Episode #20 Postoperative Recurarization and Sugammadex: Staying Safe and Strong

Hello and welcome back to the Anesthesia Patient Safety Podcast.  My name is Alli Bechtel and I am your host. Thank you for joining us for another show.

We are going to talk about one of the most popular articles on our website. We are going to talk about a threat to patient safety that combines a medication with specific monitoring with the vast experience from anesthesia professionals in Japan. I hope you are as excited for this show as I am…

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We are going to talk about one of the featured articles from the June 2020 APSF Newsletter, “Postoperative Recurarization After Sugammadex Administration Due to Lack of Appropriate Neuromuscular Monitoring: The Japanese Experience” written by Sasakawa, Miyasaka, Sawa, and Iida. You can follow along with us from the APSF website by clicking on the Newsletter heading, 4^th one down is newsletter archives. Then click on the June 2020 Newsletter. The article is the third featured article.

Are you using Sugammadex at your institution? Sugammadex is a medication that very quickly reverses neuromuscular blockade from rocuronium and other nondepolarizing aminosteroid muscle relaxant medication by selective encapsulation. This article focuses on the experience of anesthesia professionals in Japan using this medication which was first used in Japan in 2010 and has been given to about 12.32 million patients in the following 8 years. Sugammedex has helped to decrease the risk of postoperative residual neuromuscular blockade from about 25-60% with reversal with neostigmine to only 1-4% with Sugammadex reversal. It is a safe and effective medication, but that is not where this story ends.  At the end of 2018, there were 36 cases of recurrence of neuromuscular blockade reported in Japan.  This led to the Safety Committee of the Japanese Society of Anesthesiologists publishing a warning about using correct dosing for Sugammadex in 2019. The correct dosing depends on the patient’s body weight and depth of neuromuscular blockade. I will include the table for this in the show notes as well.  The correct dose for a patient with a moderate neuromuscular block as evidenced by the reappearance of T2 following train of four simulation is 2 mg per kg. Patient’s with a deep block with 1-2 on post-tetanic count, can be reversed with 4mg per kg. Finally, for immediate reversal, such as after 3 minutes of administration of rocuronium for intubation, administration of 16mg per kg is appropriate.  After reversal, it is important to monitor for any signs of an anaphylactic reaction or recurarization and monitor for return to fully intact neuromuscular function.

Let’s look closer at these cases. Many of the patients received inappropriate doses of Sugammadex without neuromuscular monitoring and inadequate management after Sugammadex administration. We have talked about this before but perioperative neuromuscular monitoring with a quantitative device is so important to help prevent postoperative residual neuromuscular blockade. Quantitative monitoring is an objective monitor for the degree of muscle relaxation and can be done with accelerometer or electromyograms in addition to electric nerve stimulation. The advantage of this monitoring is that it provides an objective measure of the train of four to determine with the recovery reaches the point of a train of four ratio greater than 0.9. Quantitative monitors can also provide information about post-tetanic count for patients who have a deeper neuromuscular blockade. Qualitative monitors are still used frequently and depend on the anesthesia professionals subjective assessment of palpating or observing muscle contractions after nerve stimulation from the device. With qualitative devices, it is possible to get an estimate for the train of four count, but anesthesia professionals are unable to determine accurately and reliably when the train of four ratio is greater than 0.9 which is imperative for perioperative neuromuscular monitoring. Survey data reveals that only 22.7% of anesthesia professionals in the United States have access to quantitative monitors and in Japan, using either a qualitative or quantitative monitor is not routine. Instead, anesthesia professionals rely on their subjective assessment for recovery from neuromuscular blockade based on clinical signs alone. An important factor in the inappropriate dosing of Sugammedex may be the lack of perioperative monitoring for neuromuscular blockade.

Let’s turn our attention to recurarization which refers to an increase in neuromuscular blockade after a certain time period of recovery in the absence of further administration of neuromuscular blocking medications. This is something that we have seen in the past with reversal with acetylcholinesterase inhibitors and there are now reports of this happening following Sugammadex administration. One study by Elveld and colleagues found that there was a recurrence of neuromuscular blockade after patients with a deep neuromuscular block were reversed with only a small dose of Sugammadex. Another case report revealed that an obese patient required reintubation due to recurarization in the setting of an inadequate Sugammadex dose even though the patient had a train of four ratio of 0.9 prior to the first extubation. This is definitely something we need to closely evaluate in order to help keep our patients safe when using neuromuscular blocking medications.

Why does recurarization occur? To understand this, we need to travel into the neuromuscular junction. It is here that even when muscle relaxants block 75% of the nicotinic acetylcholine receptors, we can still see normal neuromuscular transmission with normal muscle strength because of the other 25% of the receptors. In the case that we just talked about the patient had returned to normal muscle strength, but there was likely still low levels of muscle relaxants present. This is a set up for recurarization in the setting of respiratory acidosis, magnesium administration, or aminoglycoside administration. A small amount of remaining rocuronium can stay unbound in the central compartment in patients who do not receive an adequate dose of Sugammadex…and these remaining rocuronium molecules are then free to redistribute to the peripheral compartment, then onto the neuromuscular junction leading to return of impaired neuromuscular function.

So, what does this look like clinically? We already talked about a case briefly, but the authors include 2 cases of recurarization and I will share them now. The first case is a 70 year old 71kg man with chronic renal insufficiency who was brought to the OR for a ureterectomy. During the 7 and a half hour case, the patient received 240mg rocuronium. He then received Sugammadex 200mg 87 minutes after the last 20mg dose of rocuronium. He had return of spontaneous respiration and was following verbal commands and was extubated. There was no neuromuscular monitoring. 15 minutes after he arrived at the PACU, he became apneic and required re-intubation. Monitoring at that time revealed train of four count of 3. The patient was given another 200mg dose of Sugammadex and then resumed spontaneous respirations and had no further evidence of recurarization. The second case involved an 80 year old 61kg man who was brought to the OR for open abdominal aortic aneurysm repair. He was given rocuronium 50mg for intubation and then 25mg doses of Rocuronium every 30 minutes after the first hour of the case. Once again, there was no neuromuscular monitoring. 50 minutes after the last dose of Rocuronium, the patient was given Sugammadex 200mg and then had weak spontaneous respiratory effort. He was responsive to verbal commands though and then extubated and brought to the PACU. 15 minutes later, he was apneic. He was given Sugammadex 200mg and then had improved spontaneous respiration and did not require further ventilatory support.

These cases demonstrate what happens when neuromuscular monitoring is not used and patients are not adequately reversed with Sugammadex leading to recurarization in the setting of older patients who may have been more sensitive to rocuronium due to pharmacokinetic and pharmacodynamic factors.  Some anesthesia professionals may administer higher doses of rocuronium in order to maintain a deep neuromuscular blockade to help improve operating conditions for surgery now that Sugammadex is available for rapid reversal. Caution must be taken with this approach and intraoperative neuromuscular monitoring should be used to guide timing for reversal, ideally after there is some return of spontaneous recovery, which may be 1 or 2 twitches on the post-tetanic count.

Recognition of the problem was the first step. Another important step towards improved patient safety came out in the 2019 revised JSA Guidelines for Monitoring During Anesthesia which included the following updated wording:  “Neuromuscular monitoring should be performed in patients receiving muscle relaxants and their antagonists.” The guidelines do not recommend what type of monitor to use but quantitative monitoring is preferred. Other monitors such as qualitative devices and clinical muscle function tests such as the 5-second head lift and a sustained hand grip are only able to detect train of four ratios of 0.4 or less and cannot be used to accurately determine when the patient has crossed the threshold of a train of four ratio of 0.9.

The authors report neuromuscular monitoring and availability of quantitative monitors since Japan’s national medical insurance system does not reimburse for the medical expenses of neuromuscular monitoring and the stand-alone and portable acceleromyography devices have been discontinued and are no longer for sale. The good news is that several new quantitative neuromuscular devices are no available including electromyography-based monitors, a 3-dimensional accelerometer, and monitors that include a modified blood pressure cuff with neuromuscular electrodes inside. This is especially exciting because these newer devices also have the advantages of easy calibration, simple to use and incorporation of adaptive mechanisms to compensate for postural changes while the disadvantages include newer devices that have not stood the test of time and higher cost. The authors conclude that the lack of perioperative neuromuscular monitoring has led to an increased risk of recurarization after inadequate Sugammadex dosing in Japan. Now that Sugammadex use has increased around the world, the authors acknowledge the need to warn the medical community about the risk of recurarization. Going forward, there is a need for medical device manufacturers to create neuromuscular monitors that are easy to use, safe, reliable, and affordable and there is a call to action for anesthesia professionals to use neuromuscular monitoring to guide reversal with Sugammadex so that the patient receives the appropriate dose at the right time. Stay vigilant for clinical signs of recurarization, anaphylaxis, and other postoperative complications whenever you are using muscle relaxants and reversal agents.

Well, that’s all the time we have for today! Thank you for tuning in to learn about the vast experience of Sugammadex use for reversal of neuromuscular blockade in Japan and what we can do going forward to help keep patients safe from the risk of recurarization.

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Until next time, stay vigilant so that no one shall be harmed by anesthesia care.

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