Targeted Treatment of Microvascular Dysfunction

  • J. H. Boyd
Conference paper


Nearly all critically ill patients requiring advanced life support exhibit systemic inflammation. Septic shock, the most common disorder in the critically ill, results from the direct adverse consequences of infection combined with a maladaptive response resulting in fulminant systemic inflammation. This powerful interaction results in a mortality rate of up to 50 % for victims of this disease [1, 2, 3, 4]. While septic shock is most often described as (warm' hypotension (particularly lowering diastolic blood pressure) despite initial resuscitation, the patient often exhibits circulatory failure demonstrated by mottled extremities and low mixed or central venous oxygen saturation as a result of inadequate oxygen delivery. A key component of the shock due to severe sepsis, cardiac impairment, can be demonstrated in 50–100 0/0 of patients diagnosed with septic shock [5, 6, 7, 8, 9]. While diagnosed at the macrovascular level, cardiac pump failure is itself due to microcirculatory dysfunction and impaired oxygen extraction in the heart [10]. A daily clinical challenge faced by those caring for the critically ill is that while the patient presents with circulatory failure, advanced studies such as echo cardiography and measurement of central venous oxygen tension (ScvO2) actually demonstrate normal or even supra-normal cardiac output. This picture is often accompanied by an increasing lactate level and progressive organ dysfunction. It is now believed that this failure to adequately perfuse vital organs despite an ostensibly normal macrocirculation is due to dysfunction of the microcirculation.


Septic Shock Severe Sepsis Microvascular Dysfunction Central Venous Oxygen Saturation Survive Sepsis Guideline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29: 1303–1310CrossRefPubMedGoogle Scholar
  2. 2.
    Wang HE, Shapiro NI, Angus DC, Yealy DM (2007) National estimates of severe sepsis in United States emergency departments. Crit Care Med 35: 1928–1936CrossRefPubMedGoogle Scholar
  3. 3.
    Dellinger RP, Levy MM, Carlet JM, et al (2008) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36: 296–327CrossRefPubMedGoogle Scholar
  4. 4.
    Sprung CL, Annane D, Keh D, et al (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358: 111–124CrossRefPubMedGoogle Scholar
  5. 5.
    Parker MM, Shelhamer JH, Bacharach SL, et al (1984) Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 100:483–490PubMedGoogle Scholar
  6. 6.
    Joseph MX, Disney PJ, Da Costa R, Hutchison SJ (2004) Transthoracic echocardiography to identify or exclude cardiac cause of shock. Chest 126: 1592–1597CrossRefPubMedGoogle Scholar
  7. 7.
    Khoury AF, Afridi I, Quinones MA, Zoghbi WA (1994) Transesophageal echocardiography in critically ill patients: feasibility, safety, and impact on management. Am Heart J 127: 1363–1371CrossRefPubMedGoogle Scholar
  8. 8.
    Ognibene FP, Parker MM, Natanson C, Shelhamer JH, Parrillo JE (1988) Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest 93: 903–910CrossRefPubMedGoogle Scholar
  9. 9.
    Jardin F, Fourme T, Page B, et al (1999) Persistent preload defect in severe sepsis despite fluid loading: A longitudinal echocardiographic study in patients with septic shock. Chest 116: 1354–1359CrossRefPubMedGoogle Scholar
  10. 10.
    Herbertson MJ, Werner HA, Russell JA, Iversen K, Walley KR (1995) Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. J Appl Physiol 79: 479–486PubMedGoogle Scholar
  11. 11.
    LeDoux D, Astiz ME, Carpati CM, Rackow EC (2000) Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med 28: 2729–2732CrossRefPubMedGoogle Scholar
  12. 12.
    Anning PB, Finney SJ, Singh S, Winlove CP, Evans TW (2004) Fluids reverse the early lipopolysaccharide-induced albumin leakage in rodent mesenteric venules. Intensive Care Med 30: 1944–1949CrossRefPubMedGoogle Scholar
  13. 13.
    Arming PB, Sair M, Winlove CP, Evans TW (1999) Abnormal tissue oxygenation and cardiovascular changes in endotoxemia. Am J Respir Crit Care Med 159: 1710–1715Google Scholar
  14. 14.
    Bateman RM, Jagger JE, Sharpe MD, Ellsworth ML, Mehta S, Ellis CG (2001) Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis. Am J Physiol Heart Circ Physiol 280: H2848–2856PubMedGoogle Scholar
  15. 15.
    Ellis CG, Bateman RM, Sharpe MD, Sibbald WJ, Gill R (2002) Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis. Am J Physiol Heart Circ Physiol 282: H156–164PubMedGoogle Scholar
  16. 16.
    Goldman D, Bateman RM, Ellis CG (2004) Effect of sepsis on skeletal muscle oxygen consumption and tissue oxygenation: interpreting capillary oxygen transport data using a mathematical model. Am J Physiol Heart Circ Physiol 287: H2535–2544CrossRefPubMedGoogle Scholar
  17. 17.
    De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL (2002) Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 166: 98–104CrossRefPubMedGoogle Scholar
  18. 18.
    Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL (2004) Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 32: 1825–1831CrossRefPubMedGoogle Scholar
  19. 19.
    Trzeciak S, McCoy JV, Dellinger RP, et al (2008) Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 34: 2210–2217CrossRefPubMedGoogle Scholar
  20. 20.
    Sprung CL, Caralis PV, Marcial EH, et al (1984) The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 311: 1137–1143CrossRefPubMedGoogle Scholar
  21. 21.
    The Veterans Administration Systemic Sepsis Cooperative Study Group (1987) Effect of highdose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 317: 659–665CrossRefGoogle Scholar
  22. 22.
    Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1987) A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 317: 653–658CrossRefPubMedGoogle Scholar
  23. 23.
    Annane D, Sebille V, Charpentier C, et al (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288: 862–871CrossRefPubMedGoogle Scholar
  24. 24.
    Lopez A, Lorente JA, Steingrub J, et al (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32: 21–30CrossRefPubMedGoogle Scholar
  25. 25.
    Bernard GR, Wheeler AP, Russell JA, et al (1997) The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 336: 912–918CrossRefPubMedGoogle Scholar
  26. 26.
    Palevsky PM, Zhang JH, O'Connor TZ, et al (2008) Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 359: 7–20CrossRefPubMedGoogle Scholar
  27. 27.
    Vesconi S, Cruz DN, Fumagalli R, et al (2009) Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury. Crit Care 13:R57CrossRefPubMedGoogle Scholar
  28. 28.
    Honore PM, Jamez J, Wauthier M, et al (2000) Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 28: 3581–3587CrossRefPubMedGoogle Scholar
  29. 29.
    Alejandria MM, Lansang MA, Dans LF, Mantaring JB (2002) Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database Syst Rev CDOO1090Google Scholar
  30. 30.
    Werdan K, Pilz G, Bujdoso O, et al (2007) Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 35: 2693–2701CrossRefPubMedGoogle Scholar
  31. 31.
    Ziegler EJ, McCutchan JA, Fierer J, et al (1982) Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med 307: 1225–1230CrossRefPubMedGoogle Scholar
  32. 32.
    McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR (1994) Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern Med 121: 1–5PubMedGoogle Scholar
  33. 33.
    Angus DC, Birmingham MC, Balk RA, et al (2000) E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA 283: 1723–1730CrossRefPubMedGoogle Scholar
  34. 34.
    Albertson TE, Panacek EA, MacArthur RD, et al (2003) Multicenter evaluation of a human monoclonal antibody to Enterobacteriaceae common antigen in patients with Gram-negative sepsis. Crit Care Med 31: 419–427CrossRefPubMedGoogle Scholar
  35. 35.
    Abraham E, Glauser MP, Butler T, et al (1997) p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group. JAMA 277: 1531–1538CrossRefPubMedGoogle Scholar
  36. 36.
    Abraham E, Laterre PF, Garbino J, et al (2001) Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebocontrolled, multicenter phase III trial with 1,342 patients. Crit Care Med 29: 503–510CrossRefPubMedGoogle Scholar
  37. 37.
    Abraham E, Wunderink R, Silverman H, et al (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 273: 934–941CrossRefPubMedGoogle Scholar
  38. 38.
    Cohen J, Carlet J (1996) INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 24: 1431–1440CrossRefPubMedGoogle Scholar
  39. 39.
    Panacek EA, Marshall JC, Albertson TE, et al (2004) Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med 32: 2173–2182PubMedGoogle Scholar
  40. 40.
    Calandra T, Echtenacher B, Roy DL, et al (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6: 164–170CrossRefPubMedGoogle Scholar
  41. 41.
    Warren BL, Eid A, Singer P, et al (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286: 1869–1878CrossRefPubMedGoogle Scholar
  42. 42.
    Abraham E, Reinhart K, Opal S, et al (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290: 238–247CrossRefPubMedGoogle Scholar
  43. 43.
    Bernard GR, Vincent IL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344: 699–709CrossRefPubMedGoogle Scholar
  44. 44.
    De Backer D, Hollenberg S, Boerma C, et al (2007) How to evaluate the microcirculation: report of a round table conference. Crit Care 11: RIO1Google Scholar

Copyright information

© Springer Science + Business Media Inc. 2010

Authors and Affiliations

  • J. H. Boyd
    • 1
  1. 1.Critical Care Research Laboratories Heart and Lung InstituteSt. Paul's HospitalVancouverCanada

Personalised recommendations