Chapter Eleven: Begin Research

Chapter 11 Sub-sections

The U.S. Army Burn Unit set the stage for several decades of research. Only years later did I realize that I'd properly approached research, perhaps due to the laid back influence of my medical school mentor, Neena B. Schwartz. Much later I read the following: ‘Success must come gently, with a great deal of effort, but with no stress or obsession' (Carlos Castenada). I didn't realize that that's what I was doing. The Brooke Army anesthesia resident Bob Gunther and my burn unit colleague Paul Schaner were co-authors of our first research paper, in which we described the use of the volatile anesthetic halothane in burn patients (Gunther et al, 1969). Our next report evaluated liver function in patients exposed to halothane on multiple occasions, without evidence of hepatic damage, (Gronert, Schaner et al, 1968). Reports in the early 1960s had incriminated halothane as a liver toxin, and our article indicated that there was no evidence for that in burn patients anesthetized by it on 15 or more occasions in a two month period. This in a sense confirmed the findings of the National Halothane Study (Seeley, 1966; National Halothane Study, 1969), which showed that fatal necrosis after halothane was rare. Mortality after halothane anesthesia was overall 1.87%, and for all agents, 1.93%. There were 856,515 estimated administrations of anesthesia in the study and 254,898 involved halothane. There were nine unexplained cases of necrosis in the entire group, seven after halothane and 2 after cyclopropane or other anesthetics. Thus, if halothane was a factor, its incidence was less than 1:100,000 administrations.

Our next burn unit project had more than the usual significance.

Succinylcholine-induced Hyperkalemia

A seminal paper on hyperkalemia in burn patients, published in spring 1967 (Tolmie et al), opened an entire field involving upregulatory changes in skeletal muscle nicotinic acetylcholine receptors, although at that time, we didn't know of upregulation. I had been impressed with this article when I first read it, and, when I was assigned to the US Army Burn Unit, I jumped at the chance to pursue that lead.

A seemingly minor article had been published in 1964 (Bush). I had reviewed it when evaluating the literature concerning cardiac arrests in burn patients, but missed the point that there was resistance to the muscle relaxant curare. This, although I didn't realize it at the time, demonstrated the yin and yang between succinylcholine and non-deplarizing muscle relaxants. Non-depolarizers act by directly blocking acetylcholine in a competitive manner, and Bush's was the first report of simultaneously increased sensitivity to succinylcholine and resistance to the non-depolarizer, curare. This resistance occurs for the same reason that excess potassium is released, namely, that there are greater numbers of acetylcholine receptors in the muscle membrane, resulting in supersensitivity. Thus, a depolarizer, e.g., succinylcholine, has many more receptors to act upon. Each receptor releases a small amount of potassium, but now, with the many extra receptors, there is a cumulatively greater release of potassium. Supersensitivity means that even very small doses of succinylcholine, e.g., 10% of the usual dose, release excessive amounts of potassium, due to the extra receptors (Gronert, Lambert et al, 1973). This is also an example of upregulation.

A non-depolarizing relaxant, e.g., curare, loses potency in paralyzing skeletal muscle because there are so many extra receptors to interact with the acetylcholine released from the motor nerve, and therefore more relaxant is required before it is blocked. The numbers of acetylcholine and non-depolarizer molecules classically compete for the acetylcholine receptor. We could have improved our early research goals had we realized the implications of Bush's paper.

Burn Patient Potassium Changes after Receiving Succinylcholine

Figure 9
Fig. 9. Note that the potassium value on day 36 increased from a baseline of 4.7 to 9.1 mEq/L. (Reprinted with permission from Succinylcholine-induced hyperkalemia in burned patients – II, by Gronert GA, Dotin LN, Ritchey CR, Mason AD Jr, Anesthesia Analgesia, November-December, 1969; 48:958-62, figures 2, 3, copyright owner Lippincott, Williams & Wilkins, www.LWW.com (for figures 9 and 10 of this memoir).

We conducted a series of human studies. While Tolmie et al had potentially opened an entirely new field of investigation, which seemed to explain why any burn patient might arrest during anesthesia, we needed to confirm their single patient study. At that time, typical for the period, the burn unit research committee approved the study without requiring informed consent. I doubt that our very ill patients from the Army, Air Force, and Navy would have been able to provide a rationally informed consent. By today's standards, the study was likely unethical. When we did observe phenomenal increases in potassium after use of succinylcholine, we didn't stop the study (Fig. 9). We did not have a cardiac arrest in any study patient. Had one occurred, it's likely that we would have discontinued the project. Arrest was entirely possible had we done enough burn patients, but despite study of more than 60 patients, we saw none, in spite of high potassium levels, and abnormal EKGs (Fig. 10). Perhaps no patient had arrested because they were young and still fit as regards their cardiovascular system. We continued the study so that we could define the hyperkalemic response to succinylcholine as completely as possible, given our unique patients. We ended it after two groups of patients, given two differing doses of succinylcholine, which demonstrated that smaller and larger doses had similar results. We had examined soldiers and sailors recovering from burn injuries suffered in Viet Nam. We measured changes in plasma potassium after injection of succinylcholine at varying times after their thermal injury, and correlated them with EKG changes. (Gronert, Dotin et al, 1969).

Figure 10
Fig. 10. The prior Fig. includes the entire group of study patients. (See Fig. 9 for permission.)

The hyperkalemic response begins in burn patients about one week post-burn, and diminishes when the patient has good skin graft coverage, becomes active and mobile, begins eating well, and is gaining weight. We further noted that non-depolarizing relaxants do not result in hyperkalemia (Carr et al, 1969).

My colleague Paul Schaner was to present an abstract of our early burn succinylcholine data at the 1968 annual meeting of the American Society of Anesthesiologists in Washington DC, but a family emergency called him home. This was my first presentation at a professional meeting (Schaner, Gronert et al, 1968). It was at that meeting that Hermann Rahn, the magnificent physiologist from the State University of New York at Buffalo, presented his concepts of relative alkalinity with the best Rovenstine Memorial Lecture I have ever heard. It complemented much of what I'd learned of acid-base considerations in medical school, internship, and residency.

Late summer 1969 ended my military commitment and I returned to Mayo. Using vacation time on our way home, we traveled via Washington, DC and were at services in the National Cathedral, where we watched our astronaut walk on the moon, and heard the striking comment: "One small step for mankind."