Sugammadex – a Short Review and Clinical Reccomendations for the Cardiac Anesthesiologist

Review Article Sugammadex – A short review and clinical reccomendations for the cardiac anesthesiologist

Thomas M Hemmerling, Cedrick Zaouter, Goetz Geldner1, Dirk Nauheimer1 Department of Anesthesia, McGill University, Montreal, Canada, 1Department of Anesthesia, Ludwigsburg Hospital, University Heidelberg, Germany

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.

Received: 01-07-10 Accepted: 13-08-10 Key words: Cardiac surgery, review, sugammadex

PMID: ******** DOI: 10.4103/0971-9784.69052 www.annals.in

The ideal reversal agent should have a fast png]. It is composed of a hydrophobic core onset; it should be efficient at any time, even with peripheral hydrophilic chains. Its singular soon after curarization of the patient; it should structure allows aminosteroidal nondepolariz- be able to provide complete reversal either for ing neuromuscular blocking drugs (NMBDs) to light or profound block; it should have a longer get trapped inside. The negative charges of the half-life than the neuromuscular-blocking external chains maintain the cavity open and agent; and, it should be free of any side-effects. the core, with Van Der Waals forces, thermo- Current drugs used to reverse neuromuscular dynamic bonds and hydrophobic interactions, block are not ideal and possess many side- creates a 1-1 ratio complex with very tight bonds effects, but sugammadex is very close to be between the NMBDs and the reversal agent.[1] the ideal reversal agent. This latter complex is water soluble and can be easily excreted via urine.[2] Because of its PHARMACODYNAMIC PROPERTY singular architecture, it has a low penetration of the blood–brain barrier and a low placenta Sugammadex is a modified cyclic oligosac- transfer.[3] It has been demonstrated using iso- charide, synthesized with 1-4 glycosyl bonds thermal titration microcalorimetry that sugam- made using cyclodextrin glycosyltransferase. madex can reverse rocuronium and vecuroni- This molecule, a γ-cyclodextrin, is character- um with high affinity and pancuronium with ized by its unique tridimensional structure low affinity. It has also been shown using [Figure 1; http://commons.wikimedia.org/wiki/ the same technique that the complex sugam- File: Sugammadex_sodium_3D_front_view. madex–rocuronium maintains a high associa-

Address for correspondence: Dr. Thomas M Hemmerling, NRG Laboratory, Montreal General Hospital, 1650 Cedar Avenue, Montreal, H3G 1B7. E-mail: [email protected]

206 Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 Hemmerling, et al,: Sugammadex review for cardiac anesthesia

Sugammadex incapsulating a molecule of rocuronium Figure 1: Tri-dimensional structure of sugammadex; Space-filling model of Figure 2: sugammadex sodium. partial upper airway obstruction, increased intracranial, tion rate with a low dissociation rate. For instance, only intraocular and intragastric pressures, prolonged one complex sugammadex–rocuronium dissociates for paralysis related to acetylcholinesterase deficiency and every 25,000,000 complexes formed.[1] The affinity with also malignant hyperthermia. Using a nondepolarizing rocuronium is greater than that with vecuronium. blocking agent, such as rocuronium, with a short onset of action and a medium half-life can achieve good Both endogenous and exogenous steroidal molecules intubation conditions after a similarly short time, have a lower affinity to sugammadex because they but is associated with a longer neuromuscular block. lack the positively charged quaternary nitrogen that Recovery from a profound block cannot be attained with rocuronium and vecuronium exhibit, enabling tight acetylcholinesterase inhibitors.[7] bounds and thus high affinity with sugammadex. Therefore, the affinity of sugammadex for narcotics and High doses of sugammadex (16 mg/kg) can rapidly intravenous anesthetics is negligibly small.[2] reverse even very profound blocks induced by high doses of rocuronium (1.2 mg/kg). Naguib et al. have Because of its great affinity with rocuronium, demonstrated that recovery to the Train-of-Four (TOF) - sugammadex is more commonly administrated in ratio of 0.9 requires a shorter length when sugammadex association with this latter one. is administrated subsequently to rocuronium compared with spontaneous recovery after the administration of MECHANISM OF ACTION: CONCENTRATION GRADIENT succinylcholine.[2] Sugammadex incapsulates rocuronium, reducing its free plasma concentration, which leads to the removal DRUG INTERACTIONS of NMBDs from the neuromuscular joints to the central compartment through a concentration gradient effect Several clinical studies have looked at the possible [Figure 2].[4,5] drug interactions using simulation or modeling and in vitro data.[3] Toremifene, a selective estrogen receptor PROFOUND BLOCK modulator used for advanced breast cancer, can delay the reversal by displacing the formation of the In order to obtain adequate neuromuscular blockade rocuronium–sugammadex complex. Sugammadex can for a rapid sequence induction (RSI), succinylcholine theoretically bind with contraceptive steroids (combined is the neuromuscular blocking agent still most widely or progesterone only). Moreover, rocuronium bound to used: its onset of paralysis is short (45–60 s), very sugammadex can be displaced by the administration predictable with little interindividual variability and of fusidic acid or high dose of flucoxacillin. Repetitive short duration of paralysis (3–5 min).[6] Succinylcholine, neuromuscular monitoring for reoccurrence of however, is associated with several adverse effects, curarization is recommended.[3] Sugammadex does not such as hyperkalaemia, bradycardia, histamine release, alter laboratory tests in general, but some modification

Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 207 Hemmerling, et al,: Sugammadex review for cardiac anesthesia of the serum progesterone assay and of the coagulation pediatric populations and in parturients. It seems that parameters has been described.[3] hydroxy apatite, present in the inorganic tissue of the bone and the teeth, can bind reversibly to sugammadex. PHARMACOKINETIC PROPERTY The retention can occur at or adjacent to sites of active bone formation. However, in juvenile animal models, The pharmacokinetic properties of sugammadex have bone growth and development appear not to be affected been evaluated in phase I,[5] phase II[8,9] and phase III even by very high doses. Other investigations on young studies.[10] rats suggest that repetitive high doses of sugammadex can lead to a whitish discoloration of the incisor and Many phase II trials have described the dose-dependent molar. The dose of sugammadex used for those trials effectiveness of Sugammadex.[8,9,11-13] Administrated as was higher than the exposure at the clinical dose of intravenous bolus with a dosage ranging from 0.1 to 4 mg/kg. These findings suggest that more clinical 8 mg/kg, Gijsenbergh et al.[5] have demonstrated the investigations are needed before its use in the pediatric linear pharmacokinetic properties and have described population.[3] Compared with placebo, sugammadex a volume distribution of approximately 18 L, with the presents the same incidence (1–10%) of adverse effects, volume distribution at steady state (Vdss) estimated to such as coughing, grimacing or suckling on the tracheal range from 11 to 14 L (0.16–0.20 L/kg).[3] Sugammadex tube. Because of some concerns on hypersensitivity does not bind to plasma proteins or erythrocytes.[5,8] and allergic reactions, the United States Food and Drug It does not produce any metabolites and most of it is Administration has not yet approved sugammadex.[19] excreted in an unchanged form via urine within 24 h. An insignificant part is excreted via feces or in expired SPECIAL POPULATIONS air (0.02%).[3] In healthy adults, the plasma clearance of sugammadex ranges from 84 to 138 ml/min.[14] Patients with severe renal impairment The clearance of sugammadex is reduced in patients SUGAMMADEX–ROCURONIUM COMPLEX with a creatinine clearance below 30 ml/min by 17-fold and the elimination half-life is increased by 15 fold Rocuronium is eliminated through both biliary (>75%) compared with patients with any renal impairment. and renal excretion (26%).[15] When sugammadex Nevertheless, the efficacy of sugammadex is not is administrated to reverse rocuronium, the plasma altered and no block reoccurrence has been observed.[10] concentration of this latter increases – bound to the Others studies have not demonstrated a consistency in reversal agent – in a dose-dependent fashion. The decreasing the plasma concentration of sugammadex sugammadex–rocuronium complex is mainly excreted in patients with severe renal impairment or in those via urine (65–97%).[3,16] It has been demonstrated needing dialysis.[2,20] Therefore, it is recommended to that when rocuronium is bound to sugammadex, its avoid its use in such patients. excretion in the urine increases from two- to three-fold within the first 24 h in healthy adults[5] and in surgical Patients with hepatic impairment patients.[8] The sugammadex–rocuronium complex is not eliminated by hepatic metabolism; therefore, hepatic impairment SAFETY does not influence its excretion. However, patients with hepatic failure may have higher plasma rocuronium levels. The sugammadex–rocuronium complex is inert and therefore does not cause any muscarinic effect. Patients in the intensive care unit (ICU) In patients with severe heart disease undergoing The pharmacokinetic properties of patients admitted noncardiac surgery, sugammadex does not have any in the ICU have not been studied yet. hemodynamic effects nor does it cause any prolongation of QT interval.[17] The administration of rocuronium Elderly patients followed by sugammadex for an RSI does not affect the Plasma clearance, Vdss and terminal elimination half- genioglossus muscle activity or any partial upper airway life were homogeneous in patients over 75 years with obstruction, as may be observed with succinylcholine.[18] normal renal function (creatinine clearance of >100 ml/min) compared with patients of 40 years without The safety profile is still not well established in renal failure.[3]

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Pediatric patients µ-cyclodextrin (Org 25969) in vivo, experiments in The variations observed in the plasma of sugammadex female Rhesus monkeys at Radbound University are analogous to those seen in adult patients.[21] Plasma in Nijmegen in 2002 and in guinea pigs at Organon clearance, Vdss and terminal elimination half-life Laboratories in 2003 were performed.[1,4] Based on increase with age. There is no clinical trial in children these findings, the concept that the reversal activity of below 2 years. sugammadex depends on encapsulation and removal of rocuronium molecules from the nicotinic receptors Sex, race and body weight to the central compartment was confirmed. The Gender, race or body weight do not affect sugammadex selectivity of sugammadex specific for steroidal NMBDs or sugammadex–rocuronium complex clearance.[3] was studied in guinea pigs and primates as well.[22,23] During the in vivo experiments to determine the reversal Summary of animal and human trials effect of sugammadex in anesthetized animals, blood Animal findings pressure and heart rate were continuously monitored. The pharmacodynamics of sugammadex and related No changes in arterial blood pressure and heart rate cyclodextrins have been examined using isothermal were observed after the intravenous application of titration microcalorimetry. Nonclinical studies using sugammadex [Table 2]. in vitro techniques (tissue bath studies) and in vivo methods (muscle contraction in anesthetized animals) To clarify the pharmocokinetic characteristics, such as were performed to investigate the pharmacodynamics metabolism, excretion and toxicity, further in vivo animal and drug–drug interactions.[1] The potency, efficacy models were designed. Epemolu et al. demonstrated the and selectivity of sugammadex have been clearly excretion of the sugammadex–rocuronium complex via demonstrated in both in vitro and in vivo essays. the kidneys in guinea pigs.[4] Even animals with renal dysfunction presented fast and complete reversal of The first in vitro testing of the potency of natural neuromuscular blockade.[22,24] cyclodextrins to reverse rocuronium-induced neuromuscular blockade was performed in isolated mice Upon intravenous administration, sugammadex is hemidiaphragm. The correlation between cavity size of characterized by rapid distribution in a low-distribution the cyclodextrins (a-, ß- and µ-cyclodextrin) and their volume, reflecting the extracellular water compartment. reversal activity was demonstrated [Table 1]. In all preclinical species studied, the systemic exposure generally increased proportional to the applied dose, The effect of sugammadex was studied in a large number with no significant differences between the gender and of in vitro preparations, containing its interactions between single and multiple dosing. Metabolism is not to receptors, uptake and enzyme systems. In vitro a major route of clearance, and sugammadex is rapidly studies in mouse hemidiaphragm, mouse vas deferens, excreted in urine at a rate approximating the glomerular guinea pig right atrium, rat aorta, rat iliac artery and filtrating rate (Trial 19.4.107. Open, non randomized, guinea pig bronchus showed that sugammadex does single center trial to determine the excretion balance, not interact with endogenous neurotransmitters or metabolism profile and pharmacokinetics of Org 25969 exogenous agonists added to these preparations. It also after intravenous dose of (14C)-labeled Org 25969. demonstrated that sugammadex had no interactions to Clinical trial report). receptors, enzyme and uptake mechanisms.[22] De Boer performed pharamcodynamic investigations To prove the complex formation of rocuronium and in Rhesus monkeys to demonstrate the time course and duration of action or half-life of sugammadex as Table 1: Primary pharmocodynamics (Bom A. Non clinical pharmacology release report on Org 25969) Table 2: Secondary pharmacodynamics (Bom A. Non Species Dose (µM) Study parameter clinical pharmacology release report on Org 25969) Mouse in vitro 1.0–1,400 Muscle twitch high Species Dose Route Study parameter Mouse diaphragm 36 Muscle twitch high (µmol/kg) Mouse vas deferense 36 Muscle twitch high Rat 0.12-1.84 Intravenous Blood pressure/heart rate Rat aorta 36 Contraction Guinea pig 0.06-2.30 Intravenous Blood pressure/heart rate Rat iliac artery 100 Contraction Cat 0.46-2.30 Intravenous Blood pressure/heart rate Guinea pig atrium 100 Beat rate/contraction Rhesus 0.23-14.69 Intravenous Blood pressure/heart rate Guinea pig bronchus 36 Contraction monkey

Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 209 Hemmerling, et al,: Sugammadex review for cardiac anesthesia well as the dose–response relationship.[25] In contrast administered ranged between 2.0 and 32 mg/kg. Most to acetylcholinesterase inhibitors, the reversal subjects received sugammadex at a dose of 2.0 or 4.0 of profound neuromuscular blockade immediately mg/kg. These clinical evaluations led to the dose– after the administration of rocuronium could be effect relationship, which recommends that a dose demonstrated without any cardiovascular effects in range of 2.0–16.0 mg/kg, depending on the level of Rhesus monkeys.[26] At high concentrations in vitro neuromuscular block, leads to a reversal of moderate (0.15–1.5 mM), sugammadex induced a slight increase in block (T2; 2.0 mg/kg), reversal of more profound block the action potential duration and a slight hERG channel (posttetanic count [PTC] 1–2; 4.0 mg/kg) and for a rapid inhibition. However, these effects are considered a rescue reversal at an early stage of neuromuscular block nonspecific disturbance of the electrophysiological (16.0 mg/kg) [Table 3].[11,13,21,26-28] The majority of clinical properties of these in vitro systems, and a wide safety studies investigated the efficacy of sugammadex against margin is present. the neuromuscular block induced by rocuronium.

In all preclinical animal in vivo experiments, Phase-I trials sugammadex showed a rapid onset, with a short time to Seven phase-I studies were performed. In six of the peak effect, a faster recovery than acetylcholinesterase seven trials, the pharmacokinetic profile of sugammadex inhibitors and no adverse side-effects.[23] The findings was investigated when sugammadex was administered of these in vivo animal studies made an extrapolation alone, in healthy volunteers who did not receive to human situation very likely. anesthesia. Only in part 2 of clinical trial 19.4.101 did volunteers receive sugammadex for the reversal of Human studies the neuromuscular blockade induced by rocuronium. In 2005, the first phase I study was published. In Except trial 19.4.107, all phase-I trials were randomized, this study, 29 healthy male volunteers received a double-blind and cross-over trials. In all phase-I trials, sugammadex dose of 0.1–8.0 mg/kg for safety and 260 adult healthy volunteers received a single dose of efficacy investigations. This study reported the well- sugammadex. tolerated administration of sugammadex for reversing the neuromuscular block induced by rocuronium in Gijsenbergh et al. investigated the first exposure of humans for the first time.[5] sugammadex in humans (19.4.101).[5] The trial was divided into two parts and included 29 subjects. In part The efficacy and safety of sugammadex in the reversal 1, 19 subjects were randomized and treated with a single of rocuronium-induced neuromuscular blockades dose of sugammadex 0.1 mg/kg ranging up to 8.0 mg/kg were evaluated in 30 phase I–III studies. A total of or placebo application. In part 2, 10 randomized subjects 2,054 subjects were exposed to sugammadex. Nineteen under general anesthesia received sugammadex 0.1–8.0 hundred and twenty-six patients received sugammadex mg/kg after the application of 0.6 mg/kg of rocuronium. after the administration of a neuromuscular blocking One subject participating in part 1 described the drug (rocuronium or vecuronium). The dose occurrence of taste sensations for 43 min after the injection

Table 3: Reversal of profound neuromuscular blockade. Recovery times after 1,2 mg/kg of rocuronium, with sugammadex or placebo 3 min after the administration of rocuronium.[13] Sugammadex dose mg/kg Placebo 2.0 4.0 8.0 12.0 16.0 Recovery to TOF 0.7 min n 5 11 11 11 11 10 Mean (SD) 91.6 (27.4) 36.4 (17.2) 4.6 (1.4) 1.6 (0.7) 1.1 (0.1) 1.3 (0.5) Median 86.8 30.4 4.2 1.4 1.1 1.1 Min-Max 54.2-119.9 18.8-74.8 2.6-7.1 0.8-3.3 1.0-1.4 0.7-2.6 Recovery to TOF 0.9 min n 5 11 11 11 11 10 Mean (SD) 108.4 (31.2) 44.7 (22.2) 6.9 (2.9) 2.4 (1.2) 2.4 (2.1) 1.8 (1.1) 95% CI for the mean [70: 147] [30:60] [5.0:8.9] [1.6:3.2] [1.0:3.8] [1.0:2.6] Median 111.1 34.4 6.8 2.2 1.4 1.6 Min-max 63.7-144.8 23.3-94.3 3.4-11.9 1.3-4.8 1.0-7.1 0.9-4.8 Time was recorded when train-of-four (TOF) ratios of 0.7 and 0.9 were reached (n = 59); CI = confidence interval

210 Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 Hemmerling, et al,: Sugammadex review for cardiac anesthesia of 4.0 mg/kg of sugammadex. Other subjects had self- A/B, additional administrations of rocuronium were limiting parosmia of about 2 min, dry mouth sensations, allowed. Three trials performed the sugammadex changed temperature and coughing. In eight subjects, a administration at the reappearance of T2 of vecuronium- prolonged QT interval (>450 ms) was observed. Of note, induced neuromuscular block (19.4.207, 19.4.208A, five of the eight subjects with prolonged QT interval were 19.4.208B). documented after placebo application. They found that the mean recovery time decreased Peeters et al. administered (trial 19.4.106) high doses of from 60 min at spontaneous recovery (after placebo up to 96 mg/kg of sugammadex in 13 healthy male and administration) to 1.6 min after a dose of 2.0 mg/kg of female volunteers. Intravenous high-dose application sugammadex to the TOF ratio of 0.9. Doubling the dose of sugammadex was safe and was well tolerated. No from 2.0 to 4.0 mg/kg resulted in a small further reduction gender effects were noted. Across trials and dose groups of only 0.2 min in the overall mean recovery time, from (1.0–96 mg/kg), sugammadex was found to distribute 1.6 to 1.4 min.[8,12,30,31] The mean recovery time to TOF into the extracellular water of the body and did not bind 0.9 after the application of 2.0 mg/kg of sugammadex to plasma proteins or erythrocytes. at T2 following vecuronium was longer than the mean recovery time of the same dose of sugammadex at T2 Cammu et al. investigated, in trial 19.4.108, the safety following rocuronium (2.8 vs. 1.6 min). Nevertheless, the of the simultaneous administration of sugammadex reduction in recovery times obtained with 2.0 mg/kg of (16.0–32.0 mg/kg) with either rocuronium (1.2 mg/kg) sugammadex compared with spontaneous recovery can or vecuronium (0.1 mg/kg) in 12 healthy volunteers.[29] be considered as clinically significant for rocuronium as The doses were well tolerated. This study demonstrated well as for vecuronium [Table 4].[9] that the dose of rocuronium and vecuronium in plasma decreases faster than that of sugammadex. Only Shields et al. studied (19.4.203) the 6.0 mg/kg dose. Thirty adult patients received rocuronium to Adverse events were documented in subjects in maintain a deep block at a level of less <10 PTC <10 19.4.105, 19.4.106, 19.4.108 and 19.4.109. Headache, during propofol-nitrous oxide-opioid anesthesia. At the nausea, dry mouth or hypersensitivity (following the recovery of T2, volunteers received different doses of application of 32 mg/kg of sugammadex) were noted to sugammadex (0.5–6.0 mg/kg). The mean recovery time be possibly related to the administration of sugammadex. 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 Phase-II trials in the 4.0 mg/kg group. The observed recovery time Phase-II consists of 12 studies that included 866 subjects. after the dose of 6.0 mg/kg was unexpectedly longer than the observed recovery times after 2.0–4.0 mg/kg Six clinical trials investigated the “Routine reversal” of of sugammadex. There was no explanation found for rocuronium- and vecuronium-induced neuromuscular this outlaying result.[32] The conclusion of the authors blockade at the reappearance of the second twitch was that the administration of sugammadex was at the (19.4.201, 19.4.203, 19.4.207, 19.4.208A, 19.4.208B, reappearance of T2, which is most effective at a dose 19.4.210). In trials 19.4.201, 19.4.207 and 19.4.210, the of 2.0–4.0 mg/kg [Table 5]. neuromuscular blockade was induced by the intubating dose of rocuronium only (0.6 mg/kg), while in 19.4.208 Sugammadex for the reversal of a “deep or profound”

Table 4: Time interval from administration of sugammadex or placebo to TOF ratio of 0.7/0.8/0.9 for different times and dose groups[9] Parameter Placebo Sugammadex dose mg/kg 1.0 2.0 4.0 6.0 8.0 n 10 18 16 18 18 18 Age, yr 41 (21-63) 40 (19-57) 39 (19-62) 41 (26-60) 36 (22-59) 37 (20-63) Weight, kg 85 (12) 80 (9) 82 (8) 83 (11) 84 (16) 78 (12) Height, cm 181 (8) 179 (7) 177 (5) 181 (9) 179 (9) 182 (7) ASA I:II 8:2 14:4 11:5 15:3 15:3 14:4 Creatinine Clearence, ml/min* 164 (120-231) 142 (74-187) 137 (100 -176) 138 (95-203) 163 (93-295) 137 (85-163) Data are presented as number, mean (range), or mean (SD), *Predose, ASA = American Society of Anesthesiologists.

Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 211 Hemmerling, et al,: Sugammadex review for cardiac anesthesia neuromuscular blockade at PTC 1–2 or the application finding study. Forty-five anesthetized subjects received of sugammadex 3, 5 or 15 min after the administration 1.2 mg/kg of rocuronium to induce neuromuscular of 1.2 mg/kg rocuronium (“immediate reversal”) was blockade after a period of 5 min after the application investigated in five phase-II trials (19.4.202, 19.4.204, sugammadex (2.0–16.0 mg/kg) or after placebo was 19.4.205, 19.4.206, 19.4.209) [Table 6]. administered. Increasing the dose of sugammadex, the mean recovery time to TOF ratio 0.9 decreased from Sparr et al. (19.4.202) evaluated the recovery at 3, 5 and 122 min (spontaneous recovery) to 1.6–1.8 min (dose 15 min following the administration of the intubating dependant).[34] 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 In all phase-II trials, there was no evidence for recurrence rocuronium corresponds well with a blockade at PTC 1–2. or residual neuromuscular blockade [Table 7]. The mean recovery time to the TOF ratio of 0.9 after the administration of 8.0 mg/kg of sugammadex decreased to Phase-III trials 1.8 (3 min), 1.5 (5 min) and 1.4 min (15 min).[9] Phase-III trials consisted of 11 studies, including a total number of 872 subjects. Groudine et al. (19.4.204) anesthetized 50 volunteers receiving 0.6 or 1.2 mg/kg of rocuronium and one of Blobner et al. (19.4.301) and Flockton et al. (19.4.310) five doses of sugammadex (0.5–8.0 mg/kg) at a deep showed a faster recovery after the application of neuromuscular blockade (PTC 1–2). The mean recovery sugammadex compared with neostigmine at the times to TOF of 0.9 were reached after 4 mg/kg of reappearance of T2.[35] In 19.4.301 (n = 96), the sugammadex in 1.5–4.7 min and after 8.0 mg/kg in neuromuscular blockade was induced by rocuronium. 0.8–2.1 min.[11] At the reappearance of TOF of T2, the reversal to a TOF ratio of 0.9 by 2.0 mg/kg sugammadex was De Boer et al. (19.4.205) designed a multicenter, compared with the reversal of 50 µg/kg of neostigmine. assessor-blinded, placebo-controlled, parallel dose- The observed mean recovery time to the TOF ratio

Table 5: Recovery times (min) to TOF ratio 0.9 from moderate neuromuscular blockade induced by rocuronium[28] Sugammadex dose mg/kg 0.5 1.0 2.0 3.0 4.0 6.0 Sorgenfrei et al. 3.7 (1.0) 2.3 (0.6) 1.7 (0.6) 1.9 (1.2) 1.1 (0.3) - Suy et al. 4.3 [1.3-8.5] 3.3 [1.4-4.9] 1.3 [0.9-1.7] 1.2 [0.7-3.2] 1.1 [1.0-1.4] - Shields et al. 5;29 [4:50-11:26] 2;42 [1:49-3:40] 1;46 [1:00-2:31] - 1;04 [0.57-2:19] 2;41 [1:08-3:56] Puehringer et al. 16.3 (20.6) 4.6 (6.0) 1.4 (0.5) - 1.5 (0.4) - Plaud et al. 4.2 [2.3-4.8] 1.7 [1.2-2.10] 1.4 [1.0-2.0] - 1.2 [0.9-1.6] - Sorgenfrei et al.[8] mean (standard deviation, SD); Suy et al.,[12] median (range); Shields et al.,[32] median (range, time in min:s), Pühringer et al.,[13] mean (SD), Plaud et al.,[21] median (range).

Table 6: Recovery times (min) to TOF ratio of 0.9 from profound/deep neuromuscular blockade induced by rocuronium[28] Sugammadex dose mg/kg 0.5 1.0 2.0 4.0 6.0 8.0 Groudine et al. 44.2 [22.4-84.1] 19.1 [5.0-33.2] 5.4 [1.8-15.2] 3.3 [2.2-4.7] - 1.5 [1.0-2.1] Sparr et al. - 6.5 (1.7) 2.7 (0.7) 2.1 (1.2) 2.1 (2.0) 1.4 (0.2) Duvaldestin et al. 79.8 (33) 28 (43.7) 3.2 (1.5) 1.6 (0.7) - 1.1 (0.3) Groundine,[11] median (range); Sparr,[9] mean (SD); Duvaldestin,[33] mean (SD).

Table 7: Recovery times (min) to TOF ratio of 0.9 in immediate (rescue) reversal[28] Sugammadex dose mg/kg 2.0 4.0 8.0 12.0 16.0 de Boer et al. 55.3 [50.5-65.1] 12.3 [3.3-46.6] 2.5 [2.2-3.7] 1.3 [1.0-1.9] 1.3 [0.7-6.9] Puehringer et al. 34.4 [23.3-94.3] 6.8 [3.4-11.9] 2.2 [1.3-4.8] 1.4 [1.0-7.1] 1.3 [0.9-4.8] Puehringer et al. 63.3 [36.3-117.2] 11.3 [5.3-28.5] 3.6 [1.5-4.7] 1.9 [1.2-4.1] 1.3 [0.8-2.3] de Boer et al.,[34] median (range); sugammadex administered 5 min after 1.2 mg/kg of rocuronium; Pühringer et al,[13] mean (range); sugammadex administered 3 min after 1.0 and 1.2 mg/kg of rocuronium.

212 Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 Hemmerling, et al,: Sugammadex review for cardiac anesthesia

0.9 was estimated to be almost 13-times faster in the Table 8: Time (min) from start of administration of sugammadex group compared with the neostigmin Neuromuscular Blocking Agent to recovery of T1 to 10% and T to 90% group (1.4 vs. 17.6 min). 1 Treatment Group Trial 19.4.310 compared 84 randomized subjects in two Recuronium + Succinylcholine Sugammadex* (n=55) only (n=55) treatment groups. Thirty-four subjects received 2.0 mg/ Recovery to T1 10% kg of sugammadex at the T2 reappearance of TOF after (primary endpoint) the rocuronium-induced (0.6 mg/kg) neuromuscular Mean (SD) 4.4 (0.7) 7.1 (1.6) † blockade compared with 39 subjects that received 50 Median 4.2 7.1 µg/kg of neostigmin after cisatracurium-induced (0.15 Min-max 3.5-7.7 3.8 10.5 Recovery to T 90% mg/kg) neuromuscular blockade. The mean time of 1 recovery to the TOF ratio of 0.9 was four-times faster in Mean (SD) 6.2 (1.8) 10.9 (2.4) † Median 5.7 10.7 the sugammadex group compared with the neostigmin Min-max 4.2-13.6 5.0 16.2 group (1.9 vs. 7.2 min).[35] *Protocol-specified sugammadex administration at 3 min after the start of rocuroniurn administration (moan [SD) 3.1 [0.2]; range 2.7 to 4.2 A comparison for the reversal of deep/profound min). †P < 0.001 between treatment groups. neuromuscular blockade between sugammadex and Plaud et al. compared the reversal of rocuronium- neostigmine was designed by Jones et al. (trial 19.4.302). induced block by sugammadex in adults (n = 26), A rocuronium-induced deep neuromuscular blockade adolescents (n = 28), children (n = 22) and infants (n = (PTC 1–2) was reversed by 4.0 mg/kg of sugammadex 8). Neuromuscular blockade was induced by 0.6 mg/kg or 70 µg/kg of neostigmine. The results showed a of rocuronium. At the reappearance of T2, the patients significantly faster recovery after the administration received sugammadex (0.5–4.0 mg/kg) or placebo. At of sugammadex (17-times) compared with that in the a dose of sugammadex 2.0 mg/kg, a TOF ratio of 0.9 neostigmine group (2.7 vs. 49.0 min).[16] in children was attained in a median time of 1.2 min. Lee et al. designed a clinical trial (19.4.303) to compare This recovery time was nearly similar to the recovery the reversal of 1.2 mg/kg of rocuronium by 16.0 mg/ time in adolescents and adults. The sugammadex kg of sugammadex (applied 3 min after rocuronium plasma concentrations were similar for the children, administration) to the recovery of 1.0 mg/kg of adolescent and adult age groups across the dose range. succinylcholine. The trial showed a significantly faster No adverse events, recurrences of neuromuscular recovery of the neuromuscular blockade by the reversal blockade or significant prolonged QT interval were of rocuronium by sugammadex than the spontaneous observed. Because of the very small number of included recovery of succinylcholine. Mean times to recover infants (below 2 years), there are no comparable data [21] from T1 to the TOF ratio of 0.1 and T1 to the TOF available. ratio of 0.9 were 4.4 and 6.2 min in the rocuronium- sugammadex group compared with 7.1 and 10.9 min CLINICAL RECOMMENDATIONS FOR CARDIAC SURGERY in the succinylcholine group [Table 8].[36] The clinical recommendations for the use of sugammadex SPECIAL POPULATIONS in cardiac surgery are based on its use in three different conditions: rescue reversal for failed intubation after Staals et al. (19.4.304) administered sugammadex to either normal induction or RSI, reversal at the end renal-impaired patients (creatinine clearance <30 ml/ of surgery with the intent of immediate extubation or min) compared with 15 controls (creatinine clearance reversal of neuromuscular block after extubation in the >80 ml/min).[10] Rocuronium (0.6 mg/kg)-induced ICU or intermediate or postoperative care unit. We will neuromuscular blockade was reversed by 2.0 mg of try to summarize the clinical recommendations for the sugammadex at the reappearance of T2. The mean cardiac anesthesiologist in seven points. time of recovery to TOF of 0.9 after the application of sugammadex was 2.0 min (standard deviation 0.72) in The arrival of sugammadex does not replace good clinical renal patients and 1.65 min (standard deviation 0.63) practice.[37] Objective monitoring of neuromuscular in the control group. Neither sugammadex-related blockade remains a standard monitoring in cardiac serious adverse events nor recurrences or residuals of surgery, which is as important as any other vital neuromuscular blockade were reported. sign monitoring.[38] Monitoring of the hand muscles

Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 213 Hemmerling, et al,: Sugammadex review for cardiac anesthesia might be impaired in cardiac surgery with prolonged mg/kg of sugammadex is recommended to achieve the surgery, peripheral vasoconstriction and hypothermia. quickest reversal of neuromuscular blockade possible. Nevertheless, it is the best means to detect any residual [36] Sufficient return of neuromuscular transmission paralysis at the end of surgery. Determination of a train- should be achieved within 3–7 min, depending on of-four neuromuscular response is important before the initial dose of rocuronium given and the delay any attempt of extubation occurs after cardiac surgery, between rocuronium and sugammadex administration. either in the operating room or in the ICU. Whether Sugammadex should, regardless of its cost, be readily sugammadex has any impact on shortening recovery available and used for this indication in all cases. after cardiac surgery needs to be shown. Reversal with sugammadex: before extubation, Neuromuscular monitoring of the corrugator supercilii neuromuscular blockade should be determined using muscle is a reliable method to titrate muscle relaxation objective monitoring methods, such as acceleromyography, during cardiac surgery, since it best reflects core muscle electromyography or kinemyography. If a train-of-four relaxation.[39] Titration of muscle relaxation to a TOF of <0.9 is determined at the hand muscles, reversal of ratio of 0.1–0.25 or lower at the corrugator supercilii neuromuscular blockade is recommended. Sugammadex muscle will, for most clinicians, mean to give higher at 2 mg/kg is the recommended dose to achieve normal doses of NMBDs thus improving core muscle relaxation neuromuscular transmission predictably in all patients. and potentially improving the conditions of surgery, Higher doses of sugammadex might achieve the whereas such a profound block would have interfered establishment of normal neuromuscular transmission with the attempt to immediately extubate after cardiac quicker, but considering the high costs of sugammadex, surgery previously. This is now feasible with the arrival return of neuromuscular transmission a couple of minutes of sugammadex. earlier makes no difference after cardiac surgery.[41] In any case, reassessment of neuromuscular transmission using It will, in the future, be a question of price more than train-of-four stimulation 5 min after sugammadex is given scientific proof, which reversal drug should be used is recommended as part of good clinical practice. in cardiac surgery, or any other type of surgery for that matter. The standard combination of nestigmine/ Sugammadex can be recommended to reverse glyccopyrrolate has always been specifically difficult in neuromuscular blockade only from rocuronium or cardiac surgery because of the adverse arrythmogenic vecuronium; however, there is a significantly smaller potential of this combination with glyccopyrrolate number of studies of sugammadex use after vecuronium overdosing potentiating tachycardic arrhythmias than after rocuronium.[42] and underdosing potentially causing bradycardic arrhythmias by neostigmine. Therefore, without taking In conclusion, sugammadex provides a unique into account sugammadex’s price, sugammadex should opportunity for cardiac anesthesiologists. Reliable be the reversal drug of choice, particularly in fast-track and fast reversal of neuromuscular blockade is cardiac surgery. available without any important side-effects for this high-risk population of patients. Cardiac surgery is However, the still high price of sugammadex might still considered a type of surgery where significant tempt some clinicians to use lower doses of sugammadex neuromuscular blockade is achieved as part of routine to economize and potentially use it for several patients. practice during most of the surgery. Very profound It is important to note that sugammadex doses below 2 blockade, however, is not necessary. With the arrival mg/kg can, by no means, be recommended. As shown of sugammadex, cardiac anesthesiologists will be hard in a study by Eleveld et al.,[40] doses below 2 mg/kg can pressed to use any other NMBD than rocuronium or lead to a dangerous rebound phenomenon during which vecuronium. It is important to keep in mind that using rocuronium can leave the sugammadex–rocuronium sugammadex in doses <2 mg/kg can endanger the complex, causing recurarization. patient because of the inherent risk of recurarization. Neuromuscular monitoring and careful, titrated use In the event of failed intubation and failed ventilation, of NMBD will be the pillars of our clinical practice sugammadex offers the treatment of choice of rapid even with the more widespread use of sugammadex; reversal of neuromuscular blockade. Regardless of the unnecessary profound NMB cannot be justified by the dose of rocuronium given for induction, a dose of 16 availability of sugammadex.

214 Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 Hemmerling, et al,: Sugammadex review for cardiac anesthesia

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Neostigmine but not sugammadex impairs upper airway dilator Eur J Anaesthesiol 2004;21:322-3. muscle activity and breathing. Br J Anaesth 2008;101:344-9. 39. Hemmerling TM, Russo G, Bracco D. Neuromuscular blockade in cardiac 19. Naguib M, Brull SJ. Update on neuromuscular pharmacology. Curr Opin surgery: An update for clinicians. Ann Card Anaesth 2008;11:80-90. Anaesthesiol 2009;22:483-90. 40. Eleveld DJ, Kuizenga K, Proost JH, Wierda JM. A temporary decrease

Annals of Cardiac Anaesthesia  Vol. 13:3  Sep-Dec-2010 215 Hemmerling, et al,: Sugammadex review for cardiac anesthesia

in twitch response during reversal of rocuronium-induced muscle a selective reversal medication for preventing postoperative residual relaxation with a small dose of sugammadex. Anesth Analg neuromuscular blockade. Anesth Analg 2010;110:1239. 2007;104:582-4. 41. Duvaldestin P, Kuizenga K, Saldien V, Claudius C, Servin F, Klein J, et al. A randomized, dose-response study of sugammadex given for the Cite this article as: Hemmerling TM, Zaouter C, Geldner G, Nauheimer D,. Sugammadex – A short review and clinical reccomendations for the cardiac reversal of deep rocuronium- or vecuronium-induced neuromuscular anesthesiologist. Ann Card Anaesth 2010;13:206-16. blockade under sevoflurane anesthesia. Anesth Analg 2010;110:74-82. 42. Abrishami A, Ho J, Wong J, Yin L, Chung F. Cochrane corner: Sugammadex, Source of Support: Nil, Conflict of Interest: None declared.

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