ICULIP, Influence of Two Lipid Emulsions in the Nosocomial Infection in Critical Patients

Critical Illness Clinical Trial

— ICULIP  

Official title:

Phase IV-IV. ICULIP,a Prospective,Multi-centre,Randomised,Comparative,Double-blind Study to Evaluate Two Different Types of Lipid Emulsions Used for Total Parenteral Nutrition in Critical Patients and Their Influence on Nosocomial Infection.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00396461
• Other study ID #: HC-G-H-0510
• Secondary ID: 2005-003542-33
• Status: Terminated
• Phase: Phase 4
• First received: November 3, 2006
• Last updated: July 18, 2013
• Start date: November 2006
• Est. completion date: February 2011

Study information

• Verified date: July 2013
• Source: B. Braun Medical SA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of MedicinesSpain: Ministry of Health and Consumption
• Study type: Interventional

Clinical Trial Summary

This study aims to analyse the effect of two total parenteral nutrition diets with lipid emulsions of different compositions on the incidence of nosocomial infection in critical patients. One diet will contain an MCT/LCT emulsion concentrated to 20% (50:50 ratio) and the other will comprise an MCT/LCT/fish oil emulsion (50:40:10 ratio). The secondary objective of this study is to analyse mortality in hospital and up to 6 months of discharge.

Description:

During the last years the most widely used lipid emulsion for parenteral nutrition has been based on soybean oil. This first generation of lipid emulsions used in TPN contained w-6 series polyunsaturated long-chain fatty acids (LCT) from soy, maize, sunflower and safflower oil. LCT contain an excess of linoleic acid which, when metabolised, produce large quantities of arachidonic acid and its metabolites. Although the generally used doses seem safe (1-2 g/kg/day by continuous perfusion), alterations in pulmonary function in patients with acute adult respiratory distress syndrome have been described, as have alterations in platelet function, hepatic function and haemodynamics, which are attributed to the excess of said metabolites. However, the most important side effect of the LCT lipid infusions is its influence on the immune response. Experimental and clinical studies show that LCT can interfere with various stages of the immune response such as the production of antibodies, complement synthesis, granulocytic and lymphocytic activity and the reticuloendothelial system. Various hypotheses have been formulated to explain the modulator effect of the polyunsaturated fatty acids on immune function: changes in the permeability of the cellular membrane, modifications in the synthesis of eicosanoids and the presence of peroxides derived from the oxidation of polyunsaturated fatty acids.

In summary, although linoleic acid as a dietary essential fatty acid is important, its excessive intake is associated with undesirable immunological and inflammatory events. Thus it is recommended that soybean oil should be partly replaced by other lipids.

To avoid these side effects the second generation lipid emulsions were developed. These contain a combination of medium- and long-chain fatty acids (MCT/LCT) with lower w-6 fatty acid content. MCT/LCT lipid emulsions are safe and do not produce biochemical or metabolic alterations or gaseous exchange in patients with ARDS. MCT/LCT combinations seem to reduce the generation of eicosanoids and do not alter the immune response in in-vitro and experimental studies. The impact of these differences on the nosocomial infection and the clinical prognosis of the patients has not been studied sufficiently despite the fact that some studies show reduced mortality and morbidity using MCT/LCT emulsions when compared with the use of pure LCT emulsions. MCT/LCT emulsions are normally used in clinical practice on patients that have required parenteral nutrition for 20 years.

Recently, the clinical use in artificial nutrition of omega-3 series polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) present in many fish oils has been significant. EPA is a precursor to certain eicosanoid series that compensate the proinflammatory effects of the eicosanoids in arachidonic acid (omega-6 series). The objective is immunomodulation to attenuate the inflammatory response of patients without negatively impacting on the immune function. The use of enteral diets enriched with omega-3 series fatty acids (fish oil) in post-operation cancer patients showed a reduction in the number of days in hospital and infectious complications.

The use of fish oil or fat emulsions enriched with fish oil (omega-3) in parenteral nutrition has already been the subject of various studies: where modulation of the inflammatory response markers has been shown, reduces the stay in hospital and the need for mechanical ventilation in patients undergoing major abdominal surgery, reduces the stay in hospital in patients undergoing digestive surgery… So, w-3 lipids exhibit strong immunologic properties. They offer the possibility to counterbalance the negative effects of conventional w-6 fatty acids. Recent studies exhibit positive effects of intravenous use of fish oil on immunologic functions and clinical parameters in surgical and septic patients

The purpose of this study is to analyse the effect of two total parenteral nutrition diets with lipid emulsions of different compositions on the incidence of nosocomial infection in critical patients. One diet will contain an MCT/LCT emulsion concentrated to 20% (50:50 ratio) (w3:w6 is 1:7) and the other will comprise an MCT/LCT/fish oil emulsion (50:40:10 ratio) (w3:w6 is 1:2,7). The secondary objective of this study is to analyse mortality in hospital and up to 6 months after discharge.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 212
• Est. completion date: February 2011
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

INCLUSION CRITERIA:

Patients of both sexes, prospective admission to Intensive Care Units (ICUs), over 18 years, where TPN is required as a nutritional metabolic support for a minimum period of 5 days and where said patients have signed the informed consent form.

The indications for administration of parenteral nutrition shall be those recommended by the American Society of Parenteral and Enteral Nutrition (ASPEN), and in particular:

• Severe malnutrition

• Major intra-abdominal surgery

• Peritonitis

• Intestinal ischaemia

• Intestinal occlusion

• Gastrointestinal fistulas

• Small intestine

Patients of both sexes, over 18 years, that commencing nutritional support with enteral diets in the first 3 days of admission to ICU require parenteral nutrition as:

• 75% of the calculated energy requirements have not been reached after three days receiving enteral nutrition.

• Gastrointestinal complications have been suffered as a result of enteral nutrition that cannot be treated or are persistent in the first 3 days of admission.

In this case EN will be suspended and the patient will be included in the protocol receiving PN.

EXCLUSION CRITERIA:

• APACHE II < 13

• Morbid obesity (BMI = 39)

• Hepatic disease defined within the following set of parameters:

1. Portal hypertension with gastrointestinal bleeding on admission

2. Clinically apparent hepatocellular ascites

3. Hepatocellular bilirubin higher than 3 mg/dL

4. Serum albumin less than 30 g/L with portal hypertension

5. Grade II or higher encephalopathy

6. Clinical diagnosis of alcoholic hepatitis

• Chronic renal insufficiency defined by one of the following criteria:

1. Plasmatic creatinine greater than 4 mg/dL

2. Chronic peritoneal dialysis or haemodialysis

• Patients with severe acquired or familial hyperlipidaemias (> 400 mg/day) of any kind

• Serious chronic neurological disease defined by one of the following criteria:

1. Cerebrovascular accident with persistent neurological deficit in the past six months

2. Neurological deficit that necessitates chronic confinement

• Neoplastic patients with metastasis and a life expectancy of less than six months

• Patients that underwent chemotherapy or radiotherapy during the month prior to the study

• Patients that received chronic treatment with corticoids in the month preceding admission to ICU. Patients receiving treatment with corticoids since admission to ICU for septic shock should not be excluded.

• Continuous infusion treatment for more than 24 hours with propofol or with other pharmaceuticals where lipid emulsions are used as the vehicle

• Infectious diseases transmitted through the blood, products derived from blood or urine: hepatitis B, C and HIV

• Inclusion in another clinical trial

• Having received TPN in the month prior to inclusion in the study

• Pregnancy

• Refusal to participate in the study

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Critical Illness
• Cross Infection

Intervention

Drug:
• MCT/LCT (1:1)
Emulsion based on 20% MCT/LCT (50:50 ratio)
• MCT/LCT/omega-3 (5:4:1)
Emulsion based on 20% MCT/LCT/w3 (50:40:10 ratio), medium- and long-chain triglycerides and fish oil triglycerides.

Locations

Country	Name	City	State
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital de Cruces	Barakaldo	Bizcaya
Spain	Hospital del Mar (Institut Municipal d'Assistència Sanitària, IMAS)	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	Hospital Universitario "Puerta del Mar"	Cádiz
Spain	Hospital Universitario "Virgen de la Arrixaca"	El Palmar	Murcia
Spain	Hospital Universitari de Girona Doctor Josep Trueta	Girona
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital Universitario de Bellvitge (H.U.B.)	Hospitalet de Llobregat	Barcelona
Spain	Complejo Hospitalario Materno Insular de Gran Canaria	Las Palmas de Gran Canaria	Gran Canaria
Spain	Hospital Universitario de Gran Canaria Dr. Negrín	Las Palmas de Gran Canaria	Gran Canaria
Spain	Hospital Severo Ochoa	Leganés	Madrid
Spain	Hospital Universitario Arnau de Vilanova	Lleida
Spain	Fundación Jiménez Díaz	Madrid
Spain	Hospital Regional Universitario Carlos Haya	Málaga
Spain	Hospital General Universitario "Reina Sofía"	Murcia
Spain	Hospital Son Dureta	Palma de Mallorca	Baleares
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario de Valme	Sevilla
Spain	Hospital Clínico Universitario de Valencia	Valencia
Spain	Hospital Universitario Del Río Hortega	Valladolid
Spain	Hospital Universitario Miguel Servet	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
B. Braun Medical SA

Country where clinical trial is conducted

Spain, 

References & Publications (26)

ASPEN Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr. 2002 Jan-Feb;26(1 Suppl):1SA-138SA. Erratum in: JPEN J Parenter Enteral Nutr 2002 Mar-Apr;26(2):144. — View Citation

Bach AC, Frey A, Lutz O. Clinical and experimental effects of medium-chain-triglyceride-based fat emulsions--a review. Clin Nutr. 1989 Oct;8(5):223-35. — View Citation

Barton RG. Nutrition support in critical illness. Nutr Clin Pract. 1994 Aug;9(4):127-39. Review. — View Citation

Calder PC, Sherrington EJ, Askanazi J, Newsholme EA. Inhibition of lymphocyte proliferation in vitro by two lipid emulsions with different fatty acid compositions. Clin Nutr. 1994 Apr;13(2):69-74. — View Citation

Calder PC. Long-chain n-3 fatty acids and inflammation: potential application in surgical and trauma patients. Braz J Med Biol Res. 2003 Apr;36(4):433-46. Epub 2003 Apr 8. Review. — View Citation

Carpentier YA, Van Gossum A, Dubois D, Deckeibaum R. Lipid Metabolism in Parenteral Nutrition. In: Wilmore DW, Carpentier YA (Eds). Metabolic Support of the Critically III Patient. Berlin, Springer-Veriag 1993, pp 35-74

Cerra FB. Hypermetabolism, organ failure, and metabolic support. Surgery. 1987 Jan;101(1):1-14. Review. — View Citation

Clarke PJ, Ball MJ, Hands LJ, Dennison AR, Tunbridge A, White K, Kettlewell MG. Use of a lipid containing medium chain triglycerides in patients receiving TPN: a randomized prospective trial. Br J Surg. 1987 Aug;74(8):701-4. — View Citation

Driscoll DF, Adolph M, Bistrian BR. Lipid emulsions in parenteral nutrition. In: Rombeau JL, Rolandelli R, eds. Parenteral nutrition. Philadelphia: W. B. Saunders Company; 2000:35-39.

Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, Van Hoozen C, Wennberg AK, Nelson JL, Noursalehi M. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med. 1999 Aug;27(8):1409-20. — View Citation

García-de-Lorenzo A. Lipid emulsions with different phospholipid/triglyceride ratio in critically ill septic and traumatic patients. Crit Care Med. 1998 Dec;26(12):2094-5. — View Citation

Gogos CA, Kalfarentzos F. Total parenteral nutrition and immune system activity: a review. Nutrition. 1995 Jul-Aug;11(4):339-44. Review. — View Citation

Gogos CA, Kalfarentzos FE, Zoumbos NC. Effect of different types of total parenteral nutrition on T-lymphocyte subpopulations and NK cells. Am J Clin Nutr. 1990 Jan;51(1):119-22. — View Citation

Grau T, Ruiz de Adana JC, Zubillaga S, Fuerte S, Girón C. [Randomized study of two different fat emulsions in total parenteral nutrition of malnourished surgical patients;effect of infectious morbidity and mortality]. Nutr Hosp. 2003 May-Jun;18(3):159-66. Spanish. — View Citation

Grimminger F, Seeger W, Mayer K. Use of n-3 fatty acid-containing lipid emulsions in the intensive care unit environment: the clinician's view. Clinical Nutrition 2002, 21, Supplement 2: 23-29.

Jensen GL, Mascioli EA, Seidner DL, Istfan NW, Domnitch AM, Selleck K, Babayan VK, Blackburn GL, Bistrian BR. Parenteral infusion of long- and medium-chain triglycerides and reticuloendothelial system function in man. JPEN J Parenter Enteral Nutr. 1990 Sep-Oct;14(5):467-71. — View Citation

Kinsella JE, Lokesh B. Dietary lipids, eicosanoids, and the immune system. Crit Care Med. 1990 Feb;18(2 Suppl):S94-113. Review. — View Citation

Köller M, Senkal M, Kemen M, König W, Zumtobel V, Muhr G. Impact of omega-3 fatty acid enriched TPN on leukotriene synthesis by leukocytes after major surgery. Clin Nutr. 2003 Feb;22(1):59-64. — View Citation

Kumar SG, Das UN, Kumar KV, Madhavi N, Das NP, Tan BKH. Effect of n-6 and n-3 fatty acids on the proliferation of human lymphocyes and their secretion of TN F-alpha and IL-2 in vitro. Nutr Res 1992; 12: 815-823.

Mathru M, Dries DJ, Zecca A, Fareed J, Rooney MW, Rao TL. Effect of fast vs slow intralipid infusion on gas exchange, pulmonary hemodynamics, and prostaglandin metabolism. Chest. 1991 Feb;99(2):426-9. — View Citation

Santoli D, Zurier RB. Prostaglandin E precursor fatty acids inhibit human IL-2 production by a prostaglandin E-independent mechanism. J Immunol. 1989 Aug 15;143(4):1303-9. Erratum in: J Immunol 1990 Jan 15;144(2):774. — View Citation

Suchner U, Katz DP, Fürst P, Beck K, Felbinger TW, Senftleben U, Thiel M, Goetz AE, Peter K. Effects of intravenous fat emulsions on lung function in patients with acute respiratory distress syndrome or sepsis. Crit Care Med. 2001 Aug;29(8):1569-74. — View Citation

Suchner U, Senftleben U. Immune modulation by polyunsaturated fatty acids during nutritional therapy: interactions with synthesis and effects of eicosanoids. Infusionsther Transfusionsmed. 1994 Jun;21(3):167-82. Review. — View Citation

Tsekos E, Reuter C, Stehle P, Boeden G. Perioperative administration of parenteral fish oil supplements in a routine clinical setting improves patient outcome after major abdominal surgery. Clin Nutr. 2004 Jun;23(3):325-30. Erratum in: Clin Nutr. 2004 Aug;23(4):755-6. — View Citation

Weiss G, Meyer F, Matthies B, Pross M, Koenig W, Lippert H. Immunomodulation by perioperative administration of n-3 fatty acids. Br J Nutr. 2002 Jan;87 Suppl 1:S89-94. — View Citation

Wichmann MW, Morlion B, Czarnetzki H-D, Thul P, Jauch K-W. Reduction of length of postoperative stay by fish oil containing lipid emulsion - data from a multicenter trial. Clinical Nutrition 2004, 23: 1471

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The analyses will particularly focus on: Pneumonia associated with mechanical ventilation, Catheter infection, Bacteraemia not associated with catheter, Urinary infection, Infection of surgical wounds and Intra-abdominal abscess and peritonitis.		Patients will receive at least 5 days of PN. Clinical condition and nosocomial infection will be monitored daily until the first phase of the study is completed on day 28 or the patient is discharged from the unit.	Yes
Primary	Compare the incidence of nosocomial infection associated with the administration of two different lipid solutions in total parenteral nutrition of patients in an Intensive Care Unit.		Patients will receive at least 5 days of PN. Clinical condition and nosocomial infection will be monitored daily until the first phase of the study is completed on day 28 or the patient is discharged from the unit.	Yes
Secondary	Study mortality at the end of the study and 6 months after discharge from ICU; Hospital stay and/or in Intensive Care Unit; Mechanical ventilation days; Assessment of hepatic function; Assessment of nutritional efficacy.		At the end of the study and 6 months after discharge from ICU.	Yes

External Links

•   ASPEN, American Society for Parenteral and Enteral Nutrition --> Nutrition-related Links
•   Spanish Society for Intensive Medicine, Critical and Coronary Units
•   Spanish Society for Parenteral and Enteral Nutrition