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The administration of intravenous fluids is ubiquitous in the care of the critically ill. Commonly available isotonic crystalloid solutions contain a broad spectrum electrolyte compositions including a range chloride concentrations. Recent studies have associated solutions with supraphysiologic chloride content with hyperchloremia, metabolic acidosis and renal vasoconstriction, acute kidney injury and renal replacement therapy, and increased mortality but no large, randomized-controlled trials have been conducted. SMART-MED will be a large, cluster-randomized, multiple-crossover trial enrolling critically ill patients from the Medical ICU at Vanderbilt University from June 2015 until April 2017. The primary endpoint will be the incidence of Major Adverse Kidney Events in 30 days after enrollment (MAKE30 is the composite of death, new renal replacement, or persistent renal dysfunction at discharge).
SMART-MED is a large, cluster-randomized, multiple-crossover trial of 0.9% saline versus physiologically-balanced isotonic crystalloids (Lactated Ringers or Plasma-Lyte© A) with regard to the incidence of major adverse kidney events by 30 days in patients admitted to the medical intensive care unit. Between June 2015 and April 2017, all patients admitted to the medical intensive care unit at Vanderbilt University medical center who are 18 years or older will be enrolled. The study will occur in one-month blocks. The ICU will be randomized to an initial fluid group (0.9% saline or physiologically balanced crystalloids). The assigned fluid will be used exclusively for all patients receiving isotonic crystalloid for the duration of the month-long block (except in the presence of pre-specified contraindications). The assigned study fluid will switch at the end of each month-long block such that half of the months are assigned to 0.9% saline and half of the months are assigned to physiologically balance fluid. It is anticipated that around 5,300 patients will be enrolled from the medical ICU during the study period. All aspects of study design, intervention, and data collection will be harmonized with an independent study addressing the same question in the non-medical intensive care units at Vanderbilt University during a similar study period (SMART-SURG). A pre-specified data analysis plan will dictate the harmonized analysis of SMART-MED and SMART-SURG.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 0.9% Saline | Active Comparator | Patients in an ICU block randomized to physiologically-balanced isotonic fluid will receive 0.9% Saline whenever isotonic intravenous fluid administration is ordered by the treating provider. |
|
| Physiologically-balanced | Active Comparator | Patients in an ICU block randomized to physiologically-balanced isotonic fluid will receive Plasma-Lyte© A or Lactated Ringer's whenever isotonic intravenous fluid administration is ordered by the treating provider. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 0.9% Saline | Other | 0.9% Saline will be used whenever an isotonic crystalloid is ordered |
|
| Measure | Description | Time Frame |
|---|---|---|
| Major Adverse Kidney Event Within 30 Days | The primary outcome was the proportion of patients who met one or more criteria for a major adverse kidney event within 30 days - the composite of death, new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as a final inpatient creatinine value ≥200% of the baseline value) - all censored at hospital discharge or 30 days after enrollment, whichever came first. | 30 days after enrollment censored at hospital discharge |
| Measure | Description | Time Frame |
|---|---|---|
| 30-day In-hospital Mortality | Death before hospital discharge, censored at 30 days after enrollment | 30 days after enrollment censored at hospital discharge |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Todd W Rice, M.D. | Vanderbilt University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37209 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20950434 | Background | Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, Du B, McArthur C, Myburgh J; SAFE TRIPS Investigators. Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units. Crit Care. 2010;14(5):R185. doi: 10.1186/cc9293. Epub 2010 Oct 15. | |
| 21705897 | Background |
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For randomization, we will generate two sequences of study group assignment ([1] saline during odd-numbered months and balanced crystalloid during even-numbered months; [2] balanced crystalloid during odd-numbered months and saline during even-numbered months).
Participants will only receive 1 of the 2 interventions.
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| ID | Title | Description |
|---|---|---|
| FG000 | 0.9% Sodium Chloride (Saline) | Patients in an ICU block randomized to saline will receive 0.9% sodium chloride whenever isotonic intravenous fluid administration is ordered by the treating provider. Saline: 0.9% sodium chloride will be used whenever an isotonic crystalloid is ordered |
| FG001 | Balanced Crystalloid | Patients in an ICU block randomized to balanced crystalloid will receive Plasma-Lyte A or Lactated Ringer's whenever isotonic intravenous crystalloid administration is ordered by the treating provider. Balanced crystalloid: Lactated Ringers or Plasma-Lyte A will be used whenever an isotonic crystalloid is ordered |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Of the 15,802 patient enrolled in the SMART trial, 7860 were assigned to saline and 7,942 were assigned to balanced crystalloids. Of these, 5,381 were admitted to the medical ICU, with 2646 assigned to saline and 2735 assigned to balanced crystalliods.
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| ID | Title | Description |
|---|---|---|
| BG000 | 0.9% Sodium Chloride (Saline) | Patients in an ICU block randomized to saline will receive 0.9% sodium chloride whenever isotonic intravenous fluid administration is ordered by the treating provider. Saline: 0.9% sodium chloride will be used whenever an isotonic crystalloid is ordered |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Major Adverse Kidney Event Within 30 Days | The primary outcome was the proportion of patients who met one or more criteria for a major adverse kidney event within 30 days - the composite of death, new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as a final inpatient creatinine value ≥200% of the baseline value) - all censored at hospital discharge or 30 days after enrollment, whichever came first. | Of the 15,802 patient enrolled in the SMART trial, 5381 were admitted to the medical ICU, 2646 in the saline group and 2735 in the balanced crystalloid group. | Posted | Count of Participants | Participants | 30 days after enrollment censored at hospital discharge |
|
30 days
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered an intervention that does not necessarily have to have a causal relationship with this treatment. An adverse event therefore can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an intervention, whether or not the incident is considered to be related to the intervention.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 0.9% Sodium Chloride (Saline) | Patients in an ICU block randomized to saline will receive 0.9% sodium chloride whenever isotonic intravenous fluid administration is ordered by the treating provider. Saline: 0.9% sodium chloride will be used whenever an isotonic crystalloid is ordered |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Matthew W. Semler, MD, MSc | Vanderbilt University Medical Center | (615) 322-3412 | matthew.w.semler@vumc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 15, 2017 | Aug 19, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D016638 | Critical Illness |
| D058186 | Acute Kidney Injury |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D051437 | Renal Insufficiency |
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| ID | Term |
|---|---|
| D000077330 | Saline Solution |
| D012965 | Sodium Chloride |
| D000077325 | Ringer's Lactate |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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| Physiologically-balanced isotonic crystalloid | Other | Lactated Ringers or Plasma-Lyte© A will be used whenever an isotonic crystalloid is ordered |
|
|
| Yunos NM, Kim IB, Bellomo R, Bailey M, Ho L, Story D, Gutteridge GA, Hart GK. The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med. 2011 Nov;39(11):2419-24. doi: 10.1097/CCM.0b013e31822571e5. |
| 23073953 | Background | Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72. doi: 10.1001/jama.2012.13356. |
| 35443809 | Derived | Lombardo S, Smith MC, Semler MW, Wang L, Dear ML, Lindsell CJ, Freundlich RE, Guillamondegui OD, Self WH, Rice TW; Isotonic Solutions and Major Adverse Renal Events Trial (SMART) Investigators and Vanderbilt Learning Healthcare System Platform Investigators. Balanced Crystalloid versus Saline in Adults with Traumatic Brain Injury: Secondary Analysis of a Clinical Trial. J Neurotrauma. 2022 Sep;39(17-18):1159-1167. doi: 10.1089/neu.2021.0465. |
| 33546622 | Derived | Funke BE, Jackson KE, Self WH, Collins SP, Saunders CT, Wang L, Blume JD, Wickersham N, Brown RM, Casey JD, Bernard GR, Rice TW, Siew ED, Semler MW; SMART Investigators; Pragmatic Critical Care Research Group. Effect of balanced crystalloids versus saline on urinary biomarkers of acute kidney injury in critically ill adults. BMC Nephrol. 2021 Feb 5;22(1):54. doi: 10.1186/s12882-021-02236-x. |
| 33196806 | Derived | Self WH, Evans CS, Jenkins CA, Brown RM, Casey JD, Collins SP, Coston TD, Felbinger M, Flemmons LN, Hellervik SM, Lindsell CJ, Liu D, McCoin NS, Niswender KD, Slovis CM, Stollings JL, Wang L, Rice TW, Semler MW; Pragmatic Critical Care Research Group. Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials. JAMA Netw Open. 2020 Nov 2;3(11):e2024596. doi: 10.1001/jamanetworkopen.2020.24596. |
| 31454263 | Derived | Brown RM, Wang L, Coston TD, Krishnan NI, Casey JD, Wanderer JP, Ehrenfeld JM, Byrne DW, Stollings JL, Siew ED, Bernard GR, Self WH, Rice TW, Semler MW. Balanced Crystalloids versus Saline in Sepsis. A Secondary Analysis of the SMART Clinical Trial. Am J Respir Crit Care Med. 2019 Dec 15;200(12):1487-1495. doi: 10.1164/rccm.201903-0557OC. |
| 29485925 | Derived | Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, Guillamondegui OD, May AK, Weavind L, Casey JD, Siew ED, Shaw AD, Bernard GR, Rice TW; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584. Epub 2018 Feb 27. |
| 28302179 | Derived | Semler MW, Self WH, Wang L, Byrne DW, Wanderer JP, Ehrenfeld JM, Stollings JL, Kumar AB, Hernandez A, Guillamondegui OD, May AK, Siew ED, Shaw AD, Bernard GR, Rice TW; Isotonic Solutions and Major Adverse Renal Events Trial (SMART) Investigators; Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in the intensive care unit: study protocol for a cluster-randomized, multiple-crossover trial. Trials. 2017 Mar 16;18(1):129. doi: 10.1186/s13063-017-1871-1. |
| Balanced Crystalloid |
Patients in an ICU block randomized to balanced crystalloid will receive Plasma-Lyte A or Lactated Ringer's whenever isotonic intravenous crystalloid administration is ordered by the treating provider. Balanced crystalloid: Lactated Ringers or Plasma-Lyte A will be used whenever an isotonic crystalloid is ordered |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Balanced Crystalloid | Patients in an ICU block randomized to balanced crystalloid will receive Plasma-Lyte A or Lactated Ringer's whenever isotonic intravenous crystalloid administration is ordered by the treating provider. Balanced crystalloid: Lactated Ringers or Plasma-Lyte A will be used whenever an isotonic crystalloid is ordered |
|
|
|
| Secondary | 30-day In-hospital Mortality | Death before hospital discharge, censored at 30 days after enrollment | Posted | Count of Participants | Participants | 30 days after enrollment censored at hospital discharge |
|
|
|
|
| 467 |
| 2,646 |
| 0 |
| 2,646 |
| 0 |
| 2,646 |
| EG001 | Balanced Crystalloid | Patients in an ICU block randomized to balanced crystalloid will receive Plasma-Lyte A or Lactated Ringer's whenever isotonic intravenous crystalloid administration is ordered by the treating provider. Balanced crystalloid: Lactated Ringers or Plasma-Lyte A will be used whenever an isotonic crystalloid is ordered | 418 | 2,735 | 0 | 2,735 | 0 | 2,735 |
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| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002712 |
| Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |