Year : 2010  |  Volume : 13  |  Issue : 3  |  Page : 206--216

Sugammadex - A short review and clinical recommendations for the cardiac anesthesiologist


Thomas M Hemmerling1, Cedrick Zaouter1, Goetz Geldner2, Dirk Nauheimer2,  
1 Department of Anesthesia, McGill University, Montreal, Canada
2 Department of Anesthesia, Ludwigsburg Hospital, University Heidelberg, Germany

Correspondence Address:
Thomas M Hemmerling
NRG Laboratory, Montreal General Hospital, 1650 Cedar Avenue, Montreal, H3G 1B7
Canada

Abstract

This review outlines the basic pharmacodynamic and pharmacokinetic properties of sugammadex for the cardiac anesthesiologist. It describes the different clinical scenarios when sugammadex can be used during cardiac surgery and gives clinical recommendations. Sugammadex is a unique reversal drug that binds a chemical complex with rocuronium and vecuronium, by which the neuromuscular blockade is quickly reversed. It is free of any clinical side-effects and doses of 2 mg/kg or more reliably reverse neuromuscular blockade within 5-15 min, depending on the depth of the neuromuscular blockade. Doses below 2 mg/kg should be avoided at any time because of the inherent risk of recurarization. Sugammadex should not replace good clinical practice - titration of neuromuscular blocking drugs to clinical needs and objective monitoring of neuromuscular blockade in the operating room or intensive care unit. Neuromuscular transmission should be determined in all patients before sugammadex is considered and 5 min after its administration to ensure that extubation is performed with normal neuromuscular transmission.



How to cite this article:
Hemmerling TM, Zaouter C, Geldner G, Nauheimer D. Sugammadex - A short review and clinical recommendations for the cardiac anesthesiologist.Ann Card Anaesth 2010;13:206-216


How to cite this URL:
Hemmerling TM, Zaouter C, Geldner G, Nauheimer D. Sugammadex - A short review and clinical recommendations for the cardiac anesthesiologist. Ann Card Anaesth [serial online] 2010 [cited 2019 Jul 21 ];13:206-216
Available from: http://www.annals.in/text.asp?2010/13/3/206/69052


Full Text

The ideal reversal agent should have a fast onset; it should be efficient at any time, even soon after curarization of the patient; it should be able to provide complete reversal either for light or profound block; it should have a longer half-life than the neuromuscular-blocking agent; and, it should be free of any side-effects. Current drugs used to reverse neuromuscular block are not ideal and possess many side-effects, but sugammadex is very close to be the ideal reversal agent.

 Pharmacodynamic Property



Sugammadex is a modified cyclic oligosaccharide, synthesized with 1-4 glycosyl bonds made using cyclodextrin glycosyltransferase. This molecule, a g-cyclodextrin, is characterized by its unique tridimensional structure [[Figure 1]; http://commons.wikimedia.org/wiki/File: Sugammadex_sodium_3D_front_view.png]. It is composed of a hydrophobic core with peripheral hydrophilic chains. Its singular structure allows aminosteroidal nondepolarizing neuromuscular blocking drugs (NMBDs) to get trapped inside. The negative charges of the external chains maintain the cavity open and the core, with Van Der Waals forces, thermodynamic bonds and hydrophobic interactions, creates a 1-1 ratio complex with very tight bonds between the NMBDs and the reversal agent. [1] This latter complex is water soluble and can be easily excreted via urine. [2] Because of its singular architecture, it has a low penetration of the blood-brain barrier and a low placenta transfer. [3] It has been demonstrated using isothermal titration microcalorimetry that sugammadex can reverse rocuronium and vecuronium with high affinity and pancuronium with low affinity. It has also been shown using the same technique that the complex sugammadex-rocuronium maintains a high association rate with a low dissociation rate. For instance, only one complex sugammadex-rocuronium dissociates for every 25,000,000 complexes formed. [1] The affinity with rocuronium is greater than that with vecuronium. {Figure 1}

Both endogenous and exogenous steroidal molecules have a lower affinity to sugammadex because they lack the positively charged quaternary nitrogen that rocuronium and vecuronium exhibit, enabling tight bounds and thus high affinity with sugammadex. Therefore, the affinity of sugammadex for narcotics and intravenous anesthetics is negligibly small. [2]

Because of its great affinity with rocuronium, sugammadex is more commonly administrated in association with this latter one.

 Mechanism of Action:Concentration Gradient



Sugammadex incapsulates rocuronium, reducing its free plasma concentration, which leads to the removal of NMBDs from the neuromuscular joints to the central compartment through a concentration gradient effect [Figure 2]. [4],[5] {Figure 2}

 Profound Block



In order to obtain adequate neuromuscular blockade for a rapid sequence induction (RSI), succinylcholine is the neuromuscular blocking agent still most widely used: its onset of paralysis is short (45-60 s), very predictable with little interindividual variability and short duration of paralysis (3-5 min). [6] Succinylcholine, however, is associated with several adverse effects, such as hyperkalaemia, bradycardia, histamine release, partial upper airway obstruction, increased intracranial, intraocular and intragastric pressures, prolonged paralysis related to acetylcholinesterase deficiency and also malignant hyperthermia. Using a nondepolarizing blocking agent, such as rocuronium, with a short onset of action and a medium half-life can achieve good intubation conditions after a similarly short time, but is associated with a longer neuromuscular block. Recovery from a profound block cannot be attained with acetylcholinesterase inhibitors. [7]

High doses of sugammadex (16 mg/kg) can rapidly reverse even very profound blocks induced by high doses of rocuronium (1.2 mg/kg). Naguib et al. have demonstrated that recovery to the Train-of-Four (TOF) - ratio of 0.9 requires a shorter length when sugammadex is administrated subsequently to rocuronium compared with spontaneous recovery after the administration of succinylcholine. [2]

 Drug Interactions



Several clinical studies have looked at the possible drug interactions using simulation or modeling and in vitro data. [3] Toremifene, a selective estrogen receptor modulator used for advanced breast cancer, can delay the reversal by displacing the formation of the rocuronium-sugammadex complex. Sugammadex can theoretically bind with contraceptive steroids (combined or progesterone only). Moreover, rocuronium bound to sugammadex can be displaced by the administration of fusidic acid or high dose of flucoxacillin. Repetitive neuromuscular monitoring for reoccurrence of curarization is recommended. [3] Sugammadex does not alter laboratory tests in general, but some modification of the serum progesterone assay and of the coagulation parameters has been described. [3]

 Pharmacokinetic Property



0The pharmacokinetic properties of sugammadex have been evaluated in phase I, [5] phase II [8],[9] and phase III studies. [10]

Many phase II trials have described the dose-dependent effectiveness of Sugammadex. [8],[9],[11],[12],[13] Administrated as intravenous bolus with a dosage ranging from 0.1 to 8 mg/kg, Gijsenbergh et al.[5] have demonstrated the linear pharmacokinetic properties and have described a volume distribution of approximately 18 L, with the volume distribution at steady state (Vdss) estimated to range from 11 to 14 L (0.16-0.20 L/kg). [3] Sugammadex does not bind to plasma proteins or erythrocytes. [5],[8] It does not produce any metabolites and most of it is excreted in an unchanged form via urine within 24 h. An insignificant part is excreted via feces or in expired air (0.02%). [3] In healthy adults, the plasma clearance of sugammadex ranges from 84 to 138 ml/min. [14]

 Sugammadex-Rocuronium Complex



Rocuronium is eliminated through both biliary (>75%) and renal excretion (26%). [15] When sugammadex is administrated to reverse rocuronium, the plasma concentration of this latter increases - bound to the reversal agent - in a dose-dependent fashion. The sugammadex-rocuronium complex is mainly excreted via urine (65-97%). [3],[16] It has been demonstrated that when rocuronium is bound to sugammadex, its excretion in the urine increases from two- to three-fold within the first 24 h in healthy adults [5] and in surgical patients. [8]

 Safety



The sugammadex-rocuronium complex is inert and therefore does not cause any muscarinic effect. In patients with severe heart disease undergoing noncardiac surgery, sugammadex does not have any hemodynamic effects nor does it cause any prolongation of QT interval. [17] The administration of rocuronium followed by sugammadex for an RSI does not affect the genioglossus muscle activity or any partial upper airway obstruction, as may be observed with succinylcholine. [18]

The safety profile is still not well established in pediatric populations and in parturients. It seems that hydroxy apatite, present in the inorganic tissue of the bone and the teeth, can bind reversibly to sugammadex. The retention can occur at or adjacent to sites of active bone formation. However, in juvenile animal models, bone growth and development appear not to be affected even by very high doses. Other investigations on young rats suggest that repetitive high doses of sugammadex can lead to a whitish discoloration of the incisor and molar. The dose of sugammadex used for those trials was higher than the exposure at the clinical dose of 4 mg/kg. These findings suggest that more clinical investigations are needed before its use in the pediatric population. [3] Compared with placebo, sugammadex presents the same incidence (1-10%) of adverse effects, such as coughing, grimacing or suckling on the tracheal tube. Because of some concerns on hypersensitivity and allergic reactions, the United States Food and Drug Administration has not yet approved sugammadex. [19]

 Special Populations



Patients with severe renal impairment

The clearance of sugammadex is reduced in patients with a creatinine clearance below 30 ml/min by 17-fold and the elimination half-life is increased by 15 fold compared with patients with any renal impairment. Nevertheless, the efficacy of sugammadex is not altered and no block reoccurrence has been observed. [10] Others studies have not demonstrated a consistency in decreasing the plasma concentration of sugammadex in patients with severe renal impairment or in those needing dialysis. [2],[20] Therefore, it is recommended to avoid its use in such patients.

Patients with hepatic impairment

The sugammadex-rocuronium complex is not eliminated by hepatic metabolism; therefore, hepatic impairment does not influence its excretion. However, patients with hepatic failure may have higher plasma rocuronium levels.

Patients in the intensive care unit (ICU)

The pharmacokinetic properties of patients admitted in the ICU have not been studied yet.

Elderly patients

Plasma clearance, Vdss and terminal elimination half-life were homogeneous in patients over 75 years with normal renal function (creatinine clearance of >100 ml/min) compared with patients of 40 years without renal failure. [3]

Pediatric patients

The variations observed in the plasma of sugammadex are analogous to those seen in adult patients. [21] Plasma clearance, Vdss and terminal elimination half-life increase with age. There is no clinical trial in children below 2 years.

Sex, race and body weight

Gender, race or body weight do not affect sugammadex or sugammadex-rocuronium complex clearance. [3]

Summary of animal and human trials

Animal findings

The pharmacodynamics of sugammadex and related cyclodextrins have been examined using isothermal titration microcalorimetry. Nonclinical studies using in vitro techniques (tissue bath studies) and in vivo methods (muscle contraction in anesthetized animals) were performed to investigate the pharmacodynamics and drug-drug interactions. [1] The potency, efficacy and selectivity of sugammadex have been clearly demonstrated in both in vitro and in vivo essays.

The first in vitro testing of the potency of natural cyclodextrins to reverse rocuronium-induced neuromuscular blockade was performed in isolated mice hemidiaphragm. The correlation between cavity size of the cyclodextrins (a-, ß- and μ-cyclodextrin) and their reversal activity was demonstrated [Table 1].{Table 1}

The effect of sugammadex was studied in a large number of in vitro preparations, containing its interactions to receptors, uptake and enzyme systems. In vitro studies in mouse hemidiaphragm, mouse vas deferens, guinea pig right atrium, rat aorta, rat iliac artery and guinea pig bronchus showed that sugammadex does not interact with endogenous neurotransmitters or exogenous agonists added to these preparations. It also demonstrated that sugammadex had no interactions to receptors, enzyme and uptake mechanisms. [22]

To prove the complex formation of rocuronium and μ-cyclodextrin (Org 25969) in vivo, experiments in female Rhesus monkeys at Radbound University in Nijmegen in 2002 and in guinea pigs at Organon Laboratories in 2003 were performed. [1],[4] Based on these findings, the concept that the reversal activity of sugammadex depends on encapsulation and removal of rocuronium molecules from the nicotinic receptors to the central compartment was confirmed. The selectivity of sugammadex specific for steroidal NMBDs was studied in guinea pigs and primates as well. [22],[23] During the in vivo experiments to determine the reversal effect of sugammadex in anesthetized animals, blood pressure and heart rate were continuously monitored. No changes in arterial blood pressure and heart rate were observed after the intravenous application of sugammadex [Table 2].{Table 2}

To clarify the pharmocokinetic characteristics, such as metabolism, excretion and toxicity, further in vivo animal models were designed. Epemolu et al. demonstrated the excretion of the sugammadex-rocuronium complex via the kidneys in guinea pigs. [4] Even animals with renal dysfunction presented fast and complete reversal of neuromuscular blockade. [22],[24]

Upon intravenous administration, sugammadex is characterized by rapid distribution in a low-distribution volume, reflecting the extracellular water compartment. In all preclinical species studied, the systemic exposure generally increased proportional to the applied dose, with no significant differences between the gender and between single and multiple dosing. Metabolism is not a major route of clearance, and sugammadex is rapidly excreted in urine at a rate approximating the glomerular filtrating rate (Trial 19.4.107. Open, non randomized, single center trial to determine the excretion balance, metabolism profile and pharmacokinetics of Org 25969 after intravenous dose of (14C)-labeled Org 25969. Clinical trial report).

De Boer performed pharamcodynamic investigations in Rhesus monkeys to demonstrate the time course and duration of action or half-life of sugammadex as well as the dose-response relationship. [25] In contrast to acetylcholinesterase inhibitors, the reversal of profound neuromuscular blockade immediately after the administration of rocuronium could be demonstrated without any cardiovascular effects in Rhesus monkeys. [26] At high concentrations in vitro (0.15-1.5 mM), sugammadex induced a slight increase in the action potential duration and a slight hERG channel inhibition. However, these effects are considered a nonspecific disturbance of the electrophysiological properties of these in vitro systems, and a wide safety margin is present.

In all preclinical animal in vivo experiments, sugammadex showed a rapid onset, with a short time to peak effect, a faster recovery than acetylcholinesterase inhibitors and no adverse side-effects. [23] The findings of these in vivo animal studies made an extrapolation to human situation very likely.

Human studies

In 2005, the first phase I study was published. In this study, 29 healthy male volunteers received a sugammadex dose of 0.1-8.0 mg/kg for safety and efficacy investigations. This study reported the well-tolerated administration of sugammadex for reversing the neuromuscular block induced by rocuronium in humans for the first time. [5]

The efficacy and safety of sugammadex in the reversal of rocuronium-induced neuromuscular blockades were evaluated in 30 phase I-III studies. A total of 2,054 subjects were exposed to sugammadex. Nineteen hundred and twenty-six patients received sugammadex after the administration of a neuromuscular blocking drug (rocuronium or vecuronium). The dose administered ranged between 2.0 and 32 mg/kg. Most subjects received sugammadex at a dose of 2.0 or 4.0 mg/kg. These clinical evaluations led to the dose-effect relationship, which recommends that a dose range of 2.0-16.0 mg/kg, depending on the level of neuromuscular block, leads to a reversal of moderate block (T2; 2.0 mg/kg), reversal of more profound block (posttetanic count [PTC] 1-2; 4.0 mg/kg) and for a rapid rescue reversal at an early stage of neuromuscular block (16.0 mg/kg) [Table 3]. [11],[13],[21],[26],[27],[28] The majority of clinical studies investigated the efficacy of sugammadex against the neuromuscular block induced by rocuronium. {Table 3}

Phase-I trials

Seven phase-I studies were performed. In six of the seven trials, the pharmacokinetic profile of sugammadex was investigated when sugammadex was administered alone, in healthy volunteers who did not receive anesthesia. Only in part 2 of clinical trial 19.4.101 did volunteers receive sugammadex for the reversal of the neuromuscular blockade induced by rocuronium. Except trial 19.4.107, all phase-I trials were randomized, double-blind and cross-over trials. In all phase-I trials, 260 adult healthy volunteers received a single dose of sugammadex.

Gijsenbergh et al. investigated the first exposure of sugammadex in humans (19.4.101). [5] The trial was divided into two parts and included 29 subjects. In part 1, 19 subjects were randomized and treated with a single dose of sugammadex 0.1 mg/kg ranging up to 8.0 mg/kg or placebo application. In part 2, 10 randomized subjects under general anesthesia received sugammadex 0.1-8.0 mg/kg after the application of 0.6 mg/kg of rocuronium. One subject participating in part 1 described the occurrence of taste sensations for 43 min after the injection of 4.0 mg/kg of sugammadex. Other subjects had self-limiting parosmia of about 2 min, dry mouth sensations, changed temperature and coughing. In eight subjects, a prolonged QT interval (>450 ms) was observed. Of note, five of the eight subjects with prolonged QT interval were documented after placebo application.

Peeters et al. administered (trial 19.4.106) high doses of up to 96 mg/kg of sugammadex in 13 healthy male and female volunteers. Intravenous high-dose application of sugammadex was safe and was well tolerated. No gender effects were noted. Across trials and dose groups (1.0-96 mg/kg), sugammadex was found to distribute into the extracellular water of the body and did not bind to plasma proteins or erythrocytes.

Cammu et al. investigated, in trial 19.4.108, the safety of the simultaneous administration of sugammadex (16.0-32.0 mg/kg) with either rocuronium (1.2 mg/kg) or vecuronium (0.1 mg/kg) in 12 healthy volunteers. [29] The doses were well tolerated. This study demonstrated that the dose of rocuronium and vecuronium in plasma decreases faster than that of sugammadex.

Adverse events were documented in subjects in 19.4.105, 19.4.106, 19.4.108 and 19.4.109. Headache, nausea, dry mouth or hypersensitivity (following the application of 32 mg/kg of sugammadex) were noted to be possibly related to the administration of sugammadex.

Phase-II trials

Phase-II consists of 12 studies that included 866 subjects.

Six clinical trials investigated the "Routine reversal" of rocuronium- and vecuronium-induced neuromuscular blockade at the reappearance of the second twitch (19.4.201, 19.4.203, 19.4.207, 19.4.208A, 19.4.208B, 19.4.210). In trials 19.4.201, 19.4.207 and 19.4.210, the neuromuscular blockade was induced by the intubating dose of rocuronium only (0.6 mg/kg), while in 19.4.208 A/B, additional administrations of rocuronium were allowed. Three trials performed the sugammadex administration at the reappearance of T2 of vecuronium-induced neuromuscular block (19.4.207, 19.4.208A, 19.4.208B).

They found that the mean recovery time decreased from 60 min at spontaneous recovery (after placebo administration) to 1.6 min after a dose of 2.0 mg/kg of sugammadex to the TOF ratio of 0.9. Doubling the dose from 2.0 to 4.0 mg/kg resulted in a small further reduction of only 0.2 min in the overall mean recovery time, from 1.6 to 1.4 min. [8],[12],[30],[31] The mean recovery time to TOF 0.9 after the application of 2.0 mg/kg of sugammadex at T2 following vecuronium was longer than the mean recovery time of the same dose of sugammadex at T2 following rocuronium (2.8 vs. 1.6 min). Nevertheless, the reduction in recovery times obtained with 2.0 mg/kg of sugammadex compared with spontaneous recovery can be considered as clinically significant for rocuronium as well as for vecuronium [Table 4]. [9] {Table 4}

Only Shields et al. studied (19.4.203) the 6.0 mg/kg dose. Thirty adult patients received rocuronium to maintain a deep block at a level of less <10 PTC <10 during propofol-nitrous oxide-opioid anesthesia. At the recovery of T2, volunteers received different doses of sugammadex (0.5-6.0 mg/kg). The mean recovery time to a TOF ratio of 0.9 decreased from 6 min 49 s in the group receiving sugammadex 0.5 mg/kg to 1 min 22 s in the 4.0 mg/kg group. The observed recovery time after the dose of 6.0 mg/kg was unexpectedly longer than the observed recovery times after 2.0-4.0 mg/kg of sugammadex. There was no explanation found for this outlaying result. [32] The conclusion of the authors was that the administration of sugammadex was at the reappearance of T2, which is most effective at a dose of 2.0-4.0 mg/kg [Table 5].{Table 5}

Sugammadex for the reversal of a "deep or profound" neuromuscular blockade at PTC 1-2 or the application of sugammadex 3, 5 or 15 min after the administration of 1.2 mg/kg rocuronium ("immediate reversal") was investigated in five phase-II trials (19.4.202, 19.4.204, 19.4.205, 19.4.206, 19.4.209) [Table 6]. {Table 6}

Sparr et al. (19.4.202) evaluated the recovery at 3, 5 and 15 min following the administration of the intubating dose of rocuronium (0.6 mg/kg). It has been shown that the depth of the blockade 15 min after 0.6 mg/kg of rocuronium corresponds well with a blockade at PTC 1-2. The mean recovery time to the TOF ratio of 0.9 after the administration of 8.0 mg/kg of sugammadex decreased to 1.8 (3 min), 1.5 (5 min) and 1.4 min (15 min). [9]

Groudine et al. (19.4.204) anesthetized 50 volunteers receiving 0.6 or 1.2 mg/kg of rocuronium and one of five doses of sugammadex (0.5-8.0 mg/kg) at a deep neuromuscular blockade (PTC 1-2). The mean recovery times to TOF of 0.9 were reached after 4 mg/kg of sugammadex in 1.5-4.7 min and after 8.0 mg/kg in 0.8-2.1 min. [11]

De Boer et al. (19.4.205) designed a multicenter, assessor-blinded, placebo-controlled, parallel dose-finding study. Forty-five anesthetized subjects received 1.2 mg/kg of rocuronium to induce neuromuscular blockade after a period of 5 min after the application sugammadex (2.0-16.0 mg/kg) or after placebo was administered. Increasing the dose of sugammadex, the mean recovery time to TOF ratio 0.9 decreased from 122 min (spontaneous recovery) to 1.6-1.8 min (dose dependant). [34]

In all phase-II trials, there was no evidence for recurrence or residual neuromuscular blockade [Table 7].{Table 7}

Phase-III trials

Phase-III trials consisted of 11 studies, including a total number of 872 subjects.

Blobner et al. (19.4.301) and Flockton et al. (19.4.310) showed a faster recovery after the application of sugammadex compared with neostigmine at the reappearance of T2. [35] In 19.4.301 (n = 96), the neuromuscular blockade was induced by rocuronium. At the reappearance of TOF of T2, the reversal to a TOF ratio of 0.9 by 2.0 mg/kg sugammadex was compared with the reversal of 50 μg/kg of neostigmine. The observed mean recovery time to the TOF ratio 0.9 was estimated to be almost 13-times faster in the sugammadex group compared with the neostigmin group (1.4 vs. 17.6 min).

Trial 19.4.310 compared 84 randomized subjects in two treatment groups. Thirty-four subjects received 2.0 mg/kg of sugammadex at the T2 reappearance of TOF after the rocuronium-induced (0.6 mg/kg) neuromuscular blockade compared with 39 subjects that received 50 μg/kg of neostigmin after cisatracurium-induced (0.15 mg/kg) neuromuscular blockade. The mean time of recovery to the TOF ratio of 0.9 was four-times faster in the sugammadex group compared with the neostigmin group (1.9 vs. 7.2 min). [35]

A comparison for the reversal of deep/profound neuromuscular blockade between sugammadex and neostigmine was designed by Jones et al. (trial 19.4.302). A rocuronium-induced deep neuromuscular blockade (PTC 1-2) was reversed by 4.0 mg/kg of sugammadex or 70 μg/kg of neostigmine. The results showed a significantly faster recovery after the administration of sugammadex (17-times) compared with that in the neostigmine group (2.7 vs. 49.0 min). [16]

Lee et al. designed a clinical trial (19.4.303) to compare the reversal of 1.2 mg/kg of rocuronium by 16.0 mg/kg of sugammadex (applied 3 min after rocuronium administration) to the recovery of 1.0 mg/kg of succinylcholine. The trial showed a significantly faster recovery of the neuromuscular blockade by the reversal of rocuronium by sugammadex than the spontaneous recovery of succinylcholine. Mean times to recover from T1 to the TOF ratio of 0.1 and T1 to the TOF ratio of 0.9 were 4.4 and 6.2 min in the rocuronium-sugammadex group compared with 7.1 and 10.9 min in the succinylcholine group [Table 8]. [36] {Table 8}

 Special Populations



Staals et al. (19.4.304) administered sugammadex to renal-impaired patients (creatinine clearance <30 ml/min) compared with 15 controls (creatinine clearance >80 ml/min). [10] Rocuronium (0.6 mg/kg)-induced neuromuscular blockade was reversed by 2.0 mg of sugammadex at the reappearance of T2. The mean time of recovery to TOF of 0.9 after the application of sugammadex was 2.0 min (standard deviation 0.72) in renal patients and 1.65 min (standard deviation 0.63) in the control group. Neither sugammadex-related serious adverse events nor recurrences or residuals of neuromuscular blockade were reported.

Plaud et al. compared the reversal of rocuronium-induced block by sugammadex in adults (n = 26), adolescents (n = 28), children (n = 22) and infants (n = 8). Neuromuscular blockade was induced by 0.6 mg/kg of rocuronium. At the reappearance of T2, the patients received sugammadex (0.5-4.0 mg/kg) or placebo. At a dose of sugammadex 2.0 mg/kg, a TOF ratio of 0.9 in children was attained in a median time of 1.2 min. This recovery time was nearly similar to the recovery time in adolescents and adults. The sugammadex plasma concentrations were similar for the children, adolescent and adult age groups across the dose range. No adverse events, recurrences of neuromuscular blockade or significant prolonged QT interval were observed. Because of the very small number of included infants (below 2 years), there are no comparable data available. [21]

 Clinical Recommendations for Cardiac Surgery



The clinical recommendations for the use of sugammadex in cardiac surgery are based on its use in three different conditions: rescue reversal for failed intubation after either normal induction or RSI, reversal at the end of surgery with the intent of immediate extubation or reversal of neuromuscular block after extubation in the ICU or intermediate or postoperative care unit. We will try to summarize the clinical recommendations for the cardiac anesthesiologist in seven points.

The arrival of sugammadex does not replace good clinical practice. [37] Objective monitoring of neuromuscular blockade remains a standard monitoring in cardiac surgery, which is as important as any other vital sign monitoring. [38] Monitoring of the hand muscles might be impaired in cardiac surgery with prolonged surgery, peripheral vasoconstriction and hypothermia. Nevertheless, it is the best means to detect any residual paralysis at the end of surgery. Determination of a train-of-four neuromuscular response is important before any attempt of extubation occurs after cardiac surgery, either in the operating room or in the ICU. Whether sugammadex has any impact on shortening recovery after cardiac surgery needs to be shown.

Neuromuscular monitoring of the corrugator supercilii muscle is a reliable method to titrate muscle relaxation during cardiac surgery, since it best reflects core muscle relaxation. [39] Titration of muscle relaxation to a TOF ratio of 0.1-0.25 or lower at the corrugator supercilii muscle will, for most clinicians, mean to give higher doses of NMBDs thus improving core muscle relaxation and potentially improving the conditions of surgery, whereas such a profound block would have interfered with the attempt to immediately extubate after cardiac surgery previously. This is now feasible with the arrival of sugammadex.

It will, in the future, be a question of price more than scientific proof, which reversal drug should be used in cardiac surgery, or any other type of surgery for that matter. The standard combination of nestigmine/glyccopyrrolate has always been specifically difficult in cardiac surgery because of the adverse arrythmogenic potential of this combination with glyccopyrrolate overdosing potentiating tachycardic arrhythmias and underdosing potentially causing bradycardic arrhythmias by neostigmine. Therefore, without taking into account sugammadex's price, sugammadex should be the reversal drug of choice, particularly in fast-track cardiac surgery.

However, the still high price of sugammadex might tempt some clinicians to use lower doses of sugammadex to economize and potentially use it for several patients. It is important to note that sugammadex doses below 2 mg/kg can, by no means, be recommended. As shown in a study by Eleveld et al., [40] doses below 2 mg/kg can lead to a dangerous rebound phenomenon during which rocuronium can leave the sugammadex-rocuronium complex, causing recurarization.

In the event of failed intubation and failed ventilation, sugammadex offers the treatment of choice of rapid reversal of neuromuscular blockade. Regardless of the dose of rocuronium given for induction, a dose of 16 mg/kg of sugammadex is recommended to achieve the quickest reversal of neuromuscular blockade possible. [36] Sufficient return of neuromuscular transmission should be achieved within 3-7 min, depending on the initial dose of rocuronium given and the delay between rocuronium and sugammadex administration. Sugammadex should, regardless of its cost, be readily available and used for this indication in all cases.

Reversal with sugammadex: before extubation, neuromuscular blockade should be determined using objective monitoring methods, such as acceleromyography, electromyography or kinemyography. If a train-of-four of <0.9 is determined at the hand muscles, reversal of neuromuscular blockade is recommended. Sugammadex at 2 mg/kg is the recommended dose to achieve normal neuromuscular transmission predictably in all patients. Higher doses of sugammadex might achieve the establishment of normal neuromuscular transmission quicker, but considering the high costs of sugammadex, return of neuromuscular transmission a couple of minutes earlier makes no difference after cardiac surgery. [41] In any case, reassessment of neuromuscular transmission using train-of-four stimulation 5 min after sugammadex is given is recommended as part of good clinical practice.

Sugammadex can be recommended to reverse neuromuscular blockade only from rocuronium or vecuronium; however, there is a significantly smaller number of studies of sugammadex use after vecuronium than after rocuronium. [42]

In conclusion, sugammadex provides a unique opportunity for cardiac anesthesiologists. Reliable and fast reversal of neuromuscular blockade is available without any important side-effects for this high-risk population of patients. Cardiac surgery is still considered a type of surgery where significant neuromuscular blockade is achieved as part of routine practice during most of the surgery. Very profound blockade, however, is not necessary. With the arrival of sugammadex, cardiac anesthesiologists will be hard pressed to use any other NMBD than rocuronium or vecuronium. It is important to keep in mind that using sugammadex in doses <2 mg/kg can endanger the patient because of the inherent risk of recurarization. Neuromuscular monitoring and careful, titrated use of NMBD will be the pillars of our clinical practice even with the more widespread use of sugammadex; unnecessary profound NMB cannot be justified by the availability of sugammadex.

References

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