Computerized Glucose Control in Critically Ill Patients

NCT ID: NCT01002482

Last Updated: 2013-12-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 2684 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-10-31
• Study Completion Date: 2013-04-30

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.

Conditions

Hyperglycemia; Critical Illness

Keywords

Hyperglycemia; Hypoglycemia; Intensive Care Unit; Glucose Control; Insulin; Computer Protocol; Metabolic Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CGAO-based Glucose Control

Use of a Computerized Protocol fot Tight Glycemic Control named CGAO software in order to maintain Blood Glucose Levels between 4.4 and 6.1 mmol/l.

Group Type: EXPERIMENTAL

CGAO-based Glucose Control

Intervention Type: DEVICE

Use of a clinical computerized decision-support system named CGAOtm designed to achieve tight glucose control in various ICU settings, and fine-tuned to reduce glucose variability without increasing the incidence of severe hypoglycemia or nurse workload.

CGAOtm is based on explicit replicable recommendations following each blood glucose measurement for insulin rates and time to next measurement, and reminders, alerts, graphic tools, trends, and individual on-line data aimed at increasing confidence of the nursing staff in the computer protocol and giving care staff a method for controlling the process during the whole ICU stay, according to a "human-in-the-loop" approach.

The algorithm used in the CGAOtm software for the calculation of the recommended insulin rates derived from a PID (Proportional-integral-derivative) controller, a generic control loop feedback mechanism widely used in industrial control.

Standard-Care Glucose Gontrol

Use of Standard-Care Methods for Glucose Control targeting Blood Glucose Levels inferior to 10 mmol/l.

Group Type: ACTIVE_COMPARATOR

Standard-Care Glucose Control

Intervention Type: DEVICE

Patients in the control group will receive conventional insulin therapy using the "usual care" protocol of each participating centre (already used in the centre before the beginning of the trial and targeting blood glucose levels inferior to 180 mg/dl).

Interventions

CGAO-based Glucose Control

Use of a clinical computerized decision-support system named CGAOtm designed to achieve tight glucose control in various ICU settings, and fine-tuned to reduce glucose variability without increasing the incidence of severe hypoglycemia or nurse workload.

CGAOtm is based on explicit replicable recommendations following each blood glucose measurement for insulin rates and time to next measurement, and reminders, alerts, graphic tools, trends, and individual on-line data aimed at increasing confidence of the nursing staff in the computer protocol and giving care staff a method for controlling the process during the whole ICU stay, according to a "human-in-the-loop" approach.

The algorithm used in the CGAOtm software for the calculation of the recommended insulin rates derived from a PID (Proportional-integral-derivative) controller, a generic control loop feedback mechanism widely used in industrial control.

Intervention Type: DEVICE

Standard-Care Glucose Control

Patients in the control group will receive conventional insulin therapy using the "usual care" protocol of each participating centre (already used in the centre before the beginning of the trial and targeting blood glucose levels inferior to 180 mg/dl).

Intervention Type: DEVICE

Other Intervention Names

CGAO, LC_CGAO version1; Usual care

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Société Française d'Anesthésie et de Réanimation

OTHER

Sponsor Role: collaborator

Baxter Healthcare Corporation

INDUSTRY

Sponsor Role: collaborator

Centre Hospitalier of Chartres

OTHER

Sponsor Role: lead

Responsible Party

Dr Pierre KALFON

principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Pierre Kalfon, MD

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier de Chartres

Bruno Riou, MD PhD

Role: STUDY_DIRECTOR

G.H.U. Est, C.H.U. Pitié-Salpétriêre

Djillali Annane, MD PhD

Role: STUDY_CHAIR

G.H.U. Ouest, Hôpital Raymond Poincaré

Jean Chastre, MD PhD

Role: STUDY_CHAIR

G.H.U. Est, Pitié-Salpétriêre

Pierre-François Dequin, MD PhD

Role: STUDY_CHAIR

CHRU TOURS

Hervé Dupont, MD PhD

Role: STUDY_CHAIR

CHRU Amiens

Carole Ichai, MD PhD

Role: STUDY_CHAIR

CHRU de Nice

Yannick Malledant, MD PhD

Role: STUDY_CHAIR

CHRU Rennes

Philippe Montravers, MD PhD

Role: STUDY_CHAIR

G.H.U. Nord Bichat-Claude Bernard

Locations

C.H.U. Hôpital Nord

Amiens, , France

C.H. d'Avignon

Avignon, , France

G.H.U. Nord Hôpital Jean Verdier

Bondy, , France

Polyclinique Jean Vilar

Bruges, , France

Hôpital Sainte-Camille

Bry-sur-Marne, , France

C.H. de Chartres

Chartres, , France

C.H. Châteauroux

Châteauroux, , France

Hôpital Sud-Francilien - Site Corbeil

Corbeil-Essonnes, , France

Clinique des Cèdres

Cornebarrieu, , France

C.H. Victor Jousselin

Dreux, , France

Raymond Poincaré

Garches, , France

Centre Hospitalier Départemental Les Oudairies

La Roche-sur-Yon, , France

G.H.U. Sud Bicêtre

Le Kremlin-Bicêtre, , France

Hôpital de Mantes-La-Jolie

Mantes-la-Jolie, , France

Hôpital Paul Desbief

Marseille, , France

C.H.U. La Timone

Marseille, , France

Hôpital Ambroise Paré

Marseille, , France

C.H.U. de -Hôpital Saint-Eloi

Montpellier, , France

C.H.U. Lapeyronie

Montpellier, , France

C.H.U. Nantes - Hôpital Laennec

Nantes, , France

C.H.U. de Nice - Hôpital Saint-Roch

Nice, , France

Hôpital Européen Georges Pompidou

Paris, , France

G.H.U. Pitié-Salpétriêre

Paris, , France

Institut Mutualiste Montsouris

Paris, , France

G.H.U. Nord Claude Bernard

Paris, , France

C.H. de Pau

Pau, , France

CHU de Bordeaux - Groupe Hospitalier Sud, Hôpital Haut Lévêque

Pessac, , France

C.H. René Dubos

Pontoise, , France

C.H. Bourran

Rodez, , France

C.H.U. Hôpitaux de Rouen

Rouen, , France

Hôpital Foch

Suresnes, , France

C.H. Intercommunal - Hôpital Font-Pré

Toulon, , France

C.H.U. Purpan

Toulouse, , France

C.H.U. Rangueil

Toulouse, , France

C.H.R.U. de Tours

Tours, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 19500942 (View on PubMed)

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

PMID: 18183643 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25888011 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24420499 (View on PubMed)

Other Identifiers

CGAO-REA-01

Identifier Type: -

Identifier Source: org_study_id