Development of the neuromuscular junction and neuromuscular blocking agents in neonates, infants and children

Abstract

Neuromuscular blocking agents (NMBAs) are critical components in paediatric anaesthesia, facilitating intubation, surgical procedures and mechanical ventilation in neonates, infants and children. This narrative review examines the pharmacological properties, clinical applications, monitoring, reversal and safety of NMBAs across paediatric populations. Given the unique physiological characteristics of neonates and infants – including hepatic and renal maturation, and neuromuscular junction development – NMBA metabolism, efficacy and adverse effects in these age groups differ markedly from those in older children and adults. These physiological factors necessitate specific approaches to NMBA selection, dosing and monitoring to ensure effective blockade while minimising risks. Emphasis is placed on understanding how the pharmacokinetics and pharmacodynamics of commonly used NMBAs vary with age, influencing onset, duration and recovery. Additionally, practical strategies for the safe and effective monitoring of neuromuscular blockade using quantitative monitoring techniques are discussed to avoid residual neuromuscular blockade. Recent advances in the reversal of neuromuscular blockade, including the use of sugammadex, offer promising improvements in paediatric anaesthesia safety, though their application in neonatal populations requires further study. Finally, the review discusses current research trends, highlighting the need for age-specific guidelines and pharmacologic innovations that address the challenges unique to NMBA use in neonates, infants, and children.

KEY POINTS

• Neuromuscular junction development, as well as distribution volume, hepatic and renal maturation have an impact on NMBAs’ efficacy and metabolism in neonates and infants.

• Pharmacokinetics and pharmacodynamics of NMBAs vary with age, influencing onset, duration and recovery. Residual neuromuscular blockade can be avoided by using quantitative monitoring techniques. The sound use of acetylcholinesterase inhibitors to antagonise NMBAs or cyclodextrins (sugammadex) to encapsulate aminosteroid NMBAs offers promising improvements in the safe use of NMBAs in paediatric anaesthesia. There is a need to develop age-specific guidelines on the use of NMBAs in paediatrics.

Introduction

Neuromuscular blocking agents (NMBAs) are critical components in paediatric anaesthesia, facilitating intubation, surgical procedures and mechanical ventilation in neonates, infants and children. However, the developmental changes in the neuromuscular junction (NMJ) across paediatric age groups significantly influence the pharmacological effects, clinical applications and safety considerations of these agents. This narrative review explores the maturation of the NMJ and its impact on NMBA selection, dosing, efficacy and adverse effects. Moreover, given the distinct physiological characteristics of neonates and infants, including immature neuromuscular transmission and reduced hepatic and renal clearance, NMBAs exhibit significant age-dependent variations in pharmacokinetics and pharmacodynamics. These factors necessitate careful NMBA administration to achieve effective neuromuscular blockade while minimising risks, such as prolonged paralysis and residual neuromuscular blockade.

The review discusses the mechanisms of NMJ development, the differential responses to depolarising and nondepolarising NMBAs in early life, and the clinical implications for anaesthetic practice. Special emphasis is placed on the importance of neuromuscular monitoring, including the advantages of quantitative over qualitative techniques, to enhance patient safety. It also examines the latest advances in NMBA reversal strategies, particularly the use of sugammadex, and its evolving role in paediatric anaesthesia. By integrating current knowledge of NMJ maturation with NMBA pharmacology, the need for age-specific dosing guidelines, improved monitoring techniques and continued pharmacologic innovations to optimise the safe and effective use of NMBAs in neonates, infants and children is highlighted.

Research gaps remain, particularly concerning age-specific dosing guidelines, optimal monitoring practices and the long-term effects of NMBA use in developing children.¹

This review will complement the concurrently published European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on the use of NMBAs and reversal agents in children.

The gateway function of the neuromuscular junction in signal transmission

Neuromuscular signal communication in humans is based on cholinergic neurotransmission. This mechanism allows motor neurons to regulate and control the activity of the muscle fibres through a highly specialised chemical synapse, the NMJ. It is composed of four main intercommunicating sections: the presynaptic motor nerve terminals, the muscle fibres, the perisynaptic Schwann cells, and the extracellular matrix or basal lamina (Fig. 1).^2–5 This structure is crucial to enable fast and accurate signalling and reflects the gateway function of the NMJ.

Fig. 1.

Neuromuscular junction structure for fast and accurate neuromuscular transmission.

(1) When a motor nerve is excited, the generated action potential stimulates the merging of synaptic vesicles with the presynaptic motor nerve terminal membrane. (2) Most of these 50 nm ACh vesicles are clustered at dense patches, the ‘active zones’, and contain the neurotransmitter acetylcholine (ACh) and a large number of mitochondria for energy supply. (3) A quantum of ACh is released in the synaptic cleft and binds to the acetylcholine receptor (AChR). (4) The postsynaptic muscle membrane, facing the active zones, is deeply invaginated with a high density of ACh receptors (>10 000 μm⁻²) at the shoulders of the fold and voltage-gated sodium channels (VGSCs) in the fold valleys. (5) After ACh–AChR binding, membrane depolarisation opens the VGSCs leading to the depolarisation of the muscle membrane. (6) Membrane depolarisation provokes muscle contraction through signaling to the nearby muscle nuclei. (7) A unique assemblage of extracellular matrix proteins and receptors forms the basal lamina, which plays an essential role in the development, maturation, stability and transmission of the NMJ. (8) The synapse adjoined Schwann cell covers the nerve terminal, shielding it from noxious assaults while being responsible for axonal remodeling. Created in BioRender. https://BioRender.com/o58t736.

The development of the neuromuscular junction

Whereas the structure of the mature NMJ has been well characterised, knowledge of its development and key molecular drivers is less established.

Research indicates the involvement of complex and tightly controlled protein interactions between Agrin, a heparan sulphate proteoglycan produced by motoneurons to induces receptors clustering MuSK, the muscle-specific transmembrane protein tyrosine kinase present in the postsynaptic membrane, Lrp4, a lipoprotein receptor-related protein 4 (Lrp4), Dok-7, a phosphotyrosine-binding (PTB) domain-containing protein acting as a noncatalytic cytoplasmic adaptor expressed specifically in muscle and Rapsyn, the receptor-associated cytoplasmic scaffolding protein of the synapse – located in the extracellular matrix – in synaptic differentiation and nicotinic Acetyl Choline Receptors (AChRs) clustering (Fig. 2).^6–11 However, while the developmental events to build such a solid synaptic structure and their coincidence with muscle development are evident, the precise timescale remains largely unravelled. The current understanding of the developmental timescale is discussed in the following, while a detailed molecular description of the various protein actors falls outside the scope of this review.¹²

Fig. 2.

Structural overview of the protein interactions involved in acetylcholine receptor clustering.

Main proteins involved are: Lrp4, a single-pass transmembrane protein; MuSK, a transmembrane protein tyrosine kinase in the postsynaptic membrane; Rapsyn: a cytoplasmic scaffolding protein located in the muscle fibre; Agrin, a tissue-specific heparan sulphate proteoglycan produced by the motor neuron; Dok-7, a PTB domain-containing protein. Created in BioRender. https://BioRender.com/b18x695.

Innervation of the muscle fibre in humans starts around the eighth week of development, and by the 16th week, most motor neuron terminals are in direct contact with a myotube. Before innervation [<8 weeks gestational age (GA)], randomly distributed AChRs form spontaneous clusters in the middle of the muscle fibre. The association of Lrp4 and MuSK forms those clusters.¹³ Dok-7 binds the tyrosine phosphorylated PTB site in MuSK and thereby stabilises its activated, phosphorylated state.¹⁴ Lrp4 and MuSK also function as a retrograde signal in the differentiation of the presynaptic area through an unknown receptor. Both are necessary to halt motor neurons from growing and to induce the formation of specialised nerve terminals.

Upon innervation (8 to 16 weeks GA), Agrin is released by the motor neuron and binds to Lrp4, which further stimulates the association of Lrp4 to MuSK and increases the phosphorylation of the latter.^15,16 Prepatterned generated AChR clusters are thus converted into tightly restricted areas confined to the synapse. The nerve-derived signal of clustering AChRs is counteracted by Ach, which tends to have a dispersing effect on the density-formed clusters.

Agrin also activates the AChR beta subunit, leading to the recruitment of Rapsyn. Rapsyn binds directly to skeletal muscle AChRs and anchors these, as well as other structural proteins in the postsynaptic membrane. Rapsyn is believed to be present at the early stages of development.¹⁷

The fetal AChR consists of five subunits: two α-subunits, one β-subunit, one δ-subunit, and one γ-subunit. The γ-subunit is replaced by the ε-subunit in the adult AChR isoform with new channel properties.¹⁸ In a Xenopus oocyte model, it has been shown that fetal AChRs have a higher affinity for ACh, leading to longer open times of the AChR and resulting in a lower conductance.¹⁹ The AChR structure further matures during development into a final adult isoform. Past research investigating human samples showed that the fetal AChR isomer is no longer present after 33 weeks GA.²⁰

Concurrently, the number of nerve terminals per muscle fibre decreases from more than 3 to 1.5 in the 25th week GA, suggesting that polyneural innervation becomes mononeural.

Postsynaptic membrane length and the area of clefts and folds are small at a developmental age of 18 weeks. Between GA 16 and 18 weeks, the postsynaptic membrane slowly deepens and only reaches its mature length and area at 4 years.²⁰

Neuromuscular transmission is a very reliable process. This reliability is a consequence of the excess in ACh being released from the nerve to cause excitation of the muscle fibre. The difference between the amount of released and required transmitters is referred to as the safety factor, which is subject to changes during development.^21,22 The amount of ACh released is related to the size of the motor nerve terminal and is constant per unit area of presynaptic membrane. The mean area of the presynaptic nerve terminal increases in size during the fetal period from around 0.5 to 3 μm² around 38 weeks GA and to 4.8 μm² in the first year postnatally (PN). After the first PN year, no further growth of the presynaptic part is documented. Spontaneous fade following train-of-four (TOF) or tetanic neuromuscular stimulation is often observed in neonates. This is partly due to the reduced amount of released ACh, which is related to the smaller area of the nerve terminal. The AChR is mature at birth, unless the newborn is less than 33 weeks GA, but its function improves dramatically during the first year.

In specific inflammatory catabolic muscle conditions such as denervation, burn injury, and atrophy due to prolonged immobilisation, induced up-regulation of the fetal AChR outside the NMJ and the presence of α7AChR isoform can occur, resulting in a changed response to nondepolarising and depolarising NMB. This upregulation of AChRs provokes an increased sensitivity to succinylcholine throughout the muscle membrane. In rodents, the α7AChR can be depolarised by ACh, succinylcholine and choline (their metabolite), resulting in an excessive potassium efflux into plasma.^23–25

Acetylcholinesterase (AChE) is responsible for the hydrolysis of ACh.²⁶ AChE is an assemblage of three catalytic tetramers linked to a collagenic tail. This collagen-tailed AChE form is highly expressed within the synaptic basal lamina, reducing the amount of free ACh.^27–29 When ACh dissociates from the AChR, AChE cleaves ACh to prevent it from binding a second time, influencing the safety factor and avoiding prolonged muscle contraction.

Myasthenia gravis caused by the presence of autoantibodies against AChR, MuSK or LRP4 and congenital myasthenias caused by mutations in proteins involved in the functioning of the presynaptic, synaptic or postsynaptic areas negatively impact the development and functioning of the NMJ.⁷

Pharmacology of neuromuscular blocking agents in children

: Classification of neuromuscular blocking agents

NMBAs are classified based on their interactions with AChRs at the NMJ.

• (1)Depolarising agents. Succinylcholine (suxamethonium) is the only depolarising NMBA in clinical use.³⁰ It acts by binding to the AChR, causing an initial depolarisation, which results in transient fasciculations, followed by sustained muscle relaxation, as the receptor remains occupied. Its use in children is limited due to side effects such as hyperkalaemia, the risk of malignant hyperthermia (MH), and anaesthesia-induced rhabdomyolysis (AIR).³¹ After prolonged or repeated administration of succinylcholine, a phase II block (dual block) mimicking the characteristics of a nondepolarising block may occur, complicating the interpretation of neuromuscular monitoring.
• (2)Nondepolarising agents, including rocuronium, vecuronium, pancuronium, atracurium, mivacurium and cisatracurium, competitively occupy AChRs instead of ACh without causing initial depolarisation. They are further categorised by their duration of action into short-acting, intermediate-acting, and long-acting NMBAs. Their predictable dosing profiles and lower risk of severe side effects make them the preferred choice in children.

Age-dependent pharmacokinetics and pharmacodynamics

• (1)NMJ maturity: prematures, neonates and young infants have immature NMJs with decreased AChR density, reduced ACh release and differences in receptor subtypes, leading to spontaneous fade after repeated neuromuscular stimulation,³² heightened NMBA sensitivity and an increased risk of prolonged blockade.³³ This immaturity gradually decreases with age, reaching adult-like responses by around 2 years of age. Infants, especially under the age of 3 months, therefore, may require lower NMBA doses or longer dosing intervals to avoid excessive blockade.³³
• (2)Body water composition and distribution volume: neonates have a markedly higher total body water content – approximately 75 to 80% of body weight – compared to older children and adults, in whom total body water represents about 60% of body weight. Of particular relevance to hydrophilic NMBAs is the larger extracellular fluid (ECF) compartment in neonates, which can account for roughly 45% of body weight at birth, decreasing to adult proportions (∼20%) by 12 months of age.³⁴ Because NMBAs are largely confined to the extracellular space and do not readily cross cell membranes, this expanded ECF volume results in a larger steady-state volume of distribution (Vdss) in neonates and young infants.³⁵ This increased Vdss may dilute the drug concentration at the effect site, potentially requiring a larger initial dose per kilogram to achieve the desired level of neuromuscular blockade. However, neonates and small infants also exhibit immature hepatic and renal clearance mechanisms, which can prolong the elimination half-life of NMBAs and lead to an extended duration of action despite any adjustments to the initial dose. In contrast, older children (beyond infancy) tend to have both a lower Vdss and more efficient clearance, resulting in a shorter duration of action for agents such as rocuronium when compared to neonates and infants.³³
• (3)Hepatic and renal function: the maturation of hepatic and renal systems has a significant impact on the metabolism and elimination of NMBAs in paediatric patients. In neonates, hepatic enzyme activity is reduced, particularly within the cytochrome P450 system. CYP3A4 – the primary isoenzyme responsible for metabolising steroidal NMBAs, such as vecuronium and rocuronium – is minimally active at birth and reaches adult activity by 1 year of age.³⁵ Similarly, renal function is immature in neonates, with glomerular filtration rate (GFR), tubular secretion and reabsorption all significantly reduced; GFR typically reaches adult levels by 1 to 2 years of age.³⁵ Vecuronium elimination relies on both hepatic metabolism and renal excretion. Approximately 25 to 30% of vecuronium is excreted unchanged by the kidneys, while the majority is metabolised by the liver and eliminated via bile.^36–39 However, in neonates and young infants, both elimination pathways are functionally immature. This leads to a slower clearance rate and prolonged duration of action, a finding well documented in pharmacokinetic studies.^36–39 Clinical experience and early paediatric studies consistently demonstrate that vecuronium is not short-acting in neonates, and its use requires careful titration and extended monitoring when compared to older children and adults. These developmental considerations underscore the importance of age-adjusted NMBA selection and individualised dosing, particularly in the first months of life, where both hepatic and renal immaturity may alter the expected onset, duration and recovery profile of agents like vecuronium.

  Atracurium and cisatracurium are metabolised via Hofmann elimination, a nonenzymatic, pH-dependent and temperature-dependent reaction, and hydrolysis by plasma esterases, processes that are independent of hepatic or renal function.^40–45 Although atracurium has been associated with histamine release – manifesting as hypotension, flushing or bronchospasm – these effects are notably less common and less pronounced in neonates and young children. Cisatracurium produces less laudanosin, is more potent and has fewer side effects, such as histamine release, compared to atracurium.^46,47 Elimination of both agents are independent of liver and kidney function, making them suitable for neonates, young infants and patients with organ dysfunction. Atracurium has a shorter duration of action and a faster recovery profile, making it particularly advantageous in short procedures or when rapid emergence from neuromuscular blockade is desired. In clinical practice, atracurium remains widely used in many paediatric centres due to its predictability, shorter offset and favourable reversibility, especially when combined with neostigmine. Furthermore, factors such as cost, familiarity and local availability often influence the choice between these agents. Both drugs are effective and safe in paediatric patients when appropriately dosed and monitored, and the selection should be tailored to the clinical scenario, institutional availability and preferences and the pharmacodynamic profile best suited to the procedure and patient population.

  Mivacurium is a short-acting, nondepolarising NMBA hydrolysed by plasma cholinesterases, with its pharmacokinetics influenced by age-related differences in enzyme activity and volume of distribution (Vd). In children, higher plasma cholinesterase activity leads to faster metabolism and shorter duration of action, making it suitable for short procedures.^48–51 However, conditions with reduced cholinesterase activity (e.g. genetic deficiencies) can prolong its effects.^52,53

  Rocuronium, pancuronium and vecuronium have distinct metabolic profiles in children.^33,54,55 Rocuronium is minimally metabolised and primarily excreted unchanged in bile and urine, with faster hepatic clearance and a larger volume of distribution in children, leading to a shorter duration of action than vecuronium. Pancuronium is partially metabolised by the liver and primarily excreted by the kidneys; its action may be prolonged in neonates with immature renal function. Vecuronium exhibits age-dependent variability in both pharmacokinetics and clinical effects. In neonates and young infants, hepatic enzymatic activity and renal function are immature, resulting in reduced clearance and a prolonged duration of action.^36–38 Approximately 25 to 30% of vecuronium is excreted unchanged via the kidneys, while the remainder undergoes hepatic metabolism to active and inactive metabolites. In older children, both hepatic metabolism and renal clearance are more efficient, contributing to a shorter duration of action. It is important to distinguish between the effects of Vd and clearance on drug kinetics. An increased Vdss alone would tend to prolong elimination half-life (t½), while increased clearance would shorten it. The observed shorter duration of action of vecuronium in older children is primarily attributable to enhanced clearance, which outweighs the modest increase in Vdss. For initial dosing, the central compartment volume is more relevant and also tends to be larger in younger children, influencing loading dose requirements.

  Pharmacokinetics and pharmacodynamics (PK/PD) data of the different NMBAs are summarised in Table 1.

• (4)Neuromuscular response variability: the variability in responses due to age, developmental stage and interpersonal variability means that dosing regimens cannot simply be scaled down from adult doses. Clinical response monitoring using neuromuscular function testing is critical to adjust dosing for individual patients.

Table 1.

Pharmacokinetics and pharmacodynamics of various neuromuscular blocking agents in different age groups of children

Agent	Age group	Vd (l kg−1)	Cl (ml kg−1 min−1)	t1/2 (min)	ED50 (μg kg−1)	ED95 (μg kg−1)	Onset time (s)	Dosing (mg kg−1)
Suxamethonium	Neonates	0.4 to 0.5	2 to 4	2 to 4	270	620	60 to 90	3
	Infants	0.2 to 0.3	4 to 6	∼1 to 2	317	730	60 to 90	2
	Children	0.2	8 to 10	∼1	184	423	30 to 60	1 to 2
Vecuronium	Neonates	0.3 to 0.4	2 to 3	60 to 90	–	48	120 to 240	0.07 to 0.1
	Infants	0.25	3 to 5	30 to 60	16.5	47 ± 10	90 to 180	0.1
	Children	0.2	5 to 7	30 to 45	19	81 ± 12	120 to 240	0.1
Rocuronium	Neonates	0.3 to 0.5	2 to 3	∼90	–	-	60 to 120	0.25 to 0.50
	Infants	0.25 to 0.4	4 to 6	∼45 to 60	149 ± 36	252 ± 73	60 to 90	0.6 to 1.0
	Children	0.2	6 to 8	∼30 to 45	205 ± 52	409 ± 70	60 to 90	0.6 to 1.2
Atracurium	Neonates	∼0.5	3 to 5	30 to 40	–	220	120 to 180	0.4 to 0.5
	Infants	∼0.3	5 to 7	20 to 30	85	231 ± 69	90 to 150	0.4 to 0.5
	Children	∼0.3	6 to 8	∼20	132	327 ± 55	120 to 180	0.4- 0.5
Cisatracurium	Neonates	0.2 to 0.4	2 to 4	45 to 60	–	–	120 to 180	0.10 to 0.15
	Infants	0.2 to 0.3	4 to 6	30 to 40	29	45	90 to 180	0.10 to 0.15
	Children	0.2	5 to 7	20 to 30	29	56	120 to 180	0.10 to 0.15
Mivacurium	Neonates	∼0.3	2 to 3	∼5 to 8	–	–	120 to 180	0.15 to 0.2
	Infants	∼0.3	4 to 5	∼4 to 6	–	129 ± 48	90 to 150	0.2 to 0.25
	Children	∼0.3	6 to 8	∼3 to 5	50	90 to 110	120 to 180	0.2 to 0.25
Pancuronium	Neonates	∼0.5	1.5 to 2	∼120 to 150	39	72	180 to 300	0.08
	Infants	∼0.3 to 0.4	2 to 3	∼90 to 120	37	47 to 66	180 to 240	0.08
	Children	∼0.3	4 to 5	∼90	52	70 to 93	120 to 180	0.1

Cl, clearance; ED₅₀, the dose of an NMBA that is expected to produce 50% block at the adductor pollicis; ED₉₅, the dose of an NMBA that is expected to produce 95% block at the adductor pollicis; t_1/2, elimination half-life; Vd, volume of distribution.

Clinical applications of neuromuscular blocking agents in neonates, infants and children

: Airway management and tracheal intubation

Airway management in neonates and young infants can be particularly challenging due to anatomical and physiological features, including a relatively large occiput, high anterior larynx, large tongue and increased upper airway compliance.⁵⁶ Older children – particularly beyond the infant stage – usually have more favourable airway anatomy compared to adults, with improved mouth opening, more flexible necks and less prominent teeth, often making intubation easier in this group.

Due to its rapid onset and short duration of action, and side effect profile (bradycardia, hyperkalaemia, myalgia, risk of anaphylaxis and malignant hyperthermia), succinylcholine use is limited to emergency settings requiring rapid-sequence intubation (RSI). In severe laryngospasm, a smaller dose of succinylcholine (0.1 to 0.2 mg kg⁻¹) than for intubation remains a highly effective intervention.⁵⁷ Higher doses are generally unnecessary and may increase the risk of adverse effects and delayed return of spontaneous respiration. The use of succinylcholine for elective intubation has decreased dramatically following a series of hyperkalaemic cardiac arrests in children with undiagnosed myopathy.²⁴ Its use for emergency intubation is also decreasing since the availability of rocuronium. According to the data recorded in the APRICOT study, succinylcholine was used in only 592 of 1372 cases (43.1%) of rapid sequence induction.⁵⁸ Rocuronium, with its rapid onset, serves as an effective alternative to succinylcholine when combined with reversal agents like sugammadex.

For elective or controlled intubations, nondepolarising agents are preferred due to their lower side-effect profiles and more predictable recovery. Among nondepolarising agents, atracurium, due to its intermediate duration and relatively rapid recovery profile, is a suitable choice for procedures where short-to-moderate duration blockade is desired. In many paediatric centres, atracurium is favoured over longer acting agents – and sometimes over less commonly available short-acting agents like mivacurium – due to its predictable offset and suitability for spontaneous or pharmacologically assisted recovery.

In case of re-intubation, a repeat high dose of rocuronium, given 5 to 60 min after sugammadex reversal, produced a full neuromuscular block characterised by a delayed onset time and a prolonged duration of action in adults.⁵⁹ To avoid this variability, a nonsteroidal NMBA, such as atracurium, could be advised.

Critical care

NMBAs help critically ill children with respiratory failure or prolonged ventilation by reducing the work of breathing, preventing patient-ventilator asynchrony and protecting against ventilator-induced lung injury. Cisatracurium is often preferred for prolonged neuromuscular blockade in paediatric intensive care due to its predictable organ-independent metabolism.⁶⁰

In Table 2, we have listed critical care conditions where NMBAs may be helpful and their aims.

Table 2.

Indications and aims for the use of neuromuscular blocking agents in paediatric intensive care

Conditions	Aims
Severe respiratory distress syndrome (RDS)	(Premature) neonates to improve oxygenation and ventilation
Severe adult respiratory distress syndrome (ARDS)	To minimise ventilator-associated lung injury during lung-protective ventilation
Status epilepticus and tetanus	In uncontrolled seizures, to prevent physical harm, facilitate ventilation, and reduce complications, for example, hyperthermia, muscle damage and acidosis
Therapeutic hypothermia	To suppress shivering, reduce oxygen consumption and maintain effective cooling in neonates with hypoxic–ischaemic encephalopathy
Acute neurological conditions	To minimise intracranial pressure spikes and control intracranial pressure, prevent coughing and straining and maintain normocarbia

Monitoring of neuromuscular blockade

Monitoring of neuromuscular blockade is crucial in children to prevent complications like residual paralysis, hypoventilation and respiratory weakness. Monitoring through quantitative techniques like acceleromyography (AMG) or electromyography (EMG) is recommended,⁶¹ because clinical assessment alone is insufficient to detect residual blockade.

AMG has limitations, including the ‘staircase phenomenon’, which can result in overestimation of the TOF ratio following repeated stimulation, and challenges in the setup for small children due to difficulty securing the transducers.^62,63 EMG avoids the staircase phenomenon and is less affected by installation challenges, offering greater reliability in such cases.^32,64

TOF stimulation delivers four electrical pulses at a frequency of 2 Hz to a peripheral nerve and observes muscle responses. A TOF ratio of above 0.9 generally indicates adequate recovery.

Post-tetanic count (PTC) is useful in deep neuromuscular blockade, especially during long surgeries with high NMBA doses. Tetanic stimulation followed by single twitches estimates the blockade's depth, which can aid prolonged blockade management and recovery time estimation.

Different muscles vary in sensitivity to NMBAs; the diaphragm is more resistant than the laryngeal and peripheral muscles, which are more resistant than those maintaining upper airway patency. A TOF ratio at least 0.9 measured at the adductor pollicis does not, therefore, guarantee upper airway patency, which should be clinically assessed before or after extubation.

Last, it has been shown that neuromuscular blockade becomes clinically apparent and measurable with quantitative monitoring when more than 75% of AChR are occupied by a nondepolarising NMBA: this is called the margin of safety of neuromuscular transmission and could explain some cases of early recurarisation following seemingly adequate reversal.⁶⁵

Reversal of neuromuscular blockade

The goal is to restore normal muscle function in patients emerging from anaesthesia. Common reversal agents include AChE inhibitors and sugammadex (Table 3).

Table 3.

Pharmacokinetics of neostigmine and sugammadex for neonates, infants and children

	Neostigmine	Sugammadex
Onset time	5 to 10 min (similar across age groups, with a slight delay in neonates due to immature enzyme activity and slower clearance)	1 to 3 min (similar across all age groups after administration, but depending on level of curarisation at the time and administration and dose)
Clearance (Cl)	Dependent on the maturation of renal function:  Neonates: 5 to 7 ml kg−1 min−1  Infants: 7 to 9 ml kg−1 min−1  Children: 10 to 12 ml kg−1 min−1	Dependent on the maturation of renal function:  Neonates: 2 to 4 ml kg−1 min−1  Infants: 4 to 6 ml kg−1 min−1  Children: 6 to 8 ml kg−1 min−1
Half-life	Dependent on the maturation of renal function:  Neonates: 50 to 75 min  Infants: 40 to 50 min  Children: 20 to 30 min	Dependent on the maturation of renal function:  Neonates: 3 to 4 h  Infants: 2 to 3 h  Children: 1.5 to 2 h
Volume of distribution (Vd)	Approx. 0.7 to 0.8 l kg−1(similar across age groups, reflecting its hydrophilic nature and extracellular fluid distribution)	Neonates: 0.2 to 0.3 l kg−1  Infants/children: 0.15 to 0.2 l kg−1(higher extracellular fluid content)
Dosing	Neonates: 0.02 to 0.03 mg kg−1  Infants and Children: 0.03 to 0.05 mg kg−1(dosing to be further adapted depending on blockage depth)	Dependent on the type of reversal:  Routine Reversal: 2 mg kg−1 for moderate block (T2 reappearance) and 4 mg kg−1 for deep block (posttetanic count of 1 to 2).  Immediate reversal (e.g. after a rapid sequence intubation): 16 mg kg−1 for profound blockade (e.g. no twitch response).
NMBA reversal	All NMBAs	Aminosteroidal NMBAs (rocuronium, vecuronium and pancuronium)
Blockage depth reversal	Shallow to moderate	Moderate to deep

NMBA, neuromuscular blocking agent.

Acetylcholinesterase inhibitors

By inhibiting AChE, edrophonium and neostigmine increase the amount of acetylcholine at the NMJ, thus displacing nondepolarising NMBAs from the AChRs. Neostigmine is preferred over edrophonium in children due to its lower variability. Although the initial onset of recovery is faster with edrophonium, neostigmine reaches its maximum effect faster.^66,67

In infants and children, neostigmine's dose–response is similar to adults, with no significant differences in distribution half-life or steady-state volume, though elimination half-life is shorter. Neostigmine is used in children, with typical dosing of 30 to 70 μg kg⁻¹ based on block depth and recovery timing. Although the ED80 is lower in children, this does not justify reduced clinical dosing. Standard doses remain effective and safe, minimising residual blockade, especially with agents like rocuronium.^68–70

AChE inhibitors are ineffective for antagonising deep blockade, and dosing and timing are crucial to avoid incomplete reversal. According the ESAIC and ASA guidelines on neuromuscular blockade in adults, neostigmine should be used only when the TOF ratio is greater than 0.2 or 0.4, respectively.^71,72 Side effects like bradycardia and nausea can be managed with antimuscarinics (atropine or glycopyrrolate), though these may cause additional adverse effects.

Sugammadex

Sugammadex reverses neuromuscular blockade by encapsulating amino steroidal NMBAs like rocuronium, vecuronium and pancuronium, ensuring rapid and complete reversal without residual blockade if the adequate dose is administered. It is generally preferred over cholinesterase inhibitors for its efficiency.^73–76 For moderate or deep blockade, increasing doses of sugammadex reduce recovery times across age groups, though it temporarily increases plasma rocuronium concentration due to retro-diffusion from the synaptic cleft.^77–82

In paediatric studies, sugammadex (2 mg kg⁻¹ for moderate-TOF at least 2 and 4 mg kg⁻¹ for deep block PTC 1 or 2) showed faster recovery compared to neostigmine, with minimal adverse events like bradycardia.⁸³ No recurrence of neuromuscular block was noted. Recent studies on neonates and infants (<2 years) found that sugammadex pharmacokinetics are consistent across age groups, with effective reversal times and no increased risk of adverse events.⁸⁴

Ultrasonographic assessment revealed an enhanced early recovery of the diaphragmatic function after sugammadex reversal without reducing the incidence of postoperative atelectasis in children.⁸⁵

Sugammadex side effects include allergic reactions, bradycardia, nausea, vomiting, bleeding risks, headache, dizziness, injection site reactions and, theoretically, a reduced efficacy of hormonal contraceptives.^86,87

Residual neuromuscular blockade: risks and prevention

Residual neuromuscular blockade in paediatric patients can impair respiratory function, decrease response to hypoxaemia, cause airway obstruction and increase the risk of complications like hypoxaemia, atelectasis and pneumonia.^88,89 To reduce the risk of residual neuromuscular blockade, clinicians should use the lowest effective NMBA dose, avoid prolonged infusion and select intermediate-acting agents such as atracurium, rocuronium or cisatracurium – based on procedure type, organ type and institutional availability. Although sugammadex offers rapid and reliable reversal of steroidal NMBAs, its use remains variable due to cost, availability and evolving clinical practice patterns.

Recent large-scale data suggest that the choice of reversal agent, when used appropriately, may not significantly influence rates of major postoperative respiratory complications in children.⁹⁰

Side effects and safety considerations of neuromuscular blocking agents in children

NMBAs can cause various side effects, some more pronounced in children, and can be dose-dependent or related to NMBA duration:

• (1)Nondepolarising agents like pancuronium may cause increased heart rate and blood pressure. Atracurium and cisatracurium are generally stable but may cause mild hypotension due to histamine release.
• (2)Depending on the dose, NMBAs suppress or jeopardise spontaneous breathing, increasing the risk of hypoventilation and hypoxaemia, particularly in neonates and infants. Careful monitoring and reversal are crucial to prevent postoperative complications.
• (3)Succinylcholine carries the highest risk of anaphylaxis, and rocuronium has been associated with a similarly high incidence of anaphylaxis in some large-scale pharmacovigilance studies, particularly in France⁹¹ and Norway.⁹² However, these findings are not universally observed across other populations.⁹³ The increased incidence of rocuronium-induced anaphylaxis observed in France and Norway may be partly attributed to prior ‘pholcodine exposure’, which may promote cross-sensitisation to quaternary ammonium structures shared with rocuronium.⁹³Atracurium, in contrast, is more commonly associated with nonimmunologic histamine release rather than IgE-mediated hypersensitivity, which can lead to hypotension or flushing but does not constitute true anaphylaxis.⁹¹
• (4)Succinylcholine is contraindicated in patients with large surface area burns or denervating injuries due to the risk of severe hyperkalaemia from upregulated extrajunctional acetylcholine receptors. This risk emerges approximately 48 to 72 h after injury and can persist for many months, or even years. In some neurologic conditions – such as severe spastic quadriparesis or chronic upper motor neuron lesions – the hyperkalaemic risk may be permanent.²⁴ Nondepolarising agents are preferred in these cases.

Specific safety concerns with depolarising and nondepolarising neuromuscular blocking agents

Succinylcholine is reserved for emergencies due to risks of hyperkalaemia and cardiac complications, especially in conditions like muscular dystrophy. It can also trigger malignant hyperthermia in susceptible children.

Nondepolarising NMBAs are preferred in paediatrics for their better side-effect profile, but carry risks such as prolonged paralysis and residual blockade. Cisatracurium and atracurium, metabolised by Hofmann elimination, are particularly useful in neonates and patients with liver or kidney impairment.

Strategies to mitigate NMBA-related risks include

• (1)Tailoring dosing based on age, weight and clinical status to avoid overdose and prolonged paralysis, considering factors like concurrent medications and surgery duration.
• (2)The use of quantitative neuromuscular monitoring (e.g. AMG or EMG) is recommended to objectively confirm adequate recovery before extubation, especially in cases involving deep or prolonged blockade.
• (3)Avoiding succinylcholine in nonemergent situations.
• (4)Using reversal agents like sugammadex for rapid reversal of aminosteroid NMBAs, or administering AChE inhibitors with anticholinergics to avoid side effects in case of shallow neuromuscular blockade.

Ongoing research and future directions

Pharmacological research is focused on optimising existing NMBAs and developing new ones for paediatric use. Novel agents like Gantacurium, an ultra-short-acting NMBA, show promise for rapid intubation and short procedures with fewer side effects.⁹⁴ Sugammadex has revolutionised the reversal of steroidal NMBAs, offering faster, more complete reversal than AChE inhibitors, especially in high-risk paediatric patients. Adamgammadex is a recently developed alternative that has the potential to exhibit a more favourable side effect profile compared to sugammadex.⁹⁵

Ongoing studies aim to optimise NMBA dosing and minimise long-term effects like muscle atrophy and critical illness myopathy in paediatric ICU patients, with a focus on improving recovery and rehabilitation for neonates and young children.

Pharmacogenomics research into genetic variations influencing NMBA responses is paving the way for personalised dosing strategies, allowing for more precise NMBA selection and reducing complications related to atypical enzyme activity.

New quantitative monitoring technologies like EMG and AMG provide more accurate and reliable measurements of neuromuscular blockade, especially in paediatrics. These devices enable noninvasive, continuous monitoring, helping tailor NMBA dosing and reversal.

Miniaturised wireless monitoring devices are making it possible to monitor neuromuscular blockade in settings outside the operating room, such as ICUs, for safer NMBA administration during long surgeries or ICU stays.

Risk management and safety protocols

Professional organisations, such as the ASA and ESAIC, are refining guidelines and protocols for paediatric NMBA use, emphasising correct agent selection, objective monitoring and full reversal before extubation. The use of succinylcholine is discouraged in nonemergency situations for children.⁵⁷

Paediatric hospitals are enhancing NMBA management training for anaesthesiologists and ICU providers, focusing on pharmacology, monitoring and reversal. Simulation training is also being used to prepare clinicians for paediatric airway and anaphylaxis emergencies.

Conclusion

Advancements in paediatric neuromuscular blockade, including new pharmacological agents, improved monitoring and individualised dosing, are enhancing safety and efficacy in neonates, infants and children. These developments aim to minimise adverse effects and optimise NMBA use based on age-specific physiology. Ongoing research into NMBA pharmacodynamics, pharmacogenomics and long-term effects continues to refine clinical practice. Future efforts will focus on precision medicine, improved monitoring and tailored reversal strategies to ensure the safest and most effective management of neuromuscular blockade in paediatric patients.