of necessity indicate that the morbid phenomena under differentiate between the effects of the trauma of the consideration are due to this foodstuff. Just as a operation and those of the anesthetic. Morphin, owing syphilitic subject with a positive Wassermann reaction to its power to reduce the poignancy of centripetal may develop a skin affection which is unrelated to his impulses, has been regarded as a valuable adjuvant to systemic infection, so a patient with a positive food local anesthesia. The committee on anesthesia4 of the anaphylactic reaction may develop a cutaneous affec¬ American Medical Association, reporting in 1912, rec¬ tion due to other factors than his diet. ommended the routine administration of morphin pre¬ 7. Further studies in anaphylactic food reactions ceding the induction of general anesthesia, recognizing may shed considerable illumination on the etiology of at the same time that the imposition of one powerful certain diseases of the skin. depressant of the medullary centers, namely, morphin, 8. Hundreds and perhaps thousands of patients must on another, namely ether, might have disadvantages for be studied before any general deductions can be drawn which its antishock action could not compensate. The as to the relation between particular skin diseases and following observations are presented for study in con¬ food poisoning. nection with the preceding statements. 4037 Girard Avenue. While the recognition of shock is based on the pres¬ ence of a group of no one of which in itself is diagnostic, there are several easily deter¬ mined under certain be THE RELATION OF MORPHIN TO POST- signs which, conditions, may assumed to be quite suggestive. Of these, the pulse OPERATIVE COMPLICATIONS rate appears to be the only one which is observed as AND IMMUNITY a part of the postoperative routine in the Presbyterian and this was chosen as the FRANKLIN Hospital, sign, therefore, BENJAMIN DAVIS, Ph.D., M.D. shock indicator for the present The Nicholas Senn Fellow in Surgery, Rush Medical College study. following standard was : A rate on return CHICAGO arbitrary adopted pulse from the operating room of 100 or more per minute Because of their knowledge of the depressing influ- was assumed to indicate some degree of shock ; a pulse ence of morphin on general metabolism, many surgeons rate of 99 or less was assumed to be negative for have been inclined to blame its use for a long list of shock. Cases were taken at random, the only condition disorders appearing in the course of and following on being that they must not show evidences of shock pre¬ operations, especially operations done under general ceding the operation. Morphin, when administered, anesthesia. With the object of testing the reasonable- was given in conjunction with atropin. Study of tables ness of this idea, a study was made of the records of constructed in part according to this standard and in 469 patients operated on in the Presbyterian Hospital part showing the number of patients requiring active and of the immunity curves (opsonic and lytic) of a measures to combat postoperative shock suggests that series of morphinized animals. Particular attention morphin, in ordinary doses, may exert a slight influence was directed to the possible relationship of morphin to against the induction of shock by operative procedures. postoperative shock, postoperative ileus (paralytic), The figures are as follows : Of 89 patients under¬ postoperative acute dilatation of the stomach, post- going radical amputations of the breast, 20 were given operative retention of urine, and immunity. morphin one hour before operation; of these 11, or have unable to Physiologists been explain adequately 55 per cent., were returned to bed with a pulse rate of the mechanism of shock.1 Among clinicians, surgical 100 or more. Sixty-nine patients did not receive mor¬ shock is usually defined as a condition of depression phin before operation, and of these 48 per cent, were or mental following painful injury strong emotion, the returned with a pulse rate of 100 or more. Of the 20 a weakness symptoms varying from slight feeling of morphinized patients, none required active measures accompanied by , and perhaps a temporary loss to combat shock, while one out of 72 nonmorphinized of to of all the vital consciousness, complete paralysis patients did. In 126 laparotomies, 25 patients were processes resulting in speedy death.2 According to given preoperative morphin and 101 were not. Of the and in with the current theo¬ this definition, conformity morphinized patients, 68 per cent, were returned to bed ries of the cause of shock,3 sensory stimulation, sym¬ with a pulse rate of 100 or more, while but 50 per cent. bolized by the word "pain," appears to be the trigger of the exhibited a similar the The nonmorphinized patients which sets off shock sequences. argument fol¬ rate. Of a total of 283 cor¬ laparotomies, preoperative lows, therefore, admitting for the moment the was administered in 94 cases ; 2 of these of the that the morphin rectness preceding assumption, ques¬ patients required active antishock treatment after oper¬ the of shock becomes a of tion of prevention question ation. Of the 189 laparotomies in which no preopera¬ the of the to the nerve interruption centripetal paths tive morphin was given, 5 required active measures to centers, or a modification of those centers such that combat shock after the operation. The following are irritated to a the they not dangerous degree by were included among the : gas- Local anesthesia blocks the operations laparotomies pain impulses. centripetal trostomy, 5 cases ; anterior gastro-enterostomy, 8 ; pos¬ paths, and, when practicable, appears to be the best terior 24; in gastro-enterostomy, exploratory (carcinoma known preventive of shock surgical operations. Gen¬ of the stomach), 25; pylorectomy, 14; acute appendi¬ eral anesthesia the nerve centers but depresses appears citis, 8 ; cholecystostomy, 22 ; cholecystectomy, 7 ; to be somewhat less effective than local anesthesia in pelvic operations with appendectomy, 114; miscellane¬ off it is often difficult to warding shock, although ous intra-abdominal operations, 19 ; appendectomies From the Departments of Surgery of Rush Medical College and (chronic), 21; chronic intestinal obstruction (carci¬ of the Presbyterian Hospital. noma and adhesions), 2; colostomy (carcinoma), 6; 1. Bevan, A. D.: The Choice and Technic of the Anesthetic, The intestinal 8. Journal A. M. A., Oct. 23, 1915, p. 1418. resection, 2. Brewer: Text Book of Surgery, 1909, p. 106. 3. Henderson: Proc. Soc. Exper. Biol. and Med., 1909-1910, vii, 41. 4. Report of Committee on Anesthesia, The Journal A. M. Crile: Ibid., p. 87. June 15, 1912, p. 1908.

Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 06/08/2015 The evidence is conflicting, and the balance in favor secretion ; later the pressure of the gastric tumor on of the conclusion drawn is very meager, so meager the movable small intestines, forcing them downward, that possibly a Scotch verdict might be given with and producing thereby tension on the root of the justice. More weight has been attached to the figures mesentery, which in turn compresses the third portion showing the number of patients requiring active mea¬ of the duodenum against the spine and causes more or sures to combat shock than to those dealing with the less occlusion. Kinking of the duodenum from pro¬ pulse rate because it was felt that the addition of lapse of the distended stomach may also be a factor of atropin to the morphin might have influenced the car¬ importance. . . . The primary dilatation of the stomach diac mechanism of the morphinized patients inde¬ is probably caused by a muscular paresis from toxemia pendent of shock, and because the former figures are due to acute or chronic disease, or from surgical opera¬ absolute, while the latter are based on a standard which tion or shock. The exciting cause may be an indiscre¬ is open to criticism. tion in diet, or the ingestion of food or water too soon Because of its effectiveness in retarding gastro¬ after operation, before the stomach wall has had time intestinal peristalsis, morphin has been considered one to regain its muscular tone." 12 The rôle played by of the contributing causes of postoperative constipa¬ morphin in relation to this condition may be a very tion and gas pains. Morphin produces , minor one indeed, but its tendency to induce nausea first, by occasionally causing a spastic-contraction of and in certain individuals nausea always the pylorus, thus delaying the passage of food from the retarding gastric motility6—and its demonstrated— ability stomach into the duodenum as much as four or five to delay gastric evacuation into the bowel, suggest that hours.5 According to the observations of Dr. B. W. its use, postoperatively, may be associated with some Sippy,6 nausea from any cause retards gastric peri¬ danger. The fact that acute dilatation of the stomach stalsis. As morphin may cause nausea and vomiting in occurs under conditions similar to those under which men and in dogs, this, rather than pyloric spasm, may intestinal atony develops justifies the application of the be responsible for the delayed emptying of the stomach statements made concerning the latter to the gastric noted above. Secondly, morphin produces a consid¬ syndrone. erable diminution in the rate and force of intestinal In consideration of the conditions outlined in the peristaltic waves. Thirdly, some evidence has been foregoing discussion, tables were compiled in which an presented which suggests that the threshold for the attempt was made to trace a relation between morphin reflex may be considerably raised, or the administered and the incidence, time of onset, dura¬ reflex may be abolished by morphin, so that feces tend tion and severity of postoperative nausea and vomit¬ to accumulate in the sigmoid and rectum.7 Morphin, ing, tympanites and gas pains, and postoperative dis¬ then, definitely, decreases gastro-intestinal motor activ¬ turbances of the urinary apparatus due, when induced ity and, so far as that is true, may be of considerable morphin, to the abolition of the reflex.13 in the of by sphincter importance production gastro-intestinal paral¬ The patients were taken at random, only those being ysis. It must not be forgotten, however, that there excluded in whom preoperative symptoms were of such are other factors involved in the initiation of this con¬ a nature as to suggest their continuance after opera¬ dition. Extensive handling of the bowel is of great tion, and possible confusion in consequence with the of the bowel to the importance. Drying by exposure so-called postoperative symptoms on which observa¬ air or the introduction of hot or cold water into the tions were desired. Patients who were given morphin abdomen produce nothing more than a transient dis¬ (from one-sixth to one-fourth grain but the intestine between the hypodermically) turbance, stripping fingers before operation received at the same injection atropin or on the operations bowel, particularly resections, (from %50 to %20 grain) 5 such injections were made inhibit peristalsis for several hours longer than etheri¬ not in selected cases but as a of the routine of the alone it.s part zation and laparotomy delay Paralysis of the operator. Patients who were given morphin, from bowel wall in the late of most cases supervenes stages one-eighth to one-fourth grain, or heroin, from one- of dynamic ileus associated frequently with impor¬ twelfth to one-sixth grain the terms being used tant local vascular changes.0 The most extreme grade synonymously postoperatively— usually received the of acute intestinal the — paralysis, constituting important not as a matter of routine, but because their factor in is found in associa¬ injection paralytic ileus, usually postoperative discomfort demanded relief. The aver¬ tion with severe local or generalized intraperitoneal age number of such to each so treated an injections patient suppuration. Epinephrinemia to extent insufficient was about 3.6 in the course of hours. Those to a minimal sustained rise in blood thirty-six produce pressure who received no morphin postoperatively were patients intestinal to a standstill and brings peristalsis complete who either suffered but little discomfort or at least extreme intestinal dilatation.10 Pain or produces made but little complaint. It was not to make marked disturbances or disturbances which possible sensory even a reasonably accurate record of who induce fever are to cause Mor¬ patients apt epinephrinemia. vomited before their return from the operating room phin diminishes pain, and in full doses decreases the and before from the anesthetic. Patients who rate of the of into the blood.11 waking discharge epinephrin were recorded as being free from nausea and not an vomiting May it be, therefore,, that morphin is enemy were those who did not these after rather than an of the forces develop symptoms ally which induce post¬ consciousness. Those in whom nausea and intestinal regaining operative atony? were recorded as severe exhibited Acute dilatation of the stomach is attributed vomiting acutely usually dilated stomachs and required more or less strenuous to "a rapid dilatation of the stomach with increased gastric lavage for relief. Among the so-called mod¬ erate cases were all 5. Zunz: Bull. de l'Acad. roy. m\l=e'\d. de Belgique, 1909, xxiii, 353. included grades of nausea and 6. Sippy, B. W.: Personal communication to the author. vomiting from mild attacks of ten minutes' duration 7. Shapiro: Arch. f. d. ges. Physiol., 1913, cli, 65. up 8. Cannon and Murphy: Ann. Surg., 1906, xliii, 515. to the borderland of the severe types. The same gen- 9. Davis, B. F.: Ann. Surg., 1915, lxi, 261. 10. Hoskins and McClure: Am. Jour. Physiol., 1912, xxxi, 59. 12. Brewer: Text Book of Surgery, 1915, p. 519. 11. Hitchings, Sloan and Austin: Cleveland Med. Jour., 1913, xii, 684. 13. Cushny: Pharmacology and Therapeutics, 1906,906, p. 214.

Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 06/08/2015 eral scheme was followed in classifying the gas pains. morphin may play a part, but, at the most, an insig¬ The severe cases included all lasting without intermis¬ nificant one. sion for a number of hours and requiring vigorous In 283 laparotomies, 79 per cent, of the patients were measures for relief. The moderate types include all free from postoperative urinary disturbances ; in from those sufficient to cause somewhat more than just ninety-two radical amputations of the breast, 87 per a passing complaint up to the severe cases. cent, of the patients urinated spontaneously ; of forty- one NAUSEA AND VOMITING patients undergoing extraperitoneal operations, nineteen being done with ether anesthesia, 100 per cent. As is the case with other conditions studied, dog¬ were free from urinary disturbances ; in thirty-six matic are but it assertions probably not warranted ; herniotomies under local anesthesia, 94 per cent, of the seems to be reasonably evident that, with the possible urinated while but 77 cent. under patients spontaneously, per exception of operations done local anesthesia, in seventeen cases under ether anesthesia were able postoperative nausea and vomiting is very little influ¬ so to do. in the manner enced by morphin administered and IMMUNITY but is and dosage already described, markedly princi¬ An with to the use of influenced the and duration of the anes¬ important question regard pally by depth after is that of-its influence on the thetic The nature of the and the morphin operations (ether). operation of the to withstand infection. Lancelin14 on are doubtless of in ability body organs operated importance found that rabbits and when to but are the guinea-pigs, subjected special instances, overshadowed by impor¬ of became tance of the ether. In of this series repeated injections morphin, considerably operations requir¬ more to the attack of the that susceptible streptococci, staphy- ing deepest and most prolonged anesthesia, is, lococci and "vibrion than normal control ani¬ and of the breast, only 48 septique" laparotomies amputations mals. The leukocytosis was about equal in all animals, per cent, of the patients were free from nausea and but the the activity of the leukocytes appeared to be dis¬ vomiting ; following more shallow and less pro¬ retarded. of anesthesias for the miscellaneous tinctly Diapedesis leukocytes through longed extraperi- vessel walls and their accumulation at of local toneal cases and 75 points herniotomies, approximately per infection seemed to be much less and of lesser cent, these prompt were free from symptoms. Of hernioto¬ in than in normal animals. Death mies done under local anesthesia without the degree morphinized previous was due to an arrest of phagocytosis through the inhi¬ administration of morphin, 100 per cent, of the patients bition of the of the were When local activity leukocytes by morphin. not nauseated and did not vomit. Catacuzene15 results which anesthesia first came to be used in the Pres¬ previously reported quite extensively agree with those of Lancelin with reference to the byterian Hospital, it was uniformly preceded by an retardation of in ani¬ of and Patients so leukocytic activity morphinized injection scopolamin morphin. mals reacting to infections. to Arkin,10 treated suffered more or less from post¬ According commonly morphin sulphate has a depressing action on nausea and This noted, the phagocy¬ operative vomiting. being tosis of human up to 0.01 was omitted. Still these streptococci by leukocytes scopolamin symptoms per cent, and to a to 0.001 cent. in about 20 cent, of the slight degree up per appeared postoperatively per This action is on the for Then the was discon¬ largely leukocytes, leukocytes patients. preoperative morphin treated with 0.1 per cent, a and from that time nausea and morphin sulphate gave tinued, postoperative index of 0.63 as with 1.0 for been almost in phagocytic compared vomiting has eliminated operations treated with salt solution. That this under local anesthesia, in leukocytes only excepting thyroidectomies depressing influence of morphin may be masked by the for hyperthyroidism, in which, of course, a special type coincident action of which accelerate Even as drugs phagocy¬ of patient is encountered. here, however, tosis has been the work of who leads to in the technic of local suggested by Smith,17 experience improvement used a mixture of morphin hydrochlorid and quinin anesthesia, the postoperative discomfort decreases. in the of of With the elimination of the anesthetic hydrochlorid proportion one-eighth grain general (ether), the former to 10 of the latter. It was calculated and in the technic of local anesthesia, grains improvement that a 10-grain dose given to a person weighing 140 postoperative nausea and vomiting decreases to a if would in the minimum. pounds, entirely absorbed, represent blood a proportion of 1: 7,500. The influence of this TYMPANITES AND POSTOPERATIVE GAS PAINS solution (1:7,500) on the phagocytosis of different The importance of morphin in relation to the pro¬ kinds of pathogenic organisms (for example, strepto¬ duction of these symptoms in the present group of cocci, staphylococci, pneumococci, Bacillus influènzae, cases, taken as a whole, appears to be relatively insig¬ B. pseudodiphtheriae and B. tuberculosis) was con¬ nificant. The really important factors are, first, the trasted with that of weaker and stronger solutions. In tissues involved by the operation, and second, the gen¬ the majority of experiments there was an increased eral anesthetic. Operations involving the peritoneum, phagocytosis, always most marked with the 10-grain whether done under a general or a local anesthetic, are dose. Instead of .inhibiting phagocytosis, the addition followed by gas pains of varying grades of severity in of quinin and morphin, in what may be considered the approximately 45 per cent, of the cases. In operations ideal dose, greatly increased it. Smaller doses in all in which a general anesthetic is employed, but in which experiments were less effective. Very large doses the peritoneum is not traumatized, about 10 per cent, of (from 30 to 40 grains of quinin and from three-eighths the patients have postoperative gas pains ; while follow¬ to one-half grain of morphin), instead of increasing, ing operations in which both peritoneum and ether are diminished phagocytosis, sometimes to the extent of avoided and local anesthesia is used, tympanites and 50 per cent. gas do not appear. pains 14. Lancelin: Morphinisme et infections, r\l=o^\le des leucocytes, Bor- deaux 37. VOIDING OF URINE Theses, 1902-1903, No. 15. Catacuzene: Recherches sur le mode de destruction des vibrion and to the seem to be the chol\l=e'\rique dans l'organisme, Th\l=e'\se de Paris, 1894. Ether injury peritoneum 16. Arkin: Jour. Infect. Dis., 1913, xiii, 408. two great causes of postoperative retention of urine ; 17. Smith: Lancet, London,n 1910, ii, 1342.

Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 06/08/2015 In view of the unanimous testimony of workers in the animals, were analogous to those given to the the field of experimental medicine in confirmation of patients referred to in the preceding sections of the theory that morphin diminishes the activity of the this paper, does not retard the production of hemoly- defensive forces of the body, affecting the leukocytes sins and opsonins in response to the usual stimuli ; it especially, it became of interest to determine whether does not interfere with the activity of these bodies morphin administered to animals in therapeutic doses when they are produced ; in the concentration in which would produce changes measurable by methods intro¬ morphin was present in the serums of these animals, duced since the work of Lancelin was finished. This it does not decrease leukocytic activity. As ordinarily appeared to be advisable because all of the later work used, therefore, morphin probably does not decrease the seems to have been done in vitro, very little attention ability of the body to defend itself against infection. to the effect of on the or being paid morphin opsonic SUMMARY lytic curves in the serum of animals responding to immunizing injections of antigen. The combination of morphin (from one-eighth to one-sixth grain) and atropin (from y150 to %2o grain) OPSONINS AND LEUKOCYTIC ACTIVITY hypodermically before operations is of very little To one partner of each of four pairs of dogs, a importance so far as the prevention of postoperative quantity of morphin sulphate corresponding to about shock is concerned, and, in the general run of cases, one-sixteenth grain for 20 pounds of dog was admin¬ plays a negligible part in the production of postopera¬ istered subcutaneously daily. The morphin injection tive nausea and vomiting, tympanites and paralytic was occasionally followed within five minutes by emesis ileus, and postoperative retention of urine. It has prac¬ and defecation ; for the ensuing two or three hours tically no' effect on immunity. Morphin alone, preced¬ the animal remained somewhat torpid, but not mark¬ ing local anesthesia, adds nothing to the efficiency of edly depressed, and thereafter acted in a normal man¬ the anesthetic, and causes postoperative nausea and ner until the succeeding injection was made. As the vomiting in 25 per cent, of the patients ; it makes the period of injection extended over a couple of months patient "dopey" and hence deprives the operator of the there was a gradual loss of weight and strength shared cooperation of the patient, which at times may be by all of the animals, a result of the rather close con¬ valuable.1 In view of these conditions and in view of finement to which they were subjected, but rather more the disadvantages of imposing one powerful depres¬ marked in the morphinized than in the control dogs. sant of the medullary centers, namely, morphin, on During the two weeks preceding the morphin injec¬ another, namely, ether, the preoperative use of mor¬ tions, serum and washed leukocytes from each animal phin should be abandoned. In view of the same condi¬ were tested (according to the Wright technic) against tions, morphin in therapeutic doses, that is, from one- those of its partner, using a streptococcus as antigen eighth to one-sixteenth grain, to an adult of average according to the subjoined form : size, repeated at intervals of not less than six hours, should not be Leukocytes (morphin dog) + serum (morphin dog) 4- denied to patients whose postoperative bacteria. suffering cannot be controlled otherwise. Leukocytes (morpfiin dog) 4- serum (no morphin dog) 4- bacteria. Leukocytes (no morphin dog) + serum (no morphin dog 4- bacteria. THE STATUS OF THE CHILD IN Leukocytes (no morphin dog) + serum (morphin dog) + bacteria. OBSTETRIC PRACTICE The morphin injections were then proceeded with JOSEPH S. WALL, M.D. and the tests continued twice a week for two weeks WASHINGTON, D. C. longer. Then a large immunizing dose of killed strep¬ tococci of the strain used from the first was adminis¬ The thoughts expressed herein have been of gradual tered, and tests continued twice weekly for the succeed¬ growth, mainly gained by the experience of standing ing three weeks. sponsor for the welfare of the maternal offspring after As a result of these experiments, no constant differ¬ the obstetrician has completed his task and by every ence was noted between the activity and opsonizing good word and deed has brought to a successful end- power of the leukocytes and serums from the mor¬ ing a period of great anxiety. phinized and the control animals. Some time ago, in a discussion, I had occasion to remark on the number of children whose health had HEMOLYSIS been impaired by birth injuries, and was immediately Four rabbits, two of which were receiving one- taken to task by one of our accomplished obstetricians, sixteenth grain of morphin sulphate hypodermically just as though I had accused my obstetrical confr\l=e`\res per kilogram daily throughout the experiment, were of acts of assault and battery on the babies they were immunized to chicken erythrocytes by intravenous and assisting into the world. My intent, far from this, intraperitoneal injections. Dilutions of the immune had been simply to ascribe to injuries of the cranial serums were then made, and comparative observations contents during the act of labor those distressing afflic- taken of the dilution beyond which morphinized and tions appearing later in infant life, namely, idiocy, nonmorphinized serums failed to produce hemolysis, paraplegias, hemiplegias, and the like, which are now using a chicken-rabbit-guinea-pig system. Then tests known to be due to intracranial traumatism at birth. were repeated twice weekly for two weeks after the It cannot be charged against us as it was in the last injection of erythrocytes. At no time was there earlier days of medicine that the interests of the child any suggestion that morphin exerted an influence on are entirely subservient to those of the mother. The the hemolytic curve. abandonment of craniotomy on the living child was in From these experiments it seems probable that mor¬ itself an acknowledgment of infantile rights, which, phin administered in doses which, judging from their thanks to modern advancement in medical science, have depressing effect on the cerebral and bodily activity of attained a station hitherto unknown, so that now the

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