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An effect of magnesium on neuromuscular function in parturients
ELSEVIER
An Effect of Magnesium on Neuromuscular Function in Parturients Robert M. Ross, MD,* Anesthesiology
Department,
Thomas Baker, MS-f-
Monmouth
Medical Center, Long Branch, New Jersey
Study Objective: To determine the effprts of magnesium suljate on neuromuscular transmission in parturients. Design: Open-label, clinical study. Setting: Preeclamptic patients at a university-affiliated hospital. Patients: 12 prepant patients, ages 18 to 40 years, with preeclampsia or entm’ngpreterm labor. Interventions: Patients were treated with magnesium sulfate. Train-ofjour (7’0F) recordings of the add&or pollicis muscle were obtained before and 30 minutes ajtw the magnesium .&fate infusion. Measurements and Main Results: Each contractile response in the control 2YIF showed an intrease in the tension deuetoped in response to supramaximal stimulation. The TOF responses after magrzesium .sulfate did not demons&a& this phenomenon, hut rather developed fad?. y’he ?>/I’, ratios ranged from 0.72 to 0.92. Conclusions: In this patient population, clinically relevant injusions of magnesium sulfate produced ,signijirant rhanges in neuromusrular transmission as manifested by loss qf treppe phenomenon and diminished 7UF response to ulnar nerue stimulation.
Keywords: Magnesium: transmission/parturients:
neuromuscular train-of-four
transmission; fade.
neuromuscular
Introduction
“Chief tDirector
of Obstetrical
Magnesium sulfate affects neuromuscular transmission in part by interfering with the release of the neurotransmitter, acetylcholine. It is a double charged cation and takes the place of calcium, another double charged cation, which is needed for transmitter release.’ In fact, the quanta1 theory of neuromuscular transmission was developed using data obtained from in vitro animal studies in which calcium was replaced with magnesium. Magnesium suppresses the release of transmitter from the nerve terminals, thereby reducing the size of the endplate potential and preventing it from reaching threshold.‘,s In experiments employing in vitro methodology, high magnesium concentrations can cause a complete loss of neuromuscular transmission.’ The purpose of this study was to determine how magnesium sulfate affects neuromuscular function in parturients receiving magnesium sulfate for tocolysis or seizure prophylaxis4
Anesthesia
of Research
Address reprint requests to Dr. Ross at the Department of Anesthesiology, Monmouth Medical Center, 300 Second Avenue, Long Branch, iWJ 07740. Received for publication November 23, 1994; I-wised manuscript accepted for publication .June 6, 199.5.
~Journal of Clinical Anesthesia 8:202-204, 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York,
Materials
and Methods
Approval of the Monmouth Medical Center’s Institutional Research. Review Board was secured, and written informed consent was obtained from all patients. Patients with preexisting medical conditions or taking medications that affected
1996 NY 10010
o9.i2-8180/96/$15.00 SSDI 09.52-SISO(95)00290-8
neuromuscular function were excluded from this study. The subjects were 12 ASA physical status I and II pregnant women, who had been either identified as preeclamptic or were entering preterm labor. Consequently, they were placed on a magnesium sulfate regimen that consisted of 2 to 4 G of MgSO, * 7H,O intravenously (IV) given over 30 minutes, followed by an IV infusion of 1 G/hr for 3 hours.” During both infusion and neuromuscular testing, blood pressure (PB) and heart rate (HR) were monitored every 5 minutes. The ulnar neme was supramaximally stimulated at the wrist with surface electrodes. The mode of stimulation was train-of-four (TOF) rectangular pulses of 0.15 msec duration at a frequency of 2 Hz delivered once every 12 seconds. The contractile responses of the adductor pollicis were displayed on a standard operating room (OR) BP CRT monitor using a Professional Instruments APM monitor (Professional Instruments, Dallas, TX) and were also chart recorder running at 1 recorded on an annotating mm/set. The nerve was stimulated with 6 to 8 TOF and the last 3 TOF were measured. This was done because the first few TOF stimulations caused the patients to move, which affected the baseline. As the patients became acclimated to the stimulation, the baseline became stable. Alvake subjects would tolerate the TOF stimulation, but would not tolerate a continuous stimulation at 1 Hz. The contractile responses were recorded before the magnesium sulfate infusion (controls) and 30 minutes after its completion. The tension of each response of the TOF and the T,/ T, ratios wet-e determined. Data were analyzed using the Student’s t test; a p-value of 0.05 or less was considered statistically significant.
Results The mean age (*SD) of the 12 patients was 31 f 8 years (range 18 to 44 years). All patients were preeclamptic, and four were preterminal labor. The control TOF responses showed that each contractile response within the train was greater than its preceding contractile response (T, > T:, > T, > T,). As a result, the T,/T, ratios were greater than one: 1.17 for Train 1, 1.16 for Train 2, and 1.16 for Train 3 (?‘nblf~ 1). A typical response is seen in F&W? 1. After magnesium treatment, the increasing contractile response within the TOF was not seen. In its place, the TOF developed a small amount of fade. The mean T-+/T, ratios were 0.86 for Train 1, 0.83 for Train 2, and 0.85 for Train 3, with a range of 15% to 25%. The T, response of each TOF was compared with corresponding control. No significant differences were found.
Discussion When Fast muscle is first stimulated, each subsequent muscle contraction shows a slight increase in tension. Since the neme is being supramaximally stimulated, the increase in contractile tension is not due to the recruitment of additional motor units. After a short period, the
A. Mean Ratios (&SD) of Each T,/T, for Three C:onsecutive Trains-of-Four (TOF) TOF #2
TOF #3
Condition
TOF #l
Control M@O 1
1.17 f 0.10
1.16 f 0.07
1.11; i 0.07
0.86 f 0.07
0.83 * 0.06
0.85 * 0.05
B. Mean Contractile Tension ((: + SEM) of the First Twitch (T,) of TOF
Condition
(:ontrol MgSO,
T, of Train 1
T, of Train 2
T, of Train 3
(g)
w
(g)
?l.i2.6 k 96.6 332.0 f 96.0
357.9
F 9x.7
356.0 f 95.6
361.2 f 99.1 362.8 * 101.2
MgSO, = magnrsiwm sulfate
incremental increase of tension becomes smaller and finally stops.’ If the frequency of stimulation is not too fast (CO.1 Hz), the muscle responses then remain at the same maximum tension. This phenomenon was described in animal models well over 100 years ago and is know as treppe (German for step). Since the increase in contractile tension is not due to recruitment, treppe is a muscle phenomenon and is due to an improvement in the contractility of muscle. The mean percentage of fast fibers in the human adductor pollicis muscle is only 20%.” In these patients before the administration of any drugs, the treppe of the fast muscle was observed, and after the magnesium treatment, the treppe was lost. It has been shown that magnesium reduces miniature end plate currents in the mouse postjunctional membrane, probably by plugging channels.’ In frog skeletal muscle, calcium channels can show a small magnesium current.’ Thus, the loss of treppe could be due to magnesium interfering with tnuscle calcium, which, in turn, would affect the active state of skeletal muscle contractility.” At nerve endings, magnesium interferes with the release of transmitter (ACh) by competing with calcium, a prejunctional site of action.‘,” The reduction of ACh release by magnesium increases the potency of both depo-
L Cal
B
Figure 1. The contractile responses of the adductor pollicis muscle to 3 train-of-four supramaximal stimuli in the same patient: A. Control, recorded before magnesium sulfate (MgSO,) treatment. B. After MgSO, treatment. (:alibration bars: horizontal 10 set; vertical 400 C;.
Original
Contributions
larizing and nondepolarizing muscle relaxants.“S10 Recently, Fuchs-Buder and colleagues” showed that magnesium pretreatment shifted the dose response curve of vecuronium to the left in patients who were not pregnant. James and coworkers” demonstrated in nonpregnant patients that priming with magnesium was as effective as priming with pancuronium. The prejunctional action of magnesium can account for the TOF fade observed in pregnant patients. In summary, our study shows that in parturients, magnesium altered the TOF response to nerve stimulation. The observed absence of a treppe phenomenon after the magnesium infusion is consistent with the findings of in vitro studies demonstrating an effect of hypermagnesia on the neuromuscular transmission.
References 1. Hubbard JI, Jones SF, Landau EM: On the mechanism by which calcium and magnesium affect the release of transmitter by nerve impulses. J Physiol 1968;196:75-86. 2. Del Castillo J, Engback L: The nature of neuromuscular block produced by magnesium. J PhysioZ1954;124:553-9. 3. Del Castillo J, Katz B: Quanta1 components of the end-plate potential. J Physiol 1954;124:560-73.
204
J. Clin. Anesth., vol. 8, May 1996
4. Greasy RK, Resnik R: Maternal Fetal Medicine: Principks and PTUCtice, 3d ed. Philadelphia: W.B. Saunders Co., 1994829-31. 5. Desmedt JE, Hainaut K: Kinetics of myofilament activation in potentiated contraction: staircase phenomenon in human skeletal muscle. Nature 1968;217:529-32. 6. Johnson MA, Polgar J, Weightman D, Appleton D: Data on the distribution of fibre types in thirty-six human muscles. An autopsy study. J Neural Sti 1973;18:11 l-29. 7. McLarnon JC, Quastel DM: Postsynaptic effects of magnesium and calcium at the mouse neuromuscular junction. J Neurosci 1983;3:1626-33. 8. Almers W, Palade PT: Slow calcium and potassium currents across frog muscle membrane: measurements with a vasoline-gap technique. J Physiol 1981;312:159-76. 9. Giesecke AH Jr, Morris RE, Dalton MD, Stephen CR: Of magnesium, muscle relaxants, toxemic paturients, and cats. An&h Analg 1968;47:689-95. 10. Ghoneim MM, Long JP: The interaction between magnesium and other neuromuscular blocking agents. Anesthesiology 1970;32: 23-7. 11. Fuchs-Buder T, Wilder-Smith 0, Tassonyi E: Dose-response relationship for vecuronium with and without magnesium sulfate pretreatment [Abstract]. Anesthesiology 1994;81:A1118. 12. James MFM, Schenk PA, van der Veen BW: Priming of pancuronium with magnesium. BrJAnaesth 1991;66:247-9.
An Effect of Magnesium on Neuromuscular Function in Parturients Robert M. Ross, MD,* Anesthesiology
Department,
Thomas Baker, MS-f-
Monmouth
Medical Center, Long Branch, New Jersey
Study Objective: To determine the effprts of magnesium suljate on neuromuscular transmission in parturients. Design: Open-label, clinical study. Setting: Preeclamptic patients at a university-affiliated hospital. Patients: 12 prepant patients, ages 18 to 40 years, with preeclampsia or entm’ngpreterm labor. Interventions: Patients were treated with magnesium sulfate. Train-ofjour (7’0F) recordings of the add&or pollicis muscle were obtained before and 30 minutes ajtw the magnesium .&fate infusion. Measurements and Main Results: Each contractile response in the control 2YIF showed an intrease in the tension deuetoped in response to supramaximal stimulation. The TOF responses after magrzesium .sulfate did not demons&a& this phenomenon, hut rather developed fad?. y’he ?>/I’, ratios ranged from 0.72 to 0.92. Conclusions: In this patient population, clinically relevant injusions of magnesium sulfate produced ,signijirant rhanges in neuromusrular transmission as manifested by loss qf treppe phenomenon and diminished 7UF response to ulnar nerue stimulation.
Keywords: Magnesium: transmission/parturients:
neuromuscular train-of-four
transmission; fade.
neuromuscular
Introduction
“Chief tDirector
of Obstetrical
Magnesium sulfate affects neuromuscular transmission in part by interfering with the release of the neurotransmitter, acetylcholine. It is a double charged cation and takes the place of calcium, another double charged cation, which is needed for transmitter release.’ In fact, the quanta1 theory of neuromuscular transmission was developed using data obtained from in vitro animal studies in which calcium was replaced with magnesium. Magnesium suppresses the release of transmitter from the nerve terminals, thereby reducing the size of the endplate potential and preventing it from reaching threshold.‘,s In experiments employing in vitro methodology, high magnesium concentrations can cause a complete loss of neuromuscular transmission.’ The purpose of this study was to determine how magnesium sulfate affects neuromuscular function in parturients receiving magnesium sulfate for tocolysis or seizure prophylaxis4
Anesthesia
of Research
Address reprint requests to Dr. Ross at the Department of Anesthesiology, Monmouth Medical Center, 300 Second Avenue, Long Branch, iWJ 07740. Received for publication November 23, 1994; I-wised manuscript accepted for publication .June 6, 199.5.
~Journal of Clinical Anesthesia 8:202-204, 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York,
Materials
and Methods
Approval of the Monmouth Medical Center’s Institutional Research. Review Board was secured, and written informed consent was obtained from all patients. Patients with preexisting medical conditions or taking medications that affected
1996 NY 10010
o9.i2-8180/96/$15.00 SSDI 09.52-SISO(95)00290-8
neuromuscular function were excluded from this study. The subjects were 12 ASA physical status I and II pregnant women, who had been either identified as preeclamptic or were entering preterm labor. Consequently, they were placed on a magnesium sulfate regimen that consisted of 2 to 4 G of MgSO, * 7H,O intravenously (IV) given over 30 minutes, followed by an IV infusion of 1 G/hr for 3 hours.” During both infusion and neuromuscular testing, blood pressure (PB) and heart rate (HR) were monitored every 5 minutes. The ulnar neme was supramaximally stimulated at the wrist with surface electrodes. The mode of stimulation was train-of-four (TOF) rectangular pulses of 0.15 msec duration at a frequency of 2 Hz delivered once every 12 seconds. The contractile responses of the adductor pollicis were displayed on a standard operating room (OR) BP CRT monitor using a Professional Instruments APM monitor (Professional Instruments, Dallas, TX) and were also chart recorder running at 1 recorded on an annotating mm/set. The nerve was stimulated with 6 to 8 TOF and the last 3 TOF were measured. This was done because the first few TOF stimulations caused the patients to move, which affected the baseline. As the patients became acclimated to the stimulation, the baseline became stable. Alvake subjects would tolerate the TOF stimulation, but would not tolerate a continuous stimulation at 1 Hz. The contractile responses were recorded before the magnesium sulfate infusion (controls) and 30 minutes after its completion. The tension of each response of the TOF and the T,/ T, ratios wet-e determined. Data were analyzed using the Student’s t test; a p-value of 0.05 or less was considered statistically significant.
Results The mean age (*SD) of the 12 patients was 31 f 8 years (range 18 to 44 years). All patients were preeclamptic, and four were preterminal labor. The control TOF responses showed that each contractile response within the train was greater than its preceding contractile response (T, > T:, > T, > T,). As a result, the T,/T, ratios were greater than one: 1.17 for Train 1, 1.16 for Train 2, and 1.16 for Train 3 (?‘nblf~ 1). A typical response is seen in F&W? 1. After magnesium treatment, the increasing contractile response within the TOF was not seen. In its place, the TOF developed a small amount of fade. The mean T-+/T, ratios were 0.86 for Train 1, 0.83 for Train 2, and 0.85 for Train 3, with a range of 15% to 25%. The T, response of each TOF was compared with corresponding control. No significant differences were found.
Discussion When Fast muscle is first stimulated, each subsequent muscle contraction shows a slight increase in tension. Since the neme is being supramaximally stimulated, the increase in contractile tension is not due to the recruitment of additional motor units. After a short period, the
A. Mean Ratios (&SD) of Each T,/T, for Three C:onsecutive Trains-of-Four (TOF) TOF #2
TOF #3
Condition
TOF #l
Control M@O 1
1.17 f 0.10
1.16 f 0.07
1.11; i 0.07
0.86 f 0.07
0.83 * 0.06
0.85 * 0.05
B. Mean Contractile Tension ((: + SEM) of the First Twitch (T,) of TOF
Condition
(:ontrol MgSO,
T, of Train 1
T, of Train 2
T, of Train 3
(g)
w
(g)
?l.i2.6 k 96.6 332.0 f 96.0
357.9
F 9x.7
356.0 f 95.6
361.2 f 99.1 362.8 * 101.2
MgSO, = magnrsiwm sulfate
incremental increase of tension becomes smaller and finally stops.’ If the frequency of stimulation is not too fast (CO.1 Hz), the muscle responses then remain at the same maximum tension. This phenomenon was described in animal models well over 100 years ago and is know as treppe (German for step). Since the increase in contractile tension is not due to recruitment, treppe is a muscle phenomenon and is due to an improvement in the contractility of muscle. The mean percentage of fast fibers in the human adductor pollicis muscle is only 20%.” In these patients before the administration of any drugs, the treppe of the fast muscle was observed, and after the magnesium treatment, the treppe was lost. It has been shown that magnesium reduces miniature end plate currents in the mouse postjunctional membrane, probably by plugging channels.’ In frog skeletal muscle, calcium channels can show a small magnesium current.’ Thus, the loss of treppe could be due to magnesium interfering with tnuscle calcium, which, in turn, would affect the active state of skeletal muscle contractility.” At nerve endings, magnesium interferes with the release of transmitter (ACh) by competing with calcium, a prejunctional site of action.‘,” The reduction of ACh release by magnesium increases the potency of both depo-
L Cal
B
Figure 1. The contractile responses of the adductor pollicis muscle to 3 train-of-four supramaximal stimuli in the same patient: A. Control, recorded before magnesium sulfate (MgSO,) treatment. B. After MgSO, treatment. (:alibration bars: horizontal 10 set; vertical 400 C;.
Original
Contributions
larizing and nondepolarizing muscle relaxants.“S10 Recently, Fuchs-Buder and colleagues” showed that magnesium pretreatment shifted the dose response curve of vecuronium to the left in patients who were not pregnant. James and coworkers” demonstrated in nonpregnant patients that priming with magnesium was as effective as priming with pancuronium. The prejunctional action of magnesium can account for the TOF fade observed in pregnant patients. In summary, our study shows that in parturients, magnesium altered the TOF response to nerve stimulation. The observed absence of a treppe phenomenon after the magnesium infusion is consistent with the findings of in vitro studies demonstrating an effect of hypermagnesia on the neuromuscular transmission.
References 1. Hubbard JI, Jones SF, Landau EM: On the mechanism by which calcium and magnesium affect the release of transmitter by nerve impulses. J Physiol 1968;196:75-86. 2. Del Castillo J, Engback L: The nature of neuromuscular block produced by magnesium. J PhysioZ1954;124:553-9. 3. Del Castillo J, Katz B: Quanta1 components of the end-plate potential. J Physiol 1954;124:560-73.
204
J. Clin. Anesth., vol. 8, May 1996
4. Greasy RK, Resnik R: Maternal Fetal Medicine: Principks and PTUCtice, 3d ed. Philadelphia: W.B. Saunders Co., 1994829-31. 5. Desmedt JE, Hainaut K: Kinetics of myofilament activation in potentiated contraction: staircase phenomenon in human skeletal muscle. Nature 1968;217:529-32. 6. Johnson MA, Polgar J, Weightman D, Appleton D: Data on the distribution of fibre types in thirty-six human muscles. An autopsy study. J Neural Sti 1973;18:11 l-29. 7. McLarnon JC, Quastel DM: Postsynaptic effects of magnesium and calcium at the mouse neuromuscular junction. J Neurosci 1983;3:1626-33. 8. Almers W, Palade PT: Slow calcium and potassium currents across frog muscle membrane: measurements with a vasoline-gap technique. J Physiol 1981;312:159-76. 9. Giesecke AH Jr, Morris RE, Dalton MD, Stephen CR: Of magnesium, muscle relaxants, toxemic paturients, and cats. An&h Analg 1968;47:689-95. 10. Ghoneim MM, Long JP: The interaction between magnesium and other neuromuscular blocking agents. Anesthesiology 1970;32: 23-7. 11. Fuchs-Buder T, Wilder-Smith 0, Tassonyi E: Dose-response relationship for vecuronium with and without magnesium sulfate pretreatment [Abstract]. Anesthesiology 1994;81:A1118. 12. James MFM, Schenk PA, van der Veen BW: Priming of pancuronium with magnesium. BrJAnaesth 1991;66:247-9.