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EDITORIAL
Year : 2023 | Volume
: 24
| Issue : 1 | Page : 1-3
Sugammadex: A disruptive innovation but will it stay?
Manila Singh1, Swati Chhabra2
1 Department of Cardiothoracic Anesthesiology, Cleveland Clinic, Cleveland, OH, USA
2 Department of Anesthesiology, AIIMS, Jodhpur, Rajasthan, India
Correspondence Address:
Dr. Manila Singh
Department of Cardiothoracic Anesthesiology, Cleveland Clinic, Cleveland, OH
USA
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/TheIAForum.TheIAForum_60_23
How to cite this article:In March 1999, the first batch of Org 25,969 was produced, which we now know as sugammadex. Shortly after its first study in healthy human volunteers in 2005, it was approved for use by the European Union in 2008 and by the U.S. Food and Drug Administration (US FDA) in 2015. A modified gamma-cyclodextrin, it selectively binds to steroidal neuromuscular blocking agents (NMBAs), specifically rocuronium, and with less affinity to vecuronium and pancuronium. The biggest competitor for sugammadex is and will be neostigmine, an anticholinesterase drug used ubiquitously since 1931 to reverse neuromuscular (NM) blockade. It does have the advantages of being a relatively cheap and familiar medication to most anesthesiologists and its ability to reverse all NMBAs. The problem with neostigmine, however, lies in its mechanism of action. By increasing the acetylcholine numbers at the NM junction, it can only act when muscle recovery from NMBAs has already started. Compared to this, sugammadex completely binds with rocuronium with more affinity than ach has for its receptors at the NM junction. This characteristic gives sugammadex the ability to maintain deeper levels of muscle relaxation with a train of four (TOF) count of 0 and posttitanic count of 1–2 till the very end of surgery. Even moderate levels of TOF count of 1–2 become challenging if reversal with neostigmine is planned, given the surgical time is unpredictable more often than not.
Despite being ineffective in reversing benzylisoquinolinium NMBAs, the enhanced efficacy and safety profile of sugammadex and the speed and completeness of recovery from more profound levels of NM blockade in patients paralyzed with rocuronium makes it an ideal reversal agent. Sugammadex compared to neostigmine, completely reverses NM blockade with rocuronium due to direct action and 1:1 binding with rocuronium molecule. A Cochrane review by Hristovska et al. demonstrated that at a dose of 2 mg/kg, sugammadex reverses 6.6 times faster than 0.05 mg/kg of neostigmine from moderate levels of NM blockade. At 4 mg/kg, it reverses 16.8 times more rapidly than neostigmine from deep levels of NM blockade.[1]
Side effects of neostigmine are those of any anticholinesterase by muscarinic stimulation and require anticholinergic agents such as glycopyrrolate or atropine to combat those. This property makes its use in some instances, such as patients with obstructive lung diseases and hyperreactive airways, become risky. The biggest issue with sugammadex, which led to delayed FDA approval, was the initial concern over reports of anaphylaxis. It was demonstrated later that anaphylaxis has an incidence of 0.024%, occurring more frequently at higher doses, which can be treated with routine measures.[2] Other side effects are headaches, bradycardia, nausea, vomiting, transient increases in partial thromboplastin time, and interference with hormonal contraception.
A recent focus in anesthesiology has been postoperative pulmonary complications (POPCs) after general anesthesia (GA). This complication, in a large number of cases, maybe a by-product of muscle relaxant use itself, as demonstrated by Kirmeier et al., 2019 in the POPULAR study.[3] Schaefer et al. has shown similar findings using succinylcholine alone or in conjunction with other N-methyl-D-aspartate (NMDA).[4] Higher doses of succinylcholine seem to increase the incidence of POPC to a greater deal when compared with low doses. Although it is intuitive to think that muscle weakness from NMBA use during GA can lead to adverse respiratory outcomes, the evidence is conflicting about reversal agents. The POPULAR study, a multicenter prospective observational cohort study done across 211 hospitals across 28 European countries, suggested no difference in POPC using either sugammadex or neostigmine. Shortly after, Kheterpal et al. 2020 in the STRONGER study, a multicenter perioperative outcomes group study done across 12 US hospitals, demonstrated a significant reduction in the risk of POPC by 30%.[5] The STRONGER study group also showed a 47% reduced risk of pneumonia and a 55% reduction in risk of respiratory failure with sugammadex use compared to neostigmine. These findings were also demonstrated in a subgroup analysis of older, high-risk patients undergoing prolonged elective surgery, from the same population, in the STIL-STRONGER study.[6] The POPULAR study had a large patient registry of 22,803 patients. Still, less than half of the patients were administered any reversal agents, and <2000 patients received sugammadex, limiting meaningful matching of patients and surgical factors for drawing conclusions. This contrasts with the STRONGER study, where over 20,000 patients received sugammadex. Another difference in the studies was in the definition of a pulmonary complication. For the POPULAR group, it was primarily mild, defined by the oxygen requirement to maintain oxygen saturation above 90% by pulse oximetry. At the same time, the STRONGER study focused on pneumonia and reintubation. The results of STRONGER and STIL-STRONGER are promising but have been criticized for lack of NM monitoring in most cases, nonuniformity in the definition of POPC, attrition, and selection biases. Without NM monitoring, the dosage and timing of administration of NMBA reversal agents are questionable. As a result, neostigmine cannot be blamed for the improper administration of NMBAs and reversal agents. Leslie et al. 2020 did a feasibility pilot study and found that conducting a study without limitations that STRONGER has, is feasible, opening pathways for further research on this topic.[7] Although more pragmatic prospective randomized clinical trials are needed to corroborate the findings, the abovementioned studies give us a foundation to base our practice on.
Monetary concerns about sugammadex are, at present, the most significant deterrent to its use in most parts of the world. In the US, a 2 mg/kg dose cost, as per Federal Supply Schedule, is 93$, and 4 mg/kg costs 171$. This trend is similar in other parts of the Western world. In India, sugammadex was launched in April 2022, and the market and hospital landing prices for a 200 mg vial are 2340 Indian rupees (INR) and 1500 INR, respectively. A 500 mg vial is priced at 5380 INR, with a landing price of 3100 INR. In contrast, prices for neostigmine and glycopyrrolate for moderate NM blockade reversal are 21$ in the US and considerably lower in India. Zaouter et al. 2017 showed that sugammadex could lead to cost savings where OR times translate to productivity.[8] Hurford et al. determined that sugammadex can lead to cost savings in a health-care system where OR time is valued at $8.6/min.[9] By reducing the risk of POPC and unplanned admissions and readmissions, the cost savings could be projected to have an even more significant impact. It is, therefore, advised to be wary of the individual dosage cost and look at the bigger picture.
Usage of the sugammadex is very variable across the world, mainly secondary to its cost and availability. In some places, the use is so prevalent in GA cases with a planned postoperative reversal that planning to use any relaxant other than rocuronium poses a new problem, namely, the provider not being familiar with the routine use of other NMBAs. In some cases, the easy availability of meds such as atracurium is hampered due to problems with the demand–supply balance. Due to low demand, the cost of maintaining a cold chain for supply is no longer feasible.
So, is sugammadex the holy grail and disruptive enough to cause a paradigm shift in the type of NMBAs used? I do not believe that is going to happen anytime soon. There are many barriers to more rampant usage of this wonder drug. For an economy like ours, it is mainly financial constraints. Although not worrying about recent dosing of NMBAs at the end of surgeries is a lucrative possibility with sugammadex, it should not replace NM monitoring, and choice of reversal agent should be made and dosage determined on a case-to-case basis. As suggested in a subanalysis of POPULAR group extubation after TOF ratio of 0.95 rather than 0.90 is safer and, sugammadex is perhaps a better agent when the complete reversal is required rapidly and, from deeper levels of NM blockade. With continued research for newer NMBAs, we might achieve the ideal NMDA, e.g., chlorofumarates which can be broken down in plasma and do not require any reversal.[9] Another alternative is having a universally applicable, cost-effective reversal agent such as Calabadion 1 and 2, human trial results for which are awaited. Till that happens, we should maintain our skills with and supplies of the currently available NMBAs[10] and neostigmine, and not use sugammadex exclusively.
References
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