The Influence of Acid-Base Balance on Anesthetic Muscle Relaxants: A Comprehensive Review on Clinical Applications and Mechanisms

Introduction

Muscle relaxants are a large group of chemical compounds that can relax skeletal muscles. They play a crucial role in various clinical situations, being used as primary drugs for safe endotracheal intubation, in surgical procedures (eg, combined with anesthetics to prepare patients for surgery), or to assist ventilation in patients requiring mechanical ventilation. Muscle relaxants can be classified into 3 groups based on their mechanism of action: non-depolarizing neuromuscular-blocking drugs (NMBDs), depolarizing neuromuscular-blocking drugs, and centrally acting skeletal muscle relaxants [1–5]. Drugs belonging to the first group can further be categorized into 3 subgroups based on structure and reversal methods: steroid, benzylisoquinolinium, and asymmetrical mixed-onium chlorofumarate [2]. NMBDs, such as tubocurarine, atracurium, pipecuronium, mivacurium, pancuronium, rocuronium, and vecuronium, counteract the effects of acetylcholine on postsynaptic membranes, hindering the depolarizing impact and preventing muscle fiber stimulation. On the other hand, depolarizing relaxants, like succinylcholine and decamethonium, induce an initial activation followed by sustained blockade, acting as more enduring agonists compared to acetylcholine [4,6]. The choice of muscle relaxant should consider aspects such as the patient’s clinical condition (eg, liver and kidney function, electrolyte and acid-base balance disorders), duration of drug action, onset time, and the clinical context for which it is intended. Additionally, factors like sex, age, weight, body temperature, and concurrently administered medications can influence the effects of muscle relaxants [4,7–9].

Acid-base balance disturbances can affect the efficacy of these drugs. The normal pH in the human body ranges between 7.35 and 7.45. When the pH drops below 7.35, we refer to it as acidosis, and when it rises above 7.45, it is called alkalosis. There are 4 main acid-base balance disorders – metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis [10] – and this article discusses their impact on muscle relaxants. Currently, it is believed that non-depolarizing muscle relaxants exhibit increased efficacy in acidic conditions and decreased efficacy in alkalosis [2,9]. Conversely, the depolarizing muscle relaxant succinylcholine has the opposite effect [9].

Medications classified as centrally acting muscle relaxants form a diverse group in terms of both their structure and the receptors they target in the central nervous system. These drugs are used to alleviate tension and spasms of skeletal muscles as an adjunct therapy for discomfort and pain associated with various conditions accompanied by musculoskeletal system pain. Due to their different mechanisms of action and clinical scenarios in which drugs of this group are utilized, the article will focus on medications from the first 2 groups – those that induce neuromuscular blockade [11,12].

This work is based on the available literature and the authors’ experience. Results of studies on the effect of acid-base balance disturbances on non-depolarizing relaxants have been conflicting. This article aims to review the use of anesthetic muscle relaxants in patients with acid-base disturbances.

Acid-Base Balance Disturbances

One of the human body’s adaptations to maintain homeostasis is to keep the pH between 7.35 and 7.45. Arterial blood gas analysis is performed to assess parameters of acid-base balance. The normal values for the parameters assessed in this test are as follows: pH=7.35 to 7.45, pCO2 (partial pressure of carbon dioxide)=35 to 45 mmHg, pO2 (partial pressure of oxygen)=75 to 100 mmHg, HCO3− (bicarbonate ions)=21 to 28 mEq/L (parameters may vary between devices used for arterial blood gas analysis, so it is important to familiarize yourself with the device’s specifications and reference values determined for that particular device), and oxygen saturation ≥95% [10]. The maintenance of pH within this range is primarily governed by the buffering system based on bicarbonate ions, with involvement of the renal system and carbon dioxide regulation by the respiratory system. This mechanism allows for partial or even complete compensation of certain disturbances, whereby the pH remains within the physiological range despite the presence of disruptions. The situations where pH drops below 7.35 are called acidosis, while situations where it rises above 7.45 are termed alkalosis [10,13]. We distinguish 4 main disorders of acid-base balance: metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis [10]. Respiratory alkalosis is the most common acid-base abnormality, with no difference between males and females [14]. Table 1 shows the types of acid-base disorders and the parameters used for their differentiation [10,13–17].

Metabolic acidosis can be caused by various types of poisons, such as cyanides, carbon monoxide, arsenic, toluene, methanol, ethylene glycol, paraldehyde, or medications such as metformin or salicylates, or in the case of diarrhea, renal tubular acidosis, diabetic ketoacidosis, and accumulation of lactates (lactic acidosis) in the course of sepsis [15,18,19]. The treatment of metabolic acidosis largely depends on the underlying cause. In the case of sepsis or diabetic ketoacidosis, it involves appropriate fluid therapy and correction of electrolyte imbalances. However, in poisoning cases, it may involve administration of antidotes, dialysis therapy, or, in some cases, administration of bicarbonates [15].

Respiratory acidosis is caused by accumulation of carbon dioxide in the body. This condition can be contributed to by respiratory failure, which can be caused by chronic obstructive pulmonary disease, asthma, interstitial lung disease, myasthenia gravis, or centrally acting depressant medications such as opioids. The treatment of respiratory acidosis involves non-invasive and invasive respiratory support and medications that dilate the airways. In the case of respiratory disturbances induced by opioids, naloxone is used [16,20].

There can be several reasons for the development of metabolic alkalosis. One of them may be excessive loss of hydrogen ions due to vomiting; for example, in the case of pyloric stenosis. Metabolic alkalosis can also occur in primary hyperaldosteronism or as a result of treatment with loop or thiazide diuretics [17]. Respiratory alkalosis may occur in cases of low CO2 production due to states with reduced metabolism such as coma, or in cases of excessive loss due to psychogenic hyperventilation or mechanical ventilation. The treatment of alkalosis depends on its primary cause – in the case of pyloric stenosis, surgical treatment is indicated. During the diagnosis of alkalosis, electrolyte disturbances such as hypokalemia or hypocalcemia should be assessed, as they can lead to cardiac rhythm disturbances; their evaluation may require an EKG. If they are diagnosed, appropriate treatment should be initiated [14,17].

The symptoms of acidosis and alkalosis can vary depending on the underlying cause. In the case of acidosis, symptoms may include weakness, drowsiness, altered consciousness, excessive sweating, and warm and flushed skin. In the case of alkalosis, symptoms may include trembling hands, tingling sensations in the hands and feet, muscle cramps, nausea, vomiting, dizziness, and altered consciousness [16,17,19–22].

Characteristic of Non-Depolarizing Muscle Relaxants

The mechanism of action of NMBDs is based on competitive antagonism of acetylcholine by blocking the alpha subunit of the acetylcholine receptor on the postsynaptic membrane of the neuro-muscular junction, preventing the attachment of acetylcholine. As a result, the motor endplate cannot depolarize, leading to muscle paralysis [1,2,4,7,8,23]. In some cases, these drugs can also directly block the inotropic activity of acetylcholine receptors [2]. As previously mentioned, these drugs can be classified into several subgroups based on their structure [1,8]. This classification is clinically significant, as different methods are employed to reverse the blockade induced by them. Compounds belonging to these subgroups also exhibit varying additional activities. This classification is presented in Table 2 [1–3,24–31]. Aminosteroid drugs can induce vagolytic activity, leading to tachycardia and hypertension. On the other hand, benzylisoquinolinium compounds, especially mivacurium, atracurium, or doxacurium, demonstrate dose and delivery rate-dependent non-immunologic histamine release, causing facial flushing, hypotension, peripheral vasodilation, and, in rare cases, bronchospasm [1,2].

When selecting an appropriate skeletal muscle relaxant, considerations should be based on the onset time, duration of action, the patient’s clinical condition, and assessment of liver and kidney function. Muscle relaxants differ in their affinity to receptors (dissociation-constant), metabolism, and elimination [8].

It is believed that the ideal non-depolarizing, neuromuscular blocking drug should possess specific characteristics listed in Table 3 [32,33], but no single currently available NMBD has all of them.

Non-depolarizing drugs belonging to the aminosteroid group (such as pancuronium, vecuronium, pipecuronium, and rocuronium) are metabolized in the liver, where they undergo acetylation [1,8,23]. NMBDs belonging to the benzylo-isoquinolone group (atracurium and cisatracurium) undergo Hoffman elimination (a non-enzymatic degradation with a rate that increases with temperature and/or pH), so atracurium can be used in patients with impaired kidney or liver function, but in individuals with impaired kidney function the action of cisatracurium may be slightly affected. An exception is mivacurium, which is metabolized similarly to succinylcholine, through pseudocholinesterase [8,23]. The elimination of drugs such as vecuronium and rocuronium occurs primarily through the biliary route, while tubocurarine, metocurine, doxacurium, pancuronium, and pipecuronium are mainly excreted through the kidneys [8,23,34,35]. Table 4 presents the classification of non-depolarizing drugs based on their duration of action and route of elimination [2,8,23,27,36–45].

A clinically significant aspect is the ability to reverse the effects of muscle relaxants. Drugs with anticholinesterase activity, such as neostigmine and edrophonium, can be used for reversal. However, when using them, it is essential to also administer drugs with anticholinergic effects (such as glycopyrrolate or atropine) to block the action of acetylcholine on muscarinic receptors [1–3,29]. The use of neostigmine in reversing neuromuscular blockade should be avoided in patients with myasthenia due to its mechanism of action, posing a risk of cholinergic crisis [46]. A specific drug that can be used to reverse the effects of rocuronium and vecuronium is Sugammadex (Selective Relaxant Binding Agent – SRBA), allowing for faster reversal of blockade compared to the previously mentioned drugs, with no adverse effects on the parasympathetic nervous system. It provides more efficient and safer reversal of moderate and deep muscle blockade compared to neostigmine – patients experience fewer adverse effects such as bradycardia, postoperative nausea, or postoperative residual paralysis symptoms [2,23].

In recent years, a new group of drugs has been discovered that can reverse blockades from both the aminosteroid and benzylisoquinolinium groups – Calabadion 1 and Calabadion 2 – which have shown good results in studies on rats. However, there is still a lack of safety and efficacy results from human studies [24,47].

The Use of Non-Depolarizing Muscle Relaxants in Acidosis and Alkalosis

Many factors can influence the timing and strength of the action of drugs, including organ dysfunction, electrolyte imbalances, and disturbances in acid-base balance. The action of NMBDs, such as rocuronium, atracurium, vecuronium, pancuronium, and tubocurarine, is also affected similarly by acid-base imbalance. In general, it is believed that electrolyte abnormalities like hypokalemia, hypocalcemia, hypophosphatemia, hypermagnesemia, and respiratory and metabolic acidosis (with respiratory acidosis having a stronger effect than metabolic acidosis) potentiate neuromuscular blockade, while hypothermia can prolong blockade (due to decreased elimination and metabolism) [1–3,7,23,46,48]. Respiratory acidosis also antagonizes reversal [1]. Furthermore, acidosis can lead to a decrease in renal and hepatic blood flow, resulting in prolonged drug half-life [46]. Muscle paralysis potentiation may also occur in patients with eclampsia who have developed hypermagnesemia following magnesium sulfate treatment [1]. On the other hand, hypercalcemia, hyperkalemia, and alkalosis can diminish neuromuscular blockade [49].

In the case of sepsis, when the acid-base balance is disrupted, hemodynamic disturbances occur, and the recovery after administering NMBDs may be delayed due to reduced acetylcholinesterase activity in the neuromuscular junction space. However, sepsis does not affect the onset of NMBDs [7].

Rocuronium is a drug widely used for perioperative muscle relaxation to prepare patients for anesthetic and surgical procedures and to assist lung ventilation. It is also used off-label in defasciculating doses to prevent muscle fasciculation during muscle blockade, to prevent myalgia, and, in patients undergoing therapeutic hypothermia in post-cardiac resuscitation, to prevent shivering. The neuromuscular blocking strength of rocuronium is influenced by alterations in respiratory pH, rising with lower pH levels and falling with higher pH levels [35]. Respiratory alkalosis can delay the action of rocuronium, and it is essential to take into account the delayed effects of rocuronium during hyperventilation [50]. It was also discovered that respiratory acidosis induced by ventilation prolongs the neuromuscular blockade caused by rocuronium [51].

Atracurium is eliminated by Hoffman’s elimination and via ester hydrolysis by non-specific esterases in plasma. The speed of Hoffman’s elimination depends on temperature and pH and is slowed by acidosis and hypothermia [41]. Studies on atracurium blockade in patients undergoing renal transplantation have concluded that acid-base balance disturbances can affect recovery time and neuromuscular blockade. An acidic environment can lead to prolonged metabolism of the muscle relaxant due to diminished blood perfusion in the muscles. Lowering blood pH enhances the attraction of atracurium to the anionic acetylcholine receptors [52].

An experiment on 24 cats, in which the effects of acid-base imbalance on the neuromuscular actions of atracurium or vecuronium were studied, concluded that the potentiation of blockade induced by atracurium can be increased in both respiratory and metabolic acidosis. However, action and recovery were not influenced by experimental imbalance [53].

Research on patients undergoing abdominal surgery has established the impact of acid-base balance on vecuronium. Respiratory acidosis prolongs the duration and recovery time of vecuronium, while respiratory alkalosis shortens it [54]. Vecuronium is metabolized by the liver, so it should be used cautiously in patients with impaired liver function, which can lead to prolonged recovery from muscle paralysis. This drug should be used with caution in patients with renal failure, as elevated urea concentrations may impair elimination by the liver and can lead to accumulation of an active metabolite [34].

Pancuronium is commonly recommended for use in pediatric cardiac surgery and other high-risk procedures in infants and children [55]. It can also be used in cases of shivering during therapeutic hypothermia in patients in protocols in cardiac arrest [45]. Acidosis and hypokalemia contribute to an extended duration of paralysis, while alkalosis can counteract the blockade [56].

Tubocurarine is a myorelaxant that can cause apnea and is contraindicated in asthmatic patients. Postoperative respiratory acidosis can enhance undetected residual curarization [57].

Despite the general belief that acidosis enhances and alkalosis weakens neuromuscular blockade, there are exceptions. Pipecuronium-induced neuromuscular block is increased in metabolic alkalosis, as well as in acute respiratory and metabolic acidosis. The action of pipecuronium is decreased by respiratory alkalosis [58].

The effects of hypocalcemia, hypokalemia, hypermagnesemia, and respiratory acidosis on the benzylisoquinolinium derivative cisatracurium are unclear, but may related to metabolism through ester hydrolysis and Hoffman degradation [7].

Characteristic of Depolarizing Muscle Relaxants

Drugs that are depolarizing muscle relaxants exhibit agonistic action toward the acetylcholine receptor in the postsynaptic membrane of the neuromuscular junction, thus depolarizing the motor endplate. These drugs are resistant to the action of acetylcholinesterase, and by inducing continuous depolarization, they prevent further stimulation by acetylcholine. The block induced by depolarizing drugs occurs in 2 phases – depolarizing and desensitizing. The first phase involves stiffening and transient muscle fasciculation occurs, corresponding to muscle depolarization. In the second phase, muscles cease to respond to acetylcholine released by motoneurons, leading to complete neuromuscular block [1,4].

Succinylcholine is the most widely recognized depolarizing neuromuscular blocking drug. It is the only drug in this category used in clinical settings and is the preferred choice for rapid sequence intubation (RSI) in emergency departments. It has a rapid onset of action (approximately 30 s) and a very short duration of action (5–10 min). It is hydrolyzed by various cholinesterases present in the plasma (eg, butyrylcholinesterase) [6,59]. Another drug in this group is decamethonium, but it is rarely used in clinical practice [4].

Drugs from this group are contraindicated in individuals with degenerative neuromuscular diseases and those with a history of malignant hyperthermia. In children with skeletal muscle myopathies such as Duchenne muscular dystrophy, there is a risk of rhabdomyolysis with hyperkalemia [1].

The Use of Depolarizing Muscle Relaxants in Acidosis and Alkalosis

Information regarding the influence of acid-base metabolism on succinylcholine comes from the 1960s, when scientists studied the effect of sodium carbonate-induced alkalosis on the action of neuromuscular-blocking drugs in cat muscle preparation. The experiment showed that alkalosis potentiated the action of succinylocholine [60]. A study on the impact of acidosis on neuromuscular blockade showed that succinylocholine and decamethonium are antagonized by both metabolic and respiratory acidosis [61]. Succinylcholine remains the preferred drug for inducing paralysis, especially when there is a requirement for a swift onset and conclusion of its effects. Unfortunately, succinylocholine-induced lethal hyperkalemia is still being reported. Succinylcholine in patients with acidosis, metabolic hypovolemia, or bleeding can lead to a greater increase in serum potassium levels than in patients with maintained homeostasis. In the event of cardiac arrhythmias caused by hyperkalemia after succinylcholine administration, treatment with calcium chloride, bicarbonate, and hyperventilation should be initiated as soon as possible [46]. Table 5 summarizes the implications of acid-base disorders for non-depolarizing and depolarizing muscle drugs [7,8,23,52,54].

Monitoring and Management

An important aspect is monitoring the course of neuromuscular blockade induced by relaxants. The previously discussed changes in acid-base balance and electrolyte alterations may weaken or strengthen blocks in a patient, resulting in a change in the recovery time of neuromuscular blockade. Metabolic factors (such as hypo- and hyperglycemia), electrolyte imbalances, acid-base disorders, and hypothermia may contribute to delayed emergence from anesthesia. A case report of 2 patients undergoing surgery observed that stress, pain, increased sympathetic system activity with the release of catecholamines, and continuous stimulation of beta receptors, combined with hyperventilation leading to respiratory alkalosis, could shift potassium ions into cells. This effect may be more pronounced in individuals with preoperative hypokalemia. The report demonstrated that elevating potassium levels in these patients improved the level of consciousness, and recommended balancing serum potassium levels in cases of delayed emergence from anesthesia [48]. In a study on kidney transplant surgery patients in whom atracurium was used for blockade, a significant reduction in muscle relaxation duration and faster reversal of the blockade were observed due to treatment of acid-base imbalances using calcium carbonate. Based on this study, it was concluded that intraoperative treatment of acid-base disorders can shorten neuromuscular blockade and is a potential factor improving transplant outcomes [52].

The most popular methods for monitoring and predicting the course of blockade are Train-of-four (TOF), Train-of-four count (TOFC), and Train-of-four ratio (TOFR). TOF consists of 4 consecutive 2-Hz stimuli applied to a chosen muscle group, typically performed on the adductor pollicis muscle via stimulation of the ulnar nerve [3]. The desired response is a twitch indicating a specific muscle contraction. TOFR is determined by dividing the amplitude of the fourth twitch by the amplitude of the first twitch [1]. If TOFR is <0.9, there is a higher risk of post-residual blockade and postoperative complications, requiring use of a reversal agent. TOFR less than 0.7 indicates persistent blockade. TOFC provides information about the percentage of blocked receptors [3]. Adequate muscle blockade for surgery occurs when approximately 90% of receptors are blocked when 1 or 2 signals (twitches) are present [1,62]. The correlation between the percentage of blocked receptors and TOFC is presented in Table 6 [2].

About 75% of acetylcholine receptors become antagonized when the fourth twitch from TOF disappears, and the level of receptor occupancy increases as twitches disappear, ranging from 85% for the third twitch to 95–100% for the first twitch. Adequate relaxation for surgery is considered present when 1 to 2 twitches of the TOF are observed [2].

Assessment of TOF is largely dependent on the examiner, which leaves a wide margin of error. Therefore, other methods for evaluating the course of blockade should be considered, such as acceleromyography, strain-gauge monitoring, and electromyography [2,23]. Currently, it is recommended that the TOF ratio (TOFR) should be 0.9 for the reversal of blockade. However, due to the previously mentioned potential examiner-dependent margin of error, the patient’s muscle strength should be assessed, including sustained tetanic response and ability to lift the head for at least 5–10 s, indicating an appropriate level of reversal of blockade [1]. It is recommended that clinically weak patients should be left intubated with supported respirations until they can demonstrate return of strength [23]. In 2023, the American Society of Anesthesiologists published a report containing practical guidelines and recommendations regarding assessment of blockade reversal. The report strongly recommended:

It is also conditionally recommended (due to low strength of evidence):

Use of Muscle Relaxants in Metabolic and Neuromuscular Disorders

Patients with genetically determined metabolic disorders such as autosomal recessive inborn propionic acidemia and methylmalonic acidemia (which are organic acidemias) require special attention and assessment by an anesthesiologist. These patients may experience recurrent episodes of metabolic acidosis. Some drugs should be avoided or used with great caution in these individuals. It occurs with neuromuscular blocking agents such as succinylcholine, cisatracurium, and mivacurium, which are metabolized through ester hydrolysis to odd-chain organic acids [63].

NMBDs should be used with caution in patients with glycogen storage disease type II (Pompe disease), which is known for skeletal muscle myopathies, because residual weakness can be poorly tolerated by them [64].

Caution is also needed when using skeletal muscle relaxants in patients with neuromuscular disorders (NMDs). Their common feature is weakening of muscle strength and fatigue. This is a group of diseases that can affect both children and adults. We can divide them into 3 categories: prejunctional (including motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA); peripheral neuropathies; hereditary neuropathies such as Charcot-Marie-Tooth (CMT) disease), junctional (myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS)), and postjunctional (including muscular dystrophies such as Duchenne muscular dystrophy and Becker muscular dystrophy; and congenital myopathies). In NMDs, muscle relaxants should be used only if necessary, and use of succinylcholine should be avoided. Studies have shown that succinylcholine can be used in patients with myasthenia gravis; however, the best choice of skeletal muscle relaxants for them will be mivacurium and atracurium. Their action will be prolonged, so it is important to remember to use them in reduced doses [65]. The use of skeletal muscle relaxants is challenging, especially in the pediatric population, in patients with muscular dystrophies. Muscular dystrophies are a diverse group of genetically based diseases characterized by weakness and progressive damage of muscles, resulting from impaired synthesis or regeneration of contractile proteins. When using NMBDs in patients with muscular dystrophies, it should be remembered that they may have faster onset of action, longer duration of action, irregular action, and high risk of residual paralysis [66]. In 2007, the American College of Chest Physicians published the Consensus Statement on the Respiratory and Related Management of Patients With Duchenne Muscular Dystrophy Undergoing Anesthesia or Sedation, in which they stated that the use of depolarizing neuromuscular blocking agents such as succinylcholine in patients with Duchenne muscular dystrophy is absolutely contraindicated due to the risk of rhabdomyolysis, hyperkalemia, and cardiac arrest [67].

Future Directions

Contemporary technologies enable the design and creation of new drugs, the properties of which can be applied in clinical practice. However, there is still no ideal non-depolarizing skeletal muscle relaxant. The search for a universal drug is also underway, which would allow the reversal of muscle blockade caused by both steroid NMBDs and benzylisoquinoline. Progress in medicine will also lead to better and more accurate monitoring of the course of muscle blockade in the future.

Conclusions

Depolarizing neuromuscular blocking agents like succinylcholine provide rapid onset but with a more prolonged effect, while NMBDs offer more controllable muscle relaxation with the advantage of reversal options. The choice between them depends on the clinical scenario, patient characteristics, and the preferences of the anesthesia provider. These 2 groups of drugs are reported to act differently during acid-base balance disturbances. It is essential to consider the effects of hypo- or hyperventilation during use of myorelaxants. Regardless of the presence of acid-base balance disorders, it is important to remember that when using skeletal muscle relaxants, neuromuscular transmission should be monitored using TOF.