Medical and technological advancements allow increasingly complex invasive procedures to be performed on hospitalized patients, improving their survival rates and prognosis. However, these interventions impact physical, emotional, and psychological health. In this scenario, post-hospitalization syndrome (PHS) emerges as a concerning phenomenon characterized by functional, emotional, and social decline after discharge. Invasive procedures such as surgeries or prolonged use of catheters not only compromise physical integrity but also contribute to disorders like anxiety, depression, and post-traumatic stress. In fact, between 20% and 30% of patients admitted to the Intensive Care Unit (ICU) develop symptoms compatible with post-traumatic stress disorder. This underscores the need for a comprehensive approach focused on psychological and social well-being during and after the hospital stay. Despite humanization initiatives, few hospitals successfully implement them due to a lack of objective evaluations and clinical recommendations that justify their necessity.

In this regard, venous catheterization (VC) is the most prevalent invasive procedure. The pain, anxiety, or fear caused by this technique triggers physiological and psychological alterations that can interfere with the successful insertion of the device. This stress response induces vasoconstriction, reducing the caliber of the vein, which increases technical difficulty, elevates the risk of complications, raises healthcare costs, and negatively impacts patient satisfaction.

Natural outdoor environments have been shown to reduce stress, enhancing well-being and health in the general population. In this sense, the use of immersive virtual reality (IVR) to achieve immersion in virtual nature could help not only by diverting attention away from the painful or anxiety-inducing stimulus during invasive procedures but also by providing pleasant stimuli that could have a physiological impact.

The objective of this study is to evaluate the impact of IVR on stress and anxiety during VC using validated clinical scales, measuring the caliber of the vessel to be punctured, and determining salivary biomarkers of stress, well-being, and pain. Confirming this hypothesis will provide the evidence to integrate virtual reality into the National Health System as a standard tool for more humanized and innovative care.

BACKGROUND:

In 2010, the Society of Critical Care Medicine defined Post-Intensive Care Syndrome (PICS) to address the short- and long-term physical, cognitive, and psychological symptoms affecting ICU survivors. Clinical studies show these impairments affect up to 58% of medical ICU patients, 64% of emergency surgery patients, and 43% of elective surgery patients, prompting humanization initiatives like the "HUCI" project. Recently, evidence shows this vulnerability is not exclusive to the ICU but affects general hospitalized patients. Post-Hospitalization Syndrome (PHS) is a transient period of health vulnerability following acute illness, marked by a high risk of early readmission driven by stressors like sleep disruption, poor pain control, malnutrition, and invasive procedures. Despite humanization efforts, few hospitals successfully implement them due to a lack of objective clinical evaluations and specific recommendations justifying their necessity.

Both venipuncture and venous catheterization are the most prevalent painful invasive procedures performed on hospitalized patients. Frequently, these techniques provoke continuous fear and/or anxiety, feelings that compound the distress or fear already experienced by patients due to the mere fact of being hospitalized.

VCs are essential for intravenous therapies, blood sampling, and hemodynamic monitoring, yet they carry risks such as infection, thrombosis, nerve injury, hematoma, multiple punctures, pain, and anxiety.

Globally, approximately 2 billion VCs are placed annually. In line with this, according to the latest report from the Nosocomial Infection Prevalence Study in Spain (EPINE), 76.6% of hospitalized patients are carriers of a Peripheral Venous Catheter (PVC), while 12.3% carry a Central Venous Catheter (CVC). In recent years, the use of Peripherally Inserted Central Catheters (PICCs) has been increasing, and they are now among the most common types of CVCs inserted. The same trend is observed with Midline catheters, which are mid-length peripheral venous devices that have re-emerged and are increasingly utilized in patients requiring a PVC.

Both PICCs and Midlines have acquired a prominent role in clinical practice thanks to the introduction of ultrasound-guided puncture techniques, micro-puncture kits, new biocompatible materials, and the creation of Infusion and Vascular Access Units (IVAU).

Despite these advances, VC insertion continues to be a source of anxiety and fear for patients, which can hinder cooperation during insertion and increase complications. There is even a specific category for this type of anxiety disorder, with a definitive diagnosis of phobia of blood, injections, and injury according to the International Classification of Diseases (ICD-10).

It is estimated that between 10% and 25% of adults have a fear of needles, with a 20-30% prevalence in adults aged between 20 and 40 years. This state of anxiety can manifest cognitively, physiologically, and behaviorally.

The physiological repercussion of an anxiety state secondary to VC placement can result from the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, releasing stress hormones such as cortisol and affecting vital signs, as well as the immune system. For these reasons, cortisol levels in different biological fluids have for decades been considered the gold-standard markers for stress and anxiety. However, this reductionist view of cortisol as a solitary marker is shifting; several studies now point not only to cortisol but also to its metabolism as markers of anxious states. Thus, alterations in the levels of the 11β-HSD2 enzyme (the main enzyme responsible for inactivating cortisol by oxidation into cortisone) have been associated with higher anxiety levels.

One of the physiological reactions that can most heavily influence insertion difficulty and first-attempt success rates of a VC is peripheral vasospasm. Furthermore, cognitive and behavioral responses, such as patient tension and distress, hinder cooperation during the procedure, potentially reducing the probability of successful insertion and impacting healthcare quality, clinical safety, and cost-effectiveness.

The main clinical practice guidelines for vascular access, such as the Registered Nurses' Association of Ontario (RNAO) or the Infusion Nurses Society (INS) published in 2021 and 2024 respectively, recommend offering both pharmacological and non-pharmacological strategies to achieve proper management of pain and anxiety during VC insertion.

This aligns with current national and international humanization plans, such as the "II Healthcare Humanization Plan," which aim to increase care quality and minimize suffering during the assistance of hospitalized patients. Currently, different non-pharmacological techniques such as hypnosis, relaxation techniques, distraction strategies, and cognitive-behavioral therapy are being utilized and have proven effective during invasive procedures such as gastroscopies, colonoscopies, minor surgeries, dental procedures, or even venipuncture.

Published clinical evidence demonstrates that VR interventions are effective in reducing pain and anxiety levels during invasive clinical procedures. Additionally, it provides statistically significant improvements in patient satisfaction, perception of the procedure, and recovery time, and even reduces the need for analgesic medication.

Regarding the utilization of VR in the field of adult vascular access, limited published trials show that VR reduces pain and anxiety following the implantation of port-a-cath devices in oncological patients. Furthermore, clinical evidence reports that VR during CVC insertion in adults decreases pain and increases patient satisfaction.

On the other hand, a growing body of literature suggests that outdoor natural environments can reduce stress, positively impacting health and well-being. In recent years, studies have emerged regarding the benefits of these environments for patients, including their perception of improved health status.

The outdoor environments featuring water studied under the European Commission's "BlueHealth" project-are associated with reduced anxiety and depression, increased relaxation, and improved well-being through both direct and indirect exposure. However, accessing these natural spaces is difficult for hospitalized patients. To bridge this gap, an increasing body of research investigates replacing live experiences with virtual contact to deliver similar health benefits. While VR has proven safe and effective in medicine since the 1990s for pain control and mental health, limited studies have compared virtual nature with other VR setups. This leaves it unclear whether its benefits stem from the nature exposure itself or a simple distraction effect, though the WHO suggests VR could actively influence the mechanisms linking natural environments with health.

Omic biomarkers, which form a pillar of personalized medicine, are simultaneously essential research instruments. Biomarkers can be utilized in various steps of studying the molecular patterns that underlie different happiness phenotypes and mediate their health consequences. Research in older adults has investigated how biological markers of individual responses to stressful experiences associate with physical and mental functioning profiles. Experimental studies have also demonstrated that a reduction in cortisol responses to stress, reduced inflammatory markers in women, and higher DHEAS (dehydroepiandrosterone) in men correlate with subjective well-being.

RATIONALE / JUSTIFICATION This study proposes Immersive Virtual Reality (IVR) as a non-pharmacological tool to reduce negative emotional responses during venous catheterization, providing an insight into its impact beyond subjective metrics. By measuring vessel caliber and salivary biomarkers, it responds to the evolution toward humanized medicine. Its primary objective is to evaluate the impact of IVR on stress, anxiety, and pain during VC. Self-reported anxiety and pain will be quantified using validated clinical scales. Its physiological impact will be evaluated by measuring the caliber of the vessel to be punctured and determining salivary biomarkers related to the HPA axis (cortisol and its metabolism, well-being, and pain).

Confirming this hypothesis would provide the necessary evidence to integrate VR across all hospitals within the National Health System as a standard therapeutic tool, promoting humanized and innovative healthcare delivery, improving patient experience through safe technological strategies, and opening new avenues of research regarding the physiological response to non-pharmacological interventions.

STUDY DESCRIPTION / PROTOCOL: Study Design and Setting This is a multicenter, parallel-group, randomized controlled trial conducted across three university hospitals in Catalonia featuring Infusion and Vascular Access Units. The study focuses on patients requiring the ultrasound-guided insertion of a mid-to-long-term venous access device (PICC or Midline). Salivary bioanalytical and metabolomic analyses will be centralized and performed in collaboration with the Hospital del Mar Research Institute.

Participant Timeline and Procedural Flow:

The study protocol is organized into three distinct clinical visits integrated into the standard catheter placement workflow:

Visit 1 (Pre-implantation): Potential participants are screened for eligibility. For those included, baseline demographic and clinical data are recorded. Investigators perform a baseline assessment of self-reported pain and anxiety, and obtain a baseline ultrasound measurement of the target vein diameter. The precise ultrasound probe position is marked using a surgical marker to ensure consistency in subsequent measurements. Patients are then randomized into either the Intervention Group (Immersive Virtual Reality) or the Control Group (Standard Care).

Visit 2 (Catheter Insertion - 1 hour later): Patients receive standard clinical explanations regarding the venous catheterization. A baseline saliva sample is collected for stress biomarker analysis. During the 10-minute sterile field preparation, patients in the Intervention Group are fitted with Virtual Reality (VR) headsets connected to a tablet, while control patients receive standard preparation without VR. Immediately before skin puncture, a second assessment of anxiety and vein diameter is performed. The catheterization is then executed using a standardized technique. Immediately following the procedure, the VR headset is removed (total exposure: 20-30 minutes), and a post-procedural assessment of anxiety and pain is completed for both groups.

Visit 3 (Post-intervention - 30 minutes later): A second saliva sample is collected to assess salivary biomarkers of the hypothalamic-pituitary-adrenal (HPA) axis. Patients in both groups complete a satisfaction survey regarding the medical care received, and participants in the intervention group complete an additional survey specifically evaluating the virtual reality experience.

The ESTAR-VR Intervention: The intervention utilizes a specialized immersive virtual reality software designed for deployment during invasive medical procedures. The visual content features natural environments selected through a preliminary public engagement pilot process. The software architecture allows for real-time adjustments to match the patient's physical position on the hospital bed and enables the duration of the immersive experience to be tailored to the specific timeframe of the catheterization procedure.

Inclusion Criteria:

• Patients ≥ 18 years old
• Patients undergoing first-time CVC or Midline catheter insertion

Exclusion Criteria:

• Patients with cognitive impairment
• Communication barriers
• Acute pain (VAS > 3)
• Epilepsy
• Brain neoplasm or brain metastases
• Previous or simultaneous invasive procedures

Man / Woman / Non-binary / Prefer not to answer

Data sharing is not planned at this stage as the study is part of an ongoing PhD thesis project. The research team aims to protect the primary data until the main results are analyzed, finalized, and published in peer-reviewed journals to ensure academic priority.