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Multiple Therapeutic Agents - Will Individual Therapies, Each of Which Improves Patients, When Given Together, Change Mortality?

  • A. E. Baue
Conference paper

Abstract

Recent discouragement over the failure of many exciting potential therapeutic agents (magic bullets) to reduce 28-day mortality in patients has led to many diverse recommendations. One such recommendation is to use alternative or surrogate endpoints such as a reduction in severity of illness score, decreased ICU time, decreased time on a ventilator, and other evidence of clinical improvement. This is all well and good but if such an improved patient dies as frequently as do control patients, what have we accomplished? Another proposal is to use multi-agent therapy. There are many reasons why the older and more recent clinical trials have been negative. One important reason is that injury, infection and inflammation bring about complex changes and responses in the host. There are multiple pro-proinflammatory mediators with overlap, redundancy, and cross stimulation. This is followed by an anti-inflammatory response to try to control the process before it gets out of hand. The timing and variability of these processes are inconsistent. Even with similar diseases there is great variability [1]. This has led to consideration of multiple therapeutic agents for patients with diseases or injuries which stimulate an inflammatory response. I have recently reviewed the reasons why many of the clinical trials in the distant and recent past have failed [1].

Keywords

Acute Pancreatitis Short Bowel Syndrome Isonicotinic Acid Magic Bullet Isonicotinic Acid Hydrazide 
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.

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References

  1. 1.
    Baue AE (1997) MOF, MODS, and SIRS — Why no magic bullets? Arch Surg 132:1–5Google Scholar
  2. 2.
    Schatz A, Bugie E, Waksman SA (1944) Streptomycin, a substance exhibiting antibiotic activity against gram-positive and gram-negative bacteria. Proc Soc Exp Biol Med 4:66–69Google Scholar
  3. 3.
    Hinshaw HC, Feldman WH (1945) Streptomycin in treatment of clinical tuberculosis: A preliminary report. Proc Staff Meet, Mayo Clinic, 20:313–318Google Scholar
  4. 4.
    Hinshaw HC, Plye MM, Feldman WH (1947) Streptomycin in tuberculosis. Am J Med 2: 429–435PubMedCrossRefGoogle Scholar
  5. 5.
    McDermott W, Muschenheim C, Hadley SJ et al (1947) Streptomycin in the treatment of tuberculosis in humans. Ann Intern Med 27:769–822PubMedGoogle Scholar
  6. 6.
    Medical Research Council (1950) Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicylic acid. Br J Med 2:1073–1085CrossRefGoogle Scholar
  7. 7.
    Robitzek EH, Selikoff IJ (1952) Hydrazine derivative of isonicotinic acid (Rimifon, Marsalid) in the treatment of acute progressive caseous-pneumonic tuberculosis. A preliminary report. Am Rev Tuberc 65:402–428PubMedGoogle Scholar
  8. 8.
    Committee on Treatment, International Union Against Tuberculosis and Lung Disease (1988) Antituberculosis regimens of chemotherapy. Bull Int Union Tuberc Lung Dis 63:60–64Google Scholar
  9. 9.
    Tuberculosis Unit, Division of Communicable Diseases, World Health Organization (1991) Guidelines for tuberculosis treatment in adults and children in national tuberculosis programs. World Health Organization WHO/TB 91:161Google Scholar
  10. 10.
    MacGregor RR (1993) Treatment of mycobacterial disease of the lungs caused by mycobacterium tuberculosis. In: A Fishman (ed) Pulmonary diseases and disorders, vol. 118. McGraw Hill, New York, pp 1869–1882Google Scholar
  11. 11.
    Marchall EK Jr (1964) Historical perspectives in chemotherapy. In: Golden A, Hawking IF (eds) Advances in chemotherapy, vol 1. Academic Press, New York, p 1Google Scholar
  12. 12.
    Alexander SF (1944) Final report of Bari mustard casualties. Allied Force Headquarters, Office of the Surgeon. APO 512, June 20Google Scholar
  13. 13.
    De Vita VT (1978) The evolution of therapeutic research in cancer. N Engl J Med 298:807Google Scholar
  14. 14.
    DeVita VT Jr (1997) Principles of cancer management: Chemotherapy. In: DeVita VT Jr, Hellman S, Rosenberg SA (eds) Cancer principles & practice of oncology, 5th edn, vol 1. Lippincott-Raven, Philadelphia, pp 333–339Google Scholar
  15. 15.
    DeVita VT Jr (1978) The evolution of therapeutic research in cancer. Sounding Boards, 298(16):907–910Google Scholar
  16. 16.
    DeVita VT Jr, Schein PS (1973) Medical progress — The use of drugs in combination for the treatment of cancer, rationale and results. N Engl J Med 288:988–1006CrossRefGoogle Scholar
  17. 17.
    Aasen AO, Naess E, Carlse H et al (1995) Treatment of sepsis — Role of multiple component therapy. Shock 3 [Suppl]:65 (abstract)CrossRefGoogle Scholar
  18. 18.
    Opal S, Cross AS, Sadoff JC et al (1995) Combined immunotherapy in the treatment of septic shock. Shock 3 [Suppl]:65 (abstract)CrossRefGoogle Scholar
  19. 19.
    Faist E (1995) Immunomodulatory approaches in critically ill surgical patients. Shock 3 [Suppl]:65–66 (abstract)CrossRefGoogle Scholar
  20. 20.
    Fischer C (1995) Unpublished discussion, Fifth Vienna Shock Forum, 7–11 May 1995Google Scholar
  21. 21.
    Mannick JA, Lyons A, Kelly J et al (1998) Major injury induces increased production of IL10 by cells of the immune system with a negative impact on resistance to infection. Ann Surg (in press)Google Scholar
  22. 22.
    Dalton JM, Gore DC, DeMaria EJ et al (1998) Combined administration of interleukin-1 receptor antagonist (IL-IRA) and soluble tumor necrosis factor receptor (STNF-R) decreases mortality and organ dysfunction following hemorrhagic shock. J Trauma (in press)Google Scholar
  23. 23.
    Knox J, Demling R, Wilmore D et al (1995) Increased survival after major thermal injury: The effect of growth hormone therapy in adults. J Trauma 39:526–530PubMedCrossRefGoogle Scholar
  24. 24.
    Kirton O, Windsor J, Civetta et al (1996) Persistent uncorrected intramucosal pH in the critically injured: The impact of splanchnic and antioxidant therapy. Crit Care Med 24:A82 (abstract)Google Scholar
  25. 25.
    Gott JP, Cooper FE, Schmidt et al (1998) Documentation of risk neutralization for extracorporeal circulation in four limbed, 400 patient, risk stratified, prospective, randomized trial. J Surg Res (in press)Google Scholar
  26. 26.
    Fourrier F, Chopin C, Huart JJ et al (1993) Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 104:882–888PubMedCrossRefGoogle Scholar
  27. 27.
    Inthorn D, Hoffmann JN, Hartl WH et al (1997) Antithrombin III supplementation in severe sepsis: Beneficial effects on organ dysfunction. Shock 8(5):328–334PubMedCrossRefGoogle Scholar
  28. 28.
    Opal SM, Cross A, Jhung W et al (1996) Potential hazards of combination immunotherapy in the treatment of experimental septic shock. J Infect Dis 173:1415–1421PubMedCrossRefGoogle Scholar
  29. 29.
    Dwenger A, Remmers D, Gratz M et al (1996) Aprotinin prevents the development of the trauma-induced multiple organ failure in a chronic sheep model. Eur J Clin Chem Clin Biochem 30:204–214Google Scholar
  30. 30.
    Redl H, Schlag G, Bahrami S, Yao YM (1996) Animal models as the basis of pharmacologic intervention in trauma and sepsis patients. World J Surg 20:487–492PubMedCrossRefGoogle Scholar
  31. 31.
    Moore E, Moore F, Franciose R et al (1994) The postischemic gut serves as a priming bed for circulating neutrophils that provoke multiple organ failure. J Trauma 37:881PubMedCrossRefGoogle Scholar
  32. 32.
    Hesslin MJ, Latkany L, Leung D et al (1998) A prospective randomized trial of early enteral feeding after resection of upper GI malignancy. Ann Surg (in press)Google Scholar
  33. 33.
    Braga M, Gianotti L, Vignali A et al (1998) Artificial nutrition after major abdominal surgery: Impact of route of administration and composition of the diet. Crit Care Med 26(1): 24–30PubMedCrossRefGoogle Scholar
  34. 34.
    Bryg DJ, Beale RJ (1998) Clinical effects of enteral immunonutrition on intensive care patients: a meta-analysis. Crit Care Med 26(1):A91CrossRefGoogle Scholar
  35. 35.
    Ivatury RR, Simon RJ, Islam S et al (1996) A prospective randomized study of end points of resuscitation after major trauma. J Am Coll Surg 183:145–154PubMedGoogle Scholar
  36. 36.
    Ljubanovic M, Calvin J, Peruzzi W (1998) Meta-analysis of gastric pH as determinant of mortality in critically ill patients. Crit Care Med 26(1):A123CrossRefGoogle Scholar
  37. 37.
    Dellinger RP, Zimmerman JL, Taylor RW et al (1998) Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: Results of a randomized phase II trial. Crit Care Med 26(1): 15–23PubMedCrossRefGoogle Scholar
  38. 38.
    Matthay MA, Pittet JF, Jayr C (1998) Just say NO to inhaled nitric oxide for the acute respiratory distress syndrome. Crit Care Med 26(1): 1–2PubMedCrossRefGoogle Scholar
  39. 39.
    Zapol WM (1998) Nitric oxide inhalation in acute respiratory distress syndrome: It works, but can we prove it? Crit Care Med 26(1): 2–3PubMedCrossRefGoogle Scholar
  40. 40.
    Mathison DJ, Kuo EY, Hahn C et al(1998) Inhaled nitric oxide for adult respiratory distress syndrome following pulmonary resection. Ann Thorac Surg(in press)Google Scholar
  41. 41.
    Shoemaker WC, Appel PL, Kram HB et al(1988) Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 94:1176–1188PubMedCrossRefGoogle Scholar
  42. 42.
    Durham RM, Neunaber K, Mazuski JE et al(1996) The use of oxygen consumption and delivery as endpoints for resuscitation in critically ill patients. J Trauma 41(1): 32–40PubMedCrossRefGoogle Scholar
  43. 43.
    Moore EE(1991) Hypertonic saline dextran for post-injury resuscitation: experimental background and clinical experience. Aust N Z J Surg 61:732–736PubMedGoogle Scholar
  44. 44.
    Wade CE, Kramer GC, Grady JJ et al(1997) Efficacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of controlled clinical studies. Surgery 122:609–616PubMedCrossRefGoogle Scholar
  45. 45.
    Younes RN, Yin KC, Amino CJ et al(1998) Use of pentastarch solution in the treatment of patients with hemorrhagic hypovolemia: randomized phase II study in the emergency room. World J Surg 22:2–5PubMedCrossRefGoogle Scholar
  46. 46.
    Shackford SR, Bourguignon PR, Wald SL et al(1998) Hypertonic saline resuscitation of patients with head injury: A prospective, randomized clinical trial. J Trauma 44:50–58PubMedCrossRefGoogle Scholar
  47. 47.
    Vassar JJ, Perry CA, Gannaway WL et al(1991) 7.5% sodium chloride/dextran for resuscitation of trauma patients undergoing helicopter transport. Arch Surg 16:1065–1072Google Scholar
  48. 48.
    Thangathurai D, Charbonnet C, Wo CCJ et al(1996) Intraoperative maintenance of tissue perfusion prevents ARDS. New Horiz 4(4):466–474PubMedGoogle Scholar
  49. 49.
    Wang P, Zheng FB, Zhou M et al(1993) Pentoxifylline restores cardiac output and tissue perfusion after trauma-hemorrhage and decreases susceptibility to sepsis. Surgery 114:352–359PubMedGoogle Scholar
  50. 50.
    Bacher A, Mayer N, Klimscha W et al(1997) Effects of pentoxifylline on hemodynamics and oxygenation in septic and nonseptic patients. Crit Care Med 25(5):795–800PubMedCrossRefGoogle Scholar
  51. 51.
    Sun X, Wagner DP, Knaus WA(1996) Does selective decontamination of the digestive tract reduce mortality for severely ill patients? Crit Care Med 24(5):753–755PubMedCrossRefGoogle Scholar
  52. 52.
    Luiten EJ, Hop WCJ, Lange JF, Bruining HA(1995) Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 222(1): 57–65PubMedCrossRefGoogle Scholar
  53. 53.
    Baxby D, van Saene HKF, Stoutenbeek CP, Zandstra DF(1996) Selective decontamination of the digestive tract: 13 years on, what it is and what it is not. Intensive Care Med 22:699–706PubMedCrossRefGoogle Scholar
  54. 54.
    Kolla S, Awad SS, Rich PB et al(1997) Extracorporeal life support for 100 adult patients with severe respiratory failure. Ann Surg 226(4):5440566CrossRefGoogle Scholar
  55. 55.
    Hirasawa H, Sugai T, Oda S et al(1998) Continuous hemodiafiltration(Chdf) removes cytokine and improves respiratory index(Ri) and oxygen metabolism in patients with acute respiratory distress syndrome(Ards). Crit Care Med 26(1):A120CrossRefGoogle Scholar
  56. 56.
    Honore PM, James J, Wauthier M et al(1998) Reversal of intractable circulatory failure complicating septic shock with short time high volume haemofiltration(ST-HV-CWH) after failure of conventional therapy: a prospective evaluation. Crit Care 2:62CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia, Milano 1999

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  • A. E. Baue

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