Efficacy of Local Anesthesia for Radial Artery Puncture Pain: A Systematic Review and Network Meta-Analysis

We performed a systematic review and network meta-analysis (NMA) to assist clinicians in determining the optimal patient-specific method of analgesia during radial artery puncture by comparing radial artery puncture procedural pain. We included randomized controlled trials that assessed the prophylactic efficacy of local anesthesia for radial artery puncture-associated pain. We searched the Medical Literature Analysis and Retrieval System Online in January 2023, the Cochrane Central Register of Controlled Trials in January 2023, the Excerpta Medica Database in December 2022, the World Health Organization International Clinical Trials Platform Search Portal in January 2023, and ClinicalTrials.gov in January 2023. We synthesized the pain scores (0-100 scale) using the frequentist random-effects NMA model. We evaluated the confidence in each outcome using the CINeMA tool (https://cinema.ispm.unibe.ch/). We conducted an NMA of 1,619 patients across 14 studies on pain scores during radial artery puncture-related procedures for 12 interventions. Compared with placebo, mepivacaine infiltration and lidocaine spray probably reduce pain (mean difference (MD): −47.67, 95% confidence interval (CI): −61.45 to −33.89, confidence rating (CR): moderate; MD: −27.38, 95% CI: −37.53 to −17.22, CR: moderate). Of the 32 studies included, none reported systemic adverse events, such as anaphylaxis or local anesthetic systemic toxicity, or severe local adverse events. In conclusion, mepivacaine infiltration and lidocaine spray probably reduce the pain associated with radial artery puncture more than other local anesthesia.


Introduction And Background Background
Radial arterial puncture (RAP) is a routine medical procedure frequently employed to obtain arterial blood samples for analysis in patients with impending respiratory failure or metabolic disorders, monitor critically ill patients, and facilitate contrast studies and endovascular therapy in patients with embolism or bleeding.Despite its ubiquity, RAP is associated with intense pain, and numerous studies have been aimed at identifying interventions to reduce discomfort [1].A prior systematic review (SR) and meta-analysis (MA) highlighted the efficacy of local anesthesia categories such as infiltration anesthesia, cryotherapy, and topical anesthesia [1].However, these categories vary regarding analgesic efficacy, onset time, and local anesthesia-associated pain for each local anesthesia technique.Recent randomized controlled trials (RCTs) have demonstrated the efficacy of lidocaine spray for topical anesthesia [2,3].Despite these advancements, there remains a gap in comparative research on the efficacy of each local anesthesia technique to reduce RAP-associated intraprocedural pain.

Goals of this study
To address this gap, this SR and network meta-analysis (NMA) aimed to compare the effect sizes of multiple Study participants: We included patients of both sexes, 16 years of age or older, before undergoing RAP.We included in RAP any technique that punctures the radial artery, such as arterial blood gas sampling (ABG), cannulation for continuous blood pressure monitoring or blood sampling (A-line), and introducer sheaths for angiography or endovascular treatment.Additionally, we included all local anesthesia methods and comparators.We distinguished between drugs according to the type and route of administration and placebo for local anesthetic infiltration (placebo infiltration) from those for other interventions due to the puncture pain caused by placebo infiltration [10].For a eutectic mixture of local anesthetic creams of prilocaine and lidocaine (EMLA), if a single study involved multiple interventions based on the time from application to RAP, we chose the intervention closest to three hours [11].We excluded patients who underwent other procedures, such as puncture of arteries or veins other than the radial artery.Furthermore, we excluded patients who were unable to communicate verbally because of disturbances in consciousness, cognitive impairment, or dysphasia.

Outcomes of Interest
The primary outcome was the pain score during RAP-related procedures, including local anesthesia.We converted the pain scores used in each study, such as the visual analog scale (VAS) and numeric rating scale (NRS), into a 0-100 scale (0: no pain, 100: worst pain), and then integrated them using the mean difference (MD) [12,13].We classified infiltration anesthesia and cryotherapy as painful local anesthesia [14][15][16][17].We utilized a combined pain score for the entire procedure, which included both local anesthesia and RAP.We employed a higher score in cases where a composite pain score was unavailable, although scores for individual components (pain from local anesthesia and pain from RAP) were present.
The secondary outcomes were the pain scores during RAP alone and all adverse events.If it was not specified whether the pain was due to RAP alone or any RAP-associated pain, we inquired with the author.If the author did not respond, we regarded the pain as due to RAP alone.We used the definition of adverse events set by the original authors and evaluated the incidence proportion of all adverse events during the follow-up period.

Search Strategy
We searched the Medical Literature Analysis and Retrieval System Online, the Cochrane Central Register of Controlled Trials, and the Excerpta Medica Database for studies published after January 1, 2020, as previous research has retrieved studies published through that date [1].Furthermore, we searched the World Health Organization International Clinical Trials Platform Search Portal (ICTRP) and ClinicalTrials.govfor ongoing or unpublished trials.The details of the search strategy are provided in Supplemental Material 2 (https://osf.io/eaxrv/?view_only=557f6c09bccf4f5a8e8230f0b974e54b).We checked the reference lists of the studies, including international guidelines [18][19][20] and previous research [1], as well as the reference lists of eligible studies and articles citing eligible studies.We asked the authors of original studies for unpublished or additional data.

Study Selection and Data Extraction
Three independent reviewers (SY, MH, and CS) screened the titles and abstracts, assessed the eligibility based on the full texts, and performed independent data extraction from the included studies using a standardized data collection form.We contacted the original authors if relevant data were missing.Any disagreements were resolved through discussion, and a third reviewer acted as an arbiter (EI) if this failed.

Data Items
We extracted the following study characteristics: (1) methods: study design, author, language, year, country, and setting; (2) participants: number, sex, age, the reason for RAP, previous RAP, comorbidity, and inclusion/exclusion criteria (Allen test, allergy, cold-related reaction, etc.); (3) interventions: local anesthetic technique, needle size for RAP and infiltration, premedication, and healthcare professionals performing the procedure; and (4) outcomes: pain score (assessment tool and target) and adverse event.

Assessment of Risk of Bias
Three reviewers (SY, MH, and CS) independently evaluated the risk of bias (ROB) using the Risk of Bias 2 (The Cochrane Collaboration, London, England, UK) [21].Disagreements between the two reviewers were discussed; if this failed, a third reviewer (EI) acted as an arbiter, if necessary.

Network Geometry
We demonstrated the network geometry (Figure 1).The numbers above the lines represent the number of RCTs in direct comparisons.The size of the nodes reflects the number of direct comparisons in which the intervention took place.

Data Synthesis and Statistical Analysis
We pooled the pain scores' MDs and 95% confidence intervals (CIs).We did not perform a quantitative analysis of adverse events because there were no reports of systemic or local severe adverse events, which we were intensely interested in, and few studies described minor local adverse events in detail.All the intervention groups that are relevant to this review were included.For continuous data, we did not impute missing data based on the recommendations of the Cochrane Handbook [22].We performed a MA of the available data in the original studies.If the original studies did not report pain scores in each group as a combination of the mean and standard deviation, we calculated them based on the method described in the Cochrane Handbook [22].The validity of these methods was analyzed using sensitivity analysis.We used group-level data.We used the normal likelihood for continuous outcomes.We synthesized the study effect sizes using a random-effects NMA model.We accounted for the correlations induced by multi-group studies by using multivariate distributions.The variance in the random-effects distribution (heterogeneity variance) was used to measure the extent of the across-study and within-comparison variability in treatment effects.
To rank the treatments for each outcome, we used the surface under the cumulative ranking curve (SUCRA) [23].We used MetaInsight for NMA [24].

Subgroup Analysis
To elucidate the influence of effect modifiers on the results, we performed subgroup analyses of the primary outcomes on the reason for RAP: ABG or A-line vs. introducer sheath for coronary angiography (CAG) or percutaneous coronary intervention (PCI).

Sensitivity Analysis
We performed the sensitivity analyses for the primary outcome by excluding studies that used imputation statistics to assess whether the review results were robust to the decisions made during the review process.

Assessment of Reporting Bias
We searched the clinical trial registry system (ClinicalTrials.govand ICTRP) and performed an extensive literature search for unpublished trials.To assess the outcome reporting bias, we compared the outcomes defined in the trial protocols with those reported in the publications.

Assessment of the Confidence for Each Outcome
Two reviewers (SY and CS) evaluated the confidence for each primary outcome using the CINeMA tool [25,26].The CINeMA framework includes the following domains: within-study bias, across-study bias, indirectness, imprecision, heterogeneity, and incoherence.For within-study bias and indirectness, CINeMA calculates the contribution of each study in each network estimate and combines these contributions with the study-specific evaluations (low, moderate, or high) to rate the relative effect for each comparison in the network.The domains of imprecision, heterogeneity, and incoherence use a pre-specified clinically important effect size to specify the margin of clinical equivalence between two interventions.Although no study has examined the minimal clinically important difference (MCID) for local anesthesia in RAP pain, based on several studies [27][28][29], we determined an MCID of 16 for the pain score on a 0-100 scale.

Search Results
A flow diagram of the study selection process is shown in Figure 2.After removing duplicates, we identified 1,523 records from the databases and registers by the January 30, 2023 search, and 36 records were identified from the citation searches and reference checks of the guidelines.We screened the full texts of 51 articles to identify the eligible studies, and we identified 32 eligible studies.We included a total of 28 trials in the qualitative analysis.More details of the excluded reports are provided in Supplemental Material 3 (https://osf.io/eaxrv/?view_only=557f6c09bccf4f5a8e8230f0b974e54b).We excluded four studies from the quantitative analysis because three did not describe the required data (number of participants in each group, mean or median of pain scores, and pain scores on a scale finer than 0-10) [30][31][32], and one involved interventions that could not be networked with other interventions [33].

Primary Outcome
Pain scores during RAP-related procedures: We conducted an NMA with 1,619 patients from 14 studies on pain scores during RAP-related procedures for 12 interventions (Figure 1) [2,3,[14][15][16]34,39,40,44,46,49,50,52,53].Supplemental Materials 4, 5, and 6 display each study's results and ROB (https://osf.io/eaxrv/?view_only=557f6c09bccf4f5a8e8230f0b974e54b).A forest plot comparing each intervention with the placebo is shown in Figure 3, and the confidence ratings (CR) for the results are presented in Table 3   * The SUCRA quantifies the overall ranking: the closer the SUCRA value is to 100, the more likely the treatment is higher ranked; the closer the SUCRA value is to 0, the more likely the treatment is lower ranked.
EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, SUCRA: surface under the cumulative ranking curve
EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, NMA: network meta-analysis, MD: mean difference, CI: confidence interval Adverse events: Of the 32 studies included, none reported systemic adverse events such as anaphylaxis or local anesthetic systemic toxicity and severe local adverse events [2,3,10,[14][15][16][17].Mild adverse events, such as erythema or hematoma, have been reported and are detailed in Table 5.Many studies excluded patients with allergies to local anesthetics or those with cold-related reactions (e.g., Raynaud's phenomenon) (Table 1).

Study name Intervention/comparison
Adverse event, % (n)
EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, ABG: arterial blood gas sampling, CAG: coronary angiography, PCI: percutaneous coronary intervention, MD: mean difference, CI: confidence interval
EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, MD: mean difference, CI: confidence interval

Summary of Results
This SR and NMA included 14 RCTs that compared the efficacy and safety of all interventions on pain scores during RAP-related procedures.Mepivacaine infiltration and lidocaine spray were probably more effective than other local anesthesias.No study reported systemic adverse events such as anaphylaxis, local anesthetic systemic toxicity, or severe local adverse events.

Comparison With the Previous Studies
Our study highlights the efficacy of lidocaine spray, which is a form of topical anesthesia that has not been considered in previous research.The advantage of lidocaine spray is its more rapid effect (within four to five minutes) than other topical anesthetics [55][56][57].Physicians can utilize lidocaine spray in situations with time constraints, such as EDs.
Despite using the same route of administration and drugs with similar characteristics [58], our study demonstrated the efficacy of mepivacaine infiltration but not lidocaine infiltration.Although the apparent cause of this phenomenon remains unknown, we can attribute it to several suggested factors.
Firstly, the observed variation may have been influenced by the vasodilatory effects of these drugs.Mepivacaine demonstrated a milder vasodilatory effect than lidocaine [59].In a SR that compared mepivacaine and lidocaine for local anesthesia in dentistry, mepivacaine with adrenaline was found to be more effective than lidocaine with adrenaline.Conversely, when mepivacaine alone was compared with lidocaine with adrenaline, lidocaine with adrenaline was found to be more effective [60].This result indicates the potential influence of vasodilatory or vasoconstrictive effects on the analgesic efficacy of mepivacaine and lidocaine.A previous study has suggested that subcutaneous injection-induced pain may intensify in the presence of bleeding [61].If the milder vasodilatory effect of mepivacaine compared to that of lidocaine contributes to a reduction of RAP-linked bleeding, it may consequently alleviate the associated pain.
Secondly, the observed variation might have been influenced by the size of the needle used for subcutaneous injection.Using thinner needles for subcutaneous injections reduces patient pain scores and minimizes the percentage of patients experiencing pain [61][62][63].Moreover, employing smaller needles for subcutaneous injections may not only diminish injection pain but also alleviate the pain from RAP alone because of the potential influence of anxiety about future pain and past pain experiences on subsequent pain scores [64,65].
One study in which mepivacaine was administered used 30 G needles [16]; however, in the five studies in which lidocaine was used, three used 25, 26, and 30 G needles, respectively, and the remaining two did not mention the needle thickness [14,39,40,44,50].
Thirdly, the observed variation may have been influenced by the size of the needle used for the RAP.Earlier reports suggested that using a smaller needle for RAP, irrespective of the presence or absence of prior local anesthesia, is linked to reduced pain [16,66].Notably, studies using sheath introducers have been included in the RCTs that involved lidocaine infiltration.However, it would be desirable to conduct RCTs by directly comparing mepivacaine and lidocaine to ascertain whether differences in drug characteristics between these drugs influenced the analgesic effects on RAP-procedural pain.

Generalizability
Our results may provide insights that aid in the selection of more suitable local anesthesia methods, depending on the setting.We recommend employing mepivacaine infiltration or lidocaine spray in various settings, including EDs and other urgent situations (approximately five minutes or less).Mepivacaine infiltration may be advantageous in more pressing conditions (approximately one minute or less).Clinicians should take into consideration the pain associated with subcutaneous injections in cases of mepivacaine infiltration.The RCT included in this study used 1 mL of 1% (10 mg/mL) mepivacaine subcutaneously with 30 G needles [16].
If clinicians cannot utilize these options owing to allergies or other reasons, cryotherapy may be considered in time-sensitive settings.In non-urgent situations, such as scheduled blood draws for hospitalized patients or monitoring during planned surgeries, topical anesthesia alone or in combination with infiltration anesthesia is used, using available agents.
Due to the limited number of RCTs that employ sheath introducers for RAP, clinicians should be cautious when extrapolating the current results.The results of our subgroup analysis, which is limited explicitly to RAP for CAG or PCI, suggest that topical and infiltration anesthesia may be more effective than alone.Therefore, although clinicians can use mepivacaine infiltration and lidocaine spray separately, their combination may also be effective.Additional studies are necessary to establish the efficacy of the combination of mepivacaine infiltration and lidocaine spray.

Strengths and Limitations
Strengths: To the best of our knowledge, this is the first NMA to compare any local anesthetic techniques for pain associated with RAP.The primary strength of this NMA lies in its comparison of the efficacy of individual interventions rather than categories.Additionally, we differentiated between the RAP-procedural pain, encompassing local anesthesia, and the pain specifically from RAP alone.Therefore, clinicians can more easily apply the results of this study to their patients than those of the prior SR and MA [1].
Limitations: Nonetheless, this SR and NMA have some limitations.First, we limited the period of our database search to the period after the search period of the previous SR [1]; therefore, we may have missed some essential RCTs before that period.However, we attempted to overcome this limitation by conducting a citation search.Second, utilizing a higher score between the pain scores from local anesthesia and RAP may not replace the composite pain score associated with the entire RAP procedure.Although reports suggest that anxiety about future pain and past pain experiences may affect the perception of subsequent pain, the accurate assessment, overestimation, or underestimation of this influence remains controversial [67][68][69].Consequently, the shape of the overall pain score for the procedure based on pain from local anesthesia and pain from RAP remains uncertain.

Conclusions
Mepivacaine infiltration and lidocaine spray probably reduce the pain associated with RAP more than other local anesthesia.No study reported the occurrence of severe adverse events.Even in an emergency setting, such as the ED, clinicians should actively administer these local anesthetics to control pain proficiently.If they use sheath introducers, a combination of topical and infiltration anesthesia may be more effective than infiltration anesthesia alone.We anticipate that researchers will perform RCTs to compare the efficacy of mepivacaine and lidocaine infiltrations and evaluate the combination of lidocaine spray and mepivacaine

FIGURE 1 :
FIGURE 1: NMA for pain scores during radial artery puncture-related procedures The numbers above the lines represent the number of RCTs in direct comparisons.The size of the nodes reflects the number of direct comparisons in which the intervention took place.EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, NMA: network metaanalysis, RCTs: randomized controlled trials Image Credit: Author

FIGURE 5 :
FIGURE 5: Forest plot of subgroup analysis in pain scores during radial artery puncture-related procedures A: Radial artery puncture for CAG or PCI.B: Radial artery puncture for ABG or cannulation for continuous blood pressure monitoring or blood sampling.

FIGURE 6 :
FIGURE 6: Forest plot of sensitivity analysis in pain scores during radial artery puncture-related procedures: exclusion of studies using imputed statistics A: Interventions forming a network connected by lidocaine infiltration.B: Interventions forming a network connected by placebo.

TABLE 1 : Characteristics of studies: baseline
We stated exclude if the study excluded Allen test-negative participants and unknown if it was not known to exclude Allen test-negative patients.We included in this category an assessment of ulnar artery patency other than the Allen test.

TABLE 2 : Characteristics of studies: intervention
* We noted that "immediately" or "subsequently" is less than one minute.ABG: arterial blood gas sampling, A-line: arterial line for cannulation for continuous blood pressure monitoring or blood sampling, CAG: cardiac angiography, ED: emergency department, EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, Fr: French, G: gauze, ICU: intensive care unit, NR: no record, PCI: percutaneous coronary intervention, RAP: radial artery puncture, TRA: transradial coronary angiography, -: not applicable

TABLE 3 : The confidence for pain scores during radial artery puncture-related procedures assessed by the CINeMA tool
EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, CR: confidence rating 2024 Yasuo et al.Cureus 16(7): e64682.DOI 10.7759/cureus.64682

TABLE 5 : Adverse events
The denominator could increase by 2 in which case it would be 4.55% (2/44).†Mild blanching was observed in eight patients in the EMLA groups.EMLA groups included the EMLA-only group, EMLA + placebo infiltration group, and EMLA + lidocaine infiltration group.EMLA: eutectic mixture of local anesthetic cream of prilocaine and lidocaine, NR: no record, RA: radial artery, -: not applicable *