Effect of VExUS Ultrasound Protocol (Venous Excess Ultrasound) on Perioperative Fluid Management, on the Incidence of Postoperative Pulmonary Complications and Postoperative Acute Kidney Injury in Patients Undergoing Thoracic Surgery
Phase: NA
Conditions: Thoracic Surgery With One-lung Ventilation, VExUS, Fluid Management, Acute Kidney Injury, Postoperative Pulmonary Complications (PPCs)
Sponsor: University of Crete

27-11-2024 
RESEARCH PROTOCOL: 
Title 
Effect of a VExUS (Venous Excess Ultrasound) guided protocol of perioperative fluid 
management on the incidence of postoperative pulmonary complications and 
postoperative acute kidney injury in patients undergoing thoracic surgery. 
Introduction 
Fluid Management in Thoracic Surgery 
In thoracic surgery, intraoperative fluid management presents a challenge for 
anesthesiologists, as patients are at high risk of developing interstitial and alveolar 
edema of the lungs. A history of pulmonary disease, previous chemotherapy or 
radiation therapy in the area, one-lung ventilation, surgical manipulation, and 
ischemia-reperfusion injury can all damage the respiratory epithelium’s glycocalyx, 
the alveolar epithelium, and surfactant, ultimately leading to pulmonary injury. These 
factors, combined with liberal perioperative fluid management, increase the risk of 
acute respiratory distress syndrome (ARDS), atelectasis, pneumonia, and ultimately 
postoperative mortality. Traditionally, a restrictive fluid management strategy is 
employed intraoperatively, with crystalloid administration at a rate of 1-2 ml/kg/h, 
ensuring that the perioperative fluid balance does not exceed 1500 ml. This 
restrictive strategy may increase the risk of hypovolemia, which can lead to tissue 
hypoperfusion, target organ dysfunction, and acute kidney injury. Within the 
Enhanced Recovery After Surgery (ERAS) protocols, goal-directed therapy (GDT) for 
fluid management in thoracic surgery is discussed but not explicitly recommended. 
Recommendations include avoiding overly restrictive or completely liberal fluid 
strategies, maintaining euvolemia, and preventing tissue hypoperfusion with 
balanced use of inotropic agents and fluid administration. 
 Postoperative Respiratory Complications 
Pulmonary injury is the leading cause of death following thoracic surgery. Pre-existing 
respiratory disease, surgical manipulation, lung parenchyma resection, and the 
detrimental effects of one-lung ventilation increase the risk of postoperative 
respiratory complications. Although overhydration and ventilation with high tidal 
volumes have been replaced by a restrictive fluid strategy and the application of 
protective mechanical ventilation, it appears that all factors involved in ventilator-
induced lung injury (VILI) also play a harmful role in one-lung ventilation. High strain 
on the ventilated lung, oxidative stress, surgical trauma, recruitment maneuvers, 
biological trauma, atelectatic trauma, and ischemia-reperfusion injury are the 
pathophysiological mechanisms leading to postoperative acute respiratory failure 
and, in 2-5% of cases, to ARDS. 
 Postoperative Acute Kidney Injury 
Postoperative acute kidney injury (AKI) represents 18-47% of in-hospital AKI and is 
associated with prolonged hospitalization and high morbidity and mortality. Recently, 
the implementation of new AKI classifications (RIFLE, AKIN, KDIGO) has facilitated its 
early recognition for immediate preventive measures. Additionally, the detection of 
two early urinary biomarkers of kidney stress, the tissue inhibitor of 
metalloproteinases-2 (TIMP-2) and the insulin-like growth factor-binding protein 7 
(IGFBP7), has contributed to this. Postoperatively, an increase in serum creatinine by 
up to 0.5 mg/dL from baseline has been associated with a threefold increase in 
mortality following cardiac surgery. Potential pathophysiological mechanisms of 

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postoperative AKI include ischemia, inflammation, and toxins. However, in thoracic 
surgeries, both the hypovolemia of a restrictive fluid administration strategy and 
overhydration and venous congestion can equally lead to acute kidney injury 
postoperatively. 
VExUS Ultrasound Protocol 
The VExUS protocol is a standardized point-of-care ultrasound examination that 
includes measurements of the inferior vena cava (IVC) diameter, combined with 
Doppler analysis of waveforms in the hepatic vein, portal vein, and renal veins. From 
this analysis, the presence of venous congestion—classified as mild or severe—or its 
absence is determined. A high VExUS score (grade 3) has been strongly associated 
with the occurrence of acute kidney injury in patients undergoing cardiac surgery and 
has more recently been linked to elevated right atrial pressure (RAP ≥ 12 mmHg). The 
protocol includes the following classification: 
 
o Grade 0: IVC < 2 cm 
o Grade 1: IVC ≥ 2 cm, with normal or mildly abnormal waveforms in the 
hepatic, portal, and renal veins (mild congestion) 
o Grade 2: IVC ≥ 2 cm, with severely altered waveforms in at least one 
vein (moderate congestion) 
o Grade 3: IVC ≥ 2 cm, with severely altered waveforms in multiple veins 
(severe congestion) 
 
 
Study Aim 
This study aims to investigate the effect of a VExUS ultrasound guided protocol of 
perioperative fluid management within a goal-directed therapy framework, on 
postoperative respiratory complications, and the occurrence of acute kidney injury in 
patients undergoing thoracic surgery.  
The null hypothesis is that the application of VExUS during the perioperative period will 
not lead to a more judicious fluid administration strategy, avoiding an overly restrictive 
approach (control group), thus achieving the desired euvolemia in these patients (VExUS 
guided fluid management). 
Method 
Study Design 
A single-center clinical study conducted in the Anesthesiology Clinic of the University 
General Hospital of Heraklion. 
Parallel design in two groups. 
Data analysis: primary analysis according to the "intention to treat" principle, 
supplementary analysis according to the "as treated" principle. 
Inclusion Criteria 
Adult patients over > 18 years undergoing video assisted thoracic surgery lobectomy 
under one-lung ventilation will be studied. 
Exclusion Criteria 
Patients will be excluded from the study if they: 
 refuse to participate 
 are scheduled for pneumonectomy 

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 are young athletes due to the likelihood of having an IVC > 2 cm as a normal 
variant 
 exhibit moderate-severe tricuspid valve insufficiency, with moderate to severe 
pulmonary hypertension  
 exhibit heart failure with reduced ejection fraction, EF<35% 
 show portal hypertension, portal vein thrombosis, or liver cirrhosis 
 have a history of stage 4 or end-stage kidney disease, with measured eGFR < 
30 ml/min/1.73 m² or need for dialysis 
 receive transfusion with more than 2 packed red blood cells units 
perioperatively 
Conduct of the Trial 
Basic Perioperative Care and General Monitoring 
Preoperative assessment, fasting, and premedication according to the routine of the 
department: 
  Discontinuation of fluid intake 2 hours before surgery  
  cessation of food intake 6 hours preoperatively 
 discontinuation on the day of surgery of ACE inhibitors, angiotensin receptor 
blockers, thiazide diuretics, and loop diuretics, 
Upon entering the operating room, patients will be connected standard ASA 
monitors:  5 lead ECG, pulse oximetry (SpO2), non-invasive blood pressure 
measurement. Under local anaesthesia an arterial catheter will be placed for invasive 
blood pressure measurement and blood gas sampling, along with at least two venous 
catheters of 16-20 G. Anesthesia and postoperative analgesia management will 
depend solely on the discretion of the responsible anesthesiologist, within the 
framework of multimodal anesthesia-analgesia. After anesthesia induction and 
double-lumen endotracheal tube placement, patients will be connected to the 
anesthesia machine, recruitment maneuvers will be performed with PEEP titration, 
and they will be mechanically ventilated applying the principles of protective 
mechanical ventilation. The correct placement of the endotracheal tube will be 
confirmed with fiberoptic bronchoscopy immediately after placement. A urinary 
catheter will be placed for hourly urine measurement, along with a thermometer. 
Intraoperatively, the total administered fluids, hourly urine output, type and dose of 
vasopressor medications, and blood pressure (SAP, DAP, MAP) will be recorded every 
15 minutes (unless a significant change occurs), along with arterial blood gases and 
lactate. Pulse contour analysis of cardiac output (CO,CI,SV,SVV) should be used, yet 
only for recording. 
Protective Mechanical Ventilation of One Lung: 
Ventilated lung: 
o Tidal volume (Vt): 4-5 ml/kg ideal body weight 
o Appropriate PEEP of 5-15 cmH2O, possible repeat of recruitment maneuver 
o Plateau pressure - PEEP: up to 15 cmH2O 
o Management of respiratory rate (RR) aiming for permitted mild hypercapnia 
(PaCO2 = 40-60 mmHg) 
o Modification of the I ratio to avoid air trapping and the emergence of PEEPi 
o Titration of FiO2 to achieve SpO2 = 88-92% 

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o Protection against hypoxic pulmonary vasoconstriction by avoiding 
vasodilators, hypoventilation, alkalosis, hypothermia, and if inhaled 
anesthetics are used, maintaining MAC < 1 
o Mechanical ventilation model: Volume Control- Auto Flow on the Perseus 
A500 and Atlan A350 machines from Drager available in the Anesthesia Clinic 
Non-ventilated lung with SpO2 < 88%: 
o Recruitment maneuvers with the use of PEEP if possible 
o Use of CPAP 
o FiO2 = 100% and cessation of one lung ventilation 
 
Control Group: 
Intraoperatively patients of the control group will be administered isotonic 
crystalloids (Lactated Ringer’s, Plasma-Lyte) at a rate of 3 mL/kg/h. 
VExUS-guided Group: 
VExUS Evaluation 
The VExUS evaluation will be performed pre- and immediately post-intubation before 
one-lung ventilation initiation. A trained anesthesiologist (will evaluate the patient 
according to the VExUS protocol, measuring the IVC diameter and performing 
Doppler analysis of the hepatic, portal, and renal veins. A VExUS score will be 
assigned as outlined in the section above.  
Ultrasound monitoring will be performed according to the VExUS protocol before 
positioning the patient in the lateral decubitus position. In patients with VExUS grade 
0, a bolus of 250-500 mL (approximately 3 mL/kg) will be administered, followed by 
the infusion of crystalloids at a rate of 3 mL/kg/h. The inferior vena cava (IVC) 
diameter will be measured three times: once prior to anesthesia induction, once 
immediately after intubation, and once before patient emergence from anesthesia. 
In patients with VExUS grade 1, no bolus will be given, and only a fluid infusion at 3 
mL/kg/h will be administered. In patients with VExUS grades 2 and 3, 10 mg of 
furosemide will be administered intravenously, followed by crystalloids infusion at a 
rate of 2 mL/kg/h. 
In both groups, blood losses will be replaced with a 5% albumin solution at a 1:1 
ratio, if hemorrhage exceeds 300 ml of blood. Transfusion will be administered to 
maintain hemoglobin levels at 9 mg/dL. Both groups will follow the same multimodal 
anesthesia-analgesia protocol, with restricted opioid use in accordance with the 
departmental routine. 
Intraoperative hypotension (systolic arterial pressure < 90 mmHg or a decrease > 20% 
from baseline) will be managed with titrated norepinephrine infusion. 
 
Post-Anesthesia Care Unit (PACU) 
Control Group: 
Fluid administration will continue at a rate of 3 mL/kg/h as per standard practice. 
VExUS-guided Group: 
VExUS ultrasound will be repeated postoperatively. In patients with VExUS grade 0, a 
bolus of 250-500 mL (approximately 3 mL/kg) will be administered, followed by the 
infusion of crystalloids at a rate of 3 mL/kg/h. In patients with grades 1 to 3, 10 mg of 
intravenous furosemide will be administered, followed by a fluid infusion at 3 
mL/kg/h and reassessment. 

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Patients will be monitored daily for the occurrence of postoperative respiratory 
complications as defined by the European Society of Anaesthesiology. Preoperative 
blood gas values (PaO2, PaCO2) will be measured as baseline, and postoperative 
blood gases will be collected on the 1st and 3rd postoperative days in the PACU. 
Oxygenation will be assessed using the PaO2/FiO2 ratio, and lactate levels will be 
measured concurrently. 
Additionally, for each patient, estimated glomerular filtration rate (eGFR) will be 
calculated preoperatively and on the 1st and 3rd postoperative days in PACU. To 
assess acute kidney injury (AKI), serum creatinine will be measured on the 1st and 
3rd postoperative days, and AKI diagnosis and classification will follow KDIGO (Kidney 
Disease Improving Global Outcomes) criteria. 
The following kidney injury biomarkers will also be measured: 
 
Serum and urine cystatin C 
 
Total urine protein and albumin 
 
Urine creatinine 
 
Kidney stress biomarkers TIMP-2 and IGFBP7 in urine, as described above, will be 
measured immediately postoperatively in the PACU or ward. 
These biomarkers will also be measured in the PACU and on the 1st and 3rd 
postoperative days. 
 
Statistical Analysis 
Data analysis will be performed using RStudio (R version 4.3.2). Descriptive statistics 
will include mean and standard deviation or median and interquartile range, 
depending on the distribution of each variable. 
The primary analysis will focus on the incidence of postoperative respiratory 
complications and acute kidney injury (AKI) between the two groups, using 
multivariable logistic regression. Adjustments for confounding factors will be made 
based on literature evidence linking these factors to the outcomes of interest. 
Changes in quantitative variables (e.g., postoperative oxygenation, urea, creatinine, 
urine albumin) will be analyzed using repeated measures ANOVA. For non-normally 
distributed variables, the appropriate non-parametric tests will be applied. Statistical 
significance will be set at α = 0.05. 
Sample size calculations, assuming a 10% incidence of AKI in the control group and 
5% in the intervention group, indicate that 115 patients per group are required for a 
power of 0.8 and a significance level of 0.05. An interim analysis will be conducted 
once 1/3 and 50% of the required sample size has been enrolled in the study. 
 
Researchers  
 Bogas Manouselis Alexandros, resident of Anesthesiology, University general 
hospital of Heraklion 
 Kouvidakis Dimitrios, resident of Anesthesiology, University general hospital 
of Heraklion 
 Fytanidis Nikolaos, resident of Rheumatology, University general hospital of 
Heraklion 
 Christofaki Maria, consultant of Anesthesiology, University general hospital of 
Heraklion 
 Stylianou Konstantinos, Associate Professor of Nephrology, University of Crete 

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 Nyktari Vasileia, Assistant Professor of Anesthesiology, University of Crete 
 Papaioannou Alexandra, Professor of Anesthesiology, University of Crete 
 
Contents  
1. Batchelor TJP, Rasburn NJ, Abdelnour-Berchtold E, Brunelli A, Cerfolio RJ, 
Gonzalez M et al. Guidelines for enhanced recovery after lung surgery: 
recommendations of the Enhanced Recovery After Surgery (ERAS) Society and 
the European Society of Thoracic Surgeons (ESTS). Eur J Cardiothorac Surg 
2019; 55:91–115.  
2. John M. Tarbell, Shear stress and the endothelial transport 
barrier, Cardiovascular Research, Volume 87, Issue 2, 15 July 2010, Pages 320–
330. 
3. Effect of the amount of intraoperative fluid administration on postoperative 
pulmonary complications following anatomic lung resections 
Arslantas, Mustafa Kemal et al. The Journal of Thoracic and Cardiovascular 
Surgery (2015), Volume 149, Issue 1, 314 - 321. 
4. Lohser, Jens MD, MSc, FRCPC*; Slinger, Peter MD, FRCPC†. Lung Injury After 
One-Lung Ventilation: A Review of the Pathophysiologic Mechanisms Affecting 
the Ventilated and the Collapsed Lung. Anesthesia & Analgesia 121(2):p 302-
318, August 2015. 
5. Driving pressure-guided ventilation and postoperative pulmonary 
complications in thoracic surgery: a multicentre randomised clinical trial  Park, 
MiHye et al.British Journal of Anaesthesia, Volume 130, Issue 1, e106 - e118 
6. Romagnoli S, Ricci Z. Postoperative acute kidney injury. Minerva Anestesiol. 
2015 Jun;81(6):684-96. Epub 2014 Jul 24. PMID: 25057935. 
7. Ishikawa, Seiji MD, PhD†,‡; Griesdale, Donald E. G. MD, MPH, FRCPC†,§,‖; Lohser, 
Jens MD, MSc, FRCPC†. Acute Kidney Injury After Lung Resection Surgery: 
Incidence and Perioperative Risk Factors. Anesthesia & Analgesia 114(6):p 
1256-1262, June 2012. 
8. Zarbock, Alexander MD*; Küllmar, Mira MD*; Ostermann, Marlies MD†; 
Lucchese, Gianluca MD†; Baig, Kamran MD†; Cennamo, Armando MD†; Rajani, 
Ronak MD†; McCorkell, Stuart MD†; Arndt, Christian MD‡; Wulf, Hinnerk MD‡; 
Irqsusi, Marc MD§; Monaco, Fabrizio MD‖; Di Prima, Ambra Licia MD‖; García 
Alvarez, Mercedes MD¶; Italiano, Stefano MD¶; Miralles Bagan, Jordi MD¶; 
Kunst, Gudrun MD#; Nair, Shrijit MD#; L’Acqua, Camilla MD**; Hoste, Eric MD††; 
Vandenberghe, Wim MD††; Honore, Patrick M. MD‡‡; Kellum, John A. MD§§; 
Forni, Lui G. MD‖‖; Grieshaber, Philippe MD¶¶; Massoth, Christina MD*; Weiss, 
Raphael MD*; Gerss, Joachim PhD##; Wempe, Carola PhD*; Meersch, Melanie 
MD*. Prevention of Cardiac Surgery–Associated Acute Kidney Injury by 
Implementing the KDIGO Guidelines in High-Risk Patients Identified by 
Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial. Anesthesia 
& Analgesia 133(2):p 292-302, August 2021. 
9. Beaubien-Souligny, W., Rola, P., Haycock, K. et al. Quantifying systemic 
congestion with Point-Of-Care ultrasound: development of the venous excess 
ultrasound grading system. Ultrasound J 12, 16 (2020). 

27-11-2024 
10. Magin, J., Wrobel, J., An, X., Acton, J., Doyal, A., Jia, S., … Grant, S. (2023). 
Venous Excess Ultrasound (VExUS) Grading to Assess Perioperative Fluid Status 
for Noncardiac Surgeries: a Prospective Observational Pilot Study. POCUS 
Journal, 8(2), 223–229. 
11. Longino, A., Martin, K., Leyba, K. et al. Correlation between the VExUS score 
and right atrial pressure: a pilot prospective observational study. Crit Care 27, 
205 (2023). 
12. Jammer I, Wickboldt N, Sander M, et al. Standards for definitions and use of 
outcome measures for clinical effectiveness research in perioperative 
medicine: European Perioperative Clinical Outcome (EPCO) definitions: a 
statement from the ESA-ESICM joint taskforce on perioperative outcome 
measures. Eur J Anaesthesiol 2015; 32: 88–105 
13. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work 
vexusGroup. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney 
inter., Suppl. 2012; 2: 1–138. 
14. V. R. Dharnidharka, C. Kwon, and G. Stevens, "Serum cystatin C is superior to 
serum creatinine as a marker of kidney function: a meta-analysis," (in eng), 
Am J Kidney Dis, vol. 40, no. 2, pp. 221-6, Aug 2002.