Age-Specific Pharmacology of Neuromuscular Blocking Agents: A Comprehensive Review

Introduction

Since their introduction in 1942, neuromuscular blocking agents (NMBAs) have become a crucial part of modern anesthesiology [1]. Their main indications are enabling endotracheal intubation, status asthmaticus, decreasing intra-abdominal pressure, preventing shivering in therapeutic hypothermia, improving oxygenation in patients with acute respiratory distress syndrome (ARDS), and preventing patient–ventilator asynchrony [2]. Complications such as residual muscular blockade can increase mortality, emphasizing the need for reversal agents [3].

NMBAs can be divided into 2 main groups: the depolarizing (with currently only succinylcholine being used) and the non-depolarizing agents. The non-depolarizing agents can be further divided based on their structure into benzylisoquinolones (eg, atracurium, cisatracurium, mivacurium) and aminosteroids (eg, pancuronium, rocuronium, vecuronium) [4]. Reversal agents for non-depolarizing drugs can also be divided into 2 groups: acetylcholinesterase inhibitors (eg, neostigmine) and selective biding agents, with sugammadex being the only currently approved representative of the group [5].

Although both groups of NMBAs act at the neuromuscular junction (NMJ), they have different mechanisms of action. Succinylcholine binds with postsynaptic nicotine receptors and opens ion-gated channels, causing rapid depolarization (with fasciculations being observed at that stage) followed by muscle paralysis lasting from 3 to 12 minutes. The non-depolarizing agents act by binding to the nicotine receptors, competitively inhibiting acetylcholine-dependent muscle contractions. The length and onset of action varies between different non-depolarizing agents, but in general they have longer onset and duration of action [1,4,6,7].

A blockade caused by non-depolarizing NMBAs can be reversed via 2 different mechanisms. Firstly, acetylcholinesterase inhibitors inactivate the enzyme, decreasing acetylcholine degradation, and increasing its concentration in the NMJ. Higher concentration of acetylcholine reinstates regular neuro-muscular transmission and thus reverses the blockade. Secondly, sugammadex encapsulates free aminosteroidal NMBAs in the plasma, creating irreversible complexes. This causes a concentration gradient, which decreases the number of NMBAs molecules in the NMJ, reversing the blockade. Although, sugammadex is currently the most used reversal agent, it does not alter the blockade caused by benzylisoquinolones, which can be reversed by acetylcholinesterase inhibitors [3,8,9].

The properties and effectiveness of NMBAs can be affected by a large range of factors, including acid-base balance disorders, age, weight (especially extreme obesity), undergoing treatment (eg, chemotherapy or radiotherapy), hepatic disease, and renal impairment [10–15].

Children and elderly people have distinctive pharmacokinetic and pharmacodynamic qualities compared to the general population due to age-related physiological changes. In children, higher gastric pH and shorter transit time, different body composition and protein binding, immature liver enzymes, and kidney function affect drug absorption, distribution, metabolism, and elimination, causing significant differences in pharmacological properties compared to adults. Additionally, elderly people have reduced hepatic and kidney function and changes in body composition, leading to higher volume of distribution and slower drug clearance. Moreover, reduced functional reserves cause higher vulnerability to stress. In children, different body composition and binding to proteins, as well as immature liver enzymes and renal function affect the distribution, metabolism, and elimination of intravenously administered drugs, resulting in significant differences in pharmacological properties compared to adults. These variations highlight the need for age-specific pharmacokinetic and pharmacodynamic analysis when administering medications [13,16]. With an increasing number of preterm births and a growing elderly population, it is becoming significantly more important to address the issue of differences in medical approach according to age of the patient [17,18]. It is crucial for anesthesiologists to address and consider the issues regarding the age of the patient and its relationship to NMBAs and reversal agents.

This manuscript reviews and summarizes differences among certain age groups regarding NMBAs in anesthesiology. The article is based on clinical studies highlighting the most recent positions and available medical literature. The 131 articles published between 1987 and 2025, as well as the authors’ expertise and clinical experience, were used to prepare the review.

Children

SUCCINYLCHOLINE IN CHILDREN:

Succinylcholine (also known as suxamethonium) is currently the only depolarizing blocking agent used in clinical practice [23]. Its main advantages include very rapid onset (40–60 s), ultra-short muscle relaxation (6–10 min), and fast recovery [24,25].

Children (especially infants and neonates) are resistant to neuromuscular blockade caused by succinylcholine. It is thought that the main reason for succinylcholine resistance is a higher volume of extracellular fluid, which decreases over time. Additionally, children under the age of 6 months have a lower (compared to adults) concentration of butyrylcholinesterase, which metabolizes succinylcholine, but it does not impact the time of action of the drug. Thus, suggested doses for children to facilitate intubation are higher compared to adults: 2–3 mg/kg for neonates and infants and 1–2 mg/kg for children [26].

However, succinylcholine is associated with potentially life-threatening complications, including malignant hyperthermia, hyperkaliemia, cardiac arrest, and rhabdomyolysis, especially in children with muscular dystrophies, which can remain undiagnosed in younger patients [27,28].

A 2023 study found that rocuronium at a dose of 1.2 mg/kg creates better intubating conditions than succinylcholine at a dose of 2 mg/kg in children aged 1–14 years [28]. A 2015 study compared intubating conditions in patients aged 3–12 years who received 2 μg/kg remifentanil or 1.5 mg/kg succinylcholine in propofol-induced anesthesia. It found no significant difference in intubating conditions between the groups, with better controlled hemodynamic response in patients who received remifentanil [29]. A similar study in 2023 compared intubation conditions in patients aged 3–12 years who received succinylcholine (1.5 mg/kg) and fentanyl (3 μg/kg) in propofol-induced anesthesia. It showed that patients who received succinylcholine had better intubating conditions; however, all patients in both groups had successful intubation at the first attempt. The study concluded that a combination of propofol and fentanyl can be a viable alternative for propofol-succinylcholine [30].

ATRACURIUM IN CHILDREN:

Atracurium is a non-depolarizing NMBA that has an intermediate duration of action. It is metabolized through Hoffmann elimination, a process independent of liver or kidney function, which can be an important factor in children with conditions influencing function of these organs [11,12,31].

Neonates and infants are more sensitive to atracurium-induced muscle relaxation, and the ED95 of atracurium is lower in neonates and infants compared to children. At a dose of 0.5 mg/kg atracurium provides suitable intubating conditions after 90 seconds in children under age 1 year and after less than 2 minutes in older children. Additionally, neonates have significantly faster recovery than older children [32].

A 2018 study used a dose of atracurium of 0.3 mg/kg and an additional dose of 0.1 mg/kg, if necessary, in children with a corrected post-gestational age younger than 45 weeks – in 86.4% intubation succeeded in 1 or 2 attempts [33]. Moreover, an atracurium dose of 0.5 mg/kg in children aged 3–12 years creates better intubation conditions than cisatracurium at a 0.1 mg/kg dose. Some patients have histamine-release adverse effects, including flush, bronchospasm, hypotension, and tachycardia [34].

CISATRACURIUM IN CHILDREN:

Cisatracurium is an intermediate-acting non-depolarizing NMBA that is one of 10 stereoisomers of atracurium, and similarly, it undergoes organ-independent Hoffmann elimination, but in patients with renal disease, clearance of cisatracurium can be reduced [11,35]. Additionally, compared to atracurium, it does not cause histamine-release adverse effects [34]. The onset of action is more rapid, and the duration of action is longer in infants compared to children [36].

In 2007, Meakin et al concluded that a 0.15 mg/kg dose of cisatracurium creates excellent or good intubating conditions at 120 seconds in most children aged 1 month to 12 years after induction of anesthesia with either nitrous oxide-oxygen-halothane or nitrous oxide-oxygen-thiopental-fentanyl [37]. Similarly, a study conducted in 2008 by ShangGuan et al compared different doses of cisatracurium in children (aged 15–60 months) and concluded that a dose of 3 times the ED95 (0.15 mg/kg) is the most suitable nitrous oxide–propofol anesthesia [38].

MIVACURIUM IN CHILDREN:

Mivacurium is the only short-acting benzylisoquinolone NMBA currently used in clinical practice. It has rapid onset, lack of accumulation, and relatively few adverse effects [39]. Unlike other benzylisoquinolones, mivacurium is metabolized in plasma via pseudocholinesterase. A deficiency in this enzyme (which can be inherited) can cause a modest (15–20 minutes) or considerable (2–4 hours) delay in muscle recovery. Another important consideration is that infants (especially premature) can have lower pseudocholinesterase concentration [40].

Children have faster onset of action and quicker recovery compared to adults. The shorter recovery time is due to the higher ED95 in children than in adults. Additionally, due to higher ED95, children require higher infusion rates compared to older patients [41,42]. Interestingly, in patients aged 3–10 years, mivacurium at a dose of 0.2 mg/kg has faster onset and delayed recovery in patients receiving sevoflurane anesthesia compared to propofol anesthesia [43].

Several studies addressed the issue of dosing mivacurium in pediatric patients. In 2001 Nava-Ocampo compared 0.2 and 0.25 mg/kg doses of mivacurium in isoflurane anesthesia in children aged 6–24 months and concluded that even though the higher dose produced maximal block faster, it was associated with a more significant hemodynamic response [44]. A similar study in 2017 compared doses of 0.15, 0.2, and 0.25 mg/kg in children aged between 2 months and 14 years. It concluded that in infants, increasing the dose of mivacurium from 0.15 to 0.2 mg/kg shortened the onset time by about 30 s. Interestingly, in contrast to the first-mentioned study, in this case mivacurium produced no significant adverse effects [39]. Additionally, those findings were confirmed in a study from 2024, where a dose of 0.2 mg/kg was found to be the most suitable for laryngeal mask airway insertion in children aged 3–10 years [45].

A 2006 study of patients post-gestational age 25–38 weeks concluded that a dose of 0.2 mg/kg mivacurium allows suitable conditions to intubate the patient, even for inexperienced personnel. However, the onset time and time of action varied greatly within the studied group [46].

In conclusion, the suggested doses of mivacurium for enabling intubation is 0.15–0.2 mg/kg, but additional doses, if necessary, should be administered more often in children than in adults. However, due to possible pseudocholinesterase deficiency, caution is advised.

PANCURONIUM IN CHILDREN:

Pancuronium is a long-acting NMBA that undergoes primarily renal excretion, which is an important consideration because neonates have slower renal elimination of most drugs. Pancuronium is also known for causing tachycardia and hypertension. Although these adverse effects can be dangerous, in some age groups where bradycardia is highly undesirable (eg, neonates) they can become an advantage [47,48].

Additionally, pancuronium can be given in a continuous infusion in critically ill children. In a study by Johnson et al [47], a group of 25 children (aged 3 months to 17 years) received pancuronium at an initial dose of 0.1 mg/kg and then infusion at 0.05 mg/kg/h. The infusion rate was then increased or decreased by 0.01 mg/kg/h if necessary. The study showed a wide variability in pancuronium dosing. Patients requiring more than 5 days of infusion needed a significant increase in dose after the 5th day compared to day 1. The study found no residual block, but the sample was small.

VECURONIUM IN CHILDREN:

Vecuronium is an intermediate-acting NMBA that undergoes primarily liver elimination [49]. It has minimal cardiovascular effect and does not cause histamine-related adverse effects, making it a suitable choice in critically ill children [50].

Although vecuronium is generally an intermediate-acting agent, it can be a long-acting NMBA in children and infants. A dose of 0.1 mg/kg maintains muscle relaxation for 59 minutes in infants and neonates, 18 minutes in children aged 2–10 years, and 37 minutes in adolescents. Therefore, additional doses of vecuronium should be administered less often in infants and neonates. Additionally, children require higher doses of vecuronium to maintain neuromuscular blockade compared to other age groups. The ED95 has also been found to be the highest in children 1–13 years and lowest in infants, neonates, and adolescents in thiopental-fentanyl anesthesia [51].

ROCURONIUM IN CHILDREN:

Rocuronium is currently one of the most used NMBAs among children [50]. It has an intermediate duration of action and a fast onset. However, like vecuronium, rocuronium has a higher ED95 in children than in neonates, infants, and adolescents [52]. Time to recovery is also longer in infants compared to older children [53].

Due to its fast onset of action, rocuronium is commonly used instead of succinylcholine in rapid-sequence intubation (RSI). The main advantage of rocuronium over succinylcholine is its lack of adverse effects. However, a major concern regarding rocuronium is the risk of prolonged paralysis after RSI [54].

The standard 0.6 mg/kg dose of rocuronium effectively allows intubation among all pediatric patient groups; however, some studies addressed the possibility to reduce doses of rocuronium in certain circumstances. Pei et al concluded that combining 0.6 mg/kg of ciprofol with a reduced dose of rocuronium (0.3 mg/kg) created optimal intubating conditions in patients aged 3–12 years undergoing adenotonsillectomy. However, a lower dose of ciprofol (0.4 mg/kg) with the same dose of rocuronium did not provide suitable conditions [55]. Additionally, the same low dose of rocuronium provided optimal intubation conditions in patients aged 3–10 years under 5% sevoflurane anesthesia with 0.2 μg/kg fentanyl. Another advantage of low-dose rocuronium is the lack of delayed recovery [56]. Moreover, in neonates and infants under age 4 months, a dose of 0.45 mg/kg rocuronium allows satisfactory muscle relaxation that does not last too long [57].

It is also possible to administer rocuronium intramuscularly at a dose of 1.8 mg/kg in children and 1 mg/kg in infants. However, it is associated with long onset of action (5–9 minutes) and the reported intubating conditions were suboptimal [58].

Moreover, rocuronium is associated with injection pain and withdrawal arm movements, even in anesthetized patients, but this can be avoided by using pretreatment with antipyretic analgesics or lidocaine, with the latter being more efficient [59].

REVERSAL AGENTS IN CHILDREN:

Neostigmine is an acetylcholinesterase inhibitor used to reverse neuromuscular blockade of all non-depolarizing NMBAs. Pediatric patients require lower doses of neostigmine compared to adults, and doses of 0.02–0.05 mg/kg seem to be sufficient. Recovery time after neostigmine is around 10 minutes. Additionally, due to risk of bradycardia, neostigmine should be administered with atropine (0.02 mg/kg) [60–62]. Neostigmine is also associated with bronchospasm, nausea, vomiting, and hypersalivation. Because of that, sugammadex – a modified gamma-cyclodextrin that creates complexes with rocuronium and vecuronium reducing their concentration at the neuromuscular junction – seems to be a promising alternative to neostigmine [63].

The US FDA currently approves sugammadex for use in patients above 2 years old. The suggested dose of sugammadex is 2 mg/kg [62]. Sugammadex has fewer adverse effects and a faster onset of action compared to neostigmine. The biggest difference in time to return of the TOF to 0.9 was achieved in infants [64,65]. The median recovery time after sugammadex is 1.3 minutes [66]. Additionally, the reversal effect of sugammadex is more complete than that of neostigmine, with no significant residual weakness [64].

Several studies assessed sugammadex use in children under 2 years old. In 2019 Franz et al concluded that 2 mg/kg (the most common dose), 4 mg/kg, and 16 mg/kg sugammadex doses were an effective alternative for neostigmine in a group of 331 children below 2 years old. This study also revealed no adverse effects [67]. A 2024 study by Cates et al concluded that the hazard of sugammadex redoes decreases with age and weight. The initial median dose was 3.45 mg/kg and the median re-dose was 2.74 mg/mg. Re-doses were necessary in 4.2% of cases [68].

SUMMARY OF NMBAS USE IN CHILDREN:

Summarized recommended doses of NMBAs for children are presented below in Table 1, with additional key considerations specific for pediatric anesthesia.

Adults

SUCCINYLCHOLINE IN ADULTS:

According to the European Society of Anaesthesiology and Intensive Care guidelines, the recommended dose of succinylcholine for rapid-sequence intubation is 1 mg/kg [71].

However, some studies speculate that smaller doses might also be effective and may allow faster recovery of spontaneous respiration and airway reflexes. In 2011 Ezzat et al reported that 0.45 mg/kg, 0.6 mg/kg, and 1 mg/kg doses of succinylcholine provided suitable intubating conditions after 60 seconds in all patients under etomidate-fentanyl anesthesia. Lower doses were associated with a significant delay in onset of action; however, the difference was not clinically significant. The duration of neuromuscular block after 0.45 mg/kg succinylcholine was 5 minutes compared to 12.5 minutes after 1 mg/kg [72].

A study by Naguib et al (2006) confirmed the previously-mentioned findings regarding propofol–fentanyl anesthesia. The primary difference was that the duration of action of succinylcholine at a dose of 1 mg/kg was only 5.9 minutes. Additionally, it was concluded that there are no benefits of administering succinylcholine doses exceeding 1.5 mg/kg [73].

ATRACURIUM IN ADULTS:

The standard recommended dose of atracurium for adults is 0.5 mg/kg intravenously. It has been thoroughly determined that this dose is sufficient to create optimal intubating conditions. At this dose, the onset of action is around 2 minutes and clinically effective muscle relaxation lasts for 20–35 minutes [31]. During longer surgical procedures, additional doses are necessary to sustain sufficient neuromuscular blockade [74].

Moreover, some studies examined the possibility of using atracurium in RSI. Chalermkitpanit et al (2020) and Holkunde et al (2022) both concluded that 1 mg/kg of atracurium provides acceptable intubating conditions after 60 seconds from administrating, thus proving that atracurium can be an alternative blocking agent in RSI [75,76].

CISATRACURIUM IN ADULTS:

The generally recommended dose of cisatracurium for enabling endotracheal intubation is 0.15–0.2 mg/kg. These doses allow for intubation in clinically acceptable conditions in most patients. The time of onset decreases with dose: 2.7 minutes at 0.2 mg/kg and over 3 minutes at 0.15 mg/kg. Additionally, the duration of clinically effective neuromuscular blockade increases with dose, from 45–50 minutes at 0.15 mg/kg to 60–70 minutes at 0.2 mg/kg cisatracurium [77,78].

MIVACURIUM IN ADULTS:

The standard dose of mivacurium is 0.15–0.25 mg/kg by intravenous injection. At 0.15 mg/kg, mivacurium allows endotracheal intubation after 2–3 minutes and a divided dose of 0.25 mg/kg (0.15 mg/kg followed by 0.1 mg/kg after 30 seconds) provides suitable intubating conditions 90 seconds after the initial dose in most patients. Clinically effective block persists for 20–30 minutes [79,80].

A 2024 study by Moharam et al compared 0.4 vs 0.3 mg/kg doses of mivacurium in RSI, concluding that 0.4 mg/kg provides better intubating conditions and earlier onset of action (120.62 vs 141.52 seconds), but it results in longer recovery time (42.6 vs 32.5 minutes) compared to the lower dose [81].

PANCURONIUM IN ADULTS:

The initial dose of pancuronium utilized in endotracheal intubation is 0.1 mg/kg. Onset to optimal muscle relaxation is 3–5 minutes. The 95% effective dose is 0.07 mg/kg. Pancuronium has a long duration of action, with 60–90 minutes to a return of 25% of control twitches after a typical intubating dose. In some patients that time can increase to 100 minutes. Titration of maintenance doses usually involves 0.02 mg/kg. Infusion dosing normally is 0.7–2 μg/kg/min [82].

By blocking M2 muscarinic receptors, its administration raises cardiac output, heart rate, and mean arterial blood pressure. It is not preferable in patients with cardiac dysfunction or myocardial disease. It mainly undergoes renal elimination; however, 10% of the drug is metabolized by the liver and 10% is excreted via bile. Hepatic disorders require larger doses of pancuronium and its elimination is prolonged [12]. Renal insufficiency lowers clearance and prolongs its duration of action [11,82].

VECURONIUM IN ADULTS:

Vecuronium 0.08–0.1 mg/kg can be used in a bolus over 60 seconds or 0.04–0.06 mg/kg if suxamethonium is simultaneously used. In rapid-sequence intubation, the dose should be raised to 0.1–0.2 mg/kg, with adequate conditions developing after 2–3 minutes. For surgical procedures necessitating muscle relaxation, 0.01–0.015 mg/kg maintenance doses can be administered 20–45 minutes after the first dose and continued every 12–15 minutes [49]. At 45–65 minutes after injection, 95% recovery is achieved.

Vecuronium is approximately 60% dependent on hepatic metabolism and biliary excretion. One of its metabolites – 3-hydroxyvecuronium, constituting 80% of muscle-relaxing properties – accumulates in renal insufficiency, causing prolongation of neuromuscular block. In patients with both liver and kidney failure, reduced doses should be used [12]. Changes in acid-base equilibrium also affect vecuronium-induced block, with metabolic and respiratory acidosis reinforcing neuromuscular block and metabolic and respiratory alkalosis diminishing it [10].

ROCURONIUM IN ADULTS:

The intubation dose of rocuronium is typically 0.6 mg/kg. In rapid-sequence intubation, 1.0–1.2 mg/kg enables intubation within 60 seconds. Boluses of 0.1–0.2 mg/kg or continuous infusion of 0.01–0.012 mg/kg/min can be implemented to maintain muscle relaxation. Its half-life in adults is 1.4–2.4 hours. Biliary excretion is the major means of rocuronium elimination, with only 10–30% via the renal pathway. Most of the drug remains unchanged, with less than 10% undergoing liver metabolism [83]. Hepatic insufficiency prolongs the half-life to 4.3 hours and renal dysfunction can increase it to 2.4 hours [12,84].

REVERSAL AGENTS IN ADULTS:

Neostigmine acts as an acetylcholinesterase inhibitor, decreasing breakdown of acetylcholine at the neuromuscular junction, indirectly antagonizing the effects of NMBAs [85,86]. To avoid its muscarinic effects (eg, increased intestinal motility, bradycardia, or bronchospasm), an antimuscarinic drug must be simultaneously administered [87]. Neostigmine should be used after a high degree of recovery has been achieved or in circumstances where a recovery time of over 15 minutes is acceptable [88].

In clinical use, doses of 0.015–0.07 mg/kg up to a maximum of 5 mg total have been used [89].

Studies show the dose of neostigmine should depend on the depth of neuromuscular block. In weak to moderate block, a 20–30 μg/kg dose seems sufficient, and in the deep block, 40–50 μg/kg can be safely administered. The maximum effect is achieved after 8–10 minutes after administration. Raising a dose does not necessarily increase its efficacy due to the “ceiling effect,” but it is associated with a higher incidence of adverse effects such as paradoxical weakness. If given in excess, it can contribute to a depolarizing block [86]. Renal dysfunction also prolongs its action [87].

Sugammadex deactivates neuromuscular block caused by rocuronium or vecuronium in 1: 1 ratio with the NBA. Bolus doses of 2–16 mg/kg can be safety utilized in the reversal. Lower doses should be reserved for moderate neuromuscular blockade (2 twitches in response to TOF stimulation) and 4 mg/kg implemented in 1–2 post-tetanic counts after 5-second 50-Htz tetany, and 16 mg/kg can be used after a 1.2 mg/kg dose of rocuronium. Neuromuscular recovery is much faster than with neostigmine, with an average TOF ratio >0.9 achieved within 3 minutes [9]. For successful reversal, sugammadex dosing should be based on an actual rather than ideal body weight in obese patients [90]. It is mostly eliminated unchanged via the kidneys; therefore, caution is needed in patients with renal dysfunction [11].

According to the European Medicines Agency, sugammadex use is associated with longer APTT and PT. Coagulation can be slowed and the incidence of postoperative bleeding may increase. Caution is needed in patients with liver disease, who may have blood clotting abnormalities [12]. Sugammadex use in surgeries with high bleeding risk should be reconsidered [91].

Elderly Patients

SUCCINYLCHOLINE IN ELDERLY PATIENTS:

Plasma cholinesterase activity decreases with age. Hence, hydrolysis of succinylcholine occurs at a significantly lower rate in the elderly and its duration of action increases [94].

Vested et al (2024) examined the outcomes of using suxamethonium vs rocuronium in patients 80 years old and over. Both medications were used in endotracheal intubation at a dose of 1.0 mg/kg. After 60 seconds, intubating conditions were assessed with the Fuchs-Buder scale, assessing factors such as abduction of vocal cords, reaction to intubation by movement or coughing, jaw relaxation during laryngoscopy, and resistance to a laryngoscope. Excellent intubation conditions occurred in 75% vs 73% in the succinylcholine and rocuronium groups, respectively. Both groups had 98% success of first-attempt intubation. However, the suxamethonium onset time was almost 30 seconds shorter compared to rocuronium [95].

ATRACURIUM IN ELDERLY PATIENTS:

Atracurium infusion at 16.3±2.8 ug/kg/min depressed the twitch tension of the adductor pollicis muscle by approximately 70%. The volume of distribution was significantly greater than in studies with younger subjects. Benzylisoquinolones’ molecular size makes it impossible for them to cross lipid membranes, perhaps due to high protein-binding (approximately 80%), which is naturally decreased in elderly patients. Although atracurium primarily undergoes Hoffman elimination, which is not affected by age, 10–50% of atracurium undergoes liver metabolism and renal elimination. Kitts et al (1990) established that total clearance was similar in patients aged 74–76 years compared to those aged 22–44 years, but the proportion of liver and renal clearance was smaller, with ester hydrolysis and Hofmann elimination playing a bigger role [96]. With age, its clearance decreases, and the half-life increases by up to 15%. Recovery from neuromuscular blockade can be prolonged [94,96].

Slavov et al (1995) used an initial dose of 0.5 mg/kg with additional boluses of 0.1 mg/kg whenever twitch response recovered to 25%, and the duration of action did not differ significantly among age groups [97]. de Almeida et al (1996) administered a 0.5 mg/kg dose of atracurium and found that onset times did not differ among age groups, but the duration of action and recovery was prolonged in patients over age 65 years [98]. However, Parker et al (1992) found that a 0.25 mg/kg dose of atracurium resulted in decreased clearance, with longer elimination half-life in elderly patients [99].

Atracurium-related histamine release has been reported in people over age 65. Shorten et al assessed histamine serum concentrations after a 0.6 mg/kg dose of atracurium was administered. The correlation between clinical effects of increased histamine plasma concentration was inconsistent. Atracurium-induced histamine release in the elderly was more common than in children, but less noticeable than in young adults. There was slight hypotension after 5 minutes, similar to the group receiving vecuronium, suggesting it is independent of the influence of histamine [100]. Research on changes in atracurium dosage in elderly patients is limited [101].

CISATRACURIUM IN ELDERLY:

Up to 83% of cisatracurium undergoes Hoffman elimination. Liver metabolism and kidney excretion apply to the remaining fraction. Organ-independent metabolism makes it more predictable in elderly patients, as they have decreased hepatic and renal functions [94].

Xiaobo et al (2012) investigated the effect of 0.15 mg/kg initial and 0.025 mg/kg maintenance dose in adults aged 41.70±13.13 and elderly patients aged 71.40±5.10. Onset time estimates were 249.30±93.25 s for the younger group and 261.00±64.56 s for the older patients, and the duration of action showed no significant difference between the age groups, at around 50 minutes. The time to recovery was 15.30±2.55 min in the younger group and 15.50±2.28 min in the elderly group. A delayed beginning of action in older participants can be associated with longer time required to reach biophase equilibrium. The lack of a significant difference between the 2 groups in duration and recovery index can be attributed to the previously mentioned organ-independence [102].

Larger-volume distribution can be attributed to the large molecular size of the compound, rendering it impossible to freely pass through lipid membranes. Cisatracurium has a high degree of binding to protein, and elderly patients often have lower levels of plasma proteins. Arain et al (2005) measured inter-patient variability of duration of action of different NMBAs; among those, cisatracurium had the smallest deviance, at only 7 minutes [103]. The reliable duration time and low inter-patient variability contribute to the predictability and associated safety of cisatracurium in elderly patients [92,94,104].

MIVACURIUM IN ELDERLY PATIENTS:

Studies suggest an increased onset time in elderly patients attributed to decreased cardiac output and reduced muscle perfusion [94]. However, Stankiewicz et al (2016) reported that since the intubation dosage is 3–4 times the ED95, onset time does not differ among age groups. This is supported by a study conducted by Vested et al (2024) that found no significant difference in onset time between patients over age 80 and younger controls [92,105]. Mivacurium is entirely metabolized by plasma cholinesterase, the activity of which gradually decreases with age; hence, spontaneous recovery time is prolonged [106]. Duration of action was 52 minutes in elderly subjects, compared to 30 minutes in the control group after a 0.2 mg/kg dose [105]. Clearance and elimination half-life do not differ from those of younger patients [94].

Østergaard et al (2002) examined the dose-response relationship in patients over the age of 65. Four different initial doses were tested: 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, and 0.06 mg/kg. While monitoring neuromuscular block, an additional dose was administered to achieve a total dose of 0.1 mg/kg, followed by continuous infusion to maintain a 91–99% level of the block. The results suggest there is no difference between younger and older patients in terms of infusion requirements, as the mean dose of 6 μg/kg/min was optimal for all participants [106].

ROCURONIUM IN ELDERLY PATIENTS:

Varrique et al (2016) tested pharmacokinetic qualities after introducing bolus doses of 0.3–0.9 mg/kg. Elderly patients aged 65–85 years had a lower total clearance of 2.1 ml/kg/min compared to 2.8 ml/kg/min in a control group aged 20–50 years. The volume of distribution was also reduced: 285.4 ml/kg vs 435.6 ml/kg in young adults. Residual neuromuscular blockade is also more common in elderly patients. Age-associated renal decline and decreased liver function and hepatic blood flow might also contribute to lower clearance. Changes in drug carrier OATP1A2 activity, normally facilitating the hepatic uptake and further enabling excretion via the bile duct, could also play a role, although so far research seems inconclusive. Increased body fat and decreased body water and lean mass may reduce the distribution volume of hydrophilic rocuronium [107].

Contrary to the previously mentioned studies, Schmartz et al (2021) found slower onset in elderly people. Rocuronium at a dose of 0.6 mg/kg demonstrated delayed beginning of action (190 s vs 123 s) in people over age 80 compared to a 20–50 age group. Clinical duration also was extended in elderly patients – from 52 min to 36 min. The time to 90% of baseline recovery was 77.5 min and the time to 100% recovery of baseline was 91.2 min in patients aged 80 years and older, with corresponding values in younger patients being 53.5 min and 59.5 min. With age, rocuronium shifts from being an intermediate- to a long-acting compound. Residual paralysis in elderly patients was reported to be associated with higher incidence of postoperative complications such as hypoxic events, airway obstruction, and pulmonary complications [108].

According to Xiaobo et al (2012), rocuronium at initial dose of 0.9 mg/kg and additional dose of 0.15 mg/kg utilized when TOF reached 1 provides appropriate intubation and intraoperative conditions. The onset time was 104.25±33.75 s in patients aged 72.00 years (±3.83) compared to 115.90±37.01 in people aged 38.15±12.08 years. The duration of action (70 vs 48 min) and recovery time (22 vs 17 min) were significantly longer in elderly patients. Even after excluding patients with liver or renal dysfunction, there were decreased hepatic and renal blood flow, reduced cardiac output, lower glomerular filtration rate, and smaller liver mass. Any of those factors decrease the elimination rate of rocuronium. Hence, the difference in distribution and clearance can be explained by organ-dependent elimination [102].

Rocuronium shows a prolonged acting time in elderly patients. Yamamoto et al (2011) compared spontaneous recovery from neuromuscular blockade in various age groups after an initial dose of 0.7–1.0 mg/kg for facilitation of tracheal intubation, and additional 10-mg boluses required to maintain optimal intra-operative conditions. Alternatively, anesthesiologists used 15–25 mg/h doses for maintenance of paralysis. In cases of TOF <0.9, 2 mg/kg of sugammadex was administered with continuous TOF stimulation every 12 s. When patients reached a TOF ratio >0.9, no more anesthetic medications were administered, and after confirming the return of consciousness, they were promptly extubated. The rate of achieving TOF >0.9 in patients aged 65–85 years was significantly lower than in younger patients. Elderly patients also showed the highest variability of TOF ratio within 2 hours of administration of rocuronium, with some exhibiting significant residual paralysis even 2 hours after the last dose. TOF monitoring and the use of neuromuscular reversal agents are important in older age groups [109]. Vested et al (2022) investigated intubating conditions after 0.3 mg/kg and 0.9 mg/kg rocuronium doses in patients over age 80; in agreement with previous studies, onset time was shorter with a higher dose of the NMBA, at 108 s vs 228 s, respectively. Duration of action was decreased from 118 min to 46 min in the lower-dose group, and 33% of patients administered 0.3 mg/kg did not reach TOF of 0. Excellent intubating conditions according to the Fuchs-Buder scale were reached in 69% of patients receiving higher doses compared to 22% of those receiving lower doses [110,111].

Tagaki et al (2020) investigated the effect of rocuronium doses of 0.6 mg/kg and 1.0 mg/kg in patients aged 65–92 years. At a lower dose, onset time was 186.8 s compared to 104.3 s with the higher dose. The Fuchs-Buder scale was used, demonstrating that 65% of patients had good intubation conditions and 45%had poor intubation conditions in the 0.6 mg/kg group. All patients receiving 1.0 mg/kg had excellent intubation conditions. It is important to note that 0.6 mg/kg rocuronium dose is close to 0.5 mg/kg, which is the ED95 for laryngeal muscle and diaphragm neuromuscular block. Hence, some patients might have adverse reactions (eg, coughing) to a laryngoscope, despite the TOF count of adductor pollicis muscle being 0. Hence, utilization of higher doses of rocuronium be better in RSI [112].

PANCURONIUM IN ELDERLY:

Rupp et al (1987) investigated the effect of pancuronium pharmacokinetic and pharmacodynamic qualities in younger and elderly adults, administering a 0.25 μg/kg min infusion until the twitch response reached 20–30% of the control twitch tension. They found no significant difference in pharmacokinetic and pharmacodynamic qualities between patients aged 43±10 vs those aged 72±9 [113]. However, up to 85% of pancuronium undergoes renal elimination, with the rest being subjected to hepatic metabolism. As glomerular filtration and renal blood flow decrease with age, it could be speculated that the duration of action increases [114]. Dependence on kidney and liver elimination may make it a suboptimal choice for elderly patients with naturally decreased organ function [101].

Rivera et al (2009) found prolonged recovery time in elderly patients – 60 minutes vs 40 minutes in younger individuals [114].

There is no clear recommendation on the preferred dose of pancuronium in the elderly. Doses utilized in adults can be safely implemented. However, neuromuscular monitoring should be implemented, as it provides safety, especially since age-associated decline in organ function can make predicting the response to NMBAs challenging [114].

VECURONIUM IN ELDERLY PATIENTS:

De Almeida et al (1996) used 0.1 mg/kg dose of vecuronium. Onset time did not differ among the age groups 18–50, 51–64, and ≥65 years old [98]. The duration of neuromuscular block after vecuronium increases in the elderly. Slavov et al (1995) examined its effect on patients aged 18–50 years and those over age 65. The study also used an initial dose of 0.1 mg/kg and subsequent boluses of 0.02 mg/kg when adductor pollicis muscle response rose to up to 25% of the control twitch tension. The first dose of vecuronium caused more extended paralysis in older patients compared to the younger control group (50±18 minutes and 36±8 minutes, respectively). The duration of action in the repeated doses also increased in the elderly group [92,97,98,113].

About 40% of vecuronium undergoes biliary excretion and 30% is eliminated via the kidneys. The drug is partially deacetylated in the liver. The age-associated decline in hepatic blood flow and glomerular filtration explains the prolongation of duration of action and recovery time. When using vecuronium in elderly patients, dose titration might prove superior to a set dose to avoid prolonged recovery, and neuromuscular monitoring is therefore recommended [94].

SUGAMMADEX IN ELDERLY PATIENTS:

Reversal time in elderly patients is prolonged. McDonagh et al (2011) examined pharmacokinetic and pharmacodynamic qualities of sugammadex – 0.6 mg/kg initial dose of rocuronium was used to enable endotracheal intubation with the following doses of 0.15 mg/kg as needed. After reappearance of the second twitch of TOF, 2.0 mg/kg dose of sugammadex was introduced for reversal. Efficacy and safety were evaluated in age groups 18–64, 65–74, and over 75. The geometric mean times for the return to TOF ratio to 0.9 were 2.3, 2.6, and 3.6, respectively. Sugammadex clearance decreased with age, to 0.103 l/min, 0.076 l/min, and 0.052 l/min, respectively. The age-associated decline in kidney function explains the slower clearance in older patients. Reduced elimination yielded a slower decline in plasma concentration. It is theorized that the slower recovery relates to the decreased circulation in elderly patients, with consequent prolonged distribution of sugammadex. Rocuronium-induced neuromuscular block can be safely reversed via 2.0 mg/kg sugammadex, considering the extended time of recovery [115].

Kadoi et al (2013) examined the effect of 8.0 mg/kg sugammadex after rocuronium-induced neuromuscular block in electroconvulsive therapy in elderly patients (over 70 years old). Compared to younger controls (under 50 years old), time to recovery to TOF of 0.9 was longer in the older group (443±36 seconds vs 403±37 seconds). Surprisingly, there was no relationship between cardiac index and time of recovery of TOF to 0.9 [116].

Yamamoto et al (2015) utilized 2 mg/kg and 4 mg/kg doses of sugammadex. The larger dose disabled neuromuscular block in all patients. The time to TOF of 1.0 of adductor pollicis muscle was longer in patients over age 70 compared to those aged 20–60 (178 seconds and 120 seconds, respectively). A 2 mg/kg dose was sufficient to enable antagonism of neuromuscular block at the corrugator supercilii muscle, but not the adductor pollicis muscle. Ten patients in the younger group and 8 patients in the older group required additional doses of sugammadex [109]. A 4 mg/kg sugammadex dose also used by Suzuki et al (2011), which enabled the recovery to the TOF of 0.9 in all patients, but in patients over age 70 the process was longer (3.6 minutes) than in participants aged 20–50 (1.3 minutes), but the delay in reversal in elderly patients did not affect the efficacy and did not increase the risk of adverse effects [117,118]. Sugammadex provides faster recovery and more complete antagonism of neuromuscular block as compared to neostigmine. Its use coincides with lower incidence of postoperative nausea, vomiting, and pulmonary complications, as improves recovery of bladder and bowel function [119].

The incidence of postoperative curarization is significantly lower with sugammadex administration – 1.15% vs 34% in the NMBA only group. Similarly, minor critical respiratory events are less common with rocuronium-sugammadex (2.3%) than with rocuronium only (10.5%). Hence, the introduction of the reversal agent increases safety [120].

NEOSTIGMINE IN ELDERLY PATIENTS:

Neostigmine is a polar molecule with low lipid solubility. Its volume of distribution increases due to age-associated increase in total body fat and decrease with muscle mass. Hence, the duration of action is longer in elderly patients [94].

Cao et al (2023) tested neostigmine in cisatracurium-induced neuromuscular block in elderly patients. Patients aged 60–85 received an induction dose of 0.15–0.2 mg/kg NBA with additional doses introduced as required for completion of the surgery. At the end of surgery, when the TOF ratio reached 0.2, 3 different doses of neostigmine were administered: 20 μg/kg, 40 μg/kg, or 50 μg/kg. The results show that higher neostigmine doses allow a faster return of the TOF rate to 0.9. However, there was no significant difference between 40 μg/kg vs 50 μg/kg, but 50 μg/kg may shorten post-anesthesia care unit stay time. The incidence of postoperative nausea or vomiting and cognitive decline did not differ among the 3 neostigmine dose groups. Neostigmine at a dose of 40 μg/kg seems optimal, as it provides rapid reversal without higher incidence of adverse effects such as bradycardia, convulsions, slurred speech, nausea, vomiting, and anxiety [121,122].

Neostigmine doses equal to 25 μg/kg did not achieve a satisfactory antagonism in 0.08 mg/kg vecuronium-induced block in elderly patients after 10 minutes [123].

Mraovic et al (2021) evaluated the effects of neostigmine vs sugammadex in rocuronium-induced neuromuscular block (an initial dose of 0.6 mg/kg and maintenance 3 μg/kg/min) in patients aged ≥65 undergoing elective lumbar spine surgery. The recovery to TOF ratio of ≥0.9 was examined after an infusion of 50 μg/kg (maximum dose 5 mg) of neostigmine with glycopyrrolate dosed 10 μg/kg (maximum dose 1 mg). Reversal with neostigmine required an average of 26.3±17.5 minutes, almost 22 minutes slower than in the sugammadex group. Neostigmine has a high variability, spanning 5 to 72 minutes, making it a more unpredictable choice. Its administration is also associated with an increase by approximately 10 in total heart beats per minute, up at 2, 3, and 4 minutes after neuromuscular block reversal [124].

According to Zhu et al (2020), the postoperative incidence of cognitive decline is lower after neostigmine administration compared to 0.9% saline – 10% in the 0.04 mg/kg group and 15.7% in the 0.02 mg/kg group [125].

The incidence of postoperative residual curarization is lower after administration of neostigmine with cisatracurium vs cisatracurium alone – 28.6% vs 34%, respectively. The incidence of minor critical respiratory events was 17.4% in the group receiving the reversal agent vs 27.5% in the NMBA alone group. This suggests that neostigmine increases safety after medical procedures [120].

Summary of NMBAs Use in Elderly Patients

Table 2 summarizes the recommended doses of NMBAs for elderly patients, with additional key considerations specific for geriatric anesthesia.

Conclusions

The dosing of muscle relaxants in pediatric patients is a major challenge for the anesthesiologist, especially the youngest and the oldest patients, with a special consideration for those with progressive multiorgan failure or multimorbidity.

Because the enzymatic pathways of children are not fully developed, the pharmacokinetics of many drugs, including NMBAs, are altered. In addition, these patients, especially during the first months of life, have individual variability in response to this group of drugs, which requires special attention and dose adjustments depending on the current clinical condition. In general, these agents require dose reductions, except for succinylcholine, which is used only in exceptional circumstances due to resistance. The most common agents used in clinical practice in this population are rocuronium and mivacurium, depending on the availability of sugammadex. When using a benzylisoquinoline derivative, the possibility of pseudocholinesterase deficiency and subsequent prolonged paralysis must be considered. In addition, when considering the use of reversal agents, it must be remembered that sugammadex, although characterized by faster action and without the adverse effects characteristic of neostigmine, is approved by the FDA only for use in children over 2 years of age.

Geriatric patients, especially those with the above-mentioned problems due to inefficiency of enzymatic pathways and impaired liver and kidney function, also require a more individualized approach. Muscle relaxants, in addition to atracurium and especially cisatracurium (which are mainly broken down by Hoffmann spontaneous elimination pathway) have a longer duration of action, which carries the risk of prolonged curarization and related complications, particularly dangerous in morbid patients. For this reason, routine monitoring of the degree of relaxation and the use of relaxant reversal agents is particularly recommended. Sugammadex appears to be a better alternative due to its faster and more predictable action and lower spectrum of adverse effects.

These findings show the need for an individualized approach to extreme age groups and emphasize the importance of neuromuscular blockade monitoring, especially due to the high variability in individual responses. It has been demonstrated that different muscle groups present various recovery times, which underlines the need for objective instrumental methods assessing the level of blockade, such as mechanomyography or electromyography. As mentioned before, many factors influence the action of NMBAs. Therefore, consistent and precise monitoring improves patient safety by reducing the incidence of postoperative residual curarization [126–129].

Table 3 summarizes the recommended intubation doses of NMBAs standard for induction of anesthesia, along with sugammadex and neostigmine used in patients of various ages. However, an individualized approach to dosing is essential, and neuromuscular blockade monitoring is particularly important in very young and very old patients. Additional key considerations are summarized in Tables 1 and 2.

Future Directions

Through reviewing a large quantity of research on use of muscle relaxants in diverse age groups, it has been possible to determine optimal doses and guidelines for the safe use of NMBAs currently used in modern anesthesiology. This is particularly important in the youngest and oldest patient groups due to the immaturity and failure of organs and enzymatic pathways, respectively, which predisposes to the unpredictability of the pharmacokinetics of this group of drugs. Further studies, especially multicenter studies, would undoubtedly improve guidelines and the safety of anesthesia in these 2 extreme age groups. An issue that requires further study is the use of sugammadex in patients under 2 years of age. Given its advantages over neostigmine in terms of faster efficacy and adverse effects, it is likely that the youngest patients would benefit from its use. Despite several promising clinical trials, the FDA currently approves its use only in patients over 2 years of age. To maximize postoperative safety in pediatric and geriatric patients, the routine use of muscle relaxation monitoring should be promoted, and some authors believe that such an approach should be used as the standard, regardless of patient age [130,131].