The effect of neuromuscular blocking reversal agents on perioperative neurocognitive function after general anaesthesia: a systematic review and meta-analysis
The Takeaway
Sugammadex was associated with improved early perioperative neurocognitive function compared to neostigmine when used to reverse neuromuscular blockade
Physiology Refresh
Neostigmine works indirectly by inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine (ACh) at the neuromuscular junction. By preventing ACh degradation, neostigmine increases the concentration of ACh in the synaptic cleft, which overwhelms the competitive blockade at the receptor sites.. This competitive mechanism works primarily for non-depolarizing NMBAs like rocuronium and vecuronium but requires some spontaneous recovery to be effective.
Neostigmine inhibits acetylcholinesterase throughout the body, leading to increased acetylcholine levels not only at the nicotinic receptors of the neuromuscular junction (desired effect) but also at muscarinic receptors. This systemic increase in acetylcholine can cause significant parasympathetic side effects including bradycardia, bronchoconstriction, hypersalivation, increased secretions, and gastrointestinal hypermotility.
Glycopyrrolate, an anticholinergic medication, is coadministered with neostigmine to selectively block these muscarinic receptors, thereby preventing these adverse parasympathetic effects while allowing neostigmine's desired action at the nicotinic receptors of the neuromuscular junction.
In elderly patients, this combination can potentially contribute to cognitive delay through several mechanisms:
- Anticholinergic burden: Glycopyrrolate contributes to the overall anticholinergic load, which elderly patients are particularly sensitive to due to age-related changes in the blood-brain barrier and cholinergic function.
- Central anticholinergic syndrome: Despite glycopyrrolate's limited blood-brain barrier penetration, some central effects can occur, especially in elderly patients, manifesting as confusion, memory impairment, and attention deficits.
- Drug interactions: Elderly patients often take multiple medications with anticholinergic properties, creating additive effects.
- Altered pharmacokinetics: Age-related changes in drug metabolism and elimination can lead to prolonged drug effects and increased central nervous system exposure.
This cognitive impact is particularly concerning given that postoperative cognitive dysfunction is already more prevalent in elderly surgical patients.
Sugammadex, on the other hand, is a modified gamma-cyclodextrin with a hydrophobic core that selectively encapsulates aminosteroid NMBAs (particularly rocuronium, less so vecuronium). This forms tight 1:1 molecular complexes, rapidly removing the NMBA from circulation and the neuromuscular junction. This encapsulation creates a concentration gradient that pulls NMBA molecules away from receptors. Unlike neostigmine, sugammadex works even with profound blockade and doesn't affect cholinesterase activity or require anticholinergics.
The avoidance cholinergic system activation is what can protect post operative cognition in the elderly.
Abstract
Background: Perioperative neurocognitive dysfunction (PND) is influenced by various perioperative factors. Recent studies suggest that neuromuscular blocking reversal agents (NMBRs) may impact on PND. However, the results have been inconsistent. Therefore, we aimed to compare the effects of perioperative NMBRs on PND through this systematic review and meta-analysis.
Methods: We searched PubMed, CENTRAL, Embase, Web of Science, Scopus, and China Biology Medicine from their inception until May 2024. Two reviewers independently identified randomized controlled trials (RCTs) that compared the perioperative use of NMBRs with either a placebo or other NMBRs in patients undergoing general anaesthesia. We assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The primary outcome was the incidence of PND within 7 days following surgery, while the secondary outcomes included the time required to achieve a Train-of-Four ratio (TOF) ≥ 0.9 after administration of NMBRs, length of stay (LOS) in both the post-anaesthesia care unit (PACU) and the hospital, as well as the risk of adverse events (i.e. postoperative nausea and vomiting (PONV) and mortality).
Results: A total of 10 randomized controlled trials involving 1705 patients compared the effects of NMBRs on PND. Neostigmine and sugammadex are the most commonly used NMBRs in clinical anaesthesia practice. In the primary analyses of all regimens, sugammadex significantly reduced the incidence of PND compared to neostigmine (risk ratio [RR] 0.67; 95% confidence interval [CI]:0.48-0.94; I2 = 0%; P = 0.02; moderate quality). However, the results indicated that there is no significant association between neostigmine and PND when compared to placebo (RR 0.76; 95% CI: 0.55-1.05; I2 = 35%; P = 0.09; moderate quality). The secondary outcomes revealed that sugammadex could significantly shorten the time of TOF ≥ 0.9 compared to neostigmine (mean difference [MD] -4.52; 95%CI: -5.04 to -3.99; I2 = 80%; P < 0.01; Moderate quality). Furthermore, no significant differences were observed in the incidence of adverse events or hospital LOS.
Conclusions: This meta-analysis demonstrated that the use of sugammadex was associated with improved early perioperative neurocognitive function compared to neostigmine when used to reverse neuromuscular blockade, without an increase in the incidence of adverse events.
Excerpts
Perioperative neurocognitive disorders (PND) are a prevalent central nervous system complication in patients undergoing anaesthesia and surgery, characterized by changes in cognitive function, including memory impairment, attention shortfall, and deterioration of executive functions, which may persist for months or even years after surgery
Based on the timing of symptom onset, PND can be categorized into preoperative neurocognitive disorders (NCD), postoperative delirium (POD), and postoperative neurocognitive disorders (POND)
The occurrence of PND following major surgery varies significantly, with reported rates ranging from 17 to 28% at one month postoperatively.
PND is independently linked to prolonged hospitalization, increased 30-day mortality, elevated medical expenses, and a greater economic burden on families and society.
While the underlying causes of PND remain unclear, factors such as age, psychological stress, neuroinflammation, genetic predisposition, and neurotransmitter abnormalities may play significant roles
One of the important measures in this regard is to preserve the functionality of the cholinergic system while minimizing the perioperative anticholinergic load to safeguard cognitive function
anticholinergic agents can penetrate the BBB and have been associated with mild postoperative memory deficits [10]. Therefore, the administration of ACEIs in combination with anticholinergic drugs may disrupt the normal function of the cholinergic system and increase the risk of PND.
Evidence from preclinical and clinical studies suggests that sugammadex can potentially protect cerebral function and improve postoperative cognition. Nonetheless, a recent large retrospective study involving 49,468 patients found that sugammadex was significantly associated with an increased incidence of early postoperative delirium compared to neostigmine
The moderate certainty evidence indicates that sugammadex significantly reduces the risk of PND within 7 days compared to neostigmine when used to reverse residual neuromuscular blockade in patients undergoing non-cardiac surgery. Furthermore, in the subgroup of RCTs analyzed, patients who received sugammadex exhibited a 34.3% lower risk of PND at 24 h postoperatively.
Several factors may explain the beneficial impact of sugammadex on early postoperative cognitive function. First, sugammadex reduces postoperative pulmonary complications across various surgical procedures by adequately reversing residual neuromuscular blockade after anaesthesia, preventing the incidence of hypoxia. Impaired postoperative pulmonary function and hypoxia have also been associated with a higher risk of PND. Second, sugammadex offers a better quality of recovery compared to neostigmine, as it increases postoperative gastrointestinal motility and improves postoperative weakness. Third, sugammadex mitigates brain oxidative stress and neuroinflammation, inhibiting the release of malondialdehyde and myeloperoxidase, promoting the release of anti-inflammatory cytokines. Overall, the multimodal protective effects of sugammadex appear to collectively enhance postoperative physical comfort, facilitating cognitive function during the critical postoperative recovery period.
Our findings suggest that the use of neostigmine may not be associated with PND within 7 days postoperatively when compared to placebo. However, results from the subgroup analysis are consistent with a recent RCT, which revealed that postoperative neostigmine use is associated with a reduction in PND at 24 h postoperatively compared to placebo. As a quaternary ammonium compound, neostigmine does not readily cross the BBB and remains in the peripheral compartment when administered via non-central routes. It is speculated that peripheral neostigmine could enter the central nervous system through the compromised BBB, increasing the level and duration of acetylcholine in the brain, and amplifying the activity of the cholinergic anti-inflammatory pathway to exert cognition protective effects. Our study demonstrated that neostigmine could reduce the incidence of early PND when compared to placebo, but the protective benefits were diminished when compared to sugammadex.
The latest clinical guidelines for postoperative neurocognitive disorders recommend minimizing the anticholinergic burden in patients as a non-invasive preventive measure. However, anticholinergic agents can cross the BBB and interfere with normal brain function.
Citation
Wang H, Lv X, Wu L, Ma F, Wang L, Wang Y, Wang X, Li Y. The effect of neuromuscular blocking reversal agents on perioperative neurocognitive function after general anaesthesia: a systematic review and meta-analysis. BMC Anesthesiol. 2025 Apr 4;25(1):152. doi: 10.1186/s12871-025-03019-9. PMID: 40186115; PMCID: PMC11969733.
