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A20 · PMID:42143789

The effect of peripheral vasopressor protocols on extravasation rates: A systematic review and meta-analysis

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Bottom line

In a systematic review of 22 studies and 10,983 adult patients receiving peripheral vasopressors, extravasation rates were statistically indistinguishable between studies using a formal protocol and those without one, a negative, hypothesis-generating, study-level finding.

PICO at a glance

Clinical question and design

Central venous catheters have historically been preferred over peripheral venous catheters for administering vasoactive medications in critically ill patients, largely to reduce the risk of extravasation, leakage of a vasoconstrictive drug into surrounding tissue that can cause severe local injury. Peripheral vasopressor administration is gaining attention as a strategy to expedite treatment while avoiding the procedural risks and delays of central line placement. Prior systematic reviews on this topic focused on anatomical catheter site and peripheral catheter gauge as extravasation risk factors; whether formally adopting a peripheral vasopressor protocol, as opposed to unstructured practice, actually changes the extravasation rate had not been systematically evaluated before this review.

This systematic review and meta-analysis searched MEDLINE (Ovid), Embase (Ovid), the Cochrane Central Register of Controlled Trials (Ovid), and PubMed for studies published since January 2000, with an updated search performed in November 2025. Statistical analysis was conducted in R (v.4.4.3), with a prespecified two-tailed significance threshold of p less than 0.05. The full text was obtained on 2026-08-24, so the protocol contents, the per-agent extravasation breakdown and the central-line conversion comparison below all come from the paper itself rather than the abstract.

Intervention and outcomes measured

The intervention was care under a formal, institution-defined peripheral vasopressor protocol; the comparator was peripheral vasopressor administration without a formal protocol. Protocol contents varied substantially, which the authors name explicitly. Norepinephrine appeared in all but one protocol (Ballieu 2021 permits phenylephrine only), with phenylephrine, epinephrine, vasopressin and dopamine variously allowed. Catheters were 18 to 22 gauge, sited proximal to the wrist, in the forearm, at or above the antecubital fossa, or elsewhere in the upper extremity. Inspection was required hourly, every 2 hours, every 4 hours or daily, and the maximum permitted infusion duration ranged from 4 to 72 hours. Norepinephrine was capped at 0.125 to 0.5 mcg/kg/min in weight-based protocols or 10 to 20 mcg/min in fixed-rate protocols, at concentrations of 4 to 16 mg per 250 mL. Every protocol study reported the practice as safe.

Results

Across the 22 included studies, the median extravasation rate was 33.5 per 1,000 patients (IQR, 12.3-53.0) in studies using a peripheral vasopressor protocol, versus 31.2 per 1,000 patients (IQR, 12.0-39.6) in studies without one, numerically higher, not lower, in the protocol group, though the interquartile ranges overlap substantially. This difference was not statistically significant (Mann-Whitney U=68; p=0.78; prespecified threshold p less than 0.05).

Additional findings

This is a study-level (ecological) comparison of published rates rather than a patient-level pooled random-effects estimate, The pooled extravasation rate across all studies was 2.2% (95% CI, 2 to 2.5%), with substantial heterogeneity across the 22 studies (I-squared 74.98%, Q 91.67, p<0.001), a reason to read the null protocol comparison cautiously. Of 183 extravasation events, norepinephrine accounted for 142 (78%), phenylephrine 33 (18%), dopamine 7 (3.8%) and epinephrine 1 (0.5%), which the authors attribute to norepinephrine's greater use rather than to comparative agent risk. Phentolamine was given in 77 instances, 31% of reported events. Conversion to a central line ran numerically higher, not lower, in studies with a protocol, 484 versus 291 per 1000 patients (U=75, p=0.10)

Uncertainty and limitations

The comparison is a study-level (between-study) analysis of extravasation rates rather than a patient-level pooled estimate, so it cannot adjust for individual confounders such as vasopressor agent, dose, catheter site or gauge, infusion duration, or monitoring intensity. Full methodological detail is now available from the paper: 22 studies were included from 798 records screened, quality was assessed with the Newcastle-Ottawa Scale, and the authors note there were no randomized controlled trials to assess. The comparison remains study-level aggregate data rather than patient-level, which the authors name as a limitation on detecting modest differences. A 2015 systematic review first catalogued extravasation and local tissue injury rates across peripheral versus central venous catheters. Subsequent meta-analyses in 2020, 2020, 2021, and 2026 have progressively pooled larger adverse-event datasets for peripherally administered vasopressors. This review is the first among these to specifically isolate protocol adoption, rather than site or gauge, as the variable of interest.

How this fits with the broader evidence

The higher numerical (though non-significant) rate in protocol studies could plausibly reflect more rigorous extravasation surveillance and reporting in protocolized settings, confounding by indication (sicker patients or higher-dose vasopressors prompting protocol use), or a genuine lack of effect from protocol adoption alone; this study design cannot distinguish among these explanations. A written peripheral vasopressor protocol remains reasonable risk-mitigation practice, but this review is a reminder that protocol content and implementation fidelity, not just having a document, are what likely drive outcomes.

ACPE UAN: 0683-0000-26-036-H01-P

Study source: PMID:42143789