1792: The first attempts at neonatal resuscitation

Fig. 1 -- Represents the box-wood tube.  One end was inserted
into the infants airway.  The caregiver would lace his mouth
over the other end (bottom of the figure in the photo) and provide
breaths to the child.  Bellows may also be connected to the tube.
(14, page 77-78, 196)

Perhaps among the first attempts at artificial respiration were performed on a stillborn child. The mother and father waited patiently for nine months, a perfectly formed child was born, but it wasn't breathing.  Frantic attempts were made to excite breathing.

More often than not such attempts failed, but every so often there was success, which brought great joy and excitement, just enough to motivate the next generation to make such efforts given the same frightful situation.

Some methods used to excite a newborn's first breath included: (1, page 77) (2, page 13)

1. Talking to the baby
2. Rubbing the baby's chest 
3. Shaking the baby
4. Tickling the baby
5. Blowing in the baby's face
6. Warming the baby with warm blankets
7. Applying moderate friciton to the body by rubbing 
8. Slapping the baby on the back or heels
9. Patting the baby on the back
10. Squeezing the rib cage
11. Hugging the baby
12. Performing mouth to mouth respirations, what was called inflating the lungs
13. Inserting a tube into the airway and breathing for the child that way 
14. Suctioning the baby's airway (not available until 1937)
15. Performing gentle chest compressions or abdominal thrusts
16. Tickling the nose with a feather
17. Tickling the arm pits, temples, stomach
18. Dunking the child up to the neck in warm water
19. Other gentle stimilation

Over time, and by trial and error, better methods were developed. By the end of the 19th century a basic form of neonatal resuscitation was taught to medical students, nurses, midwives, and members of societies such as the Humane Society. In fact, the report references and quotes Curry. 

A good example can be found in James Curry's 1815 book "Observatoins on Apparent death:"

WHEN a still-born Child appears in every respect perfect, and especially when, from the circumstances of the labour, there is reason to believe that the Child has not been long dead, measures may be taken for recovery, with very great hopes of success. With this view, the Lungs should be diligently inflated, and the heat of the body kept up, by the application of Warm Flannels, or by putting the Feet and Legs, or the whole Body up to the chin, into Warm Water. Moderate frictions with the Naked Hand, and gentle agitations, may also be used; and Stimulating Remedies applied to the Nose, Temples, and Pit of the Stomach. (1, page 77-78)

If these efforts did not work, then the physician or midwife would move on to the next stage of the resuscitation attempt, which would involve inserting tubes into the airway and breathing for the baby.  An example of this is noted by Curry:

If the Wooden Tube (Fig. 1.) be not at hand, the female Catheter (an instrument which every Practitioner in Midwifery is presumed to carry constantly about with him) will answer tolerably well for inflating the Lungs in this case: in defect of it, a joint of reed, the barrel of a qiull, or a piece of still paper or a card rolled up, may be; —one end being introduced into the Mouth, and the Assistant blowing into the other with his breath,* until the Lungs are expanded; then gently pressing the Chest;—and repeating this, so as to imitate Natural Respiration.

The recommendation by the Humane Society was similar, although the 1823 report of the Society suggested that bellows should be used to breathe for stillborn infants instead of the mouth.

Curry notes that in "some cases which have come within my knowledge prove, that Still-born Children may be recovered even after an hour or more has elapsed." His explanation for this is as follows: 

There are several reasons for believing, that the Vital Principle is not so soon destroyed here, provided the warmth of the body be kept up, as when Respiration has been established for a length of time, and then interrupted: for the new-born Infant which has either not respired at all, or had its breathing suspended very soon after birth, seems in a state of susceptibility somewhat resembling that which annually takes place in certain Animals, as the bat, frog, dormouse, &c, from the influence of the Winter's cold; the one requiring only the restoration of that warmth by the return of Spring, the other the application of Air to the Blood stagnating in its Lungs, to restore the Circulation, and with it the balance of functions necessary to Life. 

His theory is actually quite interesting considering anatomical pathology was only in its infancy during this era.  Over the ensuing years better wisdom improved the steps of neonatal resuscitation.  However, it wouldn't be until the 1980s that the technology was available to save the lives of infants not so perfectly formed.

References:

1. Curry, James, "Observations on Apparent Death from drowning, hanging, suffocation by noxious vapours, fainting-fits, intoxication, lightning, exposure to cold, & etc., and an account of the means to be employed for recovery. To which are added the treatment proper in cases of poison, with caution and suggestions respecting various circumstances of sudden danger," 2nd edition, 1815, London (the 1st edition was published in 1792)
2. "The Forty Ninth Annual Report of the Royal Humane Society, For the Recovery of  Persons Apparently Drowned or Dead," 1823, London, 

RT Cave Facebook Page
RT Cave on Twitter

1790: Defending old asthma theories

Dr. Robert Bree (1790-1859), an English physician who had asthma, wrote a book about asthma in 1797 called "A Practical Inquiry into Disordered Respiration, distinguishing the Species of Convulsive Asthma, their Causes, and Indications of Cure." It would go on to become the most read asthma book of the first half of the 19th century.

Dr. Bree was an ardent proponent of the bronchitic theory of asthma, a theory that states asthma is caused by an increase of phlegm in the lungs. The theory is similar to those postulated by ancient physicians, such as Hippocrates and Galen.  In this way, he is one of the last known physicians to defend old asthma theories.

He believed that the treatment of asthma was relative to the cause. He said asthma was caused by inhaling a peccant matter, and was cured when the peccant matter was expectorated.  This explained why asthma always ended after a fit of coughing that produced a wad of phlegm.

In this way, he believed modern theories regarding diseases like asthma were often the subject of quackery.  By autopsies and experiments he performed, he attempted to prove men like William Cullen, who postulated that science was a wiser approach to medicine than ancient theories. He was also one of the first physicians to describe asthma as spasmotic and nervous. (3)

Proving Cullen wrong about asthma was the essence of Bree's 1797 book.  He said Cullen is wrong because no science proves the nervous or spasmotic theory of asthma, especially considering those two conditions cannot be seen on autopsy.

On the other hand, phlegm can be seen on autopsy. So, if anything, science supports the bronchitic theory of asthma and the theories of the ancients, more so than the ideas of Cullen.

However, Bree did not completely reject the spaspotic theory of asthma, he simply considered it as secondary to some other cause.  In reviewing the opinions of Dr. Bree in 1890, Ernest Schmiegelow said:

Bree does not actually deny the possibility of bronchial spasms taking some part in the cause of asthma, but it is only secondary; the primary cause is an exudation in the bronchial tubes, by which the lungs (specially the muscles of respiration) are stimulated to contraction, in order to expel the mucus which they contain. (4, pages 8-9)

In other words, Bree believed mucus was the cause of most diseases, including asthma.  He believed the contraction of the lungs was a defense mechanism to expel mucus from the lungs.

About 30 years after Bree published his book the stethoscope was invented, and as soon as it was used to listen to asthmatic lungs Dr. Bree's theory was disproved, said Schmiegelow.  He said that once the stethoscope gained favor, it was easy to prove that an attack of bronchitis does not precede an attack of asthma, and that rhales (a lung sound Laennec used to describe the sound of secretions in the lungs) are heard later during the attack.

While Bree waswell respected in his day, his ideas about asthma, and even most of his remedies, slowly gave way to science.  In this way, Despite Bree's noble efforts, his bronchitic theory of asthma eventually took a back seat to Cullen's nervous and spasmotic theories.

Regardless, all three theories would be debated over the course of the 19th century.

Continue the journey by clicking here.

References:

1. Pepper, William,  Louis Star, "A System of Practical Medicine," Volume 3, page 184
2. Berkart, J.B., "On Asthma: It's pathology and treatment," 1878, London,  Chapter II, "History of Asthma," page 12
3. Bree, Robert, "A Practical Inquiry into Disordered Respiration, distinguishing the Species of Convulsive Asthma, their Causes, and Indications of Cure, London, 1810.  I could not find the 1790 edition online, yet this one serves our purpose.
4. Schmiegelow, Ernest, "Asthma, considered specially in relation to nasal disease," 1890, London, page 4 
5. Jackson, Mark, "Asthma: The biography," 2009, London, pages 86-88 (If you're interested in a good asthma history book, this is it.)

RT Cave Facebook Page
RT Cave on Twitter

1800-1900: The scientific revolution and the age of progress

Charles Darwin's "Origin of Species" may have helped
to spark the scientific revolution 

Perhaps among the most important centuries in the evolution of medicine wisdom was the 19th century. The great historian Fielding Hudson Garrison explained that this was the century that put an end to old dogmatic theories, thus opening the door for medicine and science to move forward. (1, page 424)

Respiratory diseases, particularly those looped under the umbrella term asthma, benefited greatly as pathology (the study of disease) and internal medicine (diagnosis and treatment of disease) were advanced during the course of the 18th century.  This brought us a greater understanding of the physiology of respiration,  setting the stage for what would transpire in the 19th century.

For instance, Mark Jackson, in his book "Asthma: A Biography, explained the following:

Eager to reject older irrational, mystical models of health and sickness, prominent Enlightenment physicians, such as Thomas Sydenham 1624-1689), George Stahl (1660-1734), Friedrish Hoffmann (1660-1742), and Herman Boerhaave (1668-1738), not only increasingly emphasized the importance of careful observation of the patterns and presentations of disease, but also strove to develop 'a simple and logical synthesis of medical knowledge designed to replace increasingly obsolete humoral conceptions inherited from antiquity' and to alleviate and conquer ill health.  (2, page 70)

Investigations of the human body, and new ideas such as "careful observation of patters and presentations of disease" brought about a better understanding not just regarding diseases, but the treatments to remedy them.  However, old theories persisted, thus acting as fetters to the furthering of wisdom.

Such theoretic fetters holding back great minds did not exist in the 19th century, wrote Fielding Hudson Garrison in his book "An Introduction to the history of medicine,"  mainly due to such works as: (1, page 424, 426)

• Friedrich Schelling's "Natural Philosophy" in 1797, "which aimed at establishing a subjective and objective identity of all things." (1, page 425)
• Hermann von Hemholtz,'s "Conservation of Energy" in 1847, which established the idea that no energy was lost in muscle movement, and that there was no vital force that causes muscle movement (wikepedia)
• Charles Darwin's "Origin of Species" in 1859, which established the idea that living creatures, including humans, evolve over time as changes in their environments occur. 

These works were met with much reservation and controversy by a dogmatic society, although they had a significant impact on both science and medicine, helping to open up the doors for scientific progress. As the ideas put forth by these works were accepted, great minds were no longer limited by theories made by famous men of the past, thus opening up a whole new world for them. (1, page 424)

Hermann Hemholtz shot down the age old theory that
'there was a vital force responsible for muscle movement.
His scientifically proven idea helped spark a revolution.

As noted by Garrison:

"It took a long time to demonstrate that the advancement of internal medicine as a science can never be accomplished by hugging some pet theory out of a regard for it's author's personality, but only through the performance of a vast amount of chemical, physical, and biological research by thousands of willing workers." (1, page 426)

Yet even though medical theories were no longer existent, "the modern scientific movement did not attain its full stride until well after the middle of the century. The medicine of the early half was, with a few noble exceptions, only part and parcel of the stationary theorizing of the preceding age," wrote Garrison.  (1, page 425)

A good example of this we can find in our own asthma history.  Dr. Robert Bree, who was the preeminent asthma expert in the first half of the 19th century, continued to believe in old humoral theories.  On the other hand, Dr. Henry Hyde Salter, who was the preeminent asthma expert in the second half of the 19th century, devised modern conclusions regarding asthma based on scientific investigations. 

Friedrish Schelling encouraged the subjective and the objective
review of patients. His ideas helped spark the scientific revolution.

We have to under stand, however, that the fact Bree did not use science and Salter did does not mean that Salter's conclusions were flawless, because they weren't.  The fact that pure asthma left behind no scarring in the lungs caused him to deduce, as experts before him had, that asthma must be nervous in origin.  Surely he was wrong, but he also didn't know about the immune system. 

The term asthma went through an amazing transformation during the course of the 19th century, with many physicians hunting for answers, and each coming to his own conclusion.  Some were right, thus leading investigators in the right direction.  Some were wrong, thus leading investigators in the wrong direction.  Regardless, all such investigations benefited our disease, thus setting the stage for what would transpire in the 20th century. 

References:

1. Garrison, Fielding Hudson, "An introduction to the history of medicine," 1913, 1st edition, Philadelphia and London, W.B. Saunders and Company
2. Jackson, Mark, "Asthma: A biography," 2009, New York, Oxford University Press; reference quoted by Jackson: Guenter B. Risse, "Medicine in the age of Enlightenment," in Andrew Wear, editor, Medicine in Society: Historical Essays, (Cambridge, 1992), pages 149-95

RT Cave Facebook Page
RT Cave on Twitter

1790: The first feeding tube

The feeding tube may not be directly related to respiratory therapy, although when you consider the big picture, it kind of does.  For instance, to put someone on a ventilator for several weeks would be a moot point if physicians were unable to provide nutrients to the patient.

The feeding tube was invented in 1790, and was another invention by Dr. John Hunter, the same physician who mastered the use of bellows to provide mechanical breaths to asphyxiated infants.  The feeding tube was significant because it helped advance surgery from a "mere technical mode of treatment to a branch of scientific medicine, firmly grounded in physiology and pathology." (1, page 352-355)

His artificial feeding through was a flexible tube inserted into the mouth to the stomach, and it allowed physicians to feed, and thus provide adequate nutrition, patients who were otherwise unable to eat, such as those recovering from complicated operations. (1, page 352-355)

This invention was significant because many physicians prior to him (and even some after) performed surgeries with little regard for anatomy, and therefore little understanding of diseased or injured body tissues and organs.

References:

1. Garrison, Fielding Hudson, "An introduction to the history of medicine," 1922, Philadelphia, W.B. Saunders Company

RT Cave Facebook Page
RT Cave on Twitter

1786: Thomas Withers and his "Treaties on Asthma":

William Cullen was among the first physicians to form conclusions about asthma based on studies he performed, as opposed to speculating about it.  He believed a muscle was a continuation of a nerve, and therefore that asthma was a nervous disorder.  In 1786, Thomas Withers wrote a book called "A treaties on Asthma," in which he expounded on the ideas of Cullen.  (1, page 75)(2, page 17-18)

Thomas Withers (1750-1809) was a physician to the New York County Hospital.   Like Cullen, he believed asthma started in the mind and resulted in convulsions of the fibres that wrap around the lungs.  He believed in the nervous theory of asthma and in the convulsive theory of asthma.  (1, page 75)

In a review on Wither's book, Tobias George Smollettt, in 1786, compared him with John Floyer, who is considered by many to be the father of the convulsive theory of asthma.  Smollet said:

'This is an old building, with a modern front and fashionable ornaments: in other words, it is the valuable work of Floyer, with explanations from the modern nervous papathology. Dr. Withers, in his former works, adhered so closely to his master's precepts, almost to his words, that we did not expect any thing new. (2, pages 17-18)

 Smollet continued:

We hoped, indeed, that experience might have opened sources of enquiry, which his unwearied diligence would have pursued; but the little which is his own, is not of the best kind. The account of the asthma, as may be expected, when we consider the sources, is clear, intelligible, and judicious: the cafes are sometimes unnecessarily minute, at others imperfect; they arc in general very trifling, and the effects of remedies unreasonably exaggerated.  (2, page 18)

Dr. Withers believed spasmotic asthma was "a nervous disorder accompanied with great irritability of the lungs." Through his various books he provided various pithy examples of cases of asthma he witnessed, along with the remedies used. (3, page 300)

He believed a good remedy for nervous, or spasmotic, asthma was opium, which "diminishes the irritability and spasmotic contraction of the air vessels; mitigates the cough; lessens the pain, anxiety and difficulty of breathing; shortens the duration and the facilitates the cure of the asthmatic fit." (3, page 300)

References: 

1. Jackson, Mark," Asthma: The Biography," 1999, New York, London, Oxford University Press???????
2. Smollet, Tobias Georgy, ed., "The Critical review, or, Annals of literature, Volume 62, 1786 , page 17-18, a professional review of withers book, "a treaties of the asthma, to which are added cases and observations, in which the asthma is complicated with other diseases." 
3. Withers, Thomas, "Observations on the Abuse of Medicine," 1775, London, 339
4. Griffiths, Ralph, Grifiths, G.E., ed.,  "The Monthly Review, or Literary Journal," London, 1787, pages 332-334, a professional review of Wither's "A Treaties on Asthma."
5. Ramadge, Francis Hopkins, "Asthma, its species and complications, or researches into pathology or disordered respiration; with remarks on the remedial treatment applicable to each variety; being a practical and theoretical review of this malady, considered in its simple form, and in connection with disease of the heart, catarrh, indigestion, etc." 1835, London,  Longman, Rees, Orme, Brown, Green, and Longman

RT Cave Facebook Page
RT Cave on Twitter

1784: Emphysema is further defined

Charles Badham (1813-1884)

After the term emphysema was coined in 1679 the quest was on to learn more about this disease. Perhaps some best knowledge was gained from an unexpected source in Dr. Samuel Johnson, although not until he was dead, and his autopsy was performed

In 1721 F. Ruysh provided the first detailed description of emphysema coupled with pictures in his book "Observations anatomica-chirirgicae."  (1, page 85)

In 1764, W.Watson described a case of emphysema in "On account of what happened upon opening the body of an asthmatic person."  He was quoted in "Physiologic Basis of Respiratory Disease" as saying:  (1 page 85)

"The lungs were enormously distended with air... this air was extravasate and had burst through the extremities of the bronchi and vesicular substance...  In a word the lung was truly emphysematous.  In several parts this had formed large bladders... The air getting loose in the substance in the lungs cannot be parted with expiration; it subsequently is retained there and the space it occupies prevents as much of the external air being received into the lungs as its own quantity.(1 page 85)(13, pages 145-147)

Watson also described the diseased condition of the heart.

The figure of the human heart is that of a cone, divided through its axis; but in this case, the heart's figure was altered, and was more compressed than usual; and its ventricles distended with grumous blood. Every other part of the body was in its natural state. (13, page 145)

He added:

From this examination we find that in this instance respiration was greatly disturbed... The varices of the pulmonary vein not only retarded the blood in its passage to the left auricle of the heart, but, occupying a much larger space in the lungs than they naturally should, they left less room for the minute ramifications of the bronchia to extend themselves and consequently a less quantity of air was taken in at every inspiration than was necessary for the ordinary purposes of life...  But the disorder of the lungs from the varices was made infinitely worse by the emphysema. For by the extravasated air possessing so large a portion of the lungs, and which the patient could by no means part with in expiration, very little room was left for fresh air in inspiration; the lungs, from the emphysema, and from the diseased state of the pulmonary vein, filling almost the whole cavity of the thorax. (13, pages 145-146)

He said that in life the man was seized with a troublesome cough, and shortness of breath with minimal exertion.  He said there was no cure for the man because there was "no method of discharging the extravasated air from the lungs." (13, page 146)

Dr. Samuel Johnson (1709-1784)

By 1784 Dr. Samuel Johnson was well known for his medical skills,  and he also well known for his breathing trouble. He was thought to have suffered from asthma since birth, and later he was determined to have died of fibrosis of the lungs.  (6)

At any other time in history this information would have gone down as a fact and that would have been the end of it.  However, Dr. Johnson was born into a time when the medical community was searching for answers about diseases, and so, before he died he gave permission for his lungs to be preserved and studied for science.  (6)

Dr. James Arthur Wilson was only 19 when he performed the autopsy on Dr. Johnson, and he described the following:

"On opening into the cavity of the chest, the chest did not collapse as they usually do when the air is admitted, but remained distended, as they had lost the power of contraction; the air cells on the surface of the lungs were also very much enlarged... the heart was exceedingly large and strong."

Based on this autopsy report, later physicians, upon examining it, determined that Dr. Johnson did not die of asthma, nor fibrosis, but of a disease that was barely known at the time: emphysema. He was also found to have suffered from cor pulmonale, which would have been the result of his heard working so hard for many years to pump blood through his stiff lungs. (6)

Matthew Ballie was a prominent British physician who inherited his father's anatomy school in 1783. Throughout his career he studied the bodies of diseased patients, including some specimens handed down to him, such as the lungs of Dr. Samuel Johnson.

Matthew Ballie (1761-1823)

In 1799 and 1807, Ballie  described emphysema with detailed pictures.  He described the condition as "enlarged air spaces" in the lungs, and lungs that did not collapse.

He published a book in 1793, "The Morbid Anatomy of Some of the Most Important Parts of the Human Body." It's believed to be the first book on pathology.

He described the lungs of emphysema patients, which included the following description of Dr. Johnson's lungs:

"The lungs are sometimes, though I believe rarely, formed into pretty large cells to resemble the lungs of an amphibious animal. Of this I have seen three instances. It is not improbable that this accumulation (of air) may break down two or three contiguous cells into one, thereby, form a cell of very large size." (5, page 2)

In 1814 British Physician Charles Badham became the first to use the term "bronchitis" to denote "inflammatory changes in the mucous membrane." (9?)

Bronchitis would soon "supercede" the term chronic catahrr when referring to chronic inflammation of the respiratory tract that resulted in a chronic cough and the spitting up of yellow or otherwise colorful phlegm.   (9)

In 1819 a French physician would invent a device called the stethoscope that would forever change the landscape of medicine, allowing for a more precise means of diagnosing pulmonary diseases in life, as opposed to waiting for an autopsy to take place.  The inventor would be Dr. Rene Laennec.

References:

1. Qutayba Hamid, Joanne Shannon, James Martin, "Physiologic Basis of Respiratory Disease," 2005, Montreal, page 85-99
2. Bhatia, K. Sujata, "Biomaterials for Clinical Application," 2010, London, page 100
3. Petty, Thomas L, "The History of COPD,"Int. J. Chron. Obstruct. Pulmon. Dis., 2006, March; 1(1): 3-14
4. Crellin, J. M.D., "Selected Items from the history of pathology," Am J Pathol. 1980 January; 98(1): 212.
5. Thurlbeck, Wright, "Thurlbeck's Chronic Airflow Obstruction," 1999, Canada, pages 1-6
6. Reich, Jerome M, "Convulsion of the lung: an historical analysis of the cause of Dr. Johnson's fatal emphysema," Journal of the Royal Society of Medicine, Vol. 87, December, 1984, page
7. Laennec, Rene, "Treaties of the diseases of the chest," 1821
8. Stokes, William, "The Diagnosis and Treatment of Diseases of the Chest," 1837, Dublin
9. Gee, Samuel, "Bronchitis, Pulmonary Emphysema and Asthma, " The Lancet, March 18, 1899, page 51
10. Klotz, Oskar, Wm. Charles White, ed., "Papers on the Influence of Smoke on Health,"  Bulletin #9, 1914, page 36
11. Christie, Ronald V, "Emphysema of the Lungs: Part II, British Medical Journal, Jan. 29, 1944, page 143-146
12. Cleveland, Geo. Henry, "The Clinical Review: AJournal of Practical Medicine and Surgery," Vol. VIII, April-Sept. 1898, Chicago.
13. Wilson, W., "An account on what appeared on opening the body of an asthmatic person," The Philosophical Transactions of the Royal Society of London, from their commencement, in 1665, to the year 1800, abridged with biographical illustrations by Charles Hutton, George Shaw, Richard Pearson, Volume XII, 1809, London, Printed by and for C. and R. Baldwin, pages 145-147

RT Cave Facebook Page

RT Cave on Twitter

1900: The discovery of epinephrine (adrenaline)

You can thank this man, Jockichi Takamine (1854-1922),
for the discovery of Adrenaline.  T'he rescue inhalers we
use today are only available because of his discovery.  
This is a painting he did of himself 
(From Therapeutic Notes, Vol. 28-32). 

Throughout our history there were always options for asthmatics. Yet that said, what remedy worked best for an individual patients was basically a crap shoot, and the relief obtained was palliative at best. This left asthmatics wishing for a quick relief medicine, a rescue medicine, or something that would quickly relieve asthma symptoms when they occurred. That journey began in 1901 when Jokichi Takamine (1854-1922) isolated the pure form of adrenaline, also known as epinephrine.

Actually the journey began a few years earlier. By 1895 physicians began experimenting with adrenal extracts. In 1893, George Oliver (1841– 1915), using his own instruments, studied the impact of glycerol extracts on arteries. In one experiment, he had his son swallow sheep adrenal gland, and he observed how his son's vessels became constricted.  (1, page 155)

He then performed experiments on adrenal extracts at the University of London with Edward Schafer, although were unable to isolate the active ingredient. (1, page 55)(6, NCBI)

 In 1899, even though he had yet to isolate it, John Jacob Abel (1857-1938) gave the active ingredient the name epinephrine, and later Wilson referred to it as adrenaline.  (1, page 155)

Figure 1 --1944 ad showing glass epinephrine,
 ampoule,and a glass syringe with hypodermic needle.
The medicine was drawn up using the needle,
stored in the glass syringe, and either injected
into the patient or into a nebulizer cup.

Since this time, the compounds has been referred to as adrenaline in Europe and epinephrine in America. The confusion that ensued later inspired the World Health Organization to create a law banning the use of two names for the same medical compound, although epinephrine/ adrenaline was grandfathered in. I'm just writing this here to explain why both names are proper and both are still used to this day to refer to the same thing.  (1, page 155-156)

Beginning in 1895 adrenaline extracts were used in experiments to study its vasoconstricting abilities, and to see if this offered benefits for various medical conditions, including rhinitis, conjunctivitis, and asthma. Oliver and Schafer showed the effects of adrenal extract on blood pressure. In 1900, Solomon Solis-Cohen (1857-1948) of Philadelphia showed the effects of adrenal extract on asthma and hay fever. He showed that the pill version of the extract benefited asthmatics. And finally, in 1907 the bronchodilator effect of the substance was proven by Khan. (1, page 156)(14, NCBI)

In 1903, Jesse G.M. Bullowa and David M. Kaplan gave an injection of adrenaline to an asthmatic who, within only minutes, was breathing easy. This was the first known report of an asthmatic getting instant relief from a medicine. (1, page 156)(need second reference).

So, epinephrine was isolated, and then it was synthesized, and this resulted in various epinephrine products. Efforts were then made to refine the compound to obtain the desired effect while minimizing side effects.

Doctors were quick to start prescribing it for their asthmatics, who, as you might imagine, quickly fell in love with the medicine.  Yet the majority of asthmatics continued to stick with their usual asthma remedies, which mainly consisted of asthma cigarettes, powders and incense. Only in an emergency did they seek out a physician, who would give the laboring asthmatic epinephrine, and relief would come within minutes.

The question that remains here is: why did epinephrine give sudden asthma relief? At the turn of the 20th century, asthma experts believed asthma was caused by dilation of the vessels in the lungs (and this resulted in congestion).  So it only made sense that the initial theory was that epinephrine made breathing easier because it constricted vessels in the lungs.  This was also the same reason that cocaine was often used to treat asthmatics.  Many articles report the use of both adrenaline and cocaine. (4, page 854)

Yet another theory, a prominent theory from the 19th century actually, was that asthma resulted from spasming bronchiolar smooth muscles, and in 1907 Khan demonstrated the adrenaline was in fact a bronchodilator. For the next several years both the vasoconstriction and bronchoconstriction theories were believed to contribute to asthma.  (4, page 854)

Adrenaline was initially trialed both orally and subcutaneously, and ultimately it was trialed by injection into the muscles and intravenous.  Various physicians reported the oral route had no effect on asthma, and the muscular route was most effective.  However, there are some reports into the 1910s where physicians continued to debate the best route.

James Adam, in his 1913 book "Asthma and its radical treatment," describes it this way: (7, page 27)

Photo from an advertisement for Adrenaline Ampoules in the 1909-10
edition of"Therapeutic Notes" by Park Davis and Company

Part of the spasm-allaying effect may be due to absorption of the drugs from the nasal mucous membrane or larynx or trachea. But while adrenalin applied to the larynx acts fairly energetically in allaying asthma, applied to the nose it acts much less energetically than when given hypodermically (by injection). However it is given, after arriving at the right ventricle the adrenalin will pass direct to the lungs and there, probably somewhat indirectly, it will have the same effect on the congestion of the bronchi and bronchioles as on nose and larynx. In this way and by its action on the heart it will help to relieve the dyspnoea; but (Brian) Melland  makes a further interesting suggestion. 

Perhaps one first to recommend adrenaline to physicians was Brian Melland.  In the May 21, 1910, issue of Lancet, he "claims marvelous results in the treatment of the paroxysm of asthma by the hypodermic use of preparations from the suprarenal glands. One injection of 10 minims of 1:1000 solution is all that is required, but may be repeated if other attacks supervene." (5)

Melland described some of the experiments he performed on his own patients with severe asthma and hay fever.  One of the case studies is reported on here: (6, page 476)

In the first case, for example, that of a woman 30 years of age, with asthma of 6 years' standing, the first injection of 10 minims of the 1 in 1000 solution caused a paroxysm promptly to disappear and prevented a return of the trouble for seven days, whereas before this spasmodic attacks had been present nightly. After the second injection the effect did not persist so long, and for a time the patient employed every night an injection of (i minims of the solution in order to cut short the spasmodic attacks. After four or five weeks of this, the incidence of the asthma became much less frequent, and the general strength of the patient was greatly improved. The use of adrenalin by the mouth, up to 15 minims of the solution, was also tried in this case, but without result.

These are adrenaline amps from a 1909 advertisement in
Therapeutic Notes.  For the first time the medicine was
pre-measured and pre-satitized.  All that was needed was
to snap off the top and draw up the medicine with a
hypodermic needle (11, page 69)

The opinion of Melland was further expounded upon by James Adam in 1913: (7, page 27)

Adrenalin acts as a stimulant to the sympathetic**. He suggests, and gives supporting evidence, that at the same time it tends to inhibit or relax all involuntary muscles supplied by the cranial and sacral outflow of nerves. Now the constrictor muscles of the bronchi belong to this group,and assuming that spasm of these in part accounts for the asthmatic spasm, they would be relaxed by the adrenalin. Whereas, the constrictor fibre of the bronchial arteries which come off the systemic system, and are, like other systemic vessels, under sympathetic control, will be stimulated to contract, and so the congestion is reduced.

The author's of General Medicine words it in a more friendly fashion: (8, page 164)

Melland believes the adrenalin acts by relaxing the muscles supplied by the vagus nerve, and since the bronchial muscles are innervated by that nerve they are relaxed and the spasm ceases.

By the many articles, snippets and editorials about Melland's article, you can tell there must have been quite a bit of excitement among the medical community, and asthmatics, about this new medicine.  Another example of this comes from the following snippet from Therapeutic Notes in 1909:(9)

ADRENALIN IN ASTHMA.
A practitioner of wide repute in one of the Central States sends us these words: "I wish to write you a word or two about the use of Adrenalin in asthma following hay-fever. Last year my wife was suffering so greatly with this affliction that she could scarcely breathe. No ordinary remedies appeared to give her any relief, so in desperation I sprayed about twenty drops of the stock solution up into the nostrils, and in a few minutes the paroxysm was over and did not return. I am not in the habit of writing this kind of a letter, but this experience is bona fide and I think it should be known."

The hypodermic needle is a hollowed out needle that allows for medicine
to be drawn into a glass syringe and injected into a patient.  It was invented
in 1853 by Dr. Alexander Wood to make it easier to give blood tranfusions
to patients.  It is one of the top 10 medical inventions of all time.  Here is
a nice case by Park, Davis & Co. for its glass syringes. (11, page 269)

Yet there were side effects.  The vasoconstricting quality of the medicine caused blood flow to speed up and this increased blood pressure, and increased the force and rate of the heart.  It also caused asthmatics to feel jittery, anxious and hyper. And while it provided instant relief, this relief only lasted about an hour and a half to two hours.

The next revolution occurred in 1909 when Parke, Davis & Co. introduced glass ampules that they marketed  as Glaseptic Ampoules.  Ads and articles claimed this made it so accurate doses of the the companies line of soluble medicine, such as adrenaline, could be easily and quickly drawn up in an emergency using a hypodermic needle and glass syringe.  This was a major revolution because prior to this physicians or nurses had to sterilize the water to mix with the medicine, and they had to make sure they measured the medicine up correctly.  Each Glaseptic Ampoule "contains a definite quantity of medicament, an average dose," according to ads.*** (10, page 68-9)

Adrenaline solution as pictured in the 1924 edition of Therapeutic Notes

Also in 1910 British Chemist George Barger (1878-1939) and British Pharmacologist Henry Dale (1875-1968)  reported the use of adrenaline as an inhalent.  (4, page 854) Various nebulizers were available, with one of the more common ones being the Glaseptic Nebulizer marketed by Park-Davis and Company.

Another  report of adrenaline being administered by an inhaler came from a London medical practitioner in 1929. (4)( (1, page 156) By this time there were improved nebulizers on the market such as the Speiss-Drager (Apneu) Nebulizer.  During the 1930s various nebulizing products were purchased by physicians to use in their offices, and patients to use at home.  The decade also saw the birth of the electric nebulizer, the Pneumovac.  It was often purchased by pharmacists and the patient would visit the pharmacy for treatment.

Also during this time epinephrine was available under a variety of brand names, including Adrenaline, Adrenaline Chloride, and Asthma Nefrin.

So the quest was on to learn more about this medicine, to fine tune it to get rid of side effects, to make it last longer, and to discover better and faster modes of delivery.

** This will be described in the next post in this series, see "How does epinephrine work" below

***The ampoule was invented in 1886 by a French pharmacist names Stanislas Limousin.  It was invented in response to a need by physicians to conserve their stock of injectable solutions that became difficult to transport and also deteriorated rapidly due to development of moulds.

Further reading:

1. 1893-1933:  How does epinephrine (adrenaline) work?
2. 1933-1957: Research leads to asthma rescue medicine
3. 1900-present: The evolution of rescue medicine

Click here for more asthma history.  

References:

1. Sneader, Walter, "Drug Discovery: A History," 2005, Wiley, Great Britain,  page 155-157. (Sneader provides a very thorough history of the discovery of hormone therapy in the later portion of the 19th century.)
2. " Jockichi Takamine ," Encyclopedia Britannica.com,  http://www.britannica.com/EBchecked/topic/581144/Jokichi-Takamine, accessed 3/6/13
3. Jackson, Mark, "Asthma: A Biography," 2009, Great Britain, Oxford University Press
4. Rau, Joseph L., "Inhaled Adrenergic Bronchodilators: Historical Development and Clinical Application," at AARC.org (American Association of Respiratory Care, July, 2000, Vol. 45, number 7), pages 854-62
5. Melland, Brian, "Some Therapeutic Suggestions: Asthma Paroxysms," Therapeutic Notes, volumes 17 and 18, 1909 and 1910, Park Davis and Company (this snippet is from "Therapeutic Notes, who quote it from an New England Medical Monthly, July, 2010.  The original article referred to here was published in Lancet, May 21, 2010, 
6. Euchariste, Chgarles,  de Medici Sajous, John Madison Taylor, John Vietch Shoemaker, editors, "Cyclopedia of Current Literature: Asthma, Spasmotic, Hypodermic Injections of Adrenalin in the treatment of," volume 3, page 476, review of Brian Melland's report from Lancet, May 21, 2010.
7. Adam, James, "Asthma and its Radical Treatment," 1913, page 27 (Adam references from Melland, Lancet, May 21, 2010)
8. Billings, Frank, George Howitt Weaver, J.H. Salisbury, editors, "Asthma: Treatment," General Medicine, Volume 1, The Practical Medicine Series Comprising Ten Volumes On The Year's Progress In Medicine And Surgery, 1911, Chicago, The Year Book Publishers,  page 164
9. "Adrenaline in Asthma," Therapeutic Notes, Volumes 17 and 18, 1909 and 1910, page 6
10. "Already for use, Solutions we now supply in ampules for the convenience of our medical friends,"  Therapeutic Notes, volumes 17 and 18, 1909 and 1910, Park Davis and Company, pages 68 and 69.  Also see ads on page 59 and pages 259, page 69, page 269 (note: you may have to scroll down a few pages to get to the advertisements)
11. Rubin, Ronald P., "A Brief History of Great Discoveries in Pharmacology: In Celebration of teh Centennial Anniversary of the Founding of the American Socieity of Pharmacology and Experimental Therapeutics," Pharmacological Reviews, December, 2007, vol. 59, no. 4, pages 289-359 (This article provides a good history of the discoveries of the sympathetic nervous system, the neuromuscular synapse, and how hormones such as adrenaline work)
12. McFadden, E.R., "A Century of Asthma," American Journal of Respiratory Critical Care, August 1, 2004, volume 170, no. 3, pages 215-221
13. Bennett, Max R., "History of the Synapse," Chapter 4: "The discovery of adrenaline and the concept of autoreceptors and synapses," 2001, Britain,  Harwood Academic Publishers, pages 65-77, also available at the link: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.462.9571&rep=rep1&type=pdf, accessed 4/14/16
14. Barnes, Peter J, "Drugs for Asthma," British Journal of Pharmacology, January, 2006, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760737/, accessed on 4/14/16