. The course may partly be determined by resolution of emboli and partly by bronchospasm, hyperemia and edema, causing ventilation to deviate from embolized to nonembolized lung area. The significance of the latter processes is difficult to assess. Angiographic and/ or scan studies in man showed little change of emboli during the first two days, 13 and resolution usually lasted at least two weeks. 14•15 In the present study the gradient sometimes decreased within days, but often persisted for weeks and occasionally even rose, suggesting recurring embolism. In conclusion, the measurement of end-tidal and CHEST, 66: 4, OCTOBER, 1974

maximal expiratory P<::02 together with arterial P<::02 is a simple bedside method giving results which, although not conclusive, are highly indicative in diHerentiating large puhnonary emboli from other conditions which may cause similar symptoms. In patients in shock, the method was less useful in the present study. The test is rapidly performed and together with serial ECGs may strengthen clinical suspicion and assist in obtaining a sounder basis for diagnosis, early therapy and the decision to pedorm more elaborate and time-consuming laboratory examinations.

1 Robin ED, Julian DG, Travis DM, et al: A physiologic approach to the diagnosis of acute pulmonary embolism. N Engl J Med 260:586-591, 1959 2 Herzog H, Staub H, Richterich R: Gas-analytical studies in severe pneumonia. Lancet 1:593-597, 1959 3 Nutter DO, Massumi RA: The arterial-alveolar carbon dioxide tension gradient in diagnosis of pulmonary embolns. Otest 50:380-387, 1966 4 Robin ED, Forkner EC Jr, Bromberg PA, et al: Alveolar gas exchange in clinical pulmonary embolism. N Engl J Med 262:283-287, 1960 5 Colp CR, Williams MH Jr: Pulmonary function following pulmonary embolization. Am Rev Resp Dis 85:799-807,

1962 6 MacKeen AD, Landrigan PL, Dickson RC: Early diagnosis of acute pulmonary embolism. Can Med Assoc J 85:233-236, 1961 7 Tulou PP, Walsh PM: Measurement of alveolar carbon dioxide tension at maximal expiration as an estimate of arterial carbon dioxide tension in patients with airway obstruction. Am Rev Resp Dis 102:921-926, 1970 8 Ayres SM, Mueller H, Giannelli S Jr, et al: The lung in shock. Am J Cardiol26:588-594, 1970 9 Sasahara AA, Cannilla JE, Morse RL, et al: Clinical and physiologic studies in pulmonary thromboembolism. Am J Cardiol20:10-20, 1967 10 Petersen ES: Kulldioksidtensioneme i alveoleluft og 1 arterieblod ved embolia arteriae pulmonalis. Ugeskr Laeger126:1016-1018, 1964 11 Levy SE, Stein M, Totten RS, et al: Ventilation-perfusion abnormalities in experimental pulmonary embolism. J Clin Invest 44:1699-1707, 1966 12 Marshall R, Sabiston DC, Allison PR, et al: Immediate and late effects of pulmonary embolism by large thrombi in dogs. Thorax 18:1-9, 1963 13 McDonald JG, Hirsh J, Hale GS: Early rate of resolution of major pulmonary embolism. Br Heart J 33:432-437, 1971 14 Dalen JE, Banas JS Jr, Brooks HL, et al: Resolution rate of acute pulmonary embolism in man. N Engl J Med 280: 1194-1199, 1969 15 Walker RHS, Jackson RA, Goodwin J: Resolution of pulmonary embolism. Br Med J 4:135-139, 1970

Genius and Mediocrity The gene is an ultramicroscopic entity associated with chromosomes. The term "chromosome" was given because of the possibility of seeing these thread-like structures when suitably stained. Their number and shapes are very constant. The genes, according to the work of Morgan in America, are located in strings along the chromosomes. These genes determine all the characteristics of the organism with which they become associated in the process of fertilization. The normal transference of parental genes to the offspring determines the characteristics of the latter according to certain laws of inheritance. Slight variations in the number and kind of genes transmitted account for the variations of the adult offspring. Variations arise from the sudden appearance of new genes-a process known as "mutation." The muta-

CHEST, 66: 4, OCTOBER, 1974

tion of a gene may produce a genius, but it is more likely to lead to mediocrity. The reasons why genes mutate are not fully known but heat and exposure to high frequency of electromagnetic radiations (gamma rays and x-rays) do affect the rate of mutation. Another cause is hybridization between species or subspecies. A third factor affecting mutation rate is the spasmodic and random occurrence of new genes in the organisms themselves, leading to what is generally termed inheritable random variations. At the present time it is known that such random mutations occur but their cause is unknown. The probability is that some external or environmental cause is operative but if so, it has not yet been recognized. Palmer, LS: Man's Journey Through Time, New York, Philosophical Library, 1959

ARTERIAL TO END-EXPIRATORY Pco2 IN ACUTE PULMONARY EMBOLISM 357