Clinical trial NCT00700362: Insulin Infusion and Infectious Diabetic Foot Ulcers (IIIFU)
Official title: The Effect of Insulin-Glucose Infusion on Metabolic Control (Primary) and Inflammation (Secondary) in Diabetic Patients Treated for Acute Foot Ulcer Infection or Surgical Wound Infection
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Diabetes Mellitus
Insulin Resistance
Hyperglycemia
Infection
Keywords: Complications
Hyperglycemia
Insulin infusion
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
First posted: 2008-06-18
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Office patients

Brief summary: Normoglycemia is important for the outcome of surgical and medical conditions. Insulin infusions have been studied to achieve normoglycemia during these circumstances and have proved to be useful. Insulin given by subcutaneous injections has longer duration compared to intravenous given insulin which makes it more difficult to control. The hypothesis behind the trial is the concept that insulin infusion is more effective in reaching normoglycemia in diabetic subjects during foot ulcer infection and surgical wound infection.

* The study evaluates a target controlled insulin infusion or conventional therapy as antidiabetic treatment during foot ulcer infection and surgical wound infection.
* Secondary efficacy parameter will be hospital stay, laboratories for inflammation and oxidative stress.

Detailed description: Introduction:

Normoglycemia is important for the outcome of acute surgical and medical conditions. Different insulin infusions have been studied to achieve normoglycemia and have proved to be useful. Insulin given by subcutaneous injections has duration between 3- 36 hours depending on the insulin brand and injection site compared to 10 minutes for intravenous given insulin. Different insulin infusions have been studied to achieve normoglycemia but the biological and chemical effects of insulin infusions have not been studied during foot ulcer infection and surgical wound infection in patients with diabetes. Therefore, we aim to investigate the importance of normoglycemia for the optimal treatment during foot ulcer infection and surgical wound infection among diabetics.

Hypothesis:

Target controlled insulin infusion is more effective in reducing hyperglycemia, improve healing of inflammation and infection in diabetics compared to conventional antidiabetic therapy.

Study Design:

This is a randomized prospective, open controlled trial of target controlled insulin infusion vs conventional antidiabetic therapy in diabetic patients. Diabetics treated for foot ulcer infection or surgical wound infection, who met eligibility criteria and choose to participate will be included and randomized.

Duration of study:

The infusion starts when patients who met the eligibility criteria has signed the informed consent. The intervention group continues for tree full days with insulin infusion. After the transition day (the fourth day) multiple doses of mixinsulin continues until the study ends 4 weeks after the randomization.

Selection of patients:

Patients with diabetic foot ulcer infection or surgical wound infection will be enrolled. At least 90 patients will be included during a 24 month-enrollment period.

Treatment:

Eligible patients will be randomized to insulin infusion (group 1) for 3 days or therapy according to clinical practise (group 2).

Group 1 (intervention group):

The insulin infusion starts when the patient full fill the eligibility criteria and has signed the informed consent. It controls by regular capillary plasma glucose tests and continues for tree days. The infusion stop on the fourth day, the insulin demand is estimated from the last 24 infusion hours by a specific algorithm and divided to 2-4 equal mealtime doses of mixinsulin. The first mealtime dose is given to the breakfast on the fourth day and the infusion continues for another 2 hours where after it is stopped. After the transition day (the fourth day) multiple doses of mixinsulin continues until the study ends 4 weeks after the randomization.

All patients will have a stop visit at the study end.

Patient assignment to treatment group:

Patients recruited in the clinic and hospital wards and meeting the eligibility criteria and has signed the informed consent will be randomized.

Eligibility criteria: Inclusion Criteria:

Patients are eligible for inclusion if the following criteria are fulfilled:

* Postoperative or infectious patients with: skin-, airways-, urine tract- or gastro-intestinal infections.
* Hyperglycaemia: Capillary P-glucose above 8 mmol/L.
* Older than 18 years.
* Informed consent obtained.

Exclusion Criteria:

Patients having any of the following at randomization will not be included in the study:

* Unconsciousness: not possible to wake up.
* Ketoacidosis: pH less or equal to 7.30.
* Hyperosmolar syndrome: S-Na more or equal to 150 mmol/L.
* Kidney failure: calculated GFR \< 30 mL/min.
* Pregnancy.
* Mental condition making the subject unable to understand the concepts and risk of the study.

Primary outcomes:
measure: Plasma glucose level.
timeFrame: 4 weeks
Secondary outcomes:
measure: Hospital stay
timeFrame: 4 weeks
measure: HbA1c
timeFrame: 4 weeks
measure: laboratories for inflammation and oxidative stress.
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Stockholm
country: Sweden
facility: Department of Molecular Medicine and Surgery, Rolf Luft Research Center for Diabetes and Endocrinology
Study officials:
affiliation: Karolinska Institutet
name: Kerstin Brismar, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bonnier M, Lonnroth P, Gudbjornsdottir S, Attvall S, Jansson PA. Validation of a glucose-insulin-potassium infusion algorithm in hospitalized diabetic patients. J Intern Med. 2003 Feb;253(2):189-93. doi: 10.1046/j.1365-2796.2003.01085.x.
citation: Van den Berghe G, Wilmer A, Milants I, Wouters PJ, Bouckaert B, Bruyninckx F, Bouillon R, Schetz M. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes. 2006 Nov;55(11):3151-9. doi: 10.2337/db06-0855.
citation: Sjoholm A, Nystrom T. Endothelial inflammation in insulin resistance. Lancet. 2005 Feb 12-18;365(9459):610-2. doi: 10.1016/S0140-6736(05)17912-4.
citation: Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006 Mar;17(1):4-12.
citation: Sjoholm A, Nystrom T. Inflammation and the etiology of type 2 diabetes. Diabetes Metab Res Rev. 2006 Jan-Feb;22(1):4-10. doi: 10.1002/dmrr.568.
citation: Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab. 1994 Sep;79(3):872-8. doi: 10.1210/jcem.79.3.7521354.
citation: Hadi HA, Suwaidi JA. Endothelial dysfunction in diabetes mellitus. Vasc Health Risk Manag. 2007;3(6):853-76.
citation: Abourizk NN, Vora CK, Verma PK. Inpatient diabetology. The new frontier. J Gen Intern Med. 2004 May;19(5 Pt 1):466-71. doi: 10.1111/j.1525-1497.2004.30133.x.
citation: Subramaniam B, Panzica PJ, Novack V, Mahmood F, Matyal R, Mitchell JD, Sundar E, Bose R, Pomposelli F, Kersten JR, Talmor DS. Continuous perioperative insulin infusion decreases major cardiovascular events in patients undergoing vascular surgery: a prospective, randomized trial. Anesthesiology. 2009 May;110(5):970-7. doi: 10.1097/ALN.0b013e3181a1005b.
citation: Collier B, Dossett LA, May AK, Diaz JJ. Glucose control and the inflammatory response. Nutr Clin Pract. 2008 Feb;23(1):3-15. doi: 10.1177/011542650802300103.
citation: Griesdale DE, de Souza RJ, van Dam RM, Heyland DK, Cook DJ, Malhotra A, Dhaliwal R, Henderson WR, Chittock DR, Finfer S, Talmor D. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009 Apr 14;180(8):821-7. doi: 10.1503/cmaj.090206. Epub 2009 Mar 24.
citation: Campbell RK. Etiology and effect on outcomes of hyperglycemia in hospitalized patients. Am J Health Syst Pharm. 2007 May 15;64(10 Suppl 6):S4-8. doi: 10.2146/ajhp070100.
citation: Van den Berghe G, Schetz M, Vlasselaers D, Hermans G, Wilmer A, Bouillon R, Mesotten D. Clinical review: Intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose target? J Clin Endocrinol Metab. 2009 Sep;94(9):3163-70. doi: 10.1210/jc.2009-0663. Epub 2009 Jun 16.
citation: Kotronen A, Lewitt M, Hall K, Brismar K, Yki-Jarvinen H. Insulin-like growth factor binding protein 1 as a novel specific marker of hepatic insulin sensitivity. J Clin Endocrinol Metab. 2008 Dec;93(12):4867-72. doi: 10.1210/jc.2008-1245. Epub 2008 Sep 16.
citation: King GL. The role of inflammatory cytokines in diabetes and its complications. J Periodontol. 2008 Aug;79(8 Suppl):1527-34. doi: 10.1902/jop.2008.080246.
citation: Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004 Mar;27(3):813-23. doi: 10.2337/diacare.27.3.813.
citation: Haynes WG. Role of leptin in obesity-related hypertension. Exp Physiol. 2005 Sep;90(5):683-8. doi: 10.1113/expphysiol.2005.031237. Epub 2005 Aug 16.
citation: Gomes F, Telo DF, Souza HP, Nicolau JC, Halpern A, Serrano CV Jr. Obesity and coronary artery disease: role of vascular inflammation. Arq Bras Cardiol. 2010 Feb;94(2):255-61, 273-9, 260-6. doi: 10.1590/s0066-782x2010000200021. English, Portuguese, Spanish.
citation: Arai Y, Kojima T, Takayama M, Hirose N. The metabolic syndrome, IGF-1, and insulin action. Mol Cell Endocrinol. 2009 Feb 5;299(1):124-8. doi: 10.1016/j.mce.2008.07.002. Epub 2008 Jul 11.
citation: Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010 Mar 25;316(2):129-39. doi: 10.1016/j.mce.2009.08.018. Epub 2009 Aug 31.