Recovery Profile of Sugammadex versus Neostigmine in Pediatric Patients Undergoing Cardiac Catheterization: A Randomized Double-Blind Study.

Background: Sugammadex is a selective reversal agent which has the ability to reverse deep neuromuscular blockade. However, there are still controversial results as regard sugammadex effects on the quality of recovery. We hypothesized that Sugammadex may have better recovery profile compared to neostigmine in pediatric patients with congenital heart diseases undergoing cardiac catheterization. Patients and
Methods: This prospective randomized double-blind study included 50 pediatric patients aged <2 years who were divided into two groups according to the reversal agent used; Group S (Sugammadex) and Group N (Neostigmine). Both groups received the same anesthetic technique during cardiac catheterization, and basic hemodynamic monitoring was ensured in both groups. After the procedure, reversal was done using 4 mg.kg‒1 sugammadex or 0.04 mg. kg‒1 neostigmine plus 0.02 mg. kg‒1 atropine according to the group allocation. Recovery time and side effects were recorded.
Results: The two groups showed comparable findings regarding demographics. Nonetheless, the total time of anesthesia had mean values of 91.06 and 101.25 min in the two groups, respectively (P = 0.003), while recovery time had mean values of 1.61 and 9.23 min in the same groups, respectively (P < 0.001). Hemodynamic profile (heart rate and mean arterial pressure) was better after reversal with sugammadex. Blood sugar levels and side effects showed no significant difference between both groups.
Conclusion: Sugammadex can be a more rapid and effective alternative to neostigmine for reversal of rocuronium-induced neuromuscular blockade in pediatric patients undergoing cardiac catheterization. Copyright:

INTRODUCTION

Technological innovations in the medical field have changed cardiac catheterization in pediatrics from only a diagnostic tool for congenital heart diseases (CHD) toward the ability to perform some therapeutic interventions for such diseases.[12]

The development of cardiac devices and imaging gives a great range of options other than surgery, and they could even postpone or replace surgery.[34] However, reports from the perioperative cardiac Arrest registry in Pediatric found that about one-third of cardiac arrests occurred in children with CHDs, 17% of them occurred during cardiac catheterization.[5] Thus, the anesthesiologist in the catheterization lab should be familiar with CHDs and the specific limitations of this environment.[67]

Neuromuscular blocking drugs are frequently used during anesthesia to facilitate intubation, ventilation and immobility during surgery. Reversal drugs are usually administered to accelerate recovery and prevent postoperative residual blockade.[89]

One must consider that the quality of recovery is an essential factor that must be assessed in all patients undergoing surgery under general anesthesia.[10] In the past, the only option for reversal of the effect of neuromuscular blockers was cholinesterase inhibitors, which cannot be used in profound neuromuscular blockade. Also, these drugs have a variety of cholinergic side effects which need administration of an anticholinergic drug, with the adverse effects related to it.[11]

Sugammadex is a selective reversal agent which has the ability to reverse deep neuromuscular blockade.[12] However, there are still controversial results as regard sugammadex effects on the quality of recovery.[13]

In December of 2015, the US Food and Drug Administration approved sugammadex administration in adults. Although it has been used in Europe and elsewhere for the last decade, few data are published about its safety and efficacy in the pediatric population. Especially in the age <2 years old, there are minimal data available.[14] Pediatric differ from adult patients because the pharmacokinetics and pharmacodynamics of the neuromuscular blockers may change according to age.[15]

The current study was conducted to compare Sugammadex versus neostigmine as reversals to the neuromuscular blockade of rocuronium in pediatric patients undergoing cardiac catheterization.

PATIENTS AND METHODS

This prospective, randomized, controlled, and double-blind study was carried out in Mansoura University Children Hospital from January 2020 to November 2020, after approval by the local ethical and scientific committee Institutional Research Board-Mansoura Faculty of Medicine with reference number (MS.19.08.759, September 2019), the study was registered in February 2020 Clinical Trials.gov with registry number NCT04258007 and obtaining written informed consents from the legal guardians of each patient. This study was done according to the Declaration of Helsinki and good clinical practice (Brazil, 2013).

This study was carried out on 50 patients of either sex, aged <2 years, classified as American Society of Anesthesiologists physical status[16] (ASA PS) Classes I, II, III and diagnosed with CHDs who were admitted to the same hospital for cardiac catheterization. Conversely, any patients with liver failure, kidney failure, known drug hypersensitivity, diseases affecting neuromuscular junction, or previous history of malignant hyperthermia or having ASA PS Classes VI and V were excluded.

The included cases were randomly allocated (using the closed envelope method) into two equal groups, Group N included 25 patients who received neostigmine, and Group S included the remaining 25 cases who received Sugammadex. All patients were assessed clinically and radiologically before intervention. Furthermore, routine laboratory investigations were ordered.

All patients were kept fasting for 4–6 h before catheterization. On arrival to the recovery room, vascular access was secured and all patients were premedicated with midazolam (0.05 mg.kg‒1 [i.v.]). At the catheterization room, basic preanesthetic monitoring including pulse, blood pressure, electrocardiography, oxygen saturation, and axillary temperature was established. The train-of-four (TOF) Watch SX monitor; (Organon, Dublin, Ireland, 2011) was placed on the ulnar nerve trace and transducer on thumbs of the patient.

Patients preoxygenated with 100% O2 for 3–5 min, general anesthesia was induced in both groups with 1–2 mg.kg‒1 Ketamine, 1 μg.kg‒1 Fentanyl and 0.6 mg.kg‒1 Rocuronium (®Esmeron) (Adjusted according to hemodynamics). About 90 s after induction dose of Rocuronium, patients were intubated by oro-tracheal tube with suitable size (End-Tidal CO2) was monitored. The first TOF ratio was calibrated, normalized, and measured before and after injection of rocuronium.

Anesthesia was maintained with sevoflurane 2% and 50% O2_50% air. Subsequent doses of 0.2 mg.kg‒1 rocuronium were administered every 20 min to ensure adequate muscle relaxation guided by the TOF monitor.

At the end of surgery, sevoflurane was maintained at low minimum alveolar concentration (MAC) <1% (in order to avoid any interaction with muscle relaxation and If the TOF count is 3 or less, the patient was kept anesthetized or deeply sedated until the 4th twitch was clearly present.

When T2 reappeared, Group S (n = 25) received 4 mg.kg‒1 sugammadex whereas Group N received 0.02 mg.kg‒1 atropine plus 0.04 mg.kg‒1 neostigmine for neuromuscular block reversal. Patients switched to 80% O2. Hemodynamic parameters were recorded at baseline, after induction, just before reversal, and at 1, 2, 3, 4, 5, 7, 10, 15 min following reversal.

Blood sugar was recorded at baseline, 15 min before reversal and 30 min after it. When TOF reached 90%, anesthesia was completely terminated and patients were assessed clinically for neuromuscular recovery (tidal volume, movement, and eye opening) and then extubated. The total time of anesthesia was recorded.

The recovery time (time to reach TOF 0.90) was recorded, and this was our primary outcome. Secondary outcomes included hemodynamic changes after administration of either drugs, and reported side effects (bradycardia, hypotension, anaphylaxis, bronchoconstriction, vomiting, hypoglycemia, and hypersalivation). Bradycardia and hypotension were defined by more than 20% decrease of the basal heart rate and blood pressure, respectively.

Sample size calculation

The power of this study was calculated using the G power analysis program using a priory type of analysis. A pilot study held in Mansoura University Children Hospital on 10 pediatric patients (five patients in each group) was resulted in effect size 0.9 and α error of 0.05 with a desired power of 0.9. The primary outcome was the recovery time (the time interval between reappearance of T2 and TOF 90%). Twenty-two patients were required per group, and to compensate for dropout cases, 25 patients per group were used.

Statistical analysis

We used Statistical Package for the Social Sciences (SPSS 26, IBM/SPSS Inc., Chicago, IL, USA) software doe data analysis. Categorical data were expressed as frequencies and percentages (%) while in the quantitative data, we used mean and standard deviations. To compare two groups with categorical variables, Chi-square test (or Fisher's exact test) was used. To compare two groups with normally distributed quantitative variables, independent sample t-test was used and Mann–Whitney U-test was used if the data were abnormally distributed. P < 0.05 is considered significant.

RESULTS

Flow diagram of patient recruitment is shown in Figure 1.

Figure 1

Flow diagram for participants

Demographic criteria showed no significant differences between the two groups (P > 0.05). Age had mean values of 9.19 and 7.43 months in Groups S and N, respectively. Regarding gender, boys represented 48% and 52% of cases in the same groups, respectively, whereas the remaining portion was occupied by girls.

Most of the included cases were classified as ASA PS Class III (72% and 76% of cases in the two groups, respectively), while the remaining cases were ASA PS Class II. Regarding the indication of intervention, pulmonary stenosis was most common cause (40% of cases in both groups), followed by patent ductus arteriosus (28% and 24% of cases in the same groups, respectively). Other indications included aortic stenosis, atrial septal defect, ventricular septal defect, coarctation of aorta, and pulmonary atresia. The previous data are summarized in Table 1.

Table 1

Demographic criteria, American Society of Anesthesiologists class, and indication for catheterization in the study groups (n=25)

	Group S, n (%)	Group N, n (%)	P
Age (years)	9.19±7.253	7.43±6.903	0.384
Gender
Male	12 (48)	13 (52)	0.777
Female	12 (52)	12 (48)
Weight (kg)	7.32±2.774	7.00±3.473	0.717
Height (cm)	67.72±12.992	62.92±11.920	0.180
ASA class
II	7 (28)	6 (24)	0.747
III	18 (72)	19 (76)
Diagnosis
PDA	7 (28)	6 (24)	0.725
AS	4 (16)	3 (12)
PS	10 (40)	10 (40)
ASD	1 (45)	1 (4)
VSD	2 (8)	2 (8)
COA	0	3 (12)
Pulmonary atresia	1 (4)	0

AS=Aortic stenosis, ASA=American Society of Anesthesiologists, ASD=Atrial septal defect, COA=Coarctation of aorta, PDA=Patent ductus arteriosus, PS=Pulmonary stenosis, VSD=Ventricular septal defect

Table 2 shows that no significant difference was noted between the two groups regarding the intervention performed (P = 0.639). Balloon valvuloplasty was performed in 56% and 52% of cases in the two groups, respectively, followed by patent ductus arteriosus (PDA) closure (28% and 24% of cases in the same groups, respectively). Other procedures included ASD closure and PDA stent, while it was used only for diagnostic purpose in two cases in either group (8%).

Table 2

Type of procedure, duration of catheterization, duration of anesthesia, and recovery time in the study groups (n=25)

	Group S, n (%)	Group N, n (%)	P
Intervention
PDA closure	7 (28)	6 (24)	0.639
ASD closure	1 (4)	1 (4)
Diagnostic	2 (8)	2 (8)
Balloon valvuloplasty	14 (56)	13 (52)
Balloon angioplasty	0	3 (12)
PDA stent	1 (4)	0
Duration of catheterization (min)	84.13±9.500	86.92±13.224	0.396
Duration of anesthesia (min)	91.06±9.887	101.25±13.138	0.003
Recovery time (min)	1.61±0.504	9.23±3.710	<0.001

PDA=Patent ductus arteriosus, ASD=Atrial septal defect

The duration of the catheterization procedure was comparable between the two groups (84.13 versus 86.92 min in the same groups, respectively – P = 0.396). Nevertheless, the duration of anesthesia showed a significant prolongation with neostigmine administration (101.25 vs. 91.06 min in Group S – P = 0.003). It was evident that recovery time was significantly shorter with Sugammadex use (1.61 vs. 9.23 min in Group N – P < 0.001).

No significant differences were noted between the two groups regarding mean arterial blood pressure changes either before or after reversal, apart from three readings (5, 7, and 10 min after reversal) that showed significantly higher values in Group N (P < 0.05). Table 3 shows these data.

Table 3

Mean arterial blood pressure (mmHg) changes in the study groups

MAP (mmHg)	Group S (n=25)	Group N (n=25)	P
Before reversal (min)
Basal	67.00±13.644	64.68±10.896	0.510
15	62.64±11.622	60.48±8.968	0.465
30	60.04±11.574	59.36±8.602	0.815
45	59.72±11.614	57.24±10.849	0.439
60	59.60±11.543	57.84±9.330	0.556
75	61.22±12.340	58.67±9.035	0.442
90	59.70±12.711	54.20±11.253	0.319
Just before	63.04±11.949	61.28±7.808	0.540
After reversal (min)
1	62.16±10.471	61.44±7.869	0.785
2	61.32±10.475	63.96±8.309	0.328
3	60.84±10.193	64.44±8.332	0.178
4	61.16±10.311	64.40±7.895	0.218
5	60.40±10.496	68.00±8.098	0.006
7	61.00±10.480	67.24±7.639	0.020
10	61.76±10.072	69.12±9.440	0.010
15	62.44±10.736	63.16±7.116	0.781

MAP=Mean arterial pressure

As illustrated at Table 4, although heart rate readings were comparable between the two groups before reversal (P > 0.05), most readings after reversal showed a significant increase in that parameter with neostigmine administration.

Table 4

Heart rate (bpm) changes in the two study groups

Heart rate (bpm)	Group S (n=25)	Group N (n=25)	P
Before reversal (min)
Basal	148.40±13.370	143.88±13.956	0.248
15	136.80±12.997	132.24±12.468	0.212
30	131.60±13.061	128.08±12.688	0.339
45	127.16±13.146	124.88±12.892	0.539
60	124.68±15.272	124.60±12.780	0.984
75	124.78±13.460	126.48±11.729	0.660
90	123.88±18.161	127.90±13.287	0.594
Just before	127.04±14.884	128.24±10.109	0.740
After reversal (min)
1	124.56±14.861	128.00±9.862	0.340
2	124.52±14.497	133.16±9.728	0.017
3	124.80±13.979	132.28±9.715	0.033
4	124.84±13.619	133.40±9.721	0.014
5	124.48±13.953	137.56±9.452	<0.001
7	124.76±15.092	135.88±9.765	0.003
10	126.20±14.344	138.12±10.361	0.001
15	127.96±14.530	129.56±10.112	0.653

No significant difference was noted between the two groups regarding blood glucose levels (P > 0.05). Table 5 shows these findings.

Table 5

Blood sugar levels (mg/dl) in the two study groups

Blood sugar (mg/dl)	Group S (n=25)	Group N (n=25)	P
15 min before reversal	109.80±14.720	114.44±10.227	0.202
30 min after reversal	131.56±13.048	126.46±10.538	0.140

There was no significant difference between the two groups regarding postoperative complication rates (P = 0.446) as illustrated in Table 6.

Table 6

Postreversal events in the study groups (n=25)

Complications	Group S, n (%)	Group N, n (%)	P
Vomiting	2 (8)	2 (8)	0.446
Hypotension and bradycardia	2 (8)	0
Bleeding	1 (4)	0

DISCUSSION

We conducted the current study at Mansoura University hospitals aiming to compare the recovery profile of Sugammadex versus neostigmine in pediatric patients <2 years scheduled for cardiac catheterization. We included a total of 50 cases who were divided into two groups; group S received Sugammadex and group N received neostigmine.

Our results showed that the time from administration of reversal (T2 reappearance) to TOF 90% was significantly shorter (5.7fold faster) in Sugammadex group than Neostigmine group. Besides, total time of anesthesia was significantly longer in Neostigmine group when compared to Sugammadex group despite no significant difference regarding catheterization time.

It is well established that neostigmine provides slow recovery when administered for reversal of profound block.[17] Neostigmine acts by inhibition of acetylcholinesterase, the enzyme which metabolizes acetylcholine. This allows acetylcholine building up at the neuromuscular junction to overcome the competitive inhibition of neuromuscular blockers. The fewer the receptors occupied by these drugs, the faster the action of neostigmine. This is in contrast to sugammadex which encapsulate rocuronium effectively leading to clearance of rocuronium molecules from the neuromuscular junction, liberating nicotinic acetylcholine receptors and restoring neuromuscular transmission.[181920]

This prompt and smooth reversal of the neuromuscular block appears to have important clinical implications on pediatric patients with CHDs. Early extubation not only reduces the morbidity related to tracheal tube and mechanical ventilation such as accumulation of secretions, atelectasis, nosocomial infections, and airway trauma but also limits the need for sedation with its adverse effects including depression of respiratory and hemodynamic functions, delirium, tolerance and withdrawal. Most importantly, the shift from positive pressure to spontaneous ventilation can augment cardiovascular functions and improve preload.[21]

These results come in agreement with the results reported by Ozgün et al. who compared sugammadex and neostigmine in a randomized double-blinded clinical trial in 60 pediatric patients aged between 2 and 12 scheduled for ENT surgery. In their study, inhalation agents were sustained until TOF 0.9 point. Mean time to TOF 0.9 was 1.13 min (0.5–5.2 min) for Sugammadex group versus 6.53 min (2.91–12 min) for the neostigmine group.[22]

Moreover, our results also agreed with the results of Li et al., who included a total of 60 children aged 1–6 years undergoing cardiac surgery. Authors found that the recovery time to TOF 0.9 and extubation time was significantly shorter in the sugammadex group than in neostigmine group (3.4 ± 1.2 min vs. 76.2 ± 20.5 min and 31.0 ± 6.4 min vs. 125.2 ± 21.6 min, respectively).[23]

Kara et al. compared 0.01 mg.kg‒1 atropine and 0.03 mg.kg‒1 neostigmine with 2 mg.kg‒1 sugammadex as reversal to rocuronium in 80 patients aged 2–12 years, scheduled for abdominal and urogenital surgeries. They realized that time to reach TOF ≥0.9 was four-fold faster in sugammadex group (0.46 ± 0.70 min) than in the neostigmine group (1.97 ± 2.14).[24]

The recovery time in our study was faster than the study conducted by Ghoneim and El Beltagy which found that sugammadex at dose of 4 mg.kg‒1 reversed the neuromuscular block and the TOF reached 90% in a mean duration of (1.4 ± 1.2 min) which was 18 folds faster than that achieved by the neostigmine at the dose of 40 μg.kg‒1 combined with atropine 0.02 mg.kg‒1 in mean of (25.2 ± 6.5 min) in pediatric patients undergoing neurosurgery without any major adverse events.[25]

This result is probably related with our patients’ age group since elimination and biotransformation of drugs are more rapid in younger patients. Faster circulation times and increased cardiac output increase the delivery of these agents to neuromuscular junction, leading to more rapid onset of action and more rapid removal of muscle blockers.[26]

Alonso et al., in their study of 23 newborns of whom 8 were 1-day old and 15 were 1–7-day old, applied antagonization with sugammadex at a dose of 4 mg.kg‒1 and found that the time to reach TOF above 0.9 was 1.4 min for 1-day-old patients and 1.2 min for 1–7-day-old patients.[27]

Furthermore, our results correlate with a previous study by Sacan et al. who found that sugammadex at 4 mg.kg‒1 reversed rocuronium-induced neuromuscular block (by reaching TOF ratio to 90%) by 10 folds faster than that achieved by neostigmine combined with glycopyrrolate.[28] In a 2-day-old newborn with prolonged central and peripheral neuromuscular blockage due to rocuronium infusion following tracheal esophageal fistula repair, the central nervous system effects were successfully reversed with sugammadex.[29]

Our study showed that total time of anesthesia was significantly shorter in Sugammadex group than neostigmine group (P = 0.003). These results can be explained by sevoflurane inhalation that was maintained to low MAC <1% until TOF 0.9 (to avoid any interaction with muscle relaxation and if TOF count is 3 or less), the patient needs to be kept anesthetized or deeply sedated until T4 is clearly present.

This comes in agreement with the results of Deyhim et al. on 640 surgical cases who found that Anesthesia duration was significantly shorter for sugammadex compared to neostigmine/glycopyrrolate. and The time from medication administration to exit from the odds ratio was significantly shorter for sugammadex compared to neostigmine/glycopyrrolate.[30]

In terms of hemodynamic changes, our study demonstrated that the patients in sugammadex group remained stable regarding the arterial blood pressure and heart rate during the entire observation time before and after reversal. This is in contrast to those patients in the neostigmine group who demonstrated significant rise in both parameters values at some time points after administration of reversal drugs.

These results can be explained by concomitant administration of atropine with neostigmine. Sugammadex does not appear to bind to any receptors, so it does not have any significant hemodynamic effects. In addition, the sugammadex–rocuronium complex is inert, so it does not cause any muscarinic effect.[31]

Kara et al. compared neostigmine with sugammadex (2 mg.kg‒1) for reversal of rocuronium in eighty patients aged (2–12) years. They found no significant effects on heart rate with sugammadex; but, neostigmine resulted in significant increases in the mean heart rate at 2, 5, and 10 min after administration.[24]

In a previous study compared the hemodynamic parameters between sugammadex (3 mg.kg‒1) and neostigmine (0.03 mg.kg‒1) in 90 adult cardiac patients scheduled for noncardiac surgery, heart rate was significantly higher after neostigmine administration compared to sugammadex. There were higher diastolic, systolic, and mean arterial blood pressure values after neostigmine administration than sugammadex. Authors concluded that sugammadex provides more a stable cardiac function in cardiac patients.[32]

Our findings showed no significant difference between the two groups regarding blood sugar measurements. However, there was a significant increase 30 min after reversal compared to 15 min before reversal in both groups.

Another study compared between sugammadex and neostigmine in 60 adult patients scheduled for abdominal surgery. Level of blood glucose was significantly higher after sugammadex administration compared to neostigmine in acute postoperative period. They considered that sugammadex contains glucose molecules and doesn't bind to plasma proteins can cause increased level of blood glucose, and this increase may be related to chemical structure of sugammadex rather than surgical stress. They evaluated blood glucose levels at 2 and 4 h after extubation to distinguish between the two causes. Thus, they considered an increase of blood glucose at 30th min after extubation may be associated with early postoperative stress. However, the blood glucose levels were also significantly higher 2 and 4 h after extubation in sugammadex group. they concluded that it was associated with the chemical structure of sugammadex.[33]

In our study, there was no statistically significant difference between the two groups in the incidence of postreversal events. This can be explained by small sample size in our study and short duration of postoperative monitoring.

Another study in 60 children aged 1–6 years undergoing cardiac surgery found that the incidences of bradycardia, hypotension, hypoxemia, nausea, and vomiting were similar between the 2 groups (P > 0.05).[23] Another study confirmed the previous findings.[11] In addition, Ozgün et al. could not found any significance regarding vomiting-nausea.[22]

Our study has some limitations; small sample size was among the limitations of the present study. A larger population is required to study the safety of sugammadex in this age group. Another limitation was the short period of follow-up postoperative as we focused on the immediate postoperative period.

We recommend the conduction of additional studies on pediatrics, particularly in neonates and infants with larger sample size and longer duration of observation after intervention to clearly determine the safety and efficacy of sugammadex in such patients.

CONCLUSION

Based on the previous findings, Sugammadex can be a more rapid and effective alternative for reversal of rocuronium-induced neuromuscular blockade, compared to neostigmine, in pediatric patients <2 years undergoing cardiac catheterization.

Financial support and sponsorship

This study is self funding according to Mansoura University protocol.

Conflicts of interest

There are no conflicts of interest.