Computerized Glucose Control in Critically Ill Patients

Critical Illness Clinical Trial

— CGAO-REA  

Official title:

Impact of the Use of a Computerized Protocol for Glucose Control Named CGAOtm on the Outcome of Critically Ill Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01002482
• Other study ID #: CGAO-REA-01
• Status: Completed
• Phase: Phase 3
• First received: October 26, 2009
• Last updated: November 8, 2013
• Start date: October 2009
• Est. completion date: April 2013

Study information

• Verified date: November 2013
• Source: Centre Hospitalier of Chartres
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2684
• Est. completion date: April 2013
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Critical Illness
• Hyperglycemia

Intervention

Device:
• 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.
• 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).

Locations

Country	Name	City	State
France	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	Chateauroux
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	C.H.U. La Timone	Marseille
France	Hôpital Ambroise Paré	Marseille
France	Hôpital Paul Desbief	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	G.H.U. Nord Claude Bernard	Paris
France	G.H.U. Pitié-Salpétriêre	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Institut Mutualiste Montsouris	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

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier of Chartres	Baxter Healthcare Corporation, Société Française d'Anesthésie et de Réanimation

Country where clinical trial is conducted

France, 

References & Publications (4)

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. French. — View 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.

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.

Kalfon P; Marie C; Gontier O; Riou B. Improvement of glycaemic control in critically ill patients with the software CGAO. Abstract 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:S54.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-cause 90-day Mortality		Day 90	Yes
Secondary	All-cause 28-day Mortality		Day 28	Yes
Secondary	All-cause Intensive Care Unit Mortality		Date of discharge from the ICU	No
Secondary	All-cause In-hospital Mortality		Day of discharge from the hospital	No
Secondary	Intensive Care Unit Free Days	Intensive care unit free days was 28-day-ICU-free-days i.e. was calculated by subtracting the actual ICU duration in days from 28 with patients who died at day 28 or before being assigned 0 free-days and those who had a stay in ICU of 28 days or more being also assigned 0 free-days	28 days	No
Secondary	Time Spent in Blood Glucose Target		Day of discharge from the ICU	No
Secondary	Severe Hypoglycemia	Number of patients with severe biological hypoglycemia (defined as blood glucose of 40 mg per deciliter or less)regardless of clinical signs	Date of discharge from the ICU	Yes
Secondary	Hospital Length of Stay		Date of discharge from the hospital	No
Secondary	Intensive Care Unit Length of Stay		Date of discharge from the ICU	No
Secondary	Incidence of Nosocomial Bacteriemia		Date of discharge from the ICU	Yes