Chapter Twenty-One: World Congress of Anaesthesiology, den Haag, 1992

Chapter 21 Sub-sections

In October 1983 I flew with my bike to London and cycled – solo – from there to Dover, ferried across the channel, on to Köln, and up the Rhine River, eventually to Heidelberg, with help from Kit and Bob Lennon on the last segment from Frankfurt. For Fig. 18, I set my camera on the roof of a car to take this photo, just east of Lo, Belgium; note that I carried maps, slides, valuables, bicycle parts, and ‘dress clothes' in the handlebar and rear carrier bags. During the trip, I read "A Bridge Too Far" about the Market Garden

Figure 18
Fig. 18. Solo bike trip just east of Lo, Belgium

offensive of World War II, and decided that it would be worthwhile to trace the movements, since they followed Holland's canals. In 1992, Pat and I flew with our bikes to London, cycled there a few days to orient ourselves, and then traveled by train to the coast. Next, the ferry to Oostende, and cycling into Bruges: so wonderfully gracious: the hospitality --- the superb hotel kept our bicycles in its formal dining room, the food, the canals at midnight. Then to Antwerp, eastern Belgium and into Holland, where we visited some of the routes and battlefields. Various areas were vital to success or failure. Dutch intelligence was not always trusted, because of possible Nazi infiltration, but the Allies apparently erred in ignoring the small ferry at Driel, a few miles west of the main bridge crossing of the Rhine River at Nijmegen. The simple ferry crossing might have saved the offensive, and the failure of the ‘bridge too far.'

We particularly enjoyed the efficient cross country Dutch cycling routes. We visited the Kröller-Müller Museum and also found by accident a great restaurant, the Herberg de Schutter, in Woerden. We stayed overnight in Delft, then on to den Haag, its Mauritshuis, and the World Congress of Anaesthesiology, where I spoke on malignant hyperthermia. We stayed at the meeting-related tall Promenade Hotel, and stored the bikes in an underground store room. We hung out our clothes – the first time my suit had been out of my Robert Beckman pannier in two weeks – and washed our dirty laundry. The next morning we visited the Floriade (national flower celebration held every ten years) with the Dutch native Abraham van der Spek of the Children's Hospital, University of Michigan, Ann Arbor, and his family.

Origin of the Succinylcholine Regulatory Furor

The best part of the Congress (for me) was a symposium reviewing recent advances in MH, held in Amsterdam and published in several languages as a teaching videotape, distributed worldwide ("Understanding Malignant Hyperthermia" 1992). I took the train to Amsterdam, but needed a taxi to the meeting as it was in an obscure area. This was an educational program for Proctor and Gamble, not commercially overdone.

The panel included Henry Rosenberg, Philadelphia, chair, Helle Ording, Denmark, Richard Ellis, Leeds, Uwe Schulte-Sasse, Heilbronn (near Heidelberg), Jens Peter Jensen, Mainz, Vincenzo Tegazzin, Padua Italy, and me. Rosenberg, Schulte-Sasse, and I discussed episodes of succinylcholine related cardiac arrest in young children. Until then, most cases like this had been regarded as aberrant MH episodes. But this had been a mistake. We now realized that these were due to acute rhabdomyolysis and hyperkalemia related primarily to other myopathies, such as Duchenne muscular dystrophy. In many children, there may be no obvious sign of a myopathy, which does not mean that they're normal, or that their muscles would respond normally to anesthetic drugs. Some might develop MH, some might develop that other terrible problem, rhabdomyolysis: muscle breakdown and loss into the blood stream of potassium, myoglobin, and CK.

Necessary Warning Sparks the Anesthesia Furor

This conference generated a letter to the journal, Anesthesiology (Rosenberg et al,), published in December 1992, a review by the National Institutes of Health, and review of relevant publications (Delphin et al, 1987; Larach et al, 1997; Schulte-Sasse, 1993). After the publication of the material relating to sudden cardiac arrest in children given succinylcholine, the FDA and one of the pharmaceutical companies re-wrote the succinylcholine drug label to better define the problem, and recommended that succinylcholine be used in children only in emergencies or airway challenges. Furor resulted as pediatric (and other) anesthesiologists vehemently protested these restrictions. The label was modified but with essentially the same overall cautionary guidelines (Bedford et al, 1995).

Fifty- year Review of Succinylcholine Cardiac Arrests

In 2001, I published an analysis of cardiac arrests following use of succinylcholine, including all cases I could find over the prior fifty years since it had been introduced in clinical practice (Gronert, 2001). Arrests related to use of succinylcholine in myopathies were more difficult to successfully resuscitate; an added difficulty is that many of these children appear normal and show no sign of myopathy prior to anesthesia. Resuscitation following hyperkalemic cardiac arrest related to upregulation of skeletal muscle acetylcholine receptors was generally 90% successful, while resuscitation in cases involving rhabdomyolysis was about 70% successful. Statistical analysis of these results is not possible because the data are uncontrolled, representing a 50 year historical collection of case reports. The poorer result in myopathies was likely due to ongoing potassium release from damaged muscle membranes, a less fit patient due to restrictions of activity related to the myopathy, or myopathic deterioration of cardiac muscle function. The upregulatory arrest was limited in time and amount because the extra potassium channels closed again within a few minutes.

The total amount of circulating plasma potassium is small, about 12 mEq in adults. This is calculated as follows: an average adult has a five liter blood volume and hematocrit 40%. Since 40% is the volume of red cells, then 40% of the five liter blood volume equals two liters of red cells. That leaves three liters for the plasma volume, the source of potassium to the coronary arteries. Multiply the 3 liter volume of plasma by the normal concentration of potassium in that plasma, or 4 mEq/l --- 3 X 4 = 12 mEq of potassium total in the circulating plasma. The rapid release of just 12 mEq of potassium from muscle tissue into the blood stream will double the plasma potassium, from 4 to 8 mEq/l, a toxic cardiac level (Gronert, Theye, 1975; Gronert, 2001). Ordinarily, potassium is re-distributed from plasma into tissue, particularly liver, but rapid release of potassium from tissues will increase the concentration to toxic levels before re-distribution can relieve the stress.

Muscle Receptor Responses in Various Mammals

Later, at den Haag, during the meeting, I discussed some research data in several mammalian species given a single non-depolarizing muscle relaxant with the renowned muscle researchers Francis Foldes (it was his 82d birthday during the meeting) and Bill Bowman. Foldes didn't think that the receptor area for relaxants was the same in various species, could be, or should be. He cited rat data that curare-type drugs are modestly effective, and that steroid types are fifty times more effective.

However we had an interest regarding the relationship of the skeletal muscle nicotinic acetylcholine receptor and varying animal responses. And our data showed a relationship among higher mammals, perhaps supporting the belief that muscle receptors for relaxants are relatively uniform among many species (Gronert, Fung et al, 1995). This was an interesting project. We – and veterinary anesthesiologists – anesthetized various healthy species, sometimes for elective surgery, ranging in size from horse to rat, and determined their response to gradual paralysis by metocurine, much as we'd done in study of disuse atrophy.

Since the acetylcholine receptor is highly conserved among species, our simple theory was that, if receptor density and amount are similar among species, then the potency of a competitive antagonist, e.g., a non-depolarizing skeletal muscle relaxant, might be similar among species. We examined seven mammals: rat, cat, dog, sheep, pig, horse (Gronert, Fung et al, 1995), and goat (Antognini et al, 1995). We observed

Figure 19
Fig. 19. Linear relationship among various species regarding potency of the non-depolarizing muscle relaxant metocurine.

a correlation between size and potency of metocurine, for all but three of the mammals we examined. There was a linear relationship between the plasma concentration at 50% blockade of the muscle twitch and body mass. Fig. 19 (modified with permission --- by the addition of the goat point --- from Fig. 5, in Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals, Gronert GA, Fung DL, Jones JH, Shafer SL, Hildebrand SV, Disbrow EA, American Journal of Physiology, 1995; 268:R85-R91, used with permission, The American Physiological Society, www.the-aps.org; goat data point, Antognini JF, Wood R, Gronert GA, Metocurine pharmacokinetics and pharmacodynamics in goats, J Vet Pharmacol Therap 1995; 18:464-467, used with permission, Wiley-Blackwell Publishing, www.blackwellpublishing.com).

From den Haag, we cycled to Vlissingen, took the ferry to Sheerness, and cycled via Greenwich to our Crescent Hotel in London. After a day or so we flew to San Francisco. Customs x-rayed our bicycles in the boxes, and asked us where we'd last been on a foreign trip.

We said, "Germany in 1990."

Customs said, "What about Canada a month ago?"

We'd been there to celebrate the 50th anniversary of the introduction of curare into anesthesia and forgotten that, but we also didn't think that Canada was a foreign country.