Hemodynamic Resuscitation Guided by Non-Invasive Mean Systemic Filling Pressure to Prevent Acute Kidney Injury in Septic Shock

Hemodynamic Resuscitation Guided by Non-Invasive Mean Systemic Filling Pressure to Prevent Acute Kidney Injury in Septic Shock: A Randomized Controlled Trial Integrating Renal Doppler Indices

The goal of this clinical trial is to evaluate the efficacy of a hemodynamic resuscitation protocol guided by the Venous Return Gradient (Pmsf - CVP), measured via the non-invasive arm cuff technique, in reducing the incidence of Acute Kidney Injury (AKI) in patients with septic shock compared to standard care and to assess the precision and reproducibility of the non-invasive arm cuff Pmsf measurement in the septic shock population and to determine the correlation between the systemic Venous Return Gradient and the renal micro-circulatory Resistance Index (RRI).

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Kidney Injury Due to Sepsis
• Intervention / Treatment: Other: Hemodynamic measurements during reduction in Norepinephrine and fluid boli.

Detailed Description

1. Sepsis-Associated Acute Kidney Injury: The Hemodynamic Paradox

   Sepsis-associated acute kidney injury (SA-AKI) represents a distinct pathophysiological entity characterized by macro-circulatory instability and micro-circulatory dysfunction. While historical resuscitation paradigms prioritized the restoration of Mean Arterial Pressure (MAP) to drive renal perfusion, recent evidence indicates that supra-physiological fluid administration leads to a state of fluid intolerance. The kidney is an encapsulated organ with limited compliance; therefore, elevations in Central Venous Pressure (CVP) are transmitted directly to the renal vein, increasing interstitial hydrostatic pressure. When renal interstitial pressure exceeds the pressure within the renal tubules, the net ultrafiltration gradient collapses, precipitating a decline in Glomerular Filtration Rate (GFR) independent of arterial inflow. This phenomenon, termed congestive nephropathy, suggests that the management of the venous outflow pressure is as critical as the management of arterial inflow pressure for renal preservation.

2. Physiology of Venous Return: The Mean Systemic Filling Pressure

   Cardiac output in septic shock is rate-limited by venous return. According to the Guytonian model of circulatory physiology, venous return is governed by the upstream driving pressure, defined as Mean Systemic Filling Pressure (Pmsf), relative to the downstream back-pressure, defined as Right Atrial Pressure (RAP or CVP). Venous Return = (Pmsf - CVP) / Resistance to Venous Return Pmsf is the theoretical pressure in the systemic vasculature when cardiac flow ceases and all pressures equilibrate. It is determined by the total blood volume and the compliance of the vascular bed. Blood volume is functionally divided into unstressed volume (which fills the vessels without generating pressure) and stressed volume (which generates wall tension and Pmsf). In the early phase of septic shock, inflammatory mediators cause profound venodilation, increasing vascular capacitance and shifting blood from the stressed to the unstressed compartment, thereby reducing Pmsf and venous return. Effective resuscitation requires the manipulation of this gradient. While fluid boluses increase Pmsf, they also elevate CVP. If the CVP rises disproportionately to the Pmsf, the gradient for venous return remains unchanged or diminishes, leading to organ congestion without flow improvement. Conversely, vasopressors such as norepinephrine recruit unstressed volume into stressed volume, elevating Pmsf and the venous return gradient with minimal impact on total fluid volume.

3. Why the Venous Return Gradient Approach is Superior for Renal Protection

   The standard hemodynamic approach often focuses on arterial inflow (MAP) while neglecting venous outflow, yet the kidney is uniquely sensitive to venous backpressure-a phenomenon termed "Congestive Nephropathy". Physiologically, renal blood flow depends on the trans-renal pressure gradient (MAP minus Renal Venous Pressure). In septic shock, while fluids may transiently improve MAP, they frequently elevate CVP (a surrogate for Renal Venous Pressure) to a greater degree, paradoxically narrowing the perfusion gradient. By guiding resuscitation based on the Venous Return Gradient (Pmsf - CVP), this protocol shifts the focus from simply "filling the tank" to "optimizing flow." This approach allows for the precise identification of patients who will benefit from vasopressors (which recruit unstressed volume to increase Pmsf without raising CVP) versus those who genuinely require volume, thereby preventing the iatrogenic renal tamponade caused by fluid overload.

4. Measurement Modalities: Invasive versus Non-Invasive

   The clinical application of Guytonian physiology has been hindered by the difficulty of measuring Pmsf at the bedside. The reference standard involves inspiratory hold maneuvers on a mechanical ventilator to manipulate intrathoracic pressure and extrapolate the zero-flow pressure. This invasive method requires deep sedation, neuromuscular blockade, pulmonary artery catheter and controlled ventilation, limiting its utility in patients with spontaneous respiratory effort. The transient stop-flow arm arterial-venous equilibrium technique offers a non-invasive alternative. This method utilizes a pneumatic arm cuff rapidly inflated above systolic pressure to arrest brachial blood flow. As the inflow stops, the arterial and venous pressures in the distal limb equilibrate to a static pressure that correlates highly with the central Pmsf. Validation studies demonstrate that this non-invasive method has a bias of less than 1 mmHg and a percentage error of approximately 30 percent compared to invasive methods, with high intra-observer precision. This technique allows for frequent, non-invasive assessment of the fluid status without interrupting ventilation or requiring paralysis.

5. Micro-Circulatory Assessment: The Renal Resistive Index

   Macro-hemodynamic optimization does not guarantee micro-circulatory perfusion. The Renal Resistive Index (RRI), measured via Doppler ultrasonography, provides a functional assessment of renal vascular impedance. It is calculated as (Peak Systolic Velocity - End Diastolic Velocity) / Peak Systolic Velocity. An RRI greater than 0.70 is pathologically elevated and correlates with intra-renal vasoconstriction, interstitial edema, and venous congestion. In the context of septic shock, the RRI serves as a hemodynamic stop signal. A rising RRI during fluid resuscitation indicates that the limit of renal preload reserve has been exceeded and that further fluid will result in congestive injury rather than perfusion benefit.

6. Novelty of Combining Non-Invasive Pmsf with Renal Resistive Index (RRI)

This study introduces a novel "Macro-to-Micro" hemodynamic integration by coupling systemic venous return parameters with organ-specific Doppler indices. While Pmsf provides a global assessment of the potential for venous return, it does not guarantee adequate tissue perfusion at the organ level. The Renal Resistive Index (RRI) fills this gap by acting as a real-time "barometer" of renal vascular stress. Previous studies have looked at these parameters in isolation; however, combining them creates a powerful safety loop: Pmsf guides the potential for flow (the "push"), while RRI confirms the tolerance of the renal bed (the "reception"). An elevated RRI (≥0.70) in the presence of an adequate Pmsf gradient serves as an immediate "stop signal," warning that further resuscitation is causing intra-renal congestion rather than perfusion, a decision-making tool unavailable in standard protocols, making this research a multimodal renal protection study.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mark Wageh Debais, assistant lecturer; Phone Number: +201032090320; Email: markwageh@aun.edu.eg

Study Locations

• Egypt
  • Asyut Governorate
    • Asyut, Asyut Governorate, Egypt, 71511
      • Assiut University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients (Age 18 years or older) admitted to the Intensive Care Unit.
• Primary diagnosis of Septic Shock defined according to the Third International Consensus Definitions for Sepsis (Sepsis-3): Sepsis with persisting hypotension requiring vasopressors to maintain MAP 65 mmHg or greater and having a serum lactate level greater than 2 mmol/L despite adequate volume resuscitation.
• Patients must be mechanically ventilated and sedated to ensure baseline hemodynamic stability.
• Presence of an invasive arterial catheter and a central venous catheter.

Exclusion Criteria:

• Known pre-existing chronic kidney disease (CKD Stage 4 or 5) or patients on chronic renal replacement therapy.
• Contraindications to arm cuff inflation, including upper limb trauma, -lymphedema, arteriovenous fistula, or peripheral vascular disease.
• Severe valvular heart disease, specifically severe tricuspid regurgitation, which invalidates CVP interpretation.
• Intra-abdominal hypertension (Intra-abdominal pressure greater than 15 mmHg) which mechanically alters venous return independent of blood volume.
• Moribund patients with a predicted mortality within 24 hours.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Group A: Standard Care (Control Group); Patients in this group will be managed according to the Surviving Sepsis Campaign (SSC) 2021 Guidelines
Active Comparator: Group B: Pmsf-Guided Resuscitation (Intervention Group).; The Pmsf will be measured using the transient stop-flow arm cuff method. A pneumatic tourniquet cuff is placed on the upper arm. The cuff is inflated to a pressure 50 mmHg higher than the systolic arterial pressure for a duration of 60 seconds. The invasive arterial pressure and the ipsilateral peripheral venous pressure are recorded. Three consecutive measurements are performed with a 5-minute interval. Measurement Technique (RRI): Renal Doppler will be performed using a convex probe. The inter-lobar arteries will be visualized, and RRI will be calculated. Therapeutic Algorithm: State 1: Low Gradient and Low Pmsf AND RRI ≤ 0.70: Absolute Hypovolemia. Administer fluid bolus (250-500 ml crystalloid) to recruit stressed volume. State 2: Low Gradient and High Pmsf AND RRI ≥ 0.70: Vasoplegia with relative hypovolemia. Initiate or increase Norepinephrine. State 3: Adequate Gradient but High RRI ≥0.70: Renal Congestion. Discontinue fluids immediately Consider administration of diuretics	Other: Hemodynamic measurements during reduction in Norepinephrine and fluid boli.; State 1: Low Gradient and Low Pmsf AND RRI ≤ 0.70: Absolute Hypovolemia. Administer fluid bolus (250-500 ml crystalloid) to recruit stressed volume. State 2: Low Gradient and High Pmsf AND RRI ≥ 0.70: Vasoplegia with relative hypovolemia. Initiate or increase Norepinephrine. State 3: Adequate Gradient but High RRI ≥0.70: Renal Congestion. Discontinue fluids immediately Consider administration of diuretics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the incidence of Acute Kidney Injury (AKI) in septic shock in both groups after 7 days of inclusion in the study. (AKI defined by KDIGO criteria: Creatinine increase ≥ 0.3 mg/dl within 48h OR ≥ 1.5x baseline within 7 days)	To compare the incidence of Acute Kidney Injury (AKI) in septic shock in both groups after 7 days of inclusion in the study. (AKI defined by KDIGO criteria: Creatinine increase ≥ 0.3 mg/dl within 48h OR ≥ 1.5x baseline within 7 days)	7 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Renal Resistive Index (RRI): Measured and recorded at T0 (Baseline), T24, T48, and T72 hours	72 hours
Serum Lactate Clearance: Measured and recorded at T0, T6, T12, and T24 hours.	24 hours
Serum Creatinine level: Measured and recorded daily for 7 days.	7 days
Cumulative Fluid Balance: Calculated and recorded daily for 7 days.	7 days
Vasopressor Free Days: Recorded at Day 28.	28 days
ICU Mortality: Recorded at Day 28.	28 days

Collaborators and Investigators

• Sponsor: Assiut University

Publications and helpful links

General Publications

• Kellum JA, Chawla LS, Keener C, Singbartl K, Palevsky PM, Pike FL, Yealy DM, Huang DT, Angus DC; ProCESS and ProGReSS-AKI Investigators. The Effects of Alternative Resuscitation Strategies on Acute Kidney Injury in Patients with Septic Shock. Am J Respir Crit Care Med. 2016 Feb 1;193(3):281-7. doi: 10.1164/rccm.201505-0995OC. PMID: 26398704; PMCID: PMC4803059.
• Chawla LS, Davison DL, Brasha-Mitchell E, et al. Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care. 2013;17(5):R207.
• Higuera-Juan F, Blanco-García R. Renal Resistive Index as a Target for Hemodynamic Management in Septic Shock. Med Intensiva. 2019;43(8):499-500.
• Bossard G, Bourgoin P, Corbeau J, Huntzinger J, Beydon L. Early detection of postoperative acute kidney injury by Doppler renal resistive index in cardiac surgery with cardiopulmonary bypass. Br J Anaesth. 2011;107(6):891-8.
• Liu J, Xie H, Ye Z, Li F, Wang L. Incidence and Risk Factors of Sepsis-Associated Acute Kidney Injury: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2020;7:599.
• KDIGO Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1-138.
• Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021;47(11):1181-1247.
• Rozemeijer S, de Wit N, de Grooth HJ, et al. Renal perfusion pressure and renal resistive index in patients with septic shock. Ann Intensive Care. 2019;9:126.
• Darmon M, Schortgen F, Vargas F, et al. Diagnostic accuracy of Doppler renal resistive index for reversibility of acute kidney injury in critically ill patients. Intensive Care Med. 2011;37:68-76.
• Schnell D, Deruddre S, Harrois A, et al. Renal resistive index better predicts the occurrence of acute kidney injury than cystatin C. Shock. 2012;38(6):592-7.
• Viazzi F, Leoncini G, Derchi LE, Pontremoli R. Ultrasound Doppler renal resistive index: a useful tool for the management of the hypertensive patient. J Hypertens. 2014;32(1):149.
• Le Dorze M, Bouglé A, Deruddre S, Duranteau J. Renal Doppler ultrasound: a new tool to assess renal perfusion in critical illness. Shock. 2012;37(4):360-5.
• Aya HD, Rhodes A, Fletcher N, Grounds RM, Cecconi M. Transient stop-flow arm arterial-venous equilibrium pressure measurement: determination of precision of the technique. J Clin Monit Comput. 2016;30:55-61.
• Wijnberge M, Sindhunata DP, Pinsky MR, Vlaar AP, Ouweneel E, Jansen JR, et al. Estimating mean circulatory filling pressure in clinical practice: a systematic review comparing three bedside methods in the critically ill. Ann Intensive Care. 2018;8:73.
• Adda I, Lai C, Teboul JL, Guérin L, Gavelli F, Monnet X. Norepinephrine potentiates the efficacy of volume expansion on mean systemic pressure in septic shock. Crit Care. 2021;25:302.
• Malbrain MLNG, Van Regenmortel N, Saugel B, et al. Principles of fluid management and stewardship in septic shock: it is time to consider the four D's and the four phases of fluid therapy. Ann Intensive Care. 2018;8:66.
• Cecconi M, Aya HD, Geisen M, Ebm C, Fletcher N, Grounds RM, et al. Changes in the mean systemic filling pressure during a fluid challenge in postsurgical intensive care patients. Intensive Care Med. 2013;39:1299-305.
• Guérin L, Teboul JL, Persichini R, Dres M, Richard C, Monnet X. Effects of passive leg raising and volume expansion on mean systemic pressure and venous return in shock in humans. Crit Care. 2015;19:411.
• Maas JJ, Geerts BF, van den Berg PC, Pinsky MR, Jansen JR. Assessment of venous return curve and mean systemic filling pressure in postoperative cardiac surgery patients. Crit Care Med. 2009;37(3):912-8.
• Magder S. Volume and its relationship to cardiac output and venous return. Crit Care. 2016;20:271.
• Guyton AC, Polizo D, Armstrong GG. Mean circulatory filling pressure measured immediately after cessation of heart pumping. Am J Physiol. 1954;179:261-7.
• Persichini R, Lai C, Teboul JL, Adda I, Guérin L, Monnet X. Venous return and mean systemic filling pressure: physiology and clinical applications. Crit Care. 2022;26(1):150.
• Kopitkó C, Medve L, Gondos T. The value of renal resistive index in the assessment of acute kidney injury in septic shock: an observational cohort study. BMC Anesthesiol. 2019;19:210.
• Prowle JR, Ishikawa K, May CN, Bellomo R. Renal blood flow, fractional excretion of sodium and acute kidney injury: time for a new paradigm? Curr Opin Crit Care. 2020;26(6):546-552.
• Ostermann M, Hall A, Crichton S. Low mean perfusion pressure is a risk factor for progression of acute kidney injury in critically ill patients. BMC Nephrol. 2017;18:151.
• Meyhoff TS, Moller MH, Hjortrup PB, et al. Lower vs Higher Fluid Volumes During Initial Management of Sepsis: A Systematic Review with Meta-Analysis and Trial Sequential Analysis. Chest. 2020;157(6):1478-1496.
• Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, and clinical outcomes. Kidney Int. 2019;96(5):1083-1099.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: March 15, 2026
• First Submitted That Met QC Criteria: March 15, 2026
• First Posted (Actual): March 18, 2026

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 15, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: acute kidney injury; sepsis; resuscitation; renal resistive index; mean systemic filling pressure
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Acute Kidney Injury; Sepsis; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amines; Catechols; Phenols; Benzene Derivatives; Alcohols; Amino Alcohols; Ethanolamines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Norepinephrine
• Other Study ID Numbers: Mean Systemic Filling Pressure

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No