Sugammadex: Time to Fast-tracking Cardiac Surgery

INTRODUCTION

Fast tracking after cardiac surgery involves early weaning from mechanical ventilation and enhanced recovery.^[1-3] However, prolonged ventilation is common, especially following cardiac surgery and this adds to potential morbidity and mortality.^[4-6] There are potential challenges for early extubation in low-to-medium-risk cardiac surgeries, despite American College of Cardiology recommendation (class I).^[7] Residual Neuromuscular block (NMB) is a major contributing agent resulting in long mechanical ventilation and pulmonary complications after open heart surgeries.^[8] Further, this is the key factor for pulmonary adverse events postoperatively, such as hypoventilation, airway obstruction, and hypoxia, which may need reintubation.^[9,10] Because of the deep NMB along with muscarinic side effects, traditional reversal drugs like neostigmine are usually avoided in cardiac surgical patients.^[11]

Sugammadex is a gamma-cyclodextrin ring which quickly neutralizes NMB by engulfing nondepolarizing amino steroid muscle relaxants such as rocuronium and vecuronium.^[12] Moreover, muscarinic side effects, which are commonly encountered with neostigmine reversal were not seen with sugammadex.^[13] However, evidence of anaphylaxis, hypotension, and arrhythmias was reported with sugammadex reversal.^[14-16] In addition, the Food and Drug Administration enlisted sugammadex as a reversal agent to neutralize non-depolarizing neuromuscular blocking drugs (NMBDs) in a wide spectrum of surgeries, but its utilization following cardiac surgery is ambiguous due to limited evidence.^[17] As sugammadex does not have anti-cholinesterase activity, it can even be used in patients following cardiac transplantation.^[18] However, bradycardia and cardiac arrest can apprise a significant adverse effect of sugammadex. Furthermore, various trials give contradictory statements regarding its utility in cardiac surgery. Therefore, the authors synthesize the recent literature pertinent to the use of sugammadex in cardiac surgery to pave the way for clinical decision-making.

SUGAMMADEX: AN INNOVATION IN ANESTHESIA PRACTICE

Molecular structure

Sugammadex is a modified gamma-cyclodextrin and it has eight similar hydroxyl chains that bond to form a cyclical ring with a hydrophilic outer surface and a hydrophobic core.^[12,19] Its three-dimensional structure bears resemblance to a doughnut [Figure 1].

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Figure 1:

Structure of sugammadex; (a) molecular, (b) 3Dimensional.

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Mechanism of action

Sugammadex reverses NMB by encapsulating the NMBDs.^[12,13] The core of sugammadex traps the NMBDs such as vecuronium and rocuronium. Hence, this non-covalent hydrophobic bond attaches to NMBDs, forming a hydrophilic complex. This reduces plasma concentration of free NMBDs; consequently, free NMBDs are mobilized from the muscle compartment to the plasma and the vicious cycle continues.^[13] Similarly, the amount of NMBDs at the nicotinic acetylcholine receptor in the neuromuscular junction decreases rapidly, allowing resumption of neuromuscular activity.^[19] Sugammadex does not have muscarinic side effects like traditional neostigmine; thus, concomitant administration of an antimuscarinic agent like glycopyrrolate is not required.

The association constant between rocuronium and sugammadex is very high (1.79 × 10 mol/L).^[20] The more the value of the constant, the more is the bonding among the agents. Furthermore, the ratio of sugammadex and rocuronium combination complex to its dissociations is 25,000,000:1.^[21] Therefore, encapsulated rocuronium by sugammadex is irreversible and fixed. The vecuronium and sugammadex combination has a lower association constant (5.72 × 10 mol/L)^[20] [Figure 2]. Further, vecuronium has a higher potency almost 6 times than rocuronium, and therefore, is used in lesser dose.^[20] The combination of NMBDs with sugammadex is executed in a ratio of 1:1. Therefore, the lesser vecuronium and sugammadex association constant is weighted versus reduced vecuronium molecules. Hence, sugammadex has similar efficacy in neutralizing vecuronium as well as rocuronium.

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Figure 2:

Sugammadex rocuronium complex.

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SUGAMMADEX: THE LITERATURE REVIEW IN CARDIAC SURGERY

Sugammadex has been tried for adult as well as pediatric surgeries but the evidences were limited. Bardia et al.,^[28] demonstrated that sugammadex administration in cardiac surgical patients causes reduction of extubation time by approximately 1 h. Although the extubation time was significantly lower, no clinical differences were noted in negative inspiratory force between sugammadex and placebo.As 90 patients undergoing elective cardiac surgeries were included, larger trials are required to determine the clinical implications.

As per Yuki and Scholl,^[29] sugammadex had similar effects in denervated as well as innervated hearts. Furthermore, despite a lack of muscarinic side effects, it can still cause hemodynamic instability. Thus, sugammadex should be administered cautiously to heart transplant patients and preparation for hemodynamic changes is essential. Another study^[30] compared neostigmine and sugammadex in 90 adults with cardiac pathologies; they showed reduced heart rate and blood pressure with sugammadex reversal than traditional neostigmine. Arends et al.,^[31] studied variation in heart rate after sugammadex administration to children with congenital heart disease and found bradycardia in 20% patients. They concluded a lower incidence of bradycardia after sugammadex reversal, even in children with congenital cardiac pathologies. Bradycardia did not cause clinically significant hemodynamic changes and did not warrant further management.

Lam et al.,^[32] reported a substantial reduction in total intubation time following coronary artery bypass grafting by sugammadex reversal. It is in accordance with fast-track extubation protocol but could not exceed the 6-h benchmark. Furthermore, the risks of adverse effects such as anaphylaxis, heart failure, and complications such as hypoxemia and tachypnea were unaltered following sugammadex reversal. Therefore, it could reduce costs incurred due to prolonged intubation time and related complications. Deshpande and Purandare^[33] reported a successful management of cochlear implant surgery in an 83-year-old male patient with a history of coronary artery disease, atrial fibrillation, and interstitial lung disease by using sugammadex and rocuronium combination.^[32]

Martin et al.,^[34] demonstrated effective reversal of NMBDs by sugammadex to facilitate early tracheal extubation in pediatric patients after congenital cardiac surgeries. Early reversal of NMBDs allows fast-tracking after pediatric cardiac surgeries. Although no clinically significant bleeding complications were noted, mild elevation in the activated partial thromboplastin time as well as prothrombin time was noted with higher doses of sugammadex (16 mg/kg).

Xiaobing et al.,^[35] studied sugammadex effect on pulmonary complications postoperatively in pediatrics with congenital cardiac pathologies undergoing elective cardiac surgery. The postsurgical recovery time to achieve 0.9 TOF and extubation time were remarkably less in the sugammadex cohort. Further, levels of inflammation markers like procalcitonin were lower in children reversed with sugammadex. However, remarkable side effects were observed.

SUGAMMADEX: PRO VERSUS CON

Sugammadex works by encapsulating NMBDs, and further, sugammadex reversal is rapid, predictable, and carries a minimal risk of recurarization.^[13,14] Despite remarkable efficacy for reversal by sugammadex; routine quantitative neuromuscular monitoring during its use remains a topic of debate.

Sugammadex can reverse various grades of NMB due to either rocuronium or vecuronium.^[13,14] Adequate reversal from NMB is considered as 0.9 TOF ratio, and sugammadex causes not only effective but also reliable reversal of NMBDs.^[36,37] A randomized, multicentric trial confirmed sugammadex recipients recovered adequately within 5 min and had a better predictability of response.^[36] Another randomized controlled trial confirmed a 4.7 times faster recovery with a 0.9 TOF ratio in response to sugammadex than neostigmine.^[37] Both studies confirmed the absence of adverse events related to residual NMB with sugammadex reversal.^[36,37]

Although sugammadex is an effective and reliable reversal agent, it may still cause incomplete reversal, especially with deep NMB. In a recent trial, only <3% patients could not be reversed with the appropriate body weight-based sugammadex dose regimen and required additional sugammadex.^[14] The incidence of incomplete or partial reversal is minimal for moderate block (2.8%) and deep block (1%) with sugammadex as reported by recently performed systematic review and meta-analysis.^[38] They have also confirmed that incomplete or partial reversal is an almost rare event with sugammadex administration.

Overall, sugammadex has a fast onset within 1–5 min, complete reversal with only 2% risk of recurarization, safer as no side effects, and durable with only 3% needing higher than the prescribed dose. Further, vecuronium and rocuronium-induced blockade, and reversal by sugammadex, might not require the use of quantitative neuromuscular monitoring. At times, peripheral nerve stimulator-guided qualitative neuromuscular monitoring might be enough. Kotake et al.,^[39] observed that without neuromuscular monitoring, the TOF ratio <0.9 after extubation remained elevated despite sugammadex reversal. Further, the sugammadex dose might need to be titrated according to nerve stimulator-based qualitative assessment. If the twitch response reaches 1–2 post-tetanic counts or no twitch in response to TOF stimulation following NMB, higher dose of 4 mg/kg of actual body weight is sufficient. If second twitch is present in response to TOF stimulation, 2 mg/kg sugammadex is prescribed. Thus, a qualitative neuromuscular monitoring can guide the administration of sugammadex in appropriate doses and avoid residual NMB.

Quantitative neuromuscular tracking is an advanced technology but resource-utilizing modality. These monitors need regular calibration, periodic maintenance, and teaching technical staff for proper measurements. Lack of skill and knowledge leads to technical errors and inaccurate readings, thereby limiting the utility of quantitative neuromonitoring. Even, it adds new steps to anesthesia care, as the technician should confirm proper placement of sensors and regular calibration of the device. Not only it adds to human error but also extends patient recovery in case of device impairment or unskilled personnel to use the monitoring system.

Routine utilization of neuromuscular monitoring and requirement of additional time as well as costs were other disadvantages.^[40] The financial cost incurred due to the machinery cost and time required for its setup and regular calibration. Further, every disposable stimulation and monitoring leads add cost to the monitoring system. Therefore, addition of this monitoring system in every operating area may inflict additional financial burden on the health care setup. However, studies have shown cost benefits with the use of sugammadex. This is because the time to recovery was less with sugammadex; thereby, less hospital length of stay which incurs less cost.^[22,24] Systematic reviews and economic evaluation studies reported that sugammadex is cost-effective in comparison to neostigmine due to reduced anesthesia time in the operating theater. Another trial by De Boer et al.,^[41] demonstrated that early recovery with sugammadex yields faster patient turnover and efficient resource utilization. In this context, hospitals may balance the expense incurred due to regular quantitative neuromuscular monitoring with reliable, faster, and recovery with sugammadex.

SUGAMMADEX: TRANSFORMING PERIOPERATIVE PATIENT SAFETY

Corrugator supercilii muscle is used for neuromuscular monitoring to assess muscle relaxation during cardiac surgery, as it mostly represents the core muscles.^[42] In cardiac surgeries, higher doses of NMBDs were given to improve core muscle relaxation and improve surgical maneuvers. However, such a profound block would interfere with early extubation and enhanced recovery. However, now, it is feasible with the introduction of sugammadex.

The neostigmine and glycopyrrolate combination has usually been avoided in cardiac surgeries due to its arrhythmogenic potential. Further, glycopyrrolate overdosing causes tachyarrhythmias whereas underdosing leads to bradyarrhythmia due to unopposed muscarinic side effects of neostigmine. Therefore, sugammadex can be employed as a reversal agent, especially in fast-tracking cardiac surgeries. The use of sugammadex in cardiac surgery is mainly to rescue reversal in failed intubation, reversal for early extubation at the termination of surgeries, or to neutralize NMB in the intensive care unit to facilitate early extubation.

CONCLUSION

Sugammadex unquestionably provides a new scope for fast tracking with enhanced recovery following cardiac surgeries. Sugammadex is a major breakthrough for early weaning from mechanical ventilation and improving patient outcomes following cardiac surgery. Sugammadex provides a higher flexibility and better titration over wide depths of NMB, especially in deep NMB which is paramount in cardiac surgeries. However, a clear understanding of various adverse outcomes has yet to be explored, and thereby, large multicentric trials are required to evaluate the efficacy of sugammadex in broad-spectrum cardiovascular diseases.