- Dosages
- Side effects in children
- Warnings & precautions in children
- Contra-indications in children
-
Interactions - PK
- Renal impairment
- References
Pharmacokinetics in children
Pharmacokinetic parameter relationships for cisatracurium besilate are unique because of its organ-independent elimination. Cisatracurium is degraded in the body at physiological pH and temperature according to Hofmann elimination (a chemical process) in which laudanosine and a monoquaternary acrylate metabolite are formed. The monoquaternary acrylate is hydrolyzed by nonspecific plasma esterases to a monoquaternary alcohol metabolite. The elimination of cisatracurium is primarily organ-independent but the liver and kidneys are the primary routes of elimination for clearance of the metabolites. The metabolites do not possess neuromuscular blocking properties (SmPC).
The pharmacokinetics of cisatracurium are best described by the nontraditional 2-compartment open model. Due to tightly controlled temperature and pH, the organ-independent Hofmann elimination of cisatracurium besylate 'fixes' the elimination rate constant (and consequently T1/2). As a result, the CL of cisatracurium besylate is reliant on Vd, and as Vd increases (or decreases), so does the CL (Kisor 1999).
Little evidence is available on the pharmacokinetics of cisatracurium in children (see table 1). The T1/2 of cisatracurium in children is comparable to that in adults, 22.9 ± 4.5 min and 22-29 min, respectively. In comparison to adults, children have a larger volume of cisatracurium distribution (Imbeault 2006; Philips 1995; KNMP). An increase in the Vd is consistent with the extracellular fluid volume being relatively high in newborns and young children.
The Vd and CL are higher in children <2 years old than they are in those between 2 - 5 years old. Furthermore, it has been found that young infants have a shorter onset time, longer muscle blocking duration time and high amounts of cisatracurium in their skeletal muscles. This is understandable given that neuromuscular junctions are not fully developed, limiting the number of receptors that are accessible for cisatracurium to bind to at the motor end-plates. Cisatracurium may therefore build up at the motor end-plates, which would inhibit the drug's metabolism (Yihui 2012; Wei-Jia 2017; Guo 2015).
Hypothermia is known to affect neuromuscular blockade, in general increasing sensitivity to, and prolonging the effects of nondepolarizing agents. Infants and children undergoing hypothermic cardiopulmonary bypass (CPB) show a decrease in CL, which may be expected given temperature-dependent Hofmann elimination (Withington 2000 and 2011).
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dose recommendation of formulary compared to licensed use (on-label versus off-label)
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Available formulations
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Dosages
| Neuromuscular blockade |
|---|
|
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Renal impaiment in children > 3 months
No information available on dose adjustment in renal impairment.
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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here
Side effects in children
Cisatracurium is well tolerated in children. At doses that are clinically relevant, there were no significant hemodynamic effects or only minor and negligible hemodynamic effects observed. Additionally, there were no indications of potential histamine release. Cisatracurium may cause constriction of smaller airways. However, these changes were mild and not clinically detectable (Odetola 2002; Burmester 2005; ShangGuan 2008; Meretoja 1996 ).
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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here
Contra-indications
No information available on specific contra indications in children.
The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here
Warnings & precautions in children
Monitor neuromuscular function. The duration of action for muscle relaxants is so variable that relaxation measurement should be considered before extubation and antagonized if necessary.
In children with obesity, ideal body weight in calculating the dose of cisatracurium is recommended instead of use of total body weight (Ross 2015).
Cross hypersensitivity - including from other groups - is possible. This may be based on the excipients but also on the active ingredient. Advice is to consult a pediatric allergist in case of a suspected allergic reaction to a muscle relaxant and with the request to also test for safety of alternative muscle relaxants.
Neonates: The evidence on efficacy and safety for this age group is very limited. In neonates monitor hemodynamic measures and oxygen saturation carefully after administration of cisatracurium.
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Interactions
The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here
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| Choline derivatives | ||
|---|---|---|
| M03AB01 | ||
| Other quaternary ammonium compounds | ||
|---|---|---|
| M03AC04 | ||
| M03AC10 | ||
| M03AC01 | ||
| M03AC09 | ||
| M03AC03 | ||
| Other muscle relaxants, peripherally acting agents | ||
|---|---|---|
| M03AX01 | ||
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References
- ShangGuan W, et al, Clinical pharmacology of cisatracurium during nitrous oxide-propofol anesthesia in children, J Clin Anesth, 2008, 20(6), 411-4
- Dorismond C,et al., Wide range of perioperative drugs and doses used in inguinal hernia repairs for premature infants., J Perinatol., 2021, 41(3), 577-81
- Dickerson RN, et al. , Gastric feeding intolerance in critically ill patients during sustained pharmacologic neuromuscular blockade. , Nutr Clin Pract., 2023, 38(2), 350-9
- Fodale V,et al., Perinatal neuroprotection by muscle relaxants against hypoxic-ischemic lesions: is it a possible hypothesis?, J Matern Fetal Neonatal Med, 2005, 18(2), 133-6
- Odetola FO, et al, Cisatracurium infusion for neuromuscular blockade in the pediatric intensive care unit: A dose-finding study., Pediatr Crit Care Med., 2002, 3(3), 250-4
- Dickerson RN, et al., Gastric feeding intolerance in critically ill patients during sustained pharmacologic neuromuscular blockade., Nutr Clin Pract., 2023, 38(2), 350-9
- Yang CI, et al, The effect of cisatracurium and rocuronium on lung function in anesthetized children, Anesth Analg, 2013, 117(6), 1393-400
- Meretoja OA, et al, Cisatracurium during halothane and balanced anaesthesia in children, Paediatr Anaesth, 1996, 6(5), 373-8
- Kisor DF, et al, Clinical pharmacokinetics of cisatracurium besilate., Clin Pharmacokinet, 1999, 36(1), 27-40.
- Yihui L, et al, Pharmacokinetics of cisatracurium in children of different ages., Chinese Journal of Anesthesiology, 2012, 32, 51-
- Guo J, et al, Age and the neuromuscular blockading effects of cisatracurium., Int J Clin Exp Med., 2015, 8(9), 16664-9
- Wei-Jia H, et al, Pharmacokinetics and pharmacodynamics of cisatracurium in children undergoing cleft lip or cleft palate repair surgery., Chinese Journal of Pharmacology and Toxicology, 2017, 1021-1022, 2017
- Withington DE, et al, Cisatracurium pharmacokinetics and pharmacodynamics during hypothermic CPB in infants., Paediatr Anaesth, 2000, 10(6), 695
- Withington D, et al, Cisatracurium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children., Paediatr Anaesth, 2011, 21(3), 341-613
- Odetola FO, et al , Cisatracurium infusion for neuromuscular blockade in the pediatric intensive care unit: A dose-finding study. , Pediatr Crit Care Med., 2002, 3(3), 250-4
- Burmester M, et al, Randomised controlled trial comparing cisatracurium and vecuronium infusions in a paediatric intensive care unit., Intensive Care Med, 2005, 31(5), 686-92
- Aspen Pharma Trading Limited, SmPC Nimbex (RVG 19471/19472) 08-02-2023, www.geneesmiddeleninformatiebank.nl
- Taivainen T, et al., The safety and efficacy of cisatracurium 0.15 mg.kg(-1) during nitrous oxide-opioid anaesthesia in infants and children., Anaesthesia, 2000, 55(11), 1047-51
- Phillips L,et al, Population pharmacokinetics/pharmacodynamics (PK/PD) of 51W89 in healthy pediatric patients [abstract]., Clin Pharmacol Ther, 1995, 57, 213
- de Ruiter J, et al, Dose-response relationship and infusion requirement of cisatracurium besylate in infants and children during nitrous oxide-narcotic anesthesia, Anesthesiology, 2001, 4(5), 790-2
- Imbeault K, et al, Pharmacokinetics and pharmacodynamics of a 0.1 mg/kg dose of cisatracurium besylate in children during N2O/O2/propofol anesthesia, Anesth Analg., 2006, 102(3):, 738-43
- Brandom BW, et al, Effects of cisatracurium in children during halothane-nitrous oxide anesthesia., J Clin Anesth, 1998, 10(3), 195-9
- Tobias JD., A prospective evaluation of the continuous infusion of cis-atracurium for neuromuscular blockade in the pediatric intensive care unit patient: efficacy and dosage requirements., Am J Ther, 1997, 4(9-10), 287-90
- Ross EL, et al., Development of recommendations for dosing of commonly prescribed medications in critically ill obese children, Am J Health Syst Pharm, 2015, 72(7), 542-56
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