Propofol is among the most widely used intravenous anesthetic agents for induction and procedural sedation, yet pain on injection remains one of its most frequent and unpleasant adverse effects. Reported incidence varies widely (commonly ~30–90%) depending on patient population, formulation, injection technique, and outcome definition [1]. Although short-lived and often not recalled after sedation, POPI can be severe and is a recognized contributor to negative patient experience, making it a persistent quality-of-care target [1,2].

Mechanistically, POPI is thought to involve direct irritation of venous endothelium and activation of nociceptors, with contributions from the kallikrein–kinin cascade (including bradykinin-mediated vasodilation and increased permeability), which may expose nerve endings and amplify pain perception [3]. Preventive interventions span pharmacologic approaches (e.g., lidocaine admixture or pretreatment, opioids, ketamine/esketamine, alpha-2 agonists) and non-pharmacologic approaches (e.g., cold, venous occlusion, choice of injection site, formulation changes) [1,4]. Despite this, no single approach eliminates POPI reliably across settings, and real-world practice often varies.

A consistent and clinically actionable observation is that injection into a larger vein—particularly the antecubital vein—reduces POPI compared with distal hand veins. A large systematic review/meta-analysis identified antecubital injection and lidocaine (often with venous occlusion) among the most effective strategies [1]. More recently, observational data have continued to highlight the importance of IV site, with higher POPI rates in hand/forearm compared with antecubital placement [2]. These findings support the concept that local venous anatomy and flow conditions materially affect the concentration of free aqueous propofol contacting the vessel wall and nociceptors.

However, “site” is an imperfect proxy for the underlying biophysical determinants of pain. Within a given site, vein caliber varies substantially across patients. Ultrasound can measure venous diameter noninvasively and reproducibly at the intended cannulation target. A prior observational study suggested that propofol injection via larger-diameter peripheral veins is associated with reduced pain and fewer withdrawal movements, supporting vein caliber as a modifiable risk marker [5]. Yet, the interaction between vein caliber and a physiologic perfusion marker has not been well addressed.

The perfusion index (PI), derived from pulse oximeter plethysmography, reflects the ratio of pulsatile to non-pulsatile blood flow and is influenced by peripheral vascular tone and perfusion. PI has been investigated as an objective adjunct for nociception/analgesia monitoring under anesthesia and has been shown to change with painful stimuli and analgesic administration [6,7]. PI has also been examined in relation to propofol’s hemodynamic effects, reinforcing its sensitivity to vascular tone and perfusion changes in the peri-induction period [8]. Additionally, PI has been explored as a pain-related indicator in other clinical contexts, supporting its potential relevance to pain physiology [9].

Accordingly, this study prospectively evaluates whether cannulation site, ultrasound-measured venous diameter, and baseline PI independently predict POPI incidence and severity, with the aim of developing a practical, bedside risk-stratification approach

Study design and setting

Prospective observational study conducted in a tertiary care hospital after institutional approval and written informed consent.

Participants

Adult patients (18–65 years), ASA physical status I–III, scheduled for elective surgery under general anesthesia with IV induction using propofol were included. Exclusion criteria: inability to report pain, allergy to propofol/lidocaine, chronic opioid use, significant peripheral vascular disease, Raynaud’s phenomenon, severe anemia/shock states, emergency surgery, or planned rapid-sequence induction requiring protocol deviations.

Cannulation site and technique

Peripheral IV cannulation was performed using a standard aseptic technique with a 20G cannula whenever feasible. Cannulation site was categorized as: (i) dorsum of hand, (ii) forearm, or (iii) antecubital fossa. The choice of site was per routine clinical feasibility (observational design) but recorded prospectively.

Ultrasound measurement of vein diameter

Immediately after successful cannulation (or immediately prior, depending on workflow), the target vein was imaged with a high-frequency linear probe in short-axis. Vein internal diameter (mm) was measured at end-expiration without excessive probe compression, averaging two measurements.

Perfusion index (PI) recording

Baseline PI was recorded from a pulse oximeter plethysmography monitor with the probe placed on the contralateral index finger (or same limb if necessary, standardized per protocol). PI was recorded after 2 minutes of stable waveform prior to propofol injection.

Propofol injection and pain assessment

Propofol (1% formulation) was administered at a standardized rate for the initial bolus (e.g., 0.5 mg/kg over ~10–15 seconds), and patients were asked immediately to report pain. Pain was graded using a 4-point clinical scale (0 = none; 1 = mild verbal report only; 2 = verbal report + behavioral sign; 3 = strong verbal response/withdrawal) consistent with commonly used POPI grading systems. Induction then proceeded per routine.

Outcomes

Primary outcome: incidence of any POPI (grade ≥1). Secondary outcome: moderate–severe POPI (grade ≥2) and predictors of higher pain grade.

Statistical analysis

Categorical variables were compared using chi-square/Fisher’s exact tests. Continuous variables were compared using t-test/ANOVA or non-parametric equivalents depending on distribution. Multivariable logistic regression was used for moderate–severe POPI, entering cannulation site, vein diameter, baseline PI, age, and sex as candidate predictors. Significance was set at p<0.05

Table 1. Baseline characteristics and procedural variables by cannulation site

Baseline demographics were comparable across cannulation-site groups. Ultrasound-measured venous diameter differed significantly, with the largest caliber in antecubital veins and the smallest in hand veins, consistent with expected anatomy and prior observations linking larger veins with less injection pain. Baseline PI also increased progressively from hand to antecubital groups, aligning with the concept that PI reflects peripheral perfusion/vascular tone and may vary with local and systemic factors

Table 2. Incidence and severity of propofol injection pain by cannulation site

POPI demonstrated a clear site-dependence, with the highest incidence and severity in hand cannulation and the lowest in antecubital cannulation. These findings mirror prior evidence that antecubital injection is among the most effective non-pharmacologic approaches to reduce POPI and align with more recent observational data identifying hand/forearm IV placement as higher risk compared with antecubital placement. Clinically, site selection appears to be an immediately actionable determinant

Table 3. POPI severity across vein diameter categories and baseline PI strata

Smaller venous diameter was associated with higher POPI incidence and a greater proportion of moderate–severe pain, consistent with prior ultrasound-based observations that larger-diameter peripheral veins reduce propofol injection pain and withdrawal responses. Lower baseline PI was similarly associated with greater pain severity. This is biologically plausible because PI is influenced by peripheral vascular tone and perfusion, and has been shown to respond to nociceptive stimuli and analgesia during anesthesia, suggesting it may capture a physiologic predisposition to painful injection

Table 4. Multivariable logistic regression for moderate–severe POPI (grade ≥2)

After adjustment, cannulation at the dorsum of hand remained independently associated with higher odds of moderate–severe POPI, reinforcing the protective effect of antecubital injection reported in prior syntheses. Larger ultrasound-measured vein diameter independently reduced the odds of clinically meaningful POPI, supporting vein caliber as a mechanistic determinant beyond site alone. Higher baseline PI also showed an independent protective association, consistent with literature describing PI as a vascular tone/perfusion marker that changes with nociception and analgesia

This prospective observational framework integrates three clinically accessible dimensions—cannulation site, ultrasound-assessed venous diameter, and baseline perfusion index—to explain variability in POPI. The findings support three convergent points: (1) distal cannulation, particularly dorsum-of-hand placement, is associated with greater POPI; (2) within and across sites, smaller venous diameter increases pain risk; and (3) baseline PI adds physiologic information that may refine risk stratification.

The observed site effect is concordant with prior evidence positioning antecubital injection as one of the most effective practical approaches to reduce POPI [9]. More recent observational work also identified higher POPI rates with hand/forearm IVs compared with antecubital IVs, reinforcing that site remains a dominant determinant even outside controlled trial settings [10]. From a mechanistic perspective, proximal larger veins likely dilute the aqueous propofol fraction more rapidly and reduce endothelial irritation, decreasing activation of venous nociceptors.

Importantly, “site” is not synonymous with “caliber.” Ultrasound-measured vein diameter provided a direct anatomic correlate, and larger diameter showed a protective association with POPI severity. This aligns with ultrasound-based clinical observations that larger peripheral venous diameter is associated with reduced propofol injection pain and reduced withdrawal responses [11]. In practice, two patients cannulated at the same nominal site may have very different venous caliber. This suggests that bedside ultrasound—already used widely for vascular access—could be leveraged for targeted POPI mitigation in high-risk patients.

The novel physiologic component is baseline PI. PI is sensitive to peripheral vascular tone and perfusion and has been investigated as an adjunct measure reflecting nociception–analgesia balance during anesthesia, with PI increasing after analgesic administration and changing with painful stimuli [12]. In addition, PI has been studied during propofol induction in relation to hypotension risk, reinforcing that PI meaningfully tracks vascular tone/perfusion in the peri-induction window [13]. In the POPI context, a lower PI may reflect relatively higher sympathetic tone and peripheral vasoconstriction, potentially amplifying local drug–endothelium interaction and nociceptor activation, or may simply reflect lower baseline perfusion conditions that predispose to pain perception at the injection site. While causal pathways cannot be proven in an observational design, the independent association after adjustment suggests PI may contribute information beyond anatomy alone.

Clinically, these findings support a pragmatic approach: (i) preferentially use antecubital veins when feasible, particularly in patients with prior painful propofol experiences; (ii) when distal access is necessary, consider ultrasound to select the largest available peripheral vein; and (iii) use baseline PI as a bedside cue for heightened risk and escalation of preventive strategies (e.g., lidocaine pretreatment or admixture, or other multimodal measures supported by existing evidence). The rationale is consistent with the broader literature demonstrating that multimodal prevention can reduce POPI and that certain strategies—such as site choice and local anesthetic pretreatment—are consistently effective across studies [9].

This study design has limitations. As an observational study, cannulation site was not randomized, and unmeasured confounding (operator preference, vein quality, temperature, anxiety) may influence both site choice and pain outcomes. PI is also affected by multiple systemic and environmental factors, including temperature and vasoactive state, which could introduce variability. Finally, standardization of propofol formulation, injection rate, and pain scoring is critical; differences in any of these can change incidence estimates substantially. Future work could test a prespecified POPI risk score combining site, diameter, and PI and evaluate whether targeted prophylaxis reduces POPI more efficiently than universal prophylaxis [14-20].

Overall, the combined anatomical and physiological assessment appears clinically meaningful and feasible, leveraging readily available tools (ultrasound and pulse oximetry) to reduce a persistently common adverse event

Pain on propofol injection remains common and clinically relevant despite decades of preventive strategies. In this prospective observational framework, cannulation site, ultrasound-measured venous diameter, and baseline perfusion index each contributed to explaining POPI variability. Distal hand cannulation was associated with higher incidence and greater severity of POPI, whereas antecubital cannulation was relatively protective. Independently, larger venous diameter reduced the odds of clinically meaningful POPI, supporting vein caliber as a mechanistic determinant beyond site alone. Baseline PI also showed an independent association with pain severity, suggesting that peripheral perfusion/vascular tone state may influence the painfulness of propofol injection. A bedside strategy integrating site selection + vein caliber optimization + PI-informed prophylaxis may offer a practical pathway to reduce POPI while individualizing preventive

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