Study setting

Eligible recruiting sites must have a proven history of performing major elective gastrointestinal surgeries in adult patients. Additionally, they should have the capability to implement hemodynamic therapy with HPI monitoring and a demonstrated track record in participating in interventional research. Although this study is a national initiative from the SEDAR, centers from different countries are also invited to participate. The complete list of participating centers can be found at ClinicalTrials.org.

Eligibility criteria

This study will include patients over 65 years of age and/or physical condition ASA III or IV. All participants must be scheduled for major elective abdominal surgery (general, urologic, or gynecological surgery), using either a laparoscopic or open surgical approach. A surgery is deemed major if it meets at least one of the following criteria: an expected duration > 2 h or an anticipated blood loss > 15% of the patient's total blood volume.

Patients will be excluded from the study if they have stage 4 or 5 chronic kidney disease (eGFR < 15 mL/min); received a kidney transplant in the past 12 months; are diagnosed with glomerulonephritis, interstitial nephritis, or vasculitis; have anuria at the time of inclusion; have pre-existing AKI; underwent recent renal replacement therapy (RRT) within the past 90 days; require renal replacement at the time of inclusion; are participating in another trial investigating a drug or intervention affecting kidney function; have atrial fibrillation or known cardiac shunts; are undergoing urgent surgery; are pregnant or lactating; are expected to die within 30 days; experienced acute myocardial ischemia or acute pulmonary edema in the previous 30 days; or have any contraindication to low dose of vasoactive or inotropic medication.

Only eligible patients who meet all the inclusion criteria and none of the exclusion criteria and provide voluntary written informed consent will be included in the study.

Who will take informed consent?

Before trial enrollment, each participant will provide written informed consent. This procedure includes giving an information sheet to the patient, an associated consent form, and a thorough explanation of the trial’s objectives, methods, potential benefits, and risks. Patients unable to give or withhold informed consent will be not included in the trial. For eligible patients who do not participate in the trial, a detailed record including reasons for their non-participation will be kept.

Additional consent provisions for collection and use of participant data and biological specimens

No additional consent provisions are required for the collection and use of data from participants and biological specimens in ancillary studies.

InterventionsExplanation for the choice of comparators

In this study, the chosen comparator is standard intraoperative blood pressure management, grounded in conventional monitoring and clinical judgment. This choice is well-founded considering the prevailing clinical practices and the need to evaluate the potential benefits of HPI-guided hemodynamic management. The use of standard clinical judgment and conventional monitoring devices is common practice in the participating centers for managing intraoperative blood pressure during elective major abdominal surgeries. This practice involves intermittent or invasive or not invasive continuous blood pressure measurements and clinical assessment by anesthesiologists or healthcare providers. These professionals make real-time decisions on fluid and vasoactive administration based on their evaluations.

By selecting this conventional approach as the comparator, we aim to determine if HPI-based hemodynamic management, which involves a protocolized approach to administering intravenous fluids, inotropic, and/or vasoactive drugs, leads to improved clinical outcome. Specifically, this study aims to demonstrate if HPI guidance significantly reduces the incidence of moderate to severe AKI within 30 days post-surgery when compared to standard clinical judgment and conventional monitoring.

Noteworthy, the control group receiving standard care allows clinicians to exercise their judgment and manage hemodynamics as they deem fit. This might introduce variations across different centers. The study’s comparator choice aims to robustly assess the HPI-based intervention while reflecting the current clinical context and variations in practice across participating centers. By comparing the HPI-based approach with this conventional method, we seek to determine if HPI guidance offers a valuable improvement in clinical practice.

Intervention description

The trial intervention period will begin at the start of surgery, with the skin incision, and will end with the completion of surgery and closure of the skin.

Patient care protocols have been deliberately kept broad in their definition to prevent either overly conservative or misaligned clinical practices.

Control group

Patients in this group will undergo treatment as per standard clinical practice. The administration of fluids, vasoconstrictors, and/or inotropic drugs will be at the discretion of the treating clinician. These decisions may be guided by parameters such as heart rate, arterial pressure, diuresis, serum lactate levels, and base excess. While clinicians in the control group can opt to follow a GDHT algorithm by monitoring cardiac output or other hemodynamic variables, the HPI parameter and other hemodynamic variables available from the AcumenIQ sensor will not be integrated into their strategy. In the event of using this technology during the trial intervention period in any patients from the control group, this will be recorded as a protocol violation.

Intervention group

The intervention will begin with the induction of general anesthesia and continue until surgery completion. Hemodynamic management will be based on the HPI and advanced functional hemodynamic variables provided by the Hemosphere platform and the AcumenIQ sensor. Non-invasive cuff (AcumenIQ for ClearSight, Edwards Lifesciences, Irvine, USA) or the invasive arterial pressure AcumenIQ sensor (Edwards Lifesciences) could be selected based on individual patient needs. Additionally, both systems offer additional hemodynamic variables such as stroke volume variation (SVV), arterial dP/dtmax, and dynamic arterial elastance (Eadyn), to help identify the most common causes of hypotension.

Before initiating continuous blood pressure monitoring and assessing other hemodynamic variables, a maximum of 500 mL of intravenous fluid will be administered. If central venous pressure (CVP) is unavailable, a default value of 5 mmHg will be used to calculate systemic vascular resistance (SVR). The hemodynamic protocol is designed to alert for intervention when the HPI value surpasses 80, although lower values are also considered as a progressive instability warning before reaching that threshold. Once the HPI exceeds 80, therapeutic intervention is advised, involving the administration of fluids and/or vasopressors/inotropes, and is then recommended based on the values of SVV, Eadyn, dP/dtmax, and SVR, as illustrated in Fig. 1.

Fig. 1

When the hemodynamic algorithm recommends fluid administration, patients will receive a 250-mL fluid bolus of a balanced crystalloid solution. Ephedrine, administered in bolus doses of 5–10 mg, will be the vasopressor of choice. If continuous infusion is necessary, norepinephrine will be used, always in alignment with the hemodynamic algorithm. Data collection and follow-up for such participants will be performed as usual. All other medical decisions will be the responsibility of the attending physician.

Both study groups will undergo general or combined anesthesia, involving intravenous anesthetic induction and neuromuscular blockade. The choice of anesthesia type will be at the discretion of the attending anesthesiologist for pragmatic reasons.

The selection of the neuraxial analgesia technique, either epidural or intradural, will be based on the preference of the anesthesiologist prior to induction. Intraoperatively, fundamental measures will be implemented to maintain oxygen saturation above 94%, normothermia (body temperature > 36 °C), and a heart rate below 100 beats per minute. Mechanical ventilation will maintain an inspired FiO2 of 60%, targeting a PaCO2 range of 35–45 mmHg, with a tidal volume of 8 ml/kg of ideal body weight and a positive end-expiratory pressure (PEEP) of 4–6 mmHg. Basic monitoring will involve three-lead electrocardiography, pulse oximetry, and at least one peripheral intravenous catheter. Bispectral index (BIS) monitoring, targeting 40–60, will be maintained with sevoflurane or propofol. A maintenance-balanced crystalloid solution will be administered at 1–3 ml/kg/h for laparoscopic procedures and 5–7 ml/kg/h for open surgeries.

Postoperatively, balanced fluid therapy is recommended to meet ion and glucose requirements, with quantities ranging from 1.75 to 2.75 L every 24 h, determined by the responsible clinician. The decision to initiate oral tolerance will also be at the attending clinician’s discretion.

Criteria for discontinuing or modifying allocated interventions

For participants in the intervention group undergoing hemodynamic management guided by the HPI, the potential side effects or adverse reactions from pharmacological components of the hemodynamic protocol warrant careful monitoring. Specific criteria based on safety considerations have been established to modify or discontinue the intervention:

Tachycardia: Should a participant develop significant tachycardia directly linked to the administration of catecholamines or inotropes as per intervention’s hemodynamic management, their well-being and comfort must be prioritized. In such instances, the intervention might require modification of discontinuation to effectively address the tachycardic response.

Allergic Reactions: If a participant manifests allergic reactions to any of the pharmacological components of the intervention, this must be halted immediately. Addressing the allergic reactions while ensuring participant safety is paramount. Such occurrences should be documented as adverse events in the trial record.

Strategies to improve adherence to interventions

Following an initial meeting between the principal investigators and all local lead investigators, training sessions will be conducted at the partner hospitals. These sessions will cover the process of randomization, enrollment, data acquisition, and treatment strategies. Recruitment targets will be closely monitored, and regular feedback will be provided to the participating sites to ensure active management and adherence throughout the trial.

Relevant concomitant care permitted or prohibited during the trial

During the HYT study, patients are not allowed to participate in another clinical trial involving modifications to perioperative patient management.

Provisions for post-trial care

Patients participating in this study benefit from indemnity against negligent harm through the standard Spanish National Health Service Indemnity arrangements. It’s pertinent to note that this trial is classified as a low-intervention level clinical trial. Within the hemodynamic management protocol, medications are dispensed strictly according to their product data sheet and consistent with the standard clinical practice. The patient management within this study does not introduce any novel risks, and any potential risk aligns with those inherent in routine clinical care.

Healthcare professionals responsible for conducting this trial are either covered by individual or collective professional civil liability insurance or have an equivalent financial guarantee provided from the healthcare institution where the trial will be conducted. For clinical trials classified as low-intervention level clinical trials, there is no obligation for additional insurance coverage. This is because any potential damage arising from the clinical trial is already covered by the civil liability insurance—whether individual or collective—of the healthcare center or institution supervising the clinical trial. The trial sponsor will provide a certificate from the institution’s representative, confirming that the insurance policy of the healthcare center or organization adequately covers clinical trials of this nature. For further information, please refer to the following resource: https://www.aemps.gob (in Spanish).

Outcomes Primary endpoint

The primary outcome is the occurrence of moderate or severe AKI (according to KDIGO Stage 2–3 criteria [8]) within 7 days after surgery (Table 2).

Secondary endpoints

Secondary outcomes:

1.

RRT requirement and duration: Occurrence within 30 days post-surgery.

2.

Postoperative Complications defined according to the European Perioperative Clinical Outcome (EPCO) [9] definitions within 30 days post-surgery.

3.

Reoperation within 30 days post-surgery.

4.

Unplanned Intensive Care Admission for the treatment of one or more complications within 30 days of randomization.

5.

30-day mortality.

Planned process measures:

1.

Duration of hospital stay (number of days from randomization until hospital discharge).

2.

Duration of critical care stay (number of days from randomization until hospital discharge).

Participant timeline

Participants will be enrolled in the study during the pre-study period, which includes both the screening and recruitment of eligible individuals. Once enrolled, a baseline assessment will be conducted, during which informed consent will be obtained, and baseline data will be collected.

On day 0, participants will undergo randomization. The study intervention will start with the onset of the surgery (skin incision) and conclude upon its completion (skin closure). From day 0 through the duration of their hospital stay, participants will be evaluated for the primary and secondary outcomes.

On day 30, participants will return for a follow-up evaluation, where 30-day outcomes will be assessed, and the study will be completed (Table 1).

Table 1 Participant timelineSample size

To detect an absolute reduction of 5% in the incidence of AKI within 30 days after surgery, from an assumed baseline rate of 10% to a target rate of 5%, with a 1:1 allocation ratio, and maintaining an overall type I error rate of 5%, with an anticipated dropout rate of 10%, a total of 958 patients (479 per arm) are required to achieve an 80% statistical power [10].

Recruitment

To ensure adequate participant enrollment, our strategies include ensuring the attainment of the target number of appropriate recruitment sites, maintaining coordinated national leadership, actively engaging local anesthesiologists to support the screening and execution of the trial, and carefully selecting sites with highly experienced local investigators proficient in HPI utilization and well-equipped research teams.