Clinical trial NCT00396461: ICULIP, Influence of Two Lipid Emulsions in the Nosocomial Infection in Critical Patients
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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Critical Illness
Keywords: Critical Illness
Fat Emulsions, Intravenous
Superinfection
Parenteral Nutrition
Lead sponsor: B. Braun Medical SA
Sponsor class: INDUSTRY
First posted: 2006-11-07
Enrollment: 212
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 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.
measure: 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.
timeFrame: 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.
Secondary outcomes:
measure: 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.
timeFrame: At the end of the study and 6 months after discharge from ICU.
Other outcomes:
Locations:
city: Palma de Mallorca
country: Spain
facility: Hospital Son Dureta
state: Baleares
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitario de Bellvitge (H.U.B.)
state: Barcelona
city: Barakaldo
country: Spain
facility: Hospital de Cruces
state: Bizcaya
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Dr. Negrín
state: Gran Canaria
city: Las Palmas de Gran Canaria
country: Spain
facility: Complejo Hospitalario Materno Insular de Gran Canaria
state: Gran Canaria
city: Leganés
country: Spain
facility: Hospital Severo Ochoa
state: Madrid
city: El Palmar
country: Spain
facility: Hospital Universitario "Virgen de la Arrixaca"
state: Murcia
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital del Mar (Institut Municipal d'Assistència Sanitària, IMAS)
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Cádiz
country: Spain
facility: Hospital Universitario "Puerta del Mar"
city: Girona
country: Spain
facility: Hospital Universitari de Girona Doctor Josep Trueta
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Murcia
country: Spain
facility: Hospital General Universitario "Reina Sofía"
city: Málaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya
city: Sevilla
country: Spain
facility: Hospital Universitario de Valme
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valladolid
country: Spain
facility: Hospital Universitario Del Río Hortega
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Universitario La Paz
name: Abelardo García de Lorenzo, MD
role: STUDY_CHAIR
affiliation: Hospital Universitari de Girona Doctor Josep Trueta
name: Alfonso Bonet Saris, MD_Study Coordinator
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Severo Ochoa Leganés (Madrid)
name: Teodoro Grau Carmona, MD_Study Coordinator
role: STUDY_CHAIR
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