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Abstract
Introduction The dynamic arterial elastance (EaDyn), calculated as pulse pressure variation divided by stroke volume variation, has been studied as a predictor of vasopressor weaning. However, its potential as a haemodynamic tool for tapering off vasopressors in patients with sepsis remains unexplored. Therefore, our study aimed to assess whether using EaDyn for weaning vasopressor support could reduce the duration of vasopressor support in patients with sepsis.
Methods and analysis This pragmatic single-centre controlled clinical trial will take place at Fundación Santa Fe de Bogotá, Colombia. Adult patients diagnosed with septic shock according to the sepsis-3 criteria and a Sequential Organ Failure Assessment score ≥4 will be included. A total of 114 patients (57 per group) will undergo conventional critical care monitoring, and the weaning of vasopressor support will be initiated based on the EaDyn or mean arterial pressure (MAP), depending on the assigned group. EaDyn will be estimated based on the measurements obtained from a PiCCO device connected to a PulsioFlex Monitoring Platform (PULSION Medical Systems SE, Feldkirchen, Germany). Our primary outcome is the difference in vasopressor support duration between the EaDyn and MAP groups.
Participants and statisticians performing the statistical analysis will be blinded to the group allocation. Dependent and independent variables will be analysed through univariate and multivariate statistical tests. Since we will perform three repeated measurements for analysis, we will implement a Bonferroni post hoc correction. Additionally, Cox regression and Kaplan-Meier analyses will be conducted to address objectives related to time.
Ethics and dissemination This study was approved by the Ethics Committee at Fundación Santa Fe de Bogotá (CCEI-16026-2024). Written informed consent will be obtained from all participants. The results will be disseminated through publication in peer-reviewed journals and presentations at national and international events.
Trial registration number NCT06118775.
- INTENSIVE & CRITICAL CARE
- Clinical Trial
- Adult intensive & critical care
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This randomised controlled trial compares two vasopressor weaning strategies in septic shock patients.
The study will use advanced haemodynamic monitoring with the transpulmonary thermodilution system for accurate dynamic arterial elastance and mean arterial pressure measurements.
Blinding of clinical staff was not feasible due to the nature of the intervention.
Since the study will be conducted in a single centre, the generalisability of the results could be limited.
The protocol includes detailed criteria for vasopressor dose adjustments based on predefined haemodynamic targets.
Introduction
Dynamic arterial elastance (EaDyn), defined as the relationship between pulse pressure variation (PPV) and stroke volume variation (SVV), was initially considered a reflection of the patient’s arterial tone.1 However, it is now recognised as a variable that describes the dynamic interaction between changes in arterial pressure and left ventricular stroke volume related to intrathoracic pressure changes during a respiratory cycle. Thus, EaDyn evaluates the dynamic changes in arterial tone, reflecting a part of the cardiovascular function.1–3 Furthermore, it has been shown to be a reliable predictor of increased mean arterial pressure (MAP) following the administration of intravenous fluids in preload-dependent patients,4 as well as a predictor of decreased MAP following the reduction of vasopressor support.5 6
The use of vasopressor support to increase MAP and subsequently improve tissue perfusion is crucial in the management of septic shock.7 However, the dose and duration of vasopressor support have been associated with poor outcomes in critically ill patients.8–10 A recent study evaluated the efficacy of EaDyn as a tool to guide the weaning of vasopressor support in postoperative cardiovascular surgery patients with vasoplegia syndrome and revealed a lower incidence and duration of acute kidney injury (AKI), a reduction in the cumulative norepinephrine dose and shorter intensive care unit (ICU) stays.10 11
However, the application of EaDyn as a haemodynamic tool for weaning from vasopressor support has not been assessed in patients with sepsis. Therefore, the objective of our study was to evaluate whether the use of EaDyn for weaning patients with sepsis from vasopressor support in the ICU decreases the duration of vasopressor support compared with the use of MAP for vasopressor weaning. The MAP is traditionally used as the guiding tool for vasopressor weaning in the ICU.
Methods and analysis
This manuscript and the protocol were elaborated in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT).12 The protocol and the SPIRIT 2013 checklist can be consulted as online supplemental materials 1,2.
Supplemental material
Supplemental material
Objectives
The main objective and secondary objectives were formulated according to the PICO strategy, which can be consulted as online supplemental material 3. Our main aim is to determine whether compared with the traditional MAP approach, the use of EaDyn to wean patients with sepsis off vasopressor support in the ICU can shorten the duration of vasopressor support administration. Additionally, we have formulated secondary objectives comparing the following outcomes among both groups:
Supplemental material
The cumulative dose of norepinephrine.
The cumulative fluid dose administered during vasopressor weaning.
The arterial lactate concentrations before and after weaning.
The incidence of acute renal failure.
The length of hospital stay.
The length of ICU stay.
Mortality.
The need for renal replacement therapy.
The incidence of adverse events.
Study design and setting
A pragmatic parallel single-centre (Fundación Santa Fe de Bogotá, Bogotá, Colombia) controlled clinical trial will be conducted with two groups of patients. In the first group, named the ‘EaDyn weaning arm’, EaDyn will be used as a tool for weaning from vasopressor support (experimental group). In the second group, named the ‘MAP weaning arm’, the MAP will be used (control group) (figure 1). Patients will be randomly assigned to one of the two groups using computer-generated random numbers.
Flow diagram of the study. EaDyn, dynamic arterial elastance; MAP, mean arterial pressure; T, time point; VS, vasopressor support.
Eligibility criteria
Adult patients diagnosed with septic shock according to the sepsis-3 criteria13 and a Sequential Organ Failure Assessment (SOFA) score ≥4. Patients must also be monitored with a transpulmonary thermodilution (TPTD) monitor. For this purpose, we will use a Pulse index Continuous Cardiac Output device (PiCCO, PULSION Medical Systems SE, Feldkirchen, Germany) connected to a PulsioFlex Monitoring Platform (Reference PC4000, PULSION Medical Systems SE, Feldkirchen, Germany) through a PiCCO module (Reference PC4510, PULSION Medical Systems SE, Feldkirchen, Germany).
Inclusion criteria
≥18 years of age.
Admission to the ICU.
Septic shock defined according to the Third International Consensus Definitions for Sepsis and Septic Shock (sepsis-3).
Hypotension requiring vasopressor support to maintain an MAP≥65 mm Hg.
SOFA score ≥4.
Vasopressor support duration ≥4 hours.
Patients received invasive mechanical ventilation
Exclusion criteria
Pregnant individuals.
Haemodynamic instability due to cardiac arrhythmias.
Two or more vasopressors are needed.
Requiring inotropic drug administration.
Hepatic cirrhosis.
Kidney or liver transplant.
High probability of mortality within 24 hours, according to medical judgement.
Left ventricular ejection fraction is less than 50%.
Right ventricular dysfunction is defined as a tricuspid annular plane systolic excursion measurement of less than 1.6 cm.
Spontaneous breathing.
Interventions
Patients will be continuously monitored as usual in an ICU scenario (electrocardiograms, pulse oximetry, invasive blood pressure and measurement of cardiac output (CO) using TPTD). We will not restrict any medical intervention that the patient requires; hence, all monitoring, surgical or drug interventions other than the study exclusion criteria do not interfere with participant recruitment or the vasopressor weaning process. All patients will undergo daily echocardiographic evaluation, measuring variables including stroke volume and CO using the Mindray TE5 Ultrasound System (Mindray North America, Mahwah, New Jersey, USA), following widely used formulas.14 All patients will be ventilated with a tidal volume of 6–8 mL/kg of predicted body weigh to maintain a plateau pressure below 30 cmH2O and a driving pressure below 15 cmH2O. The respiratory rate will be adjusted to achieve a target CO2 level of 30–35 mm Hg, and PEEP and FiO2 will be adjusted to maintain SpO2 between 90% and 94%.
The initiation of vasopressor weaning coincides with the onset of the stabilisation phase, which occurs when patients achieve an MAP>75 mm Hg, a cardiac index (CI) >2.5 L/min/m² and a lactate level <2 mmol/L. The norepinephrine dose will be gradually reduced (0.02 μg/kg/min every 30 min) (figures 2 and 3). This strategy applies to both the experimental and control groups.
Clinical algorithm for the experimental group (dynamic arterial elastance weaning arm). EaDyn, dynamic arterial elastance; MAP, mean arterial pressure.
Clinical algorithm for the control group (mean arterial pressure weaning arm). CI, cardiac index; EaDyn, dynamic arterial elastance; MAP, mean arterial pressure.
In the experimental group, patients will be weaned according to the EaDyn value. Vasopressor weaning can continue as long as EaDyn is equal to or greater than 0.90.15 However, if the value drops below 0.90, the weaning process stops, and the norepinephrine dose is restored to the last dose at which the EaDyn value was ≥0.90. Regardless of the EaDyn value, if any patient’s MAP falls below 69 mm Hg, preload dependence will be assessed. In patients with a positive preload dependence test, a fluid load will be administered. At this point, two outcomes are possible: the MAP increases to or over 70 mm Hg or the MAP remains below 70 mm Hg. In the first scenario, vasopressor weaning will continue. If the preload assessment is negative or if MAP does not reach 70 mm Hg after the fluid load, the norepinephrine dose will be increased to its previous value (figure 2).
In the control group, vasopressor weaning will continue as long as the MAP remains above or equal to 70 mm Hg. If the MAP falls below 69 mm Hg, preload dependence will be reassessed. If preload dependence is confirmed, a fluid load will be administered. Again, two outcomes are possible: MAP≥70 mm Hg or MAP<70 mm Hg. In the former scenario, vasopressor weaning will continue. If the preload assessment is negative or the MAP remains <70 mm Hg after the fluid load, the norepinephrine dose will be increased to its previous value (figure 3)
Participant withdrawal
Study participants will be withdrawn from the study in the following scenarios:
Serious adverse events: If a participant experiences a serious adverse event related to the vasopressor weaning process (any group), they may be withdrawn for safety reasons. Adverse events include hypotension (MAP≤50 mm Hg for more than 10 min that does not respond to a fluid load or increasing norepinephrine doses), cardiac arrhythmias leading to haemodynamic instability and neurological or respiratory pattern deterioration.
Health complications: If a participant develops a health condition de novo that might affect the weaning process (eg, acute myocardial infarction, pulmonary embolism, intracerebral haemorrhage, cardiac dysfunction requiring inotropic support, requiring a vasopressor other than norepinephrine), they will be withdrawn from the study.
Revocation of informed consent: Participants and their legal representatives have the right to revoke previously given consent to participate in this trial at any time. Patient medical care will not have any repercussions.
Early discontinuation of the trial: If early evidence indicates that EaDyn is or is not beneficial for vasopressor weaning in septic shock patients, the study will be stopped, and the best weaning strategy will be offered to all patients. Similarly, if early evidence suggests that EaDyn-based weaning is harmful, the study will be discontinued.
Transference to another healthcare institution.
Adherence strategies
To improve adherence to the protocol among the clinical staff, we will use educational strategies in combination with audits, feedback and reminders in the ICU setting. We will train nurses and physicians regarding the informed consent process, the eligibility of the study participants and both weaning strategies. We will conduct a pilot study to understand the challenges of the study protocol implementation and to verify the understanding of each process and the study forms. Based on the pilot study results, we could modify the initial forms, tools and algorithms proposed. Additionally, we will evaluate the adherence to the weaning process among the nursing staff through an electronic reporting system, where they will also record the weaning process data. We will communicate with the clinical staff to divulgate these results, provide general or personal feedback, and receive feedback from their protocol implementation experience. If necessary, we will provide personal or topic-specific training to the clinical staff and research team. Once everyone is ready to recruit the first participant, we will put study reminders in the participant’s room and provide digital and paper-printed algorithms to the nursing personnel. Additionally, we will provide the clinical staff a 24-hour available phone number if they have any questions regarding the trial. We will verify the adherence to the weaning process using the aforementioned electronic system and, if necessary, provide additional general or personal training and feedback.
Outcomes
We will collect the following baseline (before vasopressor support weaning) variables: demographic data (eg, age, sex), ICU admission (cardiovascular, sepsis/respiratory, neurologic, postoperative and burn), vital signs (eg, heart rate, MAP), CO, main diagnosis, SOFA score, comorbidities, norepinephrine support duration (hours), total fluids administered, requirement of kidney replacement therapy, development of AKI, staging of AKI, lactate, creatinine and diuresis.
Primary outcome
The difference in the duration of vasopressor support, defined as the time (time to event; hours) from initiation to complete withdrawal from vasopressor support, between the experimental and control groups is our main outcome. We selected this outcome because it directly compares the efficacy of EaDyn to that of MAP for weaning from vasopressor support.
Secondary outcome
We will also measure differences between the experimental and control groups regarding the following outcomes (at the end of the vasopressor weaning or hospital stay):
Vasopressor dose (cumulative dose).
Fluid therapy (cumulative amount of isotonic crystalloid administered).
SOFA score (change from baseline).
MAP (value at each time point).
Diuresis (cumulative amount).
Length of ICU stay (final value, days).
Length of hospital stay (final value, days).
Hospital mortality (time until the event).
Adverse effects (cumulative amount of severe hypotension (MAP≤50 mm Hg), target organ damage (brain, heart)).
Exploratory outcomes
We will explore the following outcomes related to weaning from vasopressor support:
CO (value at each time point).
Arterial blood lactate (change from baseline).
Incidence of acute renal failure (final value).
Incidence of kidney replacement therapy (final value).
Safety outcomes
Safety outcomes will be assessed by comparing the experimental and control groups in terms of the following parameters, as previously outlined (refer to the Participant withdrawal section):
Hypotension is defined as MAP≤50 mm Hg sustained for more than 10 min that does not respond to a fluid load or increasing norepinephrine doses.
Cardiac arrhythmias result in haemodynamic instability.
Deterioration in neurological or respiratory patterns.
Participant timeline
Clinical variables will be collected at four specific time points: 4 hours after initiating vasopressor support, at the beginning of vasopressor weaning, on completion of vasopressor weaning and at hospital discharge. Hospital-related outcomes will be recorded on patient discharge or death (figure 1 and table 1).
Measurements per follow-up points
TPTD calibration equipment
The CO measuring equipment will be calibrated using TPTD by administering three boluses of 15 mL of isotonic crystalloid solution to patients weighing less than 100 kg. In patients weighing 100 kg or more, three boluses of 20 mL each will be administered. This calibration will be carried out every 4 hours or after three successful adjustments in the dose of norepinephrine (either increasing or decreasing the dose). The CI will be calculated as the CO divided by the total body surface area. The EaDyn is defined as the ratio between PPV and SVV (PPV/SVV) and will be averaged from three successive values obtained over a 2 min period.
Sample size
The sample size estimation was based on the results published by Ibarra-Estrada et al.16 They found that the mean duration of vasopressor support in septic shock patients was 97 (±69) hours. Considering a 24-hour reduction as clinically important, given an alpha error of 0.05 and a beta error of 0.8, we estimated the sample size according to the following formula:
where 
is the sample size, 
is the z value for a one-tailed alpha error of 0.05 (1.64), 
is the z value for a beta error of 0.80 (0.842),
S
is the SD (69 hours) and
d
is the desired difference to detect (24 hours). By replacing these values in the formula, a total of 103 patients are required to answer the main objective. Considering a 10% loss, 114 patients will be recruited, for a total of 57 patients per group.
Recruitment and allocation
During 2023, our ICU admitted 105 septic shock patients according to the International Classification of Diseases, 10th Revision (ICD-10)codes registered in the electronic medical records system. However, we expect to recruit approximately 40 patients per year, given that some patients are not eligible (patients who do not meet the inclusion or exclusion criteria and patients or legal representatives who do not give or revoke previously given consent to participate in the study).
Study participants will be randomly allocated to each group. The allocation sequence, through unrestricted randomisation, will be generated into computer-generated random numbers, which will be recorded in sequentially numbered, opaque, sealed envelopes by a central randomisation office. These envelopes will be opened exclusively after an eligible participant has been recruited. Once opened, the envelope will be irreversibly assigned to the participant, with their details written on it. The process will be monitored and recorded by at least two individuals (ICU staff or study researchers). Due to the nature of our study, which involves real-time evaluation of haemodynamic variables, it is not feasible to blind medical staff to the patient’s allocated group. However, a rigorous blinding process has been established for the statistical analysis, which will be carried out by an independent researcher who is blinded to each participant’s group assignment. Additionally, the study participants will also be blinded.
Data collection and management
The data will be collected at four time points (table 1). The case report form (CRF) will not include any personal data, and every study participant will be given a randomised identification number to anonymise the data. The CRF included demographic and clinical variables (information from T1) and information already registered in the institutional electronic medical records system. Information from time points 1 and 2 will be recorded electronically in Microsoft Forms since haemodynamic data must be recorded every 15 min for as long as the weaning of the vasopressor support lasts. Data from the last time point (T4), such as T1, will be extracted from the medical records system.
Both teams (clinical and research teams) will be trained regarding the proper filling out of the CRF and other study documents, which can be consulted as online supplemental material 4. Similarly, clear collection procedures will be established to ensure consistency in data collection among the teams. For instance, we will implement the following strategies:
Supplemental material
Data verification: Two clinical team members will verify extreme or outlier values during the vasopressor weaning process.
Electronic CRF: Using an electronic CRF and other study forms, we will capture the hours and dates related to each specific study time point, allowing monitoring of adherence to the study protocol.
If patients revoke their informed consent, we will ask them why they did not continue the study. Similarly, if the patient is retired or deviates from the study protocol for any other reason, we summarise that information and publish it in the final report and scientific paper. Nonetheless, we will perform an intention-to-treat analysis and a sensitivity analysis that includes patient data until the patient revokes consent or deviates from the protocol. Finally, all patients who experienced serious adverse events will be included in the analysis.
Data management
Data collected in the CRF will be recorded in an electronic CRF in REDCap using the randomised identification number given to each study participant. Information on interest registered in the institutional electronic medical records system will be extracted and inserted into the electronic CRF in REDCap. Information registered in Microsoft Forms will also be stored in REDCap.
We will implement the following strategies to guarantee data quality and reliability:
Data entry checking: Verification of the consistency, incongruity, reliability, outliers and missing CRF data at the time of data entry in REDCap.
Double data entry: Two independent researchers will enter the data. We compared the resulting databases to identify discrepancies.
Statistical analysis
Individuals performing the statistical analysis will be blinded to the group allocation. The normality of the quantitative variables will be assessed by the Shapiro-Wilk test. Normally distributed variables will be presented as the means (SD), and non-normally distributed variables will be presented as medians (IQRs). Qualitative variables will be reported as frequencies and proportions.
Dependent and independent variables will be analysed through univariate and multivariate statistical tests. Variables associated with the intervention or the outcome (univariate analysis p≤0.2) will be included in the multivariate analysis.
The univariate analysis will be performed using Student’s t-test or the Mann-Whitney U test for quantitative variables and the χ2 test or Fisher’s exact test for qualitative variables. We established a statistical significance level of p<0.05 for the primary endpoints. Since we will perform three repeated measurements for analysis, we will implement a Bonferroni post hoc correction, where the threshold for statistical significance will be adjusted to p<0.0167 (0.05/3).
Additionally, Cox regression and Kaplan-Meier analyses will be conducted to address objectives related to time. The statistical analysis will be performed by a statistician using R software.
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination of the research.
Ethics and dissemination
Ethics
This study was approved by the Ethics Committee at the Fundación Santa Fe de Bogotá on 8 February 2024 (CCEI-16 026-2024). Protocols and amendments will be submitted to the Ethics Committee. Once approved, we will update the ClinicalTrials.org registration (NCT06118775) and submit the amendments to this journal. Likewise, amendments will be communicated to researchers, clinical staff and study participants.
The ethics committee audits the study twice a year, with progress reports submitted every 3 months. The interim analyses will be performed by the Institutional Clinical Studies Office (Subdirección de Estudios Clínicos in Spanish). This office will provide a report to be submitted to the ethics committee. Based on the ethics committee’s analysis, the trial may be suspended or terminated, considering protocol deviations and adverse events. Non-serious adverse events will be reported every month, and serious adverse events will be immediately reported by the main investigator to the ethics committee (no more than 24 hours after identifying the event).
We designed and will conduct this study in accordance with the Declaration of Helsinki17 and Colombian legislation (Resolución No. 8430 de 1993).18 Similarly, we are committed to following the fundamental principles of the Belmont Report,19 which include respect for study participants, beneficence and justice.
ICU physicians will be trained to obtain informed consent from eligible study participants or legal representatives. Written informed consent will be obtained after the ICU physician checks the inclusion and exclusion criteria and explains the purpose, intervention, duration, benefits, risks, confidentiality measures and contact information of the study to the study participants or their legal representatives. The ICU physician will also explain that participation is voluntary and without any detriment regarding the quality of medical care in case of not participating or withdrawing their consent at any time during the study. No compensation will be given to the study participants. Nonetheless, patients with adverse events or medical complications in any group will receive complete medical assistance. Written informed consent (in Spanish) can be found in online supplemental material 5.
Supplemental material
Personal data collected from study participants will be protected under confidentiality and personal data processing clauses stated in the Colombian legislation (Ley No. 1581 de 2012).20 As mentioned above, the collected data will be recorded and stored in REDCap. The study researchers have exclusive access to the information maintained in REDCap. Additionally, the data will be anonymised, preventing the identification of individuals. Third parties (data analysts, outcome assessors and research auditors, among others) will only have access to anonymised datasets. However, the final trial dataset will be exclusively available for the research team. After trial completion, the datasets and all documentation related to the study will be stored for 20 years as stated in the Colombian legislation (Resolución No. 2378 de 2008).21
Dissemination
We are committed to the complete and transparent publication of any study results, either positive or negative. Once the data are analysed, the results will be published in a peer-review journal and will be presented at Colombian and international events.
We will include as authors every individual who fulfils the criteria and recommendations proposed by McNutt et al.22 Once the manuscript is prepared, we will submit it to American Journal Experts for grammar, style and spell checking. No other services will be used for manuscript enhancement.
Trial status
We are currently training the ICU staff on the process of weaning patients from vasopressor support. Additionally, we are divulgating the study among the ICU clinical staff. We have not yet recruited the first patient. We plan to start in July 2024 and expect to finish in July 2026.
Ethics statements
Patient consent for publication
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @jorgeialvarado
Contributors JIAS, AVM-N, YRC-B, MVS-R and AFMS contributed to the conception and design of the study. JIAS, AVM-N and AFMS will be responsible for enrolling study participants and ensuring adherence to protocol guidelines. During the implementation phase, all authors will collaboratively conduct randomisation and allocation procedures to maintain impartiality and accuracy. Throughout the follow-up period, AVM-N and AFMS will actively engage in patient monitoring and data collection to ensure the integrity of the study. JIAS will lead the drafting of the final manuscript, synthesising findings and interpretations. JIAS, AVM-N, YRC-B, MVS-R and AFMS played pivotal roles in the critical revision of the manuscript, offering valuable insights and enhancements. JIAS is responsible for the overall content as guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.