Magnesium is the second most abundant intracellular cation and plays an integral role in several biological processes. It influences membrane potentials via modulatory effects on sodium and potassium currents and serves as a cofactor for protein synthesis, nucleic acid stabilization, and neuromuscular function.1 Magnesium also acts as a calcium-channel antagonist and has inhibitory effects on the CNS, including antagonism of the TV-methyl-D-aspartate glutamate receptor and suppression of catecholamine release from the adrenal medulla and adrenergic nerve endings.1,2
The administration of MgSO4 has been associated with volatile and injectable anesthetic–sparing effects, augmentation of neuromuscular blockade, and attenuation of postoperative pain in human patients.3–5 A volatile anesthetic–sparing effect of MgSO4 has been found for human patients anesthetized with desflurane.6,7 Injectable anesthetic– and analgesic-sparing effects of MgSO4 have been reported for several agents, including propofol, fentanyl, remifentanil, and midazolam.8–10 Postoperative administration of MgSO4 decreases opioid consumption and pain scores in a variety of human surgical patients.11–13 In particular, the propofol-sparing effect of Mg has been reported for several studies14–16 of humans in which an infusion of Mg was used to decrease dose requirements of propofol during surgery and at the time of anesthetic induction. In dogs undergoing ovariohysterectomy, dose requirements of halothane and thiopental were decreased following anesthetic premedication and intraoperative infusion of MgSO4.17 The anesthetic- and analgesic-sparing properties of Mg have been attributed primarily to its antagonism of the N-methyl-D-aspar tate receptor2; thus, Mg may potentiate the effect of other agents (including volatile anesthetics, propofol, and ketamine) that act on the same receptor.18–20
On the basis of the proposed anesthetic-sparing mechanism of Mg and the reports of its volatile anesthetic– and propofol-sparing effects in humans, the objective of the study reported here was to evaluate the effects of IV administration of MgSO4, alone and in combination with propofol, on the MACNM in sevoflurane-anesthetized dogs. The MACNM was used as an endpoint that corresponds to the lack of any motor movement in response to a noxious stimulation.21–23 The hypothesis was that MgSO4 would decrease the MACNM of sevoflurane and potentiate the MAC-sparing effect of propofol.
Materials and Methods
Animals
Six healthy adult (2 to 7 years old) purpose-bred male Beagles were selected for use in the study. Least squares mean ± SEM body weight was 12.0 ± 1.1 kg. The study was approved by an institutional animal care and use committee.
Experimental design
A computer-randomizeda crossover (6 × 3) design was used. Each dog was anesthetized and evaluated 3 times. There was a minimum 7-day washout period between subsequent anesthetic episodes.
Anesthesia
Food was withheld from the dogs for 12 hours prior to anesthesia, but access to water was unrestricted. Anesthesia was induced by administration of sevofluraneb in oxygen (2 L/min) delivered via a mask attached to a circle system. An endotracheal tube was then inserted to the level of the thoracic inlet, and anesthesia was maintained with sevoflurane in oxygen (1 L/min) by use of a small animal anesthesia machine.c Anesthetized dogs were placed in right lateral recumbency and mechanically ventilated to maintain Petco2 between 35 and 45 mm Hg. Values for Petsevo and Petco2 were monitored continuously (sampling rate, 200 mL/min) with an infrared gas analyzerd placed at the proximal end of the endotracheal tube. Before the start of each experiment, the gas analyzer was calibrated in accordance with the manufacturer's instructions by use of a manufactured calibration gase containing known concentrations of desflurane, CO2, nitrous oxide, and oxygen (2%, 5%, 33%, and 55%, respectively). A 20-gauge catheterf was placed in the right cephalic vein and used for infusion of lactated Ringer solutiong (3 mL/kg/h), propofol,h and MgSO4.g A second 20-gauge catheter was placed in the left jugular vein to facilitate blood collection for analysis of propofol and Mg concentrations. The ECG and heart rate were continuously monitored.d Blood pressure was noninvasively monitored by use of an oscillometric techniqued with an appropriately sized cuff (width, approx 40% of the circumference of the limb) placed over the right dorsal pedal artery. Dobutamine was administered as a CRI, as necessary, if mean arterial blood pressure was < 60 mm Hg. An esophageal temperature probed was used to monitor body temperature, and a circulating warm water blanketi and warm-air blanketj were used to maintain normothermia (37.5° to 38.5°C). The urinary bladder was manually expressed intermittently during anesthesia to prevent overdistention.
Acceleromyography
Acceleromyographyk by use of the TOF ratio to monitor neuromuscular function was performed throughout the period of anesthesia. Two electrodes of the unit were attached to 2 needles inserted into the subcutaneous tissues over the common peroneal nerve of the left pelvic limb, and the accelerometer was affixed to the dorsal surface of the distal aspect of the metatarsal region. After anesthesia was induced but before each experiment was performed, the current for the supramaximal stimulus was determined by use of an automated function (ie, CAL2) of the unit, and 3 TOF ratios were determined every 15 minutes by use of a standard TOF stimulation (2 Hz for 0.2 milliseconds), as described elsewhere.24 An interval of at least 10 minutes was allowed between each TOF stimulation and noxious electrical stimulation for MACNM determination to avoid interference between the 2 techniques. A TOF ratio > 90% was considered to be physiologically normal.25
Determination of MACNM-B
Determination of MACNM-B was initiated 45 minutes after anesthetic induction (baseline). The Petsevo was held constant at 2.4 vol% for a minimum of 15 minutes. A noxious electrical stimulusl (50 V at 50 Hz for 10 milliseconds) was delivered to the lateral aspect of the left forelimb via two 25-gauge needle electrodes inserted into the subcutaneous tissues 5 cm apart. The stimulation pattern included 2 initial single stimuli, which were followed by 2 continuous stimuli for 5 seconds; there was a 5-second interval between stimuli.26 The MACNM was defined as the minimum Petsevo that abolished motor movement in response to noxious stimulation. Withdrawal or twitching of the nonstimulated limbs, movement of the head, licking, chewing, swallowing, or blinking was considered a positive response; twitching of the stimulated limb was not considered a positive response.21After a positive response was obtained, Petsevo was increased by 0.1 vol%; conversely, after a negative response was obtained, Petsevo was decreased by 0.1 vol%. After a 15-minute equilibration period elapsed, the noxious stimulus was reapplied. The MACNM-B was determined in duplicate, and the mean value was recorded as the MACNM-B for that dog. Blood samples for analysis of propofol and Mg concentrations were collected at these duplicate time points, combined, and analyzed to reflect the mean value. When the 2 MACNM-B values differed by > 10%, a third MACNM-B was determined, and the mean for all 3 values was used to determine MACNM-B. Time to MACNM-B was defined as the interval from anesthetic induction to the completion of the duplicate MACNM-B measurements.
Treatments
After MACNM-B was determined, dogs were initially arbitrarily assigned to receive 1 of the 3 treatments (loading dose followed by a CRI). Each treatment was administered IV. Treatment 1 was MgSO4 (loading dose, 45 mg/kg; CRI, 15 mg/kg/h). Treatment 2 was propofol (loading dose, 4 mg/kg; CRI, 9 mg/kg/h). Treatment 3 was a combination of propofol and MgSO4 at each of the aforementioned doses. The loading dose and CRI were started simultaneously. The loading dose was administered over a period of 20 minutes; the loading dose and CRI were administered with syringe pumps.m Blood samples were collected from dogs receiving treatments 1 and 3 into lithium-heparin tubes and used for measurement of the Mg concentration prior to starting administration of the loading dose. Magnesium concentrations were measured by use of a chemistry analyzer.n
The MACNM-T determination began 60 minutes after starting each treatment infusion. The Petsevo was held at each dog's MACNM-B for at least 15 minutes, and MACNM-T was determined in duplicate by use of the same technique described for MACNM-B determination. Time to MACNM-T was defined as the interval from the start of the treatment infusion to completion of the MACNM-T determination. Jugular blood samples (3 mL) were collected into a lithium-heparin tube from dogs receiving treatments 2 and 3 at the time of each MACNM-T determination and stored at −80°C; both samples subsequently were combined and used for analysis of propofol concentrations. Jugular blood samples were also collected from dogs receiving treatments 1 and 3 at the time of each MACNM-T determination; both samples were combined and used to measure the Mg concentration after treatment.
At the end of each experiment, sevoflurane and all infusions were discontinued, and the dogs were allowed to recover from anesthesia. Dogs were extubated after the swallowing reflex was detected. Time to extubation was defined as the interval from discontinuation of sevoflurane administration to extubation. Dogs were monitored continuously until they regained the ability to ambulate without assistance.
Dogs subsequently received the other 2 treatments. There was a 1-week interval between successive anesthetic episodes (ie, treatments).
Analysis of propofol concentrations
Propofol concentrations were analyzed by use of a reverse-phase high-performance liquid chromatography method; the system consisted of a separation module,° fluorescence detector,p and computer equipped with chromatography data software.q Propofol was extracted from blood samples by use of a liquid extraction technique. Frozen samples were thawed to room temperature (21°C) and mixed in a vortex device. Then, 400 μL was transferred to a new test tube, and 10 μL of an internal standard (2,4-ditert-butylphenol; 100 μg/mL) was added to each tube. One milliliter of a solution of acetonitrile-methanol (75:25 [vol/vol]) was added, and tubes were mixed in a vortex device, covered with paraffin film,r and placed in a refrigerator (4°C) for 10 minutes. Tubes were mixed again in a vortex device for 10 seconds and then centrifuged (1,000 × g for 15 minutes). Supernatant was removed and placed in a new tube. The procedure was repeated with an additional 0.5 mL of acetonitrile-methanol. Both supernatants for each dog were combined into a single tube; tubes were centrifuged (1,000 × g for 5 minutes). An aliquot (40 μL) of the resulting supernatant was harvested and placed in chromatographic vials for analysis.
Compounds were separated on a C18 columns (4.6 × 250 mm; 5 μm) with an accompanying guard column. The mobile phase was a mixture (31:69 [vol/vol]) of water (adjusted to pH 4.0 with glacial acetic acid) and acetonitrile. Flow rate was 1.5 mL/min, and the column was at room temperature. The fluorescence detector was set at an excitation wavelength of 276 nm and emission wavelength of 310 nm with the gain at 10X.
Standard curves for analysis of concentrations were prepared by fortifying untreated canine whole blood with propofol to create calibration samples that yielded a linear concentration range of 5 to 7,000 ng/mL. Calibration samples were prepared as described previously for unknown blood samples. Mean recovery for propofol was 95%; intra-assay and interassay variability ranged from 2.2% to 8.2% and 3.5% to 6.7%, respectively. The lower limit of quantification was 5 ng/mL.
Data analysis
The assumption that residuals from all models fit a normal distribution was assessed by use of the test statistic for the Shapiro-Wilk test. All data were reported as least squares mean ± SEM values.
The percentage change from MACNM-B was calculated by use of the following equation: ([MACNM-B – MACNM-T]/MACNM-B) × 100. The effect of treatment on the dependent variables MAC and Mg concentration were evaluated with a mixed-model ANOVA.t Class variables included in the model were dog, time of MAC measurement (baseline vs treatment), treatment, and treatment order (week). Independent variables included body weight of dog, treatment, time interval (time to MACNM-B or time to MACNM-T), and the interaction between treatment and time interval. Dog, week, and the 3-way interaction between dog, week, and treatment were included as random factors in the model. A second mixed model was used to assess the effect of treatment on time to extubation and effect of treatments 1 and 3 on blood propofol concentration. Class variables in this model included dog, treatment, and week. Body weight, treatment, MACNM, and time intervals were included as independent variables, with dog as a random factor in the model. A third mixed model was used to assess the effect of treatment on time to measurement of MACNM. Class variables included in this third model were dog, time of measurement, treatment, and week. Body weight, treatment, MACNM, time of measurement, and the interaction between treatment and time of measurement were included as independent variables. Dog, week, and the interaction between dog, week, and treatment were included as random factors in the model.
Adjustment for multiple levels of independent variables in all models was performed by use of the Tukey method. Fit of models to the data was assessed with the −2 log-likelihood ratio. Values of P < 0.05 were considered significant.
Results
Dobutamine (1 to 5 μg/kg/min) was administered to 2 dogs during treatment 1, 4 dogs during treatment 2, and 5 dogs during treatment 3. Dobutamine was primarily administered 30 to 60 minutes after the start of treatment infusion to maintain mean arterial blood pressure ≥ 60 mm Hg; thus, blood pressure data were not statistically analyzed.
Overall, the least squares mean ± SEM value for MACNM-B for all treatments was 2.5 ± 0.1 vol%. The percentage decrease from MACNM-B was 3.4 ± 3.1%, 48.3 ± 3.1%, and 50.3 ± 3.1%, for treatments 1, 2, and 3, respectively (Table 1). Significant decreases from MACNM-B were observed only for treatments 2 and 3. However, the percentage decrease from MACNM-B was not significantly different between treatments 2 and 3.
Effect of MgSO4 and propofol infusion on MACNM of sevoflurane in dogs (n = 6).
| Variable | Treatment 1 | Treatment 2 | Treatment 3 |
|---|---|---|---|
| MACNM-B | 2.5 ± 0.1 | 2.6 ± 0.1 | 2.3 ± 0.1 |
| MACNM-T | 2.4 ± 0.1a | 1.4 ± 0.1*b | 1.2 ± 0.1*b |
| Decrease from MACNM-B (%) | 3.4 ± 3.1a | 48.3 ± 3.1b | 50.3 ± 3.1b |
| MgP (mmol/L) | 0.7 ± 0.0 | — | 0.7 ± 0.0 |
| MgT (mmol/L) | 1.2 ± 0.0† | — | 1.2 ± 0.0† |
| Blood propofol (μg/mL) | — | 2.4 ± 0.3 | 2.4 ± 0.3 |
Data represent least squares mean ± SEM values. Treatment 1 was MgSO4 (loading dose, 45 mg/kg; CRI, 15 mg/kg/h). Treatment 2 was propofol (loading dose, 4 mg/kg; CRI, 9 mg/kg/h). Treatment 3 was a combination of propofol and MgSO4 at each of the aforementioned doses. Each dog was anesthetized 3 times; there was a 1-week interval between successive anesthetic episodes (ie, treatments). Percentage decrease in MACNM was calculated by use of the following equation: ([MACNM-B – MaCnm-t]/MACnm-b) × 100.
Within a column, value differs significantly (P < 0.05) from the value for MACNM-B.
Within a column, value differs significantly (P < 0.05) from the value for MgP.
Values in each row with different superscript letters differ significantly (P < 0.05).
MgP = Magnesium concentration prior to treatment. MgT = Magnesium concentration after treatment.
Blood propofol concentrations did not differ significantly between treatments 2 and 3 (Table 1). Administration of MgSO4 for treatments 1 and 3 was associated with a significant increase in Mg concentration.
Neuromuscular function did not change during the course of the infusions, and all TOF ratios exceeded 90%. The times to determine MACNM-B and MACNM-T did not differ significantly among treatments.
Least squares mean ± SEM time to extubation was 6.3 ± 1.5 minutes, 10.0 ± 1.5 minutes, and 7.0 ± 1.5 minutes for treatments 1, 2, and 3, respectively; these values did not differ significantly among treatments. Recovery was uneventful after all anesthetic episodes.
Discussion
Despite significant increases in blood Mg concentration for the treatments, administration of MgSO4 was not associated with a significant decrease in sevoflurane MACNM, nor did it potentiate the MACNM-sparing effect of propofol. Infusion of propofol provided a MACNM-sparing effect at blood propofol concentrations similar to those reported in a previous study23 in which investigators used the same dosing regimen. The overall MACNM-B value of 2.5 vol% in the study reported here is consistent with reports of 2.7 vol%21,22 by use of the same methods.
The selected infusion rates of MgSO4 in the present study were based on evaluation of the propofol-sparing effects of Mg27 and volatile anesthetic–sparing effects of Mg in humans6 and dogs.17 Infusion of MgSO4 at a rate of 10 mg/kg/h to humans undergoing cholecystectomy resulted in a 2-fold increase in serum Mg concentrations and was associated with a decrease in desflurane MAC of 20%.6 In another study,8 MgSO4 infusion at a rate of 8 mg/kg/h decreased propofol dose requirements by 50% and resulted in a 35% increase in baseline serum Mg concentrations. In dogs undergoing elective surgery, infusion of MgSO4 at a rate of 12 mg/kg/h increased serum Mg concentrations and resulted in a decreased requirement for halothane.17
A volatile anesthetic–sparing effect of MgSO4 has been detected in multiple studies. The MAC of desflurane in humans was decreased by 24% following MgSO4 infusion at a rate of 10 mg/kg/h.7 In another study6 that involved administration of the same dose of MgSO4 to humans, desflurane requirements were decreased by 22%. In those studies,6,7 the serum Mg concentrations of the patients were increased from baseline values by 75% and 68%, respectively. In dogs undergoing elective surgery, MgSO4 infusion at a rate of 12 mg/kg/h decreased halothane requirements by approximately 22% while increasing serum Mg concentrations by approximately 58%.17 In the present study, no significant volatile anesthetic–sparing effect was evident despite a 71% increase in blood Mg concentrations.
Additionally, the dose-sparing relationship of Mg and propofol has been evaluated in several studies. In a study8 of humans undergoing hysterectomy, an MgSO4 infusion of approximately half the dose administered to the dogs of the study reported here resulted in a significant increase in serum Mg concentration and decreased propofol dose requirements by approximately 50%. In a study14 of humans undergoing vertebral column surgery, MgSO4 infusion at a lower rate (10 mg/kg/h) than was used in the dogs of the present study resulted in a decrease in propofol consumption by approximately 15%; in a similarly designed study28 involving human orthopedic surgical patients, MgSO4 infusion at 10 mg/kg/h decreased propofol requirements by 30%. However, because plasma propofol concentrations were not determined in any of the aforementioned studies, comparison of the results of the present study with results for those studies may be inconclusive. Additionally, the only report in which serum Mg concentration was determined in the aforementioned studies indicated an increase in baseline Mg concentrations of only 35%,8 whereas baseline Mg concentrations in the dogs of the present study increased by approximately 70%. The higher serum concentrations of Mg in the dogs of the study reported here were clearly a result of the higher infusion rate for MgSO4 (15 mg/kg/h) versus the rate (8 mg/kg/h) used for humans in that other study.8
A number of studies have supported the volatile and injectable anesthetic–sparing effects of Mg, whereas other studies have reported a lack of an anesthetic-sparing effect, which is similar to the findings of the present study. Administration of MgSO4 at doses similar to the dose used in the study reported here did not cause an isoflurane-sparing effect in dogs undergoing elective surgery in another study29 and, when used alone or in combination with an infusion of ketamine, had no effect on isoflurane MAC in goats.30 Results of those studies29,30 parallel the lack of a sevoflurane-sparing effect after MgSO4 administration that was found in the present study. In humans undergoing hysterectomy, MgSO4 administration at a rate of 30 mg/kg did not decrease the doses of propofol needed for anesthetic induction,31 and infusion of MgSO4 at a rate of 10 mg/kg/h did not result in significant changes in the requirement for sevoflurane in other studies.32,33 Those studies31–33 also corroborated findings of the present study, whereby MgSO4 did not provide a decrease in the requirements for volatile or injectable anesthetics.
The exact reason for the lack of an anesthetic-sparing effect for Mg in the present study remains unknown; however, there are several possible explanations. Many of the reports describing the anesthetic-sparing effects of MgSO4 in humans and dogs are based on clinical endpoints, such as changes in blood pressure, respiratory rate, and heart rate in patients undergoing surgical procedures.8,10,17 Thus, results of those studies may have been influenced by the combined effects of multiple agents, including inhalational anesthetics, opioids, γ-aminobutyric acid agonists, and neuromuscular blockers; each of these drugs could have resulted in an additive or synergistic effect with Mg. Other factors may include differences in methods among studies, species differences, and the type of inhalation anesthetic used. For instance, MgSO4 infusion (12 mg/kg/h) significantly reduced the requirement for halothane in dogs undergoing elective ovariohysterectomy in 1 study,17 but a higher administration rate (15 mg/kg/h) failed to reduce the isoflurane requirement in dogs undergoing a similar surgical procedure29 and did not change the MAC of isoflurane in goats.30 Other studies in humans have reported that MgSO4 infusion decreased desflurane requirements,6,7 whereas it increased requirements for sevoflurane.32
The study reported here had some potentially limiting factors that may have influenced the results. Blood Mg concentrations significantly increased for both of the treatments that involved MgSO4 infusion; however, total Mg concentration was measured, rather than the biologically active ionized form. However, the authors do not consider that this influenced the results because studies of dogs34 and humans35 have revealed that changes in total serum Mg concentrations are correlated with changes in ionized Mg concentrations. Another factor to consider was the potential effect of MgSO4 on neuromuscular function because Mg can augment the effects of neuromuscular blockade associated with a decrease in acetylcholine release from motor nerve terminals,3 which could have affected the response to noxious stimulation. Although neuromuscular blockers were not used in the present study, acceleromyography was performed to rule out the potential effect of Mg on neuromuscular function. The small sample size for the study reported here also could have predisposed to a type II error, but sample size calculations based on a 24% MAC reduction for desflurane following MgSO4 infusion in humans7 indicated that only 4 dogs/treatment were needed to detect (power, 90%) a similar MAC reduction for sevoflurane. The present study had 6 dogs/treatment; thus, it was sufficiently powered. However, the expected MAC reduction for sevoflurane may not be to the same scale as the 24% decrease for desflurane MAC in humans, which would mean that the present study could have been underpowered for the detection of smaller percentages of MAC-sparing effects.
In the present study, propofol significantly decreased the MACNM of sevoflurane. However, despite a significant increase in blood Mg concentrations, MgSO4 infusion at the doses used in this study was not associated with a sevoflurane-sparing effect, and it did not potentiate the anesthetic-sparing effect of propofol. These results do not support the use of MgSO4 to decrease the anesthetic dose of sevoflurane or propofol. Nevertheless, evaluation of other potential beneficial effects of MgSO4 infusion (eg, analgesic effects) that were beyond the scope of this study is warranted.
Acknowledgments
Supported by the Companion Animal Fund of the University of Tennessee.
Presented in abstract form at the annual American College of Veterinary Anesthesia and Analgesia meeting during the 20th International Veterinary Emergency and Critical Care symposium, Indianapolis, September 2014.
ABBREVIATIONS
| CRI | Constant rate infusion |
| MAC | Minimum alveolar concentration |
| MACNM | Minimum alveolar concentration preventing motor movement |
| MACnm-b | Minimum alveolar concentration preventing motor movement measured at baseline |
| MACnm-t | Minimum alveolar concentration preventing motor movement measured after treatment |
| Petco2 | End-tidal partial pressure of carbon dioxide |
| Petsevo | End-tidal partial pressure of sevoflurane |
| TOF | Train-of-four |
Footnotes
SAS, version 9.4, SAS Institute Inc, Cary, NC.
Sevoflo, Abbott Laboratories, North Chicago, Ill.
DRE Premier XP, DRE Veterinary, Louisville, Ky.
Datex-Ohmeda S/5, Planar Systems, Beaverton, Ore.
Air Liquide Healthcare, Scott Medical Products, Plumsteadville, Pa.
ProtectIV Johnson & Johnson, North Brunswick, NJ.
Hospira Inc, Lake Forest, Ill.
PropoFlo, Abbott Laboratories, North Chicago, Ill.
K-Mod 107, Allegiance Healthcare Corp, Waukegan, Ill.
Bair Hugger, Arizant, Healthcare Inc, Saint Paul, Minn.
TOF Watch SX, Organon Ltd, Dublin, Ireland.
Grass Instrument Co, Warwick, RI.
Medfusion 2010i, Medox Inc, Wilmington, NC.
COBAS c501, Roche Diagnostics, Indianapolis, Ind.
2695 separations module, Waters Corp, Milford, Mass.
2475 fluorescence detector, Waters Corp, Milford, Mass.
Empower Software, Waters Corp, Milford, Mass.
Parafilm, Sigma-Aldrich Corp, St Louis, Mo.
Waters XBridge C18, Waters Corp, Milford, Mass.
PROC MIXED, SAS, version 9.4, SAS Institute Inc, Cary, NC.
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