Intensive Care Medicine

, Volume 33, Issue 5, pp 872–879 | Cite as

Infusions of rocuronium and cisatracurium exert different effects on rat diaphragm function

  • Dries Testelmans
  • Karen Maes
  • Patrick Wouters
  • Scott K. Powers
  • Marc Decramer
  • Ghislaine Gayan-RamirezEmail author



Aminosteroidal and benzylisoquinoline neuromuscular blocking agents are used in the intensive care unit to facilitate mechanical ventilation. The use of these agents has been associated with development of critical illness myopathy; however, the relative frequency of myopathy development among agents is not known. The aim of our study was to compare the effects of 24 h infusion of rocuronium or cisatracurium on the diaphragm in mechanically ventilated rats.


Randomized, controlled experiment.


Basic animal science laboratory.


Male Wistar rats, 14 weeks old.


Rats were divided into four groups to receive either saline, rocuronium (low dose) or cisatracurium (low or high dose).

Measurements and results

After 24 h, in vitro diaphragm tetanic force was decreased after rocuronium (–33% vs. saline), while the force was more preserved after cisatracurium, even in the high-dose group. Cross-sectional areas of the different diaphragm and gastrocnemius fibers were unaltered. Diaphragmatic MURF-1 mRNA was increased after rocuronium (+44% vs. saline), while unchanged in both cisatracurium groups. Calpain activity was increased after rocuronium (+75% vs. saline) and unchanged in the cisatracurium groups. MURF-1 mRNA expression and calpain activity were negatively correlated with diaphragm force.


Cisatracurium infusion during controlled mechanical ventilation exerted less detrimental effects on diaphragm function and proteolytic activity than infusion of rocuronium, even with the higher effective dose. These data suggest that increased calpain activity and increased activation of the ubiquitin proteasome system play a role in the different effects of these agents.


Mechanical ventilation Neuromuscular blocking agent Diaphragm 



The authors sincerely thank Mrs. Petra Weckx for cutting muscle samples and staining the histological sections. We also thank Prof. E. Verbeken for the evaluation of the H&E-stained sections. This study was supported by FWO-Vlaanderen #G.0389.03, KUL Research Foundation OT/02/44 and AstraZeneca Pharmaceuticals. Dries Testelmans is an aspirant of the “Fonds voor Wetenschappelijk Onderzoek – Vlaanderen”


  1. 1.
    Murray MJ, Cowen J, DeBlock H, Erstad B, Gray AW Jr, Tescher AN, McGee WT, Prielipp RC, Susla G, Jacobi J, Nasraway SA Jr, Lumb PD (2002) Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med 30:142–156CrossRefPubMedGoogle Scholar
  2. 2.
    Arroliga A, Frutos-Vivar F, Hall J, Esteban A, Apezteguia C, Soto L, Anzueto A (2005) Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation. Chest 128:496–506CrossRefPubMedGoogle Scholar
  3. 3.
    Sessler CN (2005) Sedation, analgesia, and neuromuscular blockade for high-frequency oscillatory ventilation. Crit Care Med 33:S209–S216CrossRefPubMedGoogle Scholar
  4. 4.
    Moore EW, Hunter JM (2001) The new neuromuscular blocking agents: do they offer any advantages? Br J Anaesth 87:912–925CrossRefPubMedGoogle Scholar
  5. 5.
    De Jonghe B, Bastuji-Garin S, Sharshar T, Outin H, Brochard L (2004) Does ICU-acquired paresis lengthen weaning from mechanical ventilation? Intensive Care Med 30:1117–1121CrossRefPubMedGoogle Scholar
  6. 6.
    Olivieri L, Plourde G (2005) Prolonged (more than ten hours) neuromuscular blockade after cardiac surgery: report of two cases. Can J Anaesth 52:88–93CrossRefPubMedGoogle Scholar
  7. 7.
    Davis NA, Rodgers JE, Gonzalez ER, Fowler AA III (1998) Prolonged weakness after cisatracurium infusion: a case report. Crit Care Med 26:1290–1292CrossRefPubMedGoogle Scholar
  8. 8.
    Tousignant CP, Bevan DR, Eisen AA, Fenwick JC, Tweedale MG (1995) Acute quadriparesis in an asthmatic treated with atracurium. Can J Anaesth 42:224–227CrossRefPubMedGoogle Scholar
  9. 9.
    Leatherman JW, Fluegel WL, David WS, Davies SF, Iber C (1996) Muscle weakness in mechanically ventilated patients with severe asthma. Am J Respir Crit Care Med 153:1686–1690CrossRefPubMedGoogle Scholar
  10. 10.
    Gehr LC, Sessler CN (2001) Neuromuscular blockade in the intensive care unit. Semin Respir Crit Care Med 22:175–188CrossRefPubMedGoogle Scholar
  11. 11.
    Gayan-Ramirez G, Decramer M (2002) Effects of mechanical ventilation on diaphragm function and biology. Eur Respir J 20:1579–1586CrossRefPubMedGoogle Scholar
  12. 12.
    Jaber S, Sebbane M, Koechlin C, Hayot M, Capdevila X, Eledjam JJ, Prefaut C, Ramonatxo M, Matecki S (2005) Effects of short vs. prolonged mechanical ventilation on antioxidant systems in piglet diaphragm. Intensive Care Med 31:1427–1433CrossRefPubMedGoogle Scholar
  13. 13.
    Testelmans D, Maes K, Wouters P, Gosselin N, Deruisseau K, Powers S, Sciot R, Decramer M, Gayan-Ramirez G (2006) Rocuronium exacerbates mechanical ventilation-induced diaphragm dysfunction in rats. Crit Care Med 34:3018–3023CrossRefPubMedGoogle Scholar
  14. 14.
    Laghi F, Tobin MJ (2003) Disorders of the respiratory muscles. Am J Respir Crit Care Med 168:10–48CrossRefPubMedGoogle Scholar
  15. 15.
    Testelmans D, Maes K, Wouters P, Decramer M, Gayan-Ramirez G (2006) Different effects of two families of neuromuscular blocking agents on rat diaphragm function during controlled mechanical ventilation. Proc Am Thoracic Soc [Abstract] 3:A137 Google Scholar
  16. 16.
    Gayan-Ramirez G, De Paepe K, Cadot P, Decramer M (2003) Detrimental effects of short-term mechanical ventilation on diaphragm function and IGF-I mRNA in rats. Intensive Care Med 29:825–833CrossRefPubMedGoogle Scholar
  17. 17.
    Dekhuijzen PN, Gayan-Ramirez G, de Bock V, Dom R, Decramer M (1993) Triamcinolone and prednisolone affect contractile properties and histopathology of rat diaphragm differently. J Clin Invest 92:1534–1542CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Takamure M, Murata KY, Tamada Y, Azuma M, Ueno S (2005) Calpain-dependent alpha-fodrin cleavage at the sarcolemma in muscle diseases.Muscle Nerve 32:303–309CrossRefPubMedGoogle Scholar
  19. 19.
    Kent MP, Veiseth E, Therkildsen M, Koohmaraie M (2005) An assessment of extraction and assay techniques for quantification of calpain and calpastatin from small tissue samples. J Anim Sci 83:2182–2188CrossRefPubMedGoogle Scholar
  20. 20.
    Czogalla A, Sikorski AF (2005) Spectrin and calpain: a `target' and a `sniper' in the pathology of neuronal cells. Cell Mol Life Sci 62:1913–1924CrossRefPubMedGoogle Scholar
  21. 21.
    Booij LH (2001) Is succinylcholine appropriate or obsolete in the intensive care unit? Crit Care 5:245–246CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Whetstone Foster JG, Clark AP (2006) Functional recovery after neuromuscular blockade in mechanically ventilated critically ill patients. Heart Lung 35:178–189CrossRefPubMedGoogle Scholar
  23. 23.
    Prielipp RC, Coursin DB, Wood KE, Murray MJ (1995) Complications associated with sedative and neuromuscular blocking drugs in critically ill patients. Crit Care Clin 11:983–1003PubMedGoogle Scholar
  24. 24.
    De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, Raphael JC, Outin H Bastuji-Garin S (2002) Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 288:2859–2867CrossRefPubMedGoogle Scholar
  25. 25.
    Filatov GN, Rich MM (2004) Hyperpolarized shifts in the voltage dependence of fast inactivation of Nav1.4 and Nav1.5 in a rat model of critical illness myopathy. J Physiol 559:813–820CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Murray MJ, Brull SJ, Bolton CF (2006) Brief review: Nondepolarizing neuromuscular blocking drugs and critical illness myopathy. Can J Anaesth 53:1148–1156CrossRefPubMedGoogle Scholar
  27. 27.
    Gutmann L, Blumenthal D, Gutmann L, Schochet SS (1996) Acute type II myofiber atrophy in critical illness. Neurology 46:819–821CrossRefPubMedGoogle Scholar
  28. 28.
    Gayan-Ramirez G, Testelmans D, Maes K, Racz GZ, Cadot P, Zador E, Wuytack F, Decramer M (2005) Intermittent spontaneous breathing protects the rat diaphragm from mechanical ventilation effects. Crit Care Med 33:2804–2809CrossRefPubMedGoogle Scholar
  29. 29.
    DeRuisseau KC, Shanely RA, Akunuri N, Hamilton MT, Van Gammeren D, Zergeroglu AM, McKenzie M, Powers SK (2005) Diaphragm unloading via controlled mechanical ventilation alters the gene expression profile. Am J Respir Crit Care Med 172:1267–1275CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Shanely RA, Zergeroglu MA, Lennon SL, Sugiura T, Yimlamai T, Enns D, Belcastro A, Powers SK (2002) Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med 166:1369–1374CrossRefPubMedGoogle Scholar
  31. 31.
    DeRuisseau KC, Kavazis AN, Deering MA, Falk DJ, Van Gammeren D, Yimlamai T, Ordway GA, Powers SK (2005) Mechanical ventilation induces alterations of the ubiquitin–proteasome pathway in the diaphragm. J Appl Physiol 98:1314–1321CrossRefPubMedGoogle Scholar
  32. 32.
    Jackman RW, Kandarian SC (2004) The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol 287:C834–C843CrossRefPubMedGoogle Scholar
  33. 33.
    Di Giovanni S, Molon A, Broccolini A, Melcon G, Mirabella M, Hoffman EP, Servidei S (2004) Constitutive activation of MAPK cascade in acute quadriplegic myopathy. Ann Neurol 55:195–206CrossRefPubMedGoogle Scholar
  34. 34.
    Latronico N, Peli E, Botteri M (2005) Critical illness myopathy and neuropathy. Curr Opin Crit Care 11:126–132CrossRefPubMedGoogle Scholar
  35. 35.
    Attaix D, Ventadour S, Codran A, Bechet D, Taillandier D, Combaret L (2005) The ubiquitin–proteasome system and skeletal muscle wasting. Essays Biochem 41:173–186CrossRefPubMedGoogle Scholar
  36. 36.
    Kandarian SC, Jackman RW (2006) Intracellular signaling during skeletal muscle atrophy. Muscle Nerve 33:155–165CrossRefPubMedGoogle Scholar
  37. 37.
    Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE (2004) IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119:285–298CrossRefPubMedGoogle Scholar
  38. 38.
    Fareed MU, Evenson AR, Wei W, Menconi M, Poylin V, Petkova V, Pignol B, Hasselgren PO (2006) Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression. Am J Physiol Regul Integr Comp Physiol 290:R1589–R1597CrossRefPubMedGoogle Scholar
  39. 39.
    McDonald MC, Mota-Filipe H, Paul A, Cuzzocrea S, Abdelrahman M, Harwood S, Plevin R, Chatterjee PK, Yaqoob MM, Thiemermann C (2001) Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. FASEB J 15:171–186CrossRefPubMedGoogle Scholar
  40. 40.
    Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The calpain system. Physiol Rev 83:731–801CrossRefPubMedGoogle Scholar
  41. 41.
    Machida K, Ishibashi R, Hara T, Ohtsuka A, Hayashi K (2003) Effects of corticosterone on Ca2+ uptake and myofibrillar disassembly in primary muscle cell culture. Biosci Biotechnol Biochem 67:244–249CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Dries Testelmans
    • 1
  • Karen Maes
    • 1
  • Patrick Wouters
    • 2
  • Scott K. Powers
    • 3
  • Marc Decramer
    • 1
  • Ghislaine Gayan-Ramirez
    • 1
    Email author
  1. 1.Respiratory Muscle Research Unit, Laboratory of Pneumology and Respiratory DivisionKatholieke Universiteit LeuvenLeuvenBelgium
  2. 2.Department of AnesthesiologyKatholieke Universiteit LeuvenLeuvenBelgium
  3. 3.Department of Applied Physiology and KinesiologyUniversity of FloridaGainesvilleUSA

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