Clinical trial NCT01002482: Computerized Glucose Control in Critically Ill Patients
Official title: Impact of the Use of a Computerized Protocol for Glucose Control Named CGAOtm on the Outcome of Critically Ill Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hyperglycemia
Critical Illness
Keywords: Hyperglycemia
Hypoglycemia
Intensive Care Unit
Glucose Control
Insulin
Computer Protocol
Metabolic Disorders
Lead sponsor: Centre Hospitalier of Chartres
Sponsor class: OTHER
Collaborators: name: Société Française d'Anesthésie et de Réanimation
name: Baxter Healthcare Corporation
First posted: 2009-10-27
Enrollment: 2684
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: The aim of the study is to determine whether the use of the CGAOtm software is associated with a decrease in 90-day mortality when compared with the use of standard care methods for glucose control with target blood glucose levels inferior to 180 mg/dl. The CGAOtm software is designed to assist physicians and nurses in achieving tight glucose control (defined by a target for blood glucose levels between 80 and 110 mg/dl) in critically ill patients.

Detailed description: Hyperglycemia in response to critical illness has long been associated with adverse outcomes.

In 2001, the first "Leuven study", a randomized controlled trial conducted in surgical intensive care patients comparing a strategy based on a nurse-driven protocol for insulin therapy in order to maintain normal blood glucose levels \[80 - 110 mg/dl\] with standard care defined at the time as intravenous insulin started only when blood glucose level exceeded 215 mg/dl and then adjusted to keep blood glucose level between 180 and 200 mg/dl, showed a reduction in hospital mortality by one third.

The results of this trial have been enthusiastically received and rapidly incorporated into guidelines, such as the Surviving Sepsis Campaign in 2004, and now endorsed internationally by numerous professional societies.

However, subsequent randomized controlled trials have failed to confirm a mortality benefit with intensive insulin therapy among critically ill patients, in whom stress hypoglycemia is common. Moreover the Normoglycemia in Intensive Care Evaluation - Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study, an international multicentre trial involving 6104 patients, the largest trial of insulin therapy to date, showed a lower 90-day mortality in the control group targeted blood glucose levels inferior to 180 mg/dl when compared to the intervention group with tight glucose control \[80 - 110 mg/dl\].

In addition, many studies and meta-analyses have reported high rates of hypoglycemia with tight glucose control. Consequently, considerable controversy has emerged as to whether tight glucose control is warranted in all critically ill patients especially as tight glucose control (without appropriate computer protocol) causes a significant increase in nurse workload.

The conflicting results between the first Leuven study and the NICE-SUGAR study could be explained by numerous differences between the two trials : the specific method (algorithms, compliance of nurses and physicians with recommendations, etc) used to achieve tight glucose control in each randomized control trial could be a major issue.

Several experimental and observational studies have highlighted the possible negative impact of glucose variability (large fluctuations in blood glucose possibly with undetected hypoglycemia and hypokalemia alternating with hyperglycemia) when implementing tight glucose control, be it due to the intrinsic properties of the algorithms used, technical factors (errors in measurements of the blood glucose level or lack of control over intravenous insulin therapy) or human factors (delay in performing glucose measurements or non respect of recommendations not based on clinical expertise but as a consequence of insufficient training inducing a lack of confidence in the algorithms by inexperienced nurses).

Therefore, remaining concerns about the best way to achieve glucose control in the ICU reduce the impact of conclusions of all of the recent randomized controlled trials on tight glucose control : are the negative results due to the concept, tight glucose control with intensive insulin therapy in critically ill patients in order to reduce the toxicity of high blood glucose levels, or are the negative results mainly due to specific methods used for achieving tight glucose control ? In most cases the methods used in clinical trials were never tested in numerical patients according to existing and validated models (in SILICO expertise) before implementing them in clinical practice on real patients.

Particularly, whether the use of a clinical computerized decision-support system (CDSS) designed for achieving tight glucose control in various ICU settings, and fine-tuned to reduce glucose variability, without increasing the incidence of severe hypoglycemia nor the nurse workload, has an impact on the outcome of patients staying at least three days in an ICU remains to be tested.

Among the different CDSS, the CGAOtm software has been developed to standardize different aspects of glucose control in an ICU setting based on 1) explicit replicable recommendations following each blood glucose level measurement concerning insulin rates and time to next measurement, 2) reminders and alerts and 3) various graphic tools, trends, and individual on-line data aiming to increase the confidence of the nursing staff in the computer protocol and therefore their adherence, to reduce necessary training time, and to give physicians and nurses a way to control the tight glucose control process during the whole ICU stay. Moreover, the CGAOtm software is designed to take into account irregular sampling, saturations, and some precision and stability issues.

The aim of the study is to evaluate the capability of the CGAOtm software to reduce 90-day mortality in a mixed ICU population of patients requiring intensive care for at least three days.

Sample size and power calculations. The expected all cause 90-day mortality in the control group is 25 % (identical to the observed all cause 90-day mortality in the control group of the NICE-SUGAR trial). Considering that all cause 90-day mortality in the experimental group (computer protocol group) is expected to be 22 % (absolute reduction of 3 %), considering an alpha risk and a beta risk respectively of 0.05 and 0.20 and three intermediate analyses performed according to the O'Brien-Fleming design, 3,211 patients per treatment arms are needed and will be recruited from the participating 60 centres, all located in France.

Eligibility criteria: Inclusion Criteria:

* At time of the patient's admission to the ICU, the treating ICU specialist expects the patient will require treatment in the ICU that extends beyond the calendar day following the day of admission.

Exclusion Criteria:

* Age \< 18 years or patient under guardianship.
* Pregnancy.
* Moribund patient or imminent death in the ICU (e.g. patient expected to die in the ICU within 24 hours).
* At time of the patient's admission, the treating physicians are not committed tu full supportive care.
* Patient admitted to the ICU for treatment of diabetic ketoacidosis or hyperosmolar state.
* Patient admitted to the ICU for hypoglycemia.
* Patient thought to be at abnormally high risk of suffering hypoglycemia (e.g. known insulin secreting tumor or history of unexplained or recurrent hypoglycemia or fulminant hepatic failure).
* Patient who have suffered hypoglycemia without documented full neurological recovery
* Patient is expected to be eating before the end of the day following admission.
* Patient previously enrolled in the CGAO-REA study.

Primary outcomes:
measure: All-cause 90-day Mortality
timeFrame: Day 90
Secondary outcomes:
measure: All-cause 28-day Mortality
timeFrame: Day 28
measure: All-cause Intensive Care Unit Mortality
timeFrame: Date of discharge from the ICU
measure: All-cause In-hospital Mortality
timeFrame: Day of discharge from the hospital
measure: Intensive Care Unit Free Days
timeFrame: 28 days
measure: Time Spent in Blood Glucose Target
timeFrame: Day of discharge from the ICU
measure: Severe Hypoglycemia
timeFrame: Date of discharge from the ICU
measure: Hospital Length of Stay
timeFrame: Date of discharge from the hospital
measure: Intensive Care Unit Length of Stay
timeFrame: Date of discharge from the ICU
measure: Incidence of Nosocomial Bacteriemia
timeFrame: Date of discharge from the ICU
Other outcomes:
Locations:
city: Amiens
country: France
facility: C.H.U. Hôpital Nord
city: Avignon
country: France
facility: C.H. d'Avignon
city: Bondy
country: France
facility: G.H.U. Nord Hôpital Jean Verdier
city: Bruges
country: France
facility: Polyclinique Jean Vilar
city: Bry sur Marne
country: France
facility: Hôpital Sainte-Camille
city: Chartres
country: France
facility: C.H. de Chartres
city: Chateauroux
country: France
facility: C.H. Châteauroux
city: Corbeil-Essonnes
country: France
facility: Hôpital Sud-Francilien - Site Corbeil
city: Cornebarrieu
country: France
facility: Clinique des Cèdres
city: Dreux
country: France
facility: C.H. Victor Jousselin
city: Garches
country: France
facility: Raymond Poincaré
city: La Roche Sur Yon
country: France
facility: Centre Hospitalier Départemental Les Oudairies
city: Le Kremlin Bicêtre
country: France
facility: G.H.U. Sud Bicêtre
city: Mantes-La-Jolie
country: France
facility: Hôpital de Mantes-La-Jolie
city: Marseille
country: France
facility: Hôpital Paul Desbief
city: Marseille
country: France
facility: C.H.U. La Timone
city: Marseille
country: France
facility: Hôpital Ambroise Paré
city: Montpellier
country: France
facility: C.H.U. de -Hôpital Saint-Eloi
city: Montpellier
country: France
facility: C.H.U. Lapeyronie
city: Nantes
country: France
facility: C.H.U. Nantes - Hôpital Laennec
city: Nice
country: France
facility: C.H.U. de Nice - Hôpital Saint-Roch
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: G.H.U. Pitié-Salpétriêre
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Paris
country: France
facility: G.H.U. Nord Claude Bernard
city: Pau
country: France
facility: C.H. de Pau
city: Pessac
country: France
facility: CHU de Bordeaux - Groupe Hospitalier Sud, Hôpital Haut Lévêque
city: Pontoise
country: France
facility: C.H. René Dubos
city: Rodez
country: France
facility: C.H. Bourran
city: Rouen
country: France
facility: C.H.U. Hôpitaux de Rouen
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulon
country: France
facility: C.H. Intercommunal - Hôpital Font-Pré
city: Toulouse
country: France
facility: C.H.U. Purpan
city: Toulouse
country: France
facility: C.H.U. Rangueil
city: Tours
country: France
facility: C.H.R.U. de Tours
Study officials:
affiliation: Centre Hospitalier de Chartres
name: Pierre Kalfon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: G.H.U. Est, C.H.U. Pitié-Salpétriêre
name: Bruno Riou, MD PhD
role: STUDY_DIRECTOR
affiliation: G.H.U. Ouest, Hôpital Raymond Poincaré
name: Djillali Annane, MD PhD
role: STUDY_CHAIR
affiliation: G.H.U. Est, Pitié-Salpétriêre
name: Jean Chastre, MD PhD
role: STUDY_CHAIR
affiliation: CHRU TOURS
name: Pierre-François Dequin, MD PhD
role: STUDY_CHAIR
affiliation: CHRU Amiens
name: Hervé Dupont, MD PhD
role: STUDY_CHAIR
affiliation: CHRU de Nice
name: Carole Ichai, MD PhD
role: STUDY_CHAIR
affiliation: CHRU Rennes
name: Yannick Malledant, MD PhD
role: STUDY_CHAIR
affiliation: G.H.U. Nord Bichat-Claude Bernard
name: Philippe Montravers, MD PhD
role: STUDY_CHAIR
References:
citation: Carli P, Martin C. [Impact of Nice-Sugar: is there a need for another study on intensive glucose control in ICU?]. Ann Fr Anesth Reanim. 2009 Jun;28(6):519-21. doi: 10.1016/j.annfar.2009.05.002. Epub 2009 Jun 4. No abstract available. French.
citation: Guerrini A; Roudillon G; Gontier O; Rebaï L; Isorni MA; Mutinelli-Szymanski P; Sorine M; Kalfon P. High glycemic variability induced by inappropriate algorithms for intensive insulinotherapy: the example of the NICE-SUGAR study. Abstract award winners: The best pre-selected abstracts of the 22th Annual Congress of the European Society of Intensive Care Medicine, 11-14 October 2009, Vienna, Austria. Intensive Care Med. 2009 Sep;35 Suppl 1:S111.
citation: Gontier O; Hamrouni M; Lherm T; Monchamps G; Ouchenir A; Kalfon P. The CGAO software improves glycaemic control in intensive care patients without increasing the incidence of severe hypoglycaemia nor the nurse workload. Abstracts of the 21th Annual Congress of the European Society of Intensive Care Medicine, 21-24 September 2007, Lisbon, Portugal. Intensive Care Med. 2008 Sep;34 Suppl 2:S220.
citation: Abstracts of the 20th Annual Congress of the European Society of Intensive Care Medicine, 7-10 October 2007, Berlin, Germany. Intensive Care Med. 2007 Sep;33 Suppl 2:S5-271. No abstract available.
citation: Kalfon P, Le Manach Y, Ichai C, Brechot N, Cinotti R, Dequin PF, Riu-Poulenc B, Montravers P, Annane D, Dupont H, Sorine M, Riou B; CGAO-REA Study Group. Severe and multiple hypoglycemic episodes are associated with increased risk of death in ICU patients. Crit Care. 2015 Apr 8;19(1):153. doi: 10.1186/s13054-015-0851-7.
citation: Kalfon P, Giraudeau B, Ichai C, Guerrini A, Brechot N, Cinotti R, Dequin PF, Riu-Poulenc B, Montravers P, Annane D, Dupont H, Sorine M, Riou B; CGAO-REA Study Group. Tight computerized versus conventional glucose control in the ICU: a randomized controlled trial. Intensive Care Med. 2014 Feb;40(2):171-181. doi: 10.1007/s00134-013-3189-0. Epub 2014 Jan 14.