JOHN Rockefeller - Journal of Clinical...

THE EFFECT OF MORPHINEON THE RESPIRATION INPNEUMONIA

BY JOHNSTAIGE DAVIS, JR.

(From the Hospital of The Rockefeller Institute for Medical Research, New York)

(Received for publication July 24, 1928)

INTRODUCTION

Opinion, as to the advisability of administering opiates to patientssuffering from respiratory disorders, especially pneumonia, is divided.For the most part, the writers of the older text books of medicine wereopposed to the use of morphine; however, in certain cases, they be-lieved that codeine was justifiable. The modern writers, particularlyCecile (1) and Cole (2), are of the opinion that the opiates are verynecessary and important drugs in the treatment of pneumonia.Cushny (3) states that severe pain indicates opium even when thedisease itself is one which in ordinary circumstances would contra-indicate it. Codeine is insufficient in severe pain. Hewlett (4)believes that codeine is the drug of choice for treatment of pain andcough in pneumonia. He agrees with Cushny that in cases where therespiration is barely sufficient to aerate the blood, or where profuseexpectoration is present, morphine is dangerous, because of its de-pressant action on the respiratory center, the tendency to abdominaldistention, and to the relaxation of the bronchial musculature and thusthe danger of edema of the lung is increased.

Macht (5) has done experimental work on normal rabbits and pup-pies to determine the volume of air respired after morphine. Heshowed that when small doses of morphine are given the volume ofair respired is increased and, what is more important, the alveolarventilation is also increased, even though the rate be slowed. When,on the other hand, a full dose of morphine is given (1 to 5 mgm. perkilogram) the rate is markedly slowed, the total volume of air respiredis diminished, and the alveolar ventilation is also diminished. Thedead space is slightly increased, pointing to a bronchial dilatation.

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Codeine has a somewhat similar effect, with less influence on the totalvolume output.

Several investigators have carried out experiments showing theeffect of morphine on the respiratory movements and gaseous metab-olism of normal human beings. Higgins and Means (6) concludedfrom their experiments on three subjects that morphine in therapeuticdoses acted as a respiratory depressant, sometimes by acting directlyon the center and sometimes by bronchoconstriction, and in one in-stance by both. The total gaseous metabolism showed as a rule nochange in oxygen consumption (or a very slight diminution) and amarked drop in CO2elimination. The respiration rate usually showeda small increase.

The object of these experiments was to determine the effect ofmorphine on the respiratory movements and the oxygen saturationof the arterial blood of pneumonia patients; From these observationsit was hoped that conclusions based on physiological evidence could bedrawn concerning the value of morphine in the treatment ofpneumomia.

METHODSAND MATERIAL

The observations have been made on human beings, the greaternumber of whomwere acutely ill with lobar pneumonia. One-hun-dred and seventy-three observations have been made on 33 differentcases of pneumonia. On these 43 arterial punctures were done.Fifteen patients were studied in a body plethysmograph recently de-scribed by us (7). They were observed in the plethysmograph from50 minutes to 1I hours An arterial puncture was done before andafter each respiratory tracing was made. Morphine was given sub-cutaneously while the patient was in the plethysmograph and a secondtracing was made from 15 to 30 minutes after the administration ofthe drug. The dose of morphine varied from 10 to 18 mgm. Onepatient was given caffeine in addition to morphine.

The oxygen analyses of the arterial blood were done by the methodof Van Slyke and Neill (8). All estimations were made in duplicate.

EXPERIMENTAL

In order to simplify the interpretation of the experimental data,we have divided the observations into two parts: (I) The effect of

191


morphine on the respiratory movements, and (II) the effect of mor-phine on the oxygen saturation of the arterial blood. The relation-ship of these two has been considered elsewhere (9). The data aretabulated in table 1.

I. The respiratory movements of 15 patients were studied in theplethysmograph before and after morphine administration.

1. Rate. In all but one case there was a drop in rate. The averagedrop in 14 cases was 4.1 to the minute. The greatest fall was from42.5 to 34.1. In one patient (number 6289) the rate increased from40 to 42 per minute. His tidal air, however, fell from 244 to 186 cc.,and his minute volume from 9.78 to 7.81 liters. His breathing indi-cated edema of the lungs and at the time of observation he was rapidlygrowing worse. His arterial saturation dropped from 85.9 to 84.7per cent after morphine, a change of little, if any, significance.

2. Tidal air. In 10 cases there was a drop in tidal air, the greatestdrop being 138 cc. This occurred in patient number 6246, whosearterial saturation diminished 21.3 per cent. The average drop intidal air was 57.7 cc. In the remaining 5 cases the tidal air increased,the greatest increase being 102 cc. In these 5 cases, pleuritic pain wasa prominent symptom, and relief of pain by morphine probablyallowed deeper breathing with more comfort. In one of the 5 cases192 mgm. of caffeine were given with the morphine. These wlll beconsidered later. In no one of these 5 cases was the increase inarterial saturation as great as 4 per cent.

3. Minute volume. In 13 cases the minute volume was diminishedafter morphine. The greatest drop in minute volume was 4.95 litersand the smallest was 0.85 liter, the average being 2.20 liters.

Two patients (numbers 6295 and 6352) showed an increase inminute volume. In both of these the breathing was extremely shal-low and the rate correspondingly rapid. In the one case the rate was42.3 and the tidal air was 196 cc., while in the other the rate was 72and the tidal air was 127 cc. In the first patient the minute volumeincreased from 8.22 to 10.51 liters, and in the second it increased from9.14 to 11.03 liters. Both patients were very ill. The first had twolobes involved, and the second had three. In neither were there anysigns of edema of the lungs. In the second patient there seems tohave been a psychic element in the excessively rapid respirations,

192


since the rate increased at once when he was under observation, eventhough he was unaware of the fact that his respirations were an objectof interest. In both these patients pleuritic pain was severe. Theincrease in minute volume following morphine administration isprobably related to the relief of pain.

In 13 cases the ratio of expiration to inspiration increased, while inthe other 2 cases there was a very slight drop in the ratio. Theonly significance to be attached to this is that the slowing of therespiravtory rate produced by morphine is accomplished by prolongingthe expiratory phase with little change in the inspiratory phase.WVhat the functional interpretation of this is is not clear.

Twenty-seven patients on the ward were observed after receivingmorphine. The observations are shown in more detail in table 2.

1. Rate. In all but one case the rate was slowed, the average dropbeing 4 and the greatest drop 14 to the minute. Wehave dividedthese 27 cases into 3 groups: (a) those who recovered and who neverappeared to be in any great danger of death; (b) those who recovered,but concerning whoma grave prognosis was given; (c) those who died.

In the first group there are 12 cases, in the second 7, and in the third8. The total dose of morphine and the time during which it was ad-ministered varied considerably, because this, of course, dependedon the individual needs of each patient. It is difficult, therefore, tomake an exact comparison of one group with the other. The differ-ences in results, however, are sufficiently striking that certain generalconclusions can be drawn. In group (a) the average drop in rateafter the total dose of morphine had been given was 2.0, while ingroup (b) the drop was 7.3, and in group (c) it was 3.4 (table 2). Itdoes not seem that the morphine had a much more depressant effecton the patients in group (c) than it did on those in group (a). If,however, one takes into consideration the fact that usually the respira-tory rate gradually increases as a pneumonia patient approachesdeath, a drop in rate of 3.5 to the minute may be significant. More-over, all of the facts are not shown by the figures, for in 2 cases (num-bers 6307 and 6315) shortly before death the rate fell in the one to 10and in the other to 18, which in the first instance represented a drop of32 to the minute and in the second a drop of 20. This occurred morethan 2 hours after morphine was given, so these figures are not in-

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cluded in the table. Webelieve that this delayed slowing of the rateis in part at least due to the cumulative action of morphine.

Wehave also studied the effect of caffeine on the respiratory move-ments and arterial saturation of one patient (number 1347). He wasobserved on 2 successive days while acutely ill. On the first dayhe was given 240 mgm. of caffeine sodium benzoate, and on the secondday he was given 192 mgm. of caffeine and 12 mgm. of morphine.After caffeine alone, his rate, tidal air, minute volume, and per centsaturation increased, while the morphine and caffeine together re-sulted in a reduction in rate, but a slight increase in tidal air and percent saturation. The minute volume on this occasion was smallerafter the drug was given than before. None of these changes was ofsufficient magnitude to attach much importance to them, but at leastthey are different from those observed after morphine alone. Thatcodeine in moderate amounts may have a detrimental effect on therespiratory center is suggested by case number 6213, whose respira-tory rate dropped to 14 and whose arterial saturation dropped to 40per cent after he had had 24 mgm. of morphineinadditionto236mgm.of codeine, which he had received during a period of 3' days. Hisbreathing was of the Cheyne-Stokes type, his lungs were filling withexudate, he rapidly passed into coma, and, had he not been imme-diately put into the oxygen chamber, he would in all probability havedied. The next morning, while breathing a 40 per cent oxgen mix-ture, his arterial saturation was 90.3 per cent and his respiratory ratewas 18.

II. Effect of morphine on the oxygen saturation of the arterial blood.In 16 patients out of 20 on whomoxygen analyses of the arterial bloodwere done before and after morphine, there was a drop in the arterialsaturation. The greatest drop was 2.1.3 per cent and the average dropwas 5 per cent (table 1). Of the remaining 4 cases, 3 showed a slightrise in 02 saturation after morphine. In one no analysis was made.One of these 3 cases (number 6232) had severe pain, which was relievedby morphine. His tidal air increased from 412 to 438 cc., though hisminute volume dropped from 13.35 to 10.96 liters. Another, casenumber 6262, was not acutely ill, and the third (case number 6347)was given caffeine with the morphine.. Moreover, in his case pain wasrelieved by morphine and his tidal air increased,

198


In only 3 cases was the change in oxygen saturation great enough tobe of significance. (1) In patient number 6246, the saturation fellfrom 82.5 to 64.9 per cent. This was in a man of 63 years, who hadbeen sick for 3 days. He appeared cyanotic and dyspneic, signs ofconsolidation extended from the left apex to the base. At the left

~~#~~~N~~&--AAA1------------ ------ M----A------ 4rw ~ ~ ~ ---- el

FIG. 1. (a) PLETHYSMOGRAPHICTRACING FROM CASE NUMBER6439, MADEBEFORETHE ADMISTRATIONOF MORPhINE; (b) PLETHYSMOGRAPHiCTRACINGFROMSAMFE PATIENT, MADE25 MIUTES AFTER 16 MGM. OF MORPNEHADBEEN GIVENThe upper line was drawn by the work-adder signal lever. Interval between

signal lever equals 12.34 liters. The lower line represents time in 2 secondintervals.

base were signs of fluid. Moist riles were present in both lungs. Hisblood culture was positive for Pneumococcus Type III. (2) In casenumber 6341, the saturation fell from 87.2 to 78.7. This was in anobese womanof 50 years, who had had a severe chill 3 days previously.The right middle and lower lobes were involved. Throughout both

199

2MORPHINEIN PNEUMONIA

lungs breath sounds were bronchovesicular and numerous rhonchiwere heard. She appeared cyanotic. Blood culture was positive forType II pneumococus. She was transferred to the oxygen chamberon the day the morphine test was made. The next day her arterialsaturation was 93.2 per cent. Five days later she died. (3) Inpatient number 6439 the saturation fell from 92.1 to 80.8 per cent.He had been acutely ill for 12 days. Tubercle bacilli had been demon-started in his sputum. His temperature fluctuated from 1010 to104°F. The only uninvolved part of his lungs was the lower right lobe,which was clear when the arterial punctures were done. Moist raleswere present throughout both lungs. Figure 1, a and b, shows partsof his respiratory tracing before and after morphine administration.These 3 patients in whom morphine administration resulted in adefinite and perhaps serious unsaturation of the arterial blood wereall extremely ill. Moreover, they showed not only extensive lunginvolvement, but the presence of diffuse, moist rales. It is to benoted that in none was anoxemia severe before morphine. A fourthcase already referred to is not included here, since no arterial bloodanalysis was made before morphine. After morphine injection, how-ever, his saturation was only 40 per cent.

DISCUSSION

In most cases of pneumonia the effect of morphine on the respiratorymovements and on the arterial oxygen saturation is slight. Certainlythe depression of respiration which follows morphine administrationis ordinarily not sufficient to contraindicate its use. The benefitswhich may accrue to the patient in the direction of relief from pain,reduction of metabolism, and sleep, undoubtedly outweigh the pos-sible ill effects of a slight reduction in pulmonary ventilation andincrease of anoxemia.

Occasionally, however, morphine may so diminish pulmonary ven-tilation as to result in serious oxygen want. This is liable to occur inpatients in whomthe pulmonary involvement is extensive and is ac-companied by diffuse moisture, and in patients who are already suffer-ing from severe oxygen want. Because of the possibility of this typeof reaction to it, morphine must always be used with caution and isbest combined with oxygen therapy.

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SUMMARYAND CONCLUSIONS

1. The respiratory rate, tidal air, and minute volume of pulmonaryventilation has been measured in 15 cases of pneumonia before andafter administration of morphine.

2. In most instances a reduction in respiratory rate, tidal air, andminute volume follows morphine administration.

3. Accompanying the reduction in pulmonary ventilation there is,as a rule, a diminution in the 02 content of the arterial blood withouta corresponding change in the 02 capacity. There occurs, therefore,a decrease in the per cent saturation of the arterial blood.

4. This change may be only a small one, but is usual. In only3 cases out of 19 was it not observed. The average drop was 5 percent. In one patient it was as great as 21.3 per cent.

5. When there is much pleuritic pain, the relief brought by mor-phine may allow the puilmonary ventilation to increase and thus raiseslightly the per cent saturation of the arterial blood.

6. In the presence of an extensive pulmonary involvement withdiffuse, moist rales morphine administration may result in a danger-ous degree of anoxemia.

I wish to express my grateful appreciation to Dr. Carl A. L. Bingerfor his assistance and advice in this work.

BIBLIOGRAPHY

1. Cecil, R. L., Text Book of Medicine, Saunders & Co., Philadelphia, 1927, 36.2. Cole, Rufus, Nelson's System of Medicine, New York, 1920, i, 258. Acute

Lobar Pneumonia.3. Cushny, A. R., A Text-book of Pharmacology and Therapeutics, Lea and

Febiger, Philadelphia, 7th ed., 1918, 255.4. Hewlett, A. W., Forchheimer's Therapeusis of Internal Diseases. New York,

1917, iii, 421. Diseases of the Lungs.5. Macht, D. I., J. Pharm. and Exp. Therap., 1915, vii, 339. Action of the Opium

Alkaloids, Individually and in Combination with Each Other, on theRespiration.

6. Higgins, H. L., and Means, J. H., J. Pharm. and Exp. Therap., 1915, vii,'1.The Effect of Certain Drugs on the Respiration and Gaseous Metabolism inNormal HumanSubjects.

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202 MORPHINEIN PNEUMONIA

7. Binger, C. A. L., and Davis, J. S., Jr., Proc. Soc. Exp. Biol. and Med., 1928,xxv, 607. A Body Plethysmograph for the Study of Respiratory Movementsin HumanBeings.

8. Van Slyke, D. D., and Neill, J. M., J. Biol. Chem., 1924, ldi, 523. The De-termination of Gases in Blood and Other Solutions by Vacuum Extractionand Manometric Measurement.

9. Binger, C. A. L., and Davis, J. S., Jr., J. Clin. Invest., 1928, vi, 171. TheRelation of Anoxemia to the Type of Breathing Seen in Pneumonia.

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