·PUBLICATTON NUMBER 76
AMERICAN LECTURE SERIES
A MOTOGRAPH IY
AMERICAN LECTURES IN CHEST DISEASES
Edited by
J ARTHUR MYERS MD, PHD, FACP.
Projessor of Medicine and Preventive Medicine
and Public Heallh
Uniersity of Alinnesota Medical School
Alinneapolis, Afinnesota

·THE MANAGEMENT OF THE PATIENT
WITH
Severe Bronchial Asthma
By
MAURICE S SEGAL, MD.
Assistant Professor in Medicine
Tufts College Medical School
Director Department of Inhalational Therapy
Boston City Hospital
Boston Massachusetts
?
CHARLES C THOMAS PUBLISHER
Springfield • Mlinois • USA

·CHARLES CTHON IS PUBLISHER
BANERSTONE HOUSE
301 327 EAST LAWRENCE IYEVUE SPRINCFIELD ILLINOIS USA
Piblished simultancously in The British Commonwealth of Nations by
BLACK WEU, SCIENTIFIC PUBLICATIOV LTD OXFORD ENGLAND
Published simultaneously in Canada by
THE RYORSOY PRESS TOROVTO
This monograph is protected by copyright to
part of it may be reproduced in any manner
without written permission from the publisher
Copyr ght 19,0 by CHARLES C THOMAS PUBLINIIFX
Innled 13 the United States of America

·INTRODUCTION The patient sath severe bronchial asthma may be re guded as a psychobiological problem The complicated pathophysiology and disturbed emotional make up require a careful integration of the multiple components such constitute the individual as a whole Proper physiologic management is based upon an understanding of all the participating forces and their relative values This calls for specific therapy formulated to minimize or improve dis turbed functions and to prevent the irreversible sequelae of the astlimatic state To achieve lasting results consider able rapport in the psychological sense must be developed and the patient must have reassurance without sacrifice of a determined positre approrch on the part of his physi cian Thuis requires the continuous education of the pa trent and lus family I know of no other disease which can tix the cluzracter and therapeutic ingenuity of the internist as much as the proper management of the very sick asth matic patient Whatever the fundamental cause of the shit CT25) (liberation of H histamine like substance C acetylcho line like substance or other chemical mediators during the intigen intibody contact) inhibition or neutralization of this substance elimination of mucus which is the product of its tction relief of the bronchospasm and finally reso lution of the emotional factors which may precipitate or modify the attach should be the aim of all therapy 'The acutely ill patient presents a far more complex problem thun thut of lus specific allergic response Allergically di rected tlicripy shoukl not be regarded as the specific theripy for the mingement of bronchial asthmr It is specific only for the management of the underlying allergy when determinable ·VI The Alanagement of the Patient Contrary to the pessimistic slew frequently expressed by the patient and his friends, considerable benefit can be giten to the very sich patient with asthma by the applica cion of procedures to be discussed The therapeutic meas ures suggested are based largely on personal observations in the management of 513 patients and have been correlated BAONCHOLAR MELAXATION METAL ( 43) WEL TANEC Nauc OD ATOM ACROIS P93 T VE PESSURE (0) STOA TOP OALANG REACHCS DRONCHIOL AR CYACUATION CITETTONANTS ODDS FTC THERAPEUTE 64363 (CO BRONCONLATOR A OSOL WITAA PAANAGE vaator ASTDw ENDOSCOP PAVAGE VTALE CONOLLOSA WTHAOS US ON TOP CAL ARTCI U ACOM ACAD10A MADALLA ALA10L WALA CEV TAM AC EWOO FC PPX LAVACC wc.co TADOncert WALAT DAS ATSPARC OGG PAAEHTONAL ANT POT CU Otel - WCACNAL DUCTCO SUPPORTIYC TKCRAPY WANAOCMENT OF INTECTION PREVENTIVE MEASURC: EL Whaton Or .. AND DLOOD SOANDRA TANTO IL MATC AND OCUPA 1 GRAL CONTROL ACENGK CLEANL 25$ WYPOTENSIAT ON RETRATON GACAT CEA 563 MENTAL NICCE THE PHYSIOLOGIC MANAGEMENT OF THE SERIOUSLY KL ASTHMATIC FIGURE 1 with extensive laboratory studies with a large variety of protecting drugs Human assay (protection studies) also have been employed l\'ith this new technique, an evalu? tion of the relatne value of net and accepted therapeutic agents for the relief of bronchospasm was possible Further. more these studies were performed under controlled con ditions wluch are usually not present in the sick patient In order to restore physiologic balance in the severe asthmatic patient, it is necessary to employ a wide range of properly balanced therapeutic measures I inse attempted ·11h Serere Bronchial Asthma to illustrate the various measures which are necessary to balance this therapeutic seesaw (Fig 1) and will discuss the more linportant ones namely protecting drugs sedation support ie therapy broncholar relaxation therapeutic use of gases broncluolar evacuation or catharsis and the management of infection in the Chapters that follow The relationship of emotional disturbances to the asthmatic paroxysm the value of therapeutic hyperpyrexri and breathing exercises the controversial aspects of climato therapy and finally a variety of miscellancous procedures not generally recommended will be discussed somewhat less detul The manuscript for this book had gone to press when we begin our studies with the spectacular pituitary adreno corticotropic hormone (ACTH) in bronchul asthm. The remarkable properties of ACTH and Cortisone and their effects on the antigen antibody mechanism is the subject of considerable study To date se le completed eight acute protecuon studies with ACTH ngainst the effects of hista mine and acetylcholine in the laboratory and have treated three patients in status asthmaticus sith ICTH therapy Then successfully employed striking subjecute and objec uve improvement appeirs within one to seven days Treat ment probably may be stopped after the fourth or fifth day in most cases lle generally employed 20 mg (Armour units) IM every six hours for the first two days and there iſter 10 mg every ste hours through the seventh dry It appears likely that the hormone may be employed in re sponsic potients for mainten ince therapy One or to day courses may be necessary at three or four week intervals In the wake of improvcntent there may be observed side effects (fargely transient) such as mooning of the facies salt and water retention rise in blood pressure hirsutes sense ·VIII The Management of the Patient of well being changes in the psyche and even mild bronchospasm following each injection (due to protein) The modus operandı of ACTH in bronchial asthma is not definitely known The exact changes in histamine metabolism and in the immune mechanism remain to be answered ·CONTENTS X112 ovo LO Page INTRODUCTION V LIST OF ILLUSTRATIONS LIST OF 'TABLES XV CHAPTER I THE CLINICAL CONCEPT OF BRONCHIAL ASTHMA 3 Pathophysiology 3 The Acute Paroxysm 6 Complications 8 Fatalities 10 Classification 14 II THE ALLERGIC CONCEPT AND MANAGEMENT OF BRONCHIAL ASTHMA 18 The Allergic State 18 The Immuno Chemical Approrch to the Allergic State 20 Drug Tolerance 21 III PROTECTION STUDIES 27 Laboratory Methods for Producing Dyspnea and Bronchospasm 28 Laboratory Evaluation of Therapeutic Agents (Protection Studies) 32 Protection Studies with Anticholinergic Drugs 37 Protection Studies with Sympathomimetic Amine Aerosols Protection Studies with Aminophyllin 49 Correlation of Laboratory and Clinical Data 52 IV SEDATION 56 The Barbiturates, Chloral hydrate and Sodium bromide 56 Morphune, Dilaudid and Demero! 57 Hvertin, Cyclopropune, Cther and Paraldehyde 61 ir ·Plie Alanagement of the Patient SUPPORTIVE TUFRAPY 01 Replacement Therapy (Water glucose srline in fusions) 61 The Role of Digitalis and Mercurul Diuretics 65 Aminophyllin Infusions 66 Ascorbic Acid Cytochrome C and Nicotinic nictd 69 llcohol Dextrose Infusions 70 Blood Plasma 70 Antihistaminics 71 VI EPIVE PURIVE 77 The Use of Epinephrine 77 The Lpinephrine Refractory Stue Its Relation ship to Histamine Sympathın Balance und the Role of Antihistaminics 79 Ephedrine Preparations 80 The Use of Epinephrine Aerosols (See Chapters III and I li) VII THE THIERAI ŁUTIC USE OF GASIS 84 Oxygen 84 Helnm Oxygen Mixtures 90 Positive Pressure Therapy 93 Carbon dioxide Oxygen and Carbon dioxide Helium Oxygen Mixtures 96 Therapeutic Aerosols (Sympathomimetic Anincs and Antibiotic Agents) 98 VIII BRONCHIAL EVACUATION CATHARSIS 106 Expectorants 107 Ipecac 109 Postural Drainage 110 Endoscopic Therapy 111 Bronchioscopy Bronchoscopic Aspitation 114 Endoscopic Installation Bronchial Lavage 114 116 ·Tatlı Ser ere Bronci tal dsthina X1 118 118 120 129 123 128 IX VANAGEVIENT OF INFECTION I BRONCHIAL ASTHMA Role of Intection in Bronchial Asthma Control of Infection with Antibiotic Aerosols Technique and Dosage of Antibiotic Aerosol Therapy Control of Para Masal Sinus Infection Y MISCELLANEOUS PROCEDURES EMPLOYED IN THE MAVACEVENT OF BRONCHIAL ASTHIVA Procedures Generally Not Recommended or of Limited Value Procedures I hat May Be of Value Psychotherapy Climatotherapy I herapeutic (Controlled) Hyperpyrexit Breatlung Exercises BIBLIOGRAPHY INDFY 128 129 129 135 137 139 141 155

·No text on this page.

·LIST OF ILLUSTRATIONS HITRE Page 1 The Physiologic. Vlanagement of the Seriously Ill Asthmic 4 J ? Effect of Isuprel on the entilatory Patterti of a Subject with Icure Asthma Typical Response of a Sensilaye Subject to Intra enous flust mine or lecholvi Chloride 29 Ilypal Responsus of an Isthm itic to Scrosol Histu inine or Mecholy? 31 1 Typical Protection Study Curve 37 6 The Structural Formulac of Three Sympithomimetic Amines 7 The Protective tue of Demeiul Hydrochloride 60 8 The Protectie Illuc of II; drylın 74 9 The Traceure Valie of Orthoxine 87 10 The Protectie lake of Fphedrine Sullak 11 The Veter Mask (Oro nasal Type) 81 12 Parts of the Veror Vash 14 The Flelmum Origen Positne Pressure Hool 88 14 THU Methanyre-- Ireless Oxygen Tent 15 The Saponeiri luokol Motor Uni 190 Vebulizer 101 16 Fiets pupeln » the entilatory Pattern of a Sulic with faute Astlımı 169 85 x111

·No text on this page.

·LIST OF TABLES
Page
17
TABLE
1 Classification of Bronchial Asthma
39
2 Comparative Protective Value of Anticholinergic
Agents
13
$ Comparative Protective Value of Sympathomimetic
Amine Aerosols
51
# Comparative Protectie Value of Iminoplıyllin Ad
ministered by Various Routes
106
Š Bronchiolar Evacuation I Physiologic Mechanisms
to This End
106
6 Bronchiolar Evacuation II Therapeutic Mechanisms
to This End
107
7 Bronchiolar Evacuation 111 Presentive Measures
XV

·No text on this page.

·THE MANAGEMENT OF THE PATIENT
WITH
Severe Bronchial Asthma

·No text on this page.

·CHAPTER I THE CLINICAL CONCEPT OF BRONCHIAL ASTHMA BRONCHIAL asthma is a distressing and common form of acute recurrent or chronic bronchial inflammation and obstructive emphysema usually of allergic origin It is characterized by recurrent cough and a wheezing type of dyspnea in which the patients main difficulty occurs par ticularly on expiration The over excitable bronchial mu cosa and musculature of asthmatic patients react to factors which generally have no effect on normal subjects Such factors include allergens infection and reflex physical and psychic stimuli It has been estimated that 35 per cent of the population are affected with this discouraging and disheartening affliction at some time during life and that 02 percent of all deaths in the United States in 1940 were due primarily to bronchial asthm With these figures confronting us it is heurtening to note that signifi cant progress luas been made in allevating this condition Inilysis of the authors series of cases revealed that ap provimately 15 per cent were completely relieved 80 per cent were more or less improved and only 5 per cent were resistant to all treatment | Pathophysiology A proper understanding of the physiological mecha nisins involved in asthmatic patients during paroxysms and during the asthma free period sheds considerable light on the difficulties attendint upon proper therapy Vumerous ini estigators notably Cournands and Balduinhne dem 3

·No text on this page.

·CHAPTER I THE CLINICAL CONCEPT OF BRONCHIAL ASTHMA BRONCHIAL AL isthm is a distressing and common form of acute recurrent or chronic bronchial inflammation and obstructive emphysema usually of allergic origin It is characterized by recurrent cough ind a wheezing type of dyspner in which the patients mun difficulty occurs par ticulurly on expiration The over excitable bronchial mu cosa ind musculature of asthmatic patients react to factors uluch generally have no effect on normal subjects Such factors include allergens infection and reflex pliysical and psychic stimul It has been estimated that 35 per cent of the population are affected with this discouragin, and disheartenin, affliction 11 some time during life and that 0 2 percent of all deaths in the United States in 1910 here duc primurily to bronchun asthma * llith these figures confronun, us it is leurtening to note that signifi { int progress has been made in allesting this condition Inalysis of the hors series of cises resealed that ap proximately 15 per cent cre completely relieved 80 per cent were more or less improved and only 5 per cent were resistant to all treatment I Pathophysiology proper understinding of the physiological mecha nisins insolved in asthmatic patients during paroxysms and during the asthmt free period sheds considerable light on the difficulties attendant upon proper therapy Tumerous investigators notabls Courmands and Balduinhue dem 3 ·+ The Management of the Patient onstrated significant findings in their subjects During the asthma free period the patient experiences 1 feeling of general well being and usually evidences no pulmonary distention (increased ratio of residual air to total capacity) Nevertheless the maximum breathing capacity during these remissions is generally 58 per cent of the predicted value and there is evidence of poor intra alveolar ventili tion This degree of ventilatory dysfunction is not suf ficient to produce signs or symptoms either it rest or upon ordinary exertion During ? pirovysm of asthma honerei a state of acute ventilatory insufficiency rapidly develops due mainly to mnadequate expiration The normally active inspiration becomes more forceful to overcome the diffuse broncholar obstruction This results in a greater intrathoracic neg atne pressure than norinal and ur passes through the constricted bronchioles into the aheoli The difficult egress of air through tle bronchioles during expiration is not is efficiently compensated for Normal expiration is largely ? passive process due to the elastic recoil of the lungs and the diminution in chest volume wuch follows relixation of the diaphragm and inspiratory muscles During normal expiration the bronchioles shorten and constrict but this degree of constriction is exaggerated in patients with bronchial asthma Fipiration being less powerful than inspiration cannot overcome this increased obstruction and so becomes greatly prolonged With fatigue of the acces sory muscles of expiration intense bronchoconstriction loss of lung recoil ind the poorly functioning diaphragm the lungs become progressively over distended and the chiest is held in the position of miximum inspiration The following changes in ventilatory dynamics and diffusion of gases huc been obserted in the laboriton) the vital capacity is well as the inspiratory and expiratory ·Iloh Setere Bronchial Asti ma 7 Telocity rite is decreased the residual air is increased intrapulmonary mixing is reduced and the ali colar oxygen tension and blood oxygen saturation tend to fall while the alveolar and blood carbon dioude tensions tend to fillo in mild or moderately severe bronchni asthm but subscquently rise in more severe and protracted bronchni spasm The low cred vital capacity and sloi ed inspiratory EFFECT OF SUPREL ON THE VENT LATORY PATTERN OF A SUBJECT W TH ACUTE ASTHMA L tu nunc IN TO WTALU NOY VA OCITT LOY MEG TY MUSCE teccfac Jasogee CC use for Teacher susci/sec FIGLRE 2 C za buc 123/ and expirtory velocity rates with the striking improvement vluch follows relief from the underlying bronchiospasm inay be observed in Ture 2 Finally because of di minished ability for the oxygenation of hemoglobin the amount of reduced hemoglobin in the capillaries rapidly increases and when thus reaches 1 level of 5 gm per cent cyanosis may be observed Based largely on clinical observations in asthmatic pa lients and studies with experimental obstructive dyspnea in dogs Brach 70 fias contributed greatly our nou) edge of the mechanics of respiration in patients sith ·6 The Vanagement of Ile Patient bronchual asthmi He attributes the intul increase in the astlimitic subjects pulmonary ventilation to reflex stimu lation of proprioceptive reflexes in the lungs and chest wall resulting from the physical effort necessary to draw air into the lung Later the consequences of obstructie dyspnea lead to changes in the lung which are responsible for hypoxia which then becomes a contributory cause of dyspnea and in addition e\ercises 7 lurmful influence When the luyns of a dog was constricted Barach observed in immediate increase in the intrapleurıl negatne pres sure during the inspiratory cycle This was obviously necessary for the inward movement of air past the point of obstruction As this pathologically elevated intrapulmo nary pressure persists over a long period of time it exercises a cupping action on the pulmonary capillaries and on the intrathoracic bronchi which causes in exudation of serum into the alveoli and an outpouring of mucus from the bron chil mucous membrane Both of these factors interfere with absorption of oxygen With the progressive conges tion and edema that followed in the dog s lung Birch observed 1 marled increase in the physical effort to breithe due both to the original obstruction in the larynx and to in increasingly engorged lung Areas of emphysem? appeared in the periphery of the lung and basılar pulmo nary edemı was finally observed He further demonstrated that when helium oygen mixtures were breathed under positile pressure of 5 cm of water the pathologically ele vated negatie intripleurl pressure observed during the inspiratory cycle was markedly decreased and the plıysıcıl effort of inspiration conspicuously diminished! 2 The Acute Paroxysm The acute paroxysm actually consists of edema of the mucosa and submucosa which may be thrown into folds ·11th Severe Bronchital Isthma 7 accumulation of thick tenacious and copious mucus and spism of the smooth muscle of the bronchi and bronchi oles The attach may vary in intensity from simple tight ness or heaviness of the chest to marked dyspnea with characteristically noisy (usheezing) respirations Attncks are more frequent at night At tlie height of the seizure the patient presents a pitiful sight He sits or stands in a flexed position with lus back rounded and his chest shoulders and head fined This posture tends to increase the effective ness of his espiratory efforts although it probably reacts to his disadvantage by reducing the lung volume ind vital capacity He is drenched with cold sweat and is tense 11x1ous and apprehensive During inspiration the acces sory muscles of respiration (sternocleidomastoids trapezu and sculeni) stand out in desperate contraction there is marked retraction in the supraclavicular and intercostal spaces as well as in the epigastrium Expiration is pro longed and labored and requires considerable effort be riuse of increased bronchoconstriction during thus plinse of respiration) The diaphra,m is usually lon and motion less and the chest is seemingly fixed in its over distended position Respirations are ordinarily slow and labored but with infection or in status asthmaticus the rate may in crease The asthunatic episode in chuldren especially those under to years of age differs from adults in that the dyspnea is not necessarily espiratory and orthopnea may not be present The acute parowysm may last for hours or Tecur in varying degrees of severity for days Tinally 1 state of intrictable astım during which the episode is continuous ind refractory to treatment may result In the initial stage in utterly useless cough may be present (tussic insufficiency) later lowever sputumn luich is thuck and tenacious or mucoid und frothy is ex pectoratel Tlus material is generally whattish but may be. come grayish or yellow is the episode progresses the ·8 The Management of the patient sputum generally becomes thinner and with improve ment it is more easily expectorated An effective cough ing piroxysm may liberate 1 large plug of mucoid spurum which may herald relief Hemoptysis in the absence of other pulmonary disease is very rare Anorexia and vomuung may occur Although the temperature is usually normal or often subnormal fever may be present especially in children and in adults with associated infec tion There may also be an increase in the white blood count as well as in the number of eosinophils in both the blood and the sputum Exumination reveals distint breath sounds prolonged expiration and the typical inusic box revue (sonorous and sibilant dry rules and rhonch of sarying grades of intensity) Moist rales are rare unless associated with pneumonitis atelectasis or bronchiectasis The percussion note is usually hyper resonant and the leart sounds are distant due to varying degrees of emphysem? 3 Complications In the severe persistent acute episode or in the contenu ous paroxysms of status asthmaticus the patient presents ? picture of marked physiological imbalance Evidence of severe hypoxia cyanosis dehydration peripheral vascular collapse and drug intoxication from previous intensive therapy may be present Death may come suddenly from any of the Intter factors but more commonly in status asthmaticus it is due to asphyva resulting from plugged and obliterated bronchi and bronchioles Death may also be brought on more quickly by the injudicious tise of mor pline and other drugs Complications in the course of the acute attack are fex Pleurisy subcutaneous emphysemii mediastinal emphy sema spontaneous pneumothorax segmental arelectasis ·11 th Severe Bronchial dsthma and heart failure (both right sided and total) may be obsersed Gradually with repeated and prolonged attacks pathological changes typical of emphysema appear in the structure of the lungs and thorax The smaller bronchi and the alveoli may be more or less enlarged depending upon the degree of emphysema McVichael'is considers emphysem as the commonest cause of pure right heart failure (pulmonary heart failure) He believes that poor ventilation of the lungs due to hypoxia induces vaso constriction of the pulmonary arteries and pre-capillaries Right sided heart struin is largely the result of this pulmo nary hypertension In the chronic state other changes in the Jungs may be observed namely bronchostenosis bronchiectasis atelectasis and non specific pulmonary in filtrations and bronchopneumonia Progressive obliterative endarteritis of adjacent pulmonary blood vessels may occur in a number of primary diseases of the lung Barden and Coopers have described the roentgenologic manifestations of a great variety of diseases which affect the peripheral blood sessels of the fung Rich and his associates"** have experimentally reproduced the characteristic response of the peripheral pulmonary vessels to 1 hypersensitivity state and have called our attention to the wide variety of diseases in whuch this non specific reaction may occur Harkavy" " de scribed reversible clunges in some forms of bronclual asthma in which the pulmonary vessels act as sloch organs With increased sensitization 1 progressise necrotizing obliterative endurtcritis of the sinaller pulmonary vessels appers The pathological lesions found in patients with histories of acute onset of bronchual astlami without de monstrable cause ind with essentially negative shin tests and clinical courses characterized by fulminating broncho spastic crises ire frequently indistinguishable from the ·10 The llanagement of the Patient lesions found in 1 great variety of clinically ind etio logically different conditions (sulfonamide sensitization fatalities serum sickness lupus erythematosis cute rheu matic fever periarteritis nodosa and others) The response #hich is the same in all of these stried ulments nimely an increased pulmonary capillary permcability (of the pulmonary sessel wall to serum and protem) resulting in prchy or massive edema of the lungs certainly suggests 1 common denominator The restricted ventilatory ca picity due to bronchospasm emphysema and these periph eral visculır changes in the lung produces pronounced symptoms of respiratory insufficiency which may lead to death in the asthmatic subject 4 Fatalities The first major study of the pathology of this disease by Huber and Loessler in 1922 was folloned by many indi vidual case reports Significant recent reviens have been made by Richemann 139 Unger" and Gay ® A possible relationship bern een bronchial asthma and the general adoptation syndrome (Selye) has been suggested by many observers According to the thesis of the general „dapta tion syndrome the so called diseases of adaptation follow the continued stimuli of 1 series of alarm reactions over an extended period of time 175 176 Among these diseases of adaptation Selye includes flypertension periarteritis nodos? rhetimitic fever and glomerulonephritis Selye!** has reported the results of various workers who hue been able to produce the alarm reaction in animals by differ ent simult employing such agents as epinephrine husta mine decreased oxygen tension and emotional stress The morphologic changes observed in animals during the alarm reaction are best noted in the lymphoid tissue and the adrenal glands Bronchial asthma appears be 1 disease ·11th Serce Broncual asthma in which z number of alarming stimuli occur during an attack from the nature of the disease many attacks occur 01er a long period of time If the theory of the diseases of daptation can be applied to man one miglit well expect to find in bronchial asthmi in increased incidence of these diseases Recently liner Bealey and Segafsu made a clinicopathologic study of 16 autopsied cases from the files of the Mallory Institute of Pathology of the Boston City Hospital For purposes of analysis the 16 cases were dided into three groups on the basis of anatomical findings (1) those patients whose death occurred during an attack of bron chual asthin (2) those pruents who died because of dis erses which frequently accompany and may be related to bronchial asthma and (3) those patients who died because of intercurrent diseases Of the 16 prtients there were 18 in Group / who died during in attack of bronchul asthmi Death during an att ick of bronchun asthma is comparatively rare Ungeri** recently estimated that approximately 200 butopsy reports of deaths during an acute attack had been published up to that ume and he discussed the reasons for the paucity of such reports The present series adds 13 cases The pathological findings of these ( uses were death occurred during en zich of bronchial asthm were essentially similar to those previously reported Thieme and Sheldon's stated that die pathological dngnosis of bronchur asthmı can be made only when the inajority of the following criteri? tre present (1) hyaline thickening of the basement mcm brine of medium sized bronchi (2) hypertrophy of the muscles of medium sized bronchi (3) mucus plugs in Irrge and small bronchi (1) cosinophilic infiltration (5) sic culton of the bronchi ind (6) excessive production of mucus and widening of the mouths of the bronchial glands ·12 The llanagement of the Patient Emphysema as uniformly present in these cases and in the great majority of reported cases Atelectasis oc curred in only one case of this group Mucus plugs were present in each case The frequent occurrence of focal groups of neutrophils in both the lumen und wall indicates the presence of focal cute bronclutis superimposed on bronchial asthma The additional exudate may increase the degree of bronchial obstruction and may contribute to the development of bronchopneumonia and telectasis The status of the heart in bronchial asthmı has been the subject of many previous studies 33 101 150 156 186 187 Dis agreement has been expressed as to the presence and im portance of right ventricular strain and hypertrophy in ncomplicite bronchial asthma It has been demonstrated by means of cardiac catheterization" that an extreme degree of pulmonary emphysema or fibrosis might exist with little evdence of strun on the right side of the heart Another approach to the subject of pulmonary heart diseise was made by Spain and Handler189 who reviened 60 cases of chronic cor pulmonale at necropsy They con cluded that the primary cause of cor pulmonale was not obliteration of the pulmonary vascular bed fibrosis of the lungs or the influence of polycythemia but rather the result of the changed pressure relation within the alveoli producing an increased resistance to the low of blood They felt that the term emphysema need not imply an as sociated pulmonary fibrosis There has also been recogni tion of the fact that asthmatics may have clinical signs and symptomis usually referable to cardiac failure but due to extracardınc factos 69 Chronic bronchitis and emphysemi may produce cough basıl rales cyanosis dyspnei and orthopnea The calibre of the pulmonary capillaries is decreased in the presence of emphysema and signs of increased enous pressure may ·Ilith Severe Bronchial Asthma 13 result However in our group of patients with uncomplı cated bronchial asthma there were four with definite hypertrophy of the riglit ventricle in the absence of hyper tensive or valvular disease One patient had signs symp toms and anatomical evidence of right sided cardiac ful ure In the other three cor pulmonale was an incidental ſinding so far as the clinical course was concerned In other studies the finding of cor pulmonale in uncomplicated bronchial asthma has been variable Tlueme and Sheldon * reported seven cases of status asthmaticus each with central congestion of the liver In this study four cases had central congestion and atrophy of liver cells one case had central hemorrhagic necrosis Rich and co workers have demonstrated that central congestion atrophy and even central hemorrhagic necrosis of the Iner inay result from anoxemia or anemia Blood counts were not available in the cases There was no sig nificant anemia in the other cases Anatomically there was evidence of cardiac failure in only one case it is possible that the asphyxia of attacks of bronchial asthma may be related to the development of these hepatic changes Particular attention was paid to lymphoid tissue and adrenul inorphology in this group A possible relationship between bronchial asthma and the general adaptation syndrome was suggested in these cases by the observ wion of lymphord changes resembling those described in the alarm tcnction - Rather than one alırmıng stimulus shortly before death there were many repeited alarming stimuli occurring for days and even weeks preceding death lymphoid and adrenal changes might be expected there fore to be sarble The lymphad changes wluch were seen in these cases hile in the past been considered either toxic or inflammatory in origin It is possible that these changes may represent those of the alarm reaction ·14 Tle Nanagement of ti e Patient Fındıngs on 16 patients in Group II showed that death was due to a pattern of diseases related to bronchial asthma the fundamental elements of which were chronic bronchitis and emphysema often associated with broncho pneumonia pulmonary fibrosis and cor pulmonale Cor pulmonale was more frequent in this group than in un complicated bronchial asthmi Cardiac decompensation appears especially likely to develop in the presence of coronary artery disease or valvular disease superimposed on hypertrophy of the right ventricle Death due to intercurrent disease was manifested in 17 patients (Group III) Emphysema was present in the ma jority of these cases There was evidence of chronic bron chitis in approximately 50 per cent of the cases Eosino phils were found in bronchial walls in one out of every four cases In this group there were diagnostic anatomical findings of periarteritis nodosa rheumatic heart disease glomeru lonephrus amyloidosis and sarcoid Hypersensitivity has been suggested in the past as the pathogenesis for each of these diseases with the exception of the latter two dis eases these diseases have been included in the theories of the general adaptation syndrome On the basis of these studies which are to be published in full Winer Beakey and Segalº concluded that alarm ing stimuli (histamine epinephrine hypoxia and emo tional stress) appear to be present during attacks of bron chial asthma that they are recurrent and that such stimul may produce in man certain of the so called diseases of adaptation 5 Classification There have been many attempts at classification of bronchial asthma One of the earbest by Salter155 (1868) ·11 oth Serere Bror chual Asthma 15 clearly defines the various inNuences which may affect the bronciuoies (intrinsic) and other mfluences mediated through the central nervous systein by reflexes and other Wise Walker 100 in 1918 used the terms intrinsic and extrinsic and this classification las been the one most commonly rought Rackemann 110 has defined at various tunes working classifications of asthma Irrsesi largely on two mun groups the first beginning before the age of 30 Seurs (extrinsic or allergic) and the other beginning after the age of 10 years (intrinsic-generally demonstrating no allergic factors) Colienaz has propounded an ingenious classification based largely on the present concept of im munochemistry His assification begins with three factors responsible for the H reaction in the bronchial mucos? ngniely the antigen antibody stimulus cholinergic stimu Intion and unknown stitnult The libertion of the H substance tlen acts to produce the 15thmatic paroxysms in any of his three main groups extrinse intrinsic and com bined entrinsic ind intrinsic Host allergists employ the last three main groups is the basis for classification The patient with extrinsic asthma is generally delined as one under 30 years of age who dem onstrates specific allergic sensitivity iss luistory environ mental control or by shin or serological tests is attacks are usually acute and (often) seasonrl in caracter with complete freedom clinically belleen attacks Specific al lergk trierups generally brings gratifying results Compit cations are feu and longevity is not affected the in trinsic patient is generily over the age of 10 The cause the factor appears to rise ishin the patient rather than in his environment Specific allergens ire usually not tentonstruite und the famils fustory for allergy is usually tiegative Fudence of sino-trong hui disense and structural einplaseint appears mate <<zmanlı m patients of ilus ·CHAPTER II THE ALLERGIC CONCEPT AND MANAGEMENT OF BRONCHIAL ASTHMA 1 The Allergic State THE terin allergy implies 1 serte of inherited hyper sensitivity to a foreign substance usually protein in na ture The hereditary factor in astlıma appeurs to be 2 tendency to any type of allergy The allergic response is the importint basic mechanism in the causition of asthma The specıſic response follows the antigen (allergen) anti body union The antigen antibody reaction causes the sensitized cells in the slioch organ to which the antibody is bound to release a touc substance Most investigators believe that an H (histamine like substance) C (choline like substance) or (an unknown substance) is released following the contact of the allergen with sensi tized cells of the bronchioles or that the notion of luista mine is mediated by acetylcholine liberated following the stimulation of prrasympatlietic nerves It is the reaction to this common substance that accounts for the allergic response which is characterized by a marled local reaction of an inflammatory type involving pirticularly the mucosa of tlie broncluoles (the sensitized cells) Thus renction is associated with muhed capillary dularition increase in the permeability of the capillaries increase in the protein content of the intercellular fluid engorgement of the lymphatic and blood capillaries increise in the lymph flow accumulation of inflammatory cells especially eosinopluils and an accumulation of mucus secretion within the lumina of the bronchioles 18 ·Itach Seiere Bronchial Asthma 19 In recent years significant adsances hase been made in our understanding of the immunological and physiological mechanisms involved and in the management of this dis order wluch ruses so much liavoc with the patient and his family Specific int1, en ants body reactions are character stic xf crperimental allergy since scrum antibodies can be demuely demonstrated and the specific sensitivits way be possively transferred to normal animals in patients tiitli allergic asthma although the specific sensitivity may Ise prassanely translerred (Praustutz hustner method) the amount of seruan antibody (referred to as rezgın) may be u diluted in the total body fluids as to become inadequate for en tidin detection *** Coole and Lovelessst? have dem onstrated that rezgin a thermolabile antibody is found oh mn the serum of naturally alleryre tndividuals Rogu & in luc possively transferred to normal subjects but its formation (not loc induced by immunizing normal inch saluts with pollen This imutboly is closels bound to the sensitied cells of the shin and mucous membranes 101 reacts on contact nusth the antigen eg nghied causing tirese cells to laberite thic tonic substance which then a mints tnx the lex?! renc 2011 (hrse) in the bronchioles This when a subject wie das inherited the capacity for descleping reigin (ilie sufisitizing mully) in huis bron chut mucous membranes inhales tiga cell poiten the inu çen wiboly tection 1X61113 and asthma develops There is tri triersc relationslup between the announts of antigen in ein necessary for tlie prodlucnon of an 1076 in duos in reagon the omnipresent therinola »le sc?sHwNy tutildy these sanie 511 isjecis mas develop mother type of antibody wluch is thermostable is no cellulir ffinity ini series in 7 more protectis c capicity The Inter is a blackms or neutralizing anuboxly (11 fically prosluced) whose function is to bini or neutralize ·20 The lanagement of the Patient the specific antigen and prevent its interaction with the troublesome reagın This antibody is found in both nor mal and allergic subjects following pollen immunization Honever it cannot be demonstrated by passive transfer tests in normal individuals Unfortunately not all types of bronchial asthma cin be expl uned on this specific im munological basis 2 The Immuno Chemical Approach to the Allergic State The immuno chemical treatment of bronchial asthima should be directed toward (1) lowering the amount of reagın or making it less capable of sensitizing the cells of the shock organ (2) producing enough thermostable antibody to block and neutralize the effects of the specific intigen and thus increise the tolerance for the specific antigen ind (3) neutralızıng and protecting against the effects of the toxic H C or substance ultimately responsible for the attack Unfortunately these theoretical aims although sery desirable are not often obtainable There appears to be no satisfactory method for producing quantitanse reduc tion of or hyposensitization against the effects of reagın Wllergic cleanliness and environmental changes can reduce the hazırd of contact with the causitre allergen After hyposensitization by injections with a specific allergen formuon of both the thermolabile sensitizing reigin and the thermostable antibody are stimulated With successful treatment sufficiently high titres of thermostable antı bodres may be developed to combine with the antigen and thus prevent its union with the reagin There are grcat individual variations in ability to form thermostable antibodies Many allergists believe that the successful inhibition of the allergic response which the allergen ·Jith Severe Bronchial Asthma 21 would otherwise initiate may depend upon the produc tion of sufficient thermostable antibodies to act as block ing and neutralızıng bodies Unfortunnely as Alexander has pointed out the mechanism by which clinical im provement occurs following specific pollen therapy re mains unknown because of the lack of correlation between the ture of thermostable antibodies and the degree of im provement Furthermore Coolest ss has called attention to the fact that there are several different and clinically actre antigens in pollen extract with a blocking antibody specific for each This may explain further the diſficulty in correlating clinical immunity with serologic determini tion of serum antiboly Finally in addition to the difficulties that arise due to the complex nature of antigens the need for more sensi the immuno-chemical methods for determining antibody in vitro Ins been called to our attention by halırt 103 104 The immuno-chemical approach to the inanagement of the asthmatic is limited because of these difficulties The allergens may be classified into four mun groups ingestints injectints inlialants and contactants Among the most common offenders (illergens) are pollens (chiefly trees grosses and seeds) anımıl and poultry danders and feathers molds and other fungi cosmetics (orris root rice ponder and hurayz gum) insect sprays (py retlirun) foods and dermal contacts searching history may reveal other concomitant allergic reactions such as infantile eczema TECHT non seasonal somotor rhinitis contact sense tivities (particularly drugs and sero) new houschold objects (bredding furniture etc) pets fur cxccupational skin and inbittory contacts Still other factors may in clude fatigue esertion coll lient" respiratory tract in fection non specific pulmonary irtints (dust fumes smoke anul alors) and psychosomatic factors all of which ·22 Tle Vanagement of the patient my asslime variable degrees of importance when initrat ing or participating in such a reaction Every attempt should be made to determine the responsible antigens A search for correlation of the attack to season and environment may reveal that the attacks occur in the spring ind summer coincident with the peak of the three pollen sersons (trees grasses and weeds) in the winter with the pret ilance of upper respiratory infec tions in the fall ind winter due to house dust molds or other fung, related and coincident with heating of hores (boxed in radiators and exposed piping systems) and during any serson with marked frequency of barometric and humidity changes Food allergens due to inhalation or ingestion may cause bronclul asthma The inhalatory mechanism may be ob served in millers or brhers but on the whole is seldom encountered The gastrointestinal route is more coinmon Any food may act as an alergen The major food allergens generally produce prompt reactions The minor food allergens on the other land produce delayed reactions Cung 2 single allergenic food may cause in explosion of allergic manifestations that may last one to tuo cehs The incidence of allergic response is generally related to the frequency of ingestion The food allergens are ab sorbed into the blood streun and piss to the sensitized cells of the shock orgins in the nose bronchi or bron choles thus producing an allergic rhinitis bronchitis or bronclul astuna Allergic bronchius may or mny not be associated with bronchial asthm: It may be associated with in allergic rhunttis or follon in upper respiratory tract infection More commonly lionerer at occurs without an per respiratory tract infection In discussing rool sensitivity in asthmatic children 11111 ? stated thit about 20 per cent of positie scriich ·11 11 Senere Bronclia! dstl ma tests to foods are of etiologic significance Furtiermore he pointed out the mother itsually knons what food produces asthma and Ins omitted it before skin tests are done Nevertheless routine procedure should include 1 searclı ing history or skin testing for all possible offending allergens Such tests however are not infallible and there fore should not be used as definite guides for diet control When the offending fools can be definitely determined their omission from the diet should bring freedom from attack The next step should be to determine the patients tolerance for the indicated allergen Tlie eliminated foods may be talen one at a time on successive days and any change in symptoms noted Oral hyposensitization may then be attempted lsy introducing the food (corn whert fish chocolate milk or eggs etc) in greatly diluted and small amounts and then gradually increasing the concen tntion and amount daily unul the whole food can be thlen When the offender is not enoun trul elitnition dicts *7 or (ther morlifications may be resorted to is n first step milk becſ broth or gruel may be given alone for two or three drys If improvement foll yns editional ſoods may be added until the offender is detecter! Rin delph. determine what he calls the base of sensitivity Iclore recommending the type and plan of diet to be followed Generally if no relief is obtained withun 1 period of seien to 10 days foods are not likely offenders It 7 detuled kustory is inconclusive shin patch scratch ind intradermal testing should be resorted to Unfor cuinately these procedures are time-consuming costly and generally disappointing Vany sul stances with mashedly positic skin reactions produce no asthma uslule at uimes substinces with negatie shin reactions produce astımı Furthermore these tests iry from time to time and 11ews allergic sensitivues may be acquired Harmful and un ·24 The Afanagement of the Patient marranted restrictions despite critical interpretation of skin tests have been prescribed too frequently Removal of the offending allergen and intensite specific hyposen sitization should be promptly instituted in all cases when ever possible It has been our custom to routinely advise perennial non specific hyposensitization with house dust extract and stock mixed bacterial accine or autogenous vaccine for patients with negative skin tests in whom a history of sensitivity to dust or upper respiratory infections can be elicited Successful preventue therapy depends upon the de termination of the causative allergens These should be removed from the patient s environment (allergic cleanlı ness) and intensive effort should be made to defend (hypo sensitize) him against these allergens Further therapy should be directed towards removing the contributory factors Because search for the responsible agents is dilli cult and often completely unsuccessful, emphasis on the allergic approach io management should not erclude physiologic therapy 3 Drug Tolerance There are certain general considerations that one should understand when employing drugs in the management of the asthmatic patient The incidence of intolerance toxic effects or true drug allergy following innocuous doses of drugs is considerably higher in asthmatics than in normal subjects Simple chemical substances are not of themselves perfect allergens but they can acquire specific allergenic activity when joined to proteins or certain complex mole cules The distinction becuseen allergic and tonic (phar macologic) reactions is often difficult Furthermore sen sitization may occur following the second administration of a drug after an interval of one to four weeks This is ·stk Saree Bronraral sikma particularly imue of pontocine and mın of the serious reactions and deaths observed have occurred with second usage at time of repeated bronchoscopy or bronchography A careful bastons of pres sous drug reactions should be soulit for an asthmatic patients The inajority of patients in starus isthmanicus soon be Cine intolerant of most drugs is tsinessed by the fre quency of musea abdominal pain vomiting restlessness nching of the skin and nose rashes and edema of the lips Other nimmfestations of drug sensitivity such as leser leucocytosis adenopallı ind arthralgias occur less frequently lo Tue SOSIth Ny to adrenalin or aminopły!!ın luas been repxited however tonic reactions and refrac toriness to both of these drugs may occur Furthermore deathst 1 179 have been reported attendant upon their lise intravenously Sherman" in a sumulatıng discussion of drug allergy classified the numerous drugs likels to act ts excitants of asthuna and rhinitis into proteins segerable gums and crystalloids Among the protein drugs (iherapeutic agents) proxlucing these reactions are various foreign sera and 10\oids virus and ticketsual vaccines from cas, volk luer insulin and pitturary extracts and papain (caroid) and pancreatin lectible guts emplosel 10 pharmaceutical preparations such as 10201 Larava and tragıcanth brave caused asthma lunitis and urticaria in suscepuble indi duls Thus tris cupljin suite of the reactions that have fotioned the use of some of the new intihustaminic tablet preparations Cristallod drugs such as quinine quinidine arseni cals phenolphuthalain thamine in drochloride procaine pontocuine comune forınalın sulfonamides penicillin and siteplomycin (acrosols) nint enous sadares (pur ticularly sodium pentothal wluch may produce broncho ·24 The Management of the Patient warranted restrictions despite critical interpretation of skin tests have been prescribed too frequently Removal of the oſſending allergen and intensive specific hyposen sitization should be promptly instituted in all cases when ever possible It has been our custom to routinely advise perennial non specific hyposensitization with house dust extract and stock mixed bacterial vaccine or autogenous vaccine for patients with negative shin tests in whom a history of sensitivity to dust or upper respiratory infections can be elicited Successful preventive therapy depends upon the de termination of the cusative allergens These should be removed from the patient s environment (allergic cleanlı ness) and intensive effort should be made to defend (hypo sensitize) lum aguinst these allergens Further therapy should be directed towards removing the contributory factors Because search for the responsible agents is difi cult and often completely unsuccessful emphasis on the allergic approach to management should not exclude physiologic therapy 3 Drug Tolerance There are certain general considerations that one should understand when employing drugs in the management of the asthmatic patient The incidence of intolerance toxic effects or true drug allergy following innocuous doses of drugs is considerably higher in asthmatics than in normal subjects Simple chemical substances are not of themselves perfect allergens but they can acquire specific allergenic activity when joined to proteins or certain complex mole cules The distinction between allergic and touc (phar macologic) reactions is often difficult Furthermore sen sitization may occur following the second administration of a drug after an interval of one to four weeks This is ·11 10 Seiere Bronchant Isthma 2) particularly truc of pontocaine, 1" and many of the serious reactions and deaths observed have occurred with second usage at time of repeated bronchoscopy or bronchography \ careful history of previous drug reactions should be sought for in tlimatic patients The majority of patients in starus asthmaricus soon be come intolerant of most drugs as witnessed by the fre quency of nausea abdominal pun somiting restlessness schung of the skin and nose rashes and edema of the lips Other manifestations of drug sensitivity such 14 fever leucocytosis adenopathy and arthralgias occur less fre quently No true sensitivity to drenalin or aminopluyltın has been reported however toxic reactions and refrac toriness to both of these druge may occur Furthermore deaths? ** 130 have been reported attendant upon their use intravenously Sherman't in a stimulating discussion of drug allergy classified the numerous drugs likely to act as excitants of asthma and rhinitis into proteins vegetable gums and crystallods Among the protein drugs (therapeutic genus) producing these reactions are various foreign sera and toxouis virus and richettsial vaccines from egg yolk hver insulin and puutary extracts and papain (ciroid) and pincreatın Vegetable gums employed in pharnıceutical preparations such as acacia Karayı und tragacinth have caused asthmt rhinitis ind urucarn in stisceptible indi siduals Tlustry expiun some of the reactions that have followed the use of some of the new antihustaminic tablet preparations Crystillod drugs such as quinine quinidine arseni cals phenolpluviale in thimine hydrochloride procaine pontocune comune formalin sulfonamides penicillin and streptomycia (acrosols) intrn enous sedatives (par cicularly sodium pentothal which may produce broncho ·26 The Management of 11e Palien! spisin per se not on 1 sensitizing basis) and intravenous sclerosing agents should be used with caution in asthmatic subjects Accidental intravenous injections of drugs or allergenic agents198 199 may also explan some instances of sudden collapse ind death (anaphylactic reactions) Even idiosyncrasy to jodides bromides and chloral may be oc casionally observed Other drugs particularly optum and morphine should be avoided As there is a high inci dence of sensinuity to acetylsalicylic acid (aspirin) in asthmatics reactions to this drug are common and apt to be severe Unſortunately skin tests except for patch tests in certain types of dermatitis are of no value for the de tection of sensitivity to most crystalloid substances be cause of the absence of demonstrable circulating antı bodies and furthermore they may be followed by severe constitutional reactions Presumably simple cheinical compounds introduced into the body when combined with protein miglı act as haptenes (pirual allergens) and determine the specificity of antibody reactions There is little evidence that the natural drug itself can produce allergy without this combination On the other hand skin tests and antibody determinations may be of salue in the drgnosis of allergy to protein drugs and vegerible gums The degree of specificity and the duruon of sensitivity to drugs vary greatly Drugs likely to produce sensitivity should be avoided in asthmatic subjects Trnal dosage by the sublingual or oral route should be resorted to when doubtful Initzlatoty or other parenteral routes slould not be employed in such instances or serious reac tions may follow ·CHAPTER III PROTECTION STUDIES The clinical evaluation of dings employed in the man igcment of bronchospasm is extremely difficult and at best inaccurate In muild and transient episodes agents of weah or doubtlul potency may give relief in status asthmaticus the desperate need for immediate relief does not allow con trolled observation of the action of single agents In view of these difficulties a method of producing dyspner and bronchospasm it well in sensitive subjects is employed The seuch for a suitable bronchospastic substance actue in the protein manifestations of allergy and anaphylaxis in inimals and man has insolved many investigators and countless studies In these vrying and conflicting reports two substinces (histamine ind acetylcholine) nie often been considered possible chenucal mediators of allergic phenomenon Both of these substances are capable of pro ducing dyspnea and bronchospasm in asthmatic sub 137 19 19 and may be used in the ev zluation of drug> capible of protecting against these effects 67 9 With tlus technique a method of human assy of the relative salue of new and accepted therapeutic agents for the relief of bronclul asthmua lazs been evolved 63 63 149194 195 By means of this technique we hope an approach may be made to the fundimental problem of the pathogenesis of bronchul astlınız and thus to its management on 1 rational basis jects 6676 • It ese st dics were carred out in the Department of Inhalat onal 11 craps of the Boston City llos ital support in part thro gh a grant from the inted States I ul lac llealth Sense I am indebted to the mem bers of t is department includug former rescared fellou s Drs J F Besley and II R busks ant my 24sociates Drs F Bresnich and L. Levinson 27 ·28 Tie Afanagement of ti e Patient I Laboratory Vethods for Producing Dyspnea and Bronchospasm The effect of intrinous administration of histamine (Histimine diplosphate solution (Abbott) each cc repre sents 0 1 mgm of histamine base) or acetyl beta methylcho line (Vecholyl cliloride solution (Verch) each cc repre sents 10 mgm) begins fifteen or twenty seconds after its administration The first effect is that of a disagreeable metallic taste thus assuring one of the intravenous admin istration accompinied or followed by the onset of a series of sensations related to vasodilatation and other compensa tory cardiovascular phenomena These responses reach their maximum in approximately 30 to 60 seconds and con sist of headache flushing palpitation and gıddıness Ad ministration of acetyl beta methylcholine often produced saluation lacrimation and a sense of substernal constric tion but headache was not noted Serial determinations of the vital capacity after the administration of either of these agents revealed that the maximum diminution in vital cipacity occurs approximately 30 seconds after the intravenous administration of the bronchospastic substance This drop was determined with stopwatch timing by har ing the pitrent perform vital capacities at specified intervals after injection The most satisfactory intervals were found to be 30 seconds and then one two three and five min utes We have repeatedly shown that a patient is capable of performing vital capacities at 30 second intervals for several minutes without appreciable change As previously noted the maximum drop in vital capacity is almost in variably seen 30 seconds after injection Figure 3 depices a typical response to the intravenous injection of a broncho spastic agent The vital capacity usually returns to normal in one to five minutes frequently it rerurns to levels some what higher than the original ( rebound phenomenon ) ·If oth Serere Bronchial dsthma 29 lfter pre treatment of the experimental subject with a protecting agent the return of the vital capacity to the resting level following injection of the bronchospastic sub stance was usually more mpid New patients generally first recened intramuscular 42- 40- 30 36- TAL. CAPAC TY A TYP CAL RESPONSE OF A SENS T VE SUBJECT TO NTRAVENOUS HSTAM NE OR MECHOLYL CHLOR DE 28- 26 20 25 5 0 5 M UTES P ADMINISTRATION FICURE 3 injections of 006 mgm of fustamine or 01 mgm of mecholyi intramuscularly as test doses in order to detect ny abnormal sensitivity no such instance was demon stratec The intravenous doses of lustamine usually ranged from 001 to 001 mgm Houcher (no subjects rected consistently to 0 005 mgm ind one subject to 0 002 mgni The hughest dose used in a protection study has been althou greiter imowits lave been ad ministered during the course of our investigations In general a dose of mecholyl sufficient to produce a signifi cant drop in vital capacity 125 attended by much less 006 mm ·30 The llanagement of the latrent severe side effects than an equally effective dose of iristamine The doses of mechiolyl chloride administered intravenously usually ranged from 0 05 mgm to 04 mgm Sometimes the scierity of the side reactions produced by histanıne necessitated discontinuing the experiment be fore z dose capable of producing 1 decrease of the val capacity could be guen Sale reactions to mecholyi kere much better tolerated The most prominent symptom from overdoses of luistinune sually was incapacitating herdache Honever excessive doses of mecholyl produced more ?lirming effects Approvnitely 25 seconds after such an injection one patient seemed to lose conscious A vacant stare appeared followed by momentary cessation of respiruuon and clonic movements of the arms and legs The entire reaction lasted only 10 to 15 seconds solution of tropine sulfite nas altı ays kept rendy in 7 syringe for inimediate intravenous administration but no recuon long enough to wariant its use occurred Patients later described such reactions as going numb all over with 1 sense of constriction in the chest and transitory inbuity to move the limbs The chical appetrance of these reactions suggests transitory asystole Idministration of bronchiospastic agents and of them? peutic substances by zerosols has been employed exten sicly in all instances we live mide use of herosols produced with the standard Vaponefru nebulizer For uniformuty a standardized technique for herosol 3d ministration was det iseck The nebulizer 175 field by the experimenter with its outlet orifice close to the patients Open mouth The experimenter slowly counted aloud and at three the nebulizer bulb 1 7$ squeezed with maxi mal force is the patient simultaneously made the deepest and most rapid inspiration possible following uch he held his brcath in inspiration for four or five seconds ·11th Seiere Bronchital Asthma 31 The procedure 1475 reperted at precisely ten second inter als unul the desired number of inhalations (generally six) had been given The stopu nchi was then immediately reset further time intervals were then calculated froin tie end of the last inhalation In contrast to the sequence of events following intra enous administration of histamine and of mecholy! the YITAL CAPACITY IN UTERS TYPICAL RESPONSES OF AN ASTAMATIC TO AEROSOL HISTAMINE OR MECHOLYL 1 RO is M NUTES 20 25 30 BIORE effect of these agents administered by the zerosol route is slower both in onset ind in recovery The maximal drop 111 satt cipicity usually excurred one or to minutes after the list anulation in occasional instances it did not ale place until three minutes thereafter Recovery 175 fisually complete within cight to ten minutes A typical response of 7 sensibile subiect to in erosol of bronchospastic zent is depicted in ligure 1 le hile not ob serical the rebound phenomenon following the ad ministration of frostimine or of mecholsi by the zerosol Touc Vany patients describe mecholyi induced dispner ·32 Tle Vaniement of the latient and bronchospasm as being more like their asthmatic paroxysms than histamine induced dyspnea and broncho spasm Side reactions have been infrequent when bronchospastic agents were administered in this way in contrast to their almost invariable occurrence to some degree ifter intravenous injection Those side effects which did occur were similar to the reactions already described but much less severe 2 Laboratory Evaluution of Therapeutic Agents (Pro tection Studies) A protection study consists of determining the effect of a bronchospastic agent on vital capacity before and at vary ing intervals after administration of the drug under in estigation (protecting drug) The resultant decreases in vital capacity are compared to the control drop Protection is demonstrated when administration of 1 bronchospastic agent causes either no drop in vital capacity or 1 drop distinctly less than the control amount I'rotection is lost when the decrease is once again equal to the control drop A typical protection study was begun with a rest period of fifteen to twenty minutes the patient sit quietly and all constricting clothing was loosened The vital capacity was determined repeatedly until several trials were within plus or minus 100 cc The dose of bronchospastic agent required to produce a significant control drop in stil capacity was then determined either by herosol or intra i enous route Such a significant drop was usually I to 2 liters although sometimes it was necessary to accept slightly smaller decreases in those patients whose basıl vital capacities kere as low is 2 liters initially In this determination graduilly increasing amounts of broncho spastic agent were administered every 20 to 30 minutes until a desirable decrease in stil capicity #tis obtained ·sloth Serere Bronchual sthma In the case of intrasenous histamine the increinents were 0005 or 001 mgm and in the case of mecholyi 003 or 01 mgm 33 Ifter the control drop for the day was established and verified at least once the protecting drug 175 adminis tered following this vital capacities were gain deter mined and followed by repe ited adınınistrition of the bronchospistic agent at intersals of not less than 20 minutes Beforc erch sucessive injection of the broncho spastic agent three to five stal capruities were always obtained at intervals of one to two minutes in order to reaffirm the basal tal capacity from winch the amount of the drop it is to be calculated the new basil val (pacities were sometimes several hundred cc higher than the origmal basal readings thus may have been due to the previously mentioned rebound phenomenon or to the therapeutic effect of the protecting agent or perhaps to the bronchodilating effect of repeuted forced eptions (positive pressure therapy) per se The decrease in ital <?picity when the bronchiospastic agent 175 re adminis tered was computed from this fugher level such as frequently inuntained for 1 considerable period of time Consequently when protection is finally lost je them the decrease is equil to the control drop the point to which the vital capacity fell molt suill have been buler than even the original basıl determinations The loss of protection 1175 usually verified by at least one furtlier dose of lustimine or mecholy The sensitivity of the truclieobronchuil liec to either or these substances varied in most subjects from day to day It was minimal during asthma free intervals and mayın! during periods of active bronchospasm Sensitivity did not usually vary within one di and thus did not affect the course of any one protection study in the vast majority of ·34 The Vanagement of the Patient cases In 1 few instances 1 singll dose of histamine or mecliolyl appeared to potentiate the bronchospasm already present over and above its usual effect particularly in subjects with seasonal bronchial astlima studied during the height of the pollen season In such cases the vital capacity would fail to rise again over 1 considerable period of time or it even would continue to decrease Studies on subjects who may hase been demonstrating mild bronchospasm on whom an adequate control drop in vital capacity could be obtained were as satisfactory 25 studies performed during periods of relative freedom from clinical asthma Sernal increases in the dose of the bronchospistic agent caused increasing drops in vital capacity which were not always in proportion to the increment in dose No cumu latite effect was noted when the dose that caused a meas urable decrease in vital capacity was repeated several times every trenty to thurty minutes Repetition of the sime dose several times during a seven hour period showed that a refractory state of the tracheobronchial tree did not develop during the course of studies carried out for thuis length of time Vital capacity determinations riere sometimes invalı dated by cough due to the stimulus created by forced expiration or by the bronchospastic agent itself If thuis effect were so marhed is to preclude accurate consistent determinations the test was discontinued It tu as possible honeler to carry out adequate protection studies on some subjects in whom z bronchitic element was present Such patients often experienced 2 marked decrease in cough and sputum after the protection study was begun Once protection wis established sprcing of basal readings, so is not to excite the cough reflex is no longer necessary Another interesting observation in such patients was the ·Jl sth Saare Bionchal isthma 35 increase in vital capacity and decrease in cough that fre quently occurred during the course of obtaining the basal readings Apparently the act of forced expiration into the apparatus produced a slight positive pressure which was exerted backards into the tracheobronchial tree as an internally distending force Consequently the 1171 capacity often reached a figure much lugher than the determinations recorded when the subject first arried at the laboratory Care Ind to be talen that studies were not begun until the vul capucity lid buen muntained con sistently over several recordings Dit? denoting the densee of protection afforded by a ghen protecting igent again a bronchospistic drug have been derived from these experiments II e hare noted and emphasized that any one protection study m a single indo vidual may have little general applrcabılın llclire at compted therefore to establish in algebruic equation by tshich the degree of protection could be expressed in terims applicable to many subjects so that the data might be subjected to soine degree of statistical analisis The decrease in una capacity produed by a ghen dose of histamine or ol mecholyt vzried greatly from induidur! to individual but remained constant in the same indı vidund for the period of one protection studs During ? period of protection the deciense in al capacity pro dered in the same dose of bronchospastie igent wall by definition be less than the control drop lle live con sidered the percentage difference betheen these two values tolx 7 mesure al protection (rx100 where p is the degree of protection in pei cent 100 per cent indicating absence of any decrease in vl capacity с ·36 The Vanagement of the Patient after the administration of histamine or of mecholyl C is the control drop in vital capacity produced by the Introduction of the same quantity of the bronchospastic agent before administration of the protecting drug and E represents the decrease similarly produced at any given time after the protecting drug has been administered Accurite evaluation of protection demands that the control drop in vital capacity exceed 1000 cc We prefer to work within the range of 1200 to 1500 cc Il hen for example 1200 cc is achiesed as the control drop 7 Jater decrease of 800 CC rould appear to indicate a protection of 331% per cent- 1200 - 800 X 100 331/3 per cent 1200 Honcier variations of plus or minus 100 cc both in the basal vital capacity and in the determination thirty seconds after an intruenous injection of the broncho spistic igent may produce in any individual instance a total difference of as much as 200 cc in the drop An additional variation of 200 cc can be accounted for by vrtue of the fact that the bronchospastic agent cannot be relied upon to produce precisely the sime effect every time The total range of sariation then might be as much as 100 cc If 600 to 800 cc "ere accepted as a control decrease in vital capacity a later drop (ifter administration of 2 protecting drug) of only 200 to 400 cc might be considered to demonstrate considerable protection Obslously hos ever this would be open to serjous error Therefore, uc have always attempted to attain control drops of 1200 lo 1500 cc and consider prolechon significant only u hen til 15 10 per cent or more This trınsformation of data from vital capacity readings ·) MOTO 1 th Seere Bronchial Asthma 37 in cubic centimeters to percentage figures eliminates the dose of the bronchospastic agent from consideration is 1 ruble factor It also faciluates the statistical presentation of such data obtained from eyperiments on different subjects into one curse of increased statistical probability Such a graph representing the missed data from four 100 RECTAL AMINOPHYLLIN VS INTRAVENOUS HISTAMINE (145) Of AL (004 JS 90 100% MG OOCOM CP VOM 40% AL 20 YR. 21 49 JS 2 Y 30-40 NG 22 YRIS S.48 P 22 YRT 28-46 50)7 % PROTECTION 1807) toon J730 WC EP (63no (25) 2201 NC 240) ON 1240120 AL (2017 MG SOGON 15 on 20 3 2 HOURS P PROTECTING DRUG FIGURE 5 i rywal Ir tection Study (unic Obtuned from the Afassed Du of Four Protection Studies Derned from a Total of I hirty Indsudul D ses of a Bronelimpasta Igent protection studies derived from a total of thurt; indi idu il doses of 1 bronchospastic vent is presented in Ligure 5 3 Protection Studies with Anticholinergic Drugs ( Atropine Scopolamine and Bellzfoline) It has been the opinion of many inuestigators that bronchnl asthmu may represent an imbalance of the ·38 Tle Mini agement of ile latrent autonomic nervous system If bronclul asthma were pre dominantly due to an over activity of the cholinergic apparatus then it should respond most satisfactorily to treatment with drugs which block the action of these neries The classical agents which inhibit the effects of postganglionıc nerve impulses are the alkaloids of the belladonni group This group of ulkaloids consists in the mun of tuo hyoscine and hyoscyamine We have limited our protection studies to the use of the trio com monly nulable alkaloids atropine (ricemic hyoscyamine) and scopolamine (lesohyoscine Hoffman LaRoche) In order to compire the effects of hyoscine and hyoscyamine directly we have also made use of a preparițion of mixed belladonna alkaloids which has been assayed in terms of levohyoscyamine only (Bellafoline Sandoz) These para sympatholytic agents atropine scapolamıne and Bella foline have demonstrated excellent anticholinergic pro tection in our laboratory (Table 2) Atropine a naturally occurring racemic belladonna alkaloid is composed of equal parts of the optical isomers of liyoscyamine Since the dextro liyoscyamine has a very werk peripheral action the potency of atropine is due to its lesohyoscyamine fraction Atropine bias consistently demonstrated greater ability to inhubit mecholyl induced bronchospasm tlian histamine induced bronchospasm Scopolamine (levo rotatory hyoscine) also occurs naturilly It demonstrated marked inticholinergic properties when administered subcutaneously (03 mgm) However Bella foline z synthetic preparation believed to be coniposed of total levo rotatory all lords of belladonna manifested the most marked anticholinergic action Since Bellafoline 1175 little or none of the inactive dextro hyoscyamine which is present in tropine its greater potency is easily expluned Oral scopolamine and Bellafoline shout excellent protec tion honeter their reaction is slower

·A IN nyt
P
VCC WOLL
A
JAD
02
MN
MECHOLVL
VA
ATMOSOL
01
M
w
11 al feiere Bronc al Istl ma
de
#
D
TABLE 93

·40 The Alanagement of the Patient Aerosols of scopolumine and Bellifolıne (1 therapeutic dose represented by sin inhalations of the solution ad ministered in one minute) demonstrated excellent but relatnely short lied protection against intravenous and ierosolized mecholyi Considering the very dilute solution employed (006 ind 005 per cent respectively) the degree of protection is truly remarkable The protective action against bronchospastic aerosols uas greater than against intravenous bronchospastics In many experiments involving the use of these para sympatholytic al aloids 7 striking seditive action lias been noted In some cases the subcutaneous administration of 03 igm of scopolumine has resulted in deep drowsiness or sleep lasting for as long as tho or three hours Similar reactions have been noted with Bellafoline Sedation was less evident following atropine whuch was to be expected It may be perceived from the data presented in Table 2 that in eich case a protecting agent reaching its site of action wi the blood streim seems more efficacious in combating the effects of a bronchospastic agent adminis tered by the same route A protecting drug given as an aerosol is more potent against bronchospastic aerosols than against bronchospastic agents given by vein This finding is difficult to interpret One may speculate that nerosols reach the motor end plutes of the bronclual musculature by direct diffusion thus differing from the path taken by substances reaching the lung vi? the pul monary circulation Perhaps aerosols and blood borne medications do not evert their action entirely in the sime effector area the protecting agent ghen by one route all the effectors which may be reached by a bronchospistic drug later administered by the same route but leaves uncovered some other effectors which still remain sensitive to bronchospastic agents administered COTers ·Il sth Sarete Bronchnal Asthma 11a a different route This concept may have wider applı cability to the nationale of treatment of bronchial asthma particularly in resistant cases and may indicate the adusa bility of simultaneous aerosol and intraenous medication This reasoning is somewhat similar to what we hue demonstrated as fact in a study of the pharmacodynamics of pulmonary absorption of penicillin in suppurative diseases of the lung " The same hypothesis may cast some light on the variations in response to therapy of patients with extrinsic (inhalınt) and intrinsic asthma Clinicalls it is well loun that atropine is not an effective bronchodilator and that it is almost useless in the treatment of bronchul asthma In addition its drying action on the mucous membranes of the tracheobronchin! tree leads to further inspissation of already semi solid mucus plugs This makes coughin, and expulsion of these plugs in even more difficult task for the asthmatic and renders him more Inable to recurrent bronchospasm and to obstructive telectasis Despite the excellent ability of these inedications to combine the effects of injected mecholy in the laboratory tropine scopol urine or Belhfolıne will serve a very limited role in the therapeutic 1rmmentarium of the pneumatologist in his attempt to counterict the bronchospasm of bronchiu asthm Sco polimine luns 1 stronger action than utropine on the secre tory glands and 11s 1 (ir more marked central sedatne eflect the latter effect is highly desirable in many cases The act siseating hypotensive asthmatic who may be exhibiting 7 systemic picture of pirasympathetic stimula uion ( pathological agoromia ) is almost completely re sistunt to ordinary methods of treatment luas possible that hyose inc hoxyamine or i derut ane may cumbit suffi cient solutne is well us bronchospasmolytic properties in sucli uslim itics that its use might 1x indented in spite ·12 Tic Management of the Patient of its drying action lle hope that the pharmacologist tuill be able to devise i compound which will retun the sedatne action and the ustral anticholinergic properties of the parent drug but with less local effect on the bron chul mucosa The results of these experiments demonstrate that the alkaloids of the belladonna group are is could have been predicted dramatic inhibiting or protecting agents against the deleterious bronchospistic effects of injected or aerosolized mecholyl and that they have little or no effect on the bronchospasm produced by the administration of histamine Although these results may have little clinical value they offer some theoretical significance In bron chial asthma we are dealing with a disease of unknown pathogenesis It has been suggested that in the astfimatic cetylcholine acts upon a sensithe end orgin the bron chual musculature and submucosi to produce bronchul edemi ( the bronclul lune ) bronchial muscular con striction and thereby bronchospisin all of which may be additive and result in 1 pirossm of asthmi lle hue been able to show conclusisely that injected mecholl has similar effects but that these effects may be completely inhibited by pre trentment with an alkaloid of the belli donna group On the other hand these alkaloids alone are ineffective in the treatment of clinical asthma These observations ure essentially similar to those of Dale und Gaddum 66 who studied the contricture wlucht occurs in denervated voluntary muscle when the para sympathetic insomotor fibers supplying the vessels within the muscle are stimulated Thus contracture occurs beyond doubt by the diffusion of acetylcholine liberated in the Talls of the blood vessels in response to vasomotor im pulses into the neigliboring muscle tissue Hovever the contracture 175 not prevented by atropine Dale and ·It all Sercre Bronchal sthma 13 Gadduin propose that in this and similar situations the Jiberation of acetylcholine occurs in an anatomical area so close to the effector tissue that atropine in unable to evert its usual inibitory effect Such a mechanism may also be present in the loroncluoles 1 Protection Stullies with Sympathomimetic Anunc Aero sols (Epinephrine, Vaponeſrin Isuprel and easyne phrin) Because of the widespread clinical mterest in the use of herosols of trious sympathomimetic umines for the inanagement of bronchial asthm we undertook a com piratic study of the protective abilities of aerosols of epinephrine (1 100) neosynephrin (1 100) Vuponefrin and Isaprel (1 200 and 1 100) against the effects of in travenous lustamine ind mccholyl induced dispnea and bronchospism in isthmatic subjects 1 The nerosols were produced by hand bulb nchuliration with the l'aponefrin nebulizer The dosage of cach the peutic or protecting nent consisted of six deep inhalations of the specific icrosol The protection allorded (inmedite protection BRONCHOCONSTRICT NG AGENT MISTAMNC IV MECHOL VLIV 0 <- t OURAN O 3 GN wutat DA on see AEA01 O ICON *46 TT 40 OL ON +0 167O. PEACEN wyt PERCEN NY KPNEMANG 75 2@ SO 24 PONER 03 27 74 B WOIMAAN 09 >2 32 Q Supa 70 22 09 42 y . + 62 9 TAMA S1N* ( niprause Preetic Jut of 5ımpaih mineta termuls aguoi 11 flistan the und Technol Induced Dipnca and Bronch pusm in Isti mata l'aficnes.

·The fanagement of the Patient in per cent ind the duration of significant protection minutes) appears in Table 3 Fpinephrine the hormone of the adrenal medulla is tlie pirent substance of the sympathomimeric amines 124 It is a secondary amine and basically an ethylamine NEOSYNEPHRIN EPINEPHRINE OH OH YOH Copen NHCH3 HC-C -H OHH NHCH3 HC-C-H OHH ISUPREL OH >OH H CH3 HC-C-N-CH OHH H CH3 FIGURE 6+1 The Structural Formulae of Three Sympathommmet Amines Under Discussion derivadle Gunnes and later Graham and Gurd separated those sympathomimetic imines which are ethylamine dern miles from a second group derned from jsopropyla mine (ephedrine and its congeners) All the substances under discussion at this time are ethylamines The struc tural formulae of the three compounds under discussion are presented in Figure 6 Chemically Isuprel differs from cpinephrine only in the substitution of an isopropyl ridical for 1 methyl group ·Il 1th Sercre Bronchial Asthina 45 in the aliphatic portion of the molecule Neosynephrin 15 even more similar to epinephrine structurally the only difference being the absence of the pura hydrol group present in epineplusine As will be demunstrated with regard to the bronchi ind as is well known so far as pressor activity is concerned us this alteration in the aromatic portion of the molecule produces greater litiations in the pharmacological properties of the compound than do changes in the alphatic chain Taponefrın is clicmically identical to cpinephrine but cpineplırıne consists solely of the levorotatory isomer whereas I aponefrin is 1 racemu inixture of both levo and destro-rotatory ionyers Since the dextro-rotatory epinephrine is less actile pharmaco logically than the levo rotatory isomer Taponefrin may be expected to be less potent by scight of the dry inaterial than epinephrine [prinephrine hydrochlorule 1 100 USP --Six mhalations of the mist produced from a solution of epinephrine lıydro chloride 1 100 by hand bulb nebulization with the Vaponeſrin nebulizer provided excellent protection (75 per cent) ngunst the bronchospastic effects of inimienous fuscamine The results were immediate (tive to 10 minutes after ad ministration) however the degree of protection decrersedi fairly rapidly reaching the level of 10 per cent after 29 inputcs In vent of the numerous sources of error Infierent in any technique of clinical 15575 we have proposed!!! *** thus 10 per cent level to be the minimun degree of protec uon wlucht le considered significantly contrast cuncplirine 1 100 1 is less jotent in counteracting the ef fects of intenons mecholyl sliowing an immediate pro tection of 56 per cent which fell to 10 per cent 11 tlie end of 18 minutes. These results and those presented below are presented in tabulir form in Tables Japoncinin (a 2 23 per cent solution of specially prepared ·46 The Ilanagement of the Patient racemic epinephrine hydrochloride)-The chemical and pharmacological properties of Vaponefrin have been de scribed by Munch, Gattone and Pratt" In acute toxicity tests on animals they found that, following injection, Va ponefrin was about to thirds as toxic as epinephrine In clironic inhalational studies on rabbits no toxic effects were observed following inhalation of up to 4000 inhalations of Vaponefrin Finally, the pressor potency of Vaponefrın base was found to be about two thirds the pressor potency of epinephrine base follou ing intravenous injection in anes thetized cats, dogs and monkeys Richards, Barach and Cromwell is considered Vaponefrin clinically preferable to the official i 100 solution of epinephrine hydrochlo ride This preparation has been extensively employer by numerous imi estigators as a potent bronchodilator aerosol 18 44 104 159 182 The Vaponefrin preparation demonstrated greater pro tecting ability in these experiments than I 100 epineph rine Against fustamine, Vaponefrin displayed essen trilly complete immediate protection (93 per cent), with significant protection (10 per cent or lugher) which per sisted for 27 minutes Its protection against the effects of mecholyl induced bronchospasm as less marked than against histamine, demonstrating an immediate protec tion of 74 per cent, with significant protection persisting for 18 minutes Thus Vaponefrin surpasses epinephrine 1 100 in the completeness of immediate protection against both hustamine and mecholy? Both Vaponefrin and epinephrine i 100 protect more efficiently against histamine than against mecholyl Neosynephrin 1 100-Neosynephrın 1 100 has often been used as a bronchodilator aerosol 22 18 119 180 Graeser*found 1 far inferior to epinephrine in the same concentration However, Richards, Barach and Cromwella's were able to ·11th Secre Bronchol Asthma 17 produce significant bronchodilation with neosynephrin 1 100 by their continuous inhalation technique It has a prolonged and marked locul 175oconstrictor action after Local application to the mucous membranes of the respin tory tract but it is a poor bronchodilator It may proude 1 more pitent airway by virtue of its action is n bron clovasoconstrictor ** 16 145 160 In our cxperiments" 169 its immediate protecting capicity against the effects of lusta mine was only 52 per cent, with significant levels being muntained for only 16 minutes lo significant protecting action agninst the bronchospastic effects of mecholy could be demonstrated Isuprel (1 (3',4'lılıydroxyphenyl) 2 isopropylaminoetlia nol hydrochloride-During the early ye11s of this decule (ccasional reports from Europe mentioned an extremely potent brunchiodiliting agent knotun as lleudrın " I TO It was extremely ellicacious in the treatment of clinical asthma and was rated superior to all other compounds rested in counteracting the dyspnet induced by acrosols of carbaminoylcholine In animal experiments lleudrın 7s described as ten times more powerful thian epineph rine Thus drug under the name of Isuprel was first introduced into the Imerican literature in 1917 by Segal ind Berlcy16 18+ who were not zware of its chemical identity with Aleudrin until their studies were nearly completed The pluırmacological properties of Isuprel line been reported i det til by Virsh l'elletrer ud Ross's und in lands Wash Dersinger Granger and McCarthy inn Ilie excititory effects of cpinephrine can be largely eliminated and the inhibitory ellects enhanc al by maling substitution on the mit nitrogen in the epinephrine molecule To prepare Isuprel the chemists substituted an Isopropyl group in place of the methyl group on the nitro gen Tlus results in a compound with less excitator ·48 The Management of die Palient effects and more inhibitory actions than epineplırıne (Fig 6) Isuprel is ordinarily employed in a dilution of 1 200 a solution one-half as concentrated as that used with epineph rine and neosynephrin and approximately one fifth as concentrated as Vaponefrin Thus solution demonstrated 70 per cent immediate protection against the effects of luistamine significant protection was maintained for 22 minutes Surprisingly it proved to be of greater pro tecting value against the effects of mecholy1 69 per cent immediate protection dropped quite slowly to 40 per cent at the end of 42 minutes Thus rerosols of Isuprel 1 200 demonstrated more prolonged and more intense protec tion against the effects of mecholy) than epinephrine Taponefrın or neosynephrin aerosols but prosed inferior as histamine antigonists to both epsneplırıne 1 100 and Vaponefrın Aerosols of Isuprel 1 100 demonstrated complete im medinte protection (98 per cent) against the effects of both fustamine und mecholyi Thus protecting action gradually lessened and dropped to 40 per cent after 62 minutes in the case of histamine and after 81 minutes with meclioly? Isuprel 1 100 proved to be the most effectnc aerosol for protection against the effects of histamine and mecholyl in our laboratory It is unfortunate that this concentrated solution is too prone to produce disturbing side effects for routine clinical use this us pirticularly true for the ambu latory patient 165 167 These laboratory studies confirm our previous reports on the clinical management of bronchual astlima 160 16 166 67 Both Isuprel 1 200 and Vaponefrin are effective bronchodılacor aerosols with powerful albest short lived bronchospasmolytic properties Isuprel is the most power fuil antagonist of acetylcholine Vaponeſrın the most 28 ·Iith Serene Brondial isti ma potent against the effects of lustamine Clinical experi ence with the two preparations reveals that either of the drugs may prole more satisfactory in any individual patient and that the coinparative potency of the two preparations may vary from time to time in the same patient Patients may become refractory to either drug but loss of sensitivity 10 one is not associated with fastness to the other Both Isuprel 1 200 and 1 aponeſrın liave valunble places in the immentarium of the clinician treating bronchual asthma One must determme which is the drug of choice for each individual patient at any given etme by careful observation and clinical trial Neosyn ephrin 1 100 an effective bronchovasoconstrictor with minimal anuluistaminic properties has in advantage in thunt refractoriness is rirely observed It may be combined with any of the other mines to provide an effectic solution for herosolization 5 Protection Studies with Aminophyllin Iminoplyllın has been called the one to remedly in bronchial asthma " minophyllin shares with the sympathomimcuc amines the ability to protect in the Izboratory against the bronchospistic effects of both hista mine and mechiolyt like them it is of great value in the clinical mını,ement of bronchospasm In comparison with the data obtined by similar examination of thic protecting ability of sirious drenergic igents against the dyspnea and bronchospasm produced by into cnous in jections of lustamine and mecholil it is apparent that aminophyllin must ciert is brunchospasmolytic action in a different manner The sympathonumetic aminc 1c10sols in minute doses bre i rapal intense protecting action , unst the bronch spastic effects of histamine (plıysiologic antigonism) whercas the cllect of amino ·50 The llanagement of tl Patient phyllın is milder and more prolonged and the dose em ployed is many times greater In dosage and in the time sequence of its protection aminophyllın approaches more closely the newer classical antihistaminic drugs (his tammolytic agents) data on which will be presented else uliere in this book 170 The protecting ability of minophyllın administered by various routes against the dyspner and bronchospism produced by the administration of hiscamine and mechalyl by various routes is presented in Table # We have long been aware of the powerful bronchospasmolytic ac tion of aminophyllın administered rectilly in the manage ment of patients with severe astlımı Thus clinical impression confirmed by these studies in which amino phyllın administered rectally exlubits 1 protecting action equal or similar to all other routes if the 45 to 60 minute absorption delay time is not objectionable Absorption after oral administration is slower and the period of signif icant protection shorter so that thus route can have only limited value Intramuscular aminophyllın shows surpris ingly poor protection wluch is not entirely unexpected from our clinical experience lere che pun usually attendant upon such an injection not already i suff cient deterrent to its clinical use the lack of significant protect ing ability should make one hesitate to employ this route for the administration of aminophıyılın It is our feeling that rectal aminophyllın affords the patient a potent means for relief of broncliospasm surpassed by the intravenous route only in speed of action The case of self administra tion of rectal solution of aminoplivilin is of course in even more important factor Our inability to demonstrate adequate protection 1ith iminophyllın aerosol is seemingly at Hariance with tle clinical observations of Prigalis2 123 s ho used much greater ·BRONCHOCONSTAICTING AGENT HISTAMINE TV MECHOLYL IV ROTECTIN LATENT PLAIOD OF URO DEYILOMENTO 40X LEVEL OMING ZAX PAN DURATION OF LEVEL TIME IN SIGN FKANT 40X (M) PROTECTION (MIR) LATENT PERIOD OF DEVELOPMENT OF 10X LEVEL RAIN !1ith Serere Bronchial dsthma PCAK PLAK DURATION OF LEVELTME SONIFICANT 40X X ww) MOTECTION (UIN) J7 IMCA O WN . IVO 130 WM 11 30 30 JO 10 . 120 130 53 S 109 . 2 • MW 103 JO 50 130 42 15 20 12 7 O #2 15 O M COMPARATIVE PROTECTIVE VALUE OF AMNOPWYLL IN ADMINISTCRCD OY VARIOUS ROUTES MAINST #STAMINE ANO MECHOLL-INDUCCO DYSPNCA AKO BRONCHO SPASM IN ASTHMATIC SUBJECT AMTOP.LIN ACNOSOL ALSO COMOTED MO SIONITICANT PROTECTION AGAINST THE CrrectS OF HISTAMINE ANO WECHOLY ACRO SOLS TABIL 41 51 ·50 The Management of the Patient phyllın is milder and more prolonged and the dose em ployed is many times greater in dosage and in the time sequence of its protection aminoplıyllın approaches more closely the newer classical anushıstımınıc drugs (his tamınolytic agents) data on which will be presented else 11 liere in this book.170 The protecting ability of uninophyllin administered by various routes against the dyspner and bronchospasen produced by the administration of histimine and mecholyl by various routes is presented in Table 4 He live long been zware of the powerful bronchospasmolytic ac tion of aminophyllın administered rectally in the manage ment of patients with severe Isthmi This clinical impression is confirmed by tliese studies in which aminophyllin administered rectally exhibits 1 protecting action equal or sunılar to all other routes if the 45 to 60 minute absorption delay time is not objectionable Absorption after oral administration is sloner und the period of signif icint protection shorter so that this route con lave only limited value Intramusculır aminophy itin shons surpris ingly poor protection which is not entirely unexpected from our clinical experience Were the pun usually attendant upon such an injection not alrezdy 1 sufficient deterrent to its clinical use the lack of significant protect ing ability should make one hesitate to employ this route for the administration of aminophyllın It is our feeling that rectal aminophyllın affords the patient a potent means for relief of bronchospasm surpassed by the intravenous route only in speed of action The ease of self administra tion of rectal solution of aminophvllın is of course an even more important factor Our inability to demonstrite adequate protection with aminophyllın aerosol is seemingly at yariance with the clinicıl observations of Prigal132 133 u ho used much greater ·HISTAMINE IV BRONCHOCONSTRICTING AGENT PROTECTING LATENT PERIOD OF DAVO DEVELOPMENT OF 40% LEVEL OMINO MOTLLO OC PEAK LEVEL % O MECHOLY IV ALIMEN UN 03 05 PE AX LEVEL % occ PEAK DURATION OF LATENT PERIOD OF TIME PINA SIGNIFICANT 40% DEVELOPMENT OF (MN) PROTECTION (MIN 40% LEVEL (MIN IMMED 130 . MARKO 046 30 49 30 04 (1) AANNN 50 0 37 105 120 PEAX DUMATION TIME PINASONIFICANT 40% (MIN) PROTECTION (MIN) TULCD O ADAM .. NA 45 150 130 30 53 90 12 SO 75 > 0 130 IOS O 42 10 135 12 20 13 COMPARATIVE PROTECTIVE VALUE OF AMINOPHYLLIN ADMINISTERED BY VARIOUS ROUTES AGAINST HISTAMINE ANO MECHOLYL -INDUCED DYSPNEA AND BRONCHO SPASM IN ASTHMATIC SUBJECTS. • AMINOPHYLLIN AEROSOL ALSO EXHIBITED NO SIGNIFICANT PROTECTION AGAINST THE EFFECTS OF HISTAMINE AND WECHOLYL ACRO SOLS TADLE 41 ·52 Tle Vanagement of tle Patient doscs of the drug vaporized by his steam vaporizer The difficulties attendant upon the use of this technique in the clinical management of asthmatic patients led us to try iminophyllin in the Vaponefrin nebulizer The results are described in Table 1 lle have also been unable to demonstrate any significant improvement in the vital capacities of our asthmatic subjects following inhalation of 0 25 gm aminoplıyllın (1 0 cc) solution 6 Correlation of Laboratory and Clinical Data We have employed by aerosol as well as by intravenous route histamine acetyl beta methylcholine and allergenic extracts as bronchospastic agents 111 With this human assay method we have investigited various classes of drugs including anticholinergic agents *3 adrenergic agents * aminophyllın by all possible routes 170 antihistaminic agents Cycochrome Chhellın (Anmıcırdıne) and a number of other miscellaneous drugs lle luase obtained statistically valuable data describing the degree of protec tion afforded by a given protecting agent against 1 bron chospastic drug Some of these obserı ntions have been presented At the present stage of our studies several correlations of this laboratory data with clinical observa tions seem noteworthy lle have demonstrated that anticholinergic drugs such is atropine scopolamine and Bellaſoline are extremely effective against the dyspnea and bronchospasm produced by mecholyl but that they have no effect on tint pro duced by lustamine Conversly antihistaminic drugs (blocking agents) abolish almost completely the decrease in vital capacity following intravenous injections of buis tamıne but most of these agents lie no significant effects against mechioly 1 154 Nevertheless both of these classes of substances huve minimal bronchospasmolytic S ·Ilith Severe Bronchial Asthma 53 properties and limited value in the clinical management of the asthmatic patient Tho drugs aminophyllin and epinephrine are very valuable in the management of the asthmatic Both are excellent bronchospasmolytic agents in the physiologic sense According to our laboratory and clinical data epinephrine is a good protecting agent against the bron chospastic effects of histamine and mecholyl and also works very well in clinical asthma Aminophyllın 10 on the other hand is a fair protecting agent gunst the bronchospastic effects of histamine but it is less efficient gunst the effects of mechnly! Hence aminophyllin because of its dual properties of being an antihistaminic and a bronchodilator drug is an excellent agent for the clinical management of the asthmatic patient when it is administered by different routes at various intervals of the putients allness The efficacy of intravenous aminophyllin in the epinephrine fast state is of pirticular inter est An examination of the structural formula of theo phylline shows that it contains an imidazol ring and there by an imino grouping which may enhance it with antı histaminic potenzialities albeit weak The cpinephrine fast patient may release more histamine with accentuation of dyspnea and bronchospasın (histamine sympathin bal ance--see Chapters V and 1I) Fundamentally the action of aminophylın at this point may be similar to that of the antihistaminics (although to a lesser degree) namely to bind the cell receptor substance in place of histamine thus bringing relief to the competition of histamine sympathin on the smooth muscle and stay the seesat to the epinephrine side ? ** 26 305 le we cognizant that the spor taneous Isthmatic paroxysm differs in many ways from the experimentally induced paroxysm of dyspnea and bronchospasm The ·54 The Aſanagement of the Patient circulating chemical mediators in both types of asthma are probably the same The intracellular release of his timine (which occurs in spontaneous bronchial asthma) is not simulated in the laboratory Nevertheless this tech nique most closely approaches the asthmatic paroxysm under ideal laboratory conditions With these protection studies the physiologic and pharmacologic effects of the sirious theripeutic agents being studied should be dis tinguished True physiologic antagonism is demonstrated by the epinephrine preparations (bronchospasmolytic properties) against the effects of lustamine wherein both drugs act on effector cells in opposite directions and the effect of one tends to neutralize that of the other 205 True pharmacologic antagonism is demonstrated by cholino lytic sympatholytic or histaminolytic agents (blocking properties) against the effects of acetylcholine sympathin and histamine respectively The cholinolytic and sym patholytic agents do not interfere with the release of the chemical mediators of pirasympathetic and sympathetic stimulation but do prevent these mediators acetylcholine and sympathin respectively from reaching the receptor mechanisms of effector cells and exerting their charac teristic action Similarly the hustiminolytic agents (antı histaminics) do not present the release of histamine but rather prevent the lustamine from reichung the receptor mechanism in the cell where the histamine everts its char acteristic effects 208 The tropine group and the antihistaminic drugs are ideal bloching agents Their shortcomings as ideal unui asthmatic drugs may be appreciated however when one realizes that the site of instimine release following the antigen antibodly reaction is probably intricellular This most likely also holds true with the liberation of scetylcholine by cholinergic nerve stimulation Thus the ·Ilith Selere Bronchial asthma 55 circulating chemical mediators of experimental and spon taneous bronchial asthmz can be blocked but the reac tions which occur within the affected cells cannot be effectively blocked The development of non toxic agents to prevent the intracellular release of histamine or acetylcholine release appears unlikely at present it would appear from our data that the combination of a good antihistaminic and a good anticholinergic drug with direct bronchospasmolytic properties (free of allergenic potentialties and possessing minimal toxicity) would be the most ideal therapeutic agent in bronchial asthma It should inhibit or neutralize the effects of histamine and acetylcholine and bring prompt relief from the asthmatic piroxysm It is not unlikely that the organic chemist will so shake up the structure of various benzene ring combinations without abolislung the activity of each moiety as to synthesize such a compound in the near future ·CHAPTER IV SEDATION Evers TERI effort should be made to put the patient at complete mental ind physical rest Psychic trauma ma be an important trigger mechanism in initiating an acute attack or modifying intractable asthma It is best to avoid heavy sedation as the incidence of obstructic asphyxia and pulmonary edema is highest in the deeply seduted patent Therefore those agents which have a wide margin of safety should be used 1 The Barbiturates Chloral hydrte and Sodium bromide The barbiturates like morphine depress the respiratory center unul it is less sensitive to stimulation than normal Phenobarbital orilly in doses of 15 10 100 mgm may pro duce adequate relaxation in the mildly dyspneic patient buc barbiturates on the whole are disappointing Sodium pentothal as previously mentioned should be used with grert cution It should not be administered during the asthmatic paroxysm Sodium phenobarbital may Sue better seduuion than sodium amytul seconal or nembutal Houerer ry of these drugs may produce irrationality and excitability A dose of 01 to 02 gm of sodium phenobırbital may be guten subcutaneously or in an in travenous inſusion once or twice 1 day If the burbiturutes or morphine must be used pre or post operatively it is ad visible to ndminister supplementary oxygen As a general rule it is best to refrain from using morphine ind aspirin in asthmatic subjects particularly post operatively The combination of chloral Rzdrute and sodom 56 ·111th Serene Bronciual Istima 57 mide is of particular value in the management of the patient in stitus asthmaticus This combination may be given rectally in doses of from 1 to 3 gm each and my be repeated at tuelve hour intervals for several days with our ſear of serious iespiratory depression Bromide intoxı cation and rash may follow prolonged usage When pro longed usage is necessary the former condition may be presented by increasing the sodium chloride intake and thereby increasin, biomine excretion 2 Morphine Dihydro morphine lıydrochloride (Dılaudid) and Meperidine (Demerol) Occasionally one sees very striking relief of dyspnea in the asthmatic patient with the initial use of morphine sulfate (8 to 10 mgm subcutaneously) I prefer to avoid the use of morphine in all asthmuc patients because with repeated doses serious sequelae may follow Such therapy has been decried for many reasons ' * " On the whole morphine tends to depress the respiratory rite diminish the tidal volume and decreise the minute volume of respiration thus increasing the degree of hypoxia It also decreases the couyli ieflex presents effective expectoration and thus may increase the tendency tou urds (segmental) atelectasis Jith repeated use the physiologic positive pressure within the tracheobronchial tree may be lost ind pulmoniry edema may follow At times morphine appeurs to produce additional i rusea vomitin and broncho spasm Desides there is alsays the possibility of Iryper sensitivity and of addiction to the drug itself Finally death following morplune therapy to patients in status asthmaticus lias been frequently reported ind i most instances could be attributed to its use Tro of the three finalities thich occurred in the authors series of cases folloned shortly after the repeated use of ·58 The Management of tle Iatient small doses of morphine The house officers who attended these illo middle aged patients described typical episodes of obstructive phenomena with markedly labored noisy respirations ostensibly refractory to epinephrine aminophyllin and a host of sedative preparations In one patient the respirations became quieter and more shallow follow ing the first injection of morplune sulphate 10 mgm This improvement was short lived and a second injection of 10 mgm was administered approximately four hours later Shortly after this injection the respirations were described as comparatively quiet though tracheal rales were audible There was evidence of pink frothing sputum in the mouth Attempts at oral suction were of no avail and the patient died about two hours after the second dose of morphine was administered The second fatality followed three hours after the administration of morphine sulphate 15 mgm and atropine sulphate 0.4 mgm The respirations ere described as quieter and there was evidence toward the end of tracheal rules and frothy sputum The majority of fatalities which appear to follow the injudicious use of morphine or of morphune combined with atropine occur at night The attending house officer or physician has observed the progressive development of the status state and is at a loss for another therapeutic agent to bring relief He may furthermore be fatigued from the stress and strain of his other responsibilities as well Hence he may administer or order a hypodermic of morphine hoping to bring relief to the struggling gasping patient Relief may follow the first injection This may lull him into a false sense of security that permits him to order a repeat dose when he is called again some time later and informed that the patient is having a desperate strug gle for his breath and is disturbing the ward or family The second hypodermic may be the fatal one ·Tith Serere Bronchial Asthma 59 We find that dihydro morphine hydrochloride (Di laudid) has a greater range of safety and less depression is observed with its use It is a more powerful analgesic has minimal hypnotic properties and is shorter acting than morphine It produces fewer side reactions and less euphoria Usually 15 mgm of Dılaudid may be given at twelve hour intervals for two or three days this procedure may be attended with strıking amelioration of asthmatic distress The sume dosage may be added to the rectal aminoplıyllın solution during the first few days of manage ment of the patient in status asthmaticus Meperidine hydrochloride (Demerol) also has a far wider range of safety than morphine and is 1 more effica cious drug in the treatment of the very sick asthmatic pa tient for it is extremely helpful in relieving an intrictable or utterly useless cough It may be given in duses of 50 to 100 mgm intramuscularly or 100 to 150 mgm orally at erght or 12 hour intervals for three to five days The use of smaller doses at the outset may minimize any side reac tions On rare occasions it may be placed directly in the intrasaneous infusion Some bronchodilation and mild sedation may be observed atropine like effects may also occasionally be observed and a few patients will complain of nausea or of dizziness The majority of patients hou ever enjoy a pleasant state of general relaxation following its use Tachyphylaxis is occasionally noted but full re sponse usually returns after a rest period We have not personally seen any respiratory depression following its use Addiction to meperidine although less frequent than to morphine does occur and may be of a severe type In the laboratory we brve found meperıdıne to be a fair antihistaminic and a somwhat better anticholinergic drug (Fig 7) Following intramuscular administration of 100 mgm to five asthmatic subjects average peak pro-

·The Nianagement of the Patient
tection of 65 per cent was reached within one hour and
adequate protection (abole 40 per cent) listed for ino and
one half hours against the bronchospastic effects of acety)
beta methylcholine administered intravenously Protec
tion against the effect of histamine was not as good al
100
DEMEROL HCL
100 MGM IM
HSTAM NE IVTA ALS
-MECHCLYL IV 6 TR ALS
% PROTECTION
4
3
Hundred mom
HOURS PROTECTING DRUG
FIGURE 7 The Protezite Value of Demerol Hydrochloride One
Given Intramuscularly against Histamine and
Vſecholy Induced Dyspnea and Bronchospasm in Asthmatic Subjects
though significant protection lasted for one and one half
hours Scopolimine (levo rotatory hyoscine) when ad
ministered subcutaneously has proven to be an excellent
anticholinergic drug' (Chapter III) A combination which
we have found effectne clinically is meperidine lydro
chloride 100 mgm and scopolimine hydrobromide 03
mgm -a modified form of twilight sleep" However, I

·Ilth Selere Bronchial Asthma tould suggest that this combination be lised with caution I would avoid its use entirely in the dry asthmatic In the Het asthmatic it may be attendant with striking success Then fast admmistered but it should not be repeated more than ttice in a 21 to 48 hour interval 61 3 Avertin, Cyclopropane, Ether and Paraldehyde The mechanism of bronchial relaxation with these agents is not entirely known It seems that the complete mental rest which follows their use in some way inhibits refle, bronchial construction However it is imperative that deep sedation or anesthesia not be employed for periods of more than one hour at 1 time in the treatment of severe bronchial asthma because of the possibility of the patient des eloping asplıyua or telecti5is These complica tions may be prevented by employing inhalations of oxy gen or of helium and oxigen mixtures Avertin (tribromethanol in mylene hydrate) ad ministered rectalls in doses of 60 to 75 mgm per hilo gram of body weight lias been employed for the inter ruption of the asthmatic crises 62 However it is generally considered a dangerous anesthetic agent with a narrow range of safety s Others have recommended the use of cyclopropane anesthesia (to the second stage) for the re Hef of paroxysms of bronchial asthmı 22 14 There is et dence however that this agent may produce broncho constriction 15 Cyclopropane as well as epinephrine muy Occasionally precipitate ventricular arrythmus hence they should not be used together for these reasons tertin or cyclopropine are generally not recommended is anes thetic agents to be commonly employed for the manage ment of severe bronclul asthimi W lien sedation to the point of actual light anesthesia is required ether is the anesthetic 1,ent of choice and may ·62 The Vanagement of the Patient be administered high rectally in doses of 60 to 90 cc dissolved in an equal amount of sucet oil This dose my be repeated hourly for several doses if needed A larger single dose (90 to 150 cc) may be gren at eight hour intervals for tro or three days Relief from intractable asthma frequently follons the mental relixation and the increased expectoration induced by ether Barach has called our attention to the synergistic relaxing effects of helium and oxygen breathing and of rectal ether - Furthermore one inay frequently observe restoration of epinephrine sensitivity in the epinephrine fast subject after he has been so trented inhalation ines thesia with ether may be resorted to on rare occasions le have found intramuscular injection of ether in oil to be of no value Parıldehyde should be used as an amnestic or hypnotic rather than as an anesthetic Paraldehyde should not be administered intravenously for deaths have been reported when thus route has been employed. Post mortem exami nation of such fatalities and also of those reproduced 111 experimental animals showed dilatation of the right side of the heart with pulmoniry hemorrhage and edem Clinically these fatal complications are preceded by signs of acute failure of the right side of the heart intra muscular administration of paraldehyde should also be noided because of the duger of accidental venipuncture and the possibility of ensuing cellulitis and abscess form? tion following the use of 10 to 20 cc of thus drug lle lule tound that the rectal route is the safest and the one I est tolerated A troublesome proctitis may follow protracted use of ether or part delıyde rectilly Paraldehyde may be administered rectally at melve hour intervals in doses of 20 to 30 cc combined with equal amounts of olive oil or prepared as a corn starch emulsion Similar doses prepared ·Il ith Severe Bronchial Asthma 63 in iced lemonade, may be given orally, however, many patients object to the taste and smell Rebreathing of paraldehyde vapor should be prevented in the sick or moribund patient confined in a tent or other closed chamber Frequently following the rectal use of paralde hyde or ether, coughing or a suddenly increased flow of mucoid secretions may be involedi, generally to the pa tient s benefit I would like to complete the subject of sedation and anesthetic drugs by adding a few words of caution about the use of atomized or topical pontocaine and cocaine | Keep in mind the latent period of sensitization of one to four weeks following the use of these preparations Serious reactions or fatalities may follow second usage (porucularly of pontocaine) 2 Skin testing, although of questionable value, should be done before using these drugs 3 Preliminary use of barbiturates and antihistaminics may minimize the extent of the reaction 4 Epinephrine and aminophyllin must be available for immediate administration 5 An aminophyllan infusion should be gren prophy Tactically to all patients who are about to receive ponto chine or cocune anesthesia for a second time within a one to four wech period ·CHAPTER V SUPPORTIVE THERAPY THE sich asthmatic patient presents a serious picture of marked physiologic imbalance Severe hypoxia cyanosis dehydration peripheral vascular shock and drug intou cation from intensive therapy may all be present Disturbance in water and clectrolyte balance usually exists which mahes absorption of liquids uncertain whether given orally or subcutaneously Because of dyspnea and rapid gasping respirations the patient finds it difficult to the adequate quantities of water or other fluids orally Anorexia and the proclivity for abdominal distension contribute further to this difficulty What little fluid and electrolytes he is able to ingest or store up may be depleted by coming excessive si caring and through respiration Combined water and salt depletion usuully ensues if adequate therapy is not employed I Replacement Therapy (water glucose saline infusions) The Nuid intake and output should be meastired and recorded in all of these patients An adequate urine volume of not less than 1 500 cc per twenty four lours should be maintained The physician should treat the patient rather than his blood chemistry He should hot ever understand the manifestations of water and salt deficit namely dehydration mealness ferer psychotic manifestations oliguria with attendant high specific grivity of urine rise in blood urer nitrogen hematocrit and plisma proteins fluctuations of blood chloride and sodium concentrations and eventually circulatory fulure 64 ·Ilith Serere Bronchial Asthma 62 and death The dehydration tends to increase the viscosity of the muco purulent exudate Thus may lead to actual bronchiolır impiction and segmental atelectasis The in effectual cough disturbs the patient and contributes greatly to lus menuıl and physicıl faugue The primary requisite is replacement of the lost fluud and electrolytes The minerals in the funds administered will supply the lost electrolytes the flud itself will hydrate the patient improve urinary excietion and help to regu late body temperature Tlus may be done most efficiently with intravenous therapy lo fixed rules should be estab Fished for the composition of this so called intravenous cocktu! The replacement fluid both in volune and composition depends upon the ige of the patient the degree of dehydration ind of bronchospasm the cardiac ind renal status ind individual tolerance to drugs and to Venipunctures It is generally my custom to begin by rising 5 per cent glucose in isotonic sodium chloride solution for the first liter und 5 per cent glucose in distilled water for the second and third laters Three liters may be given in 21 hours by employing a flow of approximately 30 drops per minute In the young patient in t hom the possibility of chronic coi pulmonale and underlying heart disease does not present itself one can safely replace the second liter of distilled water with isotonic sodium chloride solu tron When there is evidence of severe depletion with acidosis Hartman s solution (16 molar ricemic sodium factute) may be employed unul the CO (volumes per cent) returns to normal 2 The Role of Digitalis and Mercurial Diuretics In the patient with 1 complicating chronic cor pul monile the judicious use of 1 salt free diet the elimini tion of sodium chloride from the intravenous cocktail ·66 Tle Management of the Polient and the use of intramuscular injections of one of the mercurial diuretics burie been of life sating ilue I have found Mercuhydrın (N(3 methyl 2 oxy mercuripropyl) succinylurer) to be an effectue nontowic diuretic Acıdı fication of the urine with ammoniuin chloride may double Its diuretic effect On the whole I have not been able to convince myself of the value of digitalis in most of these patients with emphysema and cor pulmonale Although in occasional pitient appears to be helped some are even further in capacitated and disastrous results may occasionally follow attempts at rapid digitalization The value of digitalis in tliese patients can be largely predicted from experimental studies of the cardiac output ind senous pressure Vic Michael and Sharpey Shafer' y called attention to the fact that patients with emphysema and cor pulmonale sath gross venous congestion and very low arterial oxygen saturation may lzle a high cardiac output (high output heart failure) They suggested in their studies that digitalis in these subjects may loner the renous pressure ind with It the cardınc output Reductions of the latter would disturb the output necessary to compensate for the marked resistance to pulmonary blood flow in these pitients Hou ever in the Inter stages of cor pulmonale left ventricular failure and pulmonary edema muy occur and digitilis preparations would be of alue More definitie studies of cardiac and pulmonrry function similar to those being made by Cournind 56 58 Velfichnel118 119 and their as sociates utilizing cardiac catheterization may ultimately shed more light on the exact value of digitalis in the treat ment of pulmonary empliysema and cor pulmonale 3 Aminophyllın Infusions Aminoplıyllın (theophyllın ethylene-diamine) in vary ing dosage may be added to the intravenous infusion ·Ilith Selene Bronchial dsthina 67 Theophyllin" has been demonstrated to ciuse relaxation of bronchurl spasm and to lower intravenous and intra thecal pressures It is also 1 potent diuretic and generally stimulates the central nervous system Welo liwe been able to demonstrate that iminophyllin exerts an appreci able antihistaminic effect but a very moderate antı cholmergic effect in protecting against histamine and mecholyi induced dyspner and bronchiospasm in astlimatic subjects Goodall and Ungers have been able to relieve miny severe attacks of bronchun) asthma with continuous intravenous ammophyllın in glucose or sılıne solutions Patients vary in their tolerince to aminophyllin some become alerted others become dronsy many become nau seated and may even somit and still others complain of palpitations and sterting Syncope and peripheral vascu Iar collapse may be observed if the rate of injection is too rapid Some of these reactions may be avoided by slowing the rate of flow One may begin by adding 05 gm of ammophyllin to the first liter of solution The dose may then be decreased or increased to 1 gm per liter of solu tion depending upon the patients tolerance How long should one continue to use intravenous aminophyllın? Infusions may be run continuously for as long as 10 days The duration should depend entirely upon the patients response ind tolerance to minophylın If improvement results after one or to days of continuous therapy in fusions may then be gisen intermittently eg from 9 AV to 9 in duly reducing the total intale to 1 500 cc This schedule does not interfere with the patient s freedom of motion it might Supplementary aminophylın if necessary through the night may be given in the form of 1 20 cc intruenous solution containing 0 25 or 050 gm amino phyllin This should be administered slowly at 7 rite not exceeding 20 cc per minute The patient may sit in 1 comfortable arm chur and a moderate degree of amh ·68 The Vanagement of the Patient tion during the infusions may be allowed the dorsum of the hand is best suited for intralenous therapy in asth mitic subjects as this site permits 1 greater range of arm motion and less danger of obstruction or dislodging the needle during coughing pirovysms A different vein or segment should be selected from day to day The use of distal venous segments minimizes the danger of thrombosis of all available veins--an appreciable factor when veins in the intecubital fossi are used The moderately ill asthinatic suffering from an acute atunck uluch l12s not responded to epinephrine previously administered in one form or another usually benefits greatly by one or more intravenous injections of 05 gm aminophyllin in 20 cc of distilled water These may be repented at intervals of eight or 12 hours If they become necessary one or more times duly for as long as one need the continuous infusion technique should be started The continuous or interrupted infusions may lie omit ted when there is evidence of complete freedom from severe prro ysms of coughing or bronchospism In their place aminophyllin should then be administered rectallyas in dosage of 0 3 to 06 gm in 15 cc of top water every eight or 12 hours Thus therapy in gradually diminusling dosage should be continued for 11 leist one month after complete recovery I be kept patients on maintenance programs with rectal aminophyllin solution for as long is to years with no demonstrative ill effects and with free dom from recurrent attacks In time the rectal amino phylın solution may be replaced by in oral tablet con taining aminophyllın 02 gm ephedrine sulfate 0 025 gen and sodrum pentobarbital 0 03 gm Intramuscular aminophyllin (2 0 cc ampoule contarning 05 gm) has proven of negligible value clinically and ·11 th Setere Bronchial Istl ma 69 furtherinore patients complain of pain during its ad ministration and of residual soreness and lumps I have not found aerosols of iminophyllin employing the same upoulcth the disable cable bittel laste disguised by adding several drops of peppermint water of sufficient value to warrint the necessary expense and technical detail involved 4 Ascorbic Acid Cytochrome C and Nicotinic Acid Other therapeutic agents may be added to the intra Venous cocktail Ascorbic acid or Cytochrome C's 185 have been gnen intravenously as respiratory catalysts by various investigators in the hope that these agents will increase the oxygen uptake from the blood plasmı into the red cells themselves No striking results have been seen from their use although is much as 5 000 mgm of ascorbic acid per liter of isotonic sodium chloride solution and 100 mgm of Cytochrome C have been given intravenously every eight hours for one week to several patients in status asthmaticus Occasionally one may witness i very prompt response with ascorbic acid but it is quite difficult to at tribute this to the drug The same observations hold truc for nicotinic acid intravenously In a small but representa tive series of 18 pments in status asthmaticus I could not convince myself that any striking improvement resulted from its use One my oliserie in extensive flush and perhaps some bronchil dilatation but no lasting effects T'urthermore the side reactions of flushing warmth and throbbing bendiches are not well accepted by most p tients thougļi they »ere ſores urned of same The intra enous use of itamin B Complex preparations should be 11 orded because of the possibility of sensitization to thia mine liydrochloride ·70 The Aſanagement of the Patient 5 Alcohol Dextrose Infusions On occasion an alcohol dextrose solution may be given mtravenously in place of isotonic sodium chloride dextrose infusion Brown* and Brown and Gillespie' have to ported excellent results with infusions of 5 per cent ethyl alcohol in glucose or salıne math or without epinephrine in the solution I have generally employed one luer of 5 per cent ethyl alcohol in 5 per cent glucose solutions free of voimin supplements When necessary aminophyllin 15 added to this infusion Flows of 80 to 120 drops per minute are generally necessary for relaxation Excitement may follow too rapid rates and relaxation may fail to occur with slon rates this is due to excessive or madequate cerebral blood levels respectively Occasionally striking relaxation may be observed when the mixture is guven for the first or second time As a rule loneler, these effects do not persist with repeated use Moreover the peripheral izsodilatory effects which may occur could be deleterious in the presence of peripheral vascular collapse and thus furtlier limit the usefulness of this mixture 6 Blood Plasma I have observed in this series of 513 patients with bron chial asthma three instances of severe peripheral vascular collapse characterized by ashen colored cold and clammy skin rapid and barely perceptible pulse ind falling blood pressure These patients were given blood pism3 with verv good effect Two patients required two units cach and the third patient recerned eight units in 24 hours before recovering from profound shock The sternal route had to be employed with the last patient because of in ability to utilize the collapsed veins when death appeared imminent I would caution against exceeding 3 000 cc for the total 24 hour dose because of the danger of acute ·11th Serere Bronchial Asthma 71 Jeft ventricular failure Supplemental oxygen intravenous neosynephrin ascorbic acid and adrenal cortical Mormone were also employed in these patients Recovery in all cases was complete 7 Antihistaminic Preparations Mel's Inve been able to demonstrate with many of the new antihistaminic (histaminolytic) prepirations excellent protection against experimental lustamine induced disp nea and bronchospasm in asthmatic subjects These are ideal blocking agents in that they prevent the histamine from reaching the receptor mechanism in the cell where it exerts its characteristic effects However these prepara tions do not prevent the intracellular release of histamine Turthermore because of failure of absorption or due to inactivation in the gastro intestinal tract orally ad ministered antihistaminic agents may ful to block the action of freely circulating histamine For these reasons orally administered antihistaminic agents may afford only limited relief in the routine management of the acutely ill asthmatic patient On the other hand when ad ministered intravenously these agents can effectively bloch the action of freely circulating histamine The antılustaminic agents may be of particular value in the following instances 1 Orally-for the relief of nasal obstruction (allergy is the dominant factor in the maintenance of chronic para nasal sinus dispuse in the asthmatic patient) Para nasal sinus disease is responsible for the recurrence of cough and wheez ing in many patients with bronchial asthma Patients with pasa nasal sinus disease are more likely to have irreparable sino-bronchitic disease and scrious bronchial astlima In the acutely ill asthmatic nasal olstruction and past nasıl drip contribute further to the dyspnea and cough already ·72 Tle Vanagement of the Patient present The antihistaminic preparations in doses of “5 to 100 mgm orally at six hour intervals help considerably in relieving the nasal obstruction and secondary cough lle have on occasion employed aerosols of 2 per cent tripelen namine hydrochloride (Pyrıbenzamıne hydrochloride) na sally in these patients with good cffect If infection is present aerosols of an antihistaminic agent and penicillin employing the technique of intermittent negative pressures and replacement with the acrosol should be tried II Intravenously-for the relief of bronchos; asın in the ambulatory patient having an acute asthmatic paroxysm Thc unfavorable reports concerning the clinical cllecinc ness of the antihistaminics in hay feser and bronchial asthma may to a great extent be influenced by the inri ability of absorption incident to the routine use of the oral route lle have observed in the laboratory that a number of patients demonstrated no significant antı hıstanınıc effect in the protection afforded against hista minc induced bronchospasm and dyspncı when the antihistaminic drugs were taken orally whercas signifi cant protection occurred when the intralenous rectal or aerosol routes were employed with the same agents On the basis of these observations we administered diphen hydramınc (Benadryl) or tripelonnamine HCI (Pyruben zımınc) intravenously (30 trials in six patients) to obserie particularly any bronchospasmolytic properties of these drugs Prompt relief from the asthmatic paroxysm with increases of more than one liter in the patients utal capacity was uniformly obscried Thesc patients were asthmatic subjects employed in our protection studies who demonstrated spontaneous asthma while in the laboratory awaiting study or at home III Intrat enously--to restore the delicate histamine sympathin balance in the so called epinephrine refractory state Tie sta employed intravenous diphenhydra mine hydrochloride (Benadryl chloride) or tripelennamine hydrochloride (Pyribenzamine hydrochloride) in a series 05a ·Ilth Severe Bronchial Asthma 73 of 10 patients acutely ill in status asthmaticus The injec tions were given slowly at a rate of about 1 cc per minute either directly or via the constant intravenous infusions (aminophyllın glucose saline or distilled water) Doses of 30 to 50 mgm (10 mgm per cc of solution) at four to eight hour intervals 1 ere administered and continued for one to four days To avoid pharmacologic incompatability the antihistaminics were injected directly into the rubber tubing close to the intravenous needle With improve ment the dosage was gradually reduced to 20 mgm every eight hours and then finally discontinued A total of 62 injections were given to these patients The most striking effect observed was what appcared to be restoration of epinephrine sensitivity Follo ing these injections epine phrine administered subcutaneously or by the aerosol route appeared to bring relief from an acute paroxysm of bronchospasm whereas previously following an amino phyllın glucose salıne or distilled water infusion only the side effects of epinephrine were observed following its use The mechanism involved may have been the potentiation of adrenergically controlled functions by the antihista minic agent This will be discussed in Chapter VI IT Intravenously-for sedative effects in status asthma licus When intravenous diphenhydramine was employed in this group of patients its scdative properties were pro nounced Generally a more relaxed feeling and short periods of sleep followed each injection The addiaye effects of sedation ind restoration of epinephrine sensi tivity were more importint fictors in the recovery of these patients lle * 169 have tested 7 wide variety of antihistaminic drugs and combinations for their protectile value gunst histimine and acetyl beta methyl choline chloride induced dyspner and bronchospasm One example is presented hiere figure 8 depicts the degree of protection that is nfforded gunst intruenous histamine and acetyl beta

·74
The Management of the Patient
methylcholine chloride and histamine aerosol by a combi
nation of diphenhydramine 50 mgin and amınophyllın
200 mgm (Hydryllın Searle) in tno tablets talen oralls
The histamine curve represents five trials in five subjects
the acetyl beta methylcholine chloride curve, sıx trials in
HYDR YLLIN
TABS 2 Pa
--- STAM NE IV (STRALS)
MECHOLYL
IVOTA ALS
--HISTAM NE AEA TAALS)
100
PROTECTION
o
8
2
7
HOURS PROTECTING DRUG
FIGURE 8 The Protectie Value of Hydryllın Tuo Tablets Given
Orally Against Histamino and Mlechol1 Induced Dyspnea and Dron
chospasm in Asthmatic Subjects
$18 subjects It is our clinical impression that protection
levels of 40 per cent or fugher represent a real difference
in the renction to the bronchospastic agent, this is applı
cable to all patients thus far tested Accordingly, this lesel
may be a significant one in comparing the effectiveness of
various protecting drugs Significant protection against

·firi Setere Bronchial Astlinta hastamine is not achieved until one and one half hours after the oral administration of two tablets of 11;dryllin lt rapidly reaches levels of complete protection and remains complete for seren hours which is the longest period we have studied this phenomenon The protection against mechols) chloride is less ideal for it does not reach 7 40 per cent level unul after two hours it remains at a significant level for two hours tnore and then falls off rapidly in the fifth hour after administra tion of the protecting drug la drowsinets is noted from thes oral medication Side effects consistent with the injec tion of histamine are markedly decreased during the inters al of full protection The recent observations of Hambourger and his associ 72€5" ) their study of the protective action of combina tions of diphenhydramine and aminophyllyn in fatal bron chospasm in guinea pigs due to mecholl aerosol is timely and pertinent to our studies just described They found diphenhydramine and aminophyltın alone or in combina tion effectise in presenung the fatal bronchospasm in ducert in getanca pigs by aerosols of mecholy? When used in combination the protectie and intraperitoneal lethal actions were truly additne in nature For protecuion they found 1 gm of diphenhydramine equivalent to 322 gm of aminophyllin In the case of intraperitoneal torichy I gm of diphenhydrimine was equivalent to 2 17 gm of aminophyllını It must be recalled however that the mode of action of these two drugs is different The clinical management of the chronic asthmatic may be tremendously frcrized by the use of aminophyllın Tlus drug relaxes the bronchial musculouse and stimu frutes the central nervous system thus theoretically reduc ing tfie incidence of depression in these centers that is Frequently seen with muhistaminic agents in addition ·76 The Management of the Patient the diphenhydramine present in Hydryllin may act to pre vent or alleviate the allergic wheal or 'bronchial huse of the asthmatic In addition to the polverful antihistamınıc and teak antichloinergic properties of diphenhydramme it is also known to exert considerable antispasmodic action and to potentirte the effect of epineplırıne to some degree Correliuon of the laboratory protection afforded by Hy drylın nith the pracucal management of clinical asthma is a slou process Many pattents who have been taking Hydryllin regularly have found it of considerable value in reducing the frequency and severity of attacks ·CHAPTER VI EPINEPHRINE P PRODUCTION of symptomatic relief from a paroxysm of bronchual asthma is by no means as uncomplicated as is generally represented Chief reliance is in the administra tion of epinephrine or other sympathomimetic amines 1 The Use of Epinephrine [pinephrine has proven to be an excellent protecting agent against dyspnea and bronchospasm induced ex perimentally with histamine and mecholyl chloride in our laboratory " Tlus drug has been employed in various modifications concentrations and routes No true dio syncrasy (allergy) to epinephrine has been reported How ever, toxic reactions, intolerance, and fastness may occur These effects pre more commonly observed with repeated use and with overdosige " 136 Deaths have been reported following intravenous administration or accidental intra Tenous injection these fatalities may have been due to cpinephrine deposition in the heart muscle with ensuing ventricular tachycardia and fibrillation 12 A warning should be made about the possibility of accidents from the injection of 1 100 epinephrine and other concentrater sympathiomimetic ammes intended purely for aerosol use Moller of Copenhagen discussed the subject of acute epinephrine poisoning and reported the successful recovery of a 12 year old girl who had accidentally received twice the fatal adult dose (20 mgm of epinephrine 02 cc of a 10 per cent solution) He attributed this recovery to the persistent use of nitrites as peripheral vasodilators and epinephrine antagonists He recommends gising in 77 ·I 78 The Management of the Patient hulations of amyl nitrite vapor (3 minims) as quickly as possible followed by a larger dose (20 to 40 mgm) of oral nitroglycerin and then intravenous erythrol tetra nitrate in divided doses of 5 0 mgm to a total of 200 mgm to control the elevated blood pressure and promote re covery according to individual requirements A tourniquet should be placed proximal to the site of the original in jection and intermittently released However if acute epinephrine toxicity has resulted in peripheral vascular collapse (due possibly to its sympathin I action) the use of these powerful vasodilators may potentiate the shock Epinephrine may be injected subcutaneously in doses of 0 2 to 0 3 cc of 1 1 000 concentration Relief is generally observed in fire to 15 minutes following its administration It may be given intru enously in doses of 05 to 1 cc of 1 1 000 concentration in a liter of salıne or preferably it may be nebulized in 1 100 concentration For slow release it may be given intramuscularly in an oil or gela tin bise in doses of 0 5 to 10 cc of 1 500 concentration after shaking thoroughly I have not observed any striking value from these combinations of epinephrine (1 500) Their value is limited by the uncertainty of uniform ab sorption and action due to the sudden release of epineph rine the side reactions the residual soreness and possible oil tumors In general epinephrine parenterally is limited in its value to the relief of the acute attack The minimum dosage which will accomplish the desired effect is the best for it will also minimize the disagreeable side reactions Unfortunately few limit the dosage to the proper and effective subcutaneous injection of 0203 cc of 1 1 000 dilution Generally larger doses at unnecessarily frequent interı als are employed The use of the hypodermic needle for self medication which should be avoided is too often ·79 Ilith Seiere Bronchual Asthma encouraged Habitual users of self administered hypo dermics of epineplune become dependent upon this crutch which further contributes to the despair of the disease The epinephrine fast state is encountered most commonly in these patients They frequently present altered personalities (a prematurely aged appearance) signs of vasomotor instability irritability prlpitations tachycardia and transient hypertension As most patients in status astlimaticus are epinephrine fast the use of all ?pinephrine preparations should be avoided for at least several days until epinephrine sensitivity is restored I have made a rule of never adding epinephrine to the intravenous cocktail for these patients 2 The Epinephrine Refractory State The development of the epinephrine-fast state in the asthmatic subject is distressing to the patient and is poorly understood by hus physician The delicate histamine sympathin balınce or seestw is upset Repeated injections of epinephine no longer produce bronchial relaxation but rather maniſestations of toxicity-nimely palpitations tachycardia herdache flushung etc Staub 18 and Farrerons Co 7 fase demonstrated that epinephrine provokes the production or release of histamine in the experimental animal (probably as a homeostatic effort) Yonkman 304 and lonkman and Mohra : thought that these studies probably explained in part the mechanism involved in the potentiation of drenergically controlled functions by intu histaminic agents and furthermore thu thus hustumine release could paradoxically contribute to further broncho construction pulmonary edemi und dyspner Thus se quence for some reason may be more pronounced in the allergic thin in the normal subject They suggested that antihistaminic preparations given intruenously could lic ·80 The Management of the Patient of value in serving as histamine antigonists or epinephrine sparers in the epineplırine resistive prtient thus balincing the delicate luistamine sympathin seesat. These studies by Staub Tarrerons Co and Jonkmın and Molir are of particular interest in view of our recent observations in 10 acutely ill patients in status asthmaticus 14** 205x de scribed above (Chapter 1 Restoration of epinephrine sensitivity followed the intravenous injection of 30 to 50 mgm of an antihistaminic in these subjects Injections were repeated at four to eight hour intervals for one to four days Parenteral and aerosol epineplırıne appear much more efficacious following these injections 3 Ephedrine Preparitions The use of ephedrine preparations for the relief and prevention of asthmatic attacks has many limitations They are of no value in the acutely ill patient Side reactions notably palpitation headache jitteriness and insomnia are quite common In male patients urinary difficulties particularly dysuria and diminution of the urinary stream may appear due to spasm of the prostatic sphincter Hors ever prepirutions employing ephedrine sulfate or simi larly acting drugs combined with antılustamınıcs or theo phylline ethylenediamine and sedatie preparations are beneficial as supplementary therapy for the ambulatory mild chronic asthmatic patient Continuous use should be noided and omission for two days of each week is recom mended Several of the nener ephedrine lide synthetic drugs may produce fener side reactions One of these prep arrtions Orthovine (Upjohn) has been well tolerated in 200 mgm doses at four hour intervals and las appeared to help some patients * 113 Moreover we have demon strated with its use approximately the same degree of pro-

·81
With Seiere Bronchial Asthma
tection as ephedrine sulphate against experimentally
induced dyspnea and bronchospasm" (Fig. 9)
The protective value of ephedrine sulfate (25 mgs po)
agunst the bronchospastic effects of intras enous histamine
and intravenous mecholy was studied in four patients
ORTHOXINE
200 MGM PO
-- STAL NENTA AL SI
MECHOLYL IVO TRIALS
100
% PROTECTION
2
3
5
HOURS PROTECTING DRUG
FIGLRE 9 The Protectie Value of Orthoxınt Iwo Hundred mom
Gen Orally iguinst Ilust smine ind Mecholyl Induced Dyspnea and
Bronchospasm in Isthmatic Subjects
(Fig 10) It proved to be a poor protecting igent agiinst
mecholyl chloride induced dyspnea ind bronchospasin and
a relatively fair protecting agent agunst histamine
induced dyspnea and bronchospism Idequate protection
(10 per cent) ias observed at the end of one and one fall
hours A slightly higher degree of protection (40 to 55 per

·82
The Vanagement of the Patient
cent) persisted for approximately the same length of time
and then fell off sharply
studied the protectie capacity of antihistaminic
prepirations alone and combined with ammopluyllin and
epliedrine preparations alone, we decided to study the pro
tectie capacity of an intilustamınıc preparation combined
with ephedrine sulphate The combined oral administra
Having
100-
EPHEDRINE SULFATE
(25 MGM
PO)
----HISTAMINE IV (* TRIALS)
-MECHOLYL IV (4 TRIALS)
% PROTECTION
HOURS P PROTECTING DRUG
FIGURE 10 41 The Protectie Value of Ephedrine Sulfate 2) mgm
Given Orally Against Histamine and Mecholyl Induced Dyspries and
Bronchospasm in Asthmatic Subjects
tion of a sympathionmetic agent ephedrine sulphate (25
mgm) and an antihistaminic diphenhydramine (Bena
dryl 50 mgm ) demonstrated an additive protective action
nguinst the effects of mecholyl ind hustumise kuch er
ceeded the protectise value offered by either drug ad

·11th Severe Bronchial Asthma 83 ministered alone This synergistic effect as observed in the laboratory would suggest that improved clinical relief may follow their combined use I have found a tablet containing aminophyllın 02 gin ephedrine sulfate 0 025 gm and sodium pentobarbital 003 gm (administered upon arising and again at 3 PM of indicated) very helpful as a supplementary measure in the recovery state The Pentobarbital serves as an efficient sedative capable of offsetting the stimulatory effects of aminophyllin and ephedrine In one patient we were able to demonstrate adequate protection (40 to 50 per cent) against the bronchospastic effects of intravenous histamine tlus degree of protection appeared one and one half hours after the administration of one tablet po and lasted for cwo and one half hours In the same subject adequate protection against the effects of intravenous mecholyl ap peared two and one half hours after administration and lasted for a similar length of time A tablet containing aminophyllın 03 gm ephedrine sulfate 004 gin sodium pentobarbital 0 1 gm and phenobarbital 006 gm may be administered at bedtime for prompt and protracted hyp notic action ·CHAPTER VII THE THERAPEUTIC USE OF GASES | Oxygen FOR OR the acutely ill or status astumiticus patient dem onstrating evidence of hypovi and cyanosis ovygen in concentrations of 95 per cent or more administered with the OEM meter mash may be einployed (Figs 11 and 12) This mask is a distinct credit to the ingenuity of its inventors and is of tremendous practical value 1 An air injector (concentration meter) provides accurately con trolled air oxygen mixtures in whatever proportion is indr cated Rebreathing and carbon dioxide accumulations are MILISIS 5 FIGURE 11 Meter Vask (Oro nasal typc) for the Administration of Controlled Concentrations of Oxygen or Helium Oxygen Rfixtures Postitne Pressure in Expiration ay Be Employed if Indicated 84

·il ach Spuere Hroncinal dsthma
85
KO
7
4
2
8
5
FICE RE 12 Pirts of Veter Vask
1 Comfortable Oro-nasal Face Piece with One way Expiratory Flutter
Valse
? Oxygen Inlet Tube
3 Unidirectional Mica Valse wluch Prurenty Rebreathing Vay be
Scared or Remoned Rebreathing us Dessed as with Helum
Oxygen Therapy
4 Acrewsty Mica Inlet Valje t'erriss Room li to Enter when
Inalequarc Oxygen Hows are Entering Collecting Bag
3 Rubber Collecting-One or two Iiter Suze
6 Dye Vetered for Pytne Pressure (1 104cm walcr) in Fxpura
ton Only Expiratory one way Fluttes Valse Seated Within
7 Oxygen Concentration Meter (101°, to 950%) \lso serves as Ilu
dalice
& Special Gage Rubber Connecting Iubing

·86 The Management of the Pattent totally eliminated by meins of an inspiratory sale at the entrance to the face piece from the collecting big and an expiratory valve in the face piece itself (which inci dentally is unusually comfortable) Vechanical resistance to respiration is greatly reduced by this arrangement of Valies A large soft latex collecting bag of 1 or 2 liter capacity makes it possible for the patient to breathe deeply with comfort In addition the fice mask has an attached expiratory outlet that has been metered for positie pres sure in expiration up to 4 cm of water pressure A higher positive pressure may develop in the tace-piece during dyspnea when the 4 cm orifice is used The appiradus can be used to deliver 40 to 95 per cent ovygen or helium and oxygen mixtures with or without positise pressure if carbon dioxide therapy is desired the inspiratory valle may be removed to allow rebreathing I have used this apparatus in various types of cardio respiratory disease and find it practical and economical 160 161 107 Under normal conditions the inhalation of 100 per cent concentrations of oxygen has no deleterious effect on tissue function provided it is not maintained congnuously for longer than twelve hours Inhalations of 50 to 100 per cent concentr mons of ovygen increase the partial pressure of oxygen in the lung thus making it possible for the blood to absorb and transport a quantity of gas greater than the normal The hemoglobin saturation can be raised from 96 to practically 100 per cent and the oxygen in simple solution in the plasma from 0 3 per 100 cc of blood to a maximum of 2 2 cc This represents a possible increase of as much is 15 per cent in the oxygen carrying capacity of the blood throughout the circulatory system This in turn produces a corresponding increase in the partial pressure available for the diffusion of oxygen from the blood into the tissues In this connection Campbell and ·11 th Serere Bronchial Asthma 67 Poultont have demonstrated that the oxygen pressure in tissue is increased proportionately more tinn is the oxygen content of the blood This increase in oxygen content in the blood and oxygen pressure in the tissues is observed best in hypoxic patients in whom the Oxygen carrying capacity of hemoglobin may increase from low levels of 50 to 75 per cent to 85 to 30 per cent when high concen trations of oxygen are inhaled Frangta las for many years repentedly described bene ficial clinical results from so called 100 per cent oxygen in severe hypoxsa Concentrations of 70 to 100 per cent should be used when loner concentrations are insufficient In extensie clinical observations on approximately 800 patients Boothby and luis associatess* * * employeur concentrations of oxygen for periods as long as forty cight hours without any evidence of pulmonary irritation flow ever they did warn against continued administration for ? pesod longer than 48 houts Further clinical investu gation showed that high concentracions can be used ith relative safety for periods of two to five days when 7 muusk apparatus is employed since mask therapy is really not continuolis inasmuch as the mask is frequently removed for general nursing care feeding etc In closed respiratory chambers such as the lelum and bx) gen lool apparatus (Fig 33) it is inadvisable to use continuous oxygen concentrations of ibore 70 per cent for more than 18 lours $20* If oxygen therapy must be main tuned for longer periods i special zur Injector nitchen to the oxygen regulator provides accurately controlled air oxygen tixtures The sleeieients of the hood should be opened to allow the entrine of room w for one Inaif lour every shree or four hours when this injector is not em ployed Oxygen toxicity from the inhalation of high con cohtritions can occur in hypoxic patients Honeser when ·88 The Aſanagement of the Patient eter indicated high concentrations can be safely gren for periods at least as long as one week with the mask appi rius and intermittently for the same length of time uith the liood Ppiratiis Vany cuely ill patients in status asthm iticus connot tolerre mask therapy They complun of a sense of suffoca £60 9220 FIGURL 13 Hood Appratus-(Oxygen or Helium Oxygen Positie Pressure Breathing) tion or claustrophobia ind furthermore miny object to the smell and sensition of rubber neir them if hypoxia is not severe 7 simple large cellophine type of frce tent or conjoined bent cathieters fitted to the nires may be used to administer up to 40 per cent concentritions of oxygen in flous of 5 to 8 liters per minute Adequate humidifica tion is necessary to present the drying and irritant effects of owygen so administered If one uses the catheter metliod It is well to employ a simple water bottle liumidifier Many ·11ach Serere Bronchial Asthma 89 prefer a diffusion herd inlet and 1 kiter trap outlet type of humidifier Adequate water vapor concentrations cun be obtained with the use of the concentration meter when employing the Or V misk. If higher humidity is desired the injector may be removed and a water boule type of hamdiher substitiiter? AL FIGURE 11 Vechanaire Type Iceless Oxygen Tent I prefer the use of in oxygen tent with a transpirent cinopy enclosing the entire bed (FIG 11) The freedoni of motion and the uninlubited feeling of being able to see all r111t goes on is well appreciated by the stel patient This type of tent which employs electrical refrigeration affords more adequac ar-conditioninz humidity control and senultion without direct drafts on the patients face It is simple to operate and eliminates the need for ice and skilled personnel Oxygen concentrations of G0 to 70 per cent may be muntiined particularly if the motor is slut ·90 The Vanagement of the Patient off while the vents are opened to prevent circulation in the tent and consequent loss of oxygen It is my general custom to place the patient in the tent immediately upon arrival at the hospital Residence should be continued unul recurrent attacks of severe bronchospasm have subsided The return to room residence should be gradual if severe emphysema is present If obstructive phenomena persist the patient may be removed from the tent for intermittent positive pressure helium oxygen therapy three or four times daily Tl henever indicated 1 nebulizer apparatus for administering therapeutic aerosols may be introduced through a vent opening in the tent and the nebulizer placed in the patients mouth 2 Helium Oxygen Mixtures As Barach originally observed the inhalation of helium and oxygen mixtures relieves many patients who fail to respond to other recognized therapeutic measures :: * These observations have been confirmed by Boothby and his associates Rowe 38 40 116 15 Abramson Schwartz 158 Goldsmith 87 Eyermann ?? and Metz ? We have also been able to confirm these observations in a series of patients with severe bronchial asthma gas poisoning pulmonary edema atypical pneumonn and postoperative obstructive respiratory disease 260 261 263 Helium is an inert non combustible gas of very low molecular weight (4) and is about one-seventh as heavy as air It has a los coefficient of solubility and is 27 times more diffusible than nitrogen hence only a small amount is dissolved or lost in the body A mixture of 80 per cent helium and 20 per cent oxygen is one third as heavy as air Tlus lightness suggested to Barach that it could be moved more easily to and from the lungs in obstructive dyspnea During quiet breathing the influence of such a ·With Serere Bronchial Asthma 91 decrease in weight is practically negligible However with respiration obstructed an increased negative pressure within the chest becomes necessary for the inward more ment of air post the obstruction The pressure required for the movement of an 80 per cent helrum 20 per cent vygen mixture through a given orifice would be about half that required for air Barach demonstrated this phenomenon in normal individuals breathing through a resistance and in patients with heart disease breathing through minimal resistances Thus the principle of sub stituting helum (or nitrogen in respirable mixtures was placed on a firm physiological basis for the treatment of respiratory obstruction from the larynı to the bronchioles Tith helium oxygen mixtures it should be possible to compensate for approximately 50 per cent constriction in the lumen of the tubal respiratory tract It is noteworthy that the more localized the obstruction the better the effect This decrease in respiratory effout may be accom panied by a progressive relaxation of the constricted bronchi and may be of life saving value The type of gis mixture used will depend upon the factors responsible for the dyspnea (hypoxia or mechanical obstruction) If mechanical obstruction exists mixtures of 80 per cent lielum and 20 per cent oxygen Tre more beneficial than oxygen zlone The percentages of the helium ind oxygen mixtures can be controlled at will by using separate tinks of oxygen and 80 per cent helium with 20 per cent oxygen connected by a 1 tube to the apparatus used Tanks of helum alone should never be employed because of the dinger of asphyxit should the oxygen supply become interrupted ind the patient thus teccise only 100 per cent lielum The greater the con centration of helium (66 to 80 per cent) the more effective is the mixture in overcoming respiratory fatigue and dyspnea prosided that hyposni is avoided ·92 The Vanagement of the Patient The voice changes caused by effective helium and oxygen administration may be amusing or frightening to the ininitiated The effect on mın can best be described by the term effeminite A deep baritone voice develops 1 lyric tenor quality and a man with 1 tenor voice can only squeal si This lias been explained as due to the fact that the muscles of the larynx are unconsciously set to cilise a certain sound in ur ind that when brenthing a medum so much lighter the sound produced is much changed from normal 206 Dublin Baldes ind Walliams" made oscillogrzpłuc studies on these voice chianges They determined that the iterations consist of 2 variation in overtones The frequency of the fundamental ubrations remains the same The loss density of the helium and o\ygen mixture impedes the ubration of the vocal cords less than does air Tlus may result in 1 change in the original overtones Also because of the loner density the velocity of sound with helium and oxygen mixtures is increased Tlus probably causes the vocal resonators to amplify different overtones Tl huch of these differences is more important was not determined Such changes are fortunately not permanent The helium ind ovygen hood rebreathing apparatus is the most effective one for administering oxygen or helium and oxygen mixtures with or without positive pres sures 20 75 The percentage concentrations of the mixtures cin be exactly controlled Positive pressures up to 6 cm of water cın be applied to the inner surface of the lung during both inspiration and expiration The apparatus (Fig 13) consists of a gas tiglit motor blower (no canisters for the carbon dioxide absorber a rheostat to determine the volume of air flow and its temperature tubal connec tions in ice containing cabinet and a plastocele head hood with a closure effected by a soft rubber nech collar ·liith Severe Bronchial dsthma 93 Ilhen this rebreuung cucuit is in use, only the ovygen is utilized cooling de-humidification and removal of the carbon dioxide are efficiently performed I have found this apparatus sery saluable in the treatment of severe bron chial asthma various types of pulmonary edema and obstructie dyspnea 161 162 163 JOS 3 Positie Pressure Therapy l'ositive pressure therapy generally employing ? mi ture of oxygen ind helium has not recened the side spread use it deserves This therapy is indierted in the treatment of various types of pulmonary edema bronchial asthma und obstructive respiratory disease Barach and has associUEST* 26 75 29 105 established the clinical applıcı tion and usefulness of positive pressure and the physic logic factors involved in the treatment of obstructie dyspnea ind acute pulmonrry edem They devised the two types of appiritus prei iously described one (the lood) providing positive pressure durin, both pliases of the respiratory cycles and the other (the mash) during elpiration alone? Signs of pulmonary edem pidly dis appear and remun absent as lon, is the pressure is applied or unul the original cause is removed The application of 1 gentie internal distending force series to keep the bronclueles patent ind opposes the hydrostatic pressure within the capillaries Birich compared this process to that of putting 1 finger on the capillary will itself He demon strated by its lise a reduction of the pathologically elevated negie intrapleuril pressure present during the in spiratory cycle in patients who live developed pulmonary edem during obstruction of the air passages and fre quently i lowering of the total pulmonary senudaton le observed other modifications in circulatory function par ticularly ? diminished flot of bloxxl into the right side ·91 The Management of il e Patient of the heart in patients withi pulmonary edema These modifications which tend to prevent overfilling of the heart are similar to those seen when a tourniquet is ap plied to the extremities There was also roentgenographic cvidence of narrowing of the transierse cardiac diameter upon the application of high mask pressures Due to bronchial constriction the expiritory phase in 15timatıc dyspnea is prolonged In obstructive dyspnca the intrapleurl negative pressure is increased during inspiration then air or oxygen mixtures are breached under positne pressures the abnormally clevated negatne intrapleural pressure is diminished and the dyspner » alleviated Bıracha pointed out that nature provides a helpful mechanism in the expiratory grunt of the patient with lobar pneumonia and in the pursed lips of the asth matic patient during expiration both spontineously pro siding positue pressure Using helmm oxygen mixtures the patient can be treated for as many days is necess iry in either the hood apparatus or positive pressure mask with proper humdifi cation however the hood apprratus is better tolerated Therapy should be intermittent and generally for not more than one out of every four hours as the patient my find longer periods exhausting When the need for posi tire pressure no longer exists the mask can leased wich out employing the metered disk for positise pressure mai the desired percentages of oxygen can be given or the patient may be transferred to a tent if thus is considered more desirable In patients with underlying severe emplıysema or cerebral arteriosclerosis the percentages of oxygen should be graduilly lonered before the complete cessation of treatment in order to present the occurrence of cerebral anei cardio respiratory symptoms which may follow the sudden cessation of oxygen therapy ·Itnth Senere Bronchial Asthing 9) Generally, positive pressures of 2 to 6 cm of water are sufficient for preventing or treating pulmonary edem? and status asthmaticus Pressures above 6 cm may diminish the return flok of blood to the right side of the heart In some cases 1 lone employed higher pressures for short periods If low pressuires are used beginning with 1 pressure of 2 cm of water and cautiously increasing it as needed no difficulty need be encountered In employing positie pressure therapy cercun clinical observations are worthy of mention Vany patients find such therapy tiring when the mask is used and an o casional critically ill patient it first becomes alımmed and confused at the increased resistance in the expiratory phase Reassurance and frequent rest periods cun largely overcome thus apprehension When the houd is employed the positive pressure is effectne in both inspiration and expiration and these difficulties do not exist in the desper ately ill patient langensteen drainz,e with a double lumen tube for feeding and decompression may be used in conjunction with positne pressure whenever indicated The tube cin be introduced either throun the mish or the sleese of the hood apparatus it dy materially to the erre of the very sick parient We love not observed either gastric dilation or alxlomınıl distension as a result of posicise pressure therapy lle wish to stress once again that positne pressure therapy should be intermitent with rest periods of varying time depending upon the degree of underlying pulmomry edema The dyspneic patient is soon able to rest und sleep may follox Respirators de compensation is thus presented if therapy is continuous free productive coughing ind frec bekchung may be some uintinlubited! He hue het observed any irreversible all effects from such therapy when conuniled for as long as seven days ·96 The Management of the Pat ent 4 Carbon dioxide-Oxygen and Carbon dioxide-Helium Oxygen Mixtures 1 dry irritating non productive or poorly productne cough is frequently encountered in asthmatic subjects Every attempt should be made to reduce the viscosity of the exudate by the use of expectorant drugs therapeutic aerosols carbon dioxide and oxygen mixtures or carbon dioxide and helium oxygen mixtures Expectorant therapy is discussed more fully in Chapter VIII The principal purpose of carbon dioxide therapy is to stimulate the respiratory center An increase in the respiratory rite and in the depth of respirations charic terizes effective theripy of this type Carbon diovde may act by increasing the acidity or the carbon dioxide ten sion of the respiratory center Increase in the acidity of the blood Noning through the carotid body 75 tiell as los olygen pressures in the carotid body also stimulate breathing In ddition increise in the blood curbon diovide leads to a shift in the ovygen dissociation curie of hemoglobin to the right thus allonng increased re lease of oxygen to hypoxic tissues it also dilates the cere bral vessels Considerable controversy sull exists concerning the over all value of carbon dioude inllution is an expecto rant in pulmonary disease Alison used inhalations of 5 per cent carbon dioude with ovigen in some cases of incipient pneumonia and bronchitis in children He believed that the disease process was aborted by the removal of the mechanicıl blocking of the uri ays Campbell and Poulton also encouraged the use of carbon dioxide and oxygen in the treatment of pneumonia Banyu º 10 em ployed inhalations of 10 per cent carbon dioxide in oygen in cases of pulmonary tuberculosis ind believed thit this ·Ilith Serere Bronchial Asthma 97 forn of therapy was superior to the use of expectorants for the manageinent of strenuous exhaustite non pro ductive cough ( tussic insufficiency ) He observed that the increase in respiratory rate attendint upon inhalation of curbon diovide was usually followed by easter expectora tron and decreased cou,h The sputum chinged from heavy thick and tenacious to thin serous and watery Binya and Cadden" confirmed the value of carbon dioxided inhalations as an expectorant in pulmoniry tuberculosis They attributed its effectiveness to a poner ful stimulating effect on respiration which reflects itself in stretching and diluation of the bronchi pouerful peri staltic movements of the bronch and liquefaction of the exudate that stagnates in the bronchu free They also stressed its contra indication in recent pulmonary hemor thage in severe emphysem? in extensive pulmonary fibrosis without telectasis bronchiectasis purulent retention in the ur passages 111 route pleuris with effusion and in hypertension In their exhaustive studies on the influence of expecto rants and gases on sputum and on the mucous membranes of the tracheobronchil trec Bisch Holinger and l'onclicr" » demonstrated that the addition of 5 to 10 per cent carbon dioxide to an ovsen misture acts as in cfficient expectorant by reaching the deeper obstructie type of secretion They noted that the sputum 175 lique fied to a greiter degree by stem inhalations than by expectorant drugs Since the storm reduced the viscsity and the content of organic and inorganic substimes in the sputum its action appened to be one of simple dracion These authors regarded the inhibition of carbon and most efficient expectorant which reduces the amount of sputum within the bronchnal tree by sinnufung resorption and rendering thic remunder OT כוונון dioude 151 ncii 1 ·98 The Management of the Patient more Iiqmd so that it is coughed up more casily They concluded that the best regimen to clear the bronchnal tree of its pathological secretions was a combination of carbon dioude steam inhalations ind expectorant drugs Inhalations of carbon dioxide oygen mixtures may be employed when more conservatie mesures have failed and if there ne no contra indications (particularly pul monary emphysema or edema) to increasing the rate and depth of respirations for short periods of time If deep breathing is 1113intained for long periods of tsme the in creased negative intrapulmonary pressure inay accelerare the formation of edema from the pulmonary capillaries I have found nixtures of 5 per cent carbon dioxide 20 per cent oxygen ind 75 per cent helaim of occasional value when employed to nebulize mixtures of 0 22 cc of I per cent neosy neplırın with 050 cc of Vaponefrin or Isuprel 1 200 This mixture has generally been well tolerated Ench treatment should take five to ten munnies und should be interrupted if the respirations become too strenuouis The sputum is liquefied expectoration is facilitated and tenacious thick mucus plugs are often coughed up These inlilations are designed to clear the bronchni and bronchiolar pathways 5 The Use of Therapeutic Aerosols (sympathomimetic amines and antibiotic agents) Aerosols are relatively stable suspensions of liquids or solids in air or oyigen The terms nebulization therapy und aerosol therapy may be used interchangeably Abramson’ objects to the use of the term vaporization He points out that the term vapor designates the gaseous form which a solid or liquid takes then leated As the particles on the state are practically of a nuolecular size and are therefore about ten thousand times smaller than ·Ifith Severe Bronchial dsthma 99 the particles of therapeutic aerosols nos in use he claims that this term has been frequently misused Numerous factors are insolied in the determination of aerosol retention in the respiratory tract and their diffu sion into the blood stream: * The following are the more inportant factors the particle size distribution which depends essentially on the type of nebulizer and the pre cise technique employed tlie degree of deposition of the particles which depends for the most part upon impinge ment settling and diffusion by Brownian movement the pattern of the ventilatory curve particularly the respira Lory rate the tidal air and the degree of bronchospasm which govern the penetration of the mist to the terminal bronchioles and alveoli aerodynamic factors such as turbulence and stream line flow and finally factors which may influence the size and life of the particles themselves 371mely the stability and surface tension of the nerosols The selection of the proper nebulizer for the produc tion of aerosols is of primary importance * True nebulizers differ from atomizers in that they are constructed with 1 buffle fuch removes from the mist the large particles which cinnot penetrate the lower respiruon tract and which on impinging there may irritite the patients tongue and throat The majority of tlie nebulizers which are commercially 1311able are really womers The exact pirucle size distribution of the aerosol governs the degree of retention and the site of deposition l'indeisen" has demonstrated that particles of three micra radhus und larger will undoubtedly be deposited com pletely on the trachea the bronch the bronchioles and tle alıcolar ducts Impingement and sedimentation are the importint mechanisms of deposition of these icrosols Particles of I micron riduus and more are retained by the lungs to the extent of 97 per cent with only 3 per cent ·100 The Management of the Pilien recolered on expiation those of 0 3 micron are absorber to the e\tent of only 35 per cent with G5 per cent recover on expiration Thus by the control of the particle size tide range of deposition distributions can be predicted These obserations of Fındersen were confirmed by tłie experimental nork of Vin Wijk and Patterson who demonstrated that froin 63 to 96 per cent of solid prrticle of 06 to 20 micrı nda were returned by the lungs Although they penetrate to the alveole by Bronnian move thent particles less than 04 micron in riduus riere refined only to the extent of boue 30 per cent These studies stress (no important facts 1) Farger part cles such as those produced by most commercrl nebu luzers tend to be deposited on the tongue pharyns and lirysis and do not reach the bronclueles or alcoli and 2) particles inlich smaller in size tend to be called rather than deposited on the bronchopulmonyry surface lisse aptunum size ir mun alveoln deposition will occur 19 One mry occasionally take advamage of the fact that harge particles are deposited lugli in the respiratory prs siges in the man igement of inituninatory disease of the if xher and larger bronchu Nebulizers should be constructed u1h 7 surable De to remove the large parncles and ensure 1 utformn de livery of small porucles preferably with the majority of radu 113 the 05 to 90 micra ringe in this commry most of the iniestigutors interested in nero,ol therapy biase em ployed the l aponeirin nebuhrer (Fig 15) Here found 11 most satisfactory for the production of therapeutic Terosols for it produces ? fine voluminous mist or smoke screen in which the majority of the particle ridu 11erige about I intcron and use ciprble of penetrating the theols and remaining there Abramson? stresses the importance of prolonging the ·11th Jaere Bronchial dstheme 101 7 FICURE 151617 ! LajmeSs 150 Unix ? » ! (wr33 we can be uscit inceses cibly with acts of sha ( allowing y paratus 3 Mbuluer for em 11 mal 1 m d sto 9 Rebresckmg La, and sebahet parkusettle } t trobar teman sstration of 450 bosse 1600x3 4 Apparatus for sinus therapy ! atschneiter in drug an i senturi tunc for alletuste p stme and the pressure life of the inspiser purtules (st #Passcy} ses that the lungull Ternin 1 tugh percentage of the tu l'ensallin ind streptus myca nerosols ne sufix rently alle und do XX secure the Kklitsons of glycerin Vest of the ps! 75333 ste si prepara trons of the various epinephrunc cernate employed is aerosols con17111 up to Il pes (11 dicers » { th losers the vapor pressure st alms the most recesses * il srsta t1on and presents the pireu les from rapuely dmmustun 111 sin fier leum: the Nebula In 1910 D 23159' suissested that 10 te> 0 per cent glser $ ! there stuitable for stabiluring the mist anul thai nther substances such 75 CIT1 sumar un xulis could let emploser !!! so biese ko ·102 The Management of the Palient to stabilize the most by lowering droplet vapor pressure A second important factor which controls the particle size and persistence of aerosols is the surface tension of the droplet. Lorering of the surface tension may produce 1 different particle size distribution but the stability may also decrease if smaller particles are formed The effect of lowering the surface tension of the particles is the subject of considerable research in many laboratories Inhalation of nebulized sprays of various therapeutic agents may be employed in the management of broncuial asthma for the relief of the troublesome cough is an aid to expectoration and for the control of infection The use of antibiotic aerosols for the control of infection will be discussed in Chapter I\ I have found nerosols of the sympathomimetic drugs Vaponefrın (rucemic epinephrine hydrochloride) and Isuprel (1 (3 l'Dihydroxyphenyl) 2 ispropylaminoethanol) lıydrochloride 1 200 of particular value for the relaxation of bronchospasm As little as approximately 005 to 0 10 cc of one of these solutions nebulized by three to sin compressions of a hand bulb may abort or relieve a mild bronchospastic episode It is important that the patient actively inspire the aerosol and that he and its deposition by holding his breath after inspiration for several seconds More severe bronchospasın may require 05 to 10 cc of the bronchodılator solution nebulized by continuous flors of oxygen helium oxygen or air pump (Fig 15) A \ tube or simple button like opening in the oxygen or air feed line allows interription of verosol production during expiration (Fig 15) Bronchodilator aerosols often convert a useless cough to 1 productne one improve the vital capacity and permit deeper respiration The effect of six inhalations of Vaponefrin aerosols on the ventilatory pattern of a subject with acute bronchial asthma is shown in Figure 16 The ·lith Seiere Bronclual Astlina 103 striking improvement in the inspiratory and expiratory velocity speed and in the vital capacity is apparent These inhialuons should precede posturil drainage and anti biotic aerosol therapy whenever these measures are per formed Postural drainage may then become effectne by Tchieving the patient of retained inflammatory products CSICCT OF VAPONEFRIN ON THE VENTILATORY PATTERN OF A SUBJECT WITH ACUTE ASTHMA PONEREN WONEN .WAN we CAAMCITY A VELOC A vc 21.3cc 10 face Asht chce Buches ONCE ON cc 24 hec uru face Lychee FIGURE 16 which previously could not be c1 tunted Intibiotic aerosol therapy when indicated should follow postural drainage et cuition of the bronchial secretions ensures avoidance of dilution of the anubiotie zent by the secre tions and more efficient topical mucosal effect The combination of 05 of 1 poneſrın or Isupre! 1 200 and 0 5 cc ot! per cent neosynephrin is of partiu Tur value wlien there is bronchospasm accompanied by tluch, teucrous sputum or 1 troubleserne unproductie cough Vaponefrin o Isuprel aerosol is also of value in presenting or relieving iny allergic reaction which may ·101 The Management of the Patient follon or accompiny penicil}ın aerosol therapy Addition of neosynephrin produces particularly effectne broncho vasoconstriction which reduces mucosil congestion with out the secondary risodilitation ulich may occur with the use of topical epinephrine preparations alone It tends to duininish the secretions and to provide a more patent air way, although it is a poor bronchiodilator Refractoriness and toxicity as obseri ed Isith epinephrine and ephedrine do not develop In studying the effects of inhalations of neosynephrin in the ventilatory dynamics of the asthmatic subject, one cin frequently demonstrate improvement in the vital capacity and increase in the inspiratory and expiratory relocity rates Thiese effects, however, are not 15 great or as constant as those observed with inhalations of the epinephrine preprrations or of Isuprel Occasion ally epinephrine sensitivity may be restored more promptly with the use of neosyneplının aerosols alone As a rule the troublesome cough becomes easier and more productive after stich therapy Substituting helium and ovgen mixtures for oxygen is of further value if there is evidence of bronchial ob struction The helium oxygen mixture allows the nebit 117ed solutions (Vaponefrin, Isuprel, neosynephrin peni cillin or streptomycın) to pass through the contracted bronchu more freely and permits these preparations to act effectively on the mucosa and submucosa The solutions are placed in the nebulizer which is connected by rubber tubing to the ovjgen regulator or lit pump The patient may use 05 to 1 0 cc of the broncho dilator preparation for a single dose Flows of 1 to G liters per minute are generally used and a single treatment roles about 20 minutes This may be repeated at intervals of three or four hours Prompt relief from the bronchospasm may be observed, the dyspnea usually subsides and the ·111th Severe Bronchial Asthma 103 vital capacity and the inspiratory and expiratory relocity rates quickly approach normal once again (Figs 2 und 16) This technique can be set up in the patients home and the instructions are easily followed Many patients prefer such therapy before meals at bedtime and before under taking any unusual exertion The sympithommetic aerosols should be employed only when specifically indicated and with well defined instruc tions to both the patient and the nurse The proper in halatory technique with the use of a small pirticle size nebulizer is most important The preparations should be clearly labeled by name and concentration and miled for aerosol use only On occasion they have accidentally been gren parenterally with very disturbing side rex tions Excessive use should be firmly prohibited The pr tient must be instructed not to swallon sulay during treat ment and whenever possible to rinse huis mouth thout ughly after each treatment Abdominal crumps may occui if the salna is swalloned The salısa at times may be tinyed pink With overdosije refractoriness and the usual side reactions observed with epinephrine mn be seen linully the patient should be tought to wut a full five minutes after one to three inhalations before repentin, sime Prigal 5 has introduced the use of steam for the pro duction of medicated nerosols employing minophyllin ammonium chloride penicillin solutions and other agents The results withi aminophyllin and ammonium chloride nerosols were not impressile Our own protertion studies:40 usith aminophyllın teruso)s demonstrate that this route is ineffective in presenting the effects of lustamine and mecholyl induces bronchospasm and dyspner in asthmic subjects ·CHAPTER VIII BRONCHIAL EVACUATION CATHARSIS" EVACUATION of the bronchr or what I terme 'bronchial cuthirsis” may be accomplished by physiologie mechanisms (Table 5) or therapeutic mechanisms (Table 6), the necessity for bronchmal catharsis may be precluded by various preventive measures (Table 7) Catharsis, in the Freudiin sense, too, may be of value in the manage ment of the sick asthmatic In the physiologic sense, any BRONCHIOLAR EVACUATION == CATHARSIS I PHYSIOLOGIC MECHANISMS TO THIS ENO FROM MACKLIN 114 CRON GUNN I COUGH ACILCX -TUNCTIONS IN VPPER A RWAYS 2 ACTION OF CILIA PUNCT ONS DOWN TO fut BRONCOLS 3 CRISTAL TOO WAVE MOTION FUNCTIONS TO EVACUATC ENTRE TRACY TABLE 3 IL THERAPEUTIC MECHANISMS TO THIS END ItXPECTORANTS 100IDES AND SEDATIVE EXPECTORANTS 3 IPCCAC TRACHCAL VOMITING 3 INHALATION THERAPY CO MELIUM MIXTURES BRONCHODIL ATOR AEROSOLS * POSTURAL DRAINAGE 5 BRONCHOSCOPY 6 ENDOSCOPC ASPIRATION 7 ENDOSCOPIC FAVAGE AND INSTILLATIONS OF CHEMOTHERAPEUTIC AND ANTIB OTIC ACENTS TABLE 6 106 ·II oth severe Bronchial Asthma 10" TO PREVENTIVE MEASURES I EL MNAT ON OF AA AND BLOOD-BORNE RAITANTS ALLERGC CLEANL NESS HYPOSENST ZAT ON ARTLTRAT ON INDUSTR AL CONTACTS AEROSOL PROTECT ON STUDS * OMNUT ON OF AMOUNT OF MUCUS SECRET ONS ACROSOL THERAPY (NEO SYNC PMRN) BELLADONNA ALKALOOS OR SYNTHET C COU YALENTS 3 BRCATH NG EXERC SCS TADLE 7 medication or procedure which will facilitate the removal of the retuned impacted bronchial secretions is of greit value in the treatment of tlus disease and may be life saving Bronclural catharsis may be accomplished in ? variety of ways The expectorant drugs of luch 1pccc is probably the most effectile may be considered bronchial evacuunts 1 Expectorants Fxpectorant drugs may play an important role in the management of the sick asthmatic The mucus in the bronchioles is usually tenacious and inspissateci duc largely to dehydriuon and long retention becruse of in cllectual cough The cough may become cien more in effective because of the impacted mucus and a state of Pussic insufficiency desclops Vany expectorants and expectorant sedative mixtures hase been employed the most common being the jodides ind immonium chloride We have never been certain of any definite benefit from inhalations of compound tincture of benzoin or the Polatile oils of anise pine or euc ilyptus Steim inlialıuons are preferible for their sinple expectorant action the ' ise mixtures employing creosote or guurcol preparations

·No text on this page.

·Ilth Seiere Bronchial asthma 109 10 00 JO aqueous solutions of iodides are too irritating The follos ing mixture has prosen very helpful in produtting 1 thun watery, less tenaciouts secretion and in increasing the clliciency of cough and postural drunage Rx Solution of Potassium Irsonite Saturated Solution of Potassium locide 19 00) Sodium Phenobarbital Distilled water to make 240 00 Label 40 tidpt 2 Ipecac Ratner"has emphasized the value of india ed Somiting folloning the administration of stup of petal to infants and children He attributes this to relief from bronchini obstruction rather than to relief from bion chrolar spasm lle dades asthma into two types 1) that due to bronchual obstruction and %) that due to bron The obstructile type is usually due to mhalants and wien drenalin Tuls to chce the broncholar spism then ipec iç is mdicited the bostran tile type is usually the cruse of status asthm aucus Ile states that according to Vacken threr muslimsins huit developed physiologically to free the respiriters in from irritants and accumulated serenons I the onih relle ?) the action of the chu and {) 7 le motion sud to rescinble peristalsts (rablc » These thice factors often cooperate in the removal of forei,n mterial sucht is ciudates from the respirator unt laordm, to (runn " the cough reflex functions in the upper run the old 74 75 far down as the fire bronhiples and the peutstilt moscments C1uate the chute trit eien including the una terminals (Iible 5) These activities may over lap Remberytdeschide the effects of ipxec de is tracheal cholar spasm ·110 The Vanagement of the Patient somiting because of its resemblance to reverse peristalsis in the gastrointestinal tract By this process accumulation of tluch inspissited mucus may be released and the bronchu evacuated Ihne also found specic of 1 ilue in the management of Various singes of bronchial astum in adults The patient sliould be able to withstand the retchung associated with reverse peristalsis ficcac acts by substituting effectie relching place of meffective coughing It definitely is worth a trial before rempting bronchoscopy Once the criclical vomiting lits started positional drainage ards in eliminating the loosened secretions which under ordinary circumstvices might not be released for days Relief is often striking particularly in the chronically all and in patients with fbby musculature and low dia plurigins The patient should be informed beforehand about the effects of this bronchial purge The syrup of ipecac may be administered in one into or three teaspoon ful doses folloned by a cup of lukeutumn boiled water s smaller dose may be repeated in ane hour if no effective emesis has occurred it can of course be repeated at 11 later date providing the indications suggest its rise 3 Postural Drainage Basch Holinger and Ponchers 32 hrie deinonserated that the mechanical drainage of the bronchul secretions is accomplished by the action of the calm the respiratory movement the tissue squeeze of the cough reflex the cough itself und finally by expectoration Physically able patients are urged to do as much of their coughing as possible in the position that will best utilize the force of gruity as an aid to drunage Viny are able to avoid coughing if they empty their Jungs thoroughly while they are in this position Generally ·If ith Senere Bronchial Asthma postural drainage is of little benefit to those with useless cough but it inay be of considerable value in the manage ment of the patient with accumulated secretions that are easily productive By placmg the patient in i dependent position drainage of the involved part of the bronchial tree is facilitated Most pitients soon learn the best post tion for raismg the mouml inount of sputum The most dependent segments of the lung can be evacuated by having the patient Ancel on the edge of the bed and place both elboks on a stool in order to have the thori assume as nearly vertical a posttron as possible The pa tient should cough and expectorate for several minutes wule in this position and drunage should be repeated before meals and bedtime or before each inhalation of penıcıllın aerosol during such 1 regime Asthmatic patients who have been unsuccessfully treated with penicillin nerosol may not have had adequate bronchiolar evacumuon to permit satisfactory topical therapy Some asthmuc par tients can empty their accumulated secretions in the morning and remain free of cough throughout the day 4 Endoscopic Theripy Fndoscopic therapy (7-bronchoscopy b-bronchoscopic aspiration cmendoscopie instillation of lodızed penicillin and streptomycin suspensions and di-brunchal lavage) plays an important role in the presention and relief of bronchin obstruction in the control of infection and in the restoration of the dynamic functions of the bronchi It thus my present and reliuse the seriotis sequelic of obstructive einphysemi segmental atelectasis and bron chiectasis a Bronchoscopy-Bronchoscopy 15 7 versluzble dra. nostic and therapeutic procedure u buch as indicated when cier a harsh useless cough with dummed up secretions is ·112 The Vanagement of the Patient present and bronchospasm persists despite adequate physiologic man igement Thuck tenacious and gelatinous sputum may be removed large amounts of the thinner secretions aspirited Jux bronchin drainage facilitated Bronchoscopy permits direct inspection of the larger bronchi and their sub dnsions The remaining bronchus can be explored with the aid of forceps and secretions ispirited for diagnostic purposes Bronchoscopy may be of prrticul ir uzlue in the febrile state in the presention of treatment of segmental stelectasis and in obstructie emphysem? One of the post common and important cruses of derth in asthma is obstruction of the larger and smaller asr passages by inspassation of tenacious secre tions which may form cases of the bronchial tree Instalas asthmaucus bronchoscopy generally rescats hemorrhagic swollen redundant mucosa nith greatly narrowed bron chil diameters The bronchi constrict sul further on expiration Lelli" has described collapse of the posterior wall of the trachea during expiration in these patients Spectacular results may be observed folloning broncho scopic aspiration in such patients Finally endoscopic euzminanon may rereal 7 remediable lesion such as a loreign fody broncholithisis 7 dilnable stenosis or a broncimal adenoma responsible for the asthmatoid ueeze simulting bronchari zstima Portal broncu obstruction occurs fairly trequently in patients with bronchal astłum; and produces an obstruc tre emphysem -- function il blackout of the fung Chically this is characterized by wheezing respiration commonly noted during the expiratory phase it can be derected by anscultation of the long but is besi heird sich the stethoscope it the open mouth The common denomme nitor in all types of tlieezing respiration or astlımstoid #keezing is a narroning of the 1955 ay During expira ·Ilith lace Bronchial Asthma 113 tron the partially obstructed bronchus contracts and shortens the vibration of the out going air passing through this irregular lumen cruses the characteristic en piratory wheezing sound Because of this interference with the proper egress of air tint portion of the lung beyond the obstruction contims a greater volunie of trapped air than normally Roentgenograms made at the end of full inspiration and forced expiration releal the trapped air in the expiritory films the inspiratory films remain the same The diaphragm rises and the mechiastinum shifts towards the affected side during inspiration It is important that the errls stages of obstructive emphysema be promptls reconnued so that desclopment of complete bronchit obstruction can be presented When completc obstruction does occur w does not get in or out and the restdual ur is slowly absorbed We then linse an orginc blackout of the lung technically termed obstruc trentelectasis The degree of obstruction depends princi pally upon the character and quantity of secretions the adequacy of the cough reflex and the responsiveness of the bronchi to physiologic therapy Iccumulations of secre tions in the bronch beyond the point of obstruction may lend to i dron ned lung Bronchiectasis or so called in resolved pneumonia muy subsequentis ppcar In mng witnessed one deith ind to car funnlaues nith the use of pontocuine ind cocaine sprus and installations for local inesthesia in isthumnitre subjects I prefer deep sur,ical mestiesu for bronchoscopre ispiration Disini other (limethene) employed as a piclımnar induction agent to ether permits 1 smexth and more rapid induction lach is generalls free of laryngeal rition of spasm The bronchovopist or inesthetist should flood the airs ny With owgen during mesthesia and brone boscop 11 sth this relinque intensive brend hoxripk ispirmon in ·114 The Management of the Patient cluding culture and stain of the secretions bronchril lavage with salıne solution and installation of solutions of penıcıllın and/or streptomycin in neosy nephrin may proie of life saving value to the asthmatic subject b Bronchoscopic aspiration-Aspirition of retained bronchial secretions should conclude bronchoscopic examination The secretions and material should be carefully preserved cultured and studied by special staining techniques for foreign bodies organisms and cells Clerf and his associatesso 101 hue done much to impress us sath the value of bronschoscopy in bronchul asthma and with the importance of cytologic studies of the secretions ob tained Taldboti'vigorously stressed the value of broncho scopic ispiration and Image of the bronchial tree with salıne solution in severe attacks Proper bronchoscopic aspiration is usually folloned by miled subjective and objective improvement because it establishes drainage and rids the bronchu of accumulated secietions Removal of the bronchil obstruction may prevent or relieve the possible serious sequelle referred to previously c Endoscopic Instillation-(Intrabronchial and Intra tracheal)-The value of using solutions slionting bacteri cidal or bacteriostatic actity for intrabronchial instilla tion or luage lias long been appreciated In recent years the employment of sulfonamides penicillin and strepto mycin with more modern techniques of administration has been described for use in pulmonary suppuratie des ezse 14 N3 84 Intrabronchin instillation-Although the introduction of radiopaque preparations mto the tracheobronchni tree is essenually a dignostic procedure it can liken ise be utilized as an effective therapeutic medun $5 91 The lodine in the oils is relatnelmert and has little or no antiseptic ·Ilith Selcre Bronchial Isthma 115 aluc lloncier by mixing with the pocketed secretions the installations mechanically help the patient in cleansing the larger ind medium sized bronchial tubes thereby assistin, espectoration and subsequent postural drunage Occasional intribronctual institutions of suspensions or solutions of penicillın or streptomycin or both (depend ing upon the organisms present) in one of the iodine prepirations (Pintopique) may be of tremendous supplementary value to penıcıllın terosol therapy In several patients who were producing a great deal of purulent secretions bronchoscopic aspiration followed by bronchoscopic instillation of 230 000 units of penicillin and 05 grams (500 000 units) of streptomycin in 20 0 10 of Pantoprque 75 curried out just at the outset of penicillin nerosol therapy and on oxcasion repeated at Iscelis intervals af euidence of obstruction and or in fection persisted We have occastonally inic pencillin and streptomycin with I c of I per cent neosynephrin and 0 20 cc of I aponefun or Isuprel 1 200 in 10 to 20 cc of Pintopique The mixture was then installed directly into both lungs through the bronsehoscop. This comb 172son leads to dilution of the sputum ind loss of its tenacious mix oid character thus lessening the net essary cllort for espectoration Patients generalls tolerate tlus procedure scr well and feel considerably reliesel ifter curen, large mounts of seu retrons ind inspissate pas that the prestouss lund bxen unible to £124017 The ncos nephrin 2011, is broncheraskonstrictor and the Taponefrin o suprel icting is t brene bunlılator provide 1 more parent uru 1) The latter also presents mis on clospusm that meet som following instrumentation ind topte al inesthesia The Pintopuzque solution further fielps in cinsing thic lyonchit ind bronchioles of tent tous rictions such file berome dieront to the enticosal ·116 The Vanagement of the lattent 11alls furthermore since the solution is an aqueous one it does not cling to the bronchni mucosy and lience does not interfere with the action of the penicillin Ilchale not observed any ill effects from penicillin silme Pant opaque instillations Voderate attacks of bronciun asthma were precipitated in to patients but they were quickly relieved by epinephrine injections just what brought on the bronchospisin is questionable but it may hue been due to Pontocaine sprays wluch preceded bronchoscopy Intratricheal penicillin-Intratrichenl penicillin las proven to be of greiter value thin intramusculir penicillin in the treatment of clironic bronchitis bronchiectasis and lung abscess Tle fue been unable to demonstrate any penicillin in the spiltum of patients with suppuraine lung disease following intramuscular penıcıllın 83 84 On the other hand He have been able to demonstrate lugli sputum levels in the same patients folloning zerosol and endoscopic instillations In normal subjects we hac niso demonstrued adequate penıcıllın blood levels which per sisted for 7 longer period than those following intri muscular injections These lesels were lughest when nico synephrin and Pantoprque rere einployed as diluents in place of siline 34 35 83 The intratracheal technique is simpler than the intra loronclurl one which requires bronchoscopy Fioncser i prefer the latter becuse diagnostic assistance and proper aspiration prior to cach installation can be obtained Cleaning the bronchi of tenacious secretions by aspiration further insures a concentrated topical effect for the anni biotic If ntelectasis occurs this procelule should be re perted even more assiduously « Bronchial lasage-Penıcıllın in normal salme solu con sodrum sulfatluazole solutions or physiologic saline solutions may be used for bioncluni !21sge As the best ·11 th Sacre Bronchial Isthma preparation for lobectomy in patients with bronchiectasis Stevenson" has recommended bronchial irrigation with 20 to 30 cc of Bledsoe lischer solution (sodium potassium and calcium chloride in distilled water) (ollowed ex postural drainage and elimination Penicillin was added to the solution is a final 12 age of the bacteria inyoli ed iscre susceptible to penicillin Lavage was repeated to or three times at each treatment and direc or more trcatnients were given Wechly The patient was taught to perforin the procedure without 7551stance Reactions through uncom mon did occur 1though the principle of irrigation of in affected area may appear surgically sound it is not without danger for reinfection nou infection or spreid of infection to in solved arcas may occur Finally the possibility of sensitiza tion to pontocaine (preliminary loxal anesthetic) with re peated usage sliould be borne in mind ·CHAPTER IT MANAGEMENT OF INFECTION IN BRONCHIAL ASTHMA I The Role of Infection in Bronchial Asthmi The role of pathogenic and non pathogenic bacteria fungi and viruses in bronchil asthma continues to be a controversial issue whether or not infection acts as 7 primary excitant it is certun that infection pirys a defi nite part in producing asthmi Infection may act in any of the four following ways 1 Primary bacterial infections.There is reason to believe that some cases of bronchial asthin are initiated by bacterial infection True sensiti7101on (immunologic) slılar to the mecliznism in pulmonary tuberculosis ! though easy to invoke is difficult to prove with primary bacterial infection In suspected prunary bacterial infec tions especially when definitely positive shin tests are obtuned hyposensitization therapy employing a proper autogenous nccine may be of causiderable benefit Stock med bacterial vaccines contuning pneumococci staply lococci streptococci and other organisms act is non specific therapy only It is doubtful whether immunological te sistance to these organisins can be obtained from these mied vaccines Nevertheless in occasional striking response may be noted followmg the use of stoch vaccines prepared from virulent organisms To avoid danger of constitutional reactions the dose at the outset should be extremely small b Secondary respiratory infections-Respunton infec tion may occur secondarily in the patient with isomotor 118 ·Hath Serere Bronchial Asthma 119 thinitis allergic bronchuuis or asthma Infection may begin in poorly rerated lung seginents I bronchitis may be initiate and the cough and wheeze may persist The patient with vasomotor rhinitis (rigueed) for example, may start to snecic in lugust and develop 1 wheeze shortly thereafter I le symptoms muy improve or sulsside in Inte October then the pollen count falls Hotever a flare-up may occur in the fall and winter due to the prevalence of upper respiratory infections or due to house duse and fungi coincident with henting of homes (loved in radiators and exposed piping systems) or to mirked frequency of barometric and humidity changes the vicious cicle may continue or fire up gun in the spring due to the effects of spring louse-clerning or tice pollens c Respiratory infections may act as non specific trigger mechanisms. Thes mas set off the londed gun precip tating asthma in the sensitized indsdun! Somc alteration probrbly occurs in the immunological mechanism or respiratory mucous membrane so that the patient can no longer tolerate the extensu protein substine to which he is sensitive Wittich Attributed this to 1 lowering (by brcterial infccuon) of the threshold for the Citrince of the allergens It should be possible in these patients to obserse the effects of the upper respiratois infecuson without the wheering bis effective allergue theraps remos al of the offending allozen or by fivposensitization d Focal infections of teeth tonsils lumpled issue of the nos-pluzrynı misal polyps or sinuses ruch plis an important pruir role in nonchni ism? The should He dealt with surguully the neier proper indtions are present here nesci during the pollen seison Idenoid hypertrophy ind infection mul polyps ind pri nasıl sinus disease are frequentls related to the troublesome count observed in patients at alleigu bronchitis The ·120 The Vanagement of the Patient incidence of serious disabling chronic asthma is iery lugh in these subjects Vany allergists are of the opinion tint on allergic reaction to bacteria or their products is the cause of the stim? ind urge taccine clerups Liers effort should be made to muntun free drainage of the para nasıl sinuses ind freedom from infection in tlus group It is well recognized lowever that allerg) is the dominant factor in the muntenance of chronic pira msal sinus diseise to treat the latter without regird to the under lying allergy is poor judgment 9 Control of Infection with Antibiotic Aerosols The aim of antibiotic aerosol therapy? 8 15 110 123 12 in the management of patients with bronchopulmonary in fection is to produce as lugu a local concentruon is possible in the sputum the tracheobronchial tree and the pulmonary tissues Attempts 11 control of the primary bronchul infection with intramuscular adininistration of penicillin and oral administration of sulfonamide drugs have proven disappointing Every attempt should be made to identify the organisms from the nose throat ind sputum before during and after therapy Ilheneser feasible sensinsity tests of the identi fied organisms to penicillin should be inade at the outset and during and after treatment particularly if therapy is prolonged though bacteria have heen made resistant 10 penıcıllı in the test tube the development of chiczł resistance las not become ? major problem Once acquired honeser the resistance appears to be montuned indefinitely both in the laboratory cultures and in the body Torunitely any specific acqwred resistance to sulfonamides penicillin or streptomycin does not affect the originil susceptibility of the strain to one or more of the other drugs Tlie precise mechanisin (or site of action) ·11th Seiere Bronchial Isthma 121 of each of these therapeutic agents is evidently different This makes it practical and logical to administer them in combination whenever ſeasıble Antibiotic aerosols line proven to be of great value in the management of infections of the laryngo-tracheobron chil tree The choice of drug depends on the predomi nating organisms their sensititaly and the patients toler ance to the drug itself Penicillin is generally the primary drug employed streptomycin is added if gram negatre bacteria and bronchorrhea persist On (xcision it may be adusable to start aerosol therapy with a combination of penıcıllın ind streptomycin or to chan,e from one anubiotic to another depending on subsequent bacterio logic findings Ic is hopeful that with the dent of new anılmoucs more suntable preparations and combinations may be found although the problem of the development of resistant struins always must be kept in mund In general we hnie found penicillin aerosol disappointng in puents with so-called chronic infectious bronchial asthm although striking improiement may occasionally be observed Vost of our patients noted that they were able to raise sputum more easily while recen ing the penicillin aerosol The danger of local or generalized allergic reaction to penicillin aerosol in the asthmuc group must never be overlooked Vost of the local and Urticarne renctions which were observed when employ ing penicillin acrosol therapy 1171e been in patients with bronchial asthmı or broncbicct isis lle have also on occasion noted the onset of mild bronchial asthma in pi tients receiving penicillin aerosol therapy for the minage ment of chronic bronchitis emphyseini or bronchiectasis The attacks however subsided promptl wlien inhalations of epincplırıne were alsen after the penicillin aerosol lind Lxen discontinued ·122 The Management of the Patient 3 Technique and Dosage of Antibiotic Aerosol Therapy Hwing once determined that antibiotic aerosol therapy is indicated it is important to employ the techniques 118 best suited to the situation and to institute simultaneously supportive therapy that will restore and maintain physi ologic function Antibiotic aerosol therapy can be ad ministered to best advantage by the simple rebrething technique (Tig 15) wluch should be modified according to the pruent s age and the nuure of lus illness Helium and ovygen screus may be used in place of ovygen alone for those patients miniſesting obstructive disease of the respira tory tract This procedure is particulirly viurble in pr tients with segmental atelectatic lobes The nubiotic zerosols can be administered in tcnts loods misks or tracheotomy openings I or the treatment of parents anh scute or chronic purulent sinus disease the zerosol should be directed mostly with oi kathout the technique of inter mittent negitiie pressure We generally employ 25 000 to 100 000 units of crystal ime potassium pencıllın in 10 to 30 of salıne 7 three or four hour intertits depending upon the type and the degree of bronchopulmonary infection in the nursing (tre able If a streptomycin sensitne orgasm 1125 been isolated 0 10 grams of streptomycin may be employed alone or in combination with the penicillin This therapy sliould be maintained for at least two days after all signs of infection line subsided It the end of each treatment it least one but preferably three rinses of 0 25 cc each of physiologie saline are added to the nebulizer and inhaled Any non toxic agent which Ioners surface tension may be employed in place of the stline rinse eg several drops of 5 per cent alcohol or 005 per cent Duponol solution (T I Du Pont de Nemours Company) This prevents izstige of the drug from deposition in the nebulizer The time re ·With Sour Bronchual Asthma 133 quired for each treatment ringes from 10 to 20 minutes depending upon the type of apparatus used and the rate of oygen flou Usually, the rebreathing l'apocıllın apparitus requires flows of 6 or 7 liters of oxygen per minute The nen Taponeſrin motor bloner ur pump may be useel in place of the oxygen (Fig 15) The best results can be obtained only if the broncbul passagen lys are patent If there is evidence of bronchitis or if congestion of the bronchuil mucos? is present Neosynephrin (0 23 to l per cent) is a better diluent the salınc When bronchospasm is present we generally con plos n rosols of Vaponeſrın or Isuprel 1 200 preceding the ncosynephrin penıcıllı aerosols Generalls this therapy effects 7 freer ind more productie cough and insures greiter topical application of the peniullin lesulin, in Brugher and more prolonged blood levels in some stances it is disable to combine 1 miurc of 0 ms of the bronchiolitor drug ind 0 5 cc of I per cenu neos nephun as 7 solient for thic inubotic drug Supporınc therapy directed con rds the restration and muntenance of physiologu functon is full smpi in In the management of sino bronchul and bronchopulmomary disease associated 11th destruction pasm or suppur tron Such therapy consists of the folloning the mi!!! tenance of sino-bronchial tubil patent the 11 of 175xonstrictor drugs surgical roentgen rit rid or **** for the tradicinion of hypertrophezea lymphoud tissue of the 17so plionym ſeker te iscs the fie quency and severity of asthmatic attacks in childien aspiration and drama,c of smo-bronkhul puth 15 pre *cntion and relief of ntelectasis mini, ment of breate do spist with reputed broncholarsh Tehntion therapy control of systemie infection with sulfonamidlus or part feril pxmicillin supplemental use of streptomicin scrorulon therapy ·174 122 The Vanagement of the Patient 3 Technique and Dosage of Antibiotic Aerosol Therapy Having once determined that antibiotic aerosol therapy is indicated it is important to employ the technique35 1 best suited to the situation and to institute sinultancously supportive therapy that will restore and maintain physi ologic function Antibiotic nerosol therapy can be ad ministered to best advantage by the simple rebreathing technique (Fig 15) wlich should be modified according to the patient s age and the nature of his illness Helium and oxygen streams may be used in place of oxygen alone for triose patients minifesting obstructive disease of the respira cory tract Tlus procedure is particularly valuable in pa tients with segmentul atelectatic lobes The intibiotic nerosols can be aclmitustered in tents ligads masks or tracheotomy openings I or the treatment of patients with scute or chronic purulent sinus disease the aerosol should be directed nasılly with or without the technique of inter mittent negative pressure Tecnerally employ 25 000 to 100 000 units of crystal line potassium pencillin in 10 to 30 of saline at three or four bour intervals (lepending upon the type ind the degree of bronchopulmonary infection in the nursing care able It 7 streptomycin sensitive organism has been isolated 0 10 grams of streptomycin may be employed lone or in combination with the penicillin This therapy should be maintained for at least two days after all signs of infection have subsided It the end of each treatment at least one but preferably three rinses of 0 25 cc each of plıysiologic siline are idded to the nebulizer and inhaled Any non toxic agent which louers surface tension may be employed in place of the saline rinse eg several drops of 5 per cent alcohol or 005 per cent Duponol solution (E I Du Pont de Nemours Company) This presents 11 ?stage of the drug from deposition in the nebulizer The time re ·With Severe Bronchial dsthma 123 quired for each treatment ringes from 10 to 20 minutes depending upon the type of apparatus used and the rate of oygen flou Usually the rebreathing Vapocıllın apparatus requires flows of 6 or 7 liters of oxygen per minute The nen Vaponefrın motor blouer ur pump may be used in place of the owgen (Fig 15) The best results can be obtained only if the bronchual passagew ivs are prtent If there is evidence of bronchitis or if congestion of the bronchil mucosa is present neosynephrin (0 25 to / per cent) is a better diluent than saline When bronchospasm is present we generally em ploy aciosols of Vaponefrin or Isuprel 1 200 preceding the neosynephrin penıcıllın aerosols Generilly thus therapy effects 1 freer and more productire cough and insures frenter topical application of the penicillin nesulting in Ingler and more prolonged blood levels in some in stances it is advisable to combine 1 minture of 0 5 cc of the bronchodilator drug and 0 5 cc of I per cent neosyneplır in as a solvent for the antibiotic drug Supportive therapy directed towards the restoration and maintenance of physiology function is highly important in the management of sino bronchial and bronchopulmo nary disease associated with destruction spasm or suppura tion Such therapy consists of the following the main tenance of sino bronchial tubal patency by the use of 1 asoconstrictor drugs surgical roentgen ry ndum or radon therapy for the eradication of hypertroplued lymphoid tissue of the niso pharynx (decreases the fre quency and severity of asthmatic attacks in children) aspiration and drainage of sino bronchul path as prevention and relief of atelectists management of broncho pasin with repented bronchiolar $ 1" relivation therapy ontrol of systemic infection with sulfonimides or piren ral penicillin supplemental use of streptomycin aero ·The Management of the Patient sols" and finally direct intratracheal or intrabronchial instillations of antibiotics for the management of persis tent bronchopulmonary infection $3 84 The management of the patient with pulmonary em physema is an example of the importance of supportive physiologically directed therapy in conjunction with the employment of antibiotic nerosols 17+ Patients with chronic pulmonary emphysemi generally present ? lustory of coughi progressive dyspner even it rest loss of weight and neplness Clubbing of the fingers and cyanosis may be found in most of these patients and a small number have severe emphysem tous blebs The lung lins lost its elis ticity the ur sics lave become enlarged and the parti tions berheen them have been destroyed Bronchiectasis and evidence of bronchospisni inay also be found in miny of these patients They are subject to recurrent infections of the respirators tract and their pulmonary reserve diminishes with each episode The prognosis is generally poor and progressite respiratory fulure ensues The pa tients can be made more comtortable with the use of 50 per cent concentrations of oxygen theophylline ethylene dunitne and aerosolized bronchiodilator drugs Supple mental elevation of the dnphragms by manual minipula tion in evpiration and the use of 7 proper abdominal belt may be of conscierable value Oral administration of sulfonimides and penicillin 117s proved of little alue in our patients for the prevention of recurrent infection Furthermore these patients Tre generally not benefited by penicillin zerosol therapy alone Vany are dyspneic and sheezy ind hile shallon respirı tions Poor mixing of tical and resi air may prevent ? proper and even dısınıbution of ved distal bronchi and theoli Rec of seren kaprovement in to Isc ·lith Selere Bionchaal Astma 125 monary emphysema when penicillin aerosol was added to the treatment described above In one of these patients diffuse emphysematous blebs and a minimal basal bron clectasis complicated the picture In another patient a giant acquired cyst occupied the entire upper lobe of the riglit lung Tre patients had uncomplicated pulmonary emphysema secondıry to recurrent bronchial infections These patients were considerably improved after a course of penıcıllın aerosol therapy of from one to six weeks They had been treated with oxygen and bronchodilator drugs first but despite this more progressive dyspnea cyanosis and cough developed After administration of penıcıllın aerosol their vital capacities improved slightly and they have been able to maintun this improvement at home while continuing the previously outlined therapy These remissions huve been stuk ing though probably temporary Patients with severe pulmonary emphysema who have fuled to improve with a course of therapy employing the principles outlined should recere 1 course of penicillin aerosol therapy 4 Control of Para nasal Sinus Infection Para nasal sinus diseise may be responsible for re in fection and recurrence of cough ind wheezing in patients With bronchial asthma ligorous attempts at eradication of sinus disease should be made to prevent the irreparable sino-bronchitic syndrome winch often follows in its wale Barach and his socrates23. devised a simple venturi Talle type of appıratus (Fig 15) for the administration of penicillin nusally which alternates positive and negatne pressure with nebulization occurring during the positive phase Their patients hire shown remarkable improve ment in the condition of the sinuses after an intensive course of penicillin aerosol theripi I u thermore chronic ·126 The Ilanagement of the Patient bronchimic disease has apparently disappeared in some cises with rigorous treatment of the (concurrent) pari nasal sinusitis Tie174 hne administered nasal penicillin therapy with alternating negative pressure just prior to penicillin nerosol via the pulmonary route Many of our patients with chronic sinusitis have previously lind radicul sinus operi tions with subsequent reinfection The technique of inter mittent negiile pressure and replacement suth penicillin aerosol luas not been on the whole as helplul in thus group of patients is in those with imcomplicited nuite sinusitis l'enicillin treatment of the prrı nısal sinuses (by dis placement) througlı self induced intrunasal negative pres sure may be quite effective in certain patients Honever with the venturi technique for suction and replacement with penıcıllın aerosol considerably lugher doses of peni cillin inny be employed without danger of dimage to cih Try function It provides more uniform and diffuse murco sal application of the penicillin ind adequate penicillin blood levels in about one half of the cases Patients with clironic bronchial asthm and associated para nasıl sinus diserse derile considerable benefit from the supplementul use of antılustaminic drugs Hansel" bos estituired dirt about 90 per cent of the patients ulo con sult the otolaryngologist with the statement I 1171 sinus trouble line allergy I generlly advise (clepending upon the indivduls tolerance) 50 igm of Benadryl Pyre benrumine or Pyrrol 170te just before bed time and 25 mgm before brezh fast and gun during the afternoon Tleniliwe found Hydryllin (Tug 8) z synergistically acting combination of iminophyllın and diphenhydramine effec tlle in relieving para masal abstruction and mild broncho spasm The dosige ind choice of drug depends upon indi vidual tolerince and needs Post nasıl drip with second ry

·127
Hath Seere Bronchial Asthma
cough is made minim il, nasal potency is restored and more
restful sleep may follow
More recently welwe supplemented the abole therapy
with the use of nasal sprays containing equal amounts of
1 percent Pyrobenzamine and 1 percent neosynefrin This
has proven quite effective in preventing the troublesome
post nasal drip and cough nluch frequently precipitates
asthmatic attacks

·(hlicllın) chilone-clisulfonate cholesterol nitrohid chloric acid or potassium (lilonale roentgen theraps to th Votnithstanding the greit skull of the modern tloric surgical tem there ?ppers to be little general en un 7 for the operatic proceclures designed for the purpose Suencing thic ncuro CNIC control of the bronchioles 77 chemical secretions Winy stingcons 1ccommend them mouth of the sympathetic stellate ganglia and the secon turd md fourth thoracic anglı? if u preliminary lion block yields good results Others recommend te (on of the posterior pulmoniry plexus (bilateral) Th responsiicness of asthinatic subjects to mochols / 11.23 5 CHIPTERI MISCELLANEOUS PROCEDURES EMPLOYED IN THE MANAGEMENT OF BRONCHIAL ASTHMA 1 Procedures Generelly Ant Recommended or of Lumo Valuc Benefit has been described following a wide saries therapeutic procedures and in many instances specific hins been chimeed for these measures Very fine if a luncfit mn le altrimesi fram the following orli mine or listanınasc prrenteral histamine or hastano combined with protein (hustamine nzo protein) autol ema therapy mechions of calcium potassium sodiun m DOSTUM copper or model injections of loser or 117.3m estruts mjections of a rinn c\tracts pituin le terone popionc milk or scuom the use of immi lima spleen pincreas or lestus zal stringent dietotherapy 7s ketogenic diets 128 h ca of in ·lith Severe Bronchial Asthma 129 as a possible guide for the pre operative evaluation of this procedure Recently, there has been an increased interest in the simpler procedures designed to block vagal influ ences, such as noi ocaine injection to the vagal fibres in the mastoid region 100 Occasionally troublesome coughing paroxyms have been stopped in this manner However the incidence of recurrence of bronchial asthma even in carefully selected cases is too lugh to warrant the more extensile surgical procedures 2 Procedures That May Be of Value a Psychotherapy-The inter relationships of psychiatric phenomena with allergic reactions continue to stimulate considerable interest and discussion Emotional difficulties occur in miny patients with bronchial asthma just as they do in patients with other medical illnesses Specific emotional factors and non specific factors, such as fatigue or infection can precipitate modify or inhibit attacks of bronchual asthma These factors appear largely as precipi taling or ameliorating influences which disturb the del cate allergic threshold Curiously enough the patient with asthma shorts remarkable 1ariations in lus reactions to these influences as well as to his allergens It times he can expose himself with relative impunity to a variety of sensı tizing factors (foods dunders and pollens) as well as to almospheric changes and emotional disturbances without untoward results His psychobiologk adjustment may be maintained until a combination of factors disturb it An example of this may be observed in children with food sen sitnities who develop asthma in their homes on exposure to certain foods, but are able to eat these sime foods without ill effect when at camp nursing homes or visiting telares where they are temporarily away from a tense atmosphere This would suggest an interrelationship be ·130 The Vanagement of te Patient tween the allergic state and emotional influences the exact nature of which is difficult to delineate Another school of thought would establish a definite asthmatic (constitional) personality or profile (more than normally intelligent over anxious insecure or lacking self confidence) as 1 result of the conversion of various psy chological conflicts into somatic symptoms This is es pecially true in children who appear to suffer from a deep sented insecurity and a more or less intense need for parental lose and protection - Tension seems to be the connecting link between these conflicts and the asthm? 11 hen pent up thwarted or frustrated these patients easily develop astmatic attacks when free and relayed they can better tolerate specific and non specific stimul. The atrick of asthma itself further creates 1 vicious cycle resulting in loss of confidence interference nuith self expression greater frustration and more tension The psychomnalytic school has helped to clarify the relationship of emotional disturbances to changes in body function Followers of this school of therapy generally regard the asthmauc paroxysm is lasing a symbolic mean ing Trench and Alexanderso 61 have propounded the thesis that the asclimatic attack is the equivalent of a suppressed cry The asthmatic patient they feel as one who lias been frustrated in his affections in early life and has been for bidden to cry crying being the infants natuni call for sympathy These authors state that asthmatic attacks tend to be precipitated by situations that threaten 10 seputate the pitsent from its mother or some mother higure The separation feared may be an active physical sepertion but more frequently it is deeply repressed fear of es trangement from the purental figure due to some though or temptation (sesual) to which the patient is exposed It is this temptation rather than the granıf cation which ·Il sl Severe Bronchial Isthma usually precipicates the asthmatic attack Michaels,123 in a protocatne paper suggested that just as there is regression in psychologic reactions there may be regression in somnatic visceral functions He also pre sented the conception that the somatic components of the psychosomatic symptoms in the adult may resemble the physiological states of infancy esther is an exaggeration or an accentuation In a discussion with the author he further proposed the hypothesis that in addition to the psychological meaning of the asthmatic attack the asth matic paroxysms from a biological point of view may rep resent a regression in the play stological reactions of the re spiratory system In his above mentioned paper he called mention to the increased tendency toward spast in in fancy as manifested in laryngeal spasm stridor sneezing and wheezing An emonoul disturbince can rely be proven the re sponsible pruinary etrologic agent in the pathogenesis of bronchul asthm However the emotional disturbance renders the patient more sensitive to the arious factors which produce the attack and vice versa It is desirable that the attending plıysician cry to understand luis patient and carefully study the various components in lus life Rapport should develop between the patient and his physi crun and the former s conflicts should be explored This process of mental catharsis may preclude the need for bronchial catharsis at a later date In the case of children the problein requires even more attenuon The asthmatic prroxysm is a frighterung experi ence for the chuld and the parent The chuld with asthma 1776 often Ine in an envronment of over protection and apprehension Fastidiotis detul is placed on all of the childs iegeraune functions He us forbidden to participate in normal play and social actn itses i imiting the child s active ·132 The Management of the Patient ties actually may result in his otin withdrawal from reality He is treated as if he were an infint with respect to food clothes and bodily functions indeed to the point of being wrapped in cotton wool The child soon wants to be protected and the parent out of a sense of guilt or for other reasons over protects him and a sicious cycle is thus established Therapy in such cases is difficult because of the dis turbed parent child relationship The parents particularly the mother need most of the immediate help The child can also benefit from psychotherapy The term bronchial asthma should not connote fear however its seriousness should never be discussed in range of the child s hearing Likewise the comparative well being of other chuldren should not be discussed in his presence This occurs too frequently during the first interview and one can sense the childs resentment He may conclude erroneously that I must be different serk ind inferior Frequently the great emotional and financial strun the parents have been under is discussed in the child s presence Proper guidance should help direct the child to become more independent so that he can learn to stand on lus onn feet Situations capable of producing the extremes of suppressed rage and explosive behavior should be uverted Whenever possible attendance at school homes and camps muay from liome should be encouraged for the incidence of attacks is re markably low in such friendly surroundings In due time proper explanations of the relationship of lus ensiron ment and emotions to his disease can be made The chuld may then learn how to control the attacks he is unable to entirely prevent through understanding the precipi trting factors (physical and emotional) above al} he may learn how to be happy in spite of having been born with an allergic diathesis ·II ith Seere Bronchial Asthma Unfortunately the physician as well as the family may unwitungly traumitize the patient by stressing the or ganıc aspects of his bronchial asthm1 The child soon feels that there is something physically wrong with his lungs This situation is analogous to the announcement by the physician of the presence of a functional heart murmur The ritrogenic influence of the physician soon becomes felt and the asthmatic patient may then be said to hue atrogenic lung disease The fear of such a pronounce ment is frequently expressed by the adult patient who upon being told that he has bronctual asthmi queries Well doesnt that affect just my tubes but not my Jungs Probably all patients with bronchial asthma hate emocional components The relative proportion of allergy and emotional conflicts in the patient with bronchni asthma is difficult to determine When the conflicts seem less the parent can be treated by fuis physician where they are preponderant pschuratric evaluation should be advised Certun knowledge may aid the physician in determining the type of psychiatric care that may be necessary The age of onset is important as with other psychosomatic conditions The younger the person the greater the likelihood of con flicts becoming more deeply embedded in the character structure The patient may make use of fus illness to gain or avoid certain things (secondary gun in illness) The very actie person will fight invalıdısm and inactivity The physician should first try to determme in what sphere of activity (family spouse chuldren work society school etc) the patients asthmi interferes most He then should try to bring about a fair adjustment to present reality The physicion must disanguish symptomatic supportile and limited goal psychotherapy from psychoanalysis which consists of intensive therapy aimed to sole brasic conflicts ·134 The llanagement of tle Patient and lead to personality changes Properly directed allergic and physiologic therapy by lowering the incidence of asthmatic paroxysms may protect the indrudual from the reflex effects of neuro psychuttric factors which persist Finally it is much better for the attending physiciin to ac in as human and kindly manner as possible and not attenipe to deal psychologically with the emotional con fusion of the patient unless he has been especially truned to do so There Ins been considerable interest in the use of shock therapy (insulin hypoglycemia and electro shock) for the management of the asthmatic patient I have had no per sonal experience with the first method Three of my patients however hne been treated with electro shock therapy These patients were in the fifth to santh decides of life had seiere disabling chronic bronchial astma and presented definite evidence of depression invety excitement or insolutional changes The results were striking A remission which lasted for several months with subsequent development of a milder type of asthma 178 observed in duo of the patients Treatment of the third patient resulted in a remarkable remission which has continued for five yerrs This patient had chronic disabling bronchial asthma for more than 30 yeurs with out endence of any definite extrinsic allergens Physical und psychuc factors usually ushered in her attacks She required three courses of electro shock therapy (five three and two convulsions respectively) over a period of eight weeks Her personality changed from that of a noman who has at umes difficult doubtful despondent excited aggressile depressed and constantly concerned about her sheezing breaching and heeung to a calm roman reassured and an ious to rid liersell of an accumulation of syringes equipment and medications of a life time of ·11 th Ser ere Bronchal Asthma 135 chronic invalıdısm Shock therapy in these patients helped to restore the psychobiologic equilbrium which then per mitted the patient to better manage the underlying aller gic state This type of therapy should not be recommended for the patients asthma but rather for the personality disorder b Climatotherapy-Climatic changes are as able to only relatively fen asthmatic sufferers and the physician should hesitate to urge such a program without carefully considering the many factors involved 157 Spa therapy and climatic changes occasionally afford help which may be attributed to a psychotherapeutic basis rather than to aller gic cleanliness Separation from the mother figure mate business associate or other disturbing emotional influ ences when tempered by an enjoyable climate and refuge frequently brings relief from asthmatic pirosysms There is no general agreement as to what produces the improve ment when a patient changes climate The progress of the disease may be influenced by many physical factors such is range of temperature and barometric pressure changes humidity wind surmbility proximity to the seashore sunshine altitude and other factors Actual trial residence for at least one year may be the only certun instver Honeser a few rules should be fol loned The patient with emphysema or co existing heart disease should not be sent to altitudes above 4 000 feet Those with troublesome bronchitis and considerable sputum my prefer the dry warm ind generally calm climate of Southern Californu or Southern Arizona (Tucson or Phoenix) Those who are allergic to molds will probably he fewer symptoms in the dry climites The dry climate on the other land may be responsible for retention of mucus or obstructive phenomena Those with scant and viscid sputum muy fire better in the warm ·136 The Alanagement of the Patient moist climate of Georgia Florıdı or along the Gulf Coast These climates and regions are believed to favorably in fluence infectious respiratory processes Damp humid weather and especially fog are generally not nell tolerated by most asthmatics Sudden temperature and barometic changes and electrical storms are likely to be follored by atmospheric changes uluch may precipitate attacks At mospheres containing soot fumes and other chemical or mechanical irritants may also be precipitating factors ind these should be avoided in making any changes If pollen allergy is of major importance Southern Cali fornia (Los Angeles Pasidenı or San Diego) should be satisfactory California and all parts west of the Rockies are $id to be practically free from ragweed and there is Tule rigreed pollen in parts of Florida Sufferers from griss pollen are less fortunate and probably will have symptoms in almost any part of the United States Those sepsire to tree pollens need only avoid the specific tree or crees responsible The foliage of the Southwest is quite different from that of the Fast and the pollen season lasts considerably longer (nine to 10 months) 137 Those sensitae to Bermuda grass and dust may fire poorly in certain sections of the Southwest Temporary relief from the arts tation of pollen responsible for asthm can be found at seashore resorts on the rest Coast and mountun tesorts in New England particularly the are7 suitsounding Beth lehem (New Hampshire) the Adirondacks Presque Isle (Name) Isle Royale (Michigan) and Reno (Net ada) All of these phaces live low pollen indices" (maximum pollen concentration in the air) It is well to remember loneser that a resort area shich would make a good huen because of its own low index may have higher indices because prevailing winds sheep in the pollen from the last tag reed crop that thrises in the Midwestern States Further more a drop or sudden changes in birometric presskite ·stances remission usually followed one or methys less severe and spaced at longer intervals the the patients more amenable to therapy Theme such as actie participation of the cells in t - Tr there are numerous contri indications to il - Sr lithe Severe Bronchial Asthma during the period when the pollen concentraten in air is lou may precipitate bronchial asthma in un asthmatic sufferers An effective and enjoyable way to e cipe pollen is to take a cruise Caribbean and South Afring can cruises are frored by many Above all the plıysician should make certam that he us nor sending hus prtient to a new climate contamin, allergens (pollens then in season) to uluch the patient 11 esther already sensitive or to which lie may become un tise Unfortunately the allergic subject has the inherent capacity for becoming increasingly sensitate to an -- widening list of agents c Therapeutic (Controlled) Hyperpyrexia-The usuf hyperpyrexia is based upon the fact that prolonged some sions in bronchial asthma may frequently follon fate illnesses Hyperthermia inay be induced directly laro ploying miravenous typhoid vaccine or indirects in heat cabinet lle have on occasion method in seriously ill patients in statius asthmats tur were appirently non response to therapy In En therapy while the recurring asthmatic Ch1557 km employed due to your this non specific improvement is not clear les chemical response or environmental (chemical the autonomic nervous centers may play a tolzesponse be treated with hyperpyrexrz should be carefu.. which are adı inced cardio renal vascular pulmonary tuberculosis or pronounced deb more administrasxon of intravenous typhost on rare occasions be accompanied by sesa states ·138 The llanagement of the Patient I have employed a technique tu hicli is a modification of Solomon and Somlins method " for obrammg sustained controlled lyperthermia with intravenous triple typhoid vaccine The details of the procedure and the usual reac tions therefrom should be explained to the prtient Sodan phenobarbital 0 2 gm sc may be administered one hour before stariing the intravenous infusion If there is no history or suspicion of aspirin sensınty 0 65 gm of aspirin may be gren forty five minutes later this tends to munimize the subjecante grippelthe complaints and chills that may follow The rectal temperature pulse und blood pressure should be recorded at fifteen minute intervals Two infusion bottles (clearly labeled I and II) contain ing respectively I liter of 5 per cent glucose in Isotonic sodiun chloride and 1 liter of 5 per cent glucose in dis tilled water tuth 01 cc of triple typhoid vaccine (approxi macely 1000 million typhoid bacalli per i cc) added are suspended from a clysis stand The respective rubber tub ings are connected by a Y tube to the intravenous needle Separate clımps on the rubber tubing should be used to regulate accurately the flow from the Murphy drip attachments to each flask To insure proper hydration the patient first recenes 500 cc from the glucose salıne flash (I) at the rate of 90 drops per minute When completed the tube from this Mrs. is clamped off and the flow from the typhoid infusion Stash (IT) is permitted to run it a rate of 40 to 60 drops per minute This is continued until a temperature plateru vetreen 1029 to 101° F is rerched This temperature is maintained for three to five hours by adjusting the Ross from the respective flasks This can be controlled very simply with a little experience If this temperature range cinnot be reached the typhoid dose may be altered by ·11ith Sei ere Bronchal Asthma 139 increments of 0 1 cc Many parents require as much as 03 cc of typhoid saccine per liter of solution to obrain this goil Generally tho to four courses of therapy are sufficient to obtain 1 remission The course may be repeated at no to three day inter als Nasal catheter oygen may be ad ininistered simultaneously to pacients demonstrating the effects of seiere chronic fitique or lisporta d Breaching Exercises-- The purpose of these exercises is to re establish the upuard movement of the drphragm and the buchet handle movement of the lower ribs they should also establish the habit of proper benthing and ultnnately should render the rigid thorns more elastic To become thoronghly adept ze these exercises the patient should be under the guidance of a physical therapist Supplemental passke massage rhythmic compressions of the thorax and regulated gymnastics should be carried out The tolerance for these procedures must be pre deter mined and the exercises increised as the patients resp! fatory pattern improves This type of therapy should be continuer for a period of months or even years This pro gram can be of great value both to the young asthmatic and to patients with established emphysema however the results will vary The routine described belos may be a Saluable measure in preventing the deselopment of ob structie eraphysema I detailed analysis of vious senes of exercises may be found in Delano g" or Gay ses book Unfortunately the need for proper supervision permits but a les patients to follow such a series to completion The simpler pro cedure of attempting to elevate the shaphram manually and at the same time pushing the lower rilas outward may gre temporary relief by allevating the over-distention of the lung The patient should be instructed to place the palmar surface of both hands just below the rhs and ·140 The Management of the Patient during the end of expiration to apply firm and increasing pressure upward to elevate the diaphragin and move the Toner ribs outwards The patient may also purse his lips during the expiratory phase to produce a gentle bach pressure in the tracheobronchial tree 20 This simple form of positue pressure therapy may further relieve the under lying bronchospasm These exercises should be done in the morning med afternoon and at night Generally six to 12 such cxercises spread over i period of several minutes are sufficient they should never be done to the point of fatigue On occasion temporary relief from the dyspner due to obstructive emphysema may take place when the evercises are performed at the bedside by the physician while the patient is in the sitting position Periodic forceful sniffing may also produce some down ward motion of the diaphragm The patient should be encouraged to apply a proper fitting abdominal belt (emphysemı belt) following these exercises this helps to keep the diaphragm elevated Another modification con sists of performing the breathing exercises with the em physema belt in place and tightenmg it during expiration Improvement in the sital capacity and decrease in the expiratory time may be observed after each complete series of exercises These exercises may act by increasing expiratory force and thus reducing lung volume This ef fect can be potentiated by preceding the exercises with three liand bulb inhalations of nebulized bronchodilator aero sols The improvement in vital caprcity albeit brief may be prolonged by the administration of minophyllın 03 to 0 75 gin administered rectally one half hour prior to the inhalation exercises In less severe cases aminophyllin preferably combined with ephedrine sulphate and plieno barbital may be given orally The improvement is most marked in the patients with emphysema ·REFERENCES 1 Abramson A Improved Inhalation Therapy of Asthma Arch Phys Therap) 21 612 1910 Abramson H A Combined Penicillin and Hydrogen Peroxide Terosol Therapy in Lung Infections Preliminary Report Ann Allergy, 199 1916 3 Abramson H A and Demeret M Vethod for Experimental Control of Particle Size of Iherapeutic Aerosols ) Allergy 16 181 1915 4 Abramson HA Principles and Practice of Aerosol Therapy of Lungs and Bronchi Ann Allergy + 440 1916 5 Alexander HL Johnson M C and Bulantz S C Studies on Correlation Between Symptoms of Ragweed Hay Fever and Tuter of Thermostable Antibody ſ Allergy 191 1918 6 Alison J F Carbon Dioxide in Treatment of Acute Bronchitis and Early Pneumonia South Af I 25 386 1932 7 Applebaum IL Cerebrovascular Accidents Following Epineph rine Injections Report of two cases / Allergy 15 392 1914 8 Baldwin E Bronchial Asthma Combined Staff Clinics of the College of Physicians and Surgeons Columbia University im J Med 1 193 1946 9 Dunyat A L Carbon Dioxide Inhalation in Pulmonary Tuber culosis Am Red Tuberc 30 612 1931 10 Banyai A L Fifteen Years Experience with Carbon Doxide in Vanagement of Cough Dis of Chest 131 1917 11 Banyat L and Cadden A V Carbon Dioxide by Inhalation in Management of Cough With Observations on its Effects upon Respiration in Pulmonary Tuberculosis Br J Tuberc 38 111 1914 12 Barach AL The Use of Hel um as Men Therapeutic Gas Proc Soc Exfer Biol ( ved 32 462 1934 13 Rarach A L Use of Helium as des Therapeutic Gas Anesth @anals 14 210 1935 14 Barach 4L Use of Helium in Treatment of Asthma and Ob structie Lesions in Larynx and Trachei Ann Int Med 9 739 1933 15 Barach A L Effects of Inhalation of Heluun lixed with Oxy gen on Mechanics of Resp ration J Clin Investigation 15 47 1936 16 Burach 4 L Physiological Methods in Diagnosis and Treat ment of Asthma and Emphysema inn Int ved 19 454 1938 141 ·The Jianagement of the Patient 17 Barach AL Obstructie Lesions in the Trachea and Bronchi In Vodern Medical Theram in General Practice lol 3 5661 PP Baltimore Tilliams and Wilkins Company 1940 Pp 2472 2476 18 Barach AL Repeated Bronchial Relaxation in Treatment of Intractable Asthimi ) Nllergy 14 296 1913 19 Barach A 1. Physiologically Directed Therapy in Treatment of Intractable Bronchial Asthma Bull Tework frod Ved 90 538 1911 20 Barich IL Physiologic Therapy in Respiraton Diseases Second Edition Philadelphia J B Lippincott & Co 1948 21 Burach IL Rectal Installation of Amnophyllıne in Intrac table Isthmi Idd 728 589 1915 22 Burach IL Irejtment of Intractable Asthma ) Allergy 17 352 1946 23 Barach AL Gurthwaite B ind Rule C Use of Penicillin Aerosol in Bronc opulmonary and Smus Infect ons eu York State / Aled 16 1709 1916 24 Birch 1 L Garthwaite B Rule C Tallot TR Jr hernin D Babcock I and Brown G Penicillin Aerosol and Negative Pressure in Treatment of Sinusitis du J Vel 1 268 1916 25 Darach IL Martin J and Eckman M Positive I'ressure Respiration and its Application to the Treatment of Acute Pulmoniry Tdema and Respiratory Obstruction / Clu Investigation 16 664 1937 26 Barach Å L Martin J and Eckman V Positive I ressure Respiration and its Application to Treatment of Icute Pulmonary Edema Ann Int Ver 12 751 1998 27 Barach A L and Molomut An Oxygen Mask Vetered for Positive Pressure Ann Int lied 17 820 1919 28 Baruch IL Silberstein F II Oppenheuner CT Hunter T and Soroka M Inhalation of Penicilien ierowl in Pa tients with Bronchil Asthma Chronic Bronchitis Bronchi cctists and Lung Abscess Preliminary Report Ann Inl Wed 77 185 1915 29 Barach A L and Stenson P C Effect of Breathing Gases Under Positise Pressure on Lumens of Small and Vedium .I670.jr 1099 303 cular D case 4.11 137 584 1918 31 Basch F Holinger P H and Poncher H G Physical and Chemical Properties of Sputum Influence of Drugs Sie3 ·Tatk Severe Bronchial Asthma 113 Carbon Dioxide and Oxygen im Dis Child 62 1149 1911 52. Basch Fr Holinger P II and Poncher All Physical and Chemical Properties of Sputum Factory Deterinining Varia uops in Portions from Different Parts of Tracheobroncha) Trec Air / His Child 62 981 1911 33 Beake; Bresnick E Les inson Lind Segal MS Laluation of Therapeutic Substances Employed for the Relief of Bronchospasm. 3 Inticholinergic igents Ann Allergy 7 113 1949 34 Beakey J I Gaensler E and Segal VS The Pharmaco dynamics of Pulmonary osorprion in Yin ? Influence of Vamous Diluents on Aerosol and Intratracheal Penicillin inn Inl led 31 80) 1919 35 Beake) JF Gaensler E and Segal VS | Compratic Study of Various Apparatus and Techniques for Scrosol Ad ministration Connecteut V 13 855 191) 36 Beecher Hh Facal Toxic Reactions Associated with Tribro meshinol inesthesia JAWA 111 123 1999 $7 Ploomfiel! R4 Lauson HD Courpard | Breed ES Richards D11 r Recording of Right Heart Pressures in Normal Subjects and in Patients sith Chronic Pulovonary Descase u larious Types of Carch pulmonary Disease ) Clin Im estiganron 25 619 1916 38 Boothby WV1 Vaya G and Lovelace HR Oxygen and Oxygen and Helium Therapy Recent Idsances ! Cl» lorth America 23 977 1939 39 Boothby 1 N Vaso CW and Lorclace !! R One Hundred! Pcr cun Oxygen indications for fts Use and Hethods of Its Idmorition AMI! U3 477 1939 40 Boothbv 1 1 Vallo ( 1 and Lovelace Rjr Use of Oxygen ved Oxygen Helum wul Special Reference to Surgery Slim lurth imenica 20 1101 1910 # Bresnick E Bealey Jr Levinson and Segal VS Exalustion of Therapeutic Substances Employed for the Relief of Bronchospasm Whenergic Agents } Clin In neutigatron 240189 1919 12 Bresnick Ti oodard hand Sagemın CB Fita Re actions to Intravenous Idministration of minophytline JAVA 136 397 1918 43 Brown E 1 The Use of Intravenous Fuint llcohol in the Treatment of Status Isthmaticus Ann Allerg) 5193 1917 41 Bronn F I and Gillespie J Round Table Discussion ·141 The Management of the Patient Fall Graduate Instructional Course American College Al lergists Cincinnati Ohio (Nov ) 1917 45 Bryson V, Sansome E and Laskin E Ierosolization of Peni cillin Solutions Science 100 35 1911 46 Burrage W S Recent Therapeutic Trends in Illergy New England | Afed, 238 181 1918 17 Burstein CL The Hazard of Parldehyde dminstration JAJA, 121 187 1943 48 Campbell J M H and Poulton Ep Origen and Carbon Dioxide Therapy 195 PP New York and London Oxford Unisersity Press 193 1 49 Charler R L Utilisation des Aérosols d Ajeudrine pour le Traitement Prolongé de 1 Asthme Importance de la Rigueur dans ! Application de cette Thérapeutique Rev belge se med 17 108 1916 50 Clert 1 Bronchoscopy in Bronchopulmonary Disease Modern Vedicine 13 53 60 1915 51 Clough GM Use of Helium I J dustralia 2 400 1989 52 Cohen MB Bronchun! Asthma Classification Bascul on Etiological and Pathological Factors Ann Int Aled, 20 590 1914 5% Colton 1 1 ind Zaskin T Heart in Bronchil Asthma Allergy 8 347 1917 54 Cooke R A Allergy in Theory and Practice Chap 3 Phila delpur 11 B Saunders IIV 1947 572 55 Coole R1 The Immunology of Ullergic Disease am / Ved 3 529 1917 56 Cournind A Recent Observations on Dynamics of Pulmo nary Circulation Bull New York Acad led 23 27 19:17 57 Cournand A Richards DT Jr and Durling R C Graphic Tracings of Respiration in Study of I ulmonary Disease Am Rer Tuberc 40 487 1939 58 Cournand I Riley R L Breed E S Bildwin I deF and Richards D W Ir Measurement of Cardiac Output in Van Using Technique of Catheterization of Right Auride or Ventricle | Clin Investigation 24 106 1915 59 Craige B Jr Fatal Bronchial Asthma Report of 7 Cases Irch Int Wed 67 999 1941 60 Crone s ] Irradiation of Nasopharynx Al herry Vemorial Lecture) Trim Acad Ophth 51.99 1946 61 Crone sind 11 alz! Ev Irradiation of Hyperplastic Iymphoid Tissue in Masopharynx JAVA, 131 131 1947 62 Curry J) Iction of Histamine on Respiratory Tract in ·With Severe Bronchial Asthma 145 Normal and Asthmatic Subjects J Clin Investigation 25 785 1946 63 Curry J ) Effect of Antihistamine Substances and Other Drugs on Histamine Bronchoconstriction in Isthmic Subjects Clin Investigation 25 792 1916 64 Curry I Comparatie Iction of Icetyl Beta \lethylcholine and Histamine on the Respiratory Tract in Normals Pa tients with Hay Fever and Subjects with Bronchol Isthma J Clin Investigation 26 430 1917 65 Curry and Lonell FC Measurement of Latal Capacity in Istimatic Subjects Recening Histamine and Acetyl Betr Methylcholine Clinical Study 1 illergy 19 9 1948 66 Dale II Hand Gaddum J H Reactions of Denerated Voluntary Muscle and Their Betting on Vode of Action of Parasympathetic and Related Nerses | Plysiol 70 109 1980 67 Dautrebande L Philippot E Charler RDumoulin E and Morgaréde F Erixle des krosols Medicamenteux chez I homme Influence sur le degre d cfficacitl de la respiration pulmonaire de médicaments dits bronchodulateurs et bron choconstructeurs en inhalation Presse med 19 1081 1911 68 Dautrebunde L Philippor E Charlier Rind Dumoulin C Aérosols Médicamenteux Essais de Iraitement des Etats Asthmanformes pu lerosols de Substances Pneum dilatrices et d lutovaccins Presse med 50 566 1912 69 Dautrebande I Philippot and Charlier R Vérosols Védicamenteux Nouvelle Demonstrition de leur Iction Générale flude experimentale des acrosals de Carbaminocholine et il Atropine Presse med 50 *98 1942 70 Dutreisande L Therapeutic derosols Teri mque Physiology and Therapeutic Application Paris Maison ct Cie 1916 71 Delino S Health and Rehabilitation Through Chest Training Men Jork The Talam Frederick Press 1947 72 Dublin L I Statistics of Bronchial Isthma Chapter lll in the Treatment of Bronchialisthma Derbes I J and Engel hardt II T Philadelphia Lippincott 1916 73 Dublin B 1 aldes jud 11ams VVD Voice Changes with Mixture of Helm and Oxygen Proc Staf Meet Vaso Chin 15 586 1910 74 Durham Oren C Our National Parks as Raguced llay Feser Refuges IV 138 126 1918 75 Eckman vi and Barach IL Inhalational Therapy Equip ment lled Hosp 52 78 1939 76 Frans | The Rationale of Oxygen Dosage Anesth and Inala 21 35 1912 ·146 The Vanagement of the Patient 77 Eyermann CH Diagnosis and Treatment of Bronchial Asthms Dis of Chest 6 234 1940 78 Farrerons CoE) Histamine Sympathin Balance Ann Al lergy 746 1919 79 Findeisen 1 Uber das ihsetzen kleiner in der Luft suas pendierter Teilchen in der menschlichen Lunge bei der Atmung Pflugers Archid gest Physiol 336 367 1936 80 French IMPxychogenic Factors in Asthma Am Psychiat 96 87 1939 81 French TV and Alexander F Psychogenic Factors in Bronchial Asthma Part 1 Psychosomatic Medicine Mono graphs Vol 1 Part II Psychosomatic Medicine Vonographs vol ll 1 2 82 Tuclis A Interruption of Isthmatic Crisis by Tribromethanol (Averton) | Allergy 8 310 1937 83 Gaensler E., Beakey J F and Segal S The Pharmaco dynamics of Pulmonary Ibsorption in Van 1 Aerosol and Intratracheal Perucutlin Ann In Vled 31 582 19:19 81 Gaensler [ Beakey J F and Segal M S The Relaire Effectiveness of Parenteral Intratraci eal and Aerosol Pent cillin in Chronic Suppuratne Disease of the Lung 1 Tlor acic Surg 18 546 1949 85 Gay LN Dragnosis and Treatment of Bronchial Asthma Baltimore Will ams and Tilkins Co 1916 86 Godlowskı Z Insulin Shock Treatment of Bronchial Isthma Brit Mied / 1 717 1916 87 Goldsmith Now Helium Saves Lives Mixture of Helium with Oxygen Is Beginning to be Used by Physicians to Tide Respiratory Cripple Cases Such as Chronic Asthmatics Over Their Crises Scient Ain 160 153 1939 88 Goodall R J and Unger L. Continuous Intravenous Iminn phvilen Therapy in Status Asthmaticus dna Allergy 5 196 1947 89 Grieser B Inhalation Therapy of Bronchial Asthma JAMA 112 1223 1999 90 Graeser J B and Rone A HInhalation of Epinephrine for Relief of Asthmatic Symptoms Allergy 6 413 1935 91 Graham ) DP and Gurd M R Comparison of Epedrine and Eserine / Pharmacol & Exper Therap 72 48 1911 92 Greene A Paul ty D and reller AE The Action of Theophylline with Ethylenediamine on Intrathecal and Tenous Pressures in Cardiac Failure and on Bronchial Obstruc tron in Cardiac Failure ind in Bronchial Asthma JAJA 109 1712 1937 ·Ilith Severe Bionchual Asthma 93 Gregory J E and Rich IR Experimental Production of Inaphylactic Pulmonary Lesions with Basic Characteristics of Rheumatic Pneum jaits Bull Johns Hopkins Hosp *8! 1946 93 Gunn ) 1 Iction of Expectorants Br! 2 972 1927 93 Gunn) Pharmacological Actions and Therapeutic Uses of Some Compounds Related to Adrenaline (Olner Sharpes lecture) Brit 11 2 157 1939 96 Hambourger 1 E freese HB Winbury Vand Michiels P1 Protective Action of Combinations of Diphenhydramine and Aminophyllen in Fatal Bronchospasm in Gwnea Pigs Due to Vecholyi Aerosol / Pharmacol and Exper Therap 91 367 1948 97 Hansel Fa Otolaryngologic Phases of Allergy Panel Dis CUISSION of the American College of Wergists, March 14 1958 at Mcw York 38 Harlasy ) ftscular Ilergy in the Pathogenesis of Bronchial Isthm with Recurrent Pulmonary Infiltrations and Eosin paulic PolyserOSITIS Allergy 11 622 1910 99 Harkavy ) Vascular Wergy Pathogenesis of Bronchtal Isthma with Recurrent Pulmonary Infiltrations and Eosinophdıc Polyserosits Arch Ini Hed 67 709 1941 100 Harken D Personal Communication 103 Herbut P A and Clerk L H Cytology 1 Bronchial Secre tions Dragnostic Ird in Diagnosis of Pulmonary Tubercu losis Am Rey Tuberc 54 488 1916 102 Hill LW Food Sensitivity in 100 Isthmalic Children lew Englanl / Ved 238 657 1918 103 Kabal ( A Immunochemistry of Proteins I Immunol ** 513 1949 104 Aabatti Quantitaire Immunochemical spects of Some Werg c Reactions Medicine 3 532 1917 103 hernan Dand Burach IL Role of Helum in Cuses of Obstructive Lestons In Trachea and i atins Arch Oto loring 26 419 1937 106 LaDue S in Derbes V and Engelhardt H T Treatment of Branchmal isthma i inladelphiaj B Lippincott Co Y 166 1916 107 Tamson R and Butt EV Fatal Esthm Clinical and Pathologic Consideration of 187 Cases JAYA 105 1819 1937 108 Lapis IV Mash 1 L Dertinger BL Granger !! R and IcCarthy The Pharmacology of Compounds ·148 The Management of the Patient Structurally Related to Hydroxytyramıne J Pharmacol Exper Therap, 92 369 1918 109 Lell 11 d Treatment of AI 43 19 1916 110 Levine, 'ronchial In fectio 111 Levinson L, Bealey, J F, Bresnick, E and Segal, N S Eval uation of Therapeutic Substances Employed for the Relief of Bronchospasm 2 Historical Development and Vethods Ann Allergy, 6 705, 1918 112 Loveless, M H Immunological Studies of Pollenosts relation ship between thermostable antibody in circulation and clini cal immunity | Immunol, 47 165, 1913 118 Lowell FC The Treatment of Bronchial Asthma Address Delivered before the Mass Mcd Soc June 1918 114 Nachlin CC Musculature of Bronclu and Lungs Physiol Rev, 9 I 1929 115 Marsh Dr. Pelletier, M H and Ross CA The Compara tive Pharmacology of the N alkyl Artcrenols I Pharmacol « Exper Therap, 92 108, 1918 116 Maytum CK Prickman, LE, and Boothby, WM The Use of Helium and Oxygen in the Treatment of Severe In tractable Asthma Proc Slal Aleet, Mayo Clin, 10 788 1935 117 Melichael J Circulatory Failure Stuced by Means of Venous Catheterization Advances in Internal Medicine, 361 Mes York Interscience l'ublishers, Inc, 1917 118 Alcalichael J Heart Failure of Pulmonary Origin Edinburgh AC 1, 55 65 1918 119 Velichael J and Sharpey Schrfer, EP The action of Intravenous Digoxın in Man Quart , led, 13 123, 1941 120 Merrill G Iminophylline Deaths JAU, 123 1115 1913 (Correction Ibid, 124 250 1911) 121 Metz CW Turner, AA and Evans A E Therapeutic Use of Hellung, South M L 32 35 1939 122 Meyer NE and Schotz, S Relief of Sercre Intractable Bronchial Asthma with Cyclopropane Anesthesia Report of Case ) Allerg), 10 239, 1939 123 Michaels J J A Psychiatric Adventure in Compartise Patho physiology of the infant and Adult Tith Some Theoretical Suggestions in Regard to Regression in Somatic Visceral Functions 1 Aeru Alent Du, 100 49 1914 124 Moll, HI H Action of Parasympathetic mimetic Drugs in Asthma Quart J Med, 9 229, 1910 ·If ith Sevele Bronchial Asthma 19. Voller o Uber die Behandlung der Akuten Idrenalıyer giftung mit Bericht uber einem Vergiftungsfall deta med Scandinat 110 959 1942 126 Vunch JC Gattone H and Pratt ! ) Tressor Drugs Chemistry and Pharmacology of Inalogue of Epinephrine Am Pharm 1 (Scient Ed ) 30 183 1911 127 Nathanson VN Pathology and Pharmacology of Cardiac Syncope and Sudden Death Arch Int Ved 58 685 1936 128 Olsen AV Aebulizec Penicillin Preliminary Report of its Role u Manngement of Surgical Bruchreclass Proc Stof Meet Mayo Clin 70 181 1949 129 Olsen Nebulizat on Therapy in Bronchietectası, the Use of Peycillin ind Streptomycs lcrosols JAV 134 917 1917 130 Paul 11 D Heart in Bronchial Isthma | lour Soc 25 643 1955 331 Peters, and Silverman Role of Histamine and Acerylcholine in Niechanism of kleit Viergy Report of Studies on Soldier Arch Int Wed 7 526 1916 132 Prigels Production of Jerosols from Medicated Solutions Combined Steam Cenerator and Aeroulizer 4 131 $98 1916 133 Priga) SJ Brooks A and Warris R 'Treatment of Asthma by Imitalauon of Aerosol of Iminoplyilin ) Niergy 13 16 1917 134 Proger S and Decancas DJ Some Turther Observations on Parenteral Use of Cytochtime ( with Special Reference to Cerebral Anorn and Shock Bull Tew England Center 7 149 1915 135 Proger S Decaneas DJ and Schmidt G Some Observations on the Effect of Injected Cytochromes in lumils J Clin Investigaton 24 864 1945 136 Raab 11 Sudden Death of Seung Ithlete isch Excessive Concentration of Epinephrint like Substances in Heart Vus cle Arch Park 36 388 1919 157 Rackemann F1 Studies in Asthma Chinx Sures of 1074 Patients with Asthma Followed for Tio lears 1 Lab Chan Med 1°1181927 138 Rachemann F11 The Use of Drugs in Isthm JAYA 114 1998 1910 199 Rackem inn FV Deaths from Isthma | Allergy 15 219 1974 110 Rackemann FM Illorking Classif (atron of Isthma Am 1 Vied 3 601 1917 ·150 The Alanagement of the Patient 141 Randolph TG Food Wllergy Clin Torth America 32 245 1918 142 Ratner B Pedriatic ipproach to Vanagement of Isthma in Childhood ew York State) ved 17 861 1947 143 Ratner B Vanagement of the Isthmatic Attack in Childhood 11 Clin North America 31 537 1917 144 Reinberg S A Roentgen ray Studies on Physiology and Pa thology of Trnchenbronchri! Tree Brit Radiol 30 151 1925 145 Rich IR The Pathogenesis of Forms of Jaundice Bull Johns Hopkins Hosp 47 338 1930 146 Rich AR Role of Hypersensitivity in Pernarteritis Nodosa as Indicated By Se en Cases Developing During Serum Sch ness and Sulfonamide Therapy Bull Jolins Hopkins Hos 71 123 1912 147 Rich AR Role of Hypersensitivity in Pathogenesis of Rheu matic Fever and Periarteritis Rodosz (Lewis Linn Vcirthur lecture) Proc Inst Ved Clucago 15 270 1915 148 Richards Di Jr Barach I L and Cromi ell H I Use of Vaporized Bronchodilator Solutions in Isthmi and Em physema Continous Inhilation Vethod for Severe Isthmatic States Am ) 11 Sc 199 225 1940 149 Rogerson CH Psychological Factors in Isthma Brit VI 1 406 19:13 150 Rosenstine L A and Phelps VL Respiratory Obstruction from Bronchiolar Constriction During Cyclopropane Anes thesia ) Thoracic Surg 17 565 1919 151 Rone IH Bronchial Isthma Iis Diagnosis and Treatment Id A 111 1827 1938 152 Rone AH Eliminanon Diets and the Patients Allergies Handbook of Allerg Ph Indelphur Lea and Febiger 2 256 1914 153 Rubin EH Diseases of the Chest uith Emphasis on ray Diagnosis the Principles of Surgical Treat nent by Morris Rubin Philadelphia 11 B Saunders Co VII 685 1917 154 Rubitsky H J Bresnick . Levinson L Risman G and Segal MS Parenteral and lerosol Administration of Intthistaminic Igents in the Treatment of Sesere Bronchial Asthma New England J Aled 241 858 1919 155 Salter HH On Asthma Its Pathology and Treatment Lon don Churchill 2 64 1868 156 Schiller I T1 Colmes & and Dass D The Occurrence of Cor Pulmonale in cases of Bronchial Isthma low England Ved 328 113 1913 ·11th Severe Bronchial Asthma 157 Schutzbank FB Climatotherapy in the Treatment of Illergic Diseases ! Clinical Report | Allergy 19 214 1918 158 Schwartz AL Relief of Status Isthmaticus by lielum (Case Report) J Med 19 122 1938 359 Seegal B Combined Staff Clinics of the College of Physicians and Surgeons, Columbia University Am / Ved 1 190 1916 160 Segal MS Inhalational Therapy 1 Respiratory Disease Bull lew England at Center 5 104 1943 161 Segal al S Inhalation Therapy Treatment of Serious Res piratory Disease Mew England Ved *9 235 1913 162 Segal VS Vedical Progress Inhalation Therapy Teu England ] Ved 230 456 1944 485 1981 169 Segal VS Advances in Inhalation Therapy with Particular Reference to Cardiorespiratory Disease New England J Aled 231 553 1914 164 Segal VS Progress in Inhalation Therapy Modern Vedi Eine 1413 1916 1617 Segal VS Facts and Farmies in the Management of the Scrously 1 Patient with Bronchial Asthma Dh of Clest 1 793 1948 165 Segal V S and loner V Vanagement of Certain Ispects of Gas Poisoning with Particular Reference to Shock and Put monary Complications Ann Int Me! 20 219 1911 166 Segal VS and Beckey Jr The Use of Isuprel for the Van agement of Bronchial Isthma Bull New England Center 969 1917 167 Segal Vand Bealey y F Vanageraent of Bronchial Isthm fle Use of 1 (31 Dilaydroxyphenyl) 2 isoproprs laminocthanol Ann Allergy 5 917 1917 168 Segal M S Beakey J F Bresmick E and Lesson L uation of Therapeutic Substances Employed for the Relief of Bronchospasm Bull Aew England i Center 102) 1919 169 Segal V S Beskt) J F Nresnick E and Lessnsen L Comparative Study of the Action of various Sympathome meixc imise terosols in Connecracting the Dyspnea and Bronch spasin Induced by Ilustamine and by icetyl Beta fethylcholine J Allergy 90-97 1919 170 Segal VS Lerins in L Bresnick E and Beakey F Evaluation of Therapeutic Substances Emplosed for the Relief of Bronchospasm 6 {minophyllen ſ Clan Iniestiga tion 28 1182 1919 Esal A ·152 The Management of the Patient 171 Segal VS and Ryder CV Penicillin lerosoluzation in Treatment of Seri sus Respiritory Infections Prel minary Report New England) Med 333 747 1945 179 Segal v S and Ryder CM l'enıcıllın Aerosol in Vanage ment of Lobar Pneumonia Bronchiectasis Lung lbcess and Infectie Bronchial Asthma Bull Aew England Center 7 279 1915 173 Segal M S and Ryder CV l'encillin Inlialation Therapy New England J Med 236 132 1947 174 Segal M S Levinson L and Viller Drenicillin Inhalation Therapy in Respiratory Infections J.A 134 762 1917 175 Selye H Studies on Adaption Endocrinology 21 169 1937 176 Selye H General Adaptation Syndrome and Diseases of Adapta tion Clin Endrocrinol 6 117 1946 177 Sherman II B Drug Allergy Am J Med 3 586 1917 178 Solomon H1 and Somkın E Improved Method of Obtain ing Sustained Controlled Hyperpyrexia with Triple Typhord Vaccine Am J VSC 203 736 1942 179 Spain WC and Coole R 1 Specific Hypersensitiveness Familial Occurrence of May Fever and Bronchial Isthma Immunology 921 192 1 180 Spain D M Handler BJ Chronic Cor Pulmonale Sixty Ciscs Studied at Necropsy Arch Int ved 77 37 1916 181 Staub II Die Adrenalin Histamin Regulation mit Beitrag zum Intistin mechanismus Schuet med II chnschr 76 818 1916 182 Stevenson I P Bronchial Lavage for Bronchiectasis i Pre liminary Report of a Simplified Technique Ann Rev Tuberc 56 279 1917 189 Steglitz E Į The Histologic Detection of Iodides Plarmacol & Exper Therap 22 89 1924 181 Sweatman C Treatment of Bronchial Isthma and Hay Teser with Cyclopropine South Carolma Al A37 291 1911 185 Talbot TR Jr Quimby E H and Barach 4L A Veil od of Determining the site of Retention of Aerosols within the Respiratory Tract of Man by the Use of Rd oacuje Sodium im Al SC 214 583 1917 186 Thieme E T and Sheldon J M Correlation of Clinical and Pathologic Findings in Bronchial Asthma | Allerg 9 246 1938 187 Tiffeneau Rind Beaus aller Ar Epreuse de bronchoconstric tion et de bronchodilatation par aérosols Emploi pour le dépistage la mesure et le contre des insuff sinces respira ·lith Severe Bronchial dsthma 153 toires chroniques Bull Acad de med Parts 129 165 1915 188 Titche L L Anesthesia in Tracheo Bronchial Procedures Dis of Chest 13 452 1917 189 Tuft L and Levin N A Studies of the Expectorant Action of Iodides Am J Ai Se 203 717 1912 190 Unger L and Gordon B F Bronchial Asthma (IV) Critical Review of Literature in Allergy 6 159 1948 191 Unger L and Wolf A A Treatment of Bronchial Isthma a Survey of the Value of Treatment in 459 Cases During Twenty Years J AMA 121 325 1943 192 Unger L Pathology of Bronchial Asthma with Fre Autopsy Reports South A 38 513 1915 193 Van Wijk A V and Patterson HS Percentage of Particles of Different sizes Removed from Dust Jaden Air by Breath ang / Indust Hug and Toricol "2 31 1940 191 Villaret M Vallery Radot P Justin Besancon L and Claude F Recherches Prélımınaries Sur les Crises Provoqui es Chez les Asthmatiques par Certains esters de la Choline Compt rend Soc de Brol 116 1313 1934 195 Villaret al Vallery Radot Justin Besancon L and Clrude F Crises Isthmacſormes Expérimentales Provoquels par Lad ministration de Vagomimetiques Après Irritation Pulmon a re Compt rend Snc debrol 124 1308 1937 196 Waldbutt GL Emergencies in Allergist s Practice JAMA 123 1205 1915 reply to Engelesher 129 979 1949 197 Waldbott GL Does Routine Treatment of Asthma Need Revision? Ann Allergy 5 126 1947 198 Taldbott GL Is There An Intrinsic Asthma? Ann Int Afed 26 863 1917 199 Waldbott GL and Ascher M S Role of Iccidental Punc ture of Veins in Production of Allergic Shock Ann Int ved 9 1232 1936 200 Walker ICA Clinical Study of 100 Patients with Bronchual Asthma Boston AIES 179 288 1918 201 Winer B Beakey ] F anel Segal AS A Clinicopathologic Study of Bronchial Asthma with Consideration of its Rela tionship to the General Adaptation Syndrome Ann Int ved in Press 202 Wittich Ft The Present Day Concept of Allergic Prenom ena Medical Briefs Frederick Stearns and Co 21 1916 203 Hittich FH Bactern Illergy Regional Spring Course Amencan College of Allergist hansis City han May 5 1917 ·154 The Management of the Patient 201 lonkman F F Adrenergic Potentiation A Pharmacodynamic Effect Associated with Antihistaminic Igents am y Digest Dis , 14 360 1917 205 Yonkman F F and Mohr F L An Approach to the Problem of Epinephrine Fastness Ann Allerg) 760 1919 2051 Jonkman F F Levinson L. and Segal M S An Approach to the Problem of Epinephrine Fastness am ) Digestive Dis eates in Press 206 Editor Voice Changes from Inhalation of Helium Oxigen Queries and Minor Motes AM1 d 113 706 1939 207 Standards of Effective Administration of Inhalational Therapy By the Committees on Public Health Relations of the New York Academy of Medicine JA A, 121 755 1913 208 Gilman A The Pharmacology of Drugs Used in Allergic Con ditions ) Allergy 19 281 1918 ·INDEX A Barbiturates 56 Belladonna 38 Ierosol therapy in asthma 9A Bellafolne 37 40 72 motor blower unit in 101 123 Benadr! 72 73 7 126 nensynephrin in 46 47 103 101 Blocking antibodhes 19 20 particle size of aerovols 99 100 Blood plasma 70 penicillin in 120 121 Breathing exercises 139 140 precautions in 49 77 78 10) Bromides 26 56 sympathomimetic amines in 43 Bronchial asthma 41 49 99 108 aleolor and blood gases in 3 Icetylcholine 27 31 42 48 asthmauc prohle or pero nahtsin ICIH 511 VILE 130-132 Harm reaction (Selye) 10 11 13 14 characteristics of 3 7 8 Alu hul infusions 70 substances in IR Vieudrin 47 aumatic change in 19 137 Illergens 2121 (nanosis in s lllergic response 18 duhnition of s 1llergic state 18 20 emotional disturbances in 1.39 Ammonium chloride 10, 107 191 Iminophyllan 23 37 49 51 53 63 fatalitses from # 10 14 7 28 112 66-68 75 83 10, 126 10 general therapy in 128 Inachohnergic drugs 37 39 40 4 11 substance in 1 18 60 immunologic treatment of 2021 Intigen antibody reactions 18 19 improvement in 3 Inesthesia in status asthmalicus 61 incidence of 3 62 infections in respiratory caina Antibiotics use of in asthma 98 tion of 118 130 124 treatment of 120 Inuhistamines 5351 71 72 126- pathologic diagnosis of 11 127 pathophysiology of 36 Isorbic acid vi 69 poychoanalysis in 150 151 lepirn 2.1 56 shoch therapy in 131 13 Itelectass 8 9 12 41 sinus disease in 122 12 Heroine 5741 52 54 status state in 7 27 64 Tertin 61 streptomycin in 120 1.2 kullonamides in 120 B surgery results in 18 ventilatory dynamics in 4 3 Racteria role of in asthma 118-120 Bronchial evacuation 106 107 131 Racterial sensturation 118 Armutual lavage 111 114 116 117 155 ·115 156 The Fanagement of the Patient Bronchial obstruction 112 113 Peitlerol 57 59 60 Bronchitis 119 121 Desensitization 20 21 Bronchoscopic aspiration 111 114 Digitalis &6 Dilaudid 57 59 Bronchoscopy > J}!!! Diphenhydramine 72 73 7, 126 Bronchospasm 28 123 124 126 10 Diseases of adaptation (Selye) 10 u Bronchostenosis 9 Diuretics mercunal 65 66 Drug tolerance 2426 6$ 77 108 C Dyspnea : 28 64 Cardiac output 66 Carbon dioxide-orygen therapy 96 E 97 Carbon dioxide heliumoxygen Electrolyte balance 61 63 therany 98 Elimination duers *3 24 Cacharsis hronchial 106 107 131 Emphysema 3 89 12 14 66 191 Ceutamic acid w 60 124 12 339 340 Chloral y urate 26 56 Endoscopic insteffatton 111 114 116 Chlessergic drugs, 2333 42 49 Fphedrine 80-89 140 Chronic infection nasa) 71 279 Epinephrine 14 43 41 40 33 73 120 129 12 127 77 Classifcation of bronchial asthma hy poderouc precautions 78, 79 in stalus asthmaticus 79 Climatic treatment 13 reactions from 10 2 19 77 38 Cricaine 63 103 Complications 8 10 spray 13 atelectasis 8 9 12 41 Epinephrine fast state 55 79 73 bronchiectasis 8 9 79 80 bronchitis 12 14 119 121 Elher 6! 19 13 cor pulmonale 9 12 14 Expresses breathing 139 emphysema 8 9 121 12 Expetioranis % 97 107 1139 heart farfure 9 12 14 Extrinsic asthma 15 16 mediastinal emphysema 8 obliterative endarteritas 9 10 periarteritis nodosu 10 10 Fever therapy 137 139 physiological depletion & Tori of mfccion Tole of 119 120 pleurisy B paeumothorax 8 Innds allergy to as cailte of asthm 21.3 129 subcutaneous emphysema 8 l'owlers solution 100 Cyclopropanc GI Cytochrome C 5 69 D Death from asthma 8 10 11 57 59 U? Castrointestinal allergy 22 Clicose in status asthmat cu 61 6 70 138 ·157 Both Set ere Bronchial Asthma Obstructie enphysema 112 113 Orthoxine 80 81 Oxygen 8190 face mask apparatus 81 86 indications for USC 84 88 113 nasal catheters 88 139 oxygen toxicity 87 88 tent 88 90 H Helrum-oxygen therapy 9093 122 hond apparatus for administering 88 89 92 93 indications for use 62 87 90 91 93 101, 122 meter mask apparatus for admin istering 84-86 properties of 90 vorce changes with 92 H substance in asthma 15 18 20 Haptenes 26 Ileart in asthma 9 12 14 Histamine, 10 14 27 29 31 37 128 Tiislamuine sympalkın balance 23 72 73 79 80 House dust 22, 24 Hydryllin 74 76 126 Hyperpyrexia, 137 139 1 Iatrogenic lung disease 133 Intravenous fluids 6 Intrinsic asthma 15 16 todides 26 107 103 Ipecac, 107 109 110 Isuprel 5 43 41 47-49 103, 101 115 123 р Pantopaque 115 116 Paraldehyde 62 Para nasal snus infection 71 319 120 122 125 126 Penicillin 99 115 116 120 121 124 126 Pituitary adrenocorticotropic hor mone protection studies is van therapy in asthma u vrt Pontocaine 21 2, 113 reactions froin 63 116 117 precautions with 68 Positive pressure therapy 93 93 Postural drainage 109 110 111 Preventise therapy 21 Protection studies in experimental asthma 27 53 brunchospastic agents 28 bronchospassic techniques 28 30 determination of protection 34 $7 protection with aminophilhin 49 51 103 protection with an histaminics 7176 protection with atropine 37-41 52 51 protection with bellafoline 37 40 52 protection with demcrol 57 59 60 K haraya gum 21 25 Ahellin 52 128 M Mecholy? chloride 2731 4? 48 Vependine 57 59 GO Meter mask 81-86 Vorphine reactions from 8 56 7 58 N coxyneinn 43-46 115 116 123 127 Vicotinc aad 69 ·158 The Management of the Patient protection with ephedrine 80 82 protection will epinepatine 14 43 41 16 53 73 77 protection with Isaprel 45 !! 17-19 protection with neosynephrin 45 46 protection with Orthoxine 80 81 protection with scopolamine 57 39 40 59 60 protection with tapunefnın 43 45 46 48 reactions to technique 30 1 sychotherapy 129 130 131 I ulmonary emphyseert3 manage ment of 124 10 Pulmonary heart disease 9 12 13 Pyrıbenzamile 72 126 127 Sexium bromide 6 Sxum chloride 61 6 138 Soclum 100 de 108 Sedium pentothal 56 talu asthmale 78 )3 27 G1 central congestion of the liver in 13 Streptomycra 1119012? Sulfonamides 121 sensitization ( 10 26 190 Surgical treatment of asthmnt 1.3 128 129 Sympatomimeticamine aerovls 13 11 49 98 108 V T Theophy Men 67 Therapeutic seesam vi R Ruagen 19 20 Roentgen ray therapy 123 128 V S Scopolamine 37 39 40 2 60 Sensitizing antibodies 19 Shin tests 9 23 24 26 68 118 accines 118 120 Taponefrin +3 to fr 48 101 103 115 123 Tital capacity 98 31 32 31 52 10 125 140 sumin Compler 69

·This Book
THE MANAGEMENT OF THE PATIF\T
WITH
Severe Bronchial Asthma
B) VALRICES SEGAI VD
uas sel printed and bound by The Collegiate Press of
Venasha Il escons The page size is 1 1 844 inches
The lype page is 23 39 picas rhe type face is Linotype
Baskerville set 11 point on 13 point The text faper is
70 lb IT hute Deep Falls [namel The cover is Du Pont
Fabrikoid 700 Color 1096 A13
THOUT
Y ABUN
11ith THOMAS BOOKS careful attention is geen to all
details of manufacturing and design It is the publishers
desire to present books that are saltsfacton as to their
physical qualities and artistuossibilities and a propriate
for their particular use THOVAS BOOKS uill be
true to those laus of quality that assure
good name and good u all

·No text on this page.

·No text on this page.