Sugammadex versus neostigmine in pediatric cancer patients undergoing outpatient surgical procedures

Neuromuscular blocking agents (NMBAs) are still required for the pediatric population. Residual neuromuscular block is a common complication in the early postoperative period. The objective of this study is to compare the ef(cid:977)icacy of sugammadex versus neostigmine for reversing NMB in pediatric patients with cancer who undergo outpatient surgical procedures. This double-blinded study included 80 children with different oncological diag-noses, aged 2-18 years, scheduled for outpatient surgical procedures. They were randomly divided into two equal groups; Group N received neostigmine 0.03 mg/kg with atropine 0.02 mg/kg and Group S received sugammadex 2 mg/kg at the end of surgery. The patients were clinically assessed for NMB recovery and extubated. The primary outcome measure was the time from NMB reversal to recovery of the TOF ratio to 0.9% (recovery time). The secondary outcomes included the time between reversal injection and extubation (extubation time) and possible adverse events. The time to recovery of the TOF ratio to 0.9 and the time between reversal injection and extubation were signi(cid:977)icantly shorter in S Group (p< 0.001). The time to reach TOF ratio of 0.9 was not correlated with age, anesthesia time, or the dose of the neuromuscular blocker. None of the children developed respiratory depression or postoperative residual curarization. Relatively few patients developed arrhythmia, hypotension, and nausea and vomiting with no signi(cid:977)icant difference between the two groups. Sugammadex is a good alternative to neostigmine for reversal of neuromuscular block in outpatient surgical procedures in children with cancer; it safely provides faster NMB reversal and extubation time.

Sugammadexneostigmine, pediatriccancer-outpatient procedures ABSTRACT Neuromuscular blocking agents (NMBAs) are still required for the pediatric population. Residual neuromuscular block is a common complication in the early postoperative period. The objective of this study is to compare the ef icacy of sugammadex versus neostigmine for reversing NMB in pediatric patients with cancer who undergo outpatient surgical procedures. This double-blinded study included 80 children with different oncological diagnoses, aged 2-18 years, scheduled for outpatient surgical procedures. They were randomly divided into two equal groups; Group N received neostigmine 0.03 mg/kg with atropine 0.02 mg/kg and Group S received sugammadex 2 mg/kg at the end of surgery. The patients were clinically assessed for NMB recovery and extubated. The primary outcome measure was the time from NMB reversal to recovery of the TOF ratio to 0.9% (recovery time). The secondary outcomes included the time between reversal injection and extubation (extubation time) and possible adverse events. The time to recovery of the TOF ratio to 0.9 and the time between reversal injection and extubation were signi icantly shorter in S Group (p< 0.001). The time to reach TOF ratio of 0.9 was not correlated with age, anesthesia time, or the dose of the neuromuscular blocker. None of the children developed respiratory depression or postoperative residual curarization. Relatively few patients developed arrhythmia, hypotension, and nausea and vomiting with no signi icant difference between the two groups. Sugammadex is a good alternative to neostigmine for reversal of neuromuscular block in outpatient surgical procedures in children with cancer; it safely provides faster NMB reversal and extubation time.

INTRODUCTION
The relatively recent introduction of laryngeal masks for airway management has prejudiced the need for muscle relaxants in pediatric anesthesia (Sanwatsarkar et al., 2019). Also, the development of less-toxic, shorter-acting anesthetic drugs and adjuvants has challenged the necessity of using muscle relaxants (Meakin, 2007). However, neuromuscular blocking agents (NMBAs) will still be sometimes required to facilitate the surgeon's work and to reduce the volumes of anesthetic agents given for the pediatric population.
Unfortunately, postoperative residual curarization (PORC)is still common and usually undetected event in the early postoperative period (Cammu et al., 2006) that can contribute to morbidity in patients recovering from general anesthesia (Murphy et al., 2008). It is de ined as the presence of a T4/T1 ratio< 0.9 in response to the "trainof-four" (TOF) stimulation (Viby-Mogensen, 2000). The incidence of residual neuromuscular block varies widely from 38 to 64% of patients receiving intermediate-acting NMBAs (Kim et al., 2002). Consequently, the use of NMBAs may be associated with postoperative respiratory complications, delayed discharge from the operating room and post-anesthesia care unit(PACU) and more extended hospital stay (McLean et al., 2015). Therefore, full restoration of muscle strength is vital to guarantee a safe postoperative recovery.
Controlling the effect of NMBAs encompasses two strategies; careful monitoring of neuromuscular transmission and reversal of blockade using acetylcholine sterase inhibitors like neostigmine which increase the amount of acetylcholine in the synaptic cleft (Herbstreit et al., 2010). However, due to the limitations of Anticholinesterases and complications of residual neuromuscular block, continuous research has been done to ind the ideal reversal agent. The ideal agent should have a fast onset, ef icient at any time, able to ensure complete recovery for light as well as profound block, and free of side effects (Hemmerling et al., 2010).
Sugammadex appears to approach this ideal formula. It is a modi ied γ-cyclodextrin, which is water soluble with a hydrophobic cavity capable of encapsulating steroidal neuromuscular blockers. It is selective for steroidal neuromuscular blocking drugs, with little to no af inity to bind to benzylisoquinolinium neuromuscular blockers (Naguib and Johnson, 2017).
The purpose of this study is to compare the ef icacy of sugammadex and neostigmine in overcoming the neuromuscular block in pediatric cancer patients undergoing ambulatory surgical procedures.

PATIENTS AND METHODS
This double-blinded study included 80 children with different oncological diagnoses, aged 2-18 years, class I or II of the American Society of Anesthesiologists (ASA), planned for outpatient surgical procedures (dental surgery, strabismus correction, enucleation, port-a-cathinsertion, etc…). The study has received approval from the local ethical committee. The person legally responsible for the child had signed a formal informed consent. Research procedures were applied according to the Helsinki declaration 2013.
Exclusion criteria included a history of hepatic or renal failure, the neuromuscular disorders, known drug hypersensitivity or history of malignant hyper-thermia.
The children were randomly divided into two equal groups. Group N received neostigmine 0.03 mg/kg and atropine 0.02 mg/kg. Group S received sugammadex 2 mg/kg at the end of surgery only when T2 reappeared on TOF stimulation. Randomisation was done through a Microsoft Excel created random number table. The neuromuscular blocker (NMB) reversal syringes were prepared and coded by an independent anesthesiologist not involved inpatient care or the collection of results, and delivered them to the clinical staff. The anesthesiologists responsible for the train of four (TOF) monitoring and results collection were blinded to the administration of NMB reversal.

Anesthesia
All patients received intravenous midazolam (0.05 mg/kg) as a premedication. Standard monitoring was implemented in the operating room, including electrocardiography (ECG), noninvasive arterial pressure measurement (NIBP), pulse oximetry (SpO 2 ), and End-Tidal CO 2 (EtCO 2 ). The degree of neuromuscular blockade (NMB) was monitored by the TOF pattern of nerve stimulation. TOF scan using the Nerve-muscle acceleromyography principle (TOF Draeger Medical Systems, Inc.16 Electronic Avenue, Danvers, MA 01923 USA) was placed on the ulnar nerve to trigger stimulation of the adductor pollicis muscle.
After adequate pre-oxygenation, anesthesia was induced with fentanyl 2µg/kg IV, propofol 1.5-2.5 mg/kg, and rocuronium 0.6 mg/kg to facilitate tracheal intubation. Maintenance of anesthesia was conducted with minimum alveolar concentration (MAC) of 1.2-2% iso lurane in air/oxygen mixture (1:1). Each 10 minutes, The TOF was measured. Rocuronium (0.15 mg/kg) was given when the TOF count became ≥ 1. Throughtout the procedure, Normothermia was preserved by the warming effect of air blankets.
Paracetamol was administered at the end of surgery for both groups, in a dose of 10 mg/kg IV. At the end of the procedure, patients were shifted to 100% O 2 under TOF monitoring. When T2 reappeared, Group N received 0.03 mg/kg of neostigmine and 0.02 mg/kg of atropine and Group S received 2 mg/kg sugammadex for the NMB reversal. Patients were clinically assessed for NMB recovery (sustained head-lift for 5 seconds or sustained handgrip for 5 seconds and extubated.
Using the modi ied Aldrete scoring system, patients were evaluated every 15 min until they were eligible for discharge from the PACU. The criterion used for discharge of patients was to achieve a modi ied Aldrete score of 9.
The primary outcome measure was the time from NMB reversal to recovery of the TOF ratio to 0.9% (recovery time). The secondary outcomes included the time between reversal injection and extubation ( extubation time), injection time (from last dose of NMB to reversal administration), TOF ratio before reverse, TOF ratio at extubation, length of anesthesia (time period between induction and cessation of iso lurane inhalation) and possible adverse effects such as PORC, arrhythmias, hypotension, nausea, vomiting or rash.

Statistical methods:
Statistical analysis was done using version 22 of IBM© SPSS© Statistics (IBM© Corp., Armonk, NY, USA). Numerical data were expressed as mean and standard deviation or as a median and range. Qualitative data were expressed as frequency and percentage. Chi-square test (Fisher's exact test) was used to investigate the relationship between qualitative variables. comparison between the two groups was made using independent sample t-test or Mann-Whitney test for quantitative data. Spearman-rho method was used to test the correlation between numerical variables. A p-value < 0.05 was considered signi icant.

RESULTS
The two groups were comparable in age, sex, and body weight ( Table 1). The anesthesia time and total dose of NMB between the two groups were not signi icantly different.
Also, there was no statistically signi icant difference between the two groups in the time of injection of the reversing drug (p = 0.227). TOF ratio in N Group was signi icantly higher in N Group before reversal injection (p=0.005), and signi icantly lower after reversal injection (p< 0.001). The time to achieve a TOF ratio of 0.9 was signi icantly shorter in S Group (p< 0.001). Similarly, the time between reversal injection and extubation was signi icantly shorter in S Group (Table 2).
The time to achieve a TOF ratio of 0.9 was not correlated with age, anesthesia time, or the dose of the neuromuscular blocker (Table 3).
None of the children in the two studied groups developed postoperative desaturation, respiratory depression, or postoperative residual curarization. Relatively few patients developed arrhythmia, hypotension, and nausea and vomiting with no signi icant difference between the two groups.

DISCUSSION
In general anesthesia, complete recovery from neuromuscular blocker is essential to avoid its potentially serious adverse effects, including impaired respiration, compromised laryngeal or pharyngeal function, aspiration, and PORC (Murphy and Brull, 2010). A recent study in a pediatric population conirmed that residual neuromuscular block (RNB) is common in the operating room (48%) and postoperative care units (27%). The authors found a relationship between age and RNB, where every year of increasing age was associated with an 8% risk reduction in the incidence of RNB (Klucka et al., 2019).
Therefore, administration of effecting reversal agents is vital, especially in younger age groups. The current study compared the relatively new sugammadex with the conventional reversal agent, neostigmine in children with various types of cancer subjected to outpatient surgical procedures. The need for rapid and successful NMB reversal is more pronounced in cases of outpatient procedures, especially in the pediatric population. The study demonstrated that sugammadex is superior to neostigmine in terms of signi icantly shorter recovery time from NMBAs and extubation time. Both drugs were not associated with serious postoperative respiratory complications of residual curarization. Adverse events were minor, with no signi icant difference between the two groups.
Few previous studies investigated the safety and ef icacy of sugammadex in the pediatric population. A recent retrospective study compared sugammadex to neostigmine in a large cohort of children. The authors reported signi icantly shorter reversal time in sugammadex-treated groups except for infants 1-12 months of age. The greatest difference was observed in the neonates. Fewer side effects were observed with sugammadex (Gaver et al., 2019). (Kara et al., 2014) compared the ef icacy of sugammadex 2 mg/kg and neostigmine 0.03mg/kg in 80 children aged 2 to 12 years subjected to outpatient surgery. In agreement with the current study, signi icantly shorter time to reach train-offour > 0.9 and extubation time in children treated with sugammadex (Kara et al., 2014). Another prospective randomized study included 60 children    Arrhythmia 3 (7.5%) 3 (7.5%) Hypotension 3 (7.5%) 4 (10.0%) Nausea 2 (5.0%) 2 (5.0%) Vomiting 3 (7.5%) 2 (5.0%) Data were expressed as number (%) aged 3-12 years with a history of bronchial asthma undergoing outpatient lower abdominal or urogenital surgeries. Similar results were observed as a signi icantly shorter time of NMB reversal and time of extubation with sugammadex. Minor complications were more common in the neostigmine group (Nada, 2017).
Several studies compared sugammadex with neostigmine in adults. Similar indings were reported in these studies.
Plaud found that sugammadex was ten times more rapid than neostigmine without concomitant administration of atropine (Plaud, 2009). Another study found it 18 times faster in recovery from profound rocuronium-induced NMB (Jones et al., 2008). In a randomized trial in 304 women undergoing elective laparoscopic gynecological surgery, (Paech et al., 2018) compared sugammadex with neostigmine. The reversal was more rapid with sugammadex with comparable postoperative nausea or vomiting (Paech et al., 2018).
In a multicenter study, time to reach a TOF ratio >0.9 was 1.4 min with sugammadex and 17.6 min with neostigmine (Khuenl-Brady et al., 2010). Other investigators reported comparable results in adults (Blobner et al., 2010). Pooled analysis on data from 26 multicenter, randomized, studies including 1855 adults was performed to compare sugammadex with neostigmine or placebo. Sugammadex provided a rapid reversal of rocuronium and vecuronium-induced NMB (Herring et al., 2017).
However, investigating safety and ef icacy of sugammadex in the pediatric population is essential as owing to the different behavior of NMB in adults and children. The NMB is dispersed within the extracellular area, which is relatively larger in children than in adults. Therefore, NMBAs produce lower plasma levels in children. Besides, neuromuscular junction in children is relatively immature. Thus, doses of NMBAs have to be increased in children to provide the same degree of the block as in adults. (Vuksanaj and Fisher, 1995) found that higher doses of rocuronium may be needed for rapid onset of effect in children (Vuksanaj and Fisher, 1995). The diaphragm contains mainly type I ibrin ibers in children making them more susceptible to NMB compared with other muscles. These factors collectively increase the risk of complications in children (Meretoja, 2010).
In the current study, we used a sugammadex dose of 2 mg/kg. This was based on previous studies. Different doses of sugammadex were compared in adult males ranging from 0.5 to 4 mg/kg. The authors found that the time to reach a TOF ratio > 0.9 was signi icantly shorter, with sugammadex doses ≥ 2 mg/kg (Sorgenfrei et al., 2006). Also, other studies con irmed the ef iciency of doses ≥ 2 mg/kg (Hogg and Mirakhur, 2009).
To the best of our knowledge, this is the irst study that investigates sugammadex in pediatric cancer patients subjected to outpatient surgical procedures related to their condition.

CONCLUSIONS
The administration of sugammadex for the reversal of neuromuscular block in outpatient surgical procedures in children with cancer appears to be a good alternative Sugammadex safely provides faster NMB reversal and extubation time compared to traditional drugs as neostigmine ACKNOWLEDGEMENT I am grateful to Allah for the good health and wellbeing that were necessary to complete this work.
I would like to thank my family for supporting me spiritually throughout writing this thesis and my life in general.

Con licts of interest
None to be declared Funding source self support