Deep Neuromuscular Blockade During General Anesthesia: Advantages, Challenges, and Future Directions

Abstract

Background: Neuromuscular blocking agents play an important role in modern anesthesia by facilitating optimal surgical conditions through deep muscle relaxation. Additionally, neuromuscular monitoring and reversal ensure swift and reliable recovery from neuromuscular blockade. The evolution of neuromuscular blocking agents, from early curare derivatives to contemporary agents such as rocuronium and cisatracurium, has significantly enhanced the safety and efficacy of anesthesia. Methods: This review examines the historical development, pharmacological mechanisms, clinical applications, and innovations in managing neuromuscular blockade. Results: It underscores key milestones in the advancement of neuromuscular blockade, including the introduction of neuromuscular monitoring techniques like Train-of-Four, which improve patient safety by reducing residual neuromuscular blockade. Pharmacological advancements, particularly the emergence of sugammadex, have further revolutionized clinical practice by enabling rapid and reliable reversal of steroidal neuromuscular blocking agents. The discussion covers the role of deep neuromuscular blockade in optimizing surgical conditions, especially in minimally invasive procedures. Conclusion: Comparative analyses of standard versus deep blockade reveal potential advantages in certain surgical scenarios, although patient-specific factors and associated risks must be carefully evaluated. Future directions involve developing innovative neuromuscular blocking agents and reversal agents aimed at achieving faster onset, shorter duration, and fewer side effects. The management of neuromuscular blockade continues to evolve, propelled by advancements in pharmacology and monitoring technology. Anesthesiologists should embrace a personalized approach, integrating advanced monitoring tools and customized pharmacological strategies to enhance patient outcomes. Ongoing research into next-generation neuromuscular blocking agents and reversal agents holds the promise of further improving safety and efficiency in anesthesia practice.

1. Historical Background and Development of Non-Depolarizing Neuromuscular Blocking Agents

The historical context of non-depolarizing neuromuscular blocking agents (non-depolarizing NMBAs) dates back to the mid-20th century when their clinical utility became evident in anesthesia practices (

Table 1. History of neuromuscular blockade (NMB) during general anesthesia.

	Milestone/Event	Details
1942	Introduction of neuromuscular blocking agents	Curare (d-tubocurarine) introduced in clinical anesthesia, enabling muscle relaxation and reducing anesthetic doses.
1950s	Early use of non-depolarizing neuromuscular blockers	Pancuronium and other agents were used for muscle relaxation during surgery; however, monitoring techniques were minimal.
1970s	Advancements in monitoring neuromuscular function	Introduction of peripheral nerve stimulators to monitor the depth of NMB.
1980s	The concept of deep NMB emerges	The distinction between deep (profound) and moderate (surgical) NMB begins to take shape in clinical practice.
1990s	Rocuronium and vecuronium become widely used	More predictable onset and offset of action; better control of depth of blockade compared to older agents.
2000s	Sugammadex development revolutionizes reversal of NMB	The introduction of sugammadex allows for the rapid reversal of rocuronium and vecuronium, enhancing safety and control of deep NMB.
2010s	Increasing use of deep NMB for laparoscopic surgery	Deep NMB shown to improve surgical conditions in laparoscopic and robotic surgery, reducing insufflation pressures.
2020s	Refinement of deep NMB protocols and advanced monitoring techniques	Quantitative neuromuscular monitoring (TOF ratio and post-tetanic count) becomes the standard; focus on individualized NMB depth.
Future	Ongoing research on optimal dosing and reversal agents and tailored anesthesia approaches	The aim to improve patient outcomes, reduce residual blockade, and personalize deep NMB strategies based on surgical needs.

). In fact, non-depolarizing NMBAs were first introduced in 1942 by Harold Griffith and Enid Johnson [1]. Before their formal introduction, the pursuit of an ideal muscle relaxant centered on the need to optimize surgical conditions by achieving profound muscle relaxation without compromising patient safety. One of the earliest substances used was curare, derived from plant extracts utilized by South American indigenous tribes as arrow poison [2]. Curare’s effectiveness in inducing muscle paralysis without affecting consciousness sparked significant interest in the exploration and development of chemically synthesized NMBAs.

The 1950s and 1960s marked the advent of non-depolarizing NMBAs such as tubocurarine and pancuronium, followed by the introduction of vecuronium in the 1980s. This new agent provided more predictable and controllable muscle relaxation [3]. These compounds were pivotal in transforming anesthetic practice, enabling a range of surgical procedures that required deep muscle relaxation. However, their use was not without challenges. Anesthesiologists had to navigate the delicate balance between adequate neuromuscular blockade (NMB) and the risks of residual neuromuscular blockade (rNMB), which was associated with serious respiratory complications [2].

The incorporation of neuromuscular monitoring in the 1970s marked a significant advancement in this field. Techniques such as Train-of-Four (TOF) monitoring enabled practitioners to quantify the depth of neuromuscular blockade (NMB), thereby minimizing the risk of residual neuromuscular blockade (rNMB) [4]. This practice received further support as agents like rocuronium became more commonly used, which, although effective, required precise dosing and monitoring to prevent complications (4). Fast forward to the 21st century, the development and clinical application of new non-depolarizing NMBAs such as cisatracurium, a drug that relies neither on hepatic metabolism nor renal function, along with rocuronium and sugammadex, a specific reversal agent for aminosteroid-structured non-depolarizing NMBAs, have further refined the practice of neuromuscular blockade.

The years of market introduction of the different, clinically relevant compounds are as follows:

• Pancuronium 1967 (steroidal compound)
• Vecuronium 1980 (steroidal compound)
• Pipecuronium 1980 (steroidal compound)
• Atracurium 1982 (benzylisoquinoline derivate)
• Doxacurium 1986 (bisbenzyltetrahydroisoquinolinium)
• Rocuronium 1990 (steroidal compound)
• Cisatracurium 1995 (benzylisoquinoline derivate)
• Mivacurium 1998 (benzylisoquinoline derivate)
• Rapacuronium 2000–2001 (steroidal compound)

Sugammadex, in particular, has revolutionized NMB management by providing rapid and reliable reversal of rocuronium-induced blockade, significantly reducing the incidence of rNMB [3]. The introduction of sugammadex and its ability to titrate the degree of NMB represents a milestone, highlighting the critical need for precise neuromuscular monitoring in modern anesthetic practice [2].

Technological advancements in neuromuscular monitoring have paralleled these pharmacological innovations. As NMB monitoring devices evolved from basic twitch monitoring to advanced electromyography (EMG)-based systems, the accuracy and reliability of measurements improved [2]. Modern EMG devices address the limitations of acceleromyography (AMG), offering more precise quantitative assessments of neuromuscular function and thus enhancing patient safety [2].

A retrospective study analyzing data from over 22,000 cases highlighted significant trends in the use of NMBAs and neuromuscular transmission (NMT) monitoring. The study found a notable increase in the use of sugammadex, particularly among patients with a higher body mass index (BMI), older age, or those undergoing emergency or complex surgeries [4]. The introduction of an integrated NMT monitoring module with automatic recording in the hospital studied was correlated with a decline in patients extubated without adequately documented NMT monitoring, thereby reducing the risk of rNMB [4].

The future of NMBAs continues to evolve through ongoing research. Innovations such as chlorofumarates (e.g., gantacurium) and novel reversal agents like adamgammadex sodium and calabadions are being examined for clinical use [3]. These developments promise to produce non-depolarizing NMBAs with rapid onset and offset profiles, along with minimal side effects, potentially setting new standards in anesthetic practice.

2. Mechanisms of Action in Neuromuscular Blockade: From Acetylcholine to Receptor Interaction

The understanding of NMB mechanisms has evolved significantly over the years, with major advancements clarifying how these processes influence anesthetic practice. Central to NMB is the interaction between acetylcholine and its receptors, particularly the nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. The process begins with the synthesis and storage of acetylcholine in presynaptic vesicles. When neural stimulation occurs, acetylcholine is released into the synaptic cleft, where it binds to nAChRs on the postsynaptic membrane. This binding triggers conformational changes that open ion channels, resulting in muscle contraction.

Neuromuscular blocking agents, especially those utilized in deep neuromuscular blockade (NMB), interfere with this process by competitively inhibiting the binding of acetylcholine to its receptors. This inhibition prevents the subsequent opening of ion channels and muscle contraction, while specific inhibitors can influence the neuromuscular signaling pathway [5]. Consequently, small peptides that bind to α-cobratoxin (α-Cbtx), a potent neurotoxin found in snake venom, can obstruct its inhibition of nAChRs. Research indicates that these peptides mimic structural elements of the nAChR binding pocket, thereby reducing the toxin’s effect. These findings emphasize the potential of custom-designed peptides to modulate neuromuscular signaling, broadening their implications beyond toxins to therapeutic NMB.

The intricacies of receptor interactions are further complicated by the involvement of major muscarinic acetylcholine receptors (mAChRs), which also help regulate neuromuscular transmission. Muscarinic receptors, especially the M3 subtype, interact with G-proteins like Gq/11 to mediate various physiological functions. The connection between M3 and its downstream effector Gq entails a dynamic set of molecular interactions that are essential for receptor coupling and signal transduction [6]. Research has utilized advanced techniques like hydrogen–deuterium exchange mass spectrometry and sophisticated cell systems to reveal the binding interfaces and conformational changes that enable M3-Gq coupling [6]. Notably, it was discovered that the intracellular loop 3 (ICL3) of M3 negatively impacts this coupling, providing new insights into how receptor interactions can be subtly regulated by specific intracellular regions.

Integrating these biochemical foundations, the use of neuromuscular blocking agents in anesthesia depends on their precise interaction with acetylcholine receptors. Deep neuromuscular blockade provides a greater degree of muscle relaxation than standard methods, which is crucial for surgeries that require minimal muscle movement. This is especially vital in laparoscopic procedures [7,8], where the surgical field is limited, and any involuntary muscle activity can complicate the operation. By more effectively targeting acetylcholine receptors, deep blockade establishes a more stable and controlled environment for the surgeon, thereby optimizing patient outcomes.

3. Comparison of Standard and Deep Neuromuscular Blockade in Anesthetic Practice

The perioperative management of neuromuscular blockade (NMB) during general anesthesia requires careful decision-making, balancing the advantages of muscle relaxation with possible complications. Examining standard (moderate) and deep NMB provides a thorough understanding of their respective applications, implications, and outcomes in clinical practice.

However, sensitivity to neuromuscular blocking agents varies significantly among different muscles. Therefore, the dose required to block the diaphragm and abdominal wall muscles is approximately 1.5 to 2 times higher than that needed to block the adductor pollicis [6,9]. Unfortunately, the diaphragm cannot be monitored non-invasively. Consequently, TOF stimulation at the adductor pollicis or orbicularis oculi muscles does not provide adequate information to monitor the levels of neuromuscular block necessary to prevent movements of the diaphragm or abdominal wall muscles.

Standard NMB is often used to aid intubation and guarantee sufficient muscle relaxation during surgeries that require moderate muscle control relaxation. Deep NMB has been increasingly recognized in certain surgical contexts for optimizing procedural conditions. It is evident that deep NMB can significantly enhance surgical settings by providing a greater level of muscle relaxation, thus preventing involuntary movements that might disrupt delicate surgical procedures. This is especially crucial in minimally invasive surgeries, such as laparoscopic and robotic-assisted operations, where precision and a stable surgical field are essential. A recent systematic review compared deep NMB with moderate, shallow, or no NMB during laparoscopic intraperitoneal procedures [10]. The review included 38 randomized clinical trials that assessed deep NMB against moderate NMB, involving a total of 3898 participants. The meta-analysis provided evidence that deep NMB has certain advantages in specific outcomes. For example, deep NMB improved the surgical field by more effectively preventing abdominal contractions, which could enhance the overall surgical experience and potentially reduce postoperative pain. However, it did not conclusively show a reduction in all-cause mortality or serious adverse events due to the very low certainty of the evidence [10].

One primary consideration when choosing deep neuromuscular blockade (NMB) over standard NMB is its effect on intraoperative and postoperative outcomes. While moderate NMB is generally sufficient for most surgical procedures, deep NMB may be preferred in operations that require complete immobility and more extensive muscle relaxation. Typical instances include surgeries in the retroperitoneum due to critical structures such as the inferior vena cava and abdominal aorta, as well as other delicate structures that could be harmed by sudden patient movement. This applies to surgeries near the liver, spleen, and pancreas, including bariatric surgery, fundoplication, gastric surgery, liver resection, splenectomy, and pancreatic procedures, as well as laparoscopic surgeries assisted by a surgical robot. Other specialties also encounter similar issues with sudden movements, including ophthalmic surgery, ENT procedures, neurosurgery, neuroradiology, cardiac ablation, and advanced endoscopic gastrointestinal procedures, such as mucosectomy and endoscopic retrograde cholangiopancreatography (ERCP).

Despite these advantages, the choice between moderate and deep NMB should consider the potential for respiratory complications and prolonged recovery time associated with the deeper blockade.

The potential benefits of deep NMB must be weighed against its associated risks [11,12]. Deep NMB likely results in minimal differences in surgery duration and health-related quality of life up to four days postoperatively compared to moderate NMB [10]. Importantly, the review revealed very low-certainty evidence regarding the effects of deep NMB on intraoperative serious adverse events, short-term serious adverse events (up to 60 days), and non-serious adverse events [10]. The proportion of serious adverse events did not significantly differ between deep and shallow NMB, indicating that a deeper blockade does not necessarily correlate with increased procedural risks.

Additionally, the influence of deep neuromuscular blockade (NMB) on pain management has garnered interest. It is proposed that by minimizing muscle contractions and maintaining a more relaxed surgical site, deep NMB may contribute to a reduction in postoperative pain. A Cochrane review highlighted that the evidence regarding deep NMB’s effectiveness on postoperative pain remains uncertain, showing a slight decrease in numeric rating scale scores 24 h post-surgery [10]. Nevertheless, these findings were not statistically significant enough to warrant the widespread use of deep NMB for pain control.

Surgical procedures requiring profound muscle relaxation, such as laparoscopic surgeries, have brought deep neuromuscular blockade (NMB) into significant focus in the field of anesthesia. Laparoscopic surgeries, recognized for their minimally invasive techniques, greatly benefit from deep NMB because it improves surgical conditions. The necessity for a nearly immobile surgical field and the potential for enhanced patient outcomes make deep NMB an attractive option in these scenarios.

One of the main reasons for using deep NMB in laparoscopic surgeries is the need for a stable and relaxed abdominal wall [9]. Inadequate muscle relaxation can impede the surgeon’s ability to create an adequate working space and may complicate the procedure [13]. Laparoscopic surgeries such as cholecystectomy, prostatectomy, nephrectomy, and bariatric surgery often require a greater degree of muscle relaxation to ensure optimal surgical conditions [13,14]. This necessitates sustained deep NMB, defined as a post-tetanic count (PTC) of three or fewer, significantly reducing involuntary muscle movements that could disrupt the surgical field.

The clinical benefits of utilizing deep neuromuscular blockade (NMB) during laparoscopic surgery are well-documented. For instance, a systematic review and meta-analysis indicated that deep NMB significantly improves surgical space conditions [15]. This analysis incorporated 12 studies and demonstrated that deep NMB leads to better surgical space conditions compared to moderate NMB, with a mean difference of 0.65 (95% CI: 0.47–0.83) on a scale of 1 to 5. This enhancement in working space is crucial for the safe and efficient execution of laparoscopic surgeries, as it offers surgeons a more controlled environment and reduces the risk of intraoperative complications. Furthermore, the capacity to use low-pressure pneumoperitoneum during deep NMB contributes to these improved conditions, as lower intra-abdominal pressures mitigate the risk of respiratory complications and promote postoperative recovery [15].

In addition to enhancing surgical conditions, deep neuromuscular blockade (NMB) has been linked to improved postoperative outcomes. For instance, patients undergoing laparoscopic surgery with deep NMB experience lower postoperative pain scores in the post-anesthesia care unit, with a mean difference of −0.52 (95% CI: −0.71 to −0.32) compared to those receiving moderate NMB [15]. Reduced postoperative pain contributes to a more comfortable recovery period, potentially leading to shorter hospital stays and higher overall patient satisfaction. As deep NMB alleviates pain after surgery, it may also assist in reducing other complications, underscoring its potential benefits in enhancing patient recovery and outcomes [16].

Despite these promising findings, the routine use of deep NMB in laparoscopic surgeries remains a subject of ongoing research and debate. The relatively low number of high-quality, low-bias studies suggests caution in universally recommending this practice for all laparoscopic procedures [16]. Comprehensive studies are necessary to definitively assess the full range of benefits and any potential risks associated with deep NMB. This is especially important since patient-specific factors can significantly influence the outcomes of deep NMB. Anesthesiologists and surgeons must work together to evaluate these factors and determine the suitability of deep NMB on a case-by-case basis.

4. Patient-Specific Factors and Preoperative Risk Assessment for Deep Blockade

Several patient-specific factors must be considered when determining the appropriateness of deep neuromuscular blockade (NMB) for a patient. Comprehensive preoperative risk assessments that take into account comorbid conditions, age, and other individual health parameters are important in guiding anesthetic management. For example, patients with multiple comorbidities or those at higher risk of postoperative complications may benefit from careful consideration of these factors, as they can significantly affect outcomes following procedures involving deep NMB.

One of the key considerations in patient-specific factors is assessing comorbid conditions. The presence of chronic diseases such as diabetes, hypertension, and respiratory issues can complicate the administration and recovery from deep NMB. A study emphasized the increased risks associated with severe maternal morbidity in patients with multiple chronic conditions [17]. It was found that women with three or more comorbid conditions were 3.8 times more likely to experience severe morbidity compared to those without chronic diseases. This finding highlights the importance of a thorough preoperative evaluation to identify patients who may be at higher risk and require tailored anesthetic management.

Age is another crucial factor influencing the decision to use deep neuromuscular blockade (NMB). Elderly patients often present with a higher likelihood of comorbidities and a decreased physiological reserve, making them more vulnerable to adverse events during and after surgery. The delicate balance in these situations involves ensuring adequate muscle relaxation for optimal surgical conditions while minimizing potential respiratory complications that can arise from prolonged muscle paralysis. Therefore, anesthesiologists must weigh the benefits of deep NMB against the potential for increased postoperative recovery time and complications in older patients. However, the use of sugammadex for effective and nearly immediate reversal of NMB can mitigate these concerns [18].

Another important consideration is the patient’s baseline neuromuscular function. Individuals with preexisting neuromuscular disorders, such as myasthenia gravis or muscular dystrophy, may show an exaggerated response to neuromuscular blocking agents. This increased sensitivity requires careful titration of the drug dosage and meticulous intraoperative monitoring to avoid prolonged blockade and respiratory distress after surgery. In these cases, choosing a standard level of NMB instead of deep blockade might reduce these risks while still ensuring adequate muscle relaxation.

The surgical procedure itself, particularly in laparoscopic surgeries, often determines the depth of NMB required. A systematic review highlighted that deep NMB is associated with better visibility of the surgical field and reduced postoperative pain in laparoscopic procedures [19]. They found that deep NMB helped maintain lower insufflation pressures without compromising the surgical field, leading to minor savings in healthcare resources. This indicates that deep NMB can be particularly beneficial in minimizing intraoperative complications and enhancing recovery, especially in procedures where limited movement and optimal visualization are important.

Additionally, the patient’s overall health and fitness level should be assessed, taking into account factors such as body mass index and respiratory function. Obesity can pose challenges due to changes in pharmacokinetics and mechanics of ventilation. Patients with obesity may benefit from deep neuromuscular blockade (NMB) due to the associated reduction in intra-abdominal pressure, which may enhance ventilation and oxygenation during surgery. Conversely, patients with compromised respiratory function may face longer recovery times and higher risks of postoperative pulmonary complications, necessitating careful use of deep NMB and effective reversal.

5. Evaluating the Potential Benefits and Risks of Deep Neuromuscular Blockade

Extensive research has been conducted on deep neuromuscular blockade (NMB) in anesthesia due to its potential benefits in improving surgical conditions and reducing postoperative complications. However, implementing deep NMB also involves specific risks that must be thoroughly evaluated to enhance patient outcomes. Investigating these factors necessitates a detailed examination of both clinical advantages and associated risks.

The primary benefits of deep NMB are largely linked to improving surgical field conditions and minimizing postoperative pain. A study demonstrated that administering sevoflurane alongside continuous intravenous anesthesia could significantly reduce the dosage required for muscle relaxants while maintaining adequate deep NMB. This method was especially beneficial for obese patients undergoing laparoscopic bariatric surgery, as it decreased extubation time and lowered the risk of hypoxemia. Importantly, these findings suggest that deep NMB can enhance recovery times and decrease adverse respiratory events, which is important for patients with obesity who face a higher risk of such complications.

In alignment with these findings, a randomized controlled trial compared deep and moderate NMB during gynecologic laparoscopic surgeries [20]. The study revealed that deep NMB did not significantly improve the conditions of the surgical field compared to moderate NMB. However, patients who received deep NMB reported lower postoperative pain scores and required less opioid analgesia. These outcomes indicate that while deep NMB may not substantially enhance visibility in the operative field, it provides significant advantages in postoperative pain management, potentially reducing the reliance on opioid medications and thereby mitigating the associated risks of their use.

Conversely, another randomized controlled trial sought to determine whether deep NMB could enhance the operating conditions during minimally invasive anterolateral total hip replacements [21]. The study included 116 patients and compared both moderate and deep levels of NMB. The primary outcome measured was the number of requests from surgeons for additional blockade during the procedure. The results showed no significant difference between the deep and moderate NMB groups concerning these requests, operative times, or the surgeons’ assessment of operative conditions. The findings suggest that routinely using deep NMB during such procedures may not be warranted, as it does not provide substantial operative benefits.

These studies collectively highlight an important aspect of deep NMB: its benefits are often context-specific. While deep NMB can aid in certain surgeries that require profound muscle relaxation and provide postoperative pain relief, it does not universally enhance surgical conditions across all types of procedures. Furthermore, the associated risks of using deep NMB need careful monitoring. Potential risks include prolonged recovery from NMB, respiratory complications, and inadequate reversal of muscle relaxation, which can result in postoperative residual block and subsequent complications [22].

Another risk factor involves variability in patient responses to muscle relaxants. As discussed above, obese patients particularly benefit from reduced dosages of muscle relaxants when combined with sevoflurane [22]. However, precise dosing and vigilant monitoring are necessary to prevent under- or overdosing, which can lead to insufficient muscle relaxation or prolonged neuromuscular recovery times. Other authors also emphasize the importance of postoperative care in managing potential complications arising from deep NMB, including ensuring effective reversal and monitoring for any residual blockade effects [20].

6. Pharmacological Agents and Optimal Dosing in Deep Neuromuscular Blockade

Deep NMB in anesthesia is a complex process that necessitates precise dosages and the selection of appropriate pharmacological agents to ensure patient safety and optimal surgical conditions. Numerous studies highlight the challenges associated with NMBA administration, particularly in surgical settings where profound muscle relaxation is essential. As the practice evolves, understanding the comparative efficacy, dosing strategies, and outcomes linked to different agents becomes critical.

Neuromuscular blocking agents, such as rocuronium and, to a lesser extent, vecuronium, are commonly used to achieve deep NMB. Both compounds belong to the chemical class of aminosteroidal neuromuscular blockers. Rocuronium is characterized by a hydroxy group in place of the acetyl ester found in the steroid nucleus of vecuronium. The methyl group attached to the quaternary nitrogen of vecuronium is replaced by an allyl group in rocuronium. These modifications result in a compound that is stable in solution, less potent, but with a more rapid onset of action [23]. These agents work by competitively binding to nicotinic acetylcholine receptors at the neuromuscular junction, preventing acetylcholine from activating these receptors and, consequently, inhibiting muscle contraction [24]. Dosage and timing are important in ensuring that the blockade is sufficiently deep and reversible post-surgery. For instance, rocuronium often requires tailored dosing based on patient physiology and the nature of the surgical procedure to maintain adequate and stable blockade.

The literature indicates the use of specific reversal agents to mitigate the risks associated with NMBA use, such as postoperative rNMB. Neostigmine, a cholinesterase inhibitor, has traditionally been used for this purpose; however, recent studies have highlighted its limitations in effectively reversing deep blockade. One recent study showed that patients undergoing thoracic surgeries who were reversed with neostigmine exhibited significantly higher rates of residual paralysis compared to those reversed with sugammadex, a selective relaxant binding agent. They found that 80% of patients in the neostigmine group had residual blockade at extubation, whereas only 6% in the sugammadex group experienced the same, underscoring the latter’s efficacy.

Sugammadex’s effectiveness stems from its ability to encapsulate and neutralize steroidal NMBAs like rocuronium, allowing for a swift and complete reversal of deep blockade. This pharmacological mechanism reduces the complications associated with prolonged NMB, such as hypoxemic incidents and muscle weakness, which are often observed with less effective agents. In particular, studies have shown improved surgical conditions and fewer postoperative complications in patients who received sugammadex, highlighting its importance in modern anesthesia practices. A systematic review in the Cochrane Library [25] suggests that sugammadex appears to have a better safety profile than neostigmine. Patients treated with sugammadex encountered 40% fewer adverse events compared to those administered neostigmine. The risks of bradycardia, postoperative nausea and vomiting (PONV), and overall signs of postoperative residual paralysis were specifically reduced. Both sugammadex and neostigmine were associated with serious adverse events in less than 1% of patients, and the data showed no differences in the likelihood of serious adverse events between the groups.

Deep NMB is especially beneficial in laparoscopic surgeries, where muscle relaxation at the surgical site is essential. A notable study examined the role of deep NMB in laparoscopic gynecologic surgeries and its effects on postoperative outcomes [26]. The research compared moderate blockade with pneumoperitoneum pressures of 12 mmHg to deep blockade at 8 mmHg. The results showed that deep blockade allowed for lower insufflation pressures without compromising surgical conditions, potentially reducing postoperative pain and enhancing recovery. This study highlights the importance of optimal dosing in achieving effective muscle relaxation as well as improved patient-centered outcomes, such as less postoperative pain. Another randomized controlled trial compared deep with moderate NMB at low and standard intraabdominal pressure during laparoscopic cholecystectomy and found significantly better surgical conditions and surgeon satisfaction with deep NMB [27].

7. Advanced Intraoperative Monitoring Techniques for Neuromuscular Blockade, e.g., Train-of-Four

Intraoperative monitoring of NMB is a critical aspect of modern anesthetic practice, particularly when addressing deep NMB. Advanced monitoring techniques like Train-of-Four (TOF) have shown significant efficacy in optimizing patient outcomes by ensuring accurate dosing and timely reversal of NMBAs [28]. The TOF monitoring system functions by delivering four electrical stimuli in rapid succession to a peripheral nerve and measuring the resulting muscle contractions. This methodology offers a quantitative assessment of neuromuscular function, enabling anesthetists to evaluate the depth and recovery from NMB with high precision.

Intraoperative quantitative NMB monitoring in pediatric patients using electromyography (EMG)-based train-of-four (TOF) monitoring is feasible [28]. The referenced study involved 100 pediatric patients and successfully detected supramaximal stimulation in 95% of participants. The average baseline TOF ratio was 100%, which significantly decreased after administering neuromuscular blocking agents but recovered to a mean of 90.1% prior to tracheal extubation. This study demonstrated the effectiveness of EMG-based monitors for TOF ratio monitoring, indicating that these devices can provide reliable data for intraoperative management in pediatric populations.

Additionally, to correlate TOF measurements with other monitoring techniques, the Patient State Index (PSI) monitor can assess muscle strength alongside TOF during the extubation phase of general anesthesia [29]. In this study involving 100 patients, the researchers recorded PSI and EMG values simultaneously. They found a strong positive correlation between TOF and PSI, indicating that PSI could serve as an effective complementary tool for real-time neuromuscular assessment. The study concluded that integrating TOF with PSI monitoring could enhance the accuracy of NMB and depth of anesthesia assessments, ultimately improving overall anesthetic management.

Advanced intraoperative monitoring techniques not only optimize the use of NMBAs but also minimize the risks associated with rNMB. A retrospective cohort study involving over 101,000 adult patients assessed the effectiveness of the Residual Neuromuscular Block Prediction Score (REPS) against the Train-of-Four (TOF) ratio in predicting postoperative respiratory complications. The study revealed that a low TOF ratio (<0.9) was significantly linked to increased respiratory complications (adjusted odds ratio, 1.43) compared to high REPS scores (≥4), which exhibited no significant association. These results emphasize the importance of quantitative TOF monitoring in clinical practice for mitigating postoperative respiratory risks. By accurately predicting rNMB, TOF monitoring enables timely interventions and reversals, thereby improving patient safety.

Given the advancements in monitoring technologies, it is clear that quantitative TOF monitoring, particularly when combined with additional tools like PSI, offers a robust method for managing deep NMB. Integrating these monitoring techniques ensures that anesthetists can maintain precise control over neuromuscular function during surgical procedures, enabling optimal anesthetic outcomes and reducing the risk of residual blockade. Furthermore, as technology continues to advance, the feasibility and accuracy of these monitoring systems are expected to improve even more, making them essential tools in the field of anesthetic management [28,29,30].

8. Postoperative Care Considerations and Neuromuscular Recovery After Blockade

The postoperative care of patients undergoing deep NMB involves careful monitoring and management to ensure complete neuromuscular recovery and reduce potential complications. Nevertheless, rNMB remains a significant clinical concern, as it can lead to serious postoperative respiratory complications, which require effective strategies for detection and management in the post-anesthesia care unit (PACU).

A prospective study [31] highlights the critical importance of rNMB upon arrival in the PACU. The research evaluated 82 patients who received general anesthesia with NMB agents and utilized Train-of-Four (TOF) ratios measured through acceleromyography to quantify the extent of NMB. The study revealed that 36.6% of patients exhibited rNMB upon entering the PACU. It also demonstrated a direct correlation between rNMB and postoperative respiratory complications, with 46.7% of patients having TOF ratios below 90% experiencing complications, compared to only 9.6% of those with adequate neuromuscular recovery [31]. The study suggests that timely and accurate monitoring of neuromuscular function is important for effectively mitigating these risks.

Similarly, a multicenter observational study [32] provided significant insights into the incidence and management of rNMB. Analyzing 366 patients across 10 hospitals, the study reported an rNMB incidence of 5.5% among patients using neuromuscular blocking agents such as rocuronium. Although this figure is lower than that found in other studies [31], it aligns with similar findings, emphasizing the variability of rNMB incidence. The reduced incidence [32] was partly attributed to the use of sugammadex as a reversal agent, which demonstrated a lower rNMB incidence compared to neostigmine (5.3% vs. 16.7%, respectively).

The aforementioned studies collectively advocate for a systematic approach to postoperative care to ensure complete neuromuscular recovery. First and foremost, quantitative neuromuscular monitoring techniques, such as TOF ratios, with at least 90% being critical for minimizing respiratory complications [31,32], are utilized. These measures allow for precise assessment of the neuromuscular junction and can guide the appropriate timing for administering reversal agents.

Furthermore, the choice of reversal agents significantly impacts postoperative care strategies. It is evident that sugammadex is more effective than neostigmine in reducing rNMB incidence [32]. This suggests that sugammadex ought to be viewed as the preferred agent, especially in cases that require deep NMB. Nevertheless, it is also important to recognize the individualized nature of pharmacological management by taking into account patient-specific factors and the complexities of their health conditions.

The importance of postoperative vigilance, alongside chemical reversal techniques, cannot be overstated. The risk of rNMB causing respiratory distress requires immediate and ongoing respiratory support for affected patients [31]. Careful airway management and preparedness for intervention in the PACU are vital for reducing the adverse effects associated with rNMB.

9. Conclusions

The evolution of non-depolarizing NMBAs has significantly influenced modern anesthesia practice, transitioning from early curare derivatives to the development of selective relaxant binding agents such as sugammadex. This transformation reflects ongoing efforts to enhance patient safety, improve surgical conditions, and reduce complications like rNMB. Historical milestones, including the introduction of neuromuscular monitoring and pharmacological advancements, have been essential in optimizing the management of NMB. Today’s practice benefits from quantitative monitoring technologies such as electromyography, which ensure precise blockade depth and facilitate timely recovery.

Deep NMB, while offering significant advantages in certain surgical contexts—particularly in minimally invasive procedures—remains a complex intervention. Evidence demonstrates its effectiveness in enhancing surgical conditions and alleviating postoperative pain. Despite these encouraging findings, the routine application of deep NMB in laparoscopic surgeries continues to be a subject of ongoing research and debate. The relatively low number of high-quality, low-bias studies warrants caution in universally endorsing this practice for all laparoscopic procedures. Comprehensive research is essential to conclusively determine the range of benefits and any potential risks associated with deep NMB. This is especially important as patient-specific factors can greatly influence the outcomes of deep NMB. Anesthesiologists and surgeons must work together to assess these factors and determine the appropriateness of deep NMB on a case-by-case basis.

Recent guidelines indicate that achieving advanced spontaneous recovery to a TOF ratio greater than 0.2 or even 0.4 is essential for inducing neostigmine recovery to a TOF ratio of 0.9 or higher within a 10 min interval [33,34]. Thus, neostigmine is insufficient for antagonizing deep neuromuscular blockade; currently, sugammadex is the sole available reversal agent capable of reversing deep block. Consequently, deep neuromuscular blockade is limited to patients paralyzed with rocuronium or vecuronium. The development of a reversal agent that can counteract deep neuromuscular blockade induced by benzylisoquinolines would allow for the establishment of deep neuromuscular blockade in patients paralyzed by these agents as well. Preliminary data suggest that calabadion may be a compound capable of reversing deep block after either steroidal or benzylisoquinolines [35]. However, further research is necessary before its clinical implementation. Future studies are also needed to determine which surgical procedures would benefit from deep neuromuscular blockade. Similarly, research is required to better understand which patient populations or co-morbidities might enhance outcomes with deep blockade.