The main objective of this study was to investigate the efficacy and safety of calcium gluconate injection on the recovery of postoperative NMB in elderly patients after general anesthesia. Neostigmine is used as the most commonly used acetylcholinesterase inhibitor to antagonize postoperative residual muscle relaxation. When the anesthesiologist does not control the timing and the amount of drug administered, the patient's painful experience of general anesthesia will be derived from the adverse effects such as hypoxemia, nausea and vomiting, inadvertent aspiration and agitation caused by PORC [8]. With the concept of accelerated recovery after surgery (ERAS) promoted by modern medicine, we need to exclude the maximum perioperative safety risks caused by PORC. Murphy et al.[9、20] found that elderly patients are at high risk for postoperative myasthenic residuals, with an incidence of 60%~80%. In this study, the incidence of PORC after extubation in elderly patients was 67.5% in the control group, 52.5% in the C5 group and 30% in the C10 group, and only 17.5% in the C20 group. The Cedborg[10] study showed that the presence of myasthenic residuals in elderly patients in good general condition leads to an increased incidence of swallowing dysfunction and impaired airway pharyngeal protection. The specificity and vulnerability of the elderly patient population has led to an ongoing commitment to the perioperative protection and care of elderly patients.
Cis-atracurium is a new benzylisoquinoline-based non-depolarizing muscarinic drug, which is not affected by liver or kidney function and age, and is mainly eliminated by Hoffmann, with the advantages of rapid plasma clearance and non-accumulation. Compared with rocuronium bromide, cis-atracurium is more suitable for elderly patients. One study found that the recovery phase of cis-atracurium in elderly patients did not change significantly with patient age, and only the onset of action was prolonged[21].
Koundourakis et al.[11] found that the elimination half-life of atracurium was prolonged from 15 min to 24 min during hypothermic cardiopulmonary diversion. At present, there are few reports on the effect of body temperature on the pharmacokinetics of cis-atracurium, but because its molecular structure is similar to that of atracurium, its metabolism and elimination process in vivo may There are similarities. General anesthetic drugs and surgical operations reduce the thermoregulatory capacity of elderly patients, who are more prone to intraoperative hypothermia due to reduced muscle mass, reduced resting muscle tone, increased body surface area to body weight ratio, reduced skin vasoconstriction response, and limited cardiovascular reserve[12]. We strictly adopt intraoperative insulation measures, such as blower, warming blanket, infusion warming and adjustment of operating room temperature to maintain the patient's body temperature and avoid the occurrence of hypothermia to the greatest extent.
We observed a transient hyperdynamic state in the hemodynamics of the four groups of patients when antagonists were given alone or concomitantly with calcium gluconate injection, which stabilized after 10 min, similar to the findings of So Ron Choi[13]. The clinical onset of action was 2 min for neostigmine and 10–30 s for atropine, and generally atropine and neostigmine should be injected simultaneously in the same syringe to counteract the slowing of heart rate induced by neostigmine, thus showing early manifestations of increased heart rate. Shapira et al.[14] demonstrated that when calcium chloride was used, early hemodynamic changes were observed within 20 s and the cardiac index returned to baseline after 1 min. Although the increase in vagal tone induced by neostigmine causes a series of adverse effects such as glandular hypersecretion, it rapidly improves inotropic residuals and restores airway protective reflexes, so the Chinese Society of Anesthesia still recommends neostigmine (< 80ug/kg) for antagonizing inotropic residual effects after general anesthesia. In this study, HR and MAP were elevated in all four groups of patients immediately after antagonist administration, and although they were all within the safe range of 20% of the basal values, we considered the higher incidence of hypertension, diabetes mellitus and other underlying diseases in elderly patients in clinical work, and the hemodynamic effects produced by 40µg/kg neostigmine when used for postoperative muscarinic antagonism in elderly patients
In 1976, Ginsborg[15] demonstrated that calcium reduces the degree of depolarization produced by Ach. The effect of changes in calcium levels on neuromuscular conduction function is multifaceted: it induces the release of Ach from the presynaptic membrane, which increases Ach concentration at the junction site; it stabilizes the postsynaptic membrane and attenuates its sensitivity to Ach; and it participates in the excitation-contraction coupling of the transverse muscle at the level of myogenic fibers. One study showed that the duration of atracurium action was shortened in patients with elevated serum calcium levels secondary to hyper-Ach.[16] This shows that calcium ions not only resist neuromuscular blockade induced by myorelaxants, but also enhance recovery of non-depolarized neuromuscular function.
An interesting finding in our study is that in the early post-antagonism period the values of TOFr were more volatile in the control and low-dose calcium groups, while the high-dose calcium group appeared to be very stable. The 5mg/kg calcium group had better performance in the time to reach TOFr ≥ 0.90 and it is similar to the results of Choi and Ju[13、19]. However, for anesthesiologists, the TOFr ≥ 0.90 does not mean that the endotracheal tube can be removed immediately. We assume that there exist a competitive relationship between calcium ions, this effect does not disappear in a short period of time, continues to provide adequate amounts of calcium ions to the neuromuscular junction, and does not cause harm to the body.
In other studies, TOFr is of guiding significance for the timing of antagonist administration. In reference to a previous study suggested that antagonism with neostigmine is best delayed until at least two to three of the stimulated muscle are achieved by train-of-four stimulation.[23]As early as 1999, Kirkegaard proposed that the duration of action of muscarinic drugs in a given individual is a predictor of the timing of antagonism and that computational tools could be developed to guide neostigmine administration, and indicated that even at a time of 20–30 min after neostigmine administration, TOFr would still appear to be less than 0. 90 and therefore suggested that antagonism should be initiated at TOFc = 3[17、18]. Due to the particularity of pathophysiological changes in elderly patients, we believe that early antagonists can partially use the remaining depth of anesthesia before awakening to alleviate the hemodynamic fluctuations caused by neostigmine and protect the cardio-cerebral vascular system. Although some studies indicate that the antagonistic time should be TOFr ≥ 0.70 or even higher, But when TOFr returns to a certain value, whether there is not necessary to antagonize༟Antagonists are also known to have undesirable effects.[24] We are extremely careful with elderly patients at the antagonistic time of TOFc = 3 and obviously has a satisfactory antagonistic effect in elderly patients, moreover, it doesn't affect the surgery at all in this study.
Ju et al. [19] found that neostigmine combined with 5 mg/kg calcium chloride for antagonizing myasthenia could reduce myasthenic recovery time by 25%, favorably demonstrating the ability of calcium ions to promote myasthenic recovery; the results of So Ron Choi[4] pointed out that the myasthenic recovery time in the 10 mg/kg calcium group was 22.6% shorter than that in the control group and was more evenly distributed than that in the 5 mg/kg calcium group. In the present study, compared with the control group, the recovery time of muscle relaxation was shortened by 34. 78%, 17.39% and 13.04% in the C5, C10and C20 group, respectively, which is indicative to some extent, and the incidence of PORC, hypoxemia and dysphonia in patients after extubation was improved to a greater extent. 20 mg/kg of calcium gluconate injection did not cause hypercalcemia or calcium gluconate injection-related adverse effects in any patient.
In conclusion, calcium gluconate injection combined with neostigmine can be safely used for post-laparoscopic muscarinic antagonism in elderly patients. Compared with the low-dose group, calcium gluconate injection at 20 mg/kg can reverse the muscarinic effect of cis-atracurium more quickly, shorten the early muscarinic recovery time, reduce the incidence of PORC and shorten the PACU stay in elderly patients, and has clinical applicability.