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The use of succinylcholine for rapid sequence induction in patients with open globe injuries may be detrimental to the eye.
The aim of this study is to determine if the premedication with magnesium sulfate (MgSO4) could attenuate the increase in intraocular pressure (IOP) associated with succinylcholine injection and intubation.
Operation theaters in a tertiary care University Hospital between December 2014 and July 215.
This was a prospective, randomized, parallel three-arm, double-blind, placebo-controlled clinical trial.
One hundred and thirteen patients’ physical status ASA Classes I and II underwent elective cataract surgery under general anesthesia.
These patients allocated into three groups: Group C (control group) received 100 ml normal saline, Group M1 received 30 mg/kg MgSO4 in 100 ml normal saline, and Group M2 received 50 mg/kg MgSO4 in 100 ml normal saline. IOP, mean arterial pressure (MAP), and heart rate (HR) reported at 5-time points related to study drug administration. In addition, any adverse effects related to MgSO4 were recorded. Intragroup and between-groups differences were examined by analysis of variance test.
We noticed a significant decrease in IOP in M1 (n = 38) and M2 (n = 37) groups as compared with C group (n = 38) after study drugs infusion, 2 and 5 min after intubation, P < 0.001. While the difference between M1 and M2 groups was insignificant, P = 0.296 and P = 0.647, respectively. There was a significant decrease in MAP and HR in M1 and M2 groups as compared with C group 2 and 5 min after intubation, P = 0.01. While the difference between M1 and M2 groups was insignificant, P = 1.
MgSO4 30 mg/kg as well as 50 mg/kg effectively prevented the rise in IOP, MAP, and HR associated with rapid sequence induction by succinylcholine and endotracheal intubation.
Management of emergency anesthesia for open eye injuries in a patient having a full stomach requires a balance between the need to prevent aspiration of gastric contents against prevention of sudden significant increases in intraocular pressure (IOP) that may cause further eye damage and loss of vision. The use of succinylcholine for rapid sequence induction in patients with open-globe injuries may be detrimental to the eye as it increases IOP transiently for 2–6 min by 10–20 mmHg, in addition to the pressor response related to laryngoscopy and endotracheal intubation that causes sympathetic cardiovascular responses due to excess catecholamine release. The mechanism by which succinylcholine cause IOP rise could be attributed to its direct tonic response on extraocular muscle and its role in the increase of aqueous humor formation. So far, succinylcholine is still considered the principle muscle relaxant agent for rapid-sequence induction even with its known hazards and the availability of new nondepolarizing neuromuscular blockers with short-onset time. Many medical centers in developing countries still depend on succinylcholine as a sole rapid sequence induction agent due to the unavailability of the more recent drugs with short-onset time.
Several methods have been introduced to attenuate the effects of succinylcholine and endotracheal intubation on IOP surge as pretreatment with a nondepolarizing muscle relaxant, use of nifedipine, nitroglycerin, clonidine, dexmedetomidine, narcotics, tranquilizers, and lidocaine with a variable degree of successes, and failures.[4,5]
A lot of recent trials emphasized that perioperative magnesium sulfate (MgSO4) infusion has general anesthetic properties that could reduce anesthetic drug consumption and postoperative analgesia requirements in several types of surgery. These effects mediated through its antinociceptive properties as a noncompetitive N-methyl-D-aspartate receptor antagonist.[6,7,8,9,10,11,12] In addition to its role in procedures that necessitate deliberate hypotension as it acted as a calcium channel blocker and direct vasodilator.[13,14] Hence, it possibly controls the undesirable effects of succinylcholine and endotracheal intubation such as increased IOP, hypertension, and tachycardia.
This study aimed to determine if the intravenous administration of MgSO4 (using two different doses of 30 or 50 mg/kg) before the induction of anesthesia could attenuate the increase in IOP associated with rapid-sequence induction by succinylcholine injection and endotracheal intubation. We hypothesized that MgSO4 could be useful in the obtunding of IOP upsurge during endotracheal intubation after succinylcholine injection.
After obtaining the Local Ethical Committee clearance and the patient's informed written consent signing, this prospective, controlled, double-blind, randomized clinical trial conducted on 113 patients whose ages more than 18 years old, ASA physical status Class I and II, underwent elective cataract surgery, and refusing peribulbar blocks. The study took place from December 2014 to July 2015. Patients with known hypersensitivity to MgSO4 or succinylcholine, hypocalcemia, any degree of heart block, uncontrolled hypertension, obese (body mass index >30), any cardiovascular, renal, hepatic or muscular disease, patients with raised IOP, patients receiving any drug known to alter IOP, previous eye surgery, expected difficult intubation or required two or more attempts at laryngoscopy for endotracheal tube placement were excluded from the study.
Patients were assigned randomly into three equal groups. An online randomization program used to generate a random numbers list. The random numbers were concealed in opaque envelopes that were opened by the study investigators at operation theater after signing the consent form.
One day before surgery, all patients were interrogated for preoperative anesthesia plan discussion, signing a written informed consent, evaluation, and routine investigations. Twelve leads electrocardiography (ECG), complete blood count, coagulation profile (clotting and bleeding time, prothrombin time, international normalized ratio and partial thromboplastin time), liver functions, and kidney functions were fulfilled.
In the preanesthesia room, an intravenous line was established, and 100 ml of study solution administered by mechanical syringe pump over a period of 10 min per the assigned group as follows:
The patients randomized to Group C (control group): received 100 ml normal saline.
The patients randomized to Group M1: received 30 mg/kg MgSO4 10%, 10 ml (Magnesium sulf.® 100 mg/ml, EIPICO, 10th of Ramadan City, Egypt) in 100 ml normal saline.
The patients randomized to Group M2: received 50 mg/kg MgSO4 in 100 ml normal saline.
The study solution preparation, drugs doses calculations per body weight, and drugs concentrations were done by attending anesthetists who were not involved in anesthetic management or data collection in this trial. Members of the study group involved in obtaining functional data were blinded to groups’ allocation for the period of data acquisition and analysis.
On arrival to the operation room, basic intraoperative monitoring (pulse oximeter, five-lead ECG, and noninvasive blood pressure) were attached to the patient and baseline vital parameters were recorded.
Then, two drops of topical benoxinate hydrochloride 0.4% 10 ml (Benox®, EIPICO, 10th of Ramadan City, Egypt) was applied to the cornea in the right eye, and IOP was measured. Ophthalmologists, who were blind to the group's allocation, measured the IOP by Perkins applanation tonometer (Haag-Streit UK Ltd., Edinburgh, UK).
After 15 min of the study drug infusion completion, preoxygenation and general anesthesia were induced with fentanyl 1–2 μg/kg and propofol 2 mg/kg (Diprivan® 10 mg/ml, AstraZeneca UK Ltd., Macclesfield, UK) followed by succinylcholine chloride 1.5 mg/kg (succinylcholine® 20 mg/ml, Misr Co., Cairo, Egypt) to facilitate endotracheal intubation. Laryngoscopy and intubation were performed after 60 s of succinylcholine administration. All laryngoscopies and endotracheal intubations were carried out by attending anesthesiologists with at least 3 years’ experience. If the endotracheal intubation time was prolonged more than 15 s or if the intubation was not done from the first attempt, patients were excluded from the study.
Anesthesia was maintained with isoflurane 1.2 volume % and cisatracurium 0.1 mg/kg initially then one mg per 30 min until completion of the procedure. Ventilation parameters adjusted to maintain the end-tidal CO2 between 35 and 40 mmHg and peak inspiratory pressure between 25 and 30 cm H2O. Heart rate (HR) and mean arterial pressure (MAP) were maintained within ±20% of the preoperative baseline values.
After accomplishment of the procedure, the patients transferred to postanesthesia care unit (PACU) for 1-h observation and monitoring period for any symptoms and sign of hypermagnesemia as drowsiness, nausea, vomiting, muscle weakness, hypotension, bradypnea, and bradycardia. Patients with hypotension (<20% of baseline value) treated by 5 mg ephedrine increments, patients with bradycardia (HR <50 beat/min) treated with atropine sulfate 20 μg/kg, and patients with nausea and vomiting treated by ondansetron 0.15 mg/kg. Patients with postintubation hypertension (>20% of baseline) and tachycardia (>110 beat/min) controlled by fentanyl 0.5 μg/kg which could be repeated if the desired effect was not attained.
The primary outcome of the current trial was the IOP readings changes caused by infusion of MgSO4 premedication. Secondary outcome measures included hemodynamic parameters (MAP and HR) and any adverse effects of MgSO4 that could be detected during the study solution infusion or in the PACU.
IOP, MAP, and HR recorded at the following predefined 5-time points: before study solution infusion (T0); after study solution infusion and just before induction of general anesthesia (T1); after propofol and before succinylcholine (T2); 2 min after tracheal intubation (T3); and 5 min after tracheal intubation (T4).
Data of age, weight, duration of laryngoscopy, IOP, and hemodynamic variables presented as mean (standard deviation) and compared for the significance by using one-way analysis of variance test (ANOVA). Post hoc analysis was done if there was a significant difference between the three groups using the Bonferroni correction. Sex and ASA physical status were presented in numbers (percentages) and were analyzed by Chi-square test or Fisher's exact test as appropriate. Shapiro–Wilk test was implemented to verify the normality of continuous data distribution. P < 0.05 was considered statistically significant. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 16 (SPSS Inc., Chicago, IL, USA).
From a preliminary pilot data of the first 15 patients (five in each group), the sample size was estimated. A F-test family (one-way ANOVA test) was used to detect sample size assuming α error = 0.05 and β error = 0.20 (power = 80%). The effect size d calculated to be = 0.32 on the basis that variances of IOP (primary outcome) within groups = 5.4 mmHg and variance explained by special effect = 0.55 mmHg. The sample size was determined to be 33 patients in each group. Recruitments of 40 patients per group have been done to account for possible data loss and dropouts. Sample size calculation has been done using G*Power software version 126.96.36.199 (Institute of Experimental Psychology, Heinrich Heine University, Dusseldorf, Germany).
The consort flow diagram [Figure 1] illustrated the details of participants’ progression during the different trial phases. One hundred and thirteen out of 120 patients (38 patients in Group C, 38 patients in Group M1, and 37 patients in Group M2) completed the trial successfully, and final analysis was performed per protocol.
There were no statistically significant differences between the three groups regarding age, weight, sex, physical status ASA classes of the patients, and duration of laryngoscopy [Table 1].
There were no significant differences in mean IOP between the C, M1, and M2 groups at T0, P = 0.912. Comparison of IOP between C, M1, and M2 groups at T1 after administration of the study drug infusion showed significant IOP decrease in M1 and M2 groups as compared to C group, P < 0.001 and there was an insignificant difference between M1 and M2 groups, P = 0.960. There was an insignificant difference in IOP between the three groups at T2 after propofol injection and before succinylcholine administration, P = 0.28. Comparison of IOP changes in M1 and M2 groups at T3 and T4 after succinylcholine administration and endotracheal intubation by 2 and 5 min showed a significant decrease in IOP compared to the C group, P < 0.001. However, there was no significant difference between M1 and M2, P = 0.296 at T3 and P = 0.647 at T4 on post hoc test [Table 2 and Figure 2].
At T0 and T1, there were no statistically significant differences between the three groups regarding MAP, P = 0.59 and 0.79, respectively. Comparison of MAP between C, M1, and M2 groups at T2, T3, and T4 showed significant MAP decrease in M1 and M2 groups as compared to C group, P = 0.01. There was no significant difference between M1 and M2 groups, P = 0.56 at T2 and P = 1.0 at T3 and T4 [Figure 3].
At T0, T1, and T2, there were no statistically significant differences between the three groups regarding HR, P = 0.85, 0.94, and 0.52, respectively. Comparison of HR between C, M1, and M2 groups at T3 and T4 showed significant reduction of HR in M1 and M2 groups as compared to C group, P = 0.01. There was no significant difference between M1 and M2 groups, P = 1.0 at T3 and T4 [Figure 4].
There were three patients in the M2 group (8.11%), and two patients in the M1 group (5.26%) experienced a sense of hotness inside their bodies after study drugs administration (P = 0.62). It was a self-limited problem that needed no intervention but only assurance of the patients. In addition, there were two patients’ in the M2 group (5.13%) experienced excessive hypotension (MAP <60 mmHg) after the induction of general anesthesia, they were treated by ephedrine and excluded from the final analysis. Otherwise, no adverse reactions related to MgSO4 infusion were reported before the induction of anesthesia and during recovery period in PACU.
The findings of the current trial demonstrated that the IOP decreased significantly after 15 min of MgSO4 intravenous infusion before propofol administration in both magnesium groups similarly as compared to the control group. After propofol administration, the IOP decreased markedly in the control group below the baseline values to a level comparable to that level attained in the magnesium groups. The IOP measurements were increased after endotracheal intubation by 2 and 5 min in all groups. These values of IOP in the control group were significantly higher than that of the magnesium groups and greater than the baseline value of the control group; meanwhile, the rise of IOP in the magnesium groups limited below its baseline values, and there was no significant difference between both magnesium groups. The MgSO4 premedication attenuated the pressor response to laryngoscopy and endotracheal intubation as evident by significantly decreased MAP and HR after endotracheal intubation at 2 and 5 min after intubation as compared to the control group without significant differences between both of the magnesium groups.
Up to our best acquaintance and research, there are no adequately designed clinical trials evaluated the effect of intravenous infusion of MgSO4 premedication on IOP, especially before the induction of general anesthesia and after endotracheal intubation. The scarce available data are not conclusive and lacking precision;[15,16] hence, the importance of this unique design of the current trail as it is powered primarily to detect significant changes in IOP in healthy subjects undergone elective cataract surgeries.
The mechanism by which MgSO4 exerted these effects is not entirely verified, but magnesium may play a substantial role in nerve and muscle physiological function, cardiac excitability, neuromuscular conduction, muscular contraction, vasomotor tone, and normal blood pressure. MgSO4 inhibits endothelin-1 (ET-1)-induced contraction in porcine ciliary vessels and may regulate the perfusion abnormality at microcirculatory level. Therefore, MgSO4 may have a therapeutic effect by decreasing the IOP through the inhibition of ET-1 induced contraction. In addition, MgSO4 acting as a physiological calcium antagonist and a direct vasodilator.
The pressor response attenuation of MgSO4 could be attributed to the catecholamine release inhibition from the adrenal medulla and consequentially the stable epinephrine and norepinephrine plasma level concentration. These effects advocated by James et al. who studied the effect of a dose of 60 mg/kg MgSO4 administration on hemodynamic changes and the release of catecholamine related to tracheal intubation in healthy subjects in comparison to a placebo saline solution as a control. They concluded that MgSO4 attenuates the catecholamine-mediated responses after tracheal intubation as they found a statistically and clinically significant reduction of epinephrine and norepinephrine serum level following endotracheal intubation in MgSO4 group as compared to placebo.
In the same context, Allen et al. found that MgSO4 40 mg/kg was superior to either lidocaine 1.5 mg/kg or alfentanil 10 μg/kg for the control of the hypertensive response to tracheal intubation regarding the numbers of the hypertensive incidents found in patients with pregnancy-induced hypertension.
Park et al. found that MgSO4 50 mg/kg premedication over 15 min before rapid sequence induction by rocuronium 0.6 mg/kg improved intubation conditions and induced stable hemodynamic responses. These finding supported by the work of Kim et al., who concluded that MgSO4 delivers best intubating condition for rapid-sequence intubation when compared with ketamine, rocuronium priming, large-dose rocuronium 0.9 mg/kg, and the control. They attributed these effects to significantly shorter onset time of muscle relaxation as compared to other groups by decreasing presynaptic acetylcholine release. Onset time of muscle relaxation of MgSO4 group was significantly shorter than that of other groups and equivalent only with that of large-dose rocuronium group (0.9 mg/kg).
A regimen of intravenous MgSO4 infusion at a dose of 50 mg/kg as a bolus followed by 15 mg/kg/h intravenous infusion for hours until the end of surgical procedures was used by Ryu et al. to test the therapeutic effects of magnesium and the possibility of symptomatic hypermagnesemia. They prove the efficiency of this regimen to attain the desired therapeutic effect with an acceptable level of safety as serum magnesium level did not exceed the therapeutic level (2.5–5 mEq/L) determined by Wacker and Parisi. Our data support these findings as 50 mg/kg MgSO4 used safely without any reported signs and symptoms of MgSO4 toxicity; however, these results should be accommodated cautiously as the current trial was not designed or powered for this purpose.
In a brief clinical report, De Vore and Asrani concluded that fasciculation caused by succinylcholine administration were very unlikely to occur in pregnancy-induced hypertension patients who were pretreated by MgSO4.
Four decades ago, Meyers et al. reported that IOP rise that accompanies succinylcholine injection was not related to the existence or absence of muscle fasciculation. They attributed the succinylcholine-induced rise of IOP to its slow tonic effect on extraocular muscles dissimilar to its effects on skeletal muscles and vasodilatation of choroidal vessels. Their data demonstrated that the pretreatment with nondepolarizing neuromuscular blockers was not efficient in preventing the succinylcholine-induced rise of IOP contrary to the findings of Miller et al. a decade earlier. The conclusions suggested by Meyers et al. were reinforced by the work of Bowen et al.
IOP changes observed in both MgSO4 groups were similar in the current trial. Hence, both the doses are equally effective in attenuating the rise of IOP by succinylcholine and endotracheal intubation and produced significant fall in MAP and HR. Although the comparable effects in M1 and M2 groups regarding MAP and HR changes, two patients in Group M2 (5.13%) developed excessive hypotension, treated by ephedrine, and excluded from the final analysis. Hence, the use of 30 mg/kg MgSO4 could be more appropriate as it has the same effect as 50 mg/kg on IOP with probably better preservation of MAP and without the risk of excessive hypotension.
Considering the current findings, it is wise to avoid succinylcholine administration in open eye trauma patients due to its unfavorable effects on IOP that could endanger the eye integrity, but fair clinical judgment may occasionally necessitate succinylcholine administration in emergency situations compromising life where the eminent risks outweigh possible clinical benefits. We suggest that pretreatment with MgSO4 has many advantages over the other agents used for the same purpose, as it is a cheap, available drug with short-onset time, has extending effect with broad therapeutic range level, and could be used in emergency safely. MgSO4 has a general anesthetic and central nervous system depressant abilities that could decrease anesthetic consumptions and has analgesic potentials that could limit opioid use. In addition, hasten-onset time of neuromuscular blocking drugs potentiate muscle relaxation and could reduce the required dose of intraoperative muscle relaxants. Pretreatment with MgSO4 could induce controlled hypotension without reflex tachycardia, devoid opioid-related side effects and has a simple self-limited very unlikely adverse reaction.
As a limitation to the current trial, we have not determined magnesium serum level and serum catecholamine level to do a correlation with IOP changes and other hemodynamic variables. We recommend doing so in the future trials.
Intravenous administration of MgSO4 before induction of anesthesia at doses 30 mg/kg and 50 mg/kg was equally effective in preventing IOP upsurge accompanying the administration of succinylcholine and endotracheal intubation. MgSO4 30 mg/kg may be preferred for the prevention of rising in IOP to avoid possible undesirable detrimental hemodynamic effects.
This study was supported by Fayoum University Hospital and Benha University Hospital.
There are no conflicts of interest.
Authors would like to acknowledge all members of the Departments Of Anesthesia at Fayoum and Benha Universities hospitals, especially the two heads of the two departments for their valuable supports and special thanks to Professor Ahmed Mostafa Abd El-Hamid for his valuble contribution in this trial.