Guidance of Ultrasound in Intensive Care to Direct Euvolemia: A Cluster Randomized Crossover Comparative Effectiveness Trial (GUIDE Trial)
Phase: NA
Conditions: Acute Kidney Injury
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-M1S-19-0425 
IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Guidance of Ultrasound in Intensive Care to Direct Euvolemia: A Cluster Randomized 
Crossover Comparative Effectiveness Trial (GUIDE Trial) 
 
NCT03938038 
 
Version Date: 09/03/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB NUMBER: HSC-M1S-19-0425 
IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
Guidance of Ultrasound in Intensive Care to Direct 
Euvolemia: A Cluster Randomized Crossover 
Comparative Effectiveness Trial (GUIDE Trial) 
 
 
 
 
Study Protocol 
 
 
 
 
 
 
 
Principal Investigator:  Gabrielle Hatton MD 
 
Co-Investigators: John Harvin MD MS, Kevin Finkel MD, Charles Wade PhD, Lillian 
Kao MD MS, Timothy Donahue MD, Jessica Hudson MD, Shuyan Wei MD, Kayla Isbell 
MD 
 
 
 
 
Division of Acute Care Surgery 
Department of Surgery 
McGovern Medical School at UTHealth 

IRB APPROVAL DATE: 09/03/2019 
 
2 
Significance: 
Severe injury, which occurs in approximately one quarter of the 2 million annual 
trauma patients in the United States, [1] is a known risk factor for acute kidney injury, 
which is independently associated with increased morbidity and mortality. [2] Prevention 
of post-traumatic AKI has been identified by the International Kidney Diseases Improving 
Global Outcomes (KDIGO) group as a top research priority. [3] 
 
Background and Preliminary Observations: 
AKI complicating severe trauma is associated with increased morbidity and 
mortality. Trauma patients are subjected to multiple, additional renal insults early after 
trauma  such  as  tissue  injury  resulting  in 
rhabdomyolysis, 
systemic 
inflammatory 
response, and exposure to nephrotoxins 
such 
as 
intravenous 
contrast 
agents 
(Figure). 
Renal 
inflammation 
and 
subsequent AKI can be worsened and 
prolonged by inadequate resuscitation of 
hemorrhagic shock and/or from excess fluid 
administration leading to renal edema. [4, 5] 
Therefore, prevention and recovery from 
AKI 
requires 
optimization 
of 
fluid 
management and early identification of high- 
risk patients. 
In 2018, 46% of severely injured 
trauma patients developed AKI within    one 
week of admission to the Trauma Intensive Care Unit (ICU) at our institution. AKI was 
defined according to the KDIGO guidelines (Table 1). [3] AKI-free days is a novel metric 
of time without AKI during the first week of admission. In 2018, AKI-free days of less than 
6 was observed in 39% of ICU patients. A diagnosis of AKI and fewer AKI-free days were 
associated    with    increased    risk     of 
mortality, prolonged ICU length-of-stay, 
prolonged hospital length-of-stay, and 
discharge location other than home. 
Positive fluid balance was also common 
among this population with 49% of 
patients having a fluid balance greater 
than 2L after 48-hours. A positive fluid 
balance is an independent risk factor for 
AKI development and mortality. [6, 7] This 
is  despite  the  fact  that  euvolemia,   or 
 
GUIDE Trial Study Protocol 
Table 1:  KDIGO guideline for AKI diagnosis 
IRB NUMBER: HSC-MS-19-0425 

IRB NUMBER: HSC-M3S-19-0425 
IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
maintaining a fluid balance near zero, is a usual goal of care for the trauma patient. 
Goal-directed 
therapy 
(GDT)-based fluid 
resuscitation 
is hemodynamic 
resuscitation targeting the achievement of pre-determined end-points, which include: (1) 
correction of coagulopathy guided by rapid thromboelastography (rTEG), (2) expedient 
hemorrhage control, and (3) restoration of end-organ perfusion with balanced transfusion 
guided by hemodynamic measurements, lactic acid, and base excess. GDT has been 
studied in the peri-operative setting as part of enhanced recovery pathways and has been 
reported to decrease the incidence of AKI. [8] Given that laboratory values are only 
obtained every few hours and hemodynamic abnormalities can persist despite adequate 
fluid resuscitation, the optimal strategy for ensuring optimal fluid administration 
during GDT remains unknown. 
Dynamic evaluation of volume status complements traditional measurements used 
in GDT to improve resuscitation once a patient arrives to the ICU. A number of dynamic 
and static tests have been evaluated in assessment of fluid responsiveness, all with 
various limitations (Table 2). 
 
Method 
Threshold 
Requires invasive 
measurements 
Limitations 
Pulse Pressure/Stroke volume variation 
[9] 
12% 
Yes 
Inaccurate with spontaneous breathing, 
arrhythmias, or low Vt 
IVC diameter variations [10] 
12% 
No 
Inaccurate with spontaneous breathing or 
low Vt 
SVC diameter variations [10] 
36% 
Yes 
Requires transesophageal doppler, 
inaccurate with spontaneous breathing or 
Passive Leg Raising [11] 
10% 
Yes* 
Cannot be used if mobility limitations, 
requires direct CO measurement 
End-expiratory occlusion test [12] 
5% 
Yes 
Requires patient to be intubated 
Mini-fluid challenge (100mL) [13] 
6% 
Yes 
Requires precise CO measurement, 
irreversible fluid administration 
Conventional fluid challenge (500mL) 
[14] 
15% 
Yes 
Requires direct CO measurement 
 
Table 2: Tests for assessing fluid responsiveness. Thresholds indicate validated percent change from 
baseline that is consistent with fluid responsiveness. [15] 
Vt=tidal volume, CO=cardiac output. 
*Passive leg raising is accurate with concurrent bedside echocardiography 
 
Ultrasound assessment of volume status is appealing because it is non-invasive, 
rapidly accessible, inexpensive, and easily learned. Guidelines from the Society of Critical 
Care Medicine endorses assessment of preload responsiveness by measuring inferior 
vena cava (IVC) collapsibility by ultrasound (Grade 1B). [16] Kanji, et al. found a lower 
incidence of AKI after incorporating volume assessment by intensivist-performed limited 
bedside echocardiography for patients with shock of mixed etiologies. [17] Notably, 
volume assessment in their study frequently resulted in decreased fluid   administration. 

IRB NUMBER: HSC-M4S-19-0425 
IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
However, the effectiveness of routine ultrasound assessments for GDT in reducing AKI 
incidence and duration in trauma patients in a teaching institution is unknown. 
 
Rationale for Clinical Trial: 
Ultrasound assessment of volume status and fluid responsiveness is a technique 
frequently utilized in the trauma ICU at our institution and is performed by the ICU 
physicians. Residents are taught this technique during their clinical rotation on service, 
as well as during other intensive care rotations. Physicians utilize the information 
gathered from the IVC ultrasound for resuscitation feedback. However, obtaining 
repeated IVC measurements for feedback is uncommon and many physicians obtain 
resuscitation feedback from additional adjuncts, as listed in the table above. These 
practices are inconsistently documented in the medical record, making it difficult to 
retrospectively ascertain if and how these practices impact clinical outcomes. 
Furthermore, implementation of a protocol without proof of effectiveness would risk 
inappropriate energy expenditure by the care team. And finally, there may be risks of 
increased physician feedback. 
 
Design: 
 
Hypothesis: Ultrasound-guided GDT results in adult trauma patients with more AKI-free 
days when compared to usual care in the trauma ICU at a teaching hospital. 
 
Design: This is a single-center, pragmatic, cluster randomized crossover trial to be 
performed at The Red Duke Trauma Institute, Texas Medical Center, an academic, level- 
1 trauma center. 
 
Study Participants: Primary participants are the care providers in the Shock Trauma ICU. 
All providers will be included in this study. The care structure is comprised of post- 
graduate year 1-3 surgical, anesthesia, and emergency medicine residents, a surgical 
critical care fellow, and a surgical critical care faculty member. Secondary participants 
will include injured patients at least 16 years of age that are admitted to the Shock Trauma 
ICU will be assessed for eligibility. Exclusion criteria of secondary participants include 
prisoners and pregnancy. Prisoners will be excluded due to their vulnerable status. 
Because pregnancy results in an increase in circulating blood volume up to 50%, there is 
a high likelihood of clinical misinterpretation of ultrasound findings. [18] Therefore, 
pregnant patients will be excluded as well. Both of these exclusions are expected to 
minimally impact secondary participant enrollment. 
 
Randomization: Care teams will be clustered according to resident and fellow rotation 
schedule.  Rotations occur on the first of the month with a new care team and  therefore 

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IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
one month is considered a cluster. Clusters will be randomized at the first of the month 
using variable permuted blocks using a computer-generated random sequence. Clusters 
will be randomized by a study coordinator using sequentially numbered, opaque sealed 
envelope. Care assignment will continue until the 15th of each month, at which point the 
cluster      will      cross      over      and      provide      the      alternative        assignment. 
 
 
Procedures: 
During the assigned intervention period, a care team member will perform IVC ultrasound 
to assess volume status and fluid responsiveness upon patient arrival to the ICU, and two 
more times over a 24-hour period. Assessments will be completed at least three hours 
apart. IVC diameter and collapsibility index (IVCCI) will be measured. Use of the results 
to guide care will be at the discretion of the primary team. Usual goals of resuscitation 
include lactate concentration <1 mmol/L, base excess +2 to -2, normal rTEG values, 
mean arterial pressure >60 mmHg after hemorrhage control has been obtained. The goal 
for volume management in this study will be euvolemia, most consistent with <18% IVCCI 
and IVC diameter 15 - 25 mm. [19] Measurements are to be interpreted by the physician 
within the clinical context. Results of the ultrasound and subsequent management will be 
recorded in a study notebook by the physician at time of ultrasound. 
 
Usual Care: No changes to usual care will be made. Physicians will record results of  
IVC ultrasound, if utilized. 
 
Quality Assurance: Accuracy of technique of all care team physicians will be assessed 
during an ultrasound training session provided the day prior to the intervention arm of the 
cluster. Additional training will be provided until proficiency deemed adequate by the 
session leaders. Session leaders will include the Trauma ICU faculty and the study PI 
who has been independently certified in modified echocardiography for Critical Care, 
which includes IVC Ultrasound techniques (GH). The dedicated training session will be 
new to the rotating resident education, but represents a similar training to prior, individual 
training sessions that occur between a resident and faculty throughout an ICU rotation. 
Care Team 1 
Care Team 2 
Care Team 3 
Care Team 4 
Care Team 5 
Care Team 6 
(Month 1) 
(Month 2) 
(Month 3) 
(Month 4) 
(Month 5) 
(Month 6) 
Randomize 
First ½ 
Month 
Treatment 
Usual 
Usual 
Treatment 
Treatment 
Usual 
Crossover 
Second ½ 
Month 
Usual 
Treatment 
Treatment 
Usual 
Usual 
Treatment 

IRB NUMBER: HSC-M6S-19-0425 
IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
Troubleshooting Opportunities: At least three care team members are present in the 
STICU at all times and US for the same patient may be performed by different physicians, 
based on individual care demands within the unit. If the physician is having difficulty with 
US technique, another physician is available to attempt the ultrasound prior to indicating 
that the ultrasound was unable to be performed. 
 
Outcomes: 
Primary outcome: AKI-free days within 7 days of injury. AKI will be defined by the KDIGO 
criteria.  All stages will be considered AKI. 
 
Secondary outcomes: AKI incidence within the first 7 days of ICU admission, stage of 
AKI, need for renal replacement therapy, quantity and type of fluids administered at 24 
and 48 hours, quantity and type of diuretics admisnistered at 24 and 48 hours, time to 
lactate normalization, time to creatinine concentration <1.5 mg/dL or to prehospital 
baseline, time to base excess normalization, ventilator-free days, ICU-free days within 
first 30 days. Adverse events determined a priori include transfusion-related acute lung 
injury, acute respiratory distress syndrome, abdominal compartment syndrome, new 
onset congestive heart failure, and re-bleeding requiring unscheduled intervention. Data 
measurement will occur according to the schedule outlined in Table 3. 
 
Data and Collection Method 
24 Hours 
48 Hours 
7 Days 
30 Days 
IVC Measurements and Physician Actions – Data Forms 
x 
AKI-Free Days – Chart Review 
x 
AKI Incidence and Highest Stage – Chart Review 
x 
Fluid Administration – Chart Review 
x 
x 
Creatinine Trend – Chart Review 
x 
Lactate Trend – Chart Review 
x 
Base Excess Trend – Chart Review 
x 
Ventilator-Free Days – Chart Review 
x 
x 
ICU-Free Days – Chart Review 
x 
x 
Mortality – Chart Review 
x 
x 
Potential Adverse Events: transfusion-related acute lung injury, acute 
respiratory distress syndrome, abdominal compartment syndrome, 
and re-bleeding requiring unscheduled intervention, need for and 
duration of renal replacement therapy  – Chart Review 
x 
x 
Table 3:  Process measures and clinical outcome collection schedule 
 
Pre-planned subgroup analyses include: 
1. Resuscitation indication: hemorrhage, post-traumatic SIRS, rhabdomyolysis, 
other, and none. 
2. Ventilation Type:  Spontaneous, mechanical 
3. Order of intervention:  Intervention first, intervention second 

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IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
Statistical Analysis: 
The largest feasible study will be completed over the course of 12 months with an 
estimated enrollment of 30 secondary subjects per cluster, resulting in 360 patients 
enrolled in each treatment group and 720 total patients in the study. 
 
No interim analysis will be completed. Multilevel Bayesian analysis will be performed to 
assess the effectiveness of the intervention to account for care team cluster. Neutral, 
conservative priors will be used to estimate the probability of both benefits and harms. 
 
Safety Assessment: 
Ultrasound imaging uses high-frequency sound waves to create images from wave 
reflection from internal body structures. It has been utilized routinely for over 20 years, 
has an excellent safety record, and is considered safe when utilized by a healthcare 
provider. [20] 
 
Data Collection and Confidentiality: 
Clinical data and laboratory data will be prospectively collected as part of an ongoing, 
prospective trauma registry. Findings from both scheduled and unscheduled volume 
assessments by any modality will be recorded in a study notebook kept in a locked cabinet 
at the charge nurse’s station and transferred to a secure, Microsoft Access database 
daily. The database will be accessible only to study personnel, as approved by the 
institutional review board. 
 
Future directions: 
The results of this study will inform the feasibility and effectiveness of implementing 
scheduled ultrasound-guided fluid resuscitation for AKI prevention. 
 
Ethical Considerations: 
 
The protocol proposed aims to increase physician feedback of resuscitation by means 
of a non-invasive ultrasounds and improve healthcare delivery. This study poses 
minimal risk to subjects and will not adversely affect the rights and welfare of patients or 
physicians. The investigators seek approval through the institutional review board for 
waiver of individual consent and qualify as a quality improvement initiative. 
 
Personnel Roles: 
 
Dr. Gabrielle Hatton is a research fellow in the Department of Surgery. She is 
responsible for protocol development, physician training, troubleshooting, protocol 

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IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
implementation, data collection, data merging and cleaning, statistical analysis, 
interpretation of the results and any other primary study requirements. 
 
Dr. Lillian Kao is a Professor in the Department of Surgery. She will assist with 
protocol development, outcome measure assessment, troubleshooting, protocol 
implementation, interpretation of the results, and mentorship to the primary PI. 
 
Dr. Charles Wade is a Professor in the Department of Surgery and Director of the 
Center for Translational Injury Research (CeTIR). He will assist with protocol 
development, outcome measure assessment, troubleshooting, protocol implementation, 
interpretation of the results, and mentorship to the primary PI. 
 
Dr. Kevin Finkel is a Professor in the Department of Renal Diseases and Hypertension. 
He provides expertise in fluid management and kidney disease. He will assist with 
protocol development, outcome measure assessment, and interpretation of the results. 
 
Dr. John Harvin is an Associate Professor in the department of Surgery. He provides 
expertise in comparative effectiveness trials and will assist with protocol development, 
implementation, and interpretation of the results. 
 
Dr. Timothy Donahue is a Surgical Critical Care Fellow in the Department of Surgery. 
He will assist with protocol development, troubleshooting, process improvement, and 
implementation. 
 
Dr. Jessica Hudson is an Assistant Professor in the Department of Emergency 
Medicine. She has expertise in use of point-of-care ultrasound in clinical care for 
critically ill patients. She will assist with protocol development, physician training, and 
protocol implementation. 
 
Drs. Shuyan Wei and Kayla Isbell are research fellows in the Department of surgery. 
They will assist in physician training, protocol implementation, process improvement, 
troubleshooting, data collection, statistical analysis, and results interpretation. 

IRB NUMBER: HSC-M9S-19-0425 
IRB APPROVAL DATE: 09/03/2019 
GUIDE Trial Study Protocol 
 
 
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GUIDE Trial Study Protocol 
 
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