Preemptive Resuscitation for Eradication of Septic Shock

• ClinicalTrials.gov Identifier: NCT01449721
• Recruitment Status: Completed
• First Posted: October 10, 2011
• Results First Posted: October 4, 2017
• Last Update Posted: October 4, 2017
• Sponsor: Christiana Care Health Services
• Information provided by (Responsible Party): Christiana Care Health Services

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Sepsis; Severe Sepsis
• Intervention: Drug: Intravenous fluid
• Enrollment: 142

Participant Flow

Recruitment Details
Pre-assignment Details	Prior to interventional arm of the trial, a 5-month observational period was performed identifying 94 patients in the control arm. At the initiation of the interventional study, subjects were randomized in a 2:1 ratio to intervention:control, enrolling an additional 18 patients to the control arm, and 30 patients to the intervention.

Arm/Group Title	Control	Interventional Arm
Arm/Group Description	Standard medical care by the primary treatment team.	Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization Intravenous fluid: 0.9% Sodium chloride intravenous fluid
Period Title: Overall Study
Started	112	30
Completed	112	28
Not Completed	0	2
Reason Not Completed
Physician Decision	0	1
Physician Decision	0	1

Baseline Characteristics

Arm/Group Title		Control	Interventional Arm	Total
Arm/Group Description		Standard medical care by the primary treatment team.	Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization Intravenous fluid: 0.9% Sodium chloride intravenous fluid	Total of all reporting groups
Overall Number of Baseline Participants		112	30	142
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	112 participants	30 participants	142 participants
		58.3 (15)	56.8 (16)	58 (15)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	112 participants	30 participants	142 participants
	Female	51 45.5%	12 40.0%	63 44.4%
	Male	61 54.5%	18 60.0%	79 55.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Worsening Organ System Dysfunction Defined by SOFA Score Increase ≥ 1
Description	Development of worsening organ failure defined by the Sequential Organ Failure Assessment (SOFA) score. The SOFA score defines the presence and severity of dysfunction within 6 organ systems (cardiovascular, respiratory, coagulation, liver, renal, and nervous system) with a value of "0" for assigned to normal function to a maximum value of "4" for severe dysfunction in each of the organ systems. Each component of the SOFA score is added together, ranging from "0" indicating no organ dysfunction in any of the 6 organ systems, to "24" indicating maximal organ dysfunction across all 6 organ systems. Within this trial, the occurrence of organ failure was defined by any increase in the total SOFA score by ≥ 1 point over the first 72 hours after randomization.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Interventional Arm
Arm/Group Description:	Standard medical care by the primary treatment team.	Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization Intravenous fluid: 0.9% Sodium chloride intravenous fluid
Overall Number of Participants Analyzed	112	30
Measure Type: Count of Participants; Unit of Measure: Participants
	34 30.4%	20 66.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Interventional Arm
	Comments	Null hypothesis: In patients with moderate severity sepsis, there is no change in the incidence of organ dysfunction within 72 hours associated with the use of an empiric fluid resuscitation algorithm.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.064
	Comments	[Not Specified]
	Method	2-sample z-test
	Comments	z-test for differences in proportions

2. Secondary Outcome

Title	In-hospital Mortality
Description	Any occurrence of mortality while the participant is in-hospital is counted as an outcome.
Time Frame	In-hospital discharge or up to maximum 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Interventional Arm
Arm/Group Description:	Standard medical care by the primary treatment team.	Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization Intravenous fluid: 0.9% Sodium chloride intravenous fluid
Overall Number of Participants Analyzed	112	30
Measure Type: Count of Participants; Unit of Measure: Participants
	4 3.6%	0 0.0%

3. Secondary Outcome

Title	Number of Participants With Experiencing Complications Related to Intravascular Volume Overload
Description	Composite safety endpoint: Premature termination of the protocol-directed intravenous fluid administration by the investigator or primary physician due to presumed volume overload; Administration of intravenous diuretic for acute pulmonary edema; Respiratory failure requiring ventilatory assistance (BiPAP, CPAP, or mechanical ventilation) secondary to pulmonary edema per primary care team
Time Frame	12 hours following treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Interventional Arm
Arm/Group Description:	Standard medical care by the primary treatment team.	Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization Intravenous fluid: 0.9% Sodium chloride intravenous fluid
Overall Number of Participants Analyzed	112	30
Measure Type: Count of Participants; Unit of Measure: Participants
	4 3.6%	3 10.0%

Adverse Events

Time Frame	Respiratory failure occurring within 24 hours of enrollment. Fluid overload occurring within 24 hours of enrollment. Mortality occurring at anytime within hospital stay.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Control		Interventional Arm
Arm/Group Description	Standard medical care by the primary treatment team.		Protocolized empiric resuscitation delivering weight-based intravenous fluid resuscitation targeting lactate normalization Intravenous fluid: 0.9% Sodium chloride intravenous fluid
All-Cause Mortality
	Control		Interventional Arm
	Affected / at Risk (%)		Affected / at Risk (%)
Total	4/112 (3.57%)		0/30 (0.00%)
Serious Adverse Events
	Control		Interventional Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/112 (3.57%)		3/30 (10.00%)
General disorders
Mortality † [1]	4/112 (3.57%)	4	0/30 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure requiring mechanical intervention † [2]	4/112 (3.57%)	4	2/30 (6.67%)	2
Vascular disorders
Intravascular fluid overload † [3]	0/112 (0.00%)	0	2/30 (6.67%)	2
† Indicates events were collected by systematic assessment; [1] All cause in-hospital mortality; [2] Any mechanical ventilation within 24 hours of enrollment.; [3] Assessment by treating physician of intravascular fluid overload
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Control		Interventional Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/112 (0.00%)		0/30 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Ryan Arnold, MD, Director of Research, Emergency Medicine
• Organization: Christiana Care Health System
• Phone: 302-733-5108
• EMail: ryarnold@christianacare.org

Publications:

Sakr Y, Vincent JL, Schuerholz T, Filipescu D, Romain A, Hjelmqvist H, Reinhart K. Early- versus late-onset shock in European intensive care units. Shock. 2007 Dec;28(6):636-643.

Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, Bellamy SL, Christie JD. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009 May;37(5):1670-7. doi: 10.1097/CCM.0b013e31819fcf68.

Glickman SW, Cairns CB, Otero RM, Woods CW, Tsalik EL, Langley RJ, van Velkinburgh JC, Park LP, Glickman LT, Fowler VG Jr, Kingsmore SF, Rivers EP. Disease progression in hemodynamically stable patients presenting to the emergency department with sepsis. Acad Emerg Med. 2010 Apr;17(4):383-90. doi: 10.1111/j.1553-2712.2010.00664.x.

• Responsible Party: Christiana Care Health Services
• ClinicalTrials.gov Identifier: NCT01449721
• Other Study ID Numbers: PRESHOCK
• First Submitted: September 29, 2011
• First Posted: October 10, 2011
• Results First Submitted: November 30, 2016
• Results First Posted: October 4, 2017
• Last Update Posted: October 4, 2017