Administrative information
Title {1} | HYPOTENSION PREDICTION INDEX GUIDED GOAL DIRECTED THERAPY TO REDUCE POSTOPERATIVE ACUTE KIDNEY INJURY DURING MAJOR ABDOMINAL SURGERY: STUDY PROTOCOL FOR A MULTICENTER RANDOMIZED CONTROLLED CLINICAL TRIAL |
Trial registration {2a and 2b}. | The trial has been registered on ClinicalTrials.gov under the identifier NCT05569265 |
Protocol version {3} | Version 1, April 2022 |
Funding {4} | No funding |
Author details {5a} | Javier Ripollés-Melchor 1–3, Laura Carrasco-Sánchez 2,4–6, José L. Tomé-Roca2,7, César Aldecoa2,8, Andres Zorrilla Vaca2,9, Juan V. Lorente-Olazábal2,10, María J. Colomina2,11, Ana Pérez2,12, Juan I. Jiménez-López2,13, Rosalía Navarro-Pérez2,14,Alfredo Abad-Gurumeta1,3 Manuel I. Monge-García 2,15 on behalf of the HYT Study Group Infanta Leonor University Hospital, Madrid, Spain 2.Fluid Therapy and Hemodynamic Monitoring Group of the Spanish Society of Anesthesiology and Critical Care (SEDAR) 3.Universidad Complutense de Madrid, Madrid, Spain 4.Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Spain 5.Doctoral Program in Medicine and Biomedical Sciences, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain 6.Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central (IRIS-CC), Vic, Spain 7.Virgen de las Nieves University Hospital, Granada, Spain 8- Río Hortega University Hospital, Valladolid, Spain 9.Brigham and Women's Hospital, Boston, USA 10.Juan Ramón Jiménez University Hospital, Huelva, Spain 11.Bellvitge University Hospital, Barcelona, Spain 12.Elche University Hospital, Elche, Spain 13.Virgen del Rocío University Hospital, Seville, Spain 14.Clinico San Carlos University Hospital, Madrid, Spain 15.Jerez de la Frontera University Hospital, Jérez de la Frontera, Spain |
Name and contact information for the trial sponsor {5b} | Javier Ripollés-Melchor Ripo542@gmail.com SEDAR Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor C/ José Abascal n° 46, 1°A, 28003 Madrid Tel.: 914 419 099 Email: secretaria@sedar.es |
Role of sponsor {5c} | The sponsor (SEDAR) played no part in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication |
Introduction
Background and rationale {6a}
Objectives {7}
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
Eligibility criteria {10}
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Criteria for discontinuing or modifying allocated interventions {11b}
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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.
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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 {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary endpoint
Secondary endpoints
Participant timeline {13}
Event/Visit | Revision | Preoperative | Surgery | Hospital discharge | 30 days after IQ |
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Criteria of inclusion/exclusion | x | ||||
Informed consent | x | ||||
Demographic information | x | ||||
Medical history | x | ||||
Height and weight | x | ||||
Randomization | x | ||||
Intraoperative | x | ||||
Hemodynamic algorithm | x | ||||
Review of medical notes | x | x | x | ||
ICU days and hospitalization | x | ||||
Follow-up | x | ||||
Notification of adverse effects | x | x | x |
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Age |
Sex |
Height |
Weight |
ASA physical score |
Diagnosis of chronic lung disease (COPD, asthma, interstitial lung disease) |
Diagnosis of ischemic heart disease |
Diagnosis of diabetes mellitus |
Diagnosis of heart failure |
Diagnosis of liver cirrhosis |
Diagnosis of active cancer (indication for surgery Y/N) |
Diagnosis of previous stroke or transient ischemic attack |
Current smoker (has smoked in the last 14 days) |
Preoperative hemoglobin |
Intraoperative Variables |
Total fluid therapy during surgery: types and total amounts (ml) |
Cumulative dose during the intraoperative period of vasoactive agents: specify by drugs used (mg) |
Accumulated dose during the intraoperative period of ionotropic drug in case of indication (mg) |
Total intraoperative diuresis (ml) |
Estimated bleeding (ml) |
Transfusion of total blood products during surgery |
Use of cardiac output monitor |
Using beat-to-beat blood pressure measurement |
Related to the Intervention |
Hospital admission date |
Surgery date |
Type of anesthesia with which the intervention is performed |
Surgical technique |
Anesthesia duration |
Duration of surgical intervention |
AKI > I at 7 days |
Postoperative variables, complications, and mortality |
Presence of postoperative treatment with: diuretics, ACE inhibitors, angiotensin II receptor blocker (ARB), beta-blockers, NSAIDs, and other postoperative nephrotoxic drugs, as well as daily fluid therapy |
Length of hospital stay |
30-day mortality |
Tracking Data |
24-h and 30-day adverse cardiac events (≥ Clavien-Dindo grade II) |
Other 30-day postoperative complications |
Red blood cell transfusion within 30 days of surgery |
Endoscopic or radiological intervention within 30 days of randomization |
Reoperation within 30 days of randomization |
Unplanned intensive care admission to treat one or more complications within 30 days of randomization |
Prolonged scheduled intensive care admission due to one or more complications within 30 days of randomization |
Invasive mechanical ventilation after leaving the operating room, within 30 days of randomization |
Date of death (if applicable) |
Complication | Definition | Severity scale |
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Acute kidney injury (on 8 to 30 days) | - Mild: Serum creatinine elevation 1.5–1.9 times above baseline in 7 days or ≥ 0.3 mg/dL (30 μmol/L) in 48 h. Diuresis ≤ 0.5 ml/kg/h for 6–12 h - Moderate: Elevation of serum creatinine 2.0–2. 9 times above baseline in 7 days. Diuresis ≤ 0.5 ml/kg/h for 12 h - severe:Elevation of serum creatinine 3 times above baseline in 7 days or increase in serum creatinine ≥ 4.0 mg/dL (≥ 350 μmol/L) with an acute elevation of > 0.5 mg/dL (> 50 μmol/L) or initiation of renal replacement therapy. Diuresis ≤ 0.3 ml/kg/h for 24 h or anuria for 12 h | Included in the definition |
Acute respiratory distress syndrome (ARDS) | Respiratory failure, or new or worsening respiratory symptoms, beginning within the first week after surgery; and a chest x-ray or CT scan demonstrating bilateral opacities not fully explained by effusions, lobar/pulmonary collapse, or nodules; and respiratory failure is not fully explained by heart failure or fluid overload Needs objective evaluation (e.g., echocardiography) to exclude hydrostatic edema if no risk factor is present | - Mild: PaO2:FiO2 between 200 and 300 mmHg with PEEP or CPAP ≥ 5 cmH2O - Moderate: PaO2:FiO2 between 100 and 200 mmHg and PEEP ≥ 5 cmH2O - Serious: PaO2:FiO2 ≤ 100 mmHg with PEEP ≥ 5 cmH2O |
Pneumonia | Chest radiographs showing new or progressive and persistent infiltrates, or consolidation, or cavitation, and at least one of the following: a) Fever (> 38 °C) with no other known cause b) Leukopenia (< 4000 leukocytes/mm3) or leukocytosis (> 12,000 leukocytes/mm3) c) In adults > 70 years, altered mental status without any other recognized cause …and at least two of the following: - New appearance of purulent sputum or change in sputum characteristics, or increased respiratory secretions, or increased suction demands - New onset or worsening cough, or dyspnea, or tachypnea - Râles or bronchial breath sounds - Worsened gas exchange (hypoxia, increased oxygen, or ventilator demand) | - Mild: it produces only temporary damage and would generally not require specific clinical treatment - Moderate: more serious complication, but one that does not usually cause permanent damage or functional limitation. Usually requires clinical treatment - Serious: produces a significant prolongation of hospital stay and/or permanent functional limitation or death. It almost always requires clinical treatment |
Cardiac arrest | Cessation of cardiac mechanical activity, as confirmed by the absence of signs of circulation. ECG changes may confirm cardiac arrest | None: Binary (yes/no) |
Arrhythmia | Electrocardiographic (ECG) evidence of abnormal heart rhythm | - Mild: it produces only temporary damage and would generally not require specific clinical treatment - Moderate: more serious complication, but one that does not usually cause permanent damage or functional limitation. Usually requires clinical treatment - Serious: produces a significant prolongation of hospital stay and/or permanent functional limitation or death. It almost always requires clinical treatment |
Deep venous thrombosis | A new blood clot or thrombus within the venous system. A systematic review is required in trials in which DVT is an important outcome measure. Appropriate diagnostic tests include ultrasonography, venography, computed tomography, or magnetic resonance imaging | |
Stroke | Embolic, thrombotic, or hemorrhagic cerebral event with persistent residual motor, sensory, or cognitive dysfunction (e.g., hemiplegia, hemiparesis, aphasia, sensory deficit, impaired memory) | |
Pulmonary edema | Evidence of fluid accumulation in the alveoli due to impaired cardiac function | - Mild: it produces only temporary damage and would generally not require specific clinical treatment - Moderate: more serious complication, but one that does not usually cause permanent damage or functional limitation. Usually requires clinical treatment - Serious: produces a significant prolongation of hospital stay and/or permanent functional limitation or death. It almost always requires clinical treatment |
Pulmonary embolism | A new blood clot or thrombus within the pulmonary arterial system Guidance: Appropriate diagnostic tests include scintigraphy and computed tomography angiography. Measurement of plasma D-dimer is not recommended as a diagnostic test in the first three weeks after surgery | |
Surgical site infection (superficial) | Infection involving only the superficial surgical incision, meeting the following criteria: 1) Infection occurs within 30 days after surgery and 2) Involves only the skin and subcutaneous tissues of the incision and 3) The patient has at least one of the following: a) Purulent drainage from the superficial incision b) Organisms isolated from a fluid or tissue culture obtained aseptically from the superficial incision and at least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness or warmth, or superficial incision deliberately opened by the surgeon and is culture positive or not cultured. A negative culture does not meet this criterion c) Diagnosis of an incisional surgical site infection by a surgeon or GP | |
Surgical site infection (deep) | An infection involving superficial and deep parts of the surgical incision and meeting the following criteria: 1) Infection occurs within 30 days after surgery if a surgical implant is not left or 1 year if the implant is in place and 2) The infection appears to be related to the surgical procedure and involves the soft tissues deep to the incision (for example, the fascial and muscular layers) and 3) The patient has at least one of the following: a) Purulent drainage from the deep incision but not from the organ/space component of the surgical site b) The surgeon opens a deep incision spontaneously or is deliberately opened and has a positive culture or no cultures were performed while the patient has at least one of the following signs or symptoms of infection: fever (> 38 °C) or localized pain or sensitivity. A negative cultural finding does not meet this criterion c) An abscess or other evidence of infection involving the deep incision is found on direct examination, during surgery, or on histopathological or radiological examination d) Diagnosis of a deep incisional infection at the surgical site by a surgeon or treating physician | - Mild: it produces only temporary damage and would generally not require specific clinical treatment - Moderate: more serious complication, but one that does not usually cause permanent damage or functional limitation. Usually requires clinical treatment - Serious: produces a significant prolongation of hospital stay and/or permanent functional limitation or death. It almost always requires clinical treatment |
Surgical site infection (organ/space) | An infection that involves any part of the body excluding the fascia or muscle layers and meets the following criteria: 1) Infection occurs within 30 days after surgery and 2) The infection appears to be related to the surgical procedure and involves any part of the body, excluding the incision in the skin, fascia, or muscle layers, that is opened or manipulated during the surgical procedure, and 3) The patient has at least one of the following: a) Purulent drainage from a drain that is placed through an incision in the organ/space b) Organisms isolated from aseptically obtained fluid or tissue culture in the organ/space c) An abscess or other evidence of infection involving the organ/space found on direct examination, during reoperation, or on histopathological or radiological examination d) Diagnosis of an organ/space surgical site infection by a surgeon or treating physician | |
Bacteremia | An infection that is not related to an infection at another site and that meets any of the following criteria: 1) The patient has a recognized pathogen cultured from blood cultures that is not related to an infection at another site 2) The patient has at least one of the following signs or symptoms: fever (> 38 °C), chills, or hypotension and at least one of the following: a) Common skin contaminant cultured from two or more blood cultures drawn on separate occasions b) Common skin contaminant that is cultured from at least one blood culture from a patient with an intravascular line, and antimicrobial therapy is started by a physician c) Positive blood antigen test | - Mild: Causes only temporary damage and generally does not Mild: Causes only temporary damage and would generally not require specific clinical treatment - Moderate: more serious complication, but one that does not usually cause permanent damage or functional limitation. Usually requires clinical treatment - Serious: produces a significant prolongation of hospital stay and/or permanent functional limitation or death. It almost always requires clinical treatment |
Myocardial infarction | Increased plasma cardiac biomarker values (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit and at least one of the following criteria: - Symptoms of ischemia - New or suspected new ST-segment or T-wave ECG changes or new left bundle branch block - Development of pathological Q waves on ECG - Radiological or echocardiographic evidence of new loss of viable myocardium or new regional wall motion abnormality - Identification of an intra-coronary thrombus on angiography or autopsy | |
Urinary tract infection | An infection associated with at least one of the following signs or symptoms that must be identified within a 24-h period: fever (> 38 °C), urgency, frequency, dysuria, suprapubic tenderness, costovertebral angle pain, or tenderness without other cause recognized and a positive urine culture of ≥ 105 colony-forming units/mL with no more than two species of microorganisms | |
Paralytic ileus | Not tolerate solid food or bowel movements for three or more days after surgery | |
Delirium | Delirium can be identified using the Intensive Care Delirium Screening Checklist Patients are first evaluated for an altered level of consciousness. Those with a mild or moderate response to stimulation, an exaggerated response to stimulation, or normal wakefulness are fully evaluated. Patients receive one point for each of the following criteria: inattention, disorientation, hallucinations, psychosis, agitation or psychomotor retardation, inappropriate language or mood, sleep/wake cycle disturbance, or fluctuating symptoms | Built into the definition |
Postoperative hemorrhage | Blood loss that occurs within 72 h of the end of surgery, which would normally result in a blood transfusion | - Mild: any sign of bleeding (any bleeding that is more than expected, including bleeding only identified on imaging), that does not meet the criteria for moderate-severe type, but requires at least one of the following: • Non-surgical medical intervention by a healthcare professional (examples include stopping antiplatelet, antithrombotic medications, compression at bleeding site, use of reversal medications such as: protamine and vitamin k) • Requires hospitalization or higher level of care • It requires rapid evaluation with tests such as: complete blood count, urinalysis, coagulation tests, endoscopy and tomography - Moderate: • Bleeding with a decrease in hemoglobin of ≥ 3 to < 5 g/dl (related to bleeding) • Any need for transfusion due to obvious bleeding • Decrease in hemoglobin ≥ 5 g/dl (related to bleeding) • Bleeding that requires surgical intervention for its control • Bleeding requiring the use of vasoactive agents - Severe: Transfusion of ≥ 5 units of red blood cells, in a period of 48 h. fatal bleeding |
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Data transmission and editing
Data discrepancy inquiries and reports
Security and data back-up
Study status reports
Confidentiality {27}
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Interim analyses {21b}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant-level data, and statistical code {31c}
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
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Design and conduct of HYT
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Preparation of protocol and revisions
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Preparation of investigators brochure (IB) and CRFs [Case Report Forms]
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Organizing steering committee meetings
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Publication of study reports
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Agreement of final protocol
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Reviewing the progress of the study and if necessary agreeing to changes to the protocol and/or investigators brochure to facilitate the smooth running of the study.
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Study planning
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Organization of steering committee meetings
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Responsible for trial master file
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Budget administration and contractual issues with individual centers
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Advice for lead investigators
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Assistance with ethics committee applications
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Data verification
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Maintenance of trial IT system and data entry
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Data verification
Lead Investigators
Explanation
Composition of the data monitoring committee, its role and reporting structure {21a}
Protocol adherence monitoring and safety monitoring
Adverse event reporting and harms {22}
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Reviewing the investigator’s assessment of all adverse events and documenting their severity and relationship to the investigational product in case of any disagreement between the principal investigator(s) and the sponsor. Both assessments should be communicated to the relevant parties.
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Reviewing all product deficiencies and determining if they could have caused a serious adverse product effect, with the option to communicate differing assessments to the concerned parties.
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Reporting or ensuring that the principal investigator(s) report all serious adverse events and product deficiencies that could have led to a serious adverse product effect.
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Notifying regulatory authorities of all serious adverse events and product deficiencies that could have caused a serious adverse product effect within the required timeframe as mandated by national regulations.
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Evaluating whether the risk analysis necessitates an update and assessing whether corrective or preventive actions are needed for serious adverse product effects and product deficiencies that could have caused serious adverse product effects.
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Record each adverse event and observed product deficiency along with an assessment, and promptly notify the sponsor of all serious adverse events
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Promptly notify the sponsor of all serious adverse events and product deficiencies that could have caused a serious adverse product effect, except for those specified in this clinical investigation plan as events not requiring immediate communication
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Provide the sponsor, upon request, with additional information related to the safety report of a specific adverse event
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Report suspicions of serious and unexpected adverse reactions to AEMPS via Eudravigilance_CTM, rather than to the Ethics Committee, with the narrative of cases being acceptable in either English or Spanish, preferably accompanied by an English summary
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Not submit biannual reports regarding serious and unexpected adverse reactions
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No longer communicate suspected serious and unexpected adverse reactions (SUSAR) or annual safety reports to the health authorities of the Autonomous Communities, effective January 31, 2022