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Retrospective Investigation of Grafted Kidney Function After Reversal of Neuromuscular Blockade Using Neostigmine or Sugammadex
Retrospective Investigation of Grafted Kidney Function After Reversal of Neuromuscular Blockade Using Neostigmine or Sugammadex Reyhan Arslantas* and Banu Eler Cevik Anesthesiology and Reanimation Clinic, Dr Lütfi Kirdar Training and Research Hospital, Istanbul, Turkey
ABSTRACT Introduction. Sugammadex has the steroid-encapsulating effect that reverses neuromuscular block induced by aminosteroid neuromuscular-blocking agents. Sugammadex can interact with other drugs that have the same steroidal structure with rocuronium, such as corticosteroids. Corticosteroids play a crucial role in the immunosuppression of kidney transplantation. The purpose of this study was to determine if there are any differences in grafted kidney function in recipients of kidney transplantation when sugammadex or neostigmine is given to the recipient. Methods. The study included 42 recipients of kidney transplant, with complete, readable medical charts and anesthetic records. Fourteen recipients’ neuromuscular block was reversed with sugammadex (group S) and 28 recipients’ neuromuscular block was reversed with neostigmine (group N). We tested noninferiority for serum creatinine during the preoperative period and 5 days after transplantation. Short-term (28 days) outcomes of kidney transplantations were assessed by the incidence of acute rejection episodes, graft failure, length of stay at hospital, and mortality. Results. There were no significant differences in demographic characteristics, serum creatinine values, short-term outcomes, and graft survival rates at 28 days’ postoperatively between group S and group N (P > .05). Conclusions. Our data showed no difference in risk of serious adverse effects on shortterm graft functions in patients who underwent kidney transplantation. However, considering the sugammadex-corticosteroids interaction, the immunosuppression and long-term effects on grafted kidney functions, current safety experience is insufficient to support the recommendation of routine sugammadex use in this population. These results need to be confirmed by sufficiently powered, controlled, pharmacokinetic, and pharmacodynamic studies on larger patient populations.
S
UGAMMADEX is a modified ɣ-cyclodextrin, produced to selectively reverse the effects of aminosteroid neuromuscular-blocking agents by steroid-encapsulation, creating a stable complex [1]. Reoccurrence of the block can be seen when a drug binds with sugammadex and displaces rocuronium or vecuronium. Reduced efficacy of a drug is seen when sugammadex encapsulates that drug, that is, administration of sugammadex on the same day as the contraceptive pill may lead to reduced efficacy of progestogen. No evidence of interaction exists between sugammadex and endogenous or therapeutic steroids [2]. Corticosteroids are considered to be a ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 2265e2267 (2019)
cornerstone of immunosuppressant regimens for kidney transplantation, which are suggested to be started before or at the time of renal transplantation for prevention of acute rejection [3]. An in vitro study has demonstrated that dexamethasone dose-dependently inhibited sugammadex
*Address correspondence to Reyhan Arslantas, MD, Anesthesiology and Reanimation Clinic, Dr Lütfi Kırdar Training and Research Hospital, Cevizli Mh., S¸emsi Denizer Cad. E-5 Karayolu Cevizli Mevkii, 34890 Kartal, Istanbul, Turkey. Tel.: þ90 (216) 458 3000. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.03.051
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ARSLANTAS AND CEVIK Table 1. Demographic and Clinical Data Characteristic
Group N (n ¼ 28)
Group S (n ¼ 14)
P
Age (y), mean SD Male/female, no. Duration of anesthesia (min), mean SD Duration of surgery (min), mean SD Length of stay in hospital (d), mean SD Rejection, n Mortality, n Living donor, n Deceased donor, n Serum creatinine levels (mg/dL), mean SD Preoperative POD 1 POD 2 POD 3 POD 4 POD 5
47.39 13.56 18/10 225 44 189 46 28.5 22.7 2 2 20 8
45.78 12.95 7/7 212 42 165 55 24.4 11.7 1 1 7 7
.715 <.001 .366 .135 .526 1.000 1.000 <.001 <.001
5.5 3.5 3.1 2.7 2.7 2.6
1.7 2.3 2.5 2.6 2.6 2.5
6.2 4.5 3.4 3.2 2.9 2.8
1.6 3.1 2.8 3.1 2.8 2.8
.161 .372 .967 .670 .509 .350
Group N represents recipients were reversed with neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg). Group S represents recipients reversed with sugammadex (2e4 mg/kg). Abbreviation: POD, postoperative day.
reversal [4]. We have not found any study regarding the diminished effect of immunosuppressive drugs due to be encapsulated by sugammadex. This study aimed to determine if there were any differences in grafted kidney function in recipients of kidney transplantation when the neuromuscular block was reversed with sugammadex or neostigmine. METHODS This study employed a retrospective cohort study design based on the data from patients’ pre-existing medical records and anesthesia records. After obtaining approval from our Institutional Ethics Committee, we enrolled 42 recipients of kidney transplant who were diagnosed with end-stage renal disease and performed renal transplantation from living and deceased donors. Generally, propofol (1.5e2.0 mg/kg) and rocuronium (0.6e0.9 mg/kg) were used for the anesthesia induction and tracheal intubation. Methylprednisolone (500.0 mg) was administered around the time of venous anastomosis. Fourteen recipients’ neuromuscular block were reversed with sugammadex (2.0e4.0 mg/kg) (group S) and 28 recipients were reversed with neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg) (group N). We tested noninferiority for serum creatinine during the preoperative period and at 5 days after transplantation. Short-term (28 days) outcomes of kidney transplantation were assessed by the incidence of acute rejection episodes, graft failure, length of stay at hospital, and mortality. A power analysis was not performed to determine sample size because we did not have the preliminary data to perform a power analysis for the recipients of kidney transplant whose neuromuscular block was reversed with sugammadex and whose postoperative graft functions were evaluated. Thus, this study must be considered as an exploratory pilot study rather than a formal test of a hypothesis. All patients (n ¼ 14) whose neuromuscular block was reversed with sugammadex were included for experimental subjects in the study. The patient sample size of 42 (2 controls per experimental subject) was chosen arbitrarily. Continuous variables were reported as mean SD or median and interquartile range; categorical variables were reported as frequencies and proportions.
Intergroup comparisons were made with the Mann-Whitney U test for continuous variables, Fisher exact test, or Chi-square test for categorical variables. A value of P < .05 was considered statistically significant.
RESULTS
There were no significant differences in patients’ demographic characteristics except sex. Ages of the recruited patients ranged from 20 to 67 years old. The length of hospital stay, the duration of anesthesia, and the duration of surgery were similar between the groups (Table 1). In group N, the number of living donors compared with deceased donors was greater, but this ratio was equal in group S. Serum creatinine values in the preoperative period and 5 days’ postoperatively were similar between groups (Table 1). There were no significant differences in shortterm outcomes, mortality, and graft survival rates at 28 days’ postoperatively between group S and group N (P > .05). DISCUSSION
This retrospective cohort study showed that sugammadex administration as compared to neostigmine has no difference in risk of serious adverse effects on short-term graft functions in patients undergoing living and deceased donor kidney transplantation. In our observational period, sugammadex was efficacious and safe in patients who underwent living and deceased donor renal transplantation. Corticosteroids were one of the first classes of medications used to prevent rejection after kidney transplantation. Corticosteroids have immunosuppressive, antiinflammatory, and lympholytic effects and have these properties even if used in doses that are low by historical standards; however, their side effects may not justify their abandonment [5]. An in vitro study has shown that
KIDNEY FUNCTION AFTER REVERSAL OF NEUROMUSCULAR BLOCKADE
dexamethasone might reduce the efficacy of sugammadex [4]. So sugammadex may interact with corticosteroids, which are administered in high doses during renal transplantation. Theoretically, this interaction may reduce the blood level of corticosteroids and immunosuppressive effects of corticosteroids. In patients with end-stage renal failure, sugammadex 4.0 mg/kg can reverse deep neuromuscular blockade clinically and is statistically as rapid as in control patients not in renal failure, whereas renal elimination of sugammadex and the rocuronium- sugammadex complex is significantly reduced [6]. Due to this reduction, it is crucial to prevent postoperative residual curarization and respiratory complications. Cholinesterase inhibitors must be used in combination with muscarinic antagonists. Deep levels of neuromuscular block may not be effective and are associated with undesirable cholinergic side effects including bradycardia, hypotension, salivation, bronchoconstriction, nausea, and vomiting. Furthermore, in severe renal failure, the metabolism and redistribution of cholinesterase inhibitors are delayed, which leads to increases in the risk of side effects and potentiates the duration of their effects. In our study, administration of sugammadex or neostigmine for the reversal of neuromuscular blockade was generally well tolerated. There were no post-treatment serious adverse events in the perioperative period. There was no statistical difference in rejection and mortality rates between groups. Similar serum creatinine levels were observed in both groups during the preoperative period and 5 days’ postoperatively. In successful renal transplantation, it is estimated that creatinine clearance improves after 24 hours of reperfusion. Therefore, following successful perfusion of the transplanted kidney, it may be assumed that within 24 hours, sugammadex may be cleared in small amounts in a similar way to patients with moderate renal failure (creatinine clearance 30.0e50.0 mL/min) [7]. Our results show that there are no significant differences in short-term outcomes and graft survival rates at 28 days’ postoperatively between groups S and N. When methylprednisolone is administered at high doses, it is still able to exert immunosuppressive effects even though some portion
2267
of it is blocked by sugammadex; however, no side effects are seen due to this blockage. This study has some limitations. Firstly, our study is not a prospective, randomized, and controlled study. Secondly, pharmacokinetic and pharmacodynamic studies revealing the interaction between these administered drugs may assess these interactions more objectively.
CONCLUSIONS
Our data show no differences in the risk of serious adverse effects on short-term graft functions in patients undergoing kidney transplantation. However, considering the effect of the sugammadex-corticosteroids interaction on immunosuppression and the long-term effects on grafted kidney functions, current safety experience is insufficient to support recommended routine use of sugammadex in this population.
REFERENCES [1] Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J, Feilden H, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrinbased synthetic host. Angewandte Chemie 2002;41:266e70. [2] Hogg RMG, Mirakhur RK. Sugammadex: a selective relaxant binding agent for reversal of neuromuscular block. Expert Rev Neurother 2009;9:599e608. [3] Baker RJ, Mark PB, Patel RK, Stevens KK, Palmer N. Renal association clinical practice guideline in post-operative care in the kidney transplant recipient. BMC Nephrol 2017;18:174. [4] Rezonja K, Sostaric M, Vidmar G, Mars T. Dexamethasone produces dose-dependent inhibition of sugammadex reversal in in vitro innervated primary human muscle cells. Anesth Analg 2014;118:755e63. [5] Steiner RW, Awdishu L. Steroids in kidney transplant patients. Semin Immunopathol 2011;33:157e67. [6] Panhuizen IF, Gold SJ, Buerkle C, Snoeck MM, Harper NJ, Kaspers MJ, et al. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J Anaesth 2015;114:777e84. [7] Carlos RV, Torres ML, de Boer HD. The use of rocuronium and sugammadex in paediatric renal transplantation: two case reports. Eur J Anaesthesiol 2016;33:383e6.
ABSTRACT Introduction. Sugammadex has the steroid-encapsulating effect that reverses neuromuscular block induced by aminosteroid neuromuscular-blocking agents. Sugammadex can interact with other drugs that have the same steroidal structure with rocuronium, such as corticosteroids. Corticosteroids play a crucial role in the immunosuppression of kidney transplantation. The purpose of this study was to determine if there are any differences in grafted kidney function in recipients of kidney transplantation when sugammadex or neostigmine is given to the recipient. Methods. The study included 42 recipients of kidney transplant, with complete, readable medical charts and anesthetic records. Fourteen recipients’ neuromuscular block was reversed with sugammadex (group S) and 28 recipients’ neuromuscular block was reversed with neostigmine (group N). We tested noninferiority for serum creatinine during the preoperative period and 5 days after transplantation. Short-term (28 days) outcomes of kidney transplantations were assessed by the incidence of acute rejection episodes, graft failure, length of stay at hospital, and mortality. Results. There were no significant differences in demographic characteristics, serum creatinine values, short-term outcomes, and graft survival rates at 28 days’ postoperatively between group S and group N (P > .05). Conclusions. Our data showed no difference in risk of serious adverse effects on shortterm graft functions in patients who underwent kidney transplantation. However, considering the sugammadex-corticosteroids interaction, the immunosuppression and long-term effects on grafted kidney functions, current safety experience is insufficient to support the recommendation of routine sugammadex use in this population. These results need to be confirmed by sufficiently powered, controlled, pharmacokinetic, and pharmacodynamic studies on larger patient populations.
S
UGAMMADEX is a modified ɣ-cyclodextrin, produced to selectively reverse the effects of aminosteroid neuromuscular-blocking agents by steroid-encapsulation, creating a stable complex [1]. Reoccurrence of the block can be seen when a drug binds with sugammadex and displaces rocuronium or vecuronium. Reduced efficacy of a drug is seen when sugammadex encapsulates that drug, that is, administration of sugammadex on the same day as the contraceptive pill may lead to reduced efficacy of progestogen. No evidence of interaction exists between sugammadex and endogenous or therapeutic steroids [2]. Corticosteroids are considered to be a ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 2265e2267 (2019)
cornerstone of immunosuppressant regimens for kidney transplantation, which are suggested to be started before or at the time of renal transplantation for prevention of acute rejection [3]. An in vitro study has demonstrated that dexamethasone dose-dependently inhibited sugammadex
*Address correspondence to Reyhan Arslantas, MD, Anesthesiology and Reanimation Clinic, Dr Lütfi Kırdar Training and Research Hospital, Cevizli Mh., S¸emsi Denizer Cad. E-5 Karayolu Cevizli Mevkii, 34890 Kartal, Istanbul, Turkey. Tel.: þ90 (216) 458 3000. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.03.051
2265
2266
ARSLANTAS AND CEVIK Table 1. Demographic and Clinical Data Characteristic
Group N (n ¼ 28)
Group S (n ¼ 14)
P
Age (y), mean SD Male/female, no. Duration of anesthesia (min), mean SD Duration of surgery (min), mean SD Length of stay in hospital (d), mean SD Rejection, n Mortality, n Living donor, n Deceased donor, n Serum creatinine levels (mg/dL), mean SD Preoperative POD 1 POD 2 POD 3 POD 4 POD 5
47.39 13.56 18/10 225 44 189 46 28.5 22.7 2 2 20 8
45.78 12.95 7/7 212 42 165 55 24.4 11.7 1 1 7 7
.715 <.001 .366 .135 .526 1.000 1.000 <.001 <.001
5.5 3.5 3.1 2.7 2.7 2.6
1.7 2.3 2.5 2.6 2.6 2.5
6.2 4.5 3.4 3.2 2.9 2.8
1.6 3.1 2.8 3.1 2.8 2.8
.161 .372 .967 .670 .509 .350
Group N represents recipients were reversed with neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg). Group S represents recipients reversed with sugammadex (2e4 mg/kg). Abbreviation: POD, postoperative day.
reversal [4]. We have not found any study regarding the diminished effect of immunosuppressive drugs due to be encapsulated by sugammadex. This study aimed to determine if there were any differences in grafted kidney function in recipients of kidney transplantation when the neuromuscular block was reversed with sugammadex or neostigmine. METHODS This study employed a retrospective cohort study design based on the data from patients’ pre-existing medical records and anesthesia records. After obtaining approval from our Institutional Ethics Committee, we enrolled 42 recipients of kidney transplant who were diagnosed with end-stage renal disease and performed renal transplantation from living and deceased donors. Generally, propofol (1.5e2.0 mg/kg) and rocuronium (0.6e0.9 mg/kg) were used for the anesthesia induction and tracheal intubation. Methylprednisolone (500.0 mg) was administered around the time of venous anastomosis. Fourteen recipients’ neuromuscular block were reversed with sugammadex (2.0e4.0 mg/kg) (group S) and 28 recipients were reversed with neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg) (group N). We tested noninferiority for serum creatinine during the preoperative period and at 5 days after transplantation. Short-term (28 days) outcomes of kidney transplantation were assessed by the incidence of acute rejection episodes, graft failure, length of stay at hospital, and mortality. A power analysis was not performed to determine sample size because we did not have the preliminary data to perform a power analysis for the recipients of kidney transplant whose neuromuscular block was reversed with sugammadex and whose postoperative graft functions were evaluated. Thus, this study must be considered as an exploratory pilot study rather than a formal test of a hypothesis. All patients (n ¼ 14) whose neuromuscular block was reversed with sugammadex were included for experimental subjects in the study. The patient sample size of 42 (2 controls per experimental subject) was chosen arbitrarily. Continuous variables were reported as mean SD or median and interquartile range; categorical variables were reported as frequencies and proportions.
Intergroup comparisons were made with the Mann-Whitney U test for continuous variables, Fisher exact test, or Chi-square test for categorical variables. A value of P < .05 was considered statistically significant.
RESULTS
There were no significant differences in patients’ demographic characteristics except sex. Ages of the recruited patients ranged from 20 to 67 years old. The length of hospital stay, the duration of anesthesia, and the duration of surgery were similar between the groups (Table 1). In group N, the number of living donors compared with deceased donors was greater, but this ratio was equal in group S. Serum creatinine values in the preoperative period and 5 days’ postoperatively were similar between groups (Table 1). There were no significant differences in shortterm outcomes, mortality, and graft survival rates at 28 days’ postoperatively between group S and group N (P > .05). DISCUSSION
This retrospective cohort study showed that sugammadex administration as compared to neostigmine has no difference in risk of serious adverse effects on short-term graft functions in patients undergoing living and deceased donor kidney transplantation. In our observational period, sugammadex was efficacious and safe in patients who underwent living and deceased donor renal transplantation. Corticosteroids were one of the first classes of medications used to prevent rejection after kidney transplantation. Corticosteroids have immunosuppressive, antiinflammatory, and lympholytic effects and have these properties even if used in doses that are low by historical standards; however, their side effects may not justify their abandonment [5]. An in vitro study has shown that
KIDNEY FUNCTION AFTER REVERSAL OF NEUROMUSCULAR BLOCKADE
dexamethasone might reduce the efficacy of sugammadex [4]. So sugammadex may interact with corticosteroids, which are administered in high doses during renal transplantation. Theoretically, this interaction may reduce the blood level of corticosteroids and immunosuppressive effects of corticosteroids. In patients with end-stage renal failure, sugammadex 4.0 mg/kg can reverse deep neuromuscular blockade clinically and is statistically as rapid as in control patients not in renal failure, whereas renal elimination of sugammadex and the rocuronium- sugammadex complex is significantly reduced [6]. Due to this reduction, it is crucial to prevent postoperative residual curarization and respiratory complications. Cholinesterase inhibitors must be used in combination with muscarinic antagonists. Deep levels of neuromuscular block may not be effective and are associated with undesirable cholinergic side effects including bradycardia, hypotension, salivation, bronchoconstriction, nausea, and vomiting. Furthermore, in severe renal failure, the metabolism and redistribution of cholinesterase inhibitors are delayed, which leads to increases in the risk of side effects and potentiates the duration of their effects. In our study, administration of sugammadex or neostigmine for the reversal of neuromuscular blockade was generally well tolerated. There were no post-treatment serious adverse events in the perioperative period. There was no statistical difference in rejection and mortality rates between groups. Similar serum creatinine levels were observed in both groups during the preoperative period and 5 days’ postoperatively. In successful renal transplantation, it is estimated that creatinine clearance improves after 24 hours of reperfusion. Therefore, following successful perfusion of the transplanted kidney, it may be assumed that within 24 hours, sugammadex may be cleared in small amounts in a similar way to patients with moderate renal failure (creatinine clearance 30.0e50.0 mL/min) [7]. Our results show that there are no significant differences in short-term outcomes and graft survival rates at 28 days’ postoperatively between groups S and N. When methylprednisolone is administered at high doses, it is still able to exert immunosuppressive effects even though some portion
2267
of it is blocked by sugammadex; however, no side effects are seen due to this blockage. This study has some limitations. Firstly, our study is not a prospective, randomized, and controlled study. Secondly, pharmacokinetic and pharmacodynamic studies revealing the interaction between these administered drugs may assess these interactions more objectively.
CONCLUSIONS
Our data show no differences in the risk of serious adverse effects on short-term graft functions in patients undergoing kidney transplantation. However, considering the effect of the sugammadex-corticosteroids interaction on immunosuppression and the long-term effects on grafted kidney functions, current safety experience is insufficient to support recommended routine use of sugammadex in this population.
REFERENCES [1] Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J, Feilden H, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrinbased synthetic host. Angewandte Chemie 2002;41:266e70. [2] Hogg RMG, Mirakhur RK. Sugammadex: a selective relaxant binding agent for reversal of neuromuscular block. Expert Rev Neurother 2009;9:599e608. [3] Baker RJ, Mark PB, Patel RK, Stevens KK, Palmer N. Renal association clinical practice guideline in post-operative care in the kidney transplant recipient. BMC Nephrol 2017;18:174. [4] Rezonja K, Sostaric M, Vidmar G, Mars T. Dexamethasone produces dose-dependent inhibition of sugammadex reversal in in vitro innervated primary human muscle cells. Anesth Analg 2014;118:755e63. [5] Steiner RW, Awdishu L. Steroids in kidney transplant patients. Semin Immunopathol 2011;33:157e67. [6] Panhuizen IF, Gold SJ, Buerkle C, Snoeck MM, Harper NJ, Kaspers MJ, et al. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J Anaesth 2015;114:777e84. [7] Carlos RV, Torres ML, de Boer HD. The use of rocuronium and sugammadex in paediatric renal transplantation: two case reports. Eur J Anaesthesiol 2016;33:383e6.