A Survey of the Society for Pediatric Anesthesia on the Use, Monitoring, and Antagonism of Neuromuscular Blockade

Debra J. Faulk, MD; Thomas M. Austin, MD, MS; James J. Thomas, MD; Kim Strupp, MD; Andrew W. Macrae, BS; Myron Yaster, MD

Disclosures

Anesth Analg. 2021;132(6):1518-1526. 

In This Article

Discussion

Our survey of SPA members revealed that, despite sugammadex not being labeled for use in pediatrics, it is commonly used among all pediatric anesthesiologists and is rapidly replacing neostigmine as the drug of choice to antagonize the effects of rocuronium and vecuronium. Furthermore, we found that sugammadex's more rapid effectiveness and better safety profile compared to neostigmine outweigh its higher cost.[1,11] The survey data revealed that how pediatric anesthesiologists block, assess, and antagonize the NMB is very dependent on years of practice. Indeed, we found that anesthesiologists who trained after the introduction of sugammadex into the American marketplace in 2015 have been profoundly impacted with respect to the use and assessment of NMBAs. These younger anesthesiologists use sugammadex as their primary NMBA reversal agent and rarely assess NMB. More experienced anesthesiologists also do not universally assess NMB. This represents a training and practice failure in the profession of pediatric anesthesiology. Finally, the common use of sugammadex in postmenarchal females and the failure to warn young women of its hormonal contraception consequences may result in unintended pregnancy.[13,17]

The appeal of sugammadex is not surprising. Unlike the cholinesterase inhibitors neostigmine and edrophonium, which inhibit the breakdown of acetylcholine in the neuromuscular junction (NMJ), sugammadex does not interfere with acetylcholinesterase receptor systems. Therefore, it does not produce the muscarinic side effects associated with other reversal medications for NMBAs, such as bradycardia, hypotension, bronchospasm, and postoperative nausea and vomiting. Sugammadex is a synthetically modified gamma-cyclodextrin, a chemical structure with a hydrophilic exterior and a hydrophobic core.[1] It was designed specifically to reverse rocuronium-induced paralysis by encapsulating rocuronium; however, its inner cavity is large enough to encapsulate other aminosteroidal NMBAs such as vecuronium, pipecuronium and, to a much lesser degree, pancuronium.[1,18,19] Its potential clinical benefits include fast and predictable reversal of any degree of block, increased patient safety, reduced incidence of residual block on recovery, and more efficient use of health care resources.[1,6,11,20]

Postoperative residual paralysis after the intraoperative use of NMBAs remains a problem and can be difficult to assess.[2,5,11] Furthermore, the extent of residual paralysis and respiratory complications in pediatrics has only recently been studied. Indeed, several investigators have reported that residual NMB in children is common and can lead to postoperative pulmonary complications, especially when high doses of NMBA are utilized.[21–23] Infants and children have also been seen to have wide variations and prolonged duration of action following administration of NMBA.[21,23] The practice of using time from last administration of NMBA or clinical signs to determine return of neuromuscular function and readiness for extubation is inadequate. Objective assessment of neuromuscular function with quantitative monitoring and appropriate reversal of NMB should be used.

In adults, the application of qualitative and quantitative neuromuscular monitoring in the operating room has been demonstrated to reduce the risk of postoperative NMB ("recurarization").[8,9] Quantitative devices, which are preferred, evaluate muscle relaxation objectively by mechanomyography, accelerometry, or electromyography in conjunction with electrical nerve stimulation and display the results as a TOF ratio on a screen.[2,9] Unfortunately, our results confirm other studies that reveal that these monitors are rarely available.[2] Furthermore, quantitative monitors are difficult to use and may be inaccurate in neonates and small infants.[24] Even in older patients, electrode placement and polarity, and stimulus intensity affect NMB assessment.[1,8,20,25] Electrode placement is particularly important. Several different muscle groups can be assessed (adductor pollicis, laryngeal, orbicularis oculi, and diaphragm), with the most clinically relevant results obtained with the adductor pollicis.[2] "Monitoring of adductor pollicis muscle, which lags the recovery of the diaphragm, will ensure that if recovery is sufficient at the thumb, the diaphragm and upper airway muscles will function normally. Monitoring TOF recovery in response to facial nerve stimulation can lead to erroneous decisions: the eyebrow muscle, the corrugator supercilii, recovers faster than the upper airway or the adductor pollicis muscles."[8] Unfortunately, we found that more than half of the respondents chose a site of convenience or believed that the preferred anatomic site for NMB assessment using TOF did not matter (Table 3).

On the contrary, 80% of respondents have access to qualitative devices. These devices are the most commonly used but are also the most prone to error.[2,9] Qualitative devices deliver a stimulus to a peripheral nerve, and the anesthesia practitioner must visually or tactilely judge the muscle's response.[2,9] Hence, it is a subjective and inaccurate method of assessment.[26] Our survey results, similar to those of others, suggest that despite their availability, these monitors are increasingly being disregarded when sugammadex is the reversal agent.[7,27] Subjective clinical signs (such as the 5-second head lift or sustained handgrip) and clinical tests (such as tidal volume and vital capacity) are ineffective at assessing the incidence of residual NMB and should be discouraged. They do not guarantee complete resolution of NMB and no longer have a place as the sole determinant of adequate recovery of neuromuscular function.[9,27] Finally, the failure to assess NMB with either a qualitative or quantitative device has important implications in terms of sugammadex dosing. In adults, 4 mg/kg is the recommended dose for reversal of deep NMB (no twitch response to TOF and recovery of twitch response to 1–2 posttetanic counts), while 2 mg/kg is the recommended dose for a "shallow block" (reappearance of the second twitch to TOF stimulation).[12] Although there are no US FDA dosing guidelines for pediatrics, there are European guidelines that require an assessment of NMB.[28]

Thus, our data suggest that pediatric anesthesiologists are "flying blind" and that use of neuromuscular monitoring devices is becoming increasingly rare, particularly by practitioners with <5 years of experience who received training after sugammadex's introduction. Furthermore, many practitioners are not routinely using the adductor pollicis when they are assessing NMB. These findings have enormous training and patient safety implications going forward.

Finally, although sugammadex has fewer side effects than cholinesterase inhibitors, it is not devoid of problems. The most serious are anaphylactic reactions, including bronchospasm, bradycardia, and asystole, and its potential to reduce the effectiveness of hormonal contraceptives and increase the risk of unintended pregnancy.[13,17,29,30] Our survey results reveal that more than half of respondents use sugammadex in postmenarchal patients and that those who trained after its introduction are more likely to do so. Additionally, almost 40% of the pediatric anesthesiologists in our survey who use sugammadex in this patient population stated that they do not discuss its potential interference with hormonal contraception preoperatively.

This risk in the adolescent female population cannot be overstated. Even with appropriate counseling, and assuming that hormonal contraceptives are taken reliably by these patients, a 4 mg/kg dose of sugammadex may be equivalent to a 12-hour delay in contraceptive dosing.[31] According to the Centers for Disease Control and Prevention, 2018 saw an encouraging decline in numbers of sexually active teens and the lowest reported teen birth rates on record.[32] However, the 2018 Youth Risk Behavior Survey[33] also revealed a trend toward increasing utilization of hormonal contraception and decreasing use of barrier methods among sexually active teens between the ages of 15 and 19 years . Ultimately, we cannot ignore the possibility that adolescent girls using hormonal contraceptives may face significant barriers to finding alternative means of contraception. Therefore, we should consider whether the use of neostigmine is more appropriate in these patients. As such, the concern for anesthesiologists entering practice without the appropriate knowledge of how to assess NMB appropriately may have huge implications for the future of public health.

Interestingly, in a letter to the editor, Corda and Robards[34] point out that other commonly administered perioperative drugs such as antibiotics also interfere with oral contraceptives (and cause anaphylaxis) and suggest that a more general statement about oral contraception should be provided to patients when obtaining consent. They suggest stating "You may receive medications during your anesthetic that could interfere with the effectiveness of oral contraceptives. If you are using oral contraceptives, consider alternative methods of birth control for 7 days following your anesthetic."[34] Thus, we recommend development of a robust system of education and counseling in all perioperative postmenarchal pediatric patients to explain the risk of medication interactions with hormonal contraception and the need for alternative methods of contraception. We also suggest that this information be documented in the medical record for medical-legal purposes.

Sugammadex is hardly the only drug used in pediatric practice "off label."[35,36] Off label use is defined as "the unauthorized use of a drug for a purpose other than that approved by the US Food and Drug Administration (US FDA)." In 1979, the US FDA began requiring that specific precautions with regard to usage in pediatric patients be included on product package inserts. That same year, regulations were enacted that required any statement on pediatric use of drugs to be based on substantial evidence unless a waiver was granted by the US FDA. Subsequently, the percentage of medications listed in the Physician's Desk Reference that had either no indication for pediatric use or age-specific limitations actually increased from 78% in 1971 to 81% in 1991.[35] To remedy this situation, the US FDA has instituted multiple initiatives and regulations since 1994, including the Pediatric Rule for Labeling, the US FDA Modernization Act of 1997, the Best Pharmaceuticals for Children Act, the Pediatric Research in Equity Act, and the 2007 US FDA Amendments Act.[37–39] As a result of these initiatives, many drug labels have been revised to include new pediatric information.[35] We are aware of several clinical trials to relabel sugammadex for pediatric use and hope that these changes will occur in the near future.

This study has many of the limitations associated with online surveys. Although 419 pediatric anesthesiologists responded to the questionnaire, this number represents only 13% of potential respondents, a response rate that is consistent with survey research.[40] A low response rate is a potential source of bias and is only representative of those who replied. In addition, because the physician anesthesiologists surveyed practice primarily at American medical institutions and belong to SPA, our results may not be reflective of physicians in training, nurse anesthetists, or practices in other countries, thereby limiting the generalizability of our findings. On the contrary, the large survey sample size ensured that the demographic profile of survey respondents reflected the survey population and provided a sufficiently large data set for analysis. Additionally, as with all survey studies, respondents may not be 100% truthful in their responses and may not have carefully read the questions or thought through their responses before answering. Lastly, trainees were not separated between fellows and residents in the survey and this differentiation would influence their knowledge of sugammadex and NMB monitoring in the pediatric population.

In conclusion, we found that even though sugammadex is not labeled for use in pediatrics, its use is common among SPA members and rapidly replacing neostigmine as the drug of choice to antagonize the effects of rocuronium and vecuronium. Furthermore, we found that how the NMJ is blocked and antagonized, and how NMB is assessed is very dependent on years of practice and that anesthesiologists who primarily use sugammadex rarely assess NMB. Finally, the common use of sugammadex in postmenarchal females and the failure to warn young women of its hormonal contraception consequences may risk unintended pregnancies. This trend in preference for sugammadex, indifference toward monitoring of NMB, and disregard for potential drug-drug interactions with hormonal contraceptives may create a generation of anesthesiologists who are ill-prepared to utilize neostigmine when it may be more appropriate, increasing risks to patient safety and public health.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....