Practice of Fluid and Vasopressor Therapy in Critically Ill Invasively Ventilated Patients (PRoFLUID)—study protocol for an international multicenter observational cohort study

Introduction

Intravenous fluid is among the most prescribed medications in the intensive care unit (ICU). Most is used intentionally, to improve hemodynamics or to compensate for lost fluids (1). However, a substantial amount is administered unintentionally, as a vehicle for medication or to maintain catheter patency (2). Although, intravenous fluid administration was once considered to be ‘harmless’, it is now clear that intravenous infusion of fluids has important side-effects (3). The paradigm of ‘liberal fluid administration’ in critically ill patients has been challenged, and alternative treatment regimens have been explored and even recommended (4,5). Deresuscitation—active fluid removal in patients with fluid overload—is also increasingly studied, but the effect on outcomes remains unclear (6,7).

Like intravenous fluid, vasopressors are often prescribed in the ICU. Vasopressors are often used in conjunction with intravenous fluids to treat hypotension. Until recently, vasopressor therapy was started only after ‘sufficient’ fluid administration and through a central venous route. Recent studies suggest that earlier initiation of vasopressor therapy prevents the infusion of large volume of intravenous fluids (5,8,9). The ‘Surviving Sepsis Campaign’ guideline now recommends starting vasopressor therapy as soon as possible in hypotensive patients, even if this uses a peripheral venous route (10).

Compared to spontaneously breathing patients, fluid and vasopressor therapy in invasively ventilated patients is more challenging. Invasive ventilation disrupts fluid homeostasis and predisposes to hemodynamic intolerance of hypovolemia. This can provide a reason for fluid administration (11). Invasive ventilation also induces neurohumoral responses leading to sodium and water retention (12). This can cause hypervolemia—leading to lung edema—which in turn impairs alveolar gas exchange and jeopardizes lung-protective ventilation (11). The effect of invasive ventilation on fluid homeostasis is not static, but is instead dependent on ventilator mode and settings (13). Providing fluid and vasopressor therapy in these patients thus requires delicate titration to avoid the pitfalls of both hypo- and hypervolemia. Failure to do so can lead to worse outcomes in these vulnerable patients (14,15).

A large geographical variation in fluid and vasopressor therapy has been described (16). In resource-limited ICUs certain types of fluids and vasopressors are given less often than in resource-rich ICUs due to differences in the supply chains, shortages and costs (17). While some colloidal solutions are no longer available for use in critically ill patients in the European Union, these harmful fluids might now be marketed in low- and middle-income countries (LMICs) (18). Finally, peripheral administration of vasopressors might be more common in LMICs due to the restricted use of central venous catheters (19).

Currently, worldwide practice of fluid and vasopressor therapy in critically ill invasively ventilated patients is unknown. The here proposed study named ‘Practice of Fluid and Vasopressor Therapy in Critically Ill Invasively Ventilated Patients’ (PRoFLUID) aims to investigate this practice in a worldwide observational cohort study. Through PRoFLUID we will have better insights in current practices of fluid and vasopressor therapy, and associations with clinical outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1957/rc).

Methods

Design

PRoFLUID is an international prospective observational cohort study in critically ill invasively ventilated patients that receive ventilation for at least 24 hours. We expect a minimum of 200 ICUs from 30 countries to participate in this study. Patients in participating centers are screened on a daily basis. Eligible patients are included during a 28-day period, from Monday at 8:00 AM to the Monday 4 weeks later at 7:59 AM (in time zones of the participating centers).

Centers are expected to include 20 consecutive patients. After this, centers can either stop study inclusion or decide to enroll more patients. Centers that decide to continue enrollment will have to enroll the next 20 consecutive patients before they are given the option to stop study enrollment, until day 28.

Data regarding fluid administration, vasopressor use, diuretics use, oxygen exchange, and kidney function will be collected daily from the start of invasive ventilation. Collection will be retrospective, for the previous day. Clinical complications will be evaluated on day 90 after start of invasive ventilation, death or hospital discharge, whichever comes first.

A summary of the study design is presented in Figure 1.

Figure 1 Schematic overview of study inclusion and procedures. *, applies only to participants that are not invasively ventilated on the day of ICU admission. Detailed fluid therapy data consist of all types and volumes of fluid administered as well as vasopressor use. Selected fluid therapy data consist of the total amounts of fluid administered and vasopressor use. Patient outcomes include mortality, duration of invasive ventilation, and length of stay. ICU, intensive care unit.

Participants

Patients are eligible for participation in PRoFLUID if: (I) admitted to a participating ICU; (II) receiving invasive ventilation within three days of ICU admission; and (III) having received invasive ventilation for at least 24 hours. Patients younger than 16 years, and patients that are transferred under invasive ventilation form another ICU are excluded from participation in the study.

Data collection

Data is collected from the patient medical chart, unless a local electronic system to register data can be used (e.g., patient data management system). Local investigators transcribe the collected data onto an Internet-based electronic Case Report Form (Castor Electronic Data Capture). Access to the data-entry system is protected by a personalized username and password.

Demographics and baseline characteristics will be collected at study inclusion this will include selected comorbidities. During the first three calendar days all types and volumes of administrated fluids will be collected. From days 4–7, lower granularity data concerning the total volume of infused fluids will be collected.

The types and modalities of administration of vasopressors will be collected over a maximum of seven days from inclusion. Vital signs, limited laboratory results and treatment parameters are also collected over a maximum of seven days from inclusion.

Cumulative fluid balance will be collected daily. Clinical outcomes will be collected at 90 days, the day of death or the day of hospital discharge, whichever comes first. Dates of clinical events will be captured to facilitate analysis at days 28, 60 and 90.

Participants are subject to follow-up until hospital discharge, day 90 or death, whichever comes first. No follow-up will be performed after hospital discharge.

If the date of study start differs from the date of ICU admission, data will be collected retrospectively for the days the patient was admitted before inclusion.

A comprehensive list of collected data can be found in the supplemental information (Appendix 1).

Study endpoints

The primary outcome is a composite of various aspects of fluid therapy, including total volumes of types of fluids administered in the first three days after start of invasive ventilation and total volume of fluids infused in the first 7 days after start of invasive ventilation.

Secondary outcomes include timing of start, type, and duration of continuous administration of vasopressors; timing of start, infusion time and types of administered diuretics; daily urine output and cumulative fluid balances; and typical ICU outcomes, like duration of ventilation, lengths of stay in ICU and hospital, and mortality in the ICU and hospital, and at days 28, 60 and 90.

Sample size calculation

No formal sample size calculation is necessary for the primary endpoint. However, for investigating associations of aspects of fluid and vasopressor therapy with mortality using logistic regression and adjusting for a limited set of pre-specified confounders, we estimate to need 150 ‘events’ using the 10 event per variable rule of thumb. As fluid and vasopressor management is particularly important in patients with acute respiratory distress syndrome (ARDS), at least 150 events in this subgroup are needed. With an incidence of ARDS of approximately 20% and a mortality rate of 30%, we estimate to need 2,500 patients to have 150 events in patients with ARDS (20). Assuming that a participating ICU has 50 unique admissions in 4 weeks on average, of which 25% is invasively ventilated for >24 hours during the first 3 days of ICU admission, we expect to need a minimum of 200 participating ICUs (20-22).

Statistical analysis

Subjects that are transferred to another ICU in the first three calendar days of ICU admission will be excluded from analysis. Subjects that are transferred to another ICU after the first three calendar days, but before seven days are excluded from analysis of the secondary endpoints.

Patients admitted due to pancreatitis, burns, diabetic ketoacidosis, severe rhabdomyolysis and sub-arachnoid bleeding will be analyzed separately and excluded from analysis if less than 30 subjects are included in each category. Subjects diagnosed with severe burns, sepsis or ARDS during the first three calendar days of ICU admission will be part of a subgroup analysis.

Associations with outcomes will be assessed through regression modelling. Time to event variables is analyzed using Cox regression and visualized by Kaplan-Meier plots. For each analysis proposed, a complete statistical analysis plan will be prepared, finalized and made available before starting the analyses. Statistical analyses are conducted using R (www.r-project.org). A P value of less than 0.05 is considered statistically significant.

Ethics and dissemination

This study will be conducted in compliance with the Declaration of Helsinki (as revised in 2013) and local ethical guidelines. Ethical clearance will be sought from Institutional Review Boards or Ethics Committees at each participating center before commencement. Due to the strict observational nature of this study, informed consent may not be required in all institutions. For this, local regulations will be abided. Informed consent from patient representatives will be taken in all countries where this is required.

Patient data will be pseudonymized, with unique identification numbers assigned to each participant, ensuring no direct personal identifiers are recorded in the study database. All electronic data will be encrypted and stored securely.

Study findings will be submitted to peer-reviewed journals for publication. All investigators will be granted collaborative authorship. Key findings will also be presented at national and international conferences in critical care. Additionally, de-identified aggregate data will be accessible to the scientific community upon reasonable request.

Discussion

The here proposed international observational study named PRoFLUID will provide insight into the practice of fluid and vasopressor therapy in critically ill invasively ventilated patients. Given the ongoing debates and evolving perspectives in this field, there is a pressing need to understand the real-world practice of these therapies beyond the confines of controlled trial settings. PRoFLUID might highlight practice variation, as well as geo-economic differences.

Previous research into the practice of fluid and vasopressor management is limited. One study showed that the practice of fluid challenges (e.g., rapid fluid infusions in an effort to improve perfusion) is highly variable and that safety limits are rarely used (23). Another study showed that the type of fluid used is highly variable between different geographical locations (16). However, these studies focused only on very specific aspects of fluid therapy and did not take the role of vasopressors into account. Additionally, these studies were performed almost 10 years ago and practice might have evolved.

The proposed study has several strengths. First, PRoFLUID looks beyond resuscitation fluid, which constitutes just a fraction of total fluid volume (2). By examining all sources of fluid administration and the use of vasopressors, PRoFLUID provides a more comprehensive insight into fluid management in invasively ventilated patients. Second, enrolling patients from diverse ICUs around the globe is a major strength. Inherent differences in practice, patient profiles, and treatment protocols are expected due to this diversity. This provides an opportunity to uncover (geo-economic) differences in practice and associations with clinical outcomes. Additionally, the broad scope allows for stratified analyses, which can deliver more robust and representative data within different geo-economic regions. Third, PRoFLUID is designed specifically to minimize bias. Consecutive patients are enrolled using clear eligibility criteria to reduce selection bias. Data collection is standardized and data audits will be performed regularly to reduce information bias. Finally, data is collected on variables that are known to influence both exposure and outcome to reduce confounding bias.

This study also has limitations. First, with participating ICUs across multiple countries and health record systems, data collection could be challenging. The burden of data collection could be higher in some centers, i.e., centers using paper health records or that do not routinely collect the required data. To mitigate this, PRoFLUID uses streamlined electronic case report forms, developed with input from collaborators from low-and-middle-income countries. In addition, follow-up will end at hospital discharge, and less detailed fluid data is collected after day 3. These steps help facilitate data collection and minimize missing data. Second, due to the nature of the design, this study cannot demonstrate causality but can only describe associations between practice and outcomes. Further randomized clinical trials would be required to establish causal relationships. Despite this, associations between fluid administration—in contrast to fluid balance—and outcomes are currently unclear and could be delineated by this study. Additionally, the associations between aspects of fluid and vasopressor therapy might differ between geo-economic regions and patient categories. Third, the success of PRoFLUID hinges on active collaboration with participating ICUs. Data input will be done by local investigators. All investigators will receive collaborative authorship of the final publication and are invited to design sub-studies within the main study protocol. This approach might introduce some selection bias, as ICUs that participate in the study may have increased interest in the subject and thus not be representative of the entire population of ICUs. To improve ICU recruitment, PRoFLUID will seek endorsement from (inter)national bodies and societies for intensive care medicine.

In conclusion, PRoFLUID seeks to fill existing gaps in the knowledge about practices of fluid and vasopressor therapy in invasively ventilated patients. By capturing real-world data from diverse ICUs, we will be able to describe the current practice, uncover geo-economic variations, and determine associations with outcomes. Last but not least, the findings of PRoFLUID can be used in the designing of future randomized clinical trials of fluid and vasopressor therapy in critically ill ventilated patients.

Acknowledgments

We would like to thank Juliët van Hoorn for her indispensable help with piloting the study protocol.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-23-1957/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-23-1957/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1957/coif). M.C. received honoraria and speaker’s fees from Edwards Lifesciences and AOP Health. R.F. receives consulting fees from Inotrem, Pfizer and Cytosorbent; receives honoraria from Shionogi, MSD, Gilead, Menarini and Thermofiser; and holds stock in Grifols. N.H. reports that in relation to a clinical trial of fluid therapy in critically ill patients, Baxter Healthcare provided blinded fluid for the trial and the National Health and Medical Research Council of Australia funded the Study via a Project Grant—all monies were paid to the University of New South Wales. M.M. receives consulting fees from BBraun, Becton Dickinson, ConvaTec, Spiegelberg, Medtronic, MedCaptain and Holtech; receives honoraria from PeerVoice; participates in the advisory boards of Getinge, Serenno Medical, Potrero Medical, Sentinel Medical and Baxter; holds stock options in Sentinel, Serenno and Potrero; and is Founder and President of international fluid academy and treasurer of the Abdominal Compartment Socitety. X.M. receives consulting fees and honoraria from Pulsion Medical Systems and Baxter. L.P. receives salary support from Wellcome trust. L.R. reports that her university has received research grants from Health Research Council of New Zealand, National Institutes of Health Research, UKRI Engineering & Physical Sciences Research Council, Canadian Institutes of Health Research, and Intensive Care Society for her research programme. She has received speaking fees from Draeger Medical and has sat on a DSMB for Hamilton Medical. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval will be sought from the relevant institutional research committees in each participating country. Given the observational nature of the research, informed consent may be waived in certain jurisdictions; however, this will be subject to individual country’s ethical guidelines and regulations. Informed consent from patient representatives will be taken in all countries where this is required.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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