6-Methyl-Prednisolone for Multiple Organ Dysfunction Syndrome
6-Methyl-Prednisolone for Multiple Organ Dysfunction Syndrome
Background: Systemic corticosteroids are considered in patients with an adverse clinical
 course suffering from conditions like the acute respiratory distress syndrome (ARDS) and
 septic shock. Treated patients not only show improved respiratory function, but also
 hemodynamic status and overall multiple organ dysfunction score.

 Objective: To evaluate the safety and effectiveness of 6-methyl-prednisolone on the clinical
 course of multiple organ dysfunction syndrome (MODS).

 Design: Multi-center, double-blind, randomized, placebo-controlled.

 Intervention: Intravenous administration of 6-methyl-prednisolone or placebo (aqueous
 solution). The duration of the study medication administration protocol is 32 days (1).

 Primary Endpoints:

 1. All cause Intensive Care Unit (ICU) and 28-day mortality

 2. Organ dysfunction score on days 4, 7, 14, and 28 of the protocol.
Background:

 Worldwide intensive care physicians consider administering systemic corticosteroids in
 patients with an adverse clinical course suffering from conditions like the acute respiratory
 distress syndrome (ARDS) and septic shock. Data from recent small studies performed in
 patients with unresolving ARDS (1;2) suggest survival benefits associated with rescue therapy
 with relatively prolonged courses of corticosteroids. Treated patients not only show improved
 respiratory function, but also hemodynamic status and overall multiple organ dysfunction
 score. It has been suggested that that the integrity of the hypothalamic-pituitary-adrenal
 axis may be impaired in this patient subset (3;4)

 Objective(s):

 To evaluate the safety and effectiveness of a non-selective anti-inflammatory strategy, i.e.
 6-methyl-prednisolone, on persistent and unresolving inflammatory states, i.e. multiple organ
 dysfunction syndrome, on the degree of organ dysfunction and mortality.

 Design:

 Multi-center, double-blind, randomized, placebo-controlled. Randomization and data entry is
 internet based (htpp://www.webnaif.com). Patients will be randomized through a
 computer-generated random-number table and stratified by center in blocs of 6. Sample size,
 by group 120 patients. The study is powered to detect a 20% reduction in mortality, from 50%
 to 30% in 100 patients per study group at the 5% significance level with a power of 80%. An
 additional 20% (n=20) per group have been planned to compensate for losses.

 Main Inclusion Criteria:

 -  Patients with established, unresolving, refractory MODS, in whom all reversible and
 treatable causes of persistent MODS have been treated or ruled out.

 -  Patients under endotracheal intubation and mechanical ventilation for at least 7 days.

 -  Aggregate Multiple Organ Dysfunction Score (5) of greater than 8 over the first seven
 days of mechanical ventilation and greater than 5 on the day of inclusion.

 -  Written informed consent to participate in the trial signed by next of kin or other
 authorized person.

 Additional Inclusion Criteria:

 -  Main cause or disease at admission: Adequate "source control" is required and refers to
 optimal, complete, and definitive surgical and/or medical therapy.

 -  Infections:

 1. Infectious causes of persistence of MODS have reasonably been ruled out on clinical
 or other grounds (infectious endocarditis, undrained abscesses like sinusitis,
 empyema or abdominal pus). Consider sampling for culture of broncho-alveolar lavage
 fluid, protected specimen brush or other (empyema fluid, lung tissue) in order to
 rule out respiratory infection, as well as intra-vascular catheter change and
 culture.

 2. Present or previous infections, either documented or strongly suspected, have been
 treated for at least 3 days before inclusion.

 -  Supportive Care: Optimal hemodynamic, renal, hematologic, nutritional "supportive care"
 is provided.

 Exclusion Criteria:

 -  Decision not to provide full support.

 -  Immune status and steroid therapy.

 1. Steroid therapy

 -  Currently indicated for chronic or concurrent disease (meningitis, auto-immune
 disease, asthma, acute exacerbation of COPD, or other). Inhaled steroids are
 allowed.

 -  Administered during current admission (> 20 mg/day of 6-methyl-prednisolone or
 equivalent for >48 hours).

 -  Chronic steroid therapy prior to current admission (> 20 mg of
 6-methyl-prednisolone or equivalent/day for > 1 month during previous 3
 months).

 2. Other immune-suppressive therapy within the previous 6 months.

 3. Known AIDS.

 4. Neutropenia < 500/mcl.

 5. Preceding organ transplantation.

 -  Irreversible and or ultimately fatal clinical conditions like metastatic malignant
 disease or cardiogenic shock caused by coronary artery disease.

 -  Presence of invasive fungal infection

 -  Other significant pre-existing underlying chronic diseases:

 1. Severe parenchymal liver disease (Child-Pugh grade C)

 2. Severe and irreversible acute or chronic central nervous system disease.

 3. Severe end-stage chronic obstructive pulmonary disease (home oxygen or more than 1
 exacerbation in previous year)

 4. End-stage renal disease (Chronic dialysis).

 -  Age less than 18 years.

 -  Pregnancy.

 -  Morbid obesity: body mass index above 40.

 -  Recent (last 3 months) upper GI hemorrhage.

 -  Extensive burns (>30% BSA)

 -  Known allergy to steroids.

 -  Written informed consent not available.

 Intervention:

 Intravenous administration of 6-methyl-prednisolone or placebo(aqueous solution). The
 duration of the study medication administration protocol is 32 days (1):

 -  Initial iv loading dose of 160 mg.

 -  An iv bolus injection of 6-methyl-prednisolone is administered every 6 hours:

 1. 40 mg on days 1 to 14,

 2. 20 mg on days 15 to 21,

 3. 10 mg on days 22 to 28,

 4. 5 mg on days 29 and 30, and

 5. 2.5 mg on days 31 and 32.

 Informed consent form and information sheet have been reviewed and approved by the regional
 Ethics Committee of Madrid (10 centres), the local review boards of the other participating
 centres, and the Agencia Española del Medicamento (Spanish Ministry of Health).

 Ethical Approval:

 The study protocol has been approved by the regional Ethics Committee of Madrid (10 centres),
 the local review boards of the other participating centres, and the Agencia Española del
 Medicamento (Spanish Ministry of Health).

 Stopping Rules:

 The independent Data Monitoring Committee (DMC) will have real-time access to the main
 variable "28-day mortality" (and allocation to study group "A" or "B") and will propose
 premature interruption of the trial based on sequential analysis if significant differences
 become apparent. The DMC will perform 5 interim analysis, one every 48 included patients and
 the criterium used will be a statistically significant difference at the level of p < 0,01
 (S.J. Pocock. Clinical Trials. A practical Approach. John Wiley & Sons. New York. 1994).

 Primary Endpoints:

 1. All cause ICU and 28-day mortality

 2. Organ dysfunction score on days 4, 7, 14, and 28 of the protocol.

 Planned Subgroup Analysis:

 No subgroup analysis are planned.

 Side-effects Quantification:

 The investigators will use the NIH Toxicity Form with a scale from 1 to 5. Severe adverse
 events in this severely ill population are precisely defined and require immediate (less than
 24 hours) communication to the study website. The DMC will have access to the variables that
 define and describe the SAEs.

 Analysis Plan:

 Main comparisons are 28-day and ICU mortality between study groups (chi square test for
 percentages and log-rank test Kaplan-Meier survival curves. Multiple organ dysfunction score
 and Sequential Organ Failure Assessment score will be compared at baseline and on days 4, 7,
 14 and 28 (Student's t test and/or non-parametric tests). Independent risk factors for
 mortality will be studied by multivariate analysis (Cox regression) of significant
 comparisons of the univariate analysis. Analysis sample according to the principle of
 intention to treat.

 Finishing Date:

 The finishing date is 18 months after the first inclusion at each centre. Scheduled beginning
 of the trial is August 2005

 Reporting Date:

 First trimester 2007.

 A large study like the present trial is required to obtain definitive data about safety and
 effectiveness of 6-methyl-prednisolone administered as rescue therapy in patients with the
 multiple organ dysfunction syndrome.

 Reference List

 1. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T et al. Effect of
 prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome:
 a randomized controlled trial. JAMA 1998;280(2):159-65.

 2. Biffl WL, Moore FA, Moore EE, Haenel JB, McIntyre RC, Jr., Burch JM. Are corticosteroids
 salvage therapy for refractory acute respiratory distress syndrome? Am.J.Surg.
 1995;170(6):591-5.

 3. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med.
 2003;31(1):141-5.

 4. Loisa P, Rinne T, Kaukinen S. Adrenocortical function and multiple organ failure in
 severe sepsis. Acta Anaesthesiol.Scand. 2002;46(2):145-51.

 5. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ
 dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med.
 1995;23(10):1638-52.
Inclusion Criteria:

 Main Inclusion Criteria:

 Patients with established, unresolving, refractory MODS, in whom all reversible and
 treatable causes of persistent MODS have been treated or ruled out:

 -  Patients under endotracheal intubation and mechanical ventilation for at least 7 days.

 -  Aggregate Multiple Organ Dysfunction Score (5) of greater than 8 over the first seven
 days of mechanical ventilation and greater than 5 on the day of inclusion.

 -  Written informed consent to participate in the trial signed by next of kin or other
 authorized person.

 Additional Inclusion Criteria:

 -  Main cause or disease at admission: Adequate "source control" is required and refers
 to optimal, complete, and definitive surgical and/or medical therapy.

 -  Infections:

 1. Infectious causes of persistence of MODS have reasonably been ruled out on
 clinical or other grounds (infectious endocarditis, undrained abscesses like
 sinusitis, empyema or abdominal pus). Consider sampling for culture of
 broncho-alveolar lavage fluid, protected specimen brush or other (empyema fluid,
 lung tissue) in order to rule out respiratory infection, as well as
 intra-vascular catheter change and culture.

 2. Present or previous infections, either documented or strongly suspected, have
 been treated for at least 3 days before inclusion.

 -  Supportive Care: Optimal hemodynamic, renal, hematologic, nutritional "supportive
 care" is provided.

 Exclusion Criteria:

 -  Decision not to provide full support.

 -  Immune status and steroid therapy.

 1. Steroid therapy

 -  Currently indicated for chronic or concurrent disease (meningitis,
 auto-immune disease, asthma, acute exacerbation of chronic obstructive
 pulmonary disease [COPD], or other). Inhaled steroids are allowed.

 -  Administered during current admission (> 20 mg/day of 6-methyl-prednisolone
 or equivalent for >48 hours).

 -  Chronic steroid therapy prior to current admission (> 20 mg of
 6-methyl-prednisolone or equivalent/day for > 1 month during previous 3
 months).

 2. Other immune-suppressive therapy within the previous 6 months.

 3. Known AIDS.

 4. Neutropenia < 500/mcl.

 5. Preceding organ transplantation.

 -  Irreversible and or ultimately fatal clinical conditions like metastatic malignant
 disease or cardiogenic shock caused by coronary artery disease.

 -  Presence of invasive fungal infection

 -  Other significant pre-existing underlying chronic diseases:

 1. Severe parenchymal liver disease (Child-Pugh grade C)

 2. Severe and irreversible acute or chronic central nervous system disease.

 3. Severe end-stage chronic obstructive pulmonary disease (home oxygen or more than
 1 exacerbation in previous year)

 4. End-stage renal disease (Chronic dialysis).

 -  Age less than 18 years.

 -  Pregnancy.

 -  Morbid obesity: body mass index above 40.

 -  Recent (last 3 months) upper gastrointestinal [GI] hemorrhage.

 -  Extensive burns (>30% body surface area [BSA])

 -  Known allergy to steroids.

 -  Written informed consent not available.