Effect of metabolic alkalosis on respiratory function in patients with chronic obstructive lung disease * R. BEAR, MD, FRCP[C], FACP; M. GOLDSTEIN, MD, FRCP[C]; E. PHILLIPSON, MD, FRCP[C]; M. Ho, MD; M. HAMMEKE, MD; R. FELDMAN, MD; S. HANDELSMAN, MD; M. HALPERIN, MD, FRCP[C] Eleven instances of a mixed acid-base disorder consisting of chronic respiratory acidosis and metabolic alkalosis were recognized in eight patients with chronic obstructive lung disease and carbon dioxide retention. Correction of the metabolic alkalosis led to substantial improvement in blood gas values and clinical symptoms. Patients with mixed chronic respiratory acidosis and metabolic alkalosis constitute a common subgroup of patients with chronic obstructive lung disease and carbon dioxide retention; these patients benefit from correction of the metabolic alkalosis. Onze episodes de dereglement acide.-base mixte consistant en une acidose respiratoire chronique et en une alcalose metabolique ont ete identifies chez huit patients souffrant d'obstruction pulmonaire chronique et de retention de l'anhydride carbonique. La correction de l'alcalose metabolique a entraine une amelioration substantielle des concentrations des gaz sanguins et des sympt6mes cliniques. Les patients atteints d'acidose respiratoire chronique et d'alcalose metabolique mixtes constituent un sousgroupe frequemment rencontre chez les patients presentant une obstruction pulmonaire chronique et une retention de l'anhydride carbonique; ces patients profitent d'une correction de l'alcalose metabolique.

Chronic obstructive lung disease is frequently complicated by chronic respiratory acidosis. In patients with this complication renal compensatory mechanisms are brought into play in an attempt to minimize the change in pH. The degree to which renal compensation occurs is highly predictable and has been defined by Schwartz, Brackett and Cohen' in terms of a 95% confidence band. Using this confidence band, or nomograms derived from it,' the clinician can detect mixed acidbase disorders. For example, if a patient with chronic respiratory acidosis From the departments of medicine, St. Michael's Hospital, Toronto General Hospital and the University of Toronto *Presented in part at the 57th annual session American College of Physicians, Philadelphia, April 1976, and at the 46th annual meeting, Royal College of Physicians and Surgeons of Canada, Toronto, Jan. 29, 1977 Reprint requests to: Dr. R. Bear, Division of nephrology, St. Michael's Hospital, 30 Bond St., Toronto, Ont. M5B 1W8

is less acidemic (for a given degree of are given in Table II; in one patient elevation in PaCo,) than predicted by the results were not available but rothe confidence band, it can be predicted entgenograms of the chest showed emthat he has coexistent metabolic alka- physematous blebs and the patient had losis (Fig. 1). the physical findings typical of emThis particular combination of acid- physema. base disorders (i.e., mixed chronic rePrior to this study the patients' conspiratory acidosis and metabolic alka- ditions were stabilized maximally with losis) is not uncommon in patients with standard therapy for chronic obstrucchronic obstructive lung disease, as tive lung disease (Table I); the therapy these patients often require therapy was not altered during the study. Durwith steroids or diuretics, or both. Since ing a period of observation (mean profound metabolic alkalosis has occa- (ILlration, 8.1 days; range, 2 to 27 days) sionally been described as causing re- the diagnosis of mixed chronic reversible reduction in alveolar ventila- spiratory acidosis and metabolic alkation5'6 we decided to evaluate system- losis was made when serum bicarbonate atically the effect of coexistent meta- values were consistently on the alkabolic alkalosis on respiratory function lemic side of the confidence band for in patients with chronic respiratory pure chronic respiratory acidosis1 (Fig. acidosis. In this report we describe 11 1). A mean of 6.8 (range, 3 to 17) blood instances of mixed chronic respiratory samples were collected from each paacidosis and metabolic alkalosis in tient during this period. Of the 11 ineight patients; correction of the meta- stances of this combination of acidbolic alkalosis led to clinical improve- base disorders the metabolic alkalosis ment associated with substantial changes was "saline resistant" in 7 and "saline in Pao, and PaCo,. responsive" in 4*7 In one patient (no. 3) the superimposed metabolic alkalosis Patients and methods was reinduced intentionally with bicarbonate and diuretic therapy (with inThe study included all patients with formed consent.. chronic obstructive lung disease and The therapy for the metabolic alkamixed chronic respiratory acidosis and losis (Table I) included administration metabolic alkalosis that we were asked of acetazolamide in seven instances and to evaluate on the wards of St. Mi- ammonium chloride in three instances. chael's Hospital between February 1975 Subsequent to correction of the metaand November 1976 except for three bolic alkalosis one patient was observed with reversible causes of respiratory for 50 weeks and the others for a mean failure (such as heart failure and pneu- of 8.8 days (range, 4 to 23 days). A monia). The pertinent clinical data for mean of 5.7 (range, 3 to 14) blood gas the eight patients, who ranged in age and serum electrolyte values were obfrom 47 to 79 years, are presented tained for each patient after correction in Table I. Mean results of pulmonary of the metabolic alkalosis. The pH, function tests at the time the patients Paco, and Pao, were determined by were first evaluated for lung disease means of a blood gas analyser (Instrumentation Laboratory, Inc., Lexing50Massachusetts, model 313) with apton, 0 0 propriate temperature correction, and 40serum electrolyte concentrations were 0 C') determined by standard methods with . 30.the Technicon AutoAnalyzer II. Results

20j 30

50

70

90

110

130

PaCO2 FIG. I -Mean serum bicarbonate (mmol/ L) values in 11 instances of mixed chronic respiratory acidosis and metabolic alkalosi s are outside the confidence hand for pur e chronic respiratory acidosis.

900 CMA JOURNAL/OCTOBER 22, 1977/VOL. 117

Within 24 hours after correction of the metabolic alkalosis there was a significant decrease (P < 0.05) in the

PaCO, and a significant increase (P < 0.01) in the Pao, as the serum bicarbonate concentration decreased; consequently there was little change in the pH (Table III). Coincidentally the patients spontaneously reported a sub-

Table Il--Mean rosultsofpulmenaryfunction teats for seven of the patients at time of flit evaluation for lungdiseaso

value .1 Variable capacity Lung volumes 69 Total lung Capacity 135 Functional residual capacity 118 Residual volume 219 Flow rates Forced oxpiratory volume in I second 27 Maximum mid-expiratory flow rate 20

increased ventilation secondary to increased concentrations of ammonia in the blood, cerebrospinal fluid or extracellular fluid of the brain cannot be the only factor operative in these paients. The hydrogen ion concentration of the extracellitlar fluid of the brain has a central role in the control of ventilation.'2"5 Furthermore, it has been demonstrated that increments in ventilation that occur during inhalation of carbon dioxide are inversely related to the concentration of bicarbonate in the blood.'''5 It is possible, therefore, that in our patients increased alveolar ventilation, resulting in decreased Paco2, was secondary to a decrease in the bicarboiiate concentration, and therefore the p1-I, of the extracellular fluid of the brain. However, since the Paco7 in our patients decreased along with the serum bicarbonate concentration, there was very little change in the systemic pH. Furthermore, animal data suggest that the extracellular fluid of the brain is defended well against suduen changes in pH induced by developing metabolic acid base disturbances.'. A number of investigators,17 21 primarily in the 1950s, attempted to improve respiratory function in patients with chronic o1)structive lung disease by inducing metabolic acidosis. The results of these studies varied and this mode of therapy gradually fell into disuse. However, the results are difficult to interpret. Arterial blood gas data in several instances are incomplete and many of the values appcar incorrect when analysed in terms of the

Henderson Hasselbalch equation. Nevertheless, it appears that many of the patients who derived benefit from acetazolamide therapy had mixed respiratory acidosis and metabolic alkalosis. These results, in concert with those we have reported, suggest that it is this subgroup of patients with chronic obstructive lung disease who may benefit from therapy with acetazolamide or ammonium chloride. Administration of sodium and potassium chloride, however, is the appropriate therapy for chloride-sensitive metabolic alkalosis. Such therapy accompan ied administration of acetaLolamide or ammonium chloride in our patients, these two agents being given primarily to correct the metabolic alkalosis more rapidly. It is not rare for patients with chronic obstructive lung disease to have mixed chronic respiratory acidosis and metabolic alkalosis. In a retrospective study of blood gas values in patients with chronic obstructive lung disease studied at the Toronto General Hospital this mixed acid-base disorder was diagnosed in 26 of 71 cases (S. Handelsman, R. Feldman, M.B. Goldstein, et al: unpublished data, 1976), a finding that confirms the work of Robin3 and Martin.4 The frequency of superimposed metabolic alkalosis is not surprising because many of these patients are receiving therapy with steroids or diuretics or both and their dietary intake of sodium is restricted. Although steroid therapy is used by some clinicians for patients with severe chronic obstructive lung disease, there have 902 CMA JOURNAL/OCTOBER 22, 1977/VOL. 117

been no controlled studies to confirm its effectiveness in this condition. Hence the risks, both of steroid myopathy developing and of metabolic alkalosis being induced, make such therapy potentially dangerous in these patients. It is also not surprising that the presence of a mixed acid-base disorder was not recognized frequently before the advent of acid base confidence bands. The pH values in our patients and in those with mixed acid-base disturbances referred to in early studies'7-2' were not profoundly alkalemic and in some cases were even mildly acidemic. PrevioLisly such patients were probably thought to have well compensated chronic respiratory acidosis. Although it is well known that the metabolic response to respiratory acidosis does not return the blood pH to normal values, the basis for this incomplete recovery has been unclear, for the kidney is able to generate sufficient bicarbonate to return the pH to normal. One could speculate, on the basis of the data presented above, that further .'improvement" in the acidbase status of these patients would be detrimental to their respiratory status, and therefore that the metabolic compensation has been curtailed in some, as yet inapparent, way. Conclusion We have reviewed the physiologic basis for the diagnosis of chronic respiratory acidosis with superimposed metabolic alkalosis. In 11 instances of this mixed disorder in eight patients,

all of whose conditions had been stabiJized maximally with standard conservative therapy for chronic obstructive lung disease, we demonstrated that correction of the metabolic alkalosis improved arterial oxygenation significantly. We suggest that metabolic alkalosis occurs frequently in patients with chronic obstructive lung disease and that correction of this disorder results in substantial improvement in blood gas values and clinical symptoms. References I. SCHWARTZ WB,

2. 3.

4.

5.

BRACKETr NC,

COHEN JJ:

The response of extracellular hydrogen ion concentration to graded degrees of chronic hypercapnia: the physiologic limits of the defense of pH. J Clin Invest 44: 291, 1965 ARBUS GS: An in vivo acid-base nomogram for clinical use. Can Med Assoc 1 109: 291, 1973 ROBIN ED: Abnormalities of acid-base regulation in chronic pulmonary disease, with special reference to hypercapnia and extracellular alkalosis. N Engi J Med 268: 917, 1963 MARTIN L: Non-respiratory (metabolic) acidbase disorders in patients with pulmonary disease (abstr). Am Rev Respir Dis 113: 133, 1976 Ouv,s PB: Severe alveolar hypoventilation in a patient with metabolic alkalosis. Am I

WA SK.K NESS 9 Ii

Med 52: 817, 1972

6. LJFSCHITZ MD, BRASCH R, CuoMo AJ, et al:

Marked hypercapnia secondary to severe metabolic alkalosis. Ann Intern Med 77: 405, 1972

7. SCHWARTZ WB: Disorders of fluid, electrolyte and acid-base balance, in Textbook ol Medicine, 14th ed, BEERON PB, MCDEItMOrr W (eds), Philadelphia, Saunders, 1975, p 1579 8. WIcHSER J, KAZEMI H: CSF bicarbonate regulation so respiratory acidosis and alkalosis. I Appi Physiol 38: 504, 1975 9. Idem: Ammonia and ventilation: site and mechanism of action. Respir Physiol 20: 393, 1974

A A

tO. D,swsor. AM, DEGROOTES J, ROSENTHAL WA,

et al: The effects of Diamox on ammonia metabolism in liver disease. Gun Sci 16: 413, 1957

1. WEBSTER LT .iR, DAVIosoN CS:

Production

of impending hepatic coma by a carbonic anhydrase inhibitor, Diamox. Proc Soc Exp Jiiol Med 91: 27, 1956 12. PAPPENHEIMER JR: The ionic composition of ccrcbral extracellular fluid and its relation to control of breathing. Harvey Lect 61: 71, 1965/66 13. PAPPENHEIMER

JR,

FENCL

V,

HEISEY

SR.

et at: Role of cerebral fluids in control of respiration as studied in unanesthetized goats. Am I Physiol 208: 436, 1965 14. HEINEMANN HO, GOLORINO RM: Bicarbonate and the regulation of ventilation. Am I Med 57: 361, 1974 15. GOLDRINO

RM,

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HO: Respiratory-renal adjustments in chronic

hypercapnia in man. Am I Med 51: 772, 1971

16. LEUSEN I: Regulation of cerebrospinal fluid composition with reference to breathing. Physiol Rev 52: 1, 1972 17. GALOSTON M:

Respiratory and renal effects

of a carbonic anhydrase inhibitor (Diamox) on acid-base balance in normal man and in patients with respiratory acidosis. Am I Med 19: 516, 1955

18. L.'oNs HA, ZUHOt MN, KYDO DM: effects of carbonic arterial

blood

gases

The

anhydrase inhibitor on in

chronic

pulmonary

emphysema: a preliminary report. Am I Med Sci 229: 193. 1955 19. NADELL J: The effects of the carbonic anhydrase inhibitor "6063" on electrolytes and acid-base balance in two normal subjects and two patients with respiratory acidosis. I Clin Invest 32: 622, 1953 20. THOMPSON

WT,

RIcHARDsON

DW,

Gravol longacting capsules

Gravol

Canada's Leading Antinauseant/Antiemetic Dimenhydrinate USP INDICATIONS For prophylaxis and treatment of various forms of motion sickness, M.ni.re's syndrome, vertigo due to other labyrinthine disorders, postoperative vomiting, druginduced nausea and vomiting associated with radiation therapy, and migraine. CONTRAINDICATIONS None reported at customary doses. PRECAUTIONS Some degree of drowsiness may be experienced by certain patients and dosage should be reduced if necessary. Patients on GRAVOL should be cautioned against operating automobiles or machinery requiring alertness because of the possiblility of drowsiness associated with its use. The effects of hypnotic, sedative and tranquilizing drugs may be synergistic if given concomitantly with GRAVOL. During the administration of antiemetics the possibility of underlying organic manifestations or toxic effects of other drugs being masked should be kept in mind. ADVERSE REACTIONS Drowsiness is the most common. Dizziness may also occur. Symptoms of dry mouth, lassitude, excitement and nausea have been reported. DOSAGE AND ADMINISTRATION GRAVOL may be administered by oral, rectal or parenteral route.. Adults: The usual dose is 50-100 mg with dosage repeated every 4 hours as required. Maximum daily dose is 300 mg parenterally, 500 mg orally. Suppositories should be well inserted. Children: 6-8 years: 15-25 mg, two or three times daily 8-12 years: 25-50 mg, two or three times daily Over 12 years: 50 mg, two or three times daily For post*anestheticlpost.surgical nausea and vomiting: 50 mg i/in or i/v, about 45 minutes before surgery 50 mg i/in or i/v, immediately after surgery 50 mg i/in or i/v, every 4 hours for 3 doses For post*radiation nausea and vomiting: 50mg i/in or i/v, 30 to 60 minutes pre-therapy 50mg i/in or i/v, 1 1/2 hours post-therapy 50mg i/in or i/v, 3 hours post-therapy Pediatric suppositories: 1-2 1/2 years: properly insert 1/2 rectal suppository Over 2 1/2 years: insert 1 suppository Repeat one after 6 hours if required, or as prescribed by physician. For ease and comfort, moisten and smooth any edges on suppository before use. SUPPLY GRAVOL TABLETS Each tablet contains 50 mg dimenhydrinate GRAVOL LONG.ACTING CAPSULES Each capsule contains 75 mg dimenhydrinate For immediate release 2 dimenhydrinate 5mg For prolonged release 50 mg dimenhydrinate GRAVOL LIQUID Each S ml spoonful contains 15 mg dimenhydrinate GRAVOL ADULT SUPPOSITORIES Each suppository contains 100 mg dimenhydrinate GRAVOL PEDIATRIC SUPPOSITORIES Each suppository contains 50 mg dimenhydrinate Also available in i/in and i/v presentations Full information available on request

WINDo

CF: The treatment of respiratory acidosis with a potent carbonic anhydrase inhibitor (dichlorphenamide). Am I Med Sci 236: 603,

. Dimenhydrinate

1958

21. BELL ALL JR. SMITH CN, ANDREAE E: Effects

of carbonic anhydrase inhibitor "6063" (Diamox) on respiration and electrolyte metabolism of patients with respiratory acidosis. Am I Med 18: 536, 1955

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