Hering and Breuer Revisited in Humans
An Invasive Study before the Days of Ethics Committees

ABRAHAM GUZ

Charing Cross Hospital, London, United Kingdom

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Hering and Breuer in 1868 had shown, in animals anesthetized with opium, that expansion of the lungs reflexly inhibited inspiration and promoted expiration; the greater the expansion, the more powerful was the inhibition. The effect depended on the integrity of the vagus nervestransmitting afferent neural traffic from the expanding lung to the brainstem. Furthermore, slow, deep breathing with a prolongation of inspiratory time resulted when the vagi were sectioned during quiet resting breathing. During the 1930s, the afferent vagal neural traffic was recorded and shown to be present in the larger diameter myelinated fibers arising from slowly adapting stretch receptors in the airway wall.

In 1961, I returned to a clinical academic position in the UK, from the Cardiovascular Research Institute of the University of California at San Francisco, where I had been taught to "think" by the Director, Dr. Julius Comroe: he had the great facility of summarizing what was not known! What role did the vagus nerve play in breathing control in manboth normal or with cardiopulmonary disease? Did the respiratory sensation of "breathlessness" result from afferent neural traffic in these fibers? I decided to try and work in this area, particularly with the encouragement of Dr. John Widdicombe, a colleague who had already done considerable work on the vagus in animals, but had also recently shown that humans had an exceedingly weak Hering-Breuer inflation reflex, whereas the dog had a very powerful reflex. Our "springboard" paper (Guz A, Noble MIM, Trenchard D, Cochrane HL, Makey AR. Studies on the vagus nerves in man: their role in respiratory and circulatory control. Clin. Sci. 1964;24:293-302) was submitted for publication in December 1963. The principal finding was that under general halothane anesthesia and after administration of atropine (to block efferent parasympathetic fibers), local anesthetic block of the vagus nerves had no effect on the breathing of an anesthetized or conscious subject.

The principal motivation for the study was to understand "breathlessness." We knew very little about sensation from the lungs consequent on activation of vagal afferentsother than the sense of irritation or rawness perceived in the chest, associated with cough. However, there was another, very practical motivation. Cardiac surgeons had begun to experiment with heart or heart/lung transplantation in animalsparticularly the dog. The typical result of the inevitable vagal nerve destruction in these animals was that postoperatively they breathed very slowly (2-6 breaths/min) and deeply; this was thought to be responsible for the death of the vast majority of the animals, if they were not mechanically ventilated.

We hesitated for some months before we found two surgical colleagues with whom we could work as coinvestigators. Both were very senior experienced thyroid surgeons, and we ensured that they understood what was necessary for a definitive study. The vagus nerves are accessible in the neck. They lay behind the carotid artery within the carotid sheath. The surgical view was that during routine thyroid surgery, the nerve could be anesthetized without any additional surgical trauma other than opening the carotid sheath, so that a gauze pledget, soaked in 2% lignocaine, could be applied with precision to the nerve sheath within the carotid sheath. Precision was necessary because of the presence of the phrenic nerve behind the carotid sheath and its contents, albeit separated by a fascial plane; local anesthesia spilling over this fascia would not have been acceptable. Electrical stimulation of the vagus nerve within its sheath would be done only with the electrodes rostral to the site of the nerve block in order to prevent any bradycardia or atrioventricular nodal block resulting from stimulation of parasympathetic efferent fibers.

Were our plans safe? The literature showed that the vagus nerve had been blocked in the neck with 2% lignocaine safely, effectively, and reversibly (after some 15 min) in many animal studies. There was also a huge, albeit confusing literature of results in various animals in whom vagal afferents in the neck had been stimulated rostral to a local anesthetic block; there was no evidence of fiber damage, or of lack of complete recovery. Mechanical stimulation of vagal afferents, rostral to a local anesthetic block, had even been done in a man, in Sweden, in the late 1950s, under general anesthesia during a cardiovascular study; no residual effects had been seen. We all thought that what we were proposing to do was safe.

We spent much time thinking about appropriate ethical behavior. The surgeons selected four mature euthyroid women, intelligent and healthy, with nonmalignant thyroid nodules for whom partial thyroidectomy was planned. Our "ethics" in those days were honest and simple! There were no ethics committees! We explained that we wished to study two nerves, one on each side of the neck; we used diagrams. We said that what we wished to do would add a maximum of 15 min to the operation time. We explained that no incisions in the skin would be made beyond those necessary for the thyroid surgery. We spoke separately to each patient together with her partner and we answered all their questions. We told them that we could see no ill effects resulting from what we wished to do. We were fully aware that physicians, and more importantly surgeons, in those days, were somewhat held in awe! We tried our best to dispel such feelings, but it is unlikely that we succeeded! We made it absolutely clear that their agreement, or lack of agreement, to our planned study had nothing to do with the thyroid operation that would be carried out, as scheduled, irrespective of their decision. On the "Consent to Surgery" form the patients were asked if they agreed to the thyroid surgery and separately to the vagus nerve study. I am fully aware that by the standards of today we would not have been judged to have acted ethically. However, judged by the standards of the early 1960s, I had and still have no guilt feelings.

We had one further "ethical" task and that was to explain to the nursing staff in the clinic, ward, and operating room what we were planning to do. This turned out to be our most difficult problem. In the UK in the early 1960s, the nursing profession gave superb, dedicated, "tender loving care" but they had had no exposure to academic issues of a research nature. Some nurses regarded protecting patients from doctors as a duty! It would be difficult to count the hours spent by my surgical colleagues and myself with the nursing staff, explaining what we wished to do. My respect for the nursing staff went up in leaps and bounds. I do not think my surgical colleagues felt the same way but we were all agreed that we had to try and get the nurses "on board" for very obvious reasons. Interestingly, we did not discuss these matters with the hospital administrators!

At surgery, the vagus nerves were isolated without difficulty. Ventilation was monitored continuously with a pneumotachogram inserted within a cuffed endotracheal tube. Connecting this tube during inspiration to a weighted bag filled with air allowed inflation at constant pressure, while varying the weights changed the inflation volume. Breathing was not inhibited with inflation within the tidal range; inhibition just began with inflation volumes of 500 ml and increased as these volumes increased up to 1,200 ml. Bilateral vagal block with 2% lignocaine, applied with a gauze pledget, blocked these inhibitory effects, but had no effect on tidal breathing. Electrical stimulation of a vagus nerve above such an area of block inhibited inspiration, especially at stimulation frequencies of 50 Hz. An anesthetized dog, cat, or rabbit would have had an inflation reflex demonstrable within the tidal range and would also have developed slower, deeper breathing with bilateral nerve block. Adult humans had the Hering-Breuer system in place without any control over normal resting breathing!

We had one further patient, a man in his 40s, concerning whom there were no ethical problems. He came to see me with an inoperable carcinoma of the bronchus; his only symptoms were in the wrists and ankles, which were painful and swollen. Digital clubbing was present and the arms and legs were abnormally warm; forearm blood flow was high. The patient had learned that sarcomas of the lung in dogs rarely produced a similar syndromethey were relieved by intrathoracic vagotomy ipsilateral to the tumor. I checked this out with a prestigious veterinary school and found the patients' information to be correct! He asked us to do this operation on him. We agreed that we would do such an operation only if we could demonstrate to him and ourselves that vagal block in the neck with local anesthetic relieved his joint symptoms. The patient agreed. Sedation with promethazine hydrochloride orally and administration of atropine to block parasympathetic efferents allowed the surgeon to "fish out" the vagus nerves in the neck painlessly by the use of local anesthetic in the skin and subcutaneous tissues. The patient was fully conscious and was well aware of his joint pains. Anesthetizing the vagi sequentially with 2% lignocaine, using gauze pledgets, caused aphonia (recurrent laryngeal large fiber block) and this recovered completely after 20 min. Joint symptoms did not improve. The patient was grateful that we had tried to help. We had also established that breathing at rest (measured with a pneumogram around the chest), while conscious, did not change with bilateral vagal block in humans. We had failed to help the patient but the effect on the operating room nursing staff was striking and beneficial to us; they had seen a possible therapeutic benefit to what we were doing.

My good fortune was, first, in having been able to start this series of studies at a time when "ethics" were a matter of honesty between the patient and the doctor; and second, that I had a pair of surgical colleagues who had the same attitudes as myself and were confident of their skills in neck surgery. None of our patients suffered in any way and the four female patients requested a copy of the paper that we intended to publish. We were never concerned by "priority of publication" and the study took at least one year; selection of an appropriate patient was of key importance.

Our paper was accepted immediately for publication without any negative comments by the referees. After publication, we received many congratulatory letters and numerous requests for reprints. A particular source of gratification for me was that I began to see abstracts and then papers from cardiac surgeons stating that primates were the appropriate species on which to practice transplantation, because they did not develop slow, deep breathing. I had no idea whether these surgeons had become aware of our work. Another source of pleasure was that our study, followed by further studies conducted in humans, became a factor in the decision by Ciba to hold a symposium during 1969 entitled "Breathing: Hering-Breuer Centenary Symposium," 100 years after the publication of the original seminal work.

I would like to believe that there is a message here for fellows commencing a career in clinical research. Ethics committees should accept that verifiable honesty between patient and all the medical and nursing people involved is the essential component of a research protocol during the course of a clinical procedure.

	Footnotes

Correspondence and requests for reprints should be addressed to Abraham Guz, M.D., Charing Cross Hospital, Fulham Palace Rd., London W6 8RF, UK.