Control pigs required 109.9 ug/kg/min and MHS pigs required 72.4 ug/kg/min infusion of Organon 9426 to maintain a 90% block. It appears that Organon 9426 is only one-third to one-half as potent as Vecuronium in pigs. ...Control pigs required 109.9 ug/kg/min and MHS pigs required 72.4 ug/kg/min infusion of Organon 9426 to maintain a 90% block. It appears that Organon 9426 is only one-third to one-half as potent as Vecuronium in pigs. The fact that MHS pigs only require 66% of the infusion dose to maintain a 90% block suggests that there is difference in the neuromuscular effect of Organon 9426 in MHS vs. control pigs. A linear regression analysis of the dose response data to Organon 9426 in MHS pigs indicated that 427.033 ug/kg would be required to produce a 100% neuromuscular blockade vs. 586.31 ug/kg in control pigs. Nine of the ten MHS pigs did not develop MH or show any signs of impending MH during the halothane and succinylcholine challenge at the end of the infusion period. Organon 9426 is the first muscle relaxant to offer significant protective action at a clinical dose. This suggests that there is an allosteric site on the sodium channel (acetylcholine receptor) which regulates the flow of sodium ions through the sodium channel. Organon 9426 may be therapeutically effective in an active MH case [1].展开更多
Malignant Hyperthermia (“MH”)—the rapid onset of extremely high fever with muscle rigidity—is caused by a runaway heat production futile cycle mediated via the sodium channels at the myoneural receptor sites. MH i...Malignant Hyperthermia (“MH”)—the rapid onset of extremely high fever with muscle rigidity—is caused by a runaway heat production futile cycle mediated via the sodium channels at the myoneural receptor sites. MH is not triggered by non-depolarizing muscle relaxants;however, depolarizing muscle relaxants may trigger it [1]. Here we present a de novo hypothesis of how MH is triggered and develops. We believe that the acetylcholine receptor/sodium channels in the muscles of MH susceptible pigs initiate MH by allowing an increased flux of sodium ions when it is depolarized by acetylcholine or other depolarizing agents, such as succinylcholine and Halothane. Our theory is consistent with our observations of the effects of general anesthetics over twenty years. Succinylcholine is a depolarizing agent that is a potent MH trigger. Acetylcholine, the natural depolarizing muscle activator, may trigger MH if the susceptible patient or animal is exposed to sufficient stress, i.e., during strenuous activity, such as transport, fighting, breeding, etc. Halothane apparently destabilizes the myoneural sodium channels, which rapidly induces MH. The increased sodium channel activity releases heat with cascades that further releases of heat which results in the rapid onset of MH. MH susceptible pigs have increased action potential amplitudes at their myoneural junctions that are abnormally long in duration. This increased activity is thought to induce hypertrophy of muscle mass, increase metabolic rate, and cause other physical manifestations. When slaughtered, this increased metabolic activity causes the rapid post mortem release of heat in the muscles of MH susceptible pigs and, at the same time, the accumulation of low acidity, all of which denatures the muscle proteins to result in a pale, soft, exudative, pork meat considered to be of lesser quality for human consumption. The potency of inhalation anesthetics as a MH triggers varies widely. The inhalation anesthetic Halothane is a strong trigger of MH, causing MH within minutes of exposure. In contrast, the anesthetic Sevoflurane is a very weak trigger of MH, requiring several hours of inhalation exposure to trigger MH. Because of this, changing from Halothane to Sevoflurane as the general anesthetic of choice for surgeries in hospitals in the Greater Kansas City area during 1994 to 2006 led to an 11-fold decrease in the incidence of MH, from 1:50,000 to 1:550,000 [11]. One non-depolarizing muscle relaxant, Organon 9426 (“Rocuronium”) temporarily prevents MH in MH susceptible pigs when they are given sufficient dosages of it before being challenged with either Halothane or succinylcholine. Binding Rocuronium to the myoneural receptor sites apparently stabilizes them, thereby preventing increased sodium channel activity, and resulting MH. However, other non-depolarizing muscle relaxants do not have this protective effect— for examples Vecuronium, Arduan, and Organon 9616 do not. Uncoupling of mitochondria is not the source of accelerated heat production in MH susceptible pigs, as heart, liver, and skeletal muscle mitochondria isolated from MH susceptible pigs are all competent.展开更多
Malignant Hyperthermia (MH) is a rare genetic disease. However, it is devastating when it occurs in a patient. MH is usually triggered by inhalational anesthetics and/or depolarizing muscle relaxants. Public awareness...Malignant Hyperthermia (MH) is a rare genetic disease. However, it is devastating when it occurs in a patient. MH is usually triggered by inhalational anesthetics and/or depolarizing muscle relaxants. Public awareness of MH has increased with the presentation of an episode on the television program, “House”, and the availability of web-based information. For over 20 years, the MH susceptible pig has been used in experiments by our group as an animal model for MH in humans. The incidence of Malignant Hyperthermia in the Greater Kansas City Area has declined dramatically since the introduction of Sevoflurane in 1992 as the anesthetic of choice (over 60% usage rate) in most surgical procedures. Historically, Malignant Hyperthermia was reported to occur at a rate of 1:50,000 during surgical procedures [1]. In the Greater Kansas City Area, Malignant Hyperthermia (MH) occurred at a rate of 1:53,636 during the 1965-1985 time period, as there were 38 MH cases in 35 patients [2]. During the past ten years (1996-2006), there were only 2 cases of MH, representing an incidence rate of 1:597,240. That decrease is an 11.13 fold (or 89%) decrease which is very significant. Despite the reduced incidence of Malignant Hyperthermia, two recent cases of MH that result in deaths in Wisconsin and Florida make it imperative that MH is recognized early and appropriate treatment initiated without delay. We have expanded our analysis of the futile cycle mechanism that underlies the MH syndrome. MH is equivalent to the rapid discharge of a battery by a short circuit.展开更多
文摘Control pigs required 109.9 ug/kg/min and MHS pigs required 72.4 ug/kg/min infusion of Organon 9426 to maintain a 90% block. It appears that Organon 9426 is only one-third to one-half as potent as Vecuronium in pigs. The fact that MHS pigs only require 66% of the infusion dose to maintain a 90% block suggests that there is difference in the neuromuscular effect of Organon 9426 in MHS vs. control pigs. A linear regression analysis of the dose response data to Organon 9426 in MHS pigs indicated that 427.033 ug/kg would be required to produce a 100% neuromuscular blockade vs. 586.31 ug/kg in control pigs. Nine of the ten MHS pigs did not develop MH or show any signs of impending MH during the halothane and succinylcholine challenge at the end of the infusion period. Organon 9426 is the first muscle relaxant to offer significant protective action at a clinical dose. This suggests that there is an allosteric site on the sodium channel (acetylcholine receptor) which regulates the flow of sodium ions through the sodium channel. Organon 9426 may be therapeutically effective in an active MH case [1].
文摘Malignant Hyperthermia (“MH”)—the rapid onset of extremely high fever with muscle rigidity—is caused by a runaway heat production futile cycle mediated via the sodium channels at the myoneural receptor sites. MH is not triggered by non-depolarizing muscle relaxants;however, depolarizing muscle relaxants may trigger it [1]. Here we present a de novo hypothesis of how MH is triggered and develops. We believe that the acetylcholine receptor/sodium channels in the muscles of MH susceptible pigs initiate MH by allowing an increased flux of sodium ions when it is depolarized by acetylcholine or other depolarizing agents, such as succinylcholine and Halothane. Our theory is consistent with our observations of the effects of general anesthetics over twenty years. Succinylcholine is a depolarizing agent that is a potent MH trigger. Acetylcholine, the natural depolarizing muscle activator, may trigger MH if the susceptible patient or animal is exposed to sufficient stress, i.e., during strenuous activity, such as transport, fighting, breeding, etc. Halothane apparently destabilizes the myoneural sodium channels, which rapidly induces MH. The increased sodium channel activity releases heat with cascades that further releases of heat which results in the rapid onset of MH. MH susceptible pigs have increased action potential amplitudes at their myoneural junctions that are abnormally long in duration. This increased activity is thought to induce hypertrophy of muscle mass, increase metabolic rate, and cause other physical manifestations. When slaughtered, this increased metabolic activity causes the rapid post mortem release of heat in the muscles of MH susceptible pigs and, at the same time, the accumulation of low acidity, all of which denatures the muscle proteins to result in a pale, soft, exudative, pork meat considered to be of lesser quality for human consumption. The potency of inhalation anesthetics as a MH triggers varies widely. The inhalation anesthetic Halothane is a strong trigger of MH, causing MH within minutes of exposure. In contrast, the anesthetic Sevoflurane is a very weak trigger of MH, requiring several hours of inhalation exposure to trigger MH. Because of this, changing from Halothane to Sevoflurane as the general anesthetic of choice for surgeries in hospitals in the Greater Kansas City area during 1994 to 2006 led to an 11-fold decrease in the incidence of MH, from 1:50,000 to 1:550,000 [11]. One non-depolarizing muscle relaxant, Organon 9426 (“Rocuronium”) temporarily prevents MH in MH susceptible pigs when they are given sufficient dosages of it before being challenged with either Halothane or succinylcholine. Binding Rocuronium to the myoneural receptor sites apparently stabilizes them, thereby preventing increased sodium channel activity, and resulting MH. However, other non-depolarizing muscle relaxants do not have this protective effect— for examples Vecuronium, Arduan, and Organon 9616 do not. Uncoupling of mitochondria is not the source of accelerated heat production in MH susceptible pigs, as heart, liver, and skeletal muscle mitochondria isolated from MH susceptible pigs are all competent.
文摘Malignant Hyperthermia (MH) is a rare genetic disease. However, it is devastating when it occurs in a patient. MH is usually triggered by inhalational anesthetics and/or depolarizing muscle relaxants. Public awareness of MH has increased with the presentation of an episode on the television program, “House”, and the availability of web-based information. For over 20 years, the MH susceptible pig has been used in experiments by our group as an animal model for MH in humans. The incidence of Malignant Hyperthermia in the Greater Kansas City Area has declined dramatically since the introduction of Sevoflurane in 1992 as the anesthetic of choice (over 60% usage rate) in most surgical procedures. Historically, Malignant Hyperthermia was reported to occur at a rate of 1:50,000 during surgical procedures [1]. In the Greater Kansas City Area, Malignant Hyperthermia (MH) occurred at a rate of 1:53,636 during the 1965-1985 time period, as there were 38 MH cases in 35 patients [2]. During the past ten years (1996-2006), there were only 2 cases of MH, representing an incidence rate of 1:597,240. That decrease is an 11.13 fold (or 89%) decrease which is very significant. Despite the reduced incidence of Malignant Hyperthermia, two recent cases of MH that result in deaths in Wisconsin and Florida make it imperative that MH is recognized early and appropriate treatment initiated without delay. We have expanded our analysis of the futile cycle mechanism that underlies the MH syndrome. MH is equivalent to the rapid discharge of a battery by a short circuit.
