Activity Transcript

Joseph Tobias, MD: Hello, I'm Dr Joseph Tobias, an attending pediatric anesthesiologist and pediatric critical care physician from Nationwide Children's Hospital in Columbus, Ohio. Welcome to this program titled, “A Review of Neuromuscular Blockade and Reversal in the Pediatric Population.” Joining me today is Dr Lisa Herbinger from Samford University and a CRNA at Children's of Alabama in Birmingham.

Lisa Herbinger, DNP, CRNA: Well, thank you, Joe. It's a pleasure to be here with you.

Dr Tobias: Neuromuscular blockade is a key component of anesthetic care for adult and pediatric patients. Although generally safe and effective, neuromuscular blocking agents have been associated with several life-threatening adverse effects, including respiratory failure and the need for reintubation in the setting of residual neuromuscular blockade. Careful selection of neuromuscular blocking agents, proper use of reversal agents, monitoring of neuromuscular blockade, and a collaborative approach to care are essential measures to prevent complications and ensure good outcomes.

Let's get started by examining when we use neuromuscular blocking agents. We should, of course, always create patient-specific anesthesia plans. However, we know that neuromuscular blocking agents are commonly used for endotracheal intubation, including rapid sequence intubation and emergency airway management, during laparoscopic cardiac and neurosurgical procedures; during procedures requiring abdominal or thoracic retractors; and during procedures requiring skeletal muscle relaxation, including intra-abdominal procedures such as laparotomy. But how do we determine the best neuromuscular blocking agent for our individual pediatric patients?

Dr Herbinger: Well, Joe, that's an important question, because we know the one-size-fits-all approach is not considered best practice, especially with children. For example, the depolarizing agent succinylcholine has historically been considered the gold standard for airway management for rapid sequence inductions, difficult airways, trauma, and treatment of laryngospasm. Succinylcholine is predictable and reliable, has less than a 1-minute onset, about a 5-minute duration, and no reversal is needed. But there are contraindications to the use of succinylcholine common to all patients, such as those with malignant hyperthermia risks, burns, spinal cord injuries, hyperkalemia, or myopathic conditions. The risk and benefit ratio must always be considered.

In addition, as pediatric anesthesia practitioners, we know there are significant implications in children, such as the risk of bradycardia and the potential for life-threatening hyperkalemia with undiagnosed muscular dystrophies.

Dr Tobias: Yes. And for these reasons, many pediatric practitioners are hesitant to use succinylcholine in children. Fortunately, we have nondepolarizing neuromuscular blocking agents, which may be safer. However, these agents may also have implications we should be aware of. The steroidal group, including rocuronium, vecuronium, and pancuronium, is commonly used in clinical anesthesia practice. The advantages include hemodynamic stability and a relatively rapid onset, especially with rocuronium. However, there are significant disadvantages to these agents, including that they must undergo hepatic metabolism and renal excretion so that we must consider changes in their dosing in patients with liver or renal disease. And then there may be an immature and unpredictable pathway of metabolism due to genetic variations or age differences.

Then we also have the benzylisoquinoline group, such as cisatracurium and atracurium. Advantages of these agents include that they are eliminated without hepatic and renal processes because they undergo Hoffman degradation and metabolism by plasma esterases. However, they cannot be used for rapid sequence induction because higher doses result in histamine release and hemodynamic effects.

Regardless, with both groups of nondepolarizing agents, train-of-four monitoring is recommended. However, it may be impossible or unreliable based on conditions related to the patient or the surgical procedure. Neuromuscular blockade can outlast short cases, with a risk of postoperative residual blockade or recurarization. Only rocuronium can be used for rapid sequence intubation. And then if you have a cannot intubate-cannot ventilate scenario, the prolonged duration of these agents can be problematic. Regardless of the duration of the case, except in rare circumstances, reversal agents are necessary to ensure return of normal neuromuscular function.

Dr Herbinger: Speaking of residual neuromuscular blockade, we know there can be devastating consequences in adult and children, and there's evidence that it probably happens more than we realize. I'm probably biased, but I'm actually more frightened of residual neuromuscular blockade in children than adults. Infants and young children have compliant, easy collapsible airway structures, proportionally large tongues, and short necks, which make them more prone to obstruction. They also have lower levels of the type 1 slow-twitch muscle fibers. They're sprinters and not marathoners, so they can compensate for a little while, but then they tire out.

Dr Tobias: And if you combine their normal anatomy with the weakness and hypotonia that can result from residual neuromuscular blockade, they are set up for the development of respiratory insufficiency or failure and upper airway obstruction. These problems can lead to weakness, hypotonia, and airway obstruction, which leads to hypoxemia, which results in bradycardia, cardiac arrhythmias, and cardiac arrest.

Dr Herbinger: And that is scary. I've unfortunately seen that potential death spiral too many times. Let's talk about minimizing that risk with our reversal agents or antagonists that we most commonly use.

First, we have neostigmine. Its mechanism of action is inhibition of acetylcholinesterase, resulting in an increase in the concentration of acetylcholine at the neuromuscular junction with competitive antagonism of the effects of the residual neuromuscular blockade. Dosing recommendations vary from 30 to 70 mcg/kg up to a max of 5 mg. Its onset of action is within 1 minute, with a peak effect occurring at about 10 to 15 minutes. It's been used since the 1930s as an unapproved but grandfathered product under the Food, Drug, and Cosmetic Act of 1938. Then in 2013 the FDA approved the first version of neostigmine for use in adults and pediatric patients, specifically to reverse the effects of nondepolarizing neuromuscular blocking agents after surgery. Neostigmine approvals were based on data showing reductions in recovery time from neuromuscular blockade versus spontaneous recovery.

An advantage of neostigmine is its long history of use and that it's considered generally safe and reliable. However, disadvantages include increased risk of post-op nausea and vomiting, bronchospasm, and secretions and salivation. It needs pre- or co-treatment with atropine or glycopyrrolate for the antimuscarinic effects, which we know is to avoid bradycardia. The anticholinergic effects of atropine or glycopyrrolate can then cause tachycardia and drying, which can be significant in patients with certain diseases like cystic fibrosis. Atropine specifically crosses the blood-brain barrier, causing flushing, irritability, delirium, and that just general hot feeling that our patients will complain of. And then the risk of inadequate reversal in residual neuromuscular blockade exists. Other agents in the neostigmine class include edrophonium and pyridostigmine.

Dr Tobias: And now we have sugammadex. It was approved by the FDA in December 2015 for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in adults undergoing surgery. In the United States, it is currently used off-label in pediatric patients. [Editor’s Note: In June 2021, the FDA expanded the indication to include use in pediatric patients aged ≥ 2 years.] It has been safely used for many years in more than 60 countries, with experience in more than 10 million patients.

Sugammadex is approved for use in pediatric patients older than 2 years of age in Europe and Asia. Sugammadex is very different from neostigmine. It’s a cyclodextrin molecule with a cavity that binds to the hydrophilic steroidal neuromuscular blocking agent at a 1:1 ratio. This water-soluble complex is then excreted unchanged by the kidneys. This binding is incredibly strong. It is estimated that for every 30 million of these sugammadex neuromuscular blocking agent complexes, only 1 dissociates. There are only rare anecdotal reports of potential cases of postoperative residual recurarization after sugammadex.

Sugammadex dosing is based on the train-of-four count. With 2 twitches or a post-tetanic count of 2 twitches, residual neuromuscular blockade can be reliably reversed with 2 and 4 mg/kg, respectively. The largest dose of 16 mg/kg is reserved for a scenario when there are no twitches, perhaps immediately after the administration of rocuronium. Think of the implications, such as a cannot intubate-cannot ventilate scenario. Following the administration of sugammadex in a dose of 16 mg/kg, patients will resume spontaneous ventilation even after a 1 to 1.2 mg/kg dose of rocuronium in approximately 2.2 minutes.

Dr Herbinger: Now, let's consider this from a pediatric perspective. Although sugammadex is currently not approved for children less than 17 years of age in the United States, we often use agents that are not FDA approved in children. An example of this may be a child who needs a rapid sequence induction for a short case. [Editor’s Note: Sugammadex is now approved for use in children aged ≥ 2 years.] I confess that I avoid succinylcholine as much as possible in children, so I appreciate having the ability to use high-dose rocuronium for intubation, knowing that we can reliably reverse it if needed in just minutes.

Dr Tobias: While we are talking about sugammadex for pediatric patients, let's briefly look at some of the data we have. With sugammadex, small studies and systemic literature reviews have shown faster recovery, faster tracheal extubation, fewer adverse events, and a decreased risk for residual paralysis when using sugammadex.

In a case series, 4 mg/kg has been shown to be effective and safe in early reversal of deep neuromuscular blockade in infants and children. In another case series examining 331 doses of sugammadex administered over 2 years to children younger than 2 years of age, sugammadex was equally effective as neostigmine and no adverse effects were observed. Additionally, no increased emergence agitation was observed in a retrospective analysis of children aged 1 to 13 years undergoing strabismus surgery. Sugammadex was reported to have a more rapid effect and to be safer than neostigmine in children with asthma undergoing outpatient lower abdominal or urogenital surgeries. However, like any agent, there are implications of which we need to be aware.

There is a potential for allergic, including anaphylactoid or anaphylactic, reactions. This was the FDA's primary reason for delaying approval in the United States. It appears that the risk is the same or equivalent to many other anesthetic agents. With renal insufficiency or failure, a concern has been expressed regarding delayed elimination of the sugammadex neuromuscular blocking agent complex. This is likely not clinically significant. There may be artifactual effects on the coagulation profile.

There have been anecdotal reports of bradycardia and cardiac arrest. A 2018 randomized controlled trial evaluated the incidence of bradycardia in 200 patients less than 18 years of age. Bradycardia was noted in 8% of the patients. Half of those patients had documented heart disease, and none required treatment. Other adverse effects have included nausea, vomiting, pain, and hypotension. However, these have not been shown to be more common than with many of the other medications that we use in the perioperative period.

Sugammadex can encapsulate hormonal contraceptives. Females of childbearing age must be informed to use alternative birth control methods for 7 days after the administration of sugammadex.

Dr Herbinger: Your comments related to our female patients of childbearing age reminded me of the importance of communication and collaboration with other caregivers, patients, and the perioperative team members. Studies suggest that even adult women are not adequately counseled about this drug-to-drug interaction. Nurses, pharmacists, and other healthcare providers who may interact with patients and their families can help us in such education efforts by being aware of these drug-to-drug interactions, communicating about such risk with patients and their families, and ensuring patients understand this information.

Joe, you and your colleagues have developed an information sheet for your patients of childbearing age. Tell us some about that.

Dr Tobias: Even though we're working at a children's hospital, we have a significant percentage of our population who are of childbearing age. So, we developed a patient information sheet for any patient who has received sugammadex. This sheet is generated from our electronic medical record and is automatically printed out in the recovery room and given to the patient to take home with them.

Dr Herbinger: Joe, I love that idea, and I have a few other thoughts about communication and collaboration here. An issue that often comes up is cost. I frequently hear that anesthesia practitioners are discouraged from using sugammadex due to the expense. There are obviously cost differences in agents based on vendors, contracts, use, and other factors, but collaborating with our pharmacists can give us a more accurate cost assessment, which could be instrumental in furthering dialogue that helps us ensure our patients have access to the most appropriate agents.

For example, at my facility, a 200-mg vial of sugammadex actually costs less than the combination of a 5-mg vial of neostigmine and a 1-mg vial of glycopyrrolate. As for patient care, many of us work in an anesthesia care team model, where several members of the team often care perioperatively for the same patient. That model promotes efficiency, but I can think of so many scenarios when poor communication could result in disastrous consequences.

There are also times we should avoid neuromuscular blocking agents because of the possible effects on nerve conduction being monitored by the surgeon, such as facial nerve monitoring, evoked potentials, etc. We should always try to talk with the surgery team preoperatively if we're at all unsure of whether our agents could interfere with an optimal surgical outcome. And we can't forget that postoperatively, many children will return immediately to the care of a primary care team. In our place, the neonatal intensive care physicians have voiced concerns about sugammadex. There just hasn't been enough study done yet in this age group. So even though I've used sugammadex in neonates with good results and no apparent adverse effects, at their request, I'm no longer doing so. It's so easy to get busy and forget that communication and collaboration are key factors in patient safety and good outcomes, especially with high-risk interventions, such as neuromuscular blockade.

Let's move on now to the discussion of a couple of cases. I'll start with one looking at the use of neostigmine. Imagine a 4-year-old girl, 18 kg, with hemolytic uremic syndrome and associated acute renal failure. She's coming to the OR for a percutaneous subclavian line placement with general anesthesia for postoperative hemodialysis. She's been NPO for 10 hours, has no indication of a difficult airway, and neuromuscular blockade for the procedure is indicated.

A few discussion points we can talk about here. We know that cisatracurium and atracurium are the benzylisoquinoline muscle relaxants metabolized by nonorgan-dependent Hoffman elimination and nonspecific ester hydrolysis. Neostigmine has a long history of safe and reliable antagonism of the benzylisoquinoline and steroidal muscle relaxants. There's growing evidence that suggests that sugammadex is safe for patients with renal failure. However, there are theoretical concerns due to renal excretion. The manufacturer's guidelines state that sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis.

A good induction plan could be the IV administration of lidocaine, propofol, fentanyl, and cisatracurium or atracurium. We would antagonize the cisatracurium or atracurium when at least a 1 out of 4 train-of-four response or clinical signs of recovery are seen with the IV administration of glycopyrrolate and neostigmine. We would extubate awake with sustained tetany or signs of adequate recovery, such as tidal volume, arm and leg strength, purposeful movements -- those things that show us a patient is extubation ready.

Next, let's look at a case using sugammadex. Joe, why don't you tell us about that?

Dr Tobias: All right. Our second case is a 10-year-old boy with Duchenne muscular dystrophy requiring a laparoscopic appendectomy. He was vomiting yesterday, has been hydrated, has adequate IV access, electrolytes are normal, and his cardiac function is normal.

The clinical assumption is we cannot use succinylcholine or volatile anesthetic agents due to the risk of life-threatening rhabdomyolysis, hyperkalemia, dysrhythmias, and cardiac arrest. He is at high risk for aspiration, so he needs a rapid sequence induction. The procedure will probably be less than 30 minutes. Patients with muscular dystrophies are more sensitive to neuromuscular blocking agents, more affected by residual neuromuscular blockade, and are at high risk for postoperative respiratory complications. We know with neostigmine in this population there may be wide variability of recovery times, and it may not be effective due to profound blockade with a risk of residual neuromuscular blockade. The patient needs to be extubation-ready at the end of the procedure.

The plan would be preoxygenation, propofol for induction, rapid sequence intubation with rocuronium in a dose of 1 mg/kg with other adjuncts, such as lidocaine and fentanyl. Maintenance anesthesia would include TIVA with low-dose fentanyl or remifentanil infusion and a propofol infusion. We would ask the surgeons to infiltrate the surgical access sites with a local anesthetic agent at the end of the case. We would redose rocuronium only if necessary. We would monitor the train-of-four and reverse with sugammadex based on the train-of-four in a dose of 2 to 4 mg/kg. We would then extubate when the patient was fully awake.

Let's talk about a third case, one that we all see fairly commonly in our pediatric anesthesia practice. We have an 8-week-old with pyloric stenosis coming for a pyloromyotomy. He has been hydrated. Electrolytes are normal. He has a functioning IV, a difficult airway is not anticipated, and he is otherwise healthy. The clinical assumptions for this case would be that he has a full stomach, may be at high risk for aspiration, and therefore needs a rapid sequence induction. The procedure will probably be less than 30 minutes. Rocuronium can have a prolonged duration of action in neonates and infants due to its hepatic metabolism. The patient needs to be extubation-ready at the end of the procedure. Lisa, what are your thoughts about the anesthesia plan?

Dr Herbinger: Well, at our place, we routinely lavage them until clear with some warmed normal saline and an OG tube before induction. Then we would preoxygenate, give a dose of atropine IV -- because I personally am always concerned that if there are any airway risks, then desaturation is going to lead into bradycardia -- and then proceed with a rapid sequence induction with propofol and a 1 mg/kg dose of rocuronium. Cricoid pressure, of course, is controversial in this age group. That's a discussion for another time, but maybe or maybe not cricoid pressure depending on the practitioner. No ventilation, if possible, or, if we need to ventilate, very low pressure, intubate at 45 seconds, and then maintain with desflurane. And then at the end of the procedure, turn off the desflurane, give a dose of sugammadex at 4 mg/kg, and then extubate only when we feel that those clinical signs of extubation readiness are there.

So, what about you, Joe? Would you do something differently with this case?

Dr Tobias: I agree. I think that sounds like a great anesthetic plan. I think there may be a couple of other options that are clinically viable. One would be to use succinylcholine for the initial endotracheal intubation. The use of succinylcholine would avoid the need for reversing neuromuscular blockade later in this case. The other option would be to use succinylcholine and then a very low dose of rocuronium, maybe 0.2 or 0.3 mg/kg, if there are requirements for surgical relaxation during the laparoscopic procedure. Alternatively, a small dose of cisatracurium after succinylcholine would be another option. Then as far as reversal, I agree with you. I would use sugammadex if I had used rocuronium, and if I've used cisatracurium or atracurium, I would use neostigmine.

Let's go over a few important points. Monitoring train-of-four in neonates, infants, and children may be difficult or impossible. We may be unable to use arms as these may be tucked at their sides, and monitoring may be unreliable, especially in smaller patients. In these patients, we may need to depend on clinical signs for extubation readiness, including tidal volume, negative inspiratory force, grimace, crying, leg or arm fall, and an evaluation of skeletal muscle strength. There's current debate also in the adult world of anesthesia regarding the most effective way to monitor the train-of-four regarding the use of qualitative vs quantitative EMG monitoring. Neither of these have been well-studied in neonates and infants.

Dr Herbinger: Let's talk a little bit more about when this train-of-four monitoring is not possible or unreliable, specifically here about neostigmine. I will only give neostigmine when I see some clinical sign of neuromuscular blockade recovery, such as attempts to breathe or any kind of movement. And then, of course, to avoid bradycardia, before giving neostigmine, we give the atropine or glycopyrrolate. And for the really young infants, I will actually wait for a heart rate response before I give that neostigmine. And then I extubate when fully awake with good spontaneous ventilation and muscular strength and attempts to cry. But Joe, tell us how you would use sugammadex for infants and young children when monitoring train-of-four is either unreliable or not an option?

Dr Tobias: We encourage and try to use train-of-four monitoring whenever feasible based on our access to the patient and the patient's age and weight. We have found it's generally feasible if the patient weighs more than 10 or 15 kg, and we try to use an arm or the leg when we have access during care. It's best to place the train-of-four and check the twitch prior to giving the neuromuscular blocking agent. We then dose sugammadex based on the manufacturer's recommendation. If we have 2 twitches, we give 2 mg/kg. If there are 1 to 2 post-tetanic twitches, we give a dose of 4 mg/kg. If there are no twitches, we use the largest recommended dose of 16 mg/kg. If we're not using train-of-four monitoring, we give 2 to 4 mg based on when the last dose of the neuromuscular blocking agent was administered and the clinical evidence we have for clinical return of neuromuscular function, such as breathing, skeletal muscle movement, leg movement.

We've covered a lot of ground in a few minutes. We've hopefully presented evidence-based and clinically relevant information for all of us who provide anesthesia care to children.

To summarize, the choice of an appropriate neuromuscular blocking agent is key to the safe and effective provision of intraoperative anesthetic care. Recent work has demonstrated the potential deleterious physiologic effects of inadequate reversal of neuromuscular blockade. A growing body of evidence suggests that there may be clinical advantages to the reversal of residual neuromuscular blockade with sugammadex when compared with neostigmine. Intra-professional collaboration and communication improve outcomes and help minimize the risk of adverse events.

Lisa, thank you for your interesting discussion.

Dr Herbinger: Well, thank you, Joe. It's been a pleasure working with you and the Medscape team.

Dr Tobias: And to the audience, thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.