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| Name | Class |
|---|---|
| Istituto Di Ricerche Farmacologiche Mario Negri | OTHER |
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Septic shock is a devastating condition often observed in ICU. It is characterized by pro-inflammatory and immune responses, organ failures, high incidence of AKI and lethality. Fluid resuscitation is pivotal as supportive therapy. At present, there are no effective therapies to improve survival of such clinical condition, often characterized by a mortality as high as 40% during the first 90 days from diagnosis.
This project proposes a large 2-by-2 factorial randomized clinical trial testing the efficacy of albumin and the low- chloride balanced crystalloid solutions (either Ringer Lactate, Ringer Acetate, or Crystalsol - BAL) in septic shock.
The investigators have recently concluded a multicenter, randomized trial, the ALBIOS trial, in which, in a post-hoc analysis, albumin, in addition to crystalloids, reduced 90-day mortality in patients with septic shock, as compared to crystalloids alone (Caironi P et al, 2014). Crystalloids with supra-physiological chloride content may deteriorate renal perfusion, increasing the risk of acute kidney injury (AKI) and mortality.
The project will consist of a 2-by-2 factorial, investigator-initiated, open-label, multicenter, randomized, controlled trial, with PROBE design (Prospective Randomized Open Trial with Blinded Evaluation of Outcomes), in patients with septic shock, as defined according to clinical criteria.
Patients will be randomized in a 1:1:1:1 ratio to one of the 4 study groups (Albumin + BAL, Albumin + NS, BAL, NS).
Both the primary endpoints will include events evaluated objectively: 90-day mortality and incidence of AKI, as assessed by KDIGO criteria (KDIGO Acute Kidney Injury Work Group, 2012).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Albumin + Balanced | Experimental | Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination. Balanced crystalloid solutions According to the preference and the standard use of the participating center:
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| Albumin + Saline | Experimental | Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination. Normal Saline Na+ 154 mEq/L, Cl- 154 mEq/L (0.9% NaCl). |
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| Balanced | Experimental | Balanced crystalloid solutions (Ringer Lactate, Ringer Acetate, Crystalsol) |
|
| Saline | No Intervention | Normal Saline Na+ 154 mEq/L, Cl- 154 mEq/L (0.9% NaCl). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Albumin | Biological | Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination. |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause 90-day mortality | All-cause death from randomization to 90 days | Up to 90 days |
| Combined co-primary endpoint | The composite of all-cause death from randomization to 90 days and new occurrence of acute kidney injury (AKI). | Up to 90 days |
| Measure | Description | Time Frame |
|---|---|---|
| ICU mortality | All-cause death occurring in Intensive Care Unit (ICU) | Up to ICU discharge, a median of 9 days |
| In-hospital mortality | All-cause death occurring during hospital stay |
| Measure | Description | Time Frame |
|---|---|---|
| Severe metabolic acidosis | Incidence of severe metabolic acidosis | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| Severe hyperkalemia | Incidence of severe hyperkalemia |
Inclusion Criteria:
Patients with septic shock if they meet the two following criteria:
Presence of an infection (known or suspected) in at least one site:
Presence of a severe and acute, sepsis-related cardiovascular failure (as assessed by the SOFA score - see Annex 1), requiring vasopressor to maintain mean arterial pressure >=65 mmHg, despite adequate volume resuscitation a) Cardiovascular SOFA score > 2 (3 or 4) If the patient is unable to provide informed consent, she/he can be included in the trial provided that the requirements of ongoing laws are fulfilled; details on this approach are provided in the protocol, par 11.1 and related Annex 3. The patient will be informed about having been included in a clinical trial, as soon as she/he will regain consciousness.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pietro Caironi, MD | AOU S. Luigi Gonzaga, Orbassano | Principal Investigator |
| Giacomo Grasselli, MD | Policlinico di Milano Ospedale Maggiore | Fondazione IRCCS Ca' Granda | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ospedali Riuniti di Ancona | Ancona | AN | 60126 | Italy | ||
| AOU Policlinico di Bari |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24635772 | Result | Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L; ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727. Epub 2014 Mar 18. | |
| 20924555 |
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2-by-2 factorial design, open-label, multicenter, randomized, controlled trial, in patients with septic shock, as defined according to clinical criteria. Patients will be randomized in a 1:1:1:1 ratio to one of the 4 groups (Albumin + BAL, Albumin + NS, BAL, NS).
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| Balanced | Other | Balanced crystalloid solutions are traditionally crystalloid solutions containing a relatively low concentration of chloride as compared to 0.9% NaCl containing solutions (Normal Saline). |
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| Up to hospital discharge, a median of 20 days |
| 1-year mortality | All-cause death from randomization to 1 year | Up to 1 year |
| SOFA score | Severity and incidence of organ failures, as assessed by the Sequential Organ Failure Assessment (SOFA) score. SOFA score is used to determine the extent of organ function in a patient while in the intensive care unit. The score is based on 6 different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The scale of each score ranges from 0 (no dysfunction) to 4 (maximal dysfunction). The 6 scores are then added up to provide a global score: the highest the value, the worst the condition of the patient. | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| Incidence of AKI during ICU stay | Assessed by the Kidney Disease Improving Global Outcome (KDIGO) criteria as any of the following: (1) increase in serum creatinine >=0.3 mg/dl (26.5 mmol/l) within 48 hours; or (2) increase in SCr to >=1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or (3) urine volume <0.5 ml/kg/h for 6 hours. | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| RRT | First use of Renal Replacement Therapy (RRT) during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| Need for vasopressors | Duration of the need for vasopressors during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| Mechanical ventilation | Duration of mechanical ventilation during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| Secondary infections in ICU | Incidence of secondary-acquired infections during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| Duration of stay in ICU | Duration expressed as number of days spent in ICU | Up to ICU discharge, a median of 9 days |
| Duration of stay in hospital | Duration expressed as number of days spent in hospital | Up to hospital discharge, a median of 20 days |
| 1-year functional and physical disability | Evaluation by specific psyco-functional tests | Up to 1 year |
| Up to 90 days or ICU discharge - a median of 9 days - whichever comes first |
| Bari |
| BA |
| 70124 |
| Italy |
| ASST Papa Giovanni XXIII | Bergamo | BG | 24127 | Italy |
| ASST BG Est - Ospedale Bolognini | Seriate | BG | 24068 | Italy |
| AST BG Ovest - PO Treviglio | Treviglio | BG | 24047 | Italy |
| Policlinico Sant'Orsola-Malpighi | Bologna | BO | 40138 | Italy |
| Azienda Ospedaliero - Universitaria di Ferrara - Arcispedale Sant'Anna | Cona | FE | 44124 | Italy |
| Ospedale del Mugello | Borgo San Lorenzo | FI | 50032 | Italy |
| Ospedale San Giuseppe | Empoli | FI | 50053 | Italy |
| AOU Careggi | Florence | FI | 50134 | Italy |
| Ospedale Colline dell'Albegna | Orbetello | GR | 58045 | Italy |
| Presidio Ospedaliero di Desio | Desio | MB | 20039 | Italy |
| Fondazione IRCCS San Gerardo dei Tintori | Monza | MB | Italy |
| ASST Nord Milano - Ospedale Bassini | Cinisello Balsamo | MI | 20092 | Italy |
| ASST Ovest Milano | Legnano | MI | 20025 | Italy |
| Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico | Milan | MI | 20122 | Italy |
| ASST Fatebenefratelli - Sacco P.O. Sacco | Milan | MI | 20157 | Italy |
| ASST Grande Ospedale Metropolitano Niguarda | Milan | MI | 20162 | Italy |
| IRCCS Policlinico San Donato | San Donato Milanese | MI | 20097 | Italy |
| Azienda Ospedaliero-Universitaria di Modena, Policlinico di Modena | Modena | MO | 41125 | Italy |
| AOU Policlinico Paolo Giaccone | Palermo | PA | 90127 | Italy |
| ISMETT | Palermo | PA | 90127 | Italy |
| AOU Pisana | Pisa | PI | 56126 | Italy |
| As FO Azienda sanitaria Friuli Occidentale | Pordenone | PN | 33170 | Italy |
| Fondazione IRCCS Policlinico San Matteo | Pavia | PV | 27100 | Italy |
| IRCCS ASMN Reggio Emilia | Reggio Emilia | RE | 43123 | Italy |
| Ospedale Infermi di Rimini | Rimini | Rimini | 47923 | Italy |
| Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore | Roma | RM | 00168 | Italy |
| Ospedale Santa Chiara | Trento | TN | 38122 | Italy |
| Ospedale Santa Croce | Moncalieri | TO | 10024 | Italy |
| Azienda Ospedaliero - Universitaria S. Luigi Gonzaga | Orbassano | TO | 10043 | Italy |
| AOU Città della Salute e della Scienza di Torino | Torino | TO | 10126 | Italy |
| ASU Giuliano Isontina | Trieste | TS | 34128 | Italy |
| Azienda Sanitaria Universitaria Integrata di Udine | Udine | UD | 33100 | Italy |
| Ospedale di Circolo e Fondazione Macchi | Varese | VA | 21100 | Italy |
| Azienda Ospedaliera Universitaria Integrata di Verona | Verona | VR | 37126 | Italy |
| Ospedale SS. Antonio e Biagio e Cesare Arrigo | Alessandria | 15121 | Italy |
| SAFE Study Investigators; Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, Norton R. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011 Jan;37(1):86-96. doi: 10.1007/s00134-010-2039-6. Epub 2010 Oct 6. |
| 25099709 | Result | Patel A, Laffan MA, Waheed U, Brett SJ. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014 Jul 22;349:g4561. doi: 10.1136/bmj.g4561. |
| 29768150 | Result | Semler MW, Self WH, Rice TW. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 May 17;378(20):1951. doi: 10.1056/NEJMc1804294. |
| 23984731 | Result | Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. No abstract available. |
| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
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| ID | Term |
|---|---|
| D000418 | Albumins |
| D000077325 | Ringer's Lactate |
| ID | Term |
|---|---|
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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