Intensive Care Medicine

, Volume 40, Issue 9, pp 1220–1226 | Cite as

A paper on the pace of recovery from diaphragmatic fatigue and its unexpected dividends

  • Franco Laghi
  • Nausica D’Alfonso
  • Martin J. Tobin
My Paper 20 Years Later


Because the diaphragm is essential for survival, we wondered if it might be less vulnerable to the long-lasting effects of fatigue than limb muscles. Using a recently introduced magnetic probe to activate the phrenic nerves, we followed the evolution of twitch transdiaphragmatic pressure after inducing fatigue in healthy volunteers. Twenty-four hours after its induction, diaphragmatic fatigue had not fully recovered. Findings from this study later served as the foundation for incorporating a once-daily, T-tube-trial arm into a randomized controlled trial of techniques for ventilator weaning in intensive care unit patients and also influenced the design of a controlled trial of the weaning of tracheostomy patients who required prolonged ventilation. The research methodology was later employed to determine whether low-frequency fatigue is responsible for weaning failure. Employing a further modification of the technique—twitch airway pressure—it became evident that respiratory muscle weakness is a greater problem than fatigue in ventilated patients. Twitch airway pressure is now being used to document the prevalence and consequences of ventilator-induced respiratory muscle weakness. Our study—which began with a circumscribed, simple question—has yielded dividends in unforeseen directions, illustrating the fruitfulness of research into basic physiological mechanisms.


Respiratory muscles Mechanical ventilation Diaphragm weakness Atrophy Ventilator-induced diaphragmatic dysfunction Weaning 


  1. 1.
    Laghi F, D’Alfonso N, Tobin MJ (1995) Pattern of recovery from diaphragmatic fatigue over 24 h. J Appl Physiol 79:539–546PubMedGoogle Scholar
  2. 2.
    Anzueto A, Tobin MJ, Moore G (1987) Effect of prolonged mechanical ventilation on diaphragmatic function: a preliminary study of a baboon model. Am Rev Respir Dis 135:A201Google Scholar
  3. 3.
    Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C (1981) Aminophylline improves diaphragmatic contractility. N Engl J Med 305:249–252PubMedCrossRefGoogle Scholar
  4. 4.
    Moxham J, Morris AJ, Spiro SG, Edwards RH, Green M (1981) Contractile properties and fatigue of the diaphragm in man. Thorax 36:164–168PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Aubier M, Murciano D, Lecocguic Y, Viires N, Pariente R (1985) Bilateral phrenic stimulation: a simple technique to assess diaphragmatic fatigue in humans. J Appl Physiol 58:58–64PubMedCrossRefGoogle Scholar
  6. 6.
    Bellemare F, Bigland-Ritchie B, Woods JJ (1986) Contractile properties of the human diaphragm in vivo. J Appl Physiol 61:1153–1161PubMedGoogle Scholar
  7. 7.
    Verburg E, Murphy RM, Richard L, Lamb GD (2009) Involvement of calpains in Ca2+-induced disruption of excitation-contraction coupling in mammalian skeletal muscle fibers. Am J Physiol Cell Physiol 296:C1115–C1122PubMedCrossRefGoogle Scholar
  8. 8.
    Laghi F, Tobin MJ (2003) Disorders of the respiratory muscles. Am J Respir Crit Care Med 168:10–48PubMedCrossRefGoogle Scholar
  9. 9.
    Aubier M, Farkas G, De Troyer A, Mozes R, Roussos C (1981) Detection of diaphragmatic fatigue in man by phrenic stimulation. J Appl Physiol 50:538–544PubMedGoogle Scholar
  10. 10.
    Allen DG, Lamb GD, Westerblad H (2008) Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88:287–332PubMedCrossRefGoogle Scholar
  11. 11.
    De Troyer A, Leeper JB, McKenzie DK, Gandevia SC (1997) Neural drive to the diaphragm in patients with severe COPD. Am J Respir Crit Care Med 155:1335–1340PubMedCrossRefGoogle Scholar
  12. 12.
    Mador MJ, Acevedo FA (1985) Effect of respiratory muscle fatigue on subsequent exercise performance. J Appl Physiol 70:2059–2065Google Scholar
  13. 13.
    Yan S, Lichros I, Zakynthinos S, Macklem PT (1993) Effect of diaphragmatic fatigue on control of respiratory muscles and ventilation during CO2 rebreathing. J Appl Physiol 75:1364–1370PubMedGoogle Scholar
  14. 14.
    Laghi F, Topeli A, Tobin MJ (1998) Does resistive loading decrease diaphragmatic contractility before task failure? J Appl Physiol 85:1103–1112PubMedGoogle Scholar
  15. 15.
    Bellemare F, Bigland-Ritchie B (1984) Assessment of human diaphragm strength and activation using phrenic nerve stimulation. Respir Physiol 58:263–277PubMedCrossRefGoogle Scholar
  16. 16.
    Ferguson GT (1994) Use of twitch pressures to assess diaphragmatic function and central drive. J Appl Physiol 77:1705–1715PubMedGoogle Scholar
  17. 17.
    Al-Shekhlee A, Shapiro BE, Preston DC (2003) Iatrogenic complications and risks of nerve conduction studies and needle electromyography. Muscle Nerve 27:517–526PubMedCrossRefGoogle Scholar
  18. 18.
    Mills G, Kyroussis D, Hamnegard C, Wragg S, Green M, Moxham J (1994) Evaluation of hemidiaphragmatic contractility by unilateral magnetic phrenic nerve stimulation. Eur Respir J 8:339S (abstract)Google Scholar
  19. 19.
    Vandenboom R, Gittings W, Smith IC, Grange RW, Stull JT (2013) Myosin phosphorylation and force potentiation in skeletal muscle: evidence from animal models. J Muscle Res Cell Motil 34:317–332PubMedCrossRefGoogle Scholar
  20. 20.
    Mier A, Brophy C, Moxham J, Green M (1989) Twitch pressures in the assessment of diaphragm weakness. Thorax 44:990–996PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Similowski T, Fleury B, Launois S, Cathala HP, Bouche P, Derenne JP (1989) Cervical magnetic stimulation: a new painless method for bilateral phrenic nerve stimulation in conscious humans. J Appl Physiol 67:1311–1318PubMedGoogle Scholar
  22. 22.
    Laghi F, Harrison MJ, Tobin MJ (1996) Comparison of magnetic and electrical phrenic nerve stimulation in assessment of diaphragmatic contractility. J Appl Physiol 80:1731–1742PubMedCrossRefGoogle Scholar
  23. 23.
    Man WD, Moxham J, Polkey MI (2004) Magnetic stimulation for the measurement of respiratory and skeletal muscle function. Eur Respir J 24:846–860PubMedCrossRefGoogle Scholar
  24. 24.
    Duguet A, Demoule A, Gonzalez J, Remy-Neris O, Derenne JP, Similowski T (2006) Predicting the recovery of ventilatory activity in central respiratory paralysis. Neurology 67:288–292PubMedCrossRefGoogle Scholar
  25. 25.
    Hopkinson NS, Sharshar T, Dayer MJ, Lofaso F, Moxham J, Polkey MI (2012) The effect of acute non-invasive ventilation on corticospinal pathways to the respiratory muscles in chronic obstructive pulmonary disease. Respir Physiol Neurobiol 183:41–47PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Edwards RH, Hill DK, Jones DA, Merton PA (1977) Fatigue of long duration in human skeletal muscle after exercise. J Physiol 272:769–778PubMedCentralPubMedGoogle Scholar
  27. 27.
    Newham DJ, Mills KR, Quigley BM, Edwards RH (1983) Pain and fatigue after concentric and eccentric muscle contractions. Clin Sci (Lond) 64:55–62Google Scholar
  28. 28.
    Yan S, Similowski T, Gauthier AP, Macklem PT, Bellemare F (1992) Effect of fatigue on diaphragmatic function at different lung volumes. J Appl Physiol 72:1064–1067PubMedGoogle Scholar
  29. 29.
    Travaline JM, Sudarshan S, Criner GJ (1997) Recovery of PdiTwitch following the induction of diaphragm fatigue in normal subjects. Am J Respir Crit Care Med 156:1562–1566PubMedCrossRefGoogle Scholar
  30. 30.
    Gandevia SC (2001) Spinal and supraspinal factors in human muscle fatigue. Physiol Rev 81:1725–1789PubMedGoogle Scholar
  31. 31.
    Bellemare F, Bigland-Ritchie B (1987) Central components of diaphragmatic fatigue assessed by phrenic nerve stimulation. J Appl Physiol 62:1307–1316PubMedGoogle Scholar
  32. 32.
    Esteban A, Frutos F, Tobin MJ, Alia I, Solsona JF, Valverdu I, Fernandez R, de la Cal MA, Benito S, Tomas R, Spanish Lung Failure Collaborative Group (1995) A comparison of four methods of weaning patients from mechanical ventilation. N Engl J Med 332:345–350PubMedCrossRefGoogle Scholar
  33. 33.
    Tobin MJ, Jubran A (2013) Weaning from mechanical ventilation. In: Tobin MJ (ed) Principles and practice of mechanical ventilation, 3rd edn. McGraw Hill, New York, pp 1293–1306Google Scholar
  34. 34.
    Faulkner JA (1995) Structural and functional adaptations of skeletal muscle. In: Roussos C (ed) The thorax. Part A: physiology, 2nd edn. Marcel Dekker Inc, New York, pp 269–294Google Scholar
  35. 35.
    Rothman KJ (2002) Epidemiology: an introduction. Oxford University Press, New York, pp 20–21Google Scholar
  36. 36.
    Reichenbach H (1951) The rise of scientific philosophy. University of California Press, Berkeley, pp 5–7Google Scholar
  37. 37.
    Tobin MJ, Jubran A (2008) Meta-analysis under the spotlight: focused on a meta-analysis of ventilator weaning. Crit Care Med 36:1–7PubMedCrossRefGoogle Scholar
  38. 38.
    Jubran A, Grant BJ, Duffner LA, Collins EG, Lanuza DM, Hoffman LA, Tobin MJ (2013) Effect of pressure support vs unassisted breathing through a tracheostomy collar on weaning duration in patients requiring prolonged mechanical ventilation: a randomized trial. JAMA 309:671–677PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Cohen CA, Zagelbaum G, Gross D, Roussos C, Macklem PT (1982) Clinical manifestations of inspiratory muscle fatigue. Am J Med 73:308–316PubMedCrossRefGoogle Scholar
  40. 40.
    Brochard L, Harf A, Lorino H, Lemaire F (1989) Inspiratory pressure support prevents diaphragmatic fatigue during weaning from mechanical ventilation. Am Rev Respir Dis 139:513–521PubMedCrossRefGoogle Scholar
  41. 41.
    Goldstone JC, Green M, Moxham J (1994) Maximum relaxation rate of the diaphragm during weaning from mechanical ventilation. Thorax 49:54–60PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Tobin MJ, Perez W, Guenther SM, Lodato RF, Dantzker DR (1987) Does rib cage-abdominal paradox signify respiratory muscle fatigue? J Appl Physiol 63:851–860PubMedGoogle Scholar
  43. 43.
    Roussos C, Macklem PT (1982) The respiratory muscles. N Engl J Med 307:786–797PubMedCrossRefGoogle Scholar
  44. 44.
    Grassino A, Macklem PT (1984) Respiratory muscle fatigue and ventilatory failure. Annu Rev Med 35:625–647PubMedCrossRefGoogle Scholar
  45. 45.
    Rochester DF (1993) Respiratory muscles and ventilatory failure: 1993 perspective. Am J Med Sci 305:394–402PubMedCrossRefGoogle Scholar
  46. 46.
    Tobin MJ, Laghi F (1998) Monitoring respiratory muscle function. In: Tobin MJ (ed) Principles and practice of intensive care monitoring. McGraw-Hill, New York, pp 497–544Google Scholar
  47. 47.
    Laghi F, Cattapan SE, Jubran A, Parthasarathy S, Warshawsky P, Choi YS, Tobin MJ (2003) Is weaning failure caused by low-frequency fatigue of the diaphragm? Am J Respir Crit Care Med 167:120–127PubMedCrossRefGoogle Scholar
  48. 48.
    Laghi F, Tobin MJ (1997) Relationship between transdiaphragmatic and mouth twitch pressures at functional residual capacity. Eur Respir J 10:530–536PubMedGoogle Scholar
  49. 49.
    Topeli A, Laghi F, Tobin MJ (1999) Can diaphragmatic contractility be assessed by twitch airway pressures in patients with chronic obstructive pulmonary disease? Am J Respir Crit Care Med 160:1369–1374PubMedCrossRefGoogle Scholar
  50. 50.
    Hamnegard CH, Wragg S, Kyroussis D, Mills G, Bake B, Green M, Moxham J (1995) Mouth pressure in response to magnetic stimulation of the phrenic nerves. Thorax 50:620–624CrossRefGoogle Scholar
  51. 51.
    Cattapan SE, Laghi F, Tobin MJ (2003) Can diaphragmatic contractility be assessed by airway twitch pressure in mechanically ventilated patients? Thorax 58:58–62PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Watson AC, Hughes PD, Louise HM, Hart N, Ware RJ, Wendon J, Green M, Moxham J (2001) Measurement of twitch transdiaphragmatic, esophageal, and endotracheal tube pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients in the intensive care unit. Crit Care Med 29:1325–1331PubMedCrossRefGoogle Scholar
  53. 53.
    Kabitz HJ, Walterspacher S, Walker D, Windisch W (2007) Inspiratory muscle strength in chronic obstructive pulmonary disease depending on disease severity. Clin Sci (Lond) 113:243–249CrossRefGoogle Scholar
  54. 54.
    Tobin MJ, Laghi F, Jubran A (2010) Narrative review: ventilator-induced respiratory muscle weakness. Ann Intern Med 153:240–245PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, Rubinstein NA, Powers SK, Shrager JB (2008) Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 358:1327–1335PubMedCrossRefGoogle Scholar
  56. 56.
    Vassilakopoulos T (2013) Ventilator-induced diaphargmatic dysfunction. In: Tobin MJ (ed) Principles and practice of mechanical ventilation, 3rd edn. McGraw Hill, New York, pp 1025–1040Google Scholar
  57. 57.
    Supinski GS, Ann CL (2013) Diaphragm weakness in mechanically ventilated critically ill patients. Crit Care 17:R120PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Jaber S, Petrof BJ, Jung B, Chanques G, Berthet JP, Rabuel C, Bouyabrine H, Courouble P, Koechlin-Ramonatxo C, Sebbane M, Similowski T, Scheuermann V, Mebazaa A, Capdevila X, Mornet D, Mercier J, Lacampagne A, Philips A, Matecki S (2011) Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 183:364–371PubMedCrossRefGoogle Scholar
  59. 59.
    Demoule A, Jung B, Prodanovic H, Molinari N, Chanques G, Coirault C, Matecki S, Duguet A, Similowski T, Jaber B (2013) Diaphragm dysfunction on admission to the intensive care unit. Prevalence, risk factors, and prognostic impact-a prospective study. Am J Respir Crit Care Med 188:213–219PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2014

Authors and Affiliations

  • Franco Laghi
    • 1
    • 2
  • Nausica D’Alfonso
    • 1
    • 2
  • Martin J. Tobin
    • 1
    • 2
  1. 1.Division of Pulmonary and Critical Care MedicineEdward Hines, Jr. VA HospitalHinesUSA
  2. 2.Loyola University of Chicago Stritch School of MedicineMaywoodUSA

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