Ignite Creation Date:
2024-05-05 @ 4:48 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00318942
Status:
COMPLETED
Last Update Posted:
2014-07-01
First Post:
2005-09-02
Brief Title:
Efficacy and Safety of Colloids Versus Crystalloids for Fluid Resuscitation in Critically Ill Patients
Sponsor:
University of Versailles
Organization:
University of Versailles
Study Overview
Official Title:
CRISTAL Colloids Compared to Crystalloids in Fluid Resuscitation of Critically Ill Patients A Multinational Randomised Controlled Trial
Status:
COMPLETED
Status Verified Date:
2014-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background Two recent systematic reviews of the literature and meta-analyses have suggested that colloids administration might be deleterious in critically ill patients
Objective To compare the effects on hospital mortality of crystalloids and colloids when given for fluid resuscitation in critically ill patients
Setting Adult intensive care units ICUs in several European countries
Study design A multinational randomised controlled trial performed on two parallel groups
Intervention Any type of crystalloids control group versus any type of colloids including albumin
Patients All patients above the legal age of consent and hospitalised in an intensive care unit who need fluid resuscitation according to the physician Pregnant women moribund patients brain dead patients and patients who have a known allergy to colloids or severe head injury or major burns 20 of body surface or dehydration will not be included
Primary endpoint 28-day mortality
Hypothesis Assuming a hospital mortality rate of 20 in the crystalloids group a 005 type I error 3010 patients are needed to show a difference between the 2 groups of 5 with a 90 probability two-sided test
Objective To compare the effects on hospital mortality of crystalloids and colloids when given for fluid resuscitation in critically ill patients
Setting Adult intensive care units ICUs in several European countries
Study design A multinational randomised controlled trial performed on two parallel groups
Intervention Any type of crystalloids control group versus any type of colloids including albumin
Patients All patients above the legal age of consent and hospitalised in an intensive care unit who need fluid resuscitation according to the physician Pregnant women moribund patients brain dead patients and patients who have a known allergy to colloids or severe head injury or major burns 20 of body surface or dehydration will not be included
Primary endpoint 28-day mortality
Hypothesis Assuming a hospital mortality rate of 20 in the crystalloids group a 005 type I error 3010 patients are needed to show a difference between the 2 groups of 5 with a 90 probability two-sided test
Detailed Description:
BACKGROUND
Fluid resuscitation is a very common treatment in the ICU and every day a thousands of critically ill patients are treated around the world with crystalloids or colloids to correct hypovolaemia 1 2 A wide diversity of fluids is available and new products are coming in the very near future In 1989 a French consensus conference recommended to abandon the use of fresh frozen plasma and to limit the use of albumin to very specific situations eg contraindication to other colloids serum protein levels below 35 gl 1 Crystalloids and gelatins were considered as the best solutions for fluid resuscitation in the critically ill In 1997 as starch was increasingly used this guidelines were updated 2 It was concluded that isotonic crystalloids are as efficacious as starch pending the amount of fluid to be administered
Three systematic reviews of the literature provided an accurate summary of data available from randomised controlled trials evaluating human albumin 3 or comparing crystalloids to colloids in fluid resuscitation in critically ill patients 45 The first systematic review 3 has analysed 30 randomised trials and concluded that there is no evidence that albumin administration reduces the risk of death in critically ill patients By contrast this review suggested that albumin administration might increase by 6 the risk of death In the Cochrane Injury Review Group systematic review 4 40 randomised trials were analysed The authors concluded that the administration of colloids might be associated with an absolute increase of 38 in the risk of death The last review has analysed only 17 randomised trials as they decided to exclude studies of hypertonic saline This review showed no significant difference in the risk of death between colloids and crystalloids or in other outcomes like prevalence of pulmonary edema and length of stay at the ICU and at the hospital 5 However when the authors considered only the studies with a high methodological quality score they observed a nice trend toward an increased survival rate in favour of crystalloids They reached the same conclusions for the subset of trauma patients
JUSTIFICATION FOR THE STUDY
It seems reasonable to abandon the use of fresh frozen plasma in fluid resuscitation in critically ill patients There are no definite criteria to decide which of crystalloids and colloids should be preferred It is unquestionable that to achieve a given haemodynamic effect the amount of crystalloids needed is almost twice the amount of colloids 1 2 Colloids and crystalloids have different effects on a range of important physiological parameters As most of the critically ill patients underwent one or more volume replacements even a small increase in the risk of death around 5 has considerable clinical implications The meta analyses suggested a 5 absolute risk reduction in mortality in favour of crystalloids 4 5 The number needed to treat an estimate which is more clinically meaningful 6 is of 20 suggesting about 1 additional death with colloids for every 20 patients resuscitated Given the number of patients exposed to fluid resuscitation about 60 additional deaths might be observed per year in a ICUreceiving 600 patients a year
A large trial is needed to compare the safety and efficacy of colloids and crystalloids 45
OBJECTIVES
Primary objective
To compare the effects on 28-day mortality of colloids versus crystalloids in ICU patients who need fluid resuscitation
Secondary objectives
ICU and hospital mortality and morbidity and safety
STUDY DESIGN
A multinational randomised controlled trial on two parallel groups
STUDY TREATMENTS
Arm A crystalloids
Arm B colloids Allocated treatment must be started immediately after randomisation Day-0
The amount and speed of fluid loading will be at the physicians discretion The amount of starch should not exceed 30 mlkg24 hours In case additional volume replacement is necessary gelatins or albumin may be used During all ICU stay the patients will receive only crystalloids or only colloids for fluid resuscitation according to randomisation
Double blind seems unfeasible as the time window for inclusion is extremely short treatment should be available promptly at bedside and the amounts of volume replacement for all ICU stay could not be predicted a priori
Allowed co-interventions
Any treatment required for a pre-existing condition
Any type of inotropes or vasopressors
Red cells platelets fresh frozen plasma which are used should follow general guidelines 2
Co-interventions not allowed
Any other volume replacement solution than those above mentioned Albumin is not allowed in patients allocated to crystalloids unless plasma albumin levels are below 20 gdl 2
ENDPOINTS
Main endpoint
28-day mortality rate
Secondary endpoints
ICU and Hospital mortality rates
Number of ICU days the patient is alive and free of
mechanical ventilation
vasopressors and inotropes
renal replacement therapy
organ system failure according to the sequential organ failure assessment SOFA scoring system7
Total amount of volume replacement
Difference in
AUC of mean arterial pressure between HO and H24 at Day-0
weight between Day-0 and Day-1 and Day-2
PaO2FiO2 ratio between H0 and H12 and H24 at Day-0
chest X-ray score between day-0 and Day-1 and day-28
Frequency of adverse events
Anaphylaxis reaction skin or mucous rash nausea vomiting shock bronchial spasm respiratory or cardiac arrest
Coagulation disorders fall in prothrombin time PT rate in factor VIII
Impairment in renal function increase in creatinine 200 µmoll
Length of stay at ICU
Length of hospital stay
RANDOMISATION
The list of randomisation will be generated by computer We will use block randomisation stratified by site and diagnosis
1 trauma or haemorrhage
2 sepsis
3 other diagnoses
Modalities
Day of randomisation Day-0
The delay between the decision to resuscitate the patients with fluids and randomisation should be as short as possible 15 minutes or less Thus the use of sealed envelopes seems to be the best method for allocation concealment in this case There will be at each centre 3 sets of sealed envelopes one for each strata ie trauma or hemorrhage sepsis and other diagnoses To randomise a patient the investigator must use the first available sealed envelope according to allocation number in the corresponding ie trauma or hemorrhage sepsis other diagnoses
Choice of strata when a patient has more than one diagnosis the choice of the strata must be as follows trauma or haemorrhage sepsis others For example a patient with trauma and sepsis will be randomised in the trauma strata
An envelope must be used only once
Investigators must declare by fax to the coordinating centre each inclusion within 2 working days and provide the following information
FOLLOW UP
From H0 time of randomisation to H24
Total amount of each type of fluid infused
Number of red cell units
Mean of mean arterial pressure at hourly intervals from H0 to H24
PaO2FiO2 ratio at H0 H12 and H24
SOFA score
PT time worse values
Plasma total proteins and albumin levels
Adverse events cf supra
Daily from Day-1 to ICU discharge
Patients status dead or alive
Total amount of each type of fluid infused
SOFA score
Number of red cell units
Surgical procedures
Specialised radiographic procedures
Adverse events cf supra
Chest X-ray score annexe 6 and weight at Day-1 and day-2
At ICU discharge
Alive or date of death
Length of ICU stay
Time on mechanical ventilation
Omega scores 123 and total annexe 8 14
Number and type of adverse events cf supra
Where the patient is discharged to home another ward in the same hospital another hospital rehabilitation centre home for disabled people
At hospital discharge if not the same as that of ICU discharge
Alive or date of death
Length of hospital stay
Where the patient is discharged to home another ward in the same hospital another hospital rehabilitation centre home for disabled people
SAMPLE SIZE
This study is designed to show an absolute difference of 5 in 28-day mortality between colloids and crystalloids Assuming a mortality rate of 20 in the crystalloids group with alpha 5 and beta 10 1504 patients per treatment arm are needed A total of 3010 patients will be enrolled All randomised patients must be followed up at least till ICU discharge One hundred active centres will be recruited in Europe The participation of each centre will be around 3 to 6 months
STATISTICAL ANALYSIS
Interim analyses and stopping rules
The boundaries of the sequential plan are drawn to demonstrate an absolute difference of 5 in 28-day mortality rate between the two treatment arms assuming a 20 mortality rate in the crystalloids group and with alpha and beta of 5 and 10 respectively The analyses will be performed every 100 deaths The figure displays the boundaries of the sequential plan Briefly Z represents the difference between the two groups and V the number of patients that have been included When a boundary is crossed the enrollments in the study must be stopped and the conclusion depends on which boundary has been crossed see figure Simulations allow to estimate how many inclusions are saved when difference in mortality rates is nil 1109 patients have to be included to reach the conclusion When difference is 5 1477 patients have to be included to reach the conclusion
Final analysis
The final analysis will be performed according to the intention to treat principle after inclusions in the study will be stopped
Baseline characteristics of patients will be compared between the two treatment arms categorical variables will be expressed as number and percentage and compared by Chi-2 tests means standard deviation and range will be given for continuous variables which will be compared by Student t tests
Methods for analyses of efficacy and safety will depend on the type of outcome Survival curves will be constructed according to the Kaplan-Meyer method and compared by log-rank tests The comparison will be adjusted the main prognosis variables with Cox models Categorical variables will be compared by Chi-2 tests and continuous variables Student t tests or analysis of variance for repeated measures
STUDY ORGANISATION
Steering committee
PI Djillali Annane Garches Statistician Sylvie Chevret Paris Yves Cohen Avicenne Samir Jaber Montpellier Gilles Troché Versailles Fékri Abroug Monastir Tunisie Olivier Lesur Sherbrook Canada
Advisory Board
Jean François Baron François Feihl Lausanne Suisse Jean Louis Vincent Bruxelles Belgique
Safety and Efficacy Monitoring Board
Edward Abraham Birmingham USA Déborah Cook Hamilton Canada Mervyn Singer London UK Charles Sprung Jérusalem Israel
Fluid resuscitation is a very common treatment in the ICU and every day a thousands of critically ill patients are treated around the world with crystalloids or colloids to correct hypovolaemia 1 2 A wide diversity of fluids is available and new products are coming in the very near future In 1989 a French consensus conference recommended to abandon the use of fresh frozen plasma and to limit the use of albumin to very specific situations eg contraindication to other colloids serum protein levels below 35 gl 1 Crystalloids and gelatins were considered as the best solutions for fluid resuscitation in the critically ill In 1997 as starch was increasingly used this guidelines were updated 2 It was concluded that isotonic crystalloids are as efficacious as starch pending the amount of fluid to be administered
Three systematic reviews of the literature provided an accurate summary of data available from randomised controlled trials evaluating human albumin 3 or comparing crystalloids to colloids in fluid resuscitation in critically ill patients 45 The first systematic review 3 has analysed 30 randomised trials and concluded that there is no evidence that albumin administration reduces the risk of death in critically ill patients By contrast this review suggested that albumin administration might increase by 6 the risk of death In the Cochrane Injury Review Group systematic review 4 40 randomised trials were analysed The authors concluded that the administration of colloids might be associated with an absolute increase of 38 in the risk of death The last review has analysed only 17 randomised trials as they decided to exclude studies of hypertonic saline This review showed no significant difference in the risk of death between colloids and crystalloids or in other outcomes like prevalence of pulmonary edema and length of stay at the ICU and at the hospital 5 However when the authors considered only the studies with a high methodological quality score they observed a nice trend toward an increased survival rate in favour of crystalloids They reached the same conclusions for the subset of trauma patients
JUSTIFICATION FOR THE STUDY
It seems reasonable to abandon the use of fresh frozen plasma in fluid resuscitation in critically ill patients There are no definite criteria to decide which of crystalloids and colloids should be preferred It is unquestionable that to achieve a given haemodynamic effect the amount of crystalloids needed is almost twice the amount of colloids 1 2 Colloids and crystalloids have different effects on a range of important physiological parameters As most of the critically ill patients underwent one or more volume replacements even a small increase in the risk of death around 5 has considerable clinical implications The meta analyses suggested a 5 absolute risk reduction in mortality in favour of crystalloids 4 5 The number needed to treat an estimate which is more clinically meaningful 6 is of 20 suggesting about 1 additional death with colloids for every 20 patients resuscitated Given the number of patients exposed to fluid resuscitation about 60 additional deaths might be observed per year in a ICUreceiving 600 patients a year
A large trial is needed to compare the safety and efficacy of colloids and crystalloids 45
OBJECTIVES
Primary objective
To compare the effects on 28-day mortality of colloids versus crystalloids in ICU patients who need fluid resuscitation
Secondary objectives
ICU and hospital mortality and morbidity and safety
STUDY DESIGN
A multinational randomised controlled trial on two parallel groups
STUDY TREATMENTS
Arm A crystalloids
Arm B colloids Allocated treatment must be started immediately after randomisation Day-0
The amount and speed of fluid loading will be at the physicians discretion The amount of starch should not exceed 30 mlkg24 hours In case additional volume replacement is necessary gelatins or albumin may be used During all ICU stay the patients will receive only crystalloids or only colloids for fluid resuscitation according to randomisation
Double blind seems unfeasible as the time window for inclusion is extremely short treatment should be available promptly at bedside and the amounts of volume replacement for all ICU stay could not be predicted a priori
Allowed co-interventions
Any treatment required for a pre-existing condition
Any type of inotropes or vasopressors
Red cells platelets fresh frozen plasma which are used should follow general guidelines 2
Co-interventions not allowed
Any other volume replacement solution than those above mentioned Albumin is not allowed in patients allocated to crystalloids unless plasma albumin levels are below 20 gdl 2
ENDPOINTS
Main endpoint
28-day mortality rate
Secondary endpoints
ICU and Hospital mortality rates
Number of ICU days the patient is alive and free of
mechanical ventilation
vasopressors and inotropes
renal replacement therapy
organ system failure according to the sequential organ failure assessment SOFA scoring system7
Total amount of volume replacement
Difference in
AUC of mean arterial pressure between HO and H24 at Day-0
weight between Day-0 and Day-1 and Day-2
PaO2FiO2 ratio between H0 and H12 and H24 at Day-0
chest X-ray score between day-0 and Day-1 and day-28
Frequency of adverse events
Anaphylaxis reaction skin or mucous rash nausea vomiting shock bronchial spasm respiratory or cardiac arrest
Coagulation disorders fall in prothrombin time PT rate in factor VIII
Impairment in renal function increase in creatinine 200 µmoll
Length of stay at ICU
Length of hospital stay
RANDOMISATION
The list of randomisation will be generated by computer We will use block randomisation stratified by site and diagnosis
1 trauma or haemorrhage
2 sepsis
3 other diagnoses
Modalities
Day of randomisation Day-0
The delay between the decision to resuscitate the patients with fluids and randomisation should be as short as possible 15 minutes or less Thus the use of sealed envelopes seems to be the best method for allocation concealment in this case There will be at each centre 3 sets of sealed envelopes one for each strata ie trauma or hemorrhage sepsis and other diagnoses To randomise a patient the investigator must use the first available sealed envelope according to allocation number in the corresponding ie trauma or hemorrhage sepsis other diagnoses
Choice of strata when a patient has more than one diagnosis the choice of the strata must be as follows trauma or haemorrhage sepsis others For example a patient with trauma and sepsis will be randomised in the trauma strata
An envelope must be used only once
Investigators must declare by fax to the coordinating centre each inclusion within 2 working days and provide the following information
FOLLOW UP
From H0 time of randomisation to H24
Total amount of each type of fluid infused
Number of red cell units
Mean of mean arterial pressure at hourly intervals from H0 to H24
PaO2FiO2 ratio at H0 H12 and H24
SOFA score
PT time worse values
Plasma total proteins and albumin levels
Adverse events cf supra
Daily from Day-1 to ICU discharge
Patients status dead or alive
Total amount of each type of fluid infused
SOFA score
Number of red cell units
Surgical procedures
Specialised radiographic procedures
Adverse events cf supra
Chest X-ray score annexe 6 and weight at Day-1 and day-2
At ICU discharge
Alive or date of death
Length of ICU stay
Time on mechanical ventilation
Omega scores 123 and total annexe 8 14
Number and type of adverse events cf supra
Where the patient is discharged to home another ward in the same hospital another hospital rehabilitation centre home for disabled people
At hospital discharge if not the same as that of ICU discharge
Alive or date of death
Length of hospital stay
Where the patient is discharged to home another ward in the same hospital another hospital rehabilitation centre home for disabled people
SAMPLE SIZE
This study is designed to show an absolute difference of 5 in 28-day mortality between colloids and crystalloids Assuming a mortality rate of 20 in the crystalloids group with alpha 5 and beta 10 1504 patients per treatment arm are needed A total of 3010 patients will be enrolled All randomised patients must be followed up at least till ICU discharge One hundred active centres will be recruited in Europe The participation of each centre will be around 3 to 6 months
STATISTICAL ANALYSIS
Interim analyses and stopping rules
The boundaries of the sequential plan are drawn to demonstrate an absolute difference of 5 in 28-day mortality rate between the two treatment arms assuming a 20 mortality rate in the crystalloids group and with alpha and beta of 5 and 10 respectively The analyses will be performed every 100 deaths The figure displays the boundaries of the sequential plan Briefly Z represents the difference between the two groups and V the number of patients that have been included When a boundary is crossed the enrollments in the study must be stopped and the conclusion depends on which boundary has been crossed see figure Simulations allow to estimate how many inclusions are saved when difference in mortality rates is nil 1109 patients have to be included to reach the conclusion When difference is 5 1477 patients have to be included to reach the conclusion
Final analysis
The final analysis will be performed according to the intention to treat principle after inclusions in the study will be stopped
Baseline characteristics of patients will be compared between the two treatment arms categorical variables will be expressed as number and percentage and compared by Chi-2 tests means standard deviation and range will be given for continuous variables which will be compared by Student t tests
Methods for analyses of efficacy and safety will depend on the type of outcome Survival curves will be constructed according to the Kaplan-Meyer method and compared by log-rank tests The comparison will be adjusted the main prognosis variables with Cox models Categorical variables will be compared by Chi-2 tests and continuous variables Student t tests or analysis of variance for repeated measures
STUDY ORGANISATION
Steering committee
PI Djillali Annane Garches Statistician Sylvie Chevret Paris Yves Cohen Avicenne Samir Jaber Montpellier Gilles Troché Versailles Fékri Abroug Monastir Tunisie Olivier Lesur Sherbrook Canada
Advisory Board
Jean François Baron François Feihl Lausanne Suisse Jean Louis Vincent Bruxelles Belgique
Safety and Efficacy Monitoring Board
Edward Abraham Birmingham USA Déborah Cook Hamilton Canada Mervyn Singer London UK Charles Sprung Jérusalem Israel
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| P010308 | None | None | None |