Advertisement

Intensive Care Medicine

, 34:1843 | Cite as

Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients

  • Gaetano IapichinoEmail author
  • Maura Albicini
  • Michele Umbrello
  • Francesca Sacconi
  • Isabella Fermo
  • Radmila Pavlovich
  • Rita Paroni
  • Giacomo Bellani
  • Giovanni Mistraletti
  • Massimo Cugno
  • Antonio Pesenti
  • Luciano Gattinoni
Ôriginal

Abstract

Objective

We investigated whether preventing hyperglycemia in septic patients affected the plasma concentration of asymmetric-dimethylarginine and if this was associated with clinical benefit.

Design

A prospective, multicenter, randomized, controlled, clinical study.

Setting

Intensive care units (ICU) in three university hospitals.

Patients

A total of 72 patients admitted for severe sepsis or septic shock, who stayed at least 3 days in the ICU. At admission the patients were assigned to receive either tight or conventional glycemic control.

Interventions

Determination of circulating levels of asymmetric-dimethylarginine, arginine, interleukin-6, C-reactive-protein and tumor-necrosis-factor-α.

Measurements and results

Blood was sampled at admission (no differences between groups), and on the 3rd, 6th, 9th, and 12th (T12) days. Sequential organ failure assessment was scored at each sampling time. All the data were analyzed on an intention-to-treat basis. The control and treatment groups received the same energy intake, glycemia (110.4 ± 17.3 vs. 163.0 ± 28.9 mg/dL, P < 0.001) and insulin (P = 0.02) supply differed. No differences were found in high plasma levels of asymmetric-dimethylarginine (P = 0.812) at any time during the ICU stay. The clinical course, as indicated by markers of inflammation, average and maximum organ failure score, ICU stay and ICU and 90-day mortality, was the same.

Conclusions

Intensive insulin treatment, while achieving glucose control, did not reduce asymmetric-dimethylarginine in high-risk septic patients fed with no more than 25 kcal/kg per day to limit ventilatory demand and to simplify glucose control.

Descriptor

45 (SIRS/sepsis: clinical studies).

Keywords

ADMA Sepsis Glycemic control Insulin therapy Endocrine 

Notes

Acknowledgments

We thank Alberto Morabito, Professor of Medical Statistics, Università degli Studi di Milano, for the accurate revision of the statistical analysis of the study. We are grateful to J. D. Baggott for editing the English.

References

  1. 1.
    Kimoto M, Tsuji H, Ogawa T, Sasaoka K (1993) Detection of NG, NG-dimethylarginine dimethylaminohydrolase in the nitric oxide-generating systems of rats using monoclonal antibody. Arch Biochem Biophys 300:657–662PubMedCrossRefGoogle Scholar
  2. 2.
    Kimoto M, Whitley GS, Tsuji H, Ogawa T (1995) Detection of NG, NG-dimethylarginine dimethylaminohydrolase in human tissues using a monoclonal antibody. J Biochem 117:237–238PubMedCrossRefGoogle Scholar
  3. 3.
    Kielstein JT, Boger RH, Bode-Böger SM, Frolich JC, Haller H, Ritz E, Fliser D (2002) Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 13:170–176PubMedGoogle Scholar
  4. 4.
    Marescau B, Nagels G, Possemiers I, De Broe ME, Becaus I, Billiouw JM, Lornoy W, De Deyn PP (1997) Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. Metabolism 46:1024–1031PubMedCrossRefGoogle Scholar
  5. 5.
    Closs EI, Basha FZ, Habermeier A, Forstermann U (1997) Interference of l-arginine analogues with l-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1:65–73PubMedCrossRefGoogle Scholar
  6. 6.
    Bode-Böger SM, Scalera F, Kielstein JT, Martens-Lobenhoffer J, Breithardt G, Fobker M, Reinecke H (2006) Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease. J Am Soc Nephrol 17:1128–1134PubMedCrossRefGoogle Scholar
  7. 7.
    Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Endogenous dimethylarginine as an inibitor of nitric oxide synthesis. J Cardiovasc Pharmacol 20:S60–S62PubMedGoogle Scholar
  8. 8.
    Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP (1999) Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99:3092–3095PubMedGoogle Scholar
  9. 9.
    Siroen MP, Teerlink T, Nijveldt RJ, Prins HA, Richir MC, van Leeuwen PA (2006) The clinical significance of asymmetric dimethylarginines. Annu Rev Nutr 26:203–228PubMedCrossRefGoogle Scholar
  10. 10.
    Sydow K, Munzel T (2003) ADMA and oxidative stress. Atheroscler Suppl 4:41–51PubMedCrossRefGoogle Scholar
  11. 11.
    Stühlinger MC, Oka RK, Graf EE, Schmölzer I, Upson BM, Kapoor O, Szuba A, Malinow MR, Wascher TC, Pachinger O, Cooke JP (2003) Endothelial dysfunction induced by hyperhomocysteinemia: role of asymmetric dimethylarginine. Circulation 108:933–938PubMedCrossRefGoogle Scholar
  12. 12.
    Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Münzel T (2005) Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res 97:e53–e59PubMedCrossRefGoogle Scholar
  13. 13.
    Kielstein JT, Bode-Böger SM, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, Hoeper MM (2005) Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 25:1414–1418PubMedCrossRefGoogle Scholar
  14. 14.
    Nijveldt RJ, Teerlink T, Van Der Hoven B, Siroen MP, Kuik DJ, Rauwerda JA, van Leeuwen PA (2003) Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr 22:23–30PubMedCrossRefGoogle Scholar
  15. 15.
    Siroen MP, Van Leeuven PAM, Nijveldt RJ, Teerlink T, Wouters PJ, Van den Berghe G (2005) Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: a possible explanation of reduced morbidity and mortality? Crit Care Med 33:504–510PubMedCrossRefGoogle Scholar
  16. 16.
    O’Dwyer MJ, Dempsey F, Crowley V, Kelleher DP, McManus R, Ryan T (2006) Septic shock is correlated with asymmetrical dimethylarginine levels, which may be influenced by a polymorphism in the dimethylarginine dimethylaminohydrolase II gene: a prospective observational study. Crit Care 10:R139PubMedCrossRefGoogle Scholar
  17. 17.
    Maas R, Dentz L, Schwedhelm E, Thoms W, Kuss O, Hitmeyer N, Hdden M, Koss T, Standl T, Boger RH (2007) Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine predict adverse events in patients undergoing noncardiac surgery. Crit Care Med 35:1876–1881PubMedCrossRefGoogle Scholar
  18. 18.
    Zoccali C, Bode-Böger SM, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frölich J, Böger RH (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358:2113–2117PubMedCrossRefGoogle Scholar
  19. 19.
    Valkonen VP, Paiva H, Salonen JT, Lakka TA, Lehtimaki T, Laakso J, Laaksonen R (2001) Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 358:2127–2128PubMedCrossRefGoogle Scholar
  20. 20.
    Lu TM, Ding YA, Lin SJ, Lee WS, Tai HC (2003) Plasma levels of asymmetric dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 24:1912–1919PubMedCrossRefGoogle Scholar
  21. 21.
    Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874CrossRefGoogle Scholar
  22. 22.
    Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359–1367PubMedCrossRefGoogle Scholar
  23. 23.
    Le Gall JR, Lemeshow S, Saulnier F (1993) A new Simplified Acute Physiology Score (Simplified Acute Physiology Score II) based on a European/North American multicenter study. JAMA 270:2957–2963PubMedCrossRefGoogle Scholar
  24. 24.
    Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med 22:707–710PubMedCrossRefGoogle Scholar
  25. 25.
    Paroni R, Fermo I, Fiorina P, Cighetti G (2005) Determination of asymmetric and symmetric dimethylarginines in plasma of hyperhomocysteinemic subjects. Amino Acids 28:389–394PubMedCrossRefGoogle Scholar
  26. 26.
    Iapichino G, Radrizzani D, Solca M, Bonetti G, Leoni L, Ferro A (1985) Influence of total parenteral nutrition on protein metabolism following acute injury: assessment by urinary 3-methylhistidine excretion and nitrogen balance. J Parentr Enteral Nutr 9:42–46CrossRefGoogle Scholar
  27. 27.
    Mann GE, Yudilevich DL, Sobrevia L (2003) Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev 83:183–252PubMedGoogle Scholar
  28. 28.
    Sobrevia L, Nadal A, Yudilevich DL, Mann GE (1996) Activation of l-arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. J Physiol 490:775–781PubMedGoogle Scholar
  29. 29.
    Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106:987–992PubMedCrossRefGoogle Scholar
  30. 30.
    Nijveldt RJ, Teerlink T, Siroen MP, van Lambalgen AA, Rauwerda JA, van Leeuwen PA (2003) The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA). Clin Nutr 22:17–22PubMedCrossRefGoogle Scholar
  31. 31.
    Liu J, Hatzoglou M (1998) Control of expression of the gene for the arginine transporter Cat-1 in rat liver cells by glucocorticoids and insulin. Amino Acids 15:321–337PubMedCrossRefGoogle Scholar
  32. 32.
    Radrizzani D, Iapichino G (1998) Nutrition and lung function in the critically ill patient. Clin Nutr 17:7–10PubMedCrossRefGoogle Scholar
  33. 33.
    Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natansori C, Loeffler M, Reinhart K, German Competence Network Sepsis (SepNet) (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139PubMedCrossRefGoogle Scholar
  34. 34.
    Devos P, Preiser JC, Melot C (2007) Impact of tight glucose control by Intensive insulin therapy on ICU mortality and the rate of hypoglycaemia: final results of the Glucocontrol study. Intensive Care Med 33(Suppl 2):S189Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Gaetano Iapichino
    • 1
    Email author
  • Maura Albicini
    • 2
  • Michele Umbrello
    • 1
  • Francesca Sacconi
    • 1
  • Isabella Fermo
    • 5
  • Radmila Pavlovich
    • 4
  • Rita Paroni
    • 4
  • Giacomo Bellani
    • 3
  • Giovanni Mistraletti
    • 1
  • Massimo Cugno
    • 6
  • Antonio Pesenti
    • 3
  • Luciano Gattinoni
    • 1
  1. 1.Istituto di Anestesiologia e RianimazioneUniversità degli Studi di MilanoMilanItaly
  2. 2.U.O. Anestesia e RianimazioneAzienda Ospedaliera Polo Universitario San PaoloMilanItaly
  3. 3.Dipartimento di Medicina Perioperatoria e Terapia Intensiva, Azienda Ospedaliera San Gerardo di Monza, Dipartimento di Medicina SperimentaleUniversità degli Studi Milano-BicoccaMilanItaly
  4. 4.Department of Medicine, Surgery, Dental ScienceUniversity of MilanMilanItaly
  5. 5.Separative Techniques UnitSan Raffaele Scientific InstituteMilanItaly
  6. 6.Department of Internal MedicineUniversity of Milan, Fondazione IRCCS, Ospedale Maggiore PoliclinicoMilanItaly

Personalised recommendations