Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised open-label placebo-controlled clinical trial.

BACKGROUND: Peripheral venous cannulation is one of the most common procedures in medicine. It is associated with noticeable pain and apprehension, although in most cases it is performed without any anesthesia due to lack of a painless, cost-effective option, which would provide rapid local anesthesia with subsequent significant reduction in the experienced pain. We conducted an open-label placebo-controlled clinical trial to evaluate the efficacy and safety of a 2% lidocaine injection using the commercially available microneedle device MinronJet600 (NanoPass Technologies Ltd, Israel) to achieve rapid local anesthesia prior to peripheral venous cannulation.
METHODS: One hundred and two subjects were randomly allocated into two groups. In the first group, 100μL of lidocaine hydrochloride (2%) was injected intradermally to subjects using the MicronJet600 device in the left arm (MJ-Lido) and 100μL of saline was injected intradermally using the device in the right arm (MJ-Saline). In the second group, 100μL of lidocaine hydrochloride (2%) was injected using the MicronJet600 device into the left arm (MJ-Lido), with no injection into the right arm of subjects (No pretreatment). In both groups the intradermal injection was performed at the cannulation site prior to insertion of a 18G cannula into a median cubital vein in both arms. As a primary variable, a score of cannulation-induced pain was indicated by subjects using a 100-point visual analog scale immediately after cannulation. As a secondary variable, subjects in Group 2 also indicated their preference to receive the anaesthetic injection with MicronJet600 in the future by using the 5-point Likert scale. Also, as a secondary variable, the duration of skin numbness after lidocaine injection was indicated by performing a superficial pin-prick with a 27G needle at 15, 30 and 45 minutes, at distances of 1, 2 and 3 centimeters from the injection site.
RESULTS: A significant pain reduction (11.0-fold) was achieved due to the lidocaine injection compared to the cannulation without any pretreatment (p< 0.005). After the lidocaine injection the anesthesia was effective up to 2 centimeters from the injection site and remained for up to 30 minutes. Eighty percent of subjects from the second group preferred cannulation after the lidocaine injection over cannulation without any pretreatment. No significant side effects were identified.
CONCLUSION: Intradermal injection of anaesthetic with Micronjet600 was found to be a safe and effective option for providing rapid local anesthesia for peripheral intravenous cannulation. TRIAL REGIATRATION: The clinical trial was registered, before the patient enrollment began, in the Research Registry publicly accessible database (registration identifier: researchregistry4662). Also, the trial was registered in ClinicalTrials.gov (registration identifier: NCT05108714) after its completion.

Introduction

Intravenous cannulation is a common painful procedure which is, however, usually performed without local anaesthesia [1]. The simplest approach involving injection of a local anaesthetic into the skin using a regular needle is, in itself, painful therefore several techniques were previously tested for reducing pain in intravenous cannulation, with each having specific limitations which reduce convenience [2-7]. Intravenous cannulation requires local anaesthesia, which simultaneously provides an immediate effect, cost-effectiveness and simplicity, with a minimum of discomfort to the patient [8].

The use of hollow microneedles is currently one of the most promising techniques for providing local anaesthesia in superficial interventions involving skin and subcutaneous adipose tissue, in particular for peripheral venous cannulation [9]. To date, several commercially available, microneedle-based devices can be found on the market. Among them is the hollow microneedles based device, MicronJet600 (MJ600) by NanoPass Technologies Ltd, Israel, which was approved by regulatory authorities in many territories, including the United States and the European Union. MicronJet600 was primarily investigated as a device for nearly-painless [10] intradermal injection of vaccines [10-18]. The device is also considered promising for use in other intradermal applications [19], including intradermal injection of anaesthetics.

To test the efficacy of MicronJet600 to provide rapid local anaesthesia for peripheral intravenous cannulation via intradermal injection of micro-amounts of anaesthetic, with a subsequent decrease of the intervention-related pain score as a primary variable, an open-label placebo-controlled clinical trial was conducted. To assess safety of the intervention, potential side effects were estimated. Further, preference of cannulation, preceded by the intradermal injection of anaesthetic, over the cannulation without any pretreatment, duration and area of skin numbness after the lidocaine injection, were assessed as the secondary variables.

Materials and methods

The trial was registered prior to patient enrollment in the Research Registry publicly accessible database (registration identifier: researchregistry4662, principal investigator: Chavdar Pavlov, date of registration: 29 January 2019, URL: https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5c4d811ac413740862094f0f/). Also, the trail was registered in ClinicalTrials.gov (registration identifier: NCT05108714) after its completion. The authors confirm that all ongoing and related trials for this drug/intervention are registered. The study received ethical approval from the Local Ethics Committee of First Moscow State Medical University (Extract from Minutes No. 07–17 of the Local Ethics Committee meeting of 13.09.2017) and written informed consent was obtained from all subjects participating in the trial. The study was conducted in accordance with the Declaration of Helsinki (2013) protocol and CONSORT (Consolidated Standards of Reporting Trials) (Fig 1). Study subjects, healthy volunteers and patients at University’s Clinical Hospital №2 (Moscow, Russia) were enrolled between January 29th, 2019 and March 15th, 2019. The recruitment ended after the number of enrolled participants exceeded the designated sample size for each group.

Fig 1

Consolidated standards for reporting of trials diagram.

Study design

A single center, open-label placebo-controlled clinical trial to evaluate the efficacy and safety of 2% lidocaine injection, using the commercially available microneedle device MinronJet600 (NanoPass Technologies Ltd, Israel), to achieve rapid local anesthesia prior to peripheral venous cannulation.

Study objectives

The primary objective was to evaluate, in terms of VAS score, the efficacy of intradermal administration of low doses of lidocaine 2% solution using MicronJet600, to reduce the pain associated with peripheral venous catheter insertion. Secondary objectives included identification of potential side effects from intradermal administration of lidocaine with the MicronJet600 and assessment of the area and duration of skin numbness by performing a gentle superficial pinprick with 27 G hypodermic disposable needle, at various distances from the injection site, at various time points. Subjects’ preference for local anaesthetic injection with MicronJet600 prior to future cannulations was also assessed.

Participants

One hundred and two healthy volunteers were pre-screened for eligibility. Inclusion criteria included any gender, age between 18–65 years, and absence of all exclusion criteria. The main exclusion criteria included pregnancy or breast feeding, evidence of allergy to lidocaine, presence of pain of any localization and character not associated with the study, or treatment with any analgesics, any local tissue damage at the site of intervention, and serious systemic diseases. After being considered eligible for the study and signing the informed consent form, the subjects were randomly allocated into two groups by the first observer AR (Observer1). Simple randomization was performed to allocate subjects into two groups using the Microsoft Excel random number generator. The subjects who were allocated random even numbers were assigned to the first study group (MJ-Lido vs MJ-Saline) while the subjects who were allocated random odd numbers were assigned to the second study group (MJ-Lido vs No pretreatment).

Intervention

Prior to the intervention, each subject had his or her median cubital vein identified by palpitation of the cubital fossa area by a nurse, to determine the site for intravenous cannulation. Further, the cannulation site was wiped with ethanol swabs. Each subject from the MJ-Lido vs MJ-Saline group received an injection of 100 μL of 2% lidocaine hydrochloride injectable solution (Biokhimik, Russia) into the left arm at the cannulation site and an injection of 100 μL of saline solution (Biokhimik, Russia) placebo into the right arm at the corresponding site. Each injection was immediately (t = 0) followed by cannulation with an 18 G peripheral venous catheter. In the second group MJ-Lido vs No pretreatment, each subject received the injection of 100 μL of 2% lidocaine into the left arm at the cannulation site which was followed by the cannulation with an 18 G catheter, while the right arm of each subject was cannulated with an 18 G catheter without any pretreatment. Thus, each subject was his or her own control. This trial design was chosen to identify the presence or absence of a placebo-related effect.

The injections of both lidocaine and placebo were performed with MicronJet600 (Fig 2(A)) placed on a 1 mL syringe (Fig 2(B)), prefilled with a 27G needle. The injection procedure lasted approximately 4 seconds with the a flow rate of approximately 25 μl/sec. The intradermal injection with MicronJet600 was considered successful if a bleb, of approximately 10–15 mm in width and 3–6 mm in height, was formed at the site of injection. A cannulation was considered successful when a small amount of blood was present in the cannula’s hub following the cannula insertion. Each cannulation was performed by moving the cannula only forward when inserting into the vein. In case of unsuccessful insertion, any attempt at reinsertion was prohibited. Immediately after the insertion, the cannula was removed and the site of cannula insertion was then wiped with ethanol swabs and covered with an adhesive bandage. All injections and cannulations were performed by the same highly-qualified staff nurse of the University’s Clinical Hospital №2, who had previously undergone training on the proper use of MicronJet600 based on the training materials provided by NanoPass Technologies Ltd, Israel.

Fig 2

MicronJet600 compared to the 27 G hypodermic needle (A), and MicronJet600 placed on 1 mL syringe (B).

After each cannulation, as a primary endpoint variable, the subjects scored the pain experienced using a 100-point visual analog scale (VAS), ranging from no pain (0) to unbearable pain (100) [20], presented by the second observer AP (Observer2), and the scores were recorded. The pain experienced by subjects due to cannulation in each of the cases (following lidocaine injection, placebo injection, or without pretreatment) was also evaluated in terms of the VAS-score. Thus, in the context of the current study, VAS-score = 0 was considered as a lack of pain, VAS-score≤10 as a mild pain score, VAS-score≤20 as an acceptable pain score, VAS-score>20 as an unacceptable pain score. Аs a secondary endpoint variable, the duration of skin numbness due to lidocaine injection was assessed by performing a gentle superficial pinprick with a 27 G hypodermic disposable needle, perpendicularly to the arm at the distance of 1, 2 and 3 cm from the injection site in the distal direction at 15 (t = 15), 30 (t = 30) and 45 (t = 45) minutes after the injection. The pinpricks were performed by the Observer1. For each subject, a single 27 G hypodermic needle was used at each time point, and the needle disposed of after the procedure. The pain experienced due to the pinpricks was also assessed, by the subjects, in accordance with the provided 100-point VAS scale and recorded by Observer2. After the cannulations were performed in both arms of the subjects in the MJ-Lido vs No pretreatment group, the subjects were asked whether they would prefer to receive an anaesthetic injection with MicronJet600 prior to cannulations in future. After the cannulations were performed in both arms of the Group 1 subjects (MJ-Lido vs MJ-Saline), the subjects were asked whether they would prefer to receive anaesthetic injection with MicronJet600 prior to the cannulations in the future. The preference assessment was performed with the 5-point Likert scale where 1 was defined as strong disagreement, 2 as disagreement, 3 as lack of any preference, 4 as agreement and 5 as strong agreement. To assess possible side effects of the intervention, the cannulation site was examined for evidence of swelling, edema, hematoma, or hemorrhage at 60 minutes after the procedure. Further, the subjects were contacted by phone, 24 hours after the injection, and asked about any evidence of study-related adverse events. A general study scheme is presented in Fig 3.

Fig 3

General study scheme.

Statistical analysis

Regression modeling and results visualization were performed using R (version 3.6.3) environment for statistical computing (R Foundation for Statistical Computing, Vienna, Austria) and third-party packages lme 4 1.1–21, clubSandwich 0.4.1 and emmeans 1.4.8 available on the CRAN repository. Linear mixed effects models (implemented in the lme4 1.1–21 package) were used to model VAS scores after interventions: assuming random intercepts, random slope for repeated measurements (corresponding to coefficients for 30 min and 45 min) for each study participant, and measurement time (15, 30 and 45 min)–distance (1, 2 and 3 cm) interaction. For all models Sandwich cluster-robust variance-covariance matrix estimators (implemented in the clubSandwich 0.4.1 package) were used to address heteroskedasticity, the Satterthwaite method was used to approximate degrees of freedom and the Tukey method was used to adjust p-values obtained from pairwise comparisons. Cohen’s d was used as a standardized effect size estimate.

Sample size

A sample size of 40 subjects per group was calculated to detect an effect size of (expected difference on the VAS score between two time points at a specific distance) 1 with standard deviation in the effect of 2.2, using a paired t-test with 80% power and 5% type I error rate assuming a two-sided significance testing procedure. At the same time, an additional 22 subjects (102 subjects in total) were enrolled in order to compensate for dropouts.

Results

One hundred and twenty-nine subjects gave informed consent and were enrolled in the study; 66 subjects were allocated into Group 1 (MJ-Lido vs MJ Saline) and 63 into Group 2 (MJ-Lido vs No pretreatment). Ten subjects from Group 1 and 7 subjects from Group 2 had at least one unsuccessful cannulation; these subjects were excluded from the study. Four subjects from the Group 1 and 6 subjects from Group 2 were also excluded from the study due to unsuccessful injections with MicronJet600 at the first attempt. In these cases, owing to deviations in the technique for the injection, insufficient penetration of the microneedles into the skin led to a major leakage of the injected solution onto the skin (10 out of 186 injections, 5.4%, resulted in major leakage). Thus, data from 52 subjects from MJ-Lido vs MJ Saline (Group 1) and 50 subjects from MJ-Lido vs No pretreatment (Group 2) were analyzed (Table 1).

Table 1

Baseline demographic characteristics.

Characteristics	Treatment group
	MJ-Lido vs MJ-Saline (N = 52)	MJ-Lido vs No pretreatment (N = 50)
Sex—no (%)
Male	35 (67%)	29 (58%)
Female	17 (33%)	21 (42%)
Age–years (±)
Min	18	18
Max	59	63
Mean	28.6 (±11.3)	30.2 (±13.6)
Median	24.5	28.4
Body Mass Index (BMI)
Mean (SD)	24.8 (±3.6)	25.3 (±3.1)
Range	18.8–34.3	17.4–31.7

The results from the linear mixed effects model of VAS score after the cannulation are presented in S1 Table. According to the results (Fig 4), the mean pain score of the cannulation was 3.6 (95% CI from 2.6 to 4.6) for the MJ-Lido, 41.5 (95% CI from 38.2 to 44.8) for the MJ-Saline and 39.7 (95% CI from 35.7 to 43.7) in the absence of pretreatment. The pain reduction effect caused by intradermal administration of 100 μL of 2% lidocaine compared with both saline injection and no pretreatment was statistically significant (p < 0.0001) with corresponding Cohen’s d estimates -4.5 (95% CI from -4.9 to -4.2) and -4.3 (95% CI from -4.8 to -3.9). Also, no placebo-related effect was determined (Cohen’s d = 0.2, 95% CI from -0.4 to 0.8, p = 0.8).

Fig 4

Mean estimates of VAS scores with corresponding 95% confidence intervals for pain experienced by the subjects after cannulations preceded by the lidocaine injection (MJ-Lido vs MJ-Saline and MJ-Lido vs No pretreatment groups (red bar), saline injection (MJ-Lido vs MJ-Saline group, green bar), or performed without any pretreatment (MJ-Lido vs No pretreatment group, blue bar).

The distribution of cases between four VAS-score groups (VAS-score = 0, VAS-score≤10, VAS-score≤20 and VAS-score>20) was estimated in percentage for the scenarios with the lidocaine (n = 102) or placebo injection (n = 52) prior to cannulation, or without any pretreatment (n = 50). Thus, the distribution of cases in the scenario when lidocaine injection preceded the cannulation was 54.9%, 95.1%, 100% and 0% for VAS-score = 0, VAS-score≤10, VAS-score≤20 and VAS-score>20, respectively; the distribution of cases in the scenario when placebo injection preceded the cannulation was 0%, 1.9%, 0% and 98.1% for VAS-score = 0, VAS-score≤10, VAS-score≤20 and VAS-score>20, respectively; the distribution of cases in the scenario when cannulation was performed without any pretreatment was 0%, 4%, 8% and 92% for VAS-score = 0, VAS-score≤10, VAS-score≤20 and VAS-score>20, respectively (Fig 5).

Fig 5

The bar chart shows the distribution of subjects between the groups ranked by VAS-score for the cases of the injection of 100 μL of 2% lidocaine or placebo prior to cannulation, or cannulation without any pretreatment.

Thus, the non-shaded bar, slightly shaded bar, moderately shaded bar and entirely shaded red bar represents the percentage of subjects related to the groups: VAS-score = 0, VAS-score≤10, VAS-score≤20, VAS-score>20, respectively.

The results from the linear mixed effects model of VAS score after the cannulation are presented in S2 Table. The dependence of skin numbness after the intradermal lidocaine injection was determined to be statistically significant for both predictors: distance of the pinprick from the injection site with 27G needle, time after the injection and their interaction (p<0.0001). As expected, skin numbness was significantly higher at t = 15 and the distance of 1 cm with the mean VAS of 4.5 (95% CI from 3.5 to 5.5) as compared to other time points and distances: 9.0 (95% CI from 8.1 to 10.0), 10.9 (95% CI from 9.7 to 12.0), 11.0 (95% CI from 9.8 to 12.2), 12.4 (95% CI from 11.0 to 13.8), 12.2 (95% CI from 10.9 to 13.6), 11.7 (95% CI from 10.6 to 12.7), 12.3 (95% CI from11.0 to 13.5), 12.1 (95% CI from 11.1 to 13.2) for t = 15 and 2cm, t = 15 and 3cm, t = 30 and 1 cm, t = 30 and 2cm, t = 30 and 3cm, t = 45 and 1cm, t = 45 and 2cm, t = 45 and 3cm, respectively (Table 2). Fig 6 depicts the alteration of the average pain scores at three time points in relation to the distance from the injection site. At the end of the study (t = 60), no subjects indicated a feeling of skin numbness at the injection site.

Table 2

Mean estimates with corresponding 95% confidence intervals for VAS pain score due to pin-pricks with a 27G needle at three time points at 15, 30 and 45 minutes after the lidocaine injection with MicronJet600, and distances at 1, 2 and 3 centimeters from the injection site.

Time (min)	Distance (cm)
	1	2	3
15	4.5 (95% CI: 3.5–5.5)	9.0 (95% CI: 8.1–10.0)	10.9 (95% CI: 9.7–12.0)
30	11.0 (95% CI: 9.8–12.2)	12.4 (95% CI: 11.0–13.8)	12.2 (95% CI: 10.9–13.6)
45	11.7 (95% CI: 10.6–12.7)	12.3 (95% CI: 11.0–13.5)	12.1 (95% CI: 11.1–13.2)

Fig 6

The multi-line chart demonstrates mean estimates of VAS scores with 95% confidence intervals for pain experienced by subjects due to the superficial pin-pricks with 27 G needle for three different time points at 15, 30 and 45 minutes after the lidocaine injection with MicronJet600, and at 1, 2 and 3 centimeters from the injection site.

Adverse events of lidocaine injection with MicronJet600 were visually assessed right after the injection (t = 0) and at the end of the study (t = 60min); Thus, at t = 0, there were no adverse events indicated. A bleb (wheal) of 10–15 mm in length and 3–6 mm in height was formed in all subjects immediately after the injection, which is considered a sign of successful intradermal injection. At t = 60 min, a slight erythema of the injection site was noticeable in subjects with pale skin. Further, 24 hours after the study, there were no reports of erythema or swelling at the site of lidocaine injection and cannulation. At the same time, 9 subjects (8.8% in total from Group1 and Group2), 5 subjects (9.6%) and 4 subjects (8%) complained of local hematoma around the cannulation site for the scenarios when cannulation was performed after the lidocaine injection, after placebo injection, or without any pretreatment, respectively. However, local hematoma is considered a common adverse event of the cannulation itself and there was no evidence for correlation between the injections with MicronJet600 prior to cannulation and an increased prevalence of hematomas.

Discussion

Currently, there is an unmet need in clinical practice in which common painful procedures, including intravenous cannulation, are performed without proper or any anaesthesia. This can cause pain, anxiety and discomfort to patients. In this study, the efficacy and safety of intradermal administration of anaesthetic with MicronJet600 to provide local anaesthesia for peripheral intravenous cannulation was tested. According to the results of this open-label placebo controlled clinical trial, the intradermal injection of 100 μL of 2% lidocaine with MicronJet600 significantly decreased the pain score experienced by subjects due to insertion of 18 G cannula into a median cubital vein. The difference between pain scores experienced due to intravenous cannulation with and without local anaesthesia provided by the lidocaine injection substantially exceeded the average clinically significant difference of 9–13 on the 100-point VAS [21, 22]. Further, there were no statistically significant differences between the average VAS-scores due to cannulations after placebo injection and without any pretreatment, which demonstrates the absence of a placebo-related effect. Moreover, intradermal injection of 2% lidocaine with MicronJet600 provided local anaesthesia for 15–30 minutes, and therefore can be effectively used in diverse cases of mid-term surgical intervention involving skin and subcutaneous fat. No significant adverse events from the intervention were identified.

At the same time, this study has several limitations such as the number of subjects per group; time points for pain score measurement after the intravenous cannulation; volume and concentration of the anaesthetic and type of anaesthetic. Also blinding could has been performed more rigorously, although it is difficult to blind (disguise) the use of the MicronJet600 device; the intraindividual comparisons are confounded with the application side, which has an unclear effect on the study result; since there is no evidence regarding the difference of pain sensitivity between arms in population, arms were not randomised. Further, it is worth mentioning that the comparison within Group2 is confounded with the MicronJet600 use. In addition, the study was not powered for adverse events. Finally, the study did not involve a control group whereby subjects would receive regular intradermal injection of lidocaine with a hypodermic needle.

Although no direct comparison was made between local anaesthesia with the MicronJet600 and its most competitive alternative, Jet injectors, it is anticipated that the use of MicronJet600 is more effective. In a clinical trial by Lysakowski, Dumont, Tramer, Tassoniy [23] the effectiveness of local anaesthesia with intradermal jet injection of lidocaine with J-Tip (National Medical Products Inc, CA, USA) was investigated; the average pain scores, experienced by subjects following a 18-G cannula insertion into a vein on the dorsal part of the arm and measured with 10-point Numerical Verbal Scale (NVS), were: 3.9, 4.2 and 1.7 for the scenarios of cannulation without pretreatment, cannulation after the injection of 500 μL of saline and cannulation after the injection of 500 μL of 2% lidocaine, respectively. Consequently, the average pain scores for cannulation with no pretreatment, and cannulation with the preliminary intradermal injection of the placebo, were comparable between the current study and the study by Lysakowski, Dumont, Tramer, Tassoniy [23]. Thus, the average 100-point VAS pain scores versus 10-point NVS were: 39.7 vs 3.9 for cannulation without any pretreatment, and 41.5 vs 4.2 for cannulation after the placebo injection. The reduction in the average pain score of the cannulation by intradermal administration of 2% lidocaine, however, was substantially higher in case of the MicronJet600 intradermal administration. It resulted in an 11.0-fold reduction (from 39.7 to 3.6) in VAS pain score, compared to the jet injection intradermal administration which resulted in only 2.3-fold reduction from 3.9 to 1.7 in NVS pain score. Moreover, in the current study, a significantly lower amount (100 μL) of 2% lidocaine was administered in comparison with the study by Lysakowski, Dumont, Tramer, Tassonyi (500 μL) [23] which illustrates further the greater effectiveness of MicronJet600 as a tool for providing intradermal administration of anaesthetics to achieve rapid local anaesthesia over the jet injection method.

The adverse events of cannula insertion after the lidocaine injection with MicronJet600 were insignificant. The only obvious sign of the injection was the formation of a bleb, which is considered a sign for successful intradermal injection. Additionally, as the intradermal injection of only a small amount (100 μL) of 2% lidocaine with MicronJet600 was sufficient to achieve the substantial reduction of pain, the technique is considered safe in terms of prevention of serious complications if the injection was accidentally performed in a subject with lidocaine hypersensitivity.

Conclusions

Overall, intradermal administration of low doses of lidocaine 2% solution with MicronJet600 is effective in reducing the pain associated with a peripheral venous catheter insertion procedure, providing a sufficient rate of local anaesthesia immediately post-injection. No significant adverse events were associated with the intervention, which signifies its high safety. Further, 80% of subjects from the MJ-Lido vs No pretreatment group preferred cannulation after the lidocaine injection over the cannulation without any pretreatment.

(DOC)

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The results of the linear mixed effects model of VAS score after the cannulation.

(DOCX)

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The results from the linear mixed effects model of skin numbness after the lidocaine injection.

(DOCX)

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(PDF)

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(PDF)

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4 Feb 2020

PONE-D-19-27010

Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised double-blind placebo-controlled clinical trial

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Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors conducted a (partly) double-blinded three arm placebo-controlled clinical trial to compare the Intradermal injection of lidocaine with a placebo (100μL of saline) as well as doing nothing to provide rapid local anaesthesia for peripheral intravenous cannulation with respect to pain after cannulation. The comparison with lidocaine was done with intraindividual comparisons. They concluded, that the described MicronJet600 technique was safe and effective for providing rapid local anesthesia. The technique is also considered promising for local anesthesia in such procedures as blood gas sampling and minor surgical interventions such as excision of small skin lesions, or surgical sutures removal.

There are major points from the methods point of view which conflict the validity, but may be possibly addressed in a review.

The authors are encouraged to include an individual patient data file which may be anonymized, but let the reviewer and the reader follow the arguments.

Second, I welcome very much the effort to make the presentation consistent with the CONSORT guideline. My impression is, that this is mostly done successful. However, every point of the CONSORT like 3b,6b,7b, 11b, 14b, 17b and 20 should be addressed, at least with the statement like “no changes to the protocol are made”.

The missing line numbers influence the style of my comments:

The general comments are:

1. Restructuring along the CONSORT checklist recommendation is necessary. Some parts of the introduction belong to the Method section (treatments). Most of the study designs section is in-/exclusion criteria (section setting) as well as treatment (section interventions) which does not match to study design. A separate figure explaining the study design is helpful. Please give details / differences between applied treatments to illustrated mantainance to blinding.

2. The conclusion is not supported by the data. A reformulation along the primary hypothesis is necessary.

3. A limitation section is missing in the discussion section.

4. A statement about the ethical consideration, i.e. conduct in a group of healthy volunteers, may be worth to include in the discussion.

5. The number of patients (including diseases) and healthy volunteers should be given.

6. The intraindividual comparisons are confounded with the application side. This effect should by addressed in the limitation section “as unclear effect on the study result” and has implication on the conclusion.

7. The study is only blinded for the group1 comparison. Group2 is at most observer blinded. Effectiveness of “Blinding” is difficult to assess, as the allocation is determined by side and thus only the allocation to the type of the control group might be unclear. This should be made clear; the study design classification should be “open label” instead of blinded. The authors are welcome to describe the efforts to implement blinding.

8. The abstract is not structured according to CONSORT recommendation.

9. Definition of the primary endpoint variable is missing in the abstract as well as the method section. Please give the time of evaluation when defining the primary endpoint variable as well.

10. Characterization of secondary variables is missing.

11. At the end of the “Introduction” a clearly specified primary hypotheses (which can be answered by a suitable statistical test) is missing.

12. The text following “The results of this ..” should be deleted, while no data are presented or published.

13. Give the location of the clinic in the setting section.

14. Give the initials of the observers.

15. Please give explanation, what is gained from the second control group. Although the saline group can be followed the second control group is difficult to understand. Note, the comparison for the MicronJet600 technique (control group1 vs control group2) is not indicated as a primary research question.

16. The comparison within group2 (lido vs no pretreatment) does not answer the question about MicronJet600 use, as the treatment is confounded with the MicronJet600 use.

17. The statistical analysis model may be inadequate, depending on the primary research question/hypothesis. In particular with the comparisons to the lido pretreatment more data are available, than used for the particular analysis. A suitable linear mixed model might be helpful to address intra-patient variability as well as all treatments. Linear contrast help to answer specific questions while protecting for type one error inflation.

18. Details of the repeated measures ANOVA model should be given. I do not see two between factors here. Linear mixed effects model with a clear statement about within factors, random factors and covariance structure assumption is necessary (see comment 17).

19. Sample size calculation is difficult to understand, which the primary endpoint is not referred to, a reference of the numbers is not given and the clinical relevance of the effects is not clear, the link to a hypothesis reflecting the design is not mentioned.

20. P-Values should be given by at least 3 decimal digits.

21. Classification of VAS scale seem to be arbitrary.

Reviewer #2: Thank you for the opportunity to review your manuscript. This study concerns patient’s perception of IV cannulations and evaluates a device for ensuring immediate pain relief as an alternative to topically applied local anesthetics that requires a pause in the procedure. The design is described as a randomized double-blinded placebo controlled clinical trial and according to the study synopsis the study also follows GCP guidelines.

However, the study, as described both in researchregistry.com, the study synopsis and in the manuscript, has substantial flaws in its design. The randomization has not been implemented to optimize the study trustworthiness and the blinding procedures are insufficient.

Introduction:

How do you substantiate the claim that MicronJet600 is “the foremost device” of the commercially available?

The last paragraph would benefit by removing the comparison with the previous device and instead focus on presenting the primary and secondary objectives of the study, preferentially as testable hypothesis.

Methods

Who prepared the MicroJet600 devices before use, i.e. added saline or 2% lidocaine? Observer 1? Was it the same research nurse that inserted the 18G needles? Why was not the right vs left arm also randomized to avoid potential systematic technical issues with the IV cannulations and also blind the observers? Was the the order between right and left arm cannulations identical between all subjects?

The randomization appears to be into groups that received lidocaine (left arm) – saline (right arm), or lidocaine (left arm) – no injection (right arm). Thus, according to the protocol that was made public before the first patient was included, both the research nurse and observers potentially knew which arm that in all cases had been injected with lidocaine. This is hardly a blinded protocol. Furthermore, from the patient’s point of view the first group might have been considered blinded provided that the protocol had stipulated a randomization of which arm that received saline or lidocaine. But this was not the case according to the protocol.

Statistics

How did you test the distribution of the data, i.e. whether parametric tests are valid and mean +-SD is a valid descriptor?

Results

The results section can be substantially shorter and would benefit from being presented in line with the hypotheses that are tested.

Table 1: typo with a , instead of a .

Protocol considerations

The procedure for blinding of the patient and of the observers are flawed. The protocol that was made public before the start of the inclusion of patients states that all injections with active substance are made in the left arm, and placebo or no injection are always done in the right arm. Also Observer 1, who prepared the devices for injection, are involved in evaluations of the patients.

The amount of pain inflicted on the patients by the injection of placebo or active substance, compared to the pain inflicted by the insertion of the 18 G needle would by itself have been an interesting comparison.

Discussion

Please remove unpublished data from discussion. It does not substantiate the publication. Again, please state aims and hypothesis in introduction.

Conclusion

Should be directly in line with the stated objectives. Please avoid other assumptions in the conclusion.

Financial disclosure

The text in the manuscript does not match the text in the additional information.

Data availability

The datapoints has not been made available in this version. Please see the last sentence:

”The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available.”

Reviewer #3: Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised double-blind placebo-controlled clinical trial

Nice study, very Practical among the pediatric population and can be used in adult as well.

This study is done well with good statistical analysis.

In our institute we start using the J-tip and you can check it on www.jtip.com

It's Needle-free injecting System for subcutaneous administration of Novocaine

We found some benefit from using Compared to the EMLA cream

In the mean while we are generating a study very close to your study.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: John Seif MD, MBA

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

6 Aug 2020

4 August 2020

Dear Reviewers,

Please consider a revised version of our manuscript titled " Intradermal injection of lidocaine with a microneedle device to provide rapid local anesthesia for peripheral intravenous cannulation: A randomized double-blind placebo-controlled clinical trial”. The manuscript was revised extensively, we greatly apologize for the delay. The response to the reviewers' comments is in the "Response to Reviewers" file.

Yours sincerely,

Dr Alexey Rzhevskiy

Department of Clinical Medicine, Faculty of Medicine and Health Sciences,

Macquarie University, Sydney, Australia

Institute of Molecular Medicine, Sechenov First Moscow State Medical

University, Moscow, Russia

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

18 Jan 2021

PONE-D-19-27010R1

Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised double-blind placebo-controlled clinical trial

PLOS ONE

Dear Dr. Rzhevskiy,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript has been re-evaluated by three reviewers, and their comments are available below. You will see the reviewers have commented on the thoroughness of the response to previous reviewer comments. However, the reviewers have also highlighted persisting critical concerns and the manuscript will need significant revision before it can be considered for publication – you should anticipate that the reviewers will be re-invited to assess the revised manuscript, so please ensure that your revision is thorough. I have outlined some of the key concerns noted by the reviewers below, but you should respond all concerns mentioned by the reviewers in your response-to-reviewers document.

The key concerns noted by the reviewers relate to the blinding procedure, the lack of comparison of the study intervention to a normal intradermal needle, and the sample size calculation. Additionally, the reviewers requested clarification regarding the randomization procedure. These issues have limitations for the interpretation of the results and should be explored.

Please submit your revised manuscript by Mar 02 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Danielle Poole

Staff Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #4: (No Response)

Reviewer #5: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: No

Reviewer #4: Partly

Reviewer #5: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you for addressing the comments and vastly improving the manuscript. Now it is easy to follow your design and experimental setup.

A major issue remains. In this study, all patients according to the protocol received the active substance in the right arm and the left arm was always control. The randomization was to either receive saline injected in the left arm or not to receive an injection of saline. This was known to the investigators that made the measurements.

The protocol stating this procedure, the active substance in the right arm and saline/no-treatment in the left arm, was published on the web. Thus it cannot be ruled out that also the test subject knew which side that received the active substance. Accordingly, the study can not be said to be blinded. This needs to be changed throughout the title, abstract and manuscript.

The conclusion should be based on data from this study and answer the aim of the study . Thus the first sentence in the conclusion in the abstract is relevant but not the second sentence. I suggest that you delete it.

The conclusion in the main text is currently a repetition of results and also a sales pitch for more uses of the device. It needs to be revised.

Reviewer #4: The authors performed a double-blinded randomized trial to assess the efficacy and safey of a microneedling device to provide rapid anesthesia for the insertion of a peripheral intravenous catheter. 100 health volunteers were randomized into two groups: one with microneedle with lido 2% and saline in contralateral arm, second group one with microneedle with lido 2% and no injection in the contralateral arm. The subjects served as there own control. An 18G cannula was inserted in both arms. Intradermal injection with lido 2% reduced pain significantly and subjects preferred lido. It was concluded that injection with microjet600 was safe and effective option for rapid local anesthesia for peripheral iv cannulation.

Control group that compared a to a regular intradermal injection is not included. So it is not clear whether the injection with the micronjet600 is necessary to achieve the effect.

Would a normal intradermal needle would provide the same result?

Was the person that applied the lido 2%/saline with the micronjet blinded?

P6, sample size �  calculation of the sample size is unclear. Wat is meant by effect size 1 with and SD of 2.2? Is one point on the VAS score meant here?

P9, adverse events �  there was not powered for adverse events, question arises whether safety can be really assessed based on these data. However, it is not expected that intradermal injections cannot be considered safe, as local anesthesia with lidocaine is common practice.

P9, first paragraph of discussion: the results do not have to be repeated. Suffices to state main findings here.

Limitations:

No control with normal needle. The notion that the use of MicronJet600 is speculative

Reviewer #5: The authors have responded to most of the issues that Reviewer 1 listed about the statistical aspects of the paper. There are a few remaining issues:

1. The randomization procedure: complete, permuted blocks, etc. (see Rosenberger and Lachin, Randomization in Clinical Trials, 2016, Wiley for details). Excel is NOT a randomization procedure.

2. Sample size is still unclear. What is a treatment effect of 1? Does this mean a change in mean VAS of 1? Be more specific. Where is the standard deviation of 2.2 from? You need to reference a pilot study or the literature.

3. There are voluminous missing and incorrect definite and indefinite articles.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #4: Yes: R. Arthur Bouwman

Reviewer #5: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

4 Mar 2021

Dear Reviewers,

Please see the attached docx document "Response to Reviewers2,27.02.2021". You can also see the text from this document below.

Reviewer #2: Thank you for addressing the comments and vastly improving the manuscript. Now it is easy to follow your design and experimental setup.

A major issue remains. In this study, all patients according to the protocol received the active substance in the right arm and the left arm was always control. The randomization was to either receive saline injected in the left arm or not to receive an injection of saline. This was known to the investigators that made the measurements.

The protocol stating this procedure, the active substance in the right arm and saline/no-treatment in the left arm, was published on the web. Thus it cannot be ruled out that also the test subject knew which side that received the active substance. Accordingly, the study can not be said to be blinded. This needs to be changed throughout the title, abstract and manuscript.

Response: Yes, the blindness could has been performed more rigorously. In the title, abstract and manuscript “double-blinded” was changed to “open-label”.

The conclusion should be based on data from this study and answer the aim of the study. Thus the first sentence in the conclusion in the abstract is relevant but not the second sentence. I suggest that you delete it.

Response: Done.

The conclusion in the main text is currently a repetition of results and also a sales pitch for more uses of the device. It needs to be revised.

Response: An excess information regarding the results of the study was removed from the “Conclusions” section. However, we can not entirely rewrite the conclusions because conclusions are always drawn from results.

Reviewer #4: The authors performed a double-blinded randomized trial to assess the efficacy and safey of a microneedling device to provide rapid anesthesia for the insertion of a peripheral intravenous catheter. 100 health volunteers were randomized into two groups: one with microneedle with lido 2% and saline in contralateral arm, second group one with microneedle with lido 2% and no injection in the contralateral arm. The subjects served as there own control. An 18G cannula was inserted in both arms. Intradermal injection with lido 2% reduced pain significantly and subjects preferred lido. It was concluded that injection with microjet600 was safe and effective option for rapid local anesthesia for peripheral iv cannulation.

Control group that compared a to a regular intradermal injection is not included. So it is not clear whether the injection with the micronjet600 is necessary to achieve the effect.

Would a normal intradermal needle would provide the same result?

Response: Lidocaine injection with a normal hypodermic needle would probably have similar efficacy in terms of anaesthesia. However, because injection with a normal hypodermic needle is painful and highly-invasive, it is commonly not used in clinical practice prior to intravenous cannulation. Thus, minimally invasive and none-invasive approaches for intradermal delivery of anaesthetics have been actively investigated, please see a systematic review by Bond M, Crathorne L, Peters J, et al. 2015 (the first reference in the article). In most of the clinical trials investigating such minimally invasive or none-invasive approaches, control group with a regular intradermal injection was not included. As an example of such studies, please see Spanos S, Booth R, Koenig H, et al. 2008 (reference 7 in the article) and Lysakowski C, Dumont L, Tramèr MR, Tassonyi E 2003 (reference 23 in the article).

Was the person that applied the lido 2%/saline with the micronjet blinded?

Response: Yes, the nurse who applied the lido 2%/saline with the MicronJet600 was blinded.

P6, sample size �  calculation of the sample size is unclear. Wat is meant by effect size 1 with and SD of 2.2? Is one point on the VAS score meant here?

Response: The following has been added to the text of the article in the “Sample Size” section, marked with yellow:

“A sample size of 40 subjects per group was calculated to detect an effect size (expected difference on the VAS score between two time points at the specific distance) 1 with standard deviation of the effect at 2.2 using a paired t-test with 80% power and 5% type I error rate assuming two-sided significance testing procedure. At the same time, additional 22 subjects (102 subjects in total) were enrolled in order to overcome dropout scores.”

P9, adverse events �  there was not powered for adverse events, question arises whether safety can be really assessed based on these data. However, it is not expected that intradermal injections cannot be considered safe, as local anesthesia with lidocaine is common practice.

Response: The limitation has been added to the text of the article.

P9, first paragraph of discussion: the results do not have to be repeated. Suffices to state main findings here.

Response: The information on the results, presented in the first paragraph of the “Discussion” section, is coherent with the discussion of these results. We greatly apologize but in our opinion, this information can not be just simply removed without compromising the overall meaning of the discussion.

Limitations:

No control with normal needle. The notion that the use of MicronJet600 is speculative

Response: We agree that the study was not powered for adverse events, we did not perform statistical testing procedures on these data. The limitation has been added to the text of the article.

Reviewer #5: The authors have responded to most of the issues that Reviewer 1 listed about the statistical aspects of the paper. There are a few remaining issues:

1. The randomization procedure: complete, permuted blocks, etc. (see Rosenberger and Lachin, Randomization in Clinical Trials, 2016, Wiley for details). Excel is NOT a randomization procedure.

Response: The following has been added to the text of the article in the “Participants” section:

Response: Simple randomization was preformed to allocate subjects into 2 groups using Microsoft Excel random number generator.

2. Sample size is still unclear. What is a treatment effect of 1? Does this mean a change in mean VAS of 1? Be more specific. Where is the standard deviation of 2.2 from? You need to reference a pilot study or the literature.

Response: The following has been added to the text of the article in the Sample Size section, marked with yellow:

“A sample size of 40 subjects per group was calculated to detect an effect size (expected difference on the VAS score between two time points at the specific distance) 1 with standard deviation of the effect at 2.2 using a paired t-test with 80% power and 5% type I error rate assuming two-sided significance testing procedure. At the same time, additional 22 subjects (102 subjects in total) were enrolled in order to overcome dropout scores.”

3. There are voluminous missing and incorrect definite and indefinite articles.

Response: The manuscript has been revised and necessary corrections have been made. However, we would be happy if the Reviewer #5 specify the incorrect definite and indefinite articles.

Submitted filename: Response to Reviewers2, 04.03.2021.docx

Click here for additional data file.

13 Apr 2021

PONE-D-19-27010R2

Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised open-label placebo-controlled clinical trial

PLOS ONE

Dear Dr. Rzhevskiy,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript has been re-evaluated by three reviewers, and their comments are available below. You will see the reviewers have commented on the strengths of this revision. However, they have also raised a number of minor concerns that should be addressed before the manuscript can be further considered for publication.

The key concerns noted by the reviewers relate to the overall reporting in the manuscript. Specifically, the reviewers have requested that your manuscript be reviewed by an English language service to improve clarity.

Please submit your revised manuscript by May 27 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see:  http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at  https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Danielle Poole

Staff Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: No

Reviewer #4: Yes

Reviewer #5: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you for the adjustments to the manuscript. It addresses most of my concerns.

However, the present version of the submission still have issues that needs to be addressed.

Please update the abstract in the submission system to be identical with the abstract in the manuscript.

The study cited on page 3 was registered 2007 and has not yet been published. I would suggest that you remove the last sentence in the paragraph completely as the claimed support for the results cannot be verified.

The language needs to be edited by English editing service.

Examples:

"Consequently, the average pain scores for cannulation with no pretreatment and cannulation with the preliminary intradermal injection of the placebo were comparable in both studies – the current study and the study by Lysakowski et al.". Please rewrite without the -

"Thus, the average 100-poin VAS pain scores versus 10-poin NVS were: 39.7 and 3.9, and 41.5 and 4.2 for cannulation". Should be point instead of poin.

"It is anticipated that the technique is appropriate for a middle-term small surgical procedures such as excision of small skin lesions, or surgical skin staples or sutures removal [24], nevus removal. " Should be rephrased into correct english.

Table 1

An accidential , instead of .

Citing of references needs to be consistent and according to PlsOne standards. Eg, in the same paragraph the same paper is referenced differently:

...in comparison with the study by Lysakowski, Dumont, Tramer and Tasonyi. (500 μL) [23]

- The last author misspelled

...the study by Lysakowski et al. [23]

Including own unpublished data as in the last paragraph in the discussion (page 10) is still not appropriate as the results cannot be verified against methods used, nor have they been peer-reviewed. If the results holds for dissemination they should be published within in the present or in a separate study.

Conclusion

I expect the conclusion to be brief and directly related to the aims of the study. It would benefit by being substantially shorter and not be a repetition of the results.

Reviewer #4: This is the revised version of the manuscript “Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised open-label placebocontrolled clinical trial” by Rzhevskiy and co-authors.

The manuscript has improved and only minor issues remain.

Discussion

The first paragraph of the discussion should state the main findings, a short summary, without repeating the results section.

Figures

Resolution of the figure 2 and 3 are not optima land should be improved

Figure 2

Layout figure 2 is not optimal and can be improved

Figure 5

Is figure correct? In this figure the total of the bars per group should be 100%, this seems to be the case in the no pretreatment group and placebo group, but not in the 2% lido group: when the total of the bars is more than 100%

Reviewer #5: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #4: No

Reviewer #5: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

8 May 2021

Reviewer #2: Thank you for the adjustments to the manuscript. It addresses most of my concerns.

However, the present version of the submission still have issues that needs to be addressed.

Comment: Please update the abstract in the submission system to be identical with the abstract in the manuscript.

Response: Done

Comment: The study cited on page 3 was registered 2007 and has not yet been published. I would suggest that you remove the last sentence in the paragraph completely as the claimed support for the results cannot be verified.

Response: Done

Comment: The language needs to be edited by English editing service.

Response: Edited

Examples:

Comment: "Consequently, the average pain scores for cannulation with no pretreatment and cannulation with the preliminary intradermal injection of the placebo were comparable in both studies – the current study and the study by Lysakowski et al.". Please rewrite without the –

Response: Done

Comment: "Thus, the average 100-poin VAS pain scores versus 10-poin NVS were: 39.7 and 3.9, and 41.5 and 4.2 for cannulation". Should be point instead of poin.

Response: Done

Comment: "It is anticipated that the technique is appropriate for a middle-term small surgical procedures such as excision of small skin lesions, or surgical skin staples or sutures removal [24], nevus removal. " Should be rephrased into correct english.

Response: Done

Comment: Table 1

An accidential , instead of .

Response: Corrected

Comment: Citing of references needs to be consistent and according to PlsOne standards. Eg, in the same paragraph the same paper is referenced differently:

...in comparison with the study by Lysakowski, Dumont, Tramer and Tasonyi. (500 μL) [23]

- The last author misspelled

...the study by Lysakowski et al. [23]

Response: Done

Comment: Including own unpublished data as in the last paragraph in the discussion (page 10) is still not appropriate as the results cannot be verified against methods used, nor have they been peer-reviewed. If the results holds for dissemination they should be published within in the present or in a separate study.

Response: The paragraph has been removed

Comment: Conclusion

I expect the conclusion to be brief and directly related to the aims of the study. It would benefit by being substantially shorter and not be a repetition of the results.

Response: Done

Reviewer #4: This is the revised version of the manuscript “Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised open-label placebocontrolled clinical trial” by Rzhevskiy and co-authors.

The manuscript has improved and only minor issues remain.

Comment: Discussion

The first paragraph of the discussion should state the main findings, a short summary, without repeating the results section.

Response: Done

Comment: Figures

Resolution of the figure 2 and 3 are not optima land should be improved

Response: Improved

Comment: Figure 2

Layout figure 2 is not optimal and can be improved

Response: Improved

Comment: Figure 5

Is figure correct? In this figure the total of the bars per group should be 100%, this seems to be the case in the no pretreatment group and placebo group, but not in the 2% lido group: when the total of the bars is more than 100%

Response: Yes, the figure is correct. In this figure, the total of the bars per group should not be 100%. For better understanding, such category as VAS-score ⩽ 20 includes all cases from 0 to 20, therefore this category at the same time involves such categories as VAS-score ⩽ 10 and VAS-score=0.

Reviewer #5: (No Response)

Submitted filename: Response to reviewers3, 08.05.2021.docx

Click here for additional data file.

9 Dec 2021

Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised open-label placebo-controlled clinical trial

PONE-D-19-27010R3

Dear Dr. Alexey Rzhevskiy

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ehab Farag, MD FRCA FASA

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: No further issues. Thanks for the opportunity to review tjis manuscript.

Reviewer #4: This is the third revision of the manuscript. The authors improved the manuscript. no further comments remain

Reviewer #5: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #4: No

Reviewer #5: No

21 Jan 2022

PONE-D-19-27010R3

Intradermal injection of lidocaine with a microneedle device to provide rapid local anaesthesia for peripheral intravenous cannulation: A randomised open-label placebo-controlled clinical trial

Dear Dr. Rzhevskiy:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

Dr. Ehab Farag

Academic Editor

PLOS ONE