Chapter Twenty: University of California, Davis

Chapter 20 Sub-sections

After 20 years at Mayo, in part because of the harsh winters, Pat and I decided to move if I found a decent position. Our last child had graduated high school, so we searched a number of places, several as potential chair: George Washington University (they selected Burt Epstein, a good decision); the University of Chicago (I withdrew and they selected Mike Roizen, another good decision) and the University of Colorado (I withdrew and they selected Charles Gibbs, again a good decision). Over the years, I had seen enough picky problems for department chairs that my enthusiasm for it was limited.

UC Davis, with its veterinary school, veterinary anesthesia residency, and veterinary anesthesiologists, provided a broadening of research questions. I became Vice Chair of the human Anesthesia Department, and organized a laboratory for diagnosis of and research into MH. Also, at that time, I became Founding Chair of the Board of Directors of the North American Malignant Hyperthermia Registry, an association of the directors of the MH biopsy centers in the US and Canada. This, as a professional extension of the Malignant Hyperthermia Association of the United States (MHAUS), provided professional direction and coordination for standardization of biopsy protocols. At UC Davis, I taught or provided anesthesia in the operating rooms about 50% of the time.

The UC Davis hospital in Sacramento provided care for the huge central California valley population (it continues to do so), with considerable major challenges, e.g., auto accidents, knife and gun wounds, drug overdoses, business/home-related accidents, obstetrical emergencies. Our on-call nights were demanding, generally with two operating rooms occupied with emergencies for most of the night. The care was stretched and strained at times, but we had capable nurses, surgeons, anesthesiologists, residents in training, and CRNAs (certified registered nurse anesthetists). The teams worked well. I'll mention one incident, where the desk clerk at the entrance to the operating rooms was a heroine.

The victim of a gang war was brought to the emergency room and immediately transferred to surgery, with a devastating shotgun wound to abdomen and chest. His survival was doubtful at best, and we began resuscitation and repair. During this, we heard a loud commotion out in the corridor by the operating room front desk. About 10 members of our patient's gang had stormed into the hospital lobby and gone up the stairs to the 2d floor surgical suite. They demanded to be let into the operating room to see their friend being treated. Our desk clerk would not be intimidated --- she screamed at the gang, telling them that their invasion would totally interrupt the surgery and that their friend would then have zero chance for survival. She told them that his chances were poor, anyway, and that they would doom him. After some 5 minutes of violent loud discussion, the gang left the suite. On their way out through the hospital lobby, they trashed the entire area, breaking windows, doors, dumping the waste containers, etc. When our unsuccessful surgery was ended, I went down and examined the mess in the lobby. The gang had not been stopped by anyone down stairs, but our operating room clerk had completely intimidated them. An impossible performance at 2 a.m.

Foundation for Anesthesia Education and Research

In 1987, I was appointed to the Board of Directors of the newly established Foundation for Anesthesia Education and Research (FAER), and was elected founding Secretary-Treasurer, a non-funded position I held through 1992. I maintained the financial data and secretarial information, countersigned the checks, and reported personally at the board meetings. FAER is the independent non-profit research arm of the American Society of Anesthesiologists, a separate entity, since political donations by the Society made it impossible for it to be a charitable concern. FAER fulfilled this role and funded deserving researchers.

Greg LeMond, Shot

A dramatically unusual experience at UC Davis, covered in newspapers worldwide in those countries in which cycling was popular: in the spring following his first Tour de France win in 1986, Greg LeMond was hunting wild turkeys in the California Sierra's, east of Sacramento, wearing camouflaged clothing. His companion unintentionally shot him with a shotgun, with severe hemorrhaging in his chest and abdomen. An urgent helicopter rescue brought him to UC Davis for dramatic and bloody life-saving emergency surgery, his identity unknown. He was lucky to survive, to have a helicopter arrive soon after the shooting, and to go to a hospital experienced in trauma and equipped for it. As the Level One Trauma Center serving central California and its 7 million people, UC Davis saw many patients like this and had outstanding emergency doctors and nurses.

He stayed in the ICU a few days, and then recovered in a private room adjacent to it. His recovery among the other ICU patients was without regard to international status (or lack thereof), income, sex, or other factors. At least one of his fellow patients was a prisoner from Folsom, the prison south of Sacramento.

Beginning about his second or third postoperative day, I was the faculty anesthesiologist on pain rounds. He and I discussed bikes, and my solo cycling trip in 1983 from London to Heidelberg in which I passed through Kortrijk, Belgium, where he had owned a home. A lengthy recuperation caused him to miss the next two Tours. After that, he won the next two Tours, against virtually all expectations. Without those health crises, he might have won at least five Tours.

UC Davis Research Projects

One project was factual support of the inaccuracy of muscle calcium uptake as an MH diagnostic test (Jaffe et al, 1991). Another project involved the ‘final common path' phenomenon in apparent clinical MH episodes in muscle disorders such as Duchenne Dystrophy. The lesion in Duchenne's is lack of dystrophin, a substance that stabilizes the permeability of the surface muscle membrane, the sarcolemma. Duchenne muscular dystrophy is an X-linked chromosomal disorder, which means that it's carried by the mother and mostly passed on to boys. It seldom occurs in girls because the second normal X chromosome overpowers the effect of the abnormal X chromosome. In boys, the ‘puny' ineffective Y chromosome can not counteract the abnormal X chromosome, and Duchenne's appears. The skeletal muscles are abnormal at birth although that may not be apparent even during activity. However a muscle abnormality can be detected at birth because CK can be increased some 10 fold.

Because of evidence suggesting that MH can occur in a patient with Duchenne's, we performed muscle biopsy and contracture responses on two 2-year-old boys. The test for dystrophin showed that one boy had Duchenne's and the other, Becker Dystrophy, a weaker form of Duchenne's. The Duchenne weakened muscle membranes lose integrity when stressed and thereby promote compensatory hypermetabolism, resembling an MH episode (Gronert, Fowler et al, 1992). Our results helped demonstrate that this hypermetabolism is a resemblance to MH, unrelated to genetic MH and not an episode. Treatment with dantrolene may be indicated, to relieve the stresses and toxicity affecting the patient.

We assisted in evaluating California's Fish and Game transfer of wildlife to aid declining populations, and evaluated stress responses during capture, handling, and transfer of Bighorn sheep (Martucci et al, 1992).

We updated the MH field with chapters in monographs (Gronert, 1994; Gronert, Brandom 2002; Gronert, Pessah et al, 2005), plus an annual update article (Adnet et al, 1999). Pascal Adnet, first author, unfortunately met with disaster; this native Belgian died in Africa while working with Doctors Without Borders. In addition, I helped prepare chapters for monographs, on the effect of general anesthesia in modifying the effects of muscle relaxants (Gronert, 2003), guidance in animal research (Gronert, Antognini, 2001), and malignant hyperthermia as a pediatric neuromuscular disorder (Gronert, Brandom, 2002).

During testing on a patient's muscle specimen on one of our laboratory's contracture test days, we observed a bath temperature that was greater than the normal of 37˚ C (98.6˚ F). This mishap was due to an error in the temperature control of our muscle baths. Because we were concerned that this could alter contracture test results, we studied the effects of variations in temperature, and observed few problems, none great enough to alter a diagnosis (Antognini et al, 1997).

Publication of a fatal case of apparent awake MH in association with quite mild exercise (Ryan et al, 1997) prompted journal editors to request an editorial from Joe Antognini and me (Antognini et al, 1997). This well conditioned runner was running easily at a moderate pace on a track, when he collapsed and died. Our editorial discussed the implications of this tragedy, for his degree of activity was not sufficient to explain why he collapsed.

Computer Programs for Analysis of Muscle Relaxant Responses

Additional research at UC Davis included pharmacokinetic and pharmacodynamic analysis to quantitate altered muscle responses to non-depolarizing skeletal muscle relaxants (Gronert, Matteo et al, 1984). These non-depolarizers include curare, vecuronium, rocuronium, and metocurine. These studies were finally possible because of advances in laboratory-based muscle relaxant analysis and computer-directed determination of the relationship between plasma drug concentration and degree of paralysis. Plasma concentrations of relaxants are tiny, and newer developments in analysis made these studies possible. They could as of recently be measured accurately. In addition, mathematical analysis of plasma concentration, drug doses, time, and degree of paralysis could now be modeled via computer programs. The formula, the Hill equation, for the 50% paralyzing plasma concentration is

Degree of paralysis = (1.0 * Ceγ) / IC50γ + Ceγ)

Where 1.0 is the maximal effect (100% paralysis), Ce is the estimated plasma concentration in the theoretical effect compartment, IC50 is the effect compartment concentration at 50% paralysis, and γ is the slope factor of the sigmoidal concentration-response curve (Shafer et al, 1989). The effect compartment is the site at which the drug interacts with the receptor.

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics refers to how the body handles the drug, and pharmacodynamics refers to how the drug acts on the body. For example, succinylcholine is inactivated as it is hydrolyzed by plasma cholinesterase, but hydrolysis is slowed or halted when there is abnormal or absent cholinesterase, thereby leading to a greatly prolonged action, i.e., from about ten minutes to about six hours. This is a pharmacokinetic effect, because the body cannot break down the molecule.

When there is upregulation of acetylcholine receptors, the agonist effect of succinylcholine is exaggerated at the receptor site due to undue depolarizing sensitivity, and hyperkalemia results. This is a pharmacodynamic effect, i.e., a normal amount of drug acts on receptors that over-respond. Succinylcholine depolarizes the additional receptors, with an extraordinary extra release of potassium, because, while each receptor releases approximately a set amount of potassium, the greater numbers of receptors releasing potassium lead to a magnified cumulative increase in its amount.

The opposite effect occurs with downregulation, when there are fewer numbers of functional receptors. In myasthenia gravis, there are fewer receptors to respond to succinylcholine, so there is a modest and not dangerous resistance to succinylcholine, well demonstrated by Eisenkraft et al (1988). This is also a pharmacodynamic effect.

Exercise and Disuse Atrophy: Effects of Non-depolarizing Relaxants

Using these more sophisticated pharmacokinetic and pharmacodynamic analyses, we evaluated effects of cast immobilization disuse atrophy as a milder form of upregulation in altering the potency of succinylcholine (Fung et al, 1991), and of non-depolarizing relaxants (Fung et al, 1995). We evaluated the effects of conditioning equine exercise (running on a giant treadmill) in increasing the potency of metocurine, as down regulation (White et al, 1992), such as we had seen in dogs (Gronert, White et al, 1989). While there was a trend toward a difference, it was not significant (White et al, 1992).

It's amazing to see horses run on James Jones' treadmill; it's set up in a large room in a laboratory building and the noise is akin to that in a boiler factory. The horse wears a face mask to permit measurement of total body oxygen consumption for associated studies, so virtually everything about the experiment is weird. Horses adapt to the face mask and running in place more easily than you might expect.

Jeeva Martyn and several others of us wrote an article on up- and downregulation of acetylcholine receptors, and also discussed another risk of succinylcholine-induced hyperkalemia, namely those patients having long term intensive care unit immobilization and confinement to bed (1992). These exaggerated responses were likely due to receptor upregulation of skeletal muscle disuse atrophy and of denervation-related receptor changes secondary to patients receiving long term non-depolarizing relaxants, sometimes accentuated by steroids. These relaxants pharmacologically block the acetylcholine receptor and essentially chemically denervate the muscle, i.e., deprive it of its nerve impulses. These are vital to maintain a normal distribution of endplate receptors.