A Short Update on Sugammadex with a Special Focus on Economic Assessment of its Use in North America

Sugammadex offers significant advantages over the current anticholinesterase reversal drugs. Sugammadex used has been approved for the United Stated and for Canada since December 2015 and February 2016, respectively. The present article aims to provide a straightforward and concise review of the most recent literature describing its clinical advantages in routine use. A thorough and cost-effective evaluation has been conducted specifically for North America to determine if its price justifies its inclusion into regular patients’ care. The search examined the relevant literature from January 2013 to October 2016. The present narrative review describes how sugammadex could play a crucial role in the modern conduct of anesthesia. The particular emphasis on sugammadex cost-effective analysis performed in this article suggests that this new reversal agent should be considered for a wider use in North America.


Introduction
Worldwide, neuromuscular blockade (NMB) is reversed mostly with neostigmine, an anticholinesterase drug. However, this association of medications encompasses several threatening side effects, such as arrhythmias [1] and bronchospasms, when neostigmine outlasts the vagolytic action of the anticholinergic agents [2]. Also, neostigmine has noteworthy flaws such as a slow onset of action, as well as the impossibility to reverse deep NMB. In addition, high doses of neostigmine could trigger muscle weakness and consequently respiratory complication [3,4]. Sugammadex is a modified cyclic oligosaccharide that embraces all the characteristics of an ideal NMB reversal agent. It is a ring-shaped molecule with hydrophilic properties on its outside allowing it to be water-soluble. The inner side is hydrophobic which attracts amino-steroidal neuromuscular blocking agents (NMBA) [5]. Rapid plasmatic amino steroidal muscle relaxant encapsulation creates a concentration gradient that extracts NMBA molecules from the neuromuscular junction to shift back to the plasma. These features result in a significantly faster and safer reversal compared to standard anticholinesterase drugs [6]. Microcalorimetry tests have demonstrated that bonds with rocuronium are preserved for a longer period with a lower dissociation rate than vecuronium [7]. Consequently, rocuronium is the most common NMBA administered when sugammadex is used as a reversal agent. From its approval, sugammadex has been used in almost 60 countries, and over 15 million doses have been administered [8]. Since December 2015 and February 2016, sugammadex is available in the United-States and Canada, respectively. Thus, the present paper reviews the clinical use of sugammadex providing readers a short but comprehensive overview. A search of the PubMed database was conducted in November 2016, examining the literature during the past four years (from January 2013 to October 2016). The cut-off time for this review was chosen to assess and compile the most recent knowledge on the use, advantages, safety and economic viability of sugammadex. Then, the article focused with particular attention on the economic viability in North America simulating its use and the related cost-effectiveness in concrete clinical scenarios to determine whether its cost justifies its inclusion into routine care.
Objectives of the present review: After reading this review, the reader should be able to: 1. Prescribe the appropriate dose of sugammadex according to the depth of NMB and according to the characteristics of particular population groups.
2. Have a thorough understanding of sugammadex intraoperative and postoperative advantages. 3. Have a thorough understanding of sugammadex's safety profile. 4. Have a critical judgment on the benefit to integrate sugammadex into clinical practice not only for patients' safety purposes but also for economic advantages.

Which is The Right Dose of Sugammadex According to The Depth of The Nmb and How Long Does it Take to Fully Reverse Nmb in Comparison to Neostigmine? Moderate neuromuscular blockade (TOF count 1 to 3)
Sugammadex is also effective in reversing quickly moderate NMB defined as a TOF count of 2 [10]. In 98 patients recruited in a multicenter randomized trial with moderate levels of NMB, Blobner et al. [11] found that the mean length of time necessary to obtain a TOF ratio of 0.9 with 2.0 mgkg -1 sugammadex was 1.5 min, whereas 18.6 min were required with 50 µgkg -1 of neostigmine. Blobner and collaborators have also shown that predictability of response was greater with sugammadex than neostigmine, with 98% of sugammadex patients versus only 11% of neostigmine patients recovering to a TOF ratio of 0.9 within 5 min [11]. Interestingly, the efficacy to reverse moderate NMB does not differ whether anesthesia is maintained with halogenated agents or with propofol [12]. Sugammadex has also been shown to reverse efficiently rocuronium moderate NMB in both Caucasian and Chinese subjects [13].
Therefore, we recommend 2 mgkg -1 sugammadex to reverse moderately deep NMB (1 to 3 twitches present) in order to obtain a TOF ratio ≥ 0.9 within 2 min.

Deep neuromuscular blockade (Post-Tetanic Count=1-2)
One of the most compelling factors of sugammadex is its ability to reverse -reliably and quickly -deep NMB defined as 0 twitches after a TOF stimulation or 1 to 2 twitches after a tetanic stimulation, Post-Tetanic Count=1-2 (PTC=1-2) [9,10]. Recently, Rahe-Meyer et al. [14] enrolled patients from 10 different institutions in Germany. At the end of the surgery, 140 patients with a PTC=1-2 received randomly 4.0 mgkg -1 sugammadex or placebo. Spontaneous recovery from deep rocuronium-induced NMB is on average 40 times slower than sugammadex. Four mgkg -1 sugammadex reversed deep NMB rapidly and consistently (2 min, interquartile 1.6-2.8 min). When neostigmine is used to reverse deep NMB, a mean of 50.4 min is necessary to reach a TOF ratio of 0.9 [9]. Doses of sugammadex below 1 mg.kg-1 have been shown to be initially effective to reverse rocuronium-induced deep NMB, but lead to the gradual reappearance of the NMB in both adults [15] and children [16]. In contrast, sugammadex doses ranging from 1 to 2 mg.kg-1 have shown to reverse rocuronium-induced deep NMB with significant time variability (TOF ratio ≥ 0.9 is obtained from 1.8 to 15.2 min) [17]. At present, we recommend 4 mgkg -1 sugammadex to reverse deep NMB in order to obtain a TOF ratio ≥ 0.9 within 2 min.

Profound neuromuscular blockade (can't intubate, can't ventilate scenario)
Sugammadex is also effective for urgent reversal in emergency situations such as 'can't intubate, can't ventilate' even when a high-dose of rocuronium is administered. Chambers et al. [18] performed a systematic review and found three randomized clinical trials that compared 16 mg.kg-1 sugammadex with placebo or succinylcholine. In these trials, sugammadex was administered 3 or 5 min after 1 or 1.2 mgkg -1 rocuronium, respectively. Chambers et al. [18] concluded that after a profound NMB, recovery of neuromuscular transmission after sugammadex was markedly faster than after placebo or than spontaneous recovery from succinylcholine. Lee et al. [19] are the only ones to compare the time to recover to a TOF ratio ≥ 0.9 between the administration of 1 mgkg -1 succinylcholine and 16 mgkg -1 sugammadex administered 3 min after an intubating dose of 1.2 mgkg -1 rocuronium. Time to recovery was significantly faster for the association rocuronium-sugammadex compared with succinylcholine with 4.4 ± 0.7 vs. 7.1 ± 1.6 min, respectively. In the rocuroniumsugammadex group, 87% of the patients reached a TOF ratio of 0.9 in less than 3 min, which was shorter than in the succinylcholine group by 4 to 5 min. Although sugammadex has been shown to be rapid and efficient to reverse rocuronium-induced profound NMB, it has been reported that it could require up to 17 min to fully reverse a profound block [20]. The reason is probably related to the wide range of individual responses and receptor affinity to a single dose of rocuronium [21]. Nevertheless, it seems that there is an agreement that rapid sequence induction (RSI) performed with the rocuroniumsugammadex association could bring some advantages [22,23]. The combination is compelling especially because it does not induce fasciculations, which increase oxygen consumption during apnea [24]. It also allows regaining spontaneous ventilation on average 3 min earlier compared to succinylcholine [25]. Table 1

Considerations for Specific Population Groups Pediatric
According to a recent review, 2 mgkg -1 of sugammadex seems to be a safe dosage to reverse moderate NMB for this population [26]. A difference is that the onset time seems faster but the recovery time is similar to the adult population [27]. Sugammadex is not recommended in infants below 2 years of age [10].

Pregnant and breastfeeding women
Only one recent multicenter randomized controlled trial enrolling 240 patients undergoing a C-section has been published showing the non-inferiority of 1 mgkg -1 rocuronium for rapid-sequence induction compared with 1 mgkg -1 succinylcholine. In the rocuronium group, sugammadex was given to reverse NMB. No difference in the Apgar score between the two groups was noticed. Less resistance during laryngoscopy and a lower incidence of postoperative myalgia were found in the group receiving rocuronium and sugammadex [28]. Since there is only little oral absorption, sugammadex can be administrated safely in breastfeeding women [10]. The rocuronium-sugammadex combination has been claimed to be an advantage in parturients with neurologic disease [29]. Sugammadex is now part of the UK Obstetric Anaesthetist Association's newest algorithm for management after failed tracheal intubation as rocuronium can be fully reversed by sugammadex within 3 min instead of 9 min to reach spontaneous recovery using succinylcholine [30].

Obese patients
It is generally recommended to administer sugammadex according to the body weight [31]. In contrast, Loupec et al. [32] advocate that in morbidly obese patients, 4 mgkg -1 sugammadex using ideal body weight provides satisfactory reversal of deep rocuronium-induced NMB. To support this statement, they conducted a randomized controlled trial in 50 morbidly obese patients. They found that reversal of deep NMB occurred within 10 min in 93% (255 ± 62 sec) and in 77% (429 ± 102 sec) of the patients when they received 4 mgkg -1 or 2 mgkg -1 of sugammadex based on the ideal body weight, respectively. Objections have been raised because dosage according to the body weight could reverse NMB more rapidly, [33] but Loupec et al. claimed that longer recovery time was not clinically significant [32]. Other authors advocate that for morbidly obese patients, the total sugammadex dose could be safely reduced to the ideal body weight (IBW) + 40% [34].

Elderly patients
The time required to reach a TOF ratio of 0.9 is longer in patients older than 69 years [27]. However, this difference is not clinically significant and does not justify different dose recommendations [10].

Advantages of sugammadex when a deep NMB is performed
Maintenance of deep NMB appears to offer better postoperative pain relief and optimal surgical conditions during laparoscopic surgeries [35,36], orthopedic fracture repositioning, dislocation reduction, laparotomy, and mucosectomy [37]. However, anesthesiologists are still worried to use deep levels of NMB until the end of the surgery because of the impossibility to reverse reliably and satisfactorily such a deep NMB [38]. Deep NMB maintained by rocuronium until the end of the surgery, and reversed with sugammadex seems to be a combination that increases the quality of certain operational conditions, especially in obese patients. Table 2 summarizes the intraoperative advantages of deep NMB. Best surgical conditions  performing  deep  neuromuscular blockade   Laparoscopic  surgery,  bariatric surgery Madsen [35,36] Deep NMB until the end of the surgery orthopedic fracture repositioning, dislocation reduction, laparotomy, and mucosectomy

Intraoperative advantages Type of surgery / Patients References
Dubois et al. [37] Faster reversal than neostigmine Patients with diminished respiratory reserve (i.e. patients with obstructive lung disease, sleep apnoea and neuromuscular disease) Schaller et al. [10] Abbreviation: NMB, Neuromuscular Blockade; ENT, Ear Nose and Throat Table 2: Intraoperative advantages using sugammadex as reversal agent.

Advantages of sugammadex during the postoperative period
Although anesthesiologists believe that postoperative residual paralysis induced by non-depolarizing NMBA occurs in less than 1% of the cases [39], residual curarization is a very frequent complication that could involve up to 83% of the patients in the postoperative period even with the introduction of shorter-acting muscle relaxants [40]. Residual blockade can trigger adverse postoperative pulmonary events, pharyngeal dysfunction, the need for urgent tracheal reintubation and prolonged stay in post-anesthesia care unit (PACU) [41]. Reversal with sugammadex appears to be associated with significantly less postoperative pulmonary complications, especially in the elderly population [42]. Also, sugammadex seems to be associated with a shorter length of stay in PACU, because of a faster diaphragmatic recovery, less pain [43] and fewer episodes of PONV. Table 3 summarizes the postoperative advantages using sugammadex as a reversal agent.

Advantages of Sugammadex in Patients with Comorbidities Patients with muscular or neuromuscular disease
Patients with muscular and neuromuscular diseases could be challenging for the anesthesiologists who need to perform an endotracheal intubation to offer the best surgical conditions. The challenge is caused by the extreme sensitivity of this population to NMBAs, which could lead to an overlong period of mechanical ventilation that could trigger respiratory and cardiovascular complications and also result in death [44]. Therefore, the combination rocuronium-sugammadex seems to be a safe and reliable option for patients with myasthenia gravis, multiple sclerosis, dermatomyositis, Sjogren's syndrome, Becker muscular dystrophy, Duchene muscular dystrophy, myotonic dystrophy, spinal muscular atrophy, Strumpell-Lorrain disease, and amyotrophic lateral sclerosis [10,42,[45][46][47][48][49][50]. The rocuronium-sugammadex combination has been studied mainly in patients with myasthenia gravis. De Boer et al. [51] have published the largest case series (n=21) of patients with myasthenia gravis presenting an Osserman class II (n=13) or class III (n=8) receiving steroidal muscle relaxants followed by sugammadex. At the end of surgery, 2 or 4 mg kg -1 sugammadex were administered to reverse moderate or deep NMB, respectively. Time to recover to a TOF ratio ≥ 0.9, was 80 sec. (range 30 to 268) and 165 sec. (range 105 to 240) for moderate and deep NMB, respectively. In their case series, no patient had residual postoperative muscle paralysis and all were discharged from the PACU to the surgical ward without problem. Their results were similar to 20 other case reports describing patients with myasthenia gravis receiving the appropriate amount of sugammadex to reverse muscle paralysis found upon completion of the surgery. Only one case report described that RSI using high-dose of rocuronium followed by an adequate dose of sugammadex in a myasthenic patient is possible and should be a strategy to bear in mind for this type of population in the emergency setting [52]. In contrast, Kiss et al. [53] were the first to describe the inefficacy of a high dose of sugammadex (12 mgkg -1 ) to reverse promptly and efficiently NMB in a myasthenic patient with an Osserman score of III with a pre-endotracheal intubation TOF ratio of 0.97 receiving 30 mg of rocuronium. Unfortunately, the authors did not present the reason for the delay in recovery and no postoperative complications were presented.

Patients with liver dysfunction
Sugammadex seems to be safe and well tolerated in patients with liver dysfunction undergoing hepatic surgery as demonstrated by Fujita et al. [54]. They administered a bolus of rocuronium followed by a continuous infusion in 31 patients. In their observational study, no patients showed evidence of residual paralysis postoperatively and no adverse event related to the use of sugammadex was reported. One case report also described its safe use in a patient with acute porphyria [55]. The reason why it is safe to use it in this population is probably related to the sugammadex-rocuronium compound excretion occurring mainly via urine, thus not interacting with the liver function [7].

Patients with renal failure
The kidney excretes sugammadex rapidly and unchanged. Thus, its clearance could be delayed in patients with severe kidney failure. A prospective study has shown that 4 mgkg -1 sugammadex could be used to reverse rocuronium-induced deep NMB in patients with severe renal failure (creatinine clearance <30 mlmin -1 ) without residual postoperative NMB [56]. Nevertheless, clinicians should bear in mind that a substantial variability in the times to reach a TOF ratio of 0.9 in these patients with chronic renal failure might be observed [56]. Such variability could be explained by the kidney donor status [57]. When the transplanted kidney comes from a recently deceased donor the renal function does not recover instantly [57]. However, considering the limited number of trials and patients with severe renal impairment exposed to prolonged sugammadex-rocuronium complex, caution should be maintained in this population. A recent case report describing a patient with severe renal impairment who received 1.2 mgkg -1 rocuronium at the induction and deep NMB during surgery presented an episode of recurarization 3 h after injection of 6 mgkg -1 sugammadex and attainment of a TOF ratio of 0.9 before extubation [58]. Bellod et al. described a similar case of delayed recurarization in a patient with known chronic renal failure 2 h after arrival in the PACU, despite that the appropriate dose of sugammadex was injected at the end of surgery [59]. Bellod and colleagues managed this event successfully by administrating a second dose of sugammadex in the PACU. Postoperative neuromuscular monitoring to detect potentially delayed recurarization should be implemented in patients with renal failure throughout a prolonged postoperative period. The sugammadex-rocuronium compound has been shown to be dialyzable with a reduction of 70 % of its plasma concentration after the first session and reduced by 50% after the following sessions [22,60]. Of particular interest for patients with severe renal failure requiring a RSI, is the significantly lower increase in potassium concentration when the combination rocuronium-sugammadex is injected compared to succinylcholine [61].

Advantages of sugammadex in case of rocuroniuminduced anaphylactic shock
Anaphylaxis is a rare but life-threatening complication. Its incidence in anesthesia is estimated to range from 1 in 10000 to 1 in 20000 cases [62]. In anesthesia, the drugs inducing more frequently an anaphylactic reaction are the NMBA with the following incidence: succinylcholine (61%), atracurium (19.5%), cisatracurium (6%), vecuronium (4.5%), rocuronium (4%), pancuronium (3%), and mivacurium (2%) [63]. The incidence of anaphylaxis induced by sugammadex is significantly lower than those related to NMBA injection [64]. Via its peculiar action, sugammadex has been suggested as a novel treatment therapy to inhibit mast cells and basophils activation triggering anaphylaxis. This hypothesis was confirmed by evidence from several case reports describing hemodynamic and respiratory restoration few minutes after sugammadex administration [62]. However, a recent case report described the inefficacy of low doses of sugammadex to reverse rocuronium-induced anaphylaxis [65]. Lately, Raft et al. [66] reported that even high doses of sugammadex (14 mgkg -1 ) could be ineffective to reverse a rocuronium-induced anaphylaxis. Platt et al. [67] support the inefficacy of sugammadex to reverse rocuronium-induced anaphylaxis publishing the first case-control study on this topic describing 13 patients with a presumed rocuronium-induced anaphylaxis who received a sugammadex injection. They concluded that sugammadex does not interfere with the correction of the immune disorder caused by rocuronium but could improve the hemodynamic parameters by increasing the muscle tone thus increasing cardiac preload [67]. Platt's trial encompasses a substantial methodological flaw because there was no case to use as control [68]. Thus, further studies on that matter should be conducted to draw final conclusions looking specifically at the timing of sugammadex administration, which has been suggested to be a crucial element to gain clinical benefit [69]. In a case of an anaphylaxis reaction, conventional treatment using epinephrine and fluid loading must be the first line treatment and sugammadex as a second line might be envisioned.

Essential Knowledge to Use Sugammadex Safely Metabolism
Sugammadex and the rocuronium/sugammadex complex are watersoluble and are quickly excreted via urine [5]. The elimination half-life of sugammadex is on average 2 h in adult anesthetized patients with normal renal function. Because of its unique architecture, it has a low penetration of the blood-brain barrier and a low placenta transfer [7].

Interactions
Sugammadex possesses a positively charged quaternary nitrogen chain, which allows a strong and unique affinity for rocuronium. In contrast, both endogenous and exogenous steroidal molecules have a negligible affinity to sugammadex, because they do not have a threedimensional profile that permits strong bonds with this quaternary nitrogen chain. Consequently, affinity for cortisone, hydrocortisone, and aldosterone is 120-fold weaker than the one for rocuronium. Furthermore, affinity for atropine, verapamil, and ketamine is 400 to 700-fold lower than for rocuronium [7]. Zwiers et al. [70] analyzed the probability of the most common drugs used along with sugammadex to displace it. Among all the molecules studied, toremifene, fusidic acid, and flucloxacillin are the only molecules noticed to displace rocuronium from sugammadex. Theoretically, these molecules could generate a delay in reaching a TOF ratio of ≥ 0.9. Nonetheless, a RCT including 24 patients did not encounter residual postoperative muscle relaxation with concomitant prescription of diclofenac or flucloxacillin [71]. Gulec et al. [72] have recently conducted a randomized trial in 60 children undergoing adenotonsillectomy receiving saline or dexamethasone 0,5 mgkg -1 after induction. At the end of surgery, anesthesia was terminated, and when 2 twitches of the TOF reappeared, all patients were given 2 mgkg -1 sugammadex. There was no significant difference between groups neither in the time to recover a TOF ratio of 0.9 nor in the time to meet the extubation criteria [72]. Dexamethasone seems to decrease the effectiveness of sugammadex to reverse rocuronium-induced NMB in a dose-dependent fashion [42]. Hence, high-dose of dexamethasone used concomitantly with sugammadex should be done with caution until further research can provide more evidence. Antibiotics are known to potentiate NMB and consequently limiting the effect of the traditional anticholinesterase reversal agent. Hudson et al. [73] have conducted a study to determine whether antibiotics could reduce sugammadex's ability to reverse steroidal muscle relaxant agents. Analyzing data from 197 patients from 19 different sites, they found that antibiotics known to interfere with acetylcholine release (kanamycin, gentamicin, vancomycin, clindamycin and bacitracin) did not disturb the capacity of sugammadex (4 mgkg -1 ) to reverse NMB induced by rocuronium. Magnesium is also a factor known to inhibit neuromuscular transmission [74]. However, it seems that pre-treatment with magnesium does not alter the efficacy of the recommended dose of sugammadex after moderate and deep blockade with rocuronium [75][76][77][78]. A recent case report described the successful reversal of rocuronium using sugammadex in a patient with pre-eclampsia who received magnesium intraoperatively [79]. Finally, sugammadex may interact with hormonal contraceptive drugs via unwanted binding, potentially reducing their clinical efficacy. Thus, female patients should be informed of the reduced efficacy of hormonal contraceptives if they receive a dose of sugammadex [80]. Finally, to avoid precipitation, sugammadex should not be injected concomitantly with drugs that affect serotonin type 3 receptors (such as ondansetron), ranitidine and verapamil [60].

Hypersensitivity and Anaphylaxis
Anaphylaxis is a life-threating complication. In more than 58% of the time, the causal agent is a NMBA [81]. However, allergic anaphylaxis to sugammadex is a rare event [64]. Nonetheless, hypersensitivity is the main reason why the American Food and Drug Association raised concern and delayed approval of sugammadex [82]. In 2014, Tsur et al. [64] screened all previously reported cases on sugammadex anaphylactic reactions. They found a total of 15 probable cases of anaphylaxis to sugammadex. Anaphylaxis occurred within 5 min of sugammadex administration. None of these 15 patients who developed an allergic reaction to sugammadex died [64]. The reason why patients can develop hypersensitivity to sugammadex without previous exposure is still unknown. Tsur and colleagues hypothesized a sensitization of cyclodextrins found in foods and cosmetics [64]. To obtain the FDA approval, the company selling sugammadex sponsored a hypersensitivity trial in awake volunteers in 2014 [82]. Three hundred seventy-five individuals received an intravenous bolus of saline, 4 mg.kg-1 sugammadex or 16 mgkg -1 sugammadex. One subject met the criteria for anaphylaxis after an injection of 16 mgkg -1 sugammadex. In 2014, the same company published post-marketing data concerning 11.5 million sugammadex exposures. From these exposures, they retrieved 273 reports of anaphylaxis with 237 of 241 patients improving with conventional. By the end of 2015, after additional site inspections and sensitivity investigations, the FDA approved sugammadex [82]. In summary, the rate of anaphylactic reaction is low, and an episode can be managed with standard therapy most of the time [69,83].

Longer clotting time and increased bleeding
In a randomized, placebo-controlled, three-period cross-over trial, De Kam et al. [84] described a dose-related transient prolongation of the prothrombin time and the partial thromboplastin time in 8 healthy subjects. The same authors conducted a randomized, double-blind, placebo-controlled, four-period cross-over study and found that when healthy subjects received either unfractionated heparin or lowmolecular-weight heparin, both moderate (4 mgkg -1 ) and high (16 mgkg -1 ) doses of sugammadex did not clinically affect partial thromboplastin time nor anti-Xa activity [85]. In a prospective investigation, Raft et al. [86] looked at the effects of sugammadex administration on routine coagulation tests and bleeding. Their findings do not support that 2 or 4 mgkg -1 sugammadex is associated with a longer clotting time. Another double-blinded randomized study enrolling patients undergoing orthopedic surgery confirms that sugammadex does not increase the bleeding risk [87].

QTc prolongation
Transient prolongation of the QT interval (>500 ms) following the administration of sugammadex has been described in patients anesthetized with sevoflurane or propofol [88,89]. However, several large studies proved that sugammadex does not seem to trigger significant QT/QTc prolongation [90], even with extremely high doses of sugammadex (32 mgkg -1 ) [91]. Sugammadex does not seem to produce effects on cholinesterase, nicotinic or muscarinic receptors, consequently minimizing the risk of cardiovascular side effects. To the contrary, the association neostigmine-atropine is known to have significant cardiovascular effects and is clearly associated with significant QTc prolongation [90].

Respiratory adverse events
Negative pressure pulmonary edema is a rare complication that occurs after general anesthesia, especially after extubation in the elderly population. Suzuki et al. experienced a case of negative pressure pulmonary edema after tracheal extubation following reversal of rocuronium using sugammadex. They have attributed residual muscular blockade on the upper airway muscle associated with large inspiratory forces created by the faster respiratory muscles recovery after sugammadex injection [92]. Basaranoglu et al. [93] described an episode of respiratory distress caused by a rapid increase in chest wall rigidity after sugammadex decurarization. They attributed this event to opioid-induced chest rigidity. McGuire and Dalton reported an unexpected finding in 9 consecutive patients. They observed laryngospasms occurring two minutes after the administration of sugammadex. The laryngospasm was spontaneously reversible, and no casualties were reported [94]. Nevertheless, the clinical relevance of these findings should be elucidated with further trials.

Economic impact of sugammadex
Although no large-scale randomized study has been conducted to determine sugammadex's economic impact, recent literature gathers more and more clues that sugammadex might actually be cost effective. According to Chamber's [18] and Paton's [95] economic analysis, sugammadex cost-effectiveness relies on two concepts. The first concept is that faster recovery time can be achieved using sugammadex compared to neostigmine. The second concept is that time saving could be converted into valuable activities. Rapid NMB reversal can lower the operating room (OR) occupancy with the consequential potential to increase the OR workflow especially for short cases [96,97]. Also, by eliminating postoperative residual curarization and related pulmonary complications, sugammadex might reduce the costs related to the time necessary to discharge the patients from the PACU, which would result in a more rapid turnover between surgeries [42,[98][99][100][101].

Economic evaluation in real clinical scenario
Our hypothesis to sustain the favorable cost-effectiveness of sugammadex relies on the conversion of the time saved via a rapid NMB reversal with less postoperative complication into extra-surgical time to perform more surgical interventions. Thus, we performed an economic assessment analyzing: We based our analysis on the most recent operating time cost evaluation in Canada and United States. In Canada, the cost has been estimated, on a per-minute basis, to range from 10 to 40 $Can [102]. In the United States, it has been previously estimated to be of 2000 $US per hour (30 $US per minute) [103]. In our economic evaluation, we calculated -conservatively -the expense considering that each OR minute costs 10 $Can (or 30 $US). The price of sugammadex was calculated on the assumption that a patient has a weight of 75 kg. The cheapest combination of vials was used, and any unused drug in a vial was considered wasted. A vial with the smallest dose of sugammadex contains 200 mg and corresponds to approximately 100 $Can and 100 $US. Reversing rocuronium-induced NMB with sugammadex, we could hypothesize that the cost per case corresponds to: . We could assume that if NMB is reversed with neostigmine the total length of the procedure will take an additional 17 min (to completely reverse the blockade to a 0.9 TOF ratio) [9]. Considering an 8 h OR schedule (480 min) and assuming 20 min of turnover between two adenotonsillectomies, 8 cases could be performed using sugammadex (480 min/(40 min for surgery+20 min for turnover)=8). In contrast, only 6.2 cases could be performed using neostigmine (Total OR working hour/adenotonsillectomy conducted using neostigmine=480/ (40+17+20)=6.2). Thereby, sugammadex could be considered costeffective in short surgeries with moderate NMB (i.e. adenotonsillectomy) because it provides extra-surgical time to perform almost two more cases per day. In the United States, it could be assumed that sugammadex could also lower the daily OR cost by 716 $US (358×2).

Evaluation of both the 'value of each minute of PACU' and the 'value of each minute of hospital length of stay time saved'
Such estimation was difficult to perform because data in the literature is insufficient to determine the impact of the type of reversal agent on postoperative pulmonary complications (i.e. incidence of atelectasis, pneumonia, pulmonary edema) with the related increased cost (i.e. antibiotic therapy and the extended length of hospital stay). In addition, quantitative neuromuscular monitoring is underused in North America [105]. Thus, the association between postoperative neuromuscular recovery and the presence of residual NMB leading to postoperative complication is difficult to verify and inferences are hard to establish. However, two assumptions could be formulated. First, it could be expected that sugammadex brings potential favorable economic repercussion within the elderly population that is prone to develop postoperative pulmonary complications [99]. The latter consideration is of paramount importance bearing in mind that the elderly population will drastically increase in the near future [106]. Second, it could be assumed that administrating sugammadex routinely would force anesthesiologists to monitor the muscle relaxation depth. Hence, it could be claimed that using sugammadex, the incidence of postoperative residual curarization may lower along with the related pulmonary complications that increase patients' hospital length of stay [97].
Our economic evaluation for North America shows that sugammadex appears to be cost-effective. It seems that it allows performing a higher number of different surgical interventions accomplished under both moderate and deep NMB. It also appears that sugammadex lowers the daily OR cost for surgeries requiring deep NMB in both Canada and United States. In the United States, sugammadex could also lower the OR cost for surgeries requiring moderate NMB. Several european cost-effectiveness investigations are in-line with our estimation [95][96][97]. A recent Canadian investigation also confirmed our analysis using a discrete event simulation model specifically developed to explore the effect of sugammadex versus neostigmine on the OR efficiency and postoperative patients' outcome. The authors that have conducted this research advocate that using sugammadex to reverse moderate NMB is likely to lower the incidence of residual NMB. When it is administrated to reverse deep NMB, sugammadex is likely to increase the OR efficiency and lower the rate of postoperative residual curarization. Our analysis has several limitations; it does not take into consideration the rate of both surgery cancellation and emergency intervention. Also, the calculation of the OR time cost was based on an investigation conducted in a teaching hospital. The length of the procedure encompassing teaching time could be longer in comparison with a non-teaching hospital. Therefore, the estimation may be underestimated for a non-teaching hospital. Another limit is that reports regarding the cost-effectiveness of sugammadex on both the 'value of each minute of PACU' and 'length of hospital stay' saved are scarce and may depend on institutional habits due to the large differences in staff practice and logistics from one center to another. Finally, there is a lack of prospective large sample size conducted in North America on this topic.

Conclusions
Although more expensive than the traditional reversal agents, sugammadex shows exceptional and unique features. It is more predictable and allows much faster recovery than neostigmine for both superficial and moderate NMB. In addition, sugammadex can reverse deep NMB while neostigmine is not efficient. The sugammadex-related incidence of adverse events is very low; it can be used safely to reverse rocuronium in patients with neuromuscular disease, liver dysfunction or renal failure. However, it seems essential to routinely use quantitative neuromuscular monitoring to determine the correct dose of sugammadex. Finally, our cost-effective economic evaluation revealed that sugammadex could decrease the operating room cost allowing, concomitantly, to perform a higher number of surgical interventions within the same daily operation schedule time. Nevertheless, prospective cost-effective studies should be conducted in North America to ascertain our evaluation.