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Keywords:

  • Anesthetics, Intravenous [administration & dosage; *chemistry];
  • Anesthetics, Local [administration & dosage; *chemistry];
  • Buffers;
  • Hydrogen-Ion Concentration;
  • Lidocaine [administration & dosage; *chemistry];
  • Pain [chemically induced; *prevention & control];
  • Randomized Controlled Trials as Topic;
  • Adult;
  • Child;
  • Humans

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Background

Lidocaine administration produces pain due to its acidic pH.

Objectives

The objective of this review was to determine if adjusting the pH of lidocaine had any effect on pain resulting from non-intravascular injections in adults and children. We tested the hypothesis that adjusting the pH of lidocaine solution to a level closer to the physiologic pH reduces this pain.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); ISI Web of Science (1999 to June 2010); and abstracts of the meetings of the American Society of Anesthesiologists (ASA). We checked the full articles of selected titles. We did not apply any language restrictions.

Selection criteria

We included double-blinded, randomized controlled trials that compared pH-adjusted lidocaine with unadjusted lidocaine. We evaluated pain at the injection site, satisfaction and adverse events. We excluded studies in healthy volunteers.

Data collection and analysis

We separately analysed parallel-group and crossover trials; trials that evaluated lidocaine with or without epinephrine; and trials with pH-adjusted lidocaine solutions < 7.35 and ≥ 7.35. To explain heterogeneity, we separately analysed studies with a low and higher risk of bias due to the level of allocation concealment; studies that employed a low and a higher volume of injection; and studies that used lidocaine for different types of procedures.

Main results

We included 23 studies of which 10 had a parallel design and 13 were crossover studies. Eight of the 23 studies had moderate to high risk of bias due to the level of allocation concealment.

Pain associated with the infiltration of buffered lidocaine was less than the pain associated with infiltration of unbuffered lidocaine in both parallel and crossover trials. In the crossover studies, the difference was -1.98 units (95% confidence interval (CI) -2.62 to -1.34) and in the parallel-group studies it was -0.98 units (95% CI -1.49 to -0.47) on a 0 to 10 scale. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine. The risk of bias, volume of injection, and type of procedure failed to explain the heterogeneity of the results.

Patients preferred buffered lidocaine (odds ratio 3.01, 95% CI 2.19 to 4.15). No adverse events or toxicity were reported.

Authors' conclusions

Increasing the pH of lidocaine decreased pain on injection and augmented patient comfort and satisfaction.

Plain Language Summary

Adjusting the pH of lidocaine solution for reducing pain on injection

Lidocaine is frequently used to anaesthetize the skin prior to invasive procedures. Its administration produces pain that is thought to be due to the acidic pH of commercial preparations (pH levels between 3.5 and 7.0 compared with the physiologic pH which is between 7.35 and 7.45). The objective of this review was to determine the effect of increasing the pH of a commercial lidocaine preparation on pain associated with its injection in adults and children. We included 23 studies with 1067 participants in the meta-analysis. Increasing the pH of lidocaine reduced pain and improved patients' comfort and satisfaction. No adverse events were reported. Therefore, increasing the pH of commercial lidocaine solutions with bicarbonate immediately prior to their use should be considered.

Summary of findings for the main comparison [Explanation]
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Background

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Lidocaine is one of the most commonly used local anaesthetics (Corbett 2005; Haas 1995; Koeppe 2005) due to its rapid onset of action, safety profile, low cost and wide availability. It is frequently used in medical care to facilitate a variety of invasive procedures including anaesthetizing the skin prior to venous or arterial cannulation and providing analgesia and anaesthesia for surgical procedures. When lidocaine is used for local, subcutaneous injections patients often complain of pain thought to be related to the pH of most commercial lidocaine solutions, which is between 3.5 and 7.0 (Mosby 2006). This pain, often present as a burning sensation, can be quite severe (McKay 1987; Parham 1996). Since physiologic pH is between 7.35 and 7.45, it is suggested that this pain is likely to result from the increase in hydrogen ions in the local tissue environment due to the acidity of lidocaine. Nociceptors are activated leading to subsequent pain sensation and sometimes sustained pain (Issberner 1996; Reeh 1996; Steen 1992; Steen 1993; Steen 1995).

Although increasing the pH of commercial lidocaine solutions with or without epinephrine admixture decreases pain intensity and increases patient preference for the adjusted lidocaine (Brogan 1995), this alkalinization could affect the onset, duration or degree of analgesia (Gaggero 1995).

Epinephrine is commonly co-administered with lidocaine. Adding epinephrine to lidocaine potentiates and prolongs lidocaine's action in a dose-related manner (Liu 1995). In addition, the higher pH of the lidocaine-epinephrine solution could influence pain on injection (Colaric 1998).

The clinical experiences of care providers in healthcare facilities suggest that alkalinization of lidocaine does in fact reduce the level of pain associated with its injection. However, conclusive evidence for this clinical perception is not available. This knowledge gap contributes to a reluctance to commit additional time and cost for pH adjustment of a lidocaine solution in a busy clinical practice. Although many randomized controlled trials have evaluated the effect of lidocaine alkalinization on pain at the site of injection, this outcome has never been comprehensively reviewed (Burns 2006; Vossinakis 2004; Watts 2004). We performed a systematic review of the literature to fill this knowledge gap. The results of this review could lead to evidence-based practice recommendations for the clinical use of lidocaine and may potentially foster changes in the manufacture of lidocaine.

One reason for the current absence of such a pH-adjusted solution from the market could be storage restrictions. There are studies that suggest that buffered lidocaine stays effective for up to one week after preparation and remains less painful on injection than the unbuffered solution over that time (Bartfield 1992).

Objectives

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

The objective of this review was to determine if adjusting the pH of lidocaine had any effect on pain in non-intravascular injections in adults and children. We tested the hypothesis that adjusting the pH of lidocaine to a level closer to physiologic pH reduces this pain.

Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Criteria for considering studies for this review

Types of studies

We included only double-blinded, randomized controlled trials (RCTs). We included both parallel group and crossover RCTs. Double blinding is essential in studies evaluating subjective outcomes such as pain intensity and RCTs are the best study design to evaluate effectiveness.

Types of participants

We included studies that evaluated either adults or children. We did not exclude studies because of participants' ages, underlying disease, condition or diagnosis. We also included healthy people in need of local anaesthesia like those undergoing dental procedures.

Types of interventions

We included studies that compared pH-adjusted lidocaine with unadjusted lidocaine solutions for non-intravascular injection. We included studies using plain or epinephrine-containing lidocaine solutions.

We excluded studies using lidocaine mixed with other local anaesthetics or studies that evaluated local anaesthetics other than lidocaine. We also excluded studies where there was a temperature difference between the interventions and studies in which none of the study arms used lidocaine or buffered lidocaine.

Types of outcome measures

The primary outcome was pain intensity at injection of buffered and unbuffered lidocaine administered to adults or children in order to provide local anaesthesia prior to epidural catheter insertion, intravascular cannulation or a small surgical procedure. We excluded studies if pain intensity was not self-reported, if the subjects were healthy volunteers, or if the unit of analysis was not the patient but the site of injection.

Secondary outcomes were patient satisfaction and adverse events.

Search methods for identification of studies

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); and ISI Web of Science (1999 to June 2010). We developed a specific strategy for each database. The search strategies used for Ovid MEDLINE, CENTRAL, EMBASE, LILACS, CINAHL and ISI Web of Science are found in detail in the appendices (Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6).

We based each search strategy on that developed for MEDLINE (Appendix 1). We combined the MEDLINE search strategy with the Cochrane highly sensitive search strategy phases one and two as described in the Cochrane Handbook for Reviews of Interventions (Higgins 2005). The Cochrane highly sensitive search strategy was modified to exclude single-blinded trials. We did not apply any language restrictions.

In addition, we searched abstracts of the annual meetings of the American Society of Anesthesiologists (ASA) over the last seven years (2002 to October 2009). For each article we checked the references in the full text. We also searched for relevant ongoing trials posted at www.controlled-trials.com.

Data collection and analysis

Trial identification

Four authors (AT, MT, JH, and PA) independently screened the titles and abstracts of reports resulting from the electronic database search.

We retrieved full-text versions of any potentially relevant studies chosen by at least one author. We were not blinded with respect to the journal, study authors, institution or the magnitude and direction of the study results because it has been shown that knowledge of this information by the investigators has no significant impact on the results of systematic reviews (Berlin 1997).

Trial selection

We included the following.

  • Double-blinded, randomized controlled trials (RCTs).

  • Studies that evaluated adults or children of any age, underlying disease, condition or diagnosis.

  • Studies that compared pH-adjusted lidocaine with unadjusted lidocaine solutions for non-intravascular injection, with or without epinephrine.

  • Studies that assessed self-reported pain intensity at injection, satisfaction or acceptability.

We excluded the following.

  • Studies using lidocaine mixed with other local anaesthetics or studies that evaluated local anaesthetics other than lidocaine.

  • Studies where there was a temperature difference between interventions.

  • Studies where the unit of analysis was not the patient.

Four authors (AT, MT, JH and PA) independently selected trials that met the inclusion criteria using a checklist designed in advance for that purpose. A separate author (MSC) settled any disagreements. We performed all trial selections in duplicate.

Quality assessment

We judged the quality of the studies on the basis of the methods of randomization and allocation concealment. We categorized studies into four categories.

Category A: low risk of bias - adequate allocation concealment with central randomization (e.g. allocation by a central office unaware of patient characteristics, computer file that could be accessed only after the characteristics of an enrolled participant had been entered, or other description containing elements suggesting adequate concealment).

Category B: moderate risk of bias - unclear allocation concealment in which the authors either did not report an allocation concealment approach at all or reported an approach that did not fall into category A.

Category C: high risk of bias - inadequate allocation concealment such as alternation or reference to case numbers or dates of birth.

Category D: no allocation concealment used - any procedure that was entirely transparent such as an open list of random numbers or other description that contained elements indicating no concealment of allocation.

In addition, we considered the similarity of treatment arms at baseline, completeness of follow up, and the use of intention to treat in the analysis as further indicators of good quality studies. All studies were double blinded. The quality assessments were included in the risk of bias tables for each study included in the systematic review.

Data extraction

Five authors (MT, AT, JH, PA, MSC) independently extracted data using a standardized data extraction form. We resolved conflicts through consultation with one author (MSC).

Statistics
Primary outcome
Pain intensity

Measurements using visual analogue scales or numerical scales from 0 to 100 were converted to 0 to 10 values. In the parallel group studies, we extracted the mean and standard deviation (SD) of pain intensity after infiltration in each study arm. To pool the data we calculated a weighted mean difference using the random-effects model.

In the crossover studies, we extracted the mean difference in pain intensity and the SD or standard error of the difference. To pool the data we used the generic inverse variance method in RevMan software.

In studies reporting the difference in pain intensity without measure of dispersion, we estimated the SD from the P value and the number of participants in the study.

Secondary outcomes
Patient preference and patient satisfaction

In parallel studies reporting patient preference or satisfaction, we extracted the proportion of patients who preferred one treatment over the other, or who were satisfied in each treatment arm. For crossover studies, we calculated the odds ratio (OR) for preferring buffered over unbuffered lidocaine and the 95% confidence interval (CI) using the McNemar test and STATA®. This test takes into account the crossover design, and produces correct 95% CIs and the desired M-H OR for crossover studies (Elbourne 2002). We then used the generic inverse variance method to pool the study estimates.

Adverse events

We extracted the number of patients presenting with adverse events, such as toxicity, skin rash, allergic reactions, or other.

Subgroup analysis

We separately analysed parallel and crossover trials; paediatric and adult trials; trials that evaluated lidocaine with and without epinephrine; and trials with pH-adjusted lidocaine solutions of pH < 7.35 and ≥ 7.35.

To determine if the use of epinephrine augmented the reduction in pain we used the metareg command in STATA™. The outcome variable was the mean pain difference with the presence of epinephrine in the solution as an explanatory variable.

Heterogeneity

We measured heterogeneity by the Higgins test (Higgins 2003). To pool the data we used a random-effects model since I2 values were higher than 50%.

To explain heterogeneity, we separately analysed studies with low risk (category A) and higher risk of bias (categories B, C, D) due to allocation concealment, as well as studies that employed low volumes of injection (< 2.5 ml) and higher volumes for injection (> 2.5 ml). The 2.5 ml cutoff limit was chosen because it was the median volume injected in the studies meeting the inclusion criteria. In addition, we separately analysed trials on different procedures. We divided them into three groups: lidocaine use for intravenous cannulation; lidocaine use for nerve block or epidural catheter insertion; and lidocaine use for minor surgical procedures.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

We searched CENTRAL; Ovid MEDLINE; EMBASE; LILACS; CINAHL; ISI Web of Science; and abstracts of the ASA annual meetings. We came up with 2067 studies from which we excluded 1987 in the first cut. We retrieved the remaining 80 studies in full text. From these studies 23 fulfilled the inclusion criteria.

We excluded 54 studies. The reasons for exclusion are shown in the Characteristics of excluded studies tables. The ow diagram of included and excluded studies is shown in Figure 1.

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Figure 1. Searching flow diagram

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We included 23 studies in the review, a total of 1067 patients were included in the meta-analysis. Ten studies were parallel-group design and 13 were crossover studies. Two of the studies included in the meta-analysis had more than two treatment arms. We split those treatments up and referred to them as Carvalho 2007a; Carvalho 2007b and Nakayama 2001a; Nakayama 2001b. This meant that although there were only 23 included studies we refer to 25 references.

All studies evaluated pain intensity. However six studies, three parallel-group design (Ernst 1996; Gershon 1991; Martin 1990) and three crossover (Orlinsky 1992; Richtsmeier 1995; Yuen 1999), were not included in the meta-analysis of pain intensity on injection of lidocaine. The study by Orlinsky (Orlinsky 1992) did not report the data on pain intensity. In the studies by Ernst (Ernst 1996), Gerhson (Gershon 1991) and Yuen ( Yuen 1999) no measures of dispersion nor exact P values were provided. The study by Martin (Martin 1990) used medians not means and the study by Richtsmeier (Richtsmeier 1995) used the Oucher scale. In addition, for the Fitton study (Fitton 1996) we excluded the treatment arm that received lidocaine solution at body temperature instead of room temperature (10 patients); for Nuttal's parallel-group study (Nuttall 1993) we excluded five of the seven treatment arms (200 patients), each receiving an anaesthetic other than lidocaine.

Data suitable for the analysis of pain intensity were provided by seven parallel-group studies (two with two treatment arms) (Carvalho 2007a; Carvalho 2007b; Fatovich 1999; Nakayama 2001a; Nakayama 2001b; Nuttall 1993; Steinbrook 1993; Watts 2003; Yiannakopoulos 2004) with 635 patients (from which 321 received unbuffered lidocaine and 314 buffered lidocaine); and 10 crossover studies (Bartfield 1993; Cornelius 1996; Fitton 1996; Masters 1998; Metzinger 1994; Nelson 1995; Samdal 1994; Sapin 1991; Vossinakis 2004; Younis 2004) with 432 patients.

Nineteen studies evaluated adults, two studies evaluated both children and adults (Cornelius 1996; Fitton 1996), one study evaluated children (Richtsmeier 1995), and one study did not describe the type of population included (Masters 1998).

Following the data extraction process we found that there was a very high agreement among authors in extracted data: for categorical variables the kappa statistics ranged from 0.9 to 1, and for continuous variables the intra-class correlation ranged from 0.9 to 1.

The average number of participants in the parallel-group studies was 42 years, range 20 to 95 years, and in the crossover studies the average age was 43 years, range 7 to 98 years. The mean age of participants ranged from 11 to 61 years.

All of the studies evaluated the lidocaine solution at room temperature. Eleven of the studies evaluated lidocaine with epinephrine. Eighteen studies measured the pH of the solution; the pH for unbuffered lidocaine was 5.4 ± 1.1 and the pH for buffered lidocaine was 7.3 ± 0.2.

All studies used sodium bicarbonate as the buffer agent. Although in each of the included trials patients received the same volume of the corresponding solution, nine studies added normal saline or sterile water to the lidocaine in the control group (Bartfield 1993; Cornelius 1996; Fatovich 1999; Gershon 1991; Nakayama 2001a; Nakayama 2001b; Orlinsky 1992; Samdal 1994; Watts 2003; Yiannakopoulos 2004).

Median volume injected was 2.5 ml. Using the median volume as a cutoff point we separated the studies into those injecting a volume equal or lower than 2.5 ml (13 low volume studies) and those injecting a volume higher than 2.5 ml (11 high volume studies). The study by Nelson provided data for both low and high volumes and is included in both groups. The median volume injected in the low dose studies was 1.0 ml and the median volume injected in the high dose studies was 7.0 ml.

Seven studies used the local anaesthetic infiltration for intravenous cannulation (Gershon 1991; Martin 1990; Nakayama 2001a; Nuttall 1993; Richtsmeier 1995; Sapin 1991; Steinbrook 1993); four (one with two treatment arms) used it for placement of a nerve block or an epidural needle (Bartfield 1993; Carvalho 2007a; Carvalho 2007b; Cornelius 1996; Nakayama 2001b); and in the remainder of studies it was used to provide local anaesthesia for minor surgical procedures, such as repairing small lacerations (Ernst 1996; Fatovich 1999; Orlinsky 1992), bilateral pinnaplasty (Fitton 1996), bilateral blepharoplasty or other eyelid procedures (Metzinger 1994; Samdal 1994; Yuen 1999), mammoplasty (Samdal 1994), liposuction (Samdal 1994), Norplant injection (Nelson 1995), carpal tunnel decompression (Vossinakis 2004; Watts 2003; Yiannakopoulos 2004), bilateral vasectomy (Younis 2004), or other elective outpatient procedures requiring subcutaneous injection of lidocaine (Masters 1998).

The calibre of the needles used for the infiltration ranged from 22 G to 30 G. Three studies used 22 G or 23 G needles (Nelson 1995; Vossinakis 2004; Watts 2003).

Risk of bias in included studies

Seven of the 23 studies had moderate or high risk of bias due to the lack of allocation concealment or missing information on allocation concealment ‘see ‘Risk of bias’ tables, Figure 2, Figure 3’.

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Figure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Although there are 23 studies included in this meta-analysis in this figure it appears as if there were 25 studies. This is because two of the studies had more than two treatment arms. We have spit these treatments up and refer to them as Carvalho a and b and Nakayama a and b.

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Figure 3. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Allocation

Ten of the 23 included studies (Figure 2) provided an adequate method of sequence generation and 16 mentioned adequate allocation concealment.

Blinding

All included studies were double blinded. However, upon closer assessment the blinding was unclear in three studies (Gershon 1991; Nuttall 1993; Samdal 1994).

Incomplete outcome data

All studies had complete outcome data.

Selective reporting

There was no selective reporting of outcomes in any of the studies.

Effects of interventions

See: Summary of findings for the main comparison Plain lidocaine compared to buffered lidocaine for patients requiring local anaesthesia

Pain intensity

All 23 studies evaluated pain intensity. Twenty studies evaluated pain intensity using a numerical or visual analogue scale, two studies used descriptive scales, one used a 4-point scale (Martin 1990), another used a 6-point scale (Yuen 1999), and there was also a study that used the Oucher scale (Richtsmeier 1995).

Seven studies were parallel-group design and 10 were crossover studies. In the parallel-group studies 314 participants were exposed to buffered lidocaine and 321 were exposed to unbuffered lidocaine. These numbers are slightly lower than the total numbers in the tables and forest plots (339 and 346 respectively) because the study by Nakayama evaluated a total of 50 patients but reported data separately by site of injection (Nakayama 2001a; Nakayama 2001b). The total number of participants in the meta-analysed crossover studies was 432.

Pain associated with the infiltration of buffered lidocaine was lower than the pain associated with the infiltration of unbuffered lidocaine in both crossover and parallel trials (see Summary of findings for the main comparison).

In the crossover studies the decrease in pain intensity with buffered compared to unbuffered lidocaine was -1.98 units (95% CI -2.62 to -1.34) (see Analysis 3.1; Analysis 1.1); in the parallel-group studies the difference was -0.95 units (95% CI -1.42 to -0.49). The results were heterogenous both in the crossover trials (I2 = 90%) and the parallel-group studies (I2 = 87%).

Subgroup analysis
Lidocaine with or without epinephrine

Of the 10 crossover studies that evaluated pain intensity, six evaluated buffered lidocaine with epinephrine versus unbuffered lidocaine with epinephrine and four studies evaluated buffered lidocaine without epinephrine versus unbuffered lidocaine without epinephrine. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine than when the solution lacked epinephrine (see Analysis 3.1). For the crossover studies that evaluated buffered lidocaine with epinephrine the magnitude of the decrease was -2.46 units (95% CI -3.20 to -1.72) (I2 = 88%). This compared to a decrease of -1.15 units (95% CI -1.67 to -0.63) in the studies that evaluated buffered lidocaine without epinephrine. The latter results were homogeneous (I2= 50%) (Analysis 3.1 ).

In the parallel-group studies the effect of adding epinephrine to buffered lidocaine could not be evaluated because there was only one study that evaluated lidocaine with epinephrine.

The magnitude of pain decrease in the parallel-group studies comparing buffered lidocaine without epinephrine to unbuffered lidocaine without epinephrine was -0.93 units (95% CI -1.41 to -0.45), however the results were heterogenous (I2 = 89%) (see Analysis 1.1).

pH of buffered lidocaine

All studies with the exception of one (Carvalho 2007a; Carvalho 2007b) reported the pH of the buffered lidocaine.

The effect of lidocaine solutions with pH of 7.3 or higher on the decrease in pain intensity was not clear as the results were in opposite directions in the crossover and parallel studies. In the crossover studies, trials using solutions with a higher pH produced larger decreases in pain intensity (-2.44 units, 95% CI -3.96 to -0.92) than trials using solutions with a lower pH (-1.70 units, 95% CI -2.19 to -1.22) (see Analysis 4.1). However, in parallel-group trials the solutions with a higher pH were associated with smaller decreases in pain intensity, -0.81 unit decrease (95% CI -1.46 to -0.15) versus -1.24 unit decrease (95% CI -2.04 to -0.44) in trials using solutions with a lower pH (see Analysis 2.1). The results were heterogeneous in both parallel-group (I2 = 74% and I2 = 93%) and crossover studies (I2=66% and I2 = 96%) respectively.

Children

The study that focused on children (Richtsmeier 1995) included seven participants and reported no difference (P = 0.13) in pain intensity between buffered and unbuffered lidocaine using an Oucher scale.

Secondary outcomes
Patient preference

Eleven studies with a total of 418 participants reported patient preference (Bartfield 1993; Cornelius 1996; Fitton 1996; Masters 1998; Metzinger 1994; Nelson 1995; Orlinsky 1992; Samdal 1994; Sapin 1991; Vossinakis 2004; Yuen 1999). All of these trials were crossover studies. In three studies (Fitton 1996; Samdal 1994; Vossinakis 2004) the odds ratio (OR) could not be estimated due to the presence of zeros (none of the patients preferred unbuffered lidocaine) and therefore could not be included in the meta-analysis (see Analysis 5.1; Summary of findings for the main comparison).

Patients preferred buffered lidocaine over unbuffered lidocaine (OR 3.01, 95% CI 2.19 to 4.15). The results were homogenous (I2 = 0%).

Patient satisfaction

The study by Yiannakopoulos was the only study that evaluated patients' satisfaction (Yiannakopoulos 2004); 55% of participants in the unbuffered lidocaine group would refuse to undergo the same anaesthetic technique again versus 18% in the buffered lidocaine group (P = 0.01).

Adverse events

Three of the 23 studies specifically mentioned the assessment of adverse events or complications (Carvalho 2007a; Carvalho 2007b; Fitton 1996; Samdal 1994). With the exception of the study by Fitton (Fitton 1996), which reported a hematoma (no description in which treatment arm), the studies reported an absence of adverse events or toxicity in buffered and unbuffered arms (see Summary of findings for the main comparison).

Heterogeneity

The risk of bias due to level of allocation concealment in the studies helped explain the heterogeneity of the results. In parallel-group studies with low risk of bias the decrease in pain intensity was -0.30 units (95% CI -0.41 to -0.19; I2 = 0%) versus -1.54 units (95% CI -2.39 to -0.68; I2 = 85%) in parallel-group studies with higher risk of bias (see Analysis 6.1).

The volume of injection did not explain the heterogeneity of the results. In low volume parallel-group studies the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was -0.97 (95% CI -1.58 to -0.36) and in high volume trials it was -0.94 (95% CI -1.88 to 0.01); I2 = 79% and 91% respectively (see Analysis 7.1). In low volume crossover studies the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was -0.97 (95% CI -1.57 to -0.37), in high volume trials it was -2.22 (95% CI -2.87 to -1.58); I2 = 47% and 86% respectively (see Analysis 8.1).

Similarly, the reason for using lidocaine did not explain heterogeneity of results. In parallel-group studies that evaluated intravenous cannulation the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was -0.60 (95% CI -0.91 to -0.28), in the studies that evaluated nerve block of epidural catheter insertion it was -1.36 (95% CI -2.43 to -0.30), and in those that evaluated minor surgical procedures it was -0.98 (95% CI -2.28 to 0.32); I2 = 30%, 62%, and 95% respectively (see Analysis 9.1).

In crossover studies that evaluated minor surgical procedures the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was 0.10 (95% CI 0.05 to 0.20; I2 = 88%) and in the studies evaluating nerve block or epidural catheter placement it was 0.28 (95% CI 0.08 to 0.91; I2 = 83%). However, the latter analysis involved only two studies. Only one study provided data on intravenous cannulation therefore it was impossible to provide a pooled estimate (see Analysis 10.1).

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Increasing the pH of lidocaine decreases the pain associated with its infiltration and increases patient preference for the pH-adjusted lidocaine.

With the exception of patient preference the study results were heterogeneous and remained so despite the analysis of factors that could explain the heterogeneity. However, none of the studies showed that buffered lidocaine produced more pain than unbuffered lidocaine. The basis for discrepancy was the magnitude of the decline in pain intensity. In the worst scenario the decrease in pain intensity was 0.3 units, which is considered to be of small clinical importance (Cepeda 2003). However, the fact that patients preferred buffered lidocaine over unbuffered solution (see Figure 4) provides support to the utility of the alkalinization to decrease pain associated with injection and strengthens the clinical importance of the decrease in pain intensity with buffered lidocaine (see Summary of findings for the main comparison).

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Figure 4. Forest plot of comparison: 5 Preference, outcome: 5.1 Preference in cross over studies.

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This systematic review did not evaluate the effect of alkalization of lidocaine on the quality of the sensory blockade. Results of studies that have assessed the effect of alkalinization on the quality of sensory blockade range from alkalinization decreasing the onset of analgesia and increasing potency to alkalinization decreasing the degree and duration of the anaesthesia block (Gaggero 1995). In addition, the effect of alkalization on the quality of anaesthetic blockade seems to vary both with the presence of epinephrine and the type of agent used to increase the pH (sodium bicarbonate versus sodium hydroxide) (Sinnott 2000). Clinicians should be mindful of the limitation that this systematic review focused on the pain on injection and did not evaluate the quality of the anaesthetic blockade when interpreting the results of the review.

We found that the difference in the magnitude of the decrease in pain intensity between buffered and unbuffered lidocaine is larger when the solution contains epinephrine (Figure 5; Figure 6). This may not be surprising as the pH of these solutions is lower than that of the solutions without epinephrine (pH 4.94 versus 5.09) (Robinson 2000).

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Figure 5. Forest plot of comparison: 1 Mean pain difference in parallel studies, outcome: 1.1 Mean difference in parallel studies by presence of epinephrine.

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Figure 6. Forest plot of comparison: 3 Mean pain difference in crossover studies with and without epinephrine, outcome: 3.1 Mean pain difference in crossover studies with and without epinephrine.

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Other factors, in addition to the pH of the solution injected, that could affect the pain associated with injection are needle size, speed of injection and temperature of the local anaesthetic solution (Redd 1990); however, these factors were not evaluated in this review.

The pain associated with local anaesthetic infiltration may be considered short lived and moderate in intensity, putting into question its clinical relevance and the need for efforts to decrease it. However, multiple attempts or injections at different locations are not uncommonly needed to complete clinical tasks such as intravenous cannulation or anaesthetizing soft tissue. In addition, some patients are likely to require similar procedures in the future. A previous poor experience may increase the patient's anxiety, interfere with the ability to cooperate and may even lead to refusal of a procedure that has proven benefits for them (Siddiqui 2007).

Alkalinization of lidocaine is most commonly performed by adding 1 ml of 8.4% sodium bicarbonate to 9 ml of 1% or 2% lidocaine. However, alkalinization of lidocaine could cause precipitation and loss of potency. No precipitation was mentioned in any of the studies, even with higher concentrations of bicarbonate. Buffered lidocaine has been shown to maintain pharmacologic activity when refrigerated for two weeks and to maintain clinical activity when stored for one week at room temperature (Bartfield 1993; Larson 1991; Stewart 1990). As for its antimicrobial activity, buffering lidocaine seems to potentiate the bacteriocidal effects (Thompson 1993).

Although the number of studies in some analyses was limited and heterogeneity existed despite our attempts to explain it, the results of this systematic review indicate that increasing the pH of commercial lidocaine solutions admixture immediately prior to clinical use decreases pain intensity and increases patient preference for the adjusted lidocaine. These findings were evident with or without epinephrine. A commercially produced buffered lidocaine would be likely to facilitate wider use.

Authors' conclusions

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Implications for practice

Increasing the pH of commercial lidocaine preparations with bicarbonate should be considered in order to systematically decrease pain on injection and augment patients' comfort and satisfaction. The acidic pH of commercial solutions is mostly a consequence of the need for effective preservation of the solution. Manufacturers should be encouraged to search for alternatives for local anaesthetic preservation that permit a more physiologic pH and abolish the need for pH adjustment prior to use.

Another alternative is the preparation of double vials. The upper vial will have bicarbonate as a dry substance and the lower vial the anaesthetic solution so that the bicarbonate can be introduced into the local anaesthetic solution at the time of injection.

Clinicians need to be aware that although the lidocaine concentration in alkalinized solutions remains constant over time, epinephrine concentrations in alkalinized lidocaine solutions decrease substantially over 24 hours (Robinson 2000).

Implications for research

We could not explain the large variation in the magnitude of pain decrease with buffered lidocaine. Therefore, we need a better understanding of the conditions or circumstances in which buffered lidocaine has maximum benefits.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

This work was in part supported by Saltonstall Fund for Pain Research, USA.

We would like to thank Anna Lee, Phil Wiffen, Scott Strassels and Kathie Godfrey for their help and editorial advice during the preparation of the protocol for the systematic review.

We would like to thank Anna Lee, Marialena Trivella, Mona Nasser, Scott Strassels, Milli Reddy, Anne Peticolas, Suzanne Cunliffe, Karen Hovhannisyan and Jane Cracknell for their help and editorial advice during the preparation of the current systematic review.

Characteristics of studies

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Characteristics of included studies [ordered by study ID]

Bartfield 1993
Methods Crossover double-blind RCT.
Participants Adults entering ED requiring digital nerve block. People with lidocaine allergy, altered mental status, or abnormal sensory examination of the digit were excluded. n = 31
Interventions Control: 2.5 ml (22.5 mg) 1% lidocaine with normal saline at a 9:1 ratio. Treatment: 2.5 ml (22.5 mg) 1% lidocaine with sodium bicarbonate at a 9:1 ratio.
Outcomes Pain intensity measured using VAS. Preference to interventions also reported. No withdrawals. Buffered lidocaine was significantly less painful than plain lidocaine.
Notes Mean difference in pain scores not reported, only graphed with P value given. We extracted the information from the graph.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "The order that the injections were given was predetermined and randomized". Comment: Method of randomization not described.
Allocation concealment? Yes Quote: "The same investigator prepared all study solutions and was not subsequently involved in data acquisition. The resulting study solutions were letter coded....and stored at room temperature". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Neither the physician administering nor the patient receiving the anaesthetic was aware of the contents of the vials". Comment: adequate blinding.
Incomplete outcome data addressed? All outcomes Yes Comment: There is no incomplete data addressed because it is a short term study.
Free of selective reporting? Yes No selective reporting.
Free of other bias? Yes Free of bias.
Carvalho 2007a
Methods Parallel double-blind RCT.
Participants 80 women were randomized to four groups, each group had 20 patients.
Interventions 1. Lidocaine 1.5%. 2. Buffered lidocaine (8.4% sodium bicarbonate) 1.5%. 3. Lidocaine 1.5% with epinephrine. 4. Buffered (8.4% sodium bicarbonate) 1.5% lidocaine with epinephrine 1:200000. A total of 2.5 cc were injected (0.5 cc as intradermal skin wheal and 2.0 cc subcutaneously) to prevent pain of epidural catheter insertion.
Outcomes Pain during local anaesthetic infiltration. No withdrawals.
Notes Because all the four treatment arms were of interest, we analysed this study as if the results would come from two different studies (lidocaine versus buffered lidocaine and lidocaine with epinephrine versus buffered lidocaine with epinephrine). This entry makes reference to groups 1 and 2.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "Group allocation was determined by computer-generated random numbers". Comment: Adequate sequence generation.
Allocation concealment? Yes Quote: "Group assignments were contained in opaque sealed envelopes". Comments: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Group assignments were contained in opaque envelopes to assure blinding of the study investigators". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Carvalho 2007b
Methods Parallel double-blind RCT.
Participants 80 women were randomized to four groups each group had 20 patients.
Interventions 1. Lidocaine 1.5%. 2. Buffered lidocaine (8.4% sodium bicarbonate) 1.5%. 3. Lidocaine 1.5% with epinephrine. 4. Buffered (8.4% sodium bicarbonate) 1.5% lidocaine with epinephrine 1:200000. A total of 2.5 cc were injected (0.5 cc as intradermal skin wheal and 2.0 cc subcutaneously) to prevent pain of epidural catheter insertion.
Outcomes Pain during local anaesthetic infiltration. No withdrawals.
Notes Because all the four treatment arms were of interest, we analysed this study as if the results would come from two different studies (lidocaine versus buffered lidocaine and lidocaine with epinephrine versus buffered lidocaine with epinephrine). This entry makes reference to groups 3 and 4.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "Group allocation was determined by computer-generated random numbers". Comment: Adequate sequence generation.
Allocation concealment? Yes Quote: "Group assignments were contained in opaque sealed envelopes". Comments: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Group assignments were contained in opaque envelopes to assure blinding of the study investigators". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Cornelius 1996
Methods Crossover double-blind RCT.
Participants People age 16-80 y entering accident and emergency department requiring digital nerve blockade. n = 98
Interventions Control intervention was 1.5ml (13.2 mg) unbuffered 1% lidocaine with normal saline at 4.4:0.6 ratio. Treatment intervention was 1.5 ml (13.2 mg) 1% lidocaine buffered 8.4% sodium bicarbonate at 4.4:0.6 ratio.
Outcomes Difference in pain intensity of infiltration measured using VAS. Preferences of control or treatment also listed. No withdrawals.
Notes
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "The study was prospective, randomized, and double blind in design. ...Each patient received an injection of both alkalinized lignocaine and non-alkalinized lignocaine. The order of injection and the side of injection were both randomized; patients with an even A&E number received the first injection on the radial side of the digit, whereas those with an odd A&E number received the first injection on the ulnar side. The lignocaine mixed with diluent A was always given first". Comment: adequate sequence generation.
Allocation concealment? Yes Quote: "Each patient was randomly assigned a trial pack which contained a 10 ml ampoule of lignocaine and two glass ampoules of diluent marked A and B. These had previously been prepared by the hospital pharmacy and had been randomized to contain either normal saline or 8.4% sodium bicarbonate". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Each patient was randomly assigned a trial pack which contained a 10 ml ampoule of lignocaine and two glass ampoules of diluent marked A and B. These had previously been prepared by the hospital pharmacy". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes It is a short term study and no incomplete data are addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other risk of bias.
Ernst 1996
Methods Parallel double-blind RCT.
Participants Adults with simple linear lacerations. 200 subjects enrolled and 180 analysed.
Interventions Subjects were randomized to four groups. 1. Lidocaine with epinephrine (n = 47). 2. Buffered lidocaine 1% with epinephrine (n = 46). 3. Buffered lidocaine 1% (n = 45). 4. Diphenhydramine with epinephrine (n = 42). Mean volume injected was 5.3 cc ± 2.8 cc.
Outcomes Pain during local anaesthetic infiltration (0 to 10 scale). Mean pain in lidocaine with epinephrine group was 2.7, mean pain in buffered lidocaine with epinephrine group was 1.8 and mean pain in buffered lidocaine was 1.8.
Notes Results of this study could not be included in the meta-analysis because the authors did not provide any measure of dispersions or exact P values for the treatment comparison(s) of interest.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "The study was a prospective, randomized, double blind....The.syringes were numbered 1-200 according to a computer-generated random table of numbers. Comment: Adequate sequence generation.
Allocation concealment? Yes Quote: "The solutions were prepared by one of the authors of the study who did not perform laceration repair." " All solutions were stored at room temperature and were available in 10-mL aliquots. The syringes were labelled only with the study number for the solution (numbers 1-200). Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote:" The syringes were labelled only with the study number for the solution (numbers 1-200). The physician performing the suturing and the patient were blinded to which solution was being used as an anaesthetic. Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Fatovich 1999
Methods Parallel double-blind RCT.
Participants Children and adults with simple lacerations. 135 adult subjects defined by the authors as individuals older than 10 years of age.
Interventions Control: lidocaine 1% plus normal saline (n = 69). Treatment: lidocaine 1% plus 8.4% sodium bicarbonate (n = 66).
Outcomes Pain during local anaesthetic infiltration (0 to 10 scale).
Notes For the analysis we used only the data for the "adult group" (10 years of age or older) because this group self reported the pain intensity with the infiltration of local anaesthetic.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "A prospective, randomized, double blind, placebo controlled trial" Eligible patients were randomly allocated with the use of opaque sealed envelopes. Comment: Adequate sequence generation.
Allocation concealment? Yes Quote: "Opaque envelopes". "A manufacturing pharmacist prepared the materials." Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Each envelope contained ... a unique consecutive identification number assigned". "They also contained a 5 mL ampoule of 1% plain lidocaine, identical sealed vials containing study drugs." Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Fitton 1996
Methods Crossover double-blind RCT.
Participants Forty adults and children receiving bilateral pinnaplasty. In 30 subjects the solutions were evaluated at room temperature and in 10 the solutions were evaluated at body temperature.
Interventions Control Intervention I: 6-10ml (60-100mg) 1% lidocaine with epinephrine at 1:200,000 ratio and room temperature. Control Intervention II: 6-10ml (60-100mg) 1% lidocaine with epinephrine at 1:200,000 ratio at body temperature. Treatment Intervention I and II: 6-10ml (54-90 mg) 1% lidocaine with epinephrine at 1:200,000 ratio at room temperature.
Outcomes Pain intensity measured on linear analogue scale from 0 to 100. Results reported as mean difference with standard deviation (SD). No withdrawals.
Notes Results converted to 0 to 10 scale by review team. Results comparing groups receiving differing temperatures of interventions were excluded from the meta-analysis.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Randomization was performed using pre-arranged sealed envelopes in which a card was marked “Infiltrate with buffered to the right (or left) ear and operate on the right (or left) ear first”, resulting in four possible combinations. Comment: Adequate sequence generation.
Allocation concealment? Yes Quote: "The scrub nurse prepared the control and test solutions". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Test solutions blinded to the operating surgeon and the patient". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Gershon 1991
Methods Parallel double-blind RCT.
Participants 100 adults of ASA physical status I or II receiving intradermal anaesthesia prior to IV cannulation. Control n = 50. Treatment n = 50.
Interventions Control: 0.25ml (1.67mg) 1% lidocaine with sterile water at a 2:1 ratio. Treatment: 0.25ml (1.67mg) 1% lidocaine with 8.4% sodium bicarbonate at a 2:1 ratio.
Outcomes Pain intensity measured using VAS. No withdrawals. Mean pain in plain lidocaine group = 1.24. Mean pain in buffered lidocaine group = 0.81.
Notes Measure of dispersion or exact P values not reported and therefore study not included in the meta-analysis.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "They were randomized to receive 0.25 ml intradermal anaesthesia with either lidocaine plain (n = 50) or lidocaine adjusted to a pH of 7.3 with sodium bicarbonate (n = 50)". Comment: Unclear method of randomization
Allocation concealment? Unclear Comment: Unclear allocation concealment.
Blinding? All outcomes Unclear Quote: "The investigator was blinded to the anaesthetic". Comment: Unclear method to ensure investigators blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Martin 1990
Methods Parallel double-blind RCT.
Participants 100 adult patients requiring IV cannulation prior to surgery. Buffered group n = 26. Buffered group with epinephrine n = 24. Plain n = 22. Plain with epinephrine n = 28.
Interventions Control I: 0.1ml (1mg) 1% lidocaine. Control II: 0.1ml (1mg) 1% lidocaine with epinephrine at 1:200,000 ratio. Treatment I: 0.1ml (0.91mg) 1% lidocaine with 8.4% sodium bicarbonate at 10:1 ratio. Treatment II: 0.1ml (0.91mg) 1% lidocaine with epinephrine at 1:200,000 ratio and 8.4% sodium bicarbonate at 10:1 ratio.
Outcomes Pain intensity measured using descriptive scale. Buffered lidocaine produced less pain at infiltration than unbuffered lidocaine. No withdrawals.
Notes Not included in the meta-analysis as used medians not means.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "The patient was then randomly allocated (by means of a random number generator)". Comment: Adequate sequence generation.
Allocation concealment? Unclear B - Unclear.
Blinding? All outcomes Yes Quote: "..double-blind manner to receive one of the four prepared local anaesthetic solutions". Comment: Unclear method to ensure double blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Masters 1998
Methods Crossover double-blind RCT.
Participants Forty individuals of unspecified age undergoing various elective outpatient procedures requiring subcutaneous lidocaine injection were included.
Interventions Control: 2.2ml (40mg) of 2% lidocaine with epinephrine at 1:80,000 ratio. Treatment: 2.2ml (40mg) of 2% lidocaine with epinephrine at 1:80,000 ratio with 8.4% sodium bicarbonate at 10:1 ratio.
Outcomes Pain intensity measured on VAS. Preferences of control or treatment also listed. No withdrawals.
Notes  
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "Patients were randomized for the side of the first injection and either the buffered solution or the control solution first". Comment: Unclear method of sequence generation.
Allocation concealment? Yes Quote: "Inject comparable volumes". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Both the surgeon and the patient were blind to which solution was being injected into each side. The seven surgeons participating in the study were asked to inject comparable volumes of each solution in their normal manner". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Metzinger 1994
Methods Crossover double-blind RCT.
Participants Adult patients undergoing blepharoplasty.
Interventions 40 men and women received 5 cc of lidocaine 2% with 1:100000 epinephrine and 1 cc of 8.4% sodium bicarbonate or 6 cc of lidocaine 2% with 1:100000 epinephrine. The volume injected to each side of the face was 3 cc.
Outcomes Pain during local anaesthetic infiltration (0 to 10 scale).
Notes Method of randomization was not described.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "Crossover double-blind RCT". Comment: Method of sequence generation unclear.
Allocation concealment? Yes Quote: "The surgeon injecting the solution was unaware of which formula he was using".
Blinding? All outcomes Yes Quote: "The surgeon injecting the solution was unaware of which formula he was using. Patients knew they were going to be injected with one of the two different solutions." Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Nakayama 2001a
Methods Parallel double-blind RCT.
Participants Adult patients undergoing surgery with epidural anaesthesia. 50 patients.
Interventions 50 patients were randomized to two groups. Control: lidocaine 1% with preservative-free sterile water at a ratio (n = 25). Treatment: alkalinized lidocaine with 8.4% sodium bicarbonate at a ratio of 1:10 (n = 25). A volume of 0.2 ml of the corresponding solution was injected in the dorsum of left hand (for IV cannulation), then the same solution was injected in the back (for epidural catheter insertion); 0.5 cc intradermally and 1 cc subcutaneously.
Outcomes Pain during local anaesthetic infiltration (0 to 10 scale).
Notes Authors separately reported pain intensity by site of infiltration (hand and back). Therefore, we had to analyse this study as if the results came from two different studies. This approach leads to an overestimation of the sample size (only 50 patients were included but the analysis implies 100 subjects). This study corresponds to hand infiltration.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "A randomized double blind study was undertaken in patients who were allocated to receive topical anaesthesia with either plain or alkalinized lidocaine". "Patients were randomly allocated in a double blinded manner." Comment: Unclear method of randomization.
Allocation concealment? Unclear Unclear method of allocation concealment.
Blinding? All outcomes Yes Quote: "The patients were blinded to these procedures." "..the investigators were blinded to the patient's group." Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Nakayama 2001b
Methods Parallel double-blind RCT.
Participants Adult patients undergoing surgery with epidural anaesthesia.
Interventions 50 patients were randomized to receive lidocaine 1% (n=25) or alkalinized lidocaine (n=25). 8.4% sodium bicarbonate or preservative-free sterile water was added to lidocaine 1% at a ratio of 1:100. A volume of 2 ml of the corresponding solution was injected in the dorsum of left hand (for IV cannulation), then the same solution was injected in the back (for epidural catheter insertion); 0.5 cc intradermally and 1 cc subcutaneously.
Outcomes Pain during local anaesthetic infiltration (0 to 10 scale).
Notes Authors separately reported pain intensity by site of infiltration (hand and back). Therefore, we had to analyse this study as if the results came from two different studies. This approach leads to an overestimation of the sample size (only 50 patients were included but the analysis implies 100 subjects). This study corresponds to back infiltration.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "A randomized double blind study was undertaken in patients who were allocated to receive topical anaesthesia with either plain or alkalinized lidocaine". "Patients were randomly allocated in a double blinded manner." Comment: Unclear method of randomization.
Allocation concealment? Unclear Unclear method of allocation concealment.
Blinding? All outcomes Yes Quote: "The patients were blinded to these procedures." "..the investigators were blinded to the patient's group." Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Nelson 1995
Methods Crossover double-blind RCT.
Participants Adult women receiving Norplant injection. Total n = 46.
Interventions Control Intervention: 2.45-2.63 ml (49.0-52.6 mg) 2% lidocaine. Treatment Intervention: 2.45-2.67 ml (40.84 - 44.50 mg) 2% lidocaine with 7.4% sodium bicarbonate at 5:1 ratio.
Outcomes Pain intensity measured using 0-10 numeric scale. Results reported as mean difference in pain intensity with P value. Patient preference also reported. No withdrawals.
Notes We calculated the standard error.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "Women were randomly assigned to one of two groups". Comment: Method of randomization was unclear.
Allocation concealment? Yes Quote: "The mixtures were infiltrated at a steady rate using the 22-gauge needles provided in the Norplant System kit. The pH measurements were made by an Orion Research digital ion analyser model 501 and agreed with package labelling". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Patients and all personnel were blinded to the solutions. This was possible because the appearance of the two solutions is identical after mixing". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Nuttall 1993
Methods Parallel double-blind RCT.
Participants 280 healthy adults scheduled for elective surgery. Lidocaine was used to anaesthetize skin before IV cannulation. Lidocaine with preservative group: n = 40. Alkalinized lidocaine with preservative group: n = 40. The rest of subjects were randomized to normal saline, chloroprocaine.
Interventions Control intervention: 0.5 ml (5.0 mg) 1% lidocaine with preservative. Treatment Intervention: 0.5 ml (4.55 mg) 1% lidocaine with preservative and 8.4% sodium bicarbonate at 10:1 ratio.
Outcomes Pain intensity measured with VAS. Results reported as mean ± standard error. No withdrawals.
Notes We calculated the standard deviation.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "The patients were randomized into seven groups, each receiving a different pre-IV anaesthetic". Comment: Method of randomization unclear.
Allocation concealment? Unclear B - Unclear.
Blinding? All outcomes Unclear Quote: "The patient and the investigator were blinded to type of drug". Comment: Adequate blinding as the syringes were identical but it is not mentioned who prepared the study solutions.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Orlinsky 1992
Methods Crossover double-blind RCT.
Participants Adults with laceration greater than 2 cm in length requiring sutures. People with a history of allergic or adverse reactions to lidocaine or sodium bicarbonate, an altered mental status, and those with major trauma posing a distraction to pain perception were excluded. n = 61.
Interventions Control intervention was 0.5 ml (4.55 mg) unbuffered 1% lidocaine with normal saline at 10:1 ratio. Treatment intervention was 0.5 ml (4.55 mg) 1% lidocaine buffered 7.5% sodium bicarbonate at 10:1 ratio.
Outcomes Pain intensity measured using VAS. Patient preferences. Patients preferred buffered lidocaine over unbuffered lidocaine.
Notes Pain intensity was not reported by treatment received but by patient preference and therefore the results were not included in the meta-analysis for pain intensity.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "In all 4 groups each subject was given the injection in random order by a randomization code". Comment: Randomization was not used for grouping of the patients but for site of injection and type of solution. Furthermore method of randomization code generation was not clear.
Allocation concealment? Unclear Method not described.
Blinding? All outcomes Yes Quote: "Neither subject nor investigator were aware of the contents of any syringe before randomization code was broken". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Richtsmeier 1995
Methods Crossover double-blind RCT.
Participants Seven children age 6-18 with each one receiving multiple injections (101 total interventions) for blood vessel cannulation prior to haemodialysis. They were randomized by which site (arterial or venous) would receive the buffered lidocaine. Children who did not speak English or who had a chronological or mental age of less than six years, as determined by the Peabody Picture Vocabulary Test, were excluded. Oucher-rated events: n = 101. VAS-rated events: n = 48.
Interventions Control intervention: 0.5 ml (5 mg) unbuffered 1% lidocaine. Treatment intervention: 0.5 ml (4.55 mg) 1% lidocaine with 8.4% sodium bicarbonate at 10:1 ratio.
Outcomes Pain of infiltration measured using VAS and Oucher (FACES) scales and third party behavioral observation. No withdrawals. Authors reported no difference in pain intensity or pain behavior between buffered and unbuffered lidocaine.
Notes Only three of the seven children reported pain using the VAS. Due to the use of the Oucher scale the results of this study were not included in the meta-analysis.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "This study was a double-blind randomized comparison of buffered versus unbuffered lidocaine". "The local anaesthetic used for a subject's cannulation of the arterial or venous site on a given day was randomized to be either unbuffered lidocaine (L) or buffered lidocaine (BL)." Comment: Unclear method of randomization.
Allocation concealment? Yes Quote: "For each subject undergoing haemodialysis, one syringe containing L and one containing BL were prepared by a nurse different from the nurse who administered the lidocaine". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Nurses, raters, and subjects were blind to syringe contents". Comments: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Samdal 1994
Methods Crossover double-blind RCT.
Participants 21 adults receiving either blepharoplasty, mammoplasty, or liposuction. Group II: n = 7. Group III: n = 6. Group IV: n = 8.
Interventions Controls-II: 5 ml (43.5 mg) 1% lidocaine with epinephrine at a 1:200,000 ratio and normal saline at a 20:3 ratio. Control III: 180 ml (600 mg) 1% lidocaine with epinephrine at a 1:200,000 ratio and normal saline at a 20:3 ratio (69 ml) with additional normal saline (111 ml). Control IV: 400-600 ml (368.5-537.5 mg) 1% lidocaine with epinephrine at a 1:200,000 ratio and normal saline at a 20:3 ratio (115 ml) with additional normal saline (1000 ml). Treatment II: 5 ml (43.5 mg) 1% lidocaine with epinephrine at a 1:200,000 ratio and sodium bicarbonate at a 20:3 ratio. Treatment III: 180ml (600mg) 1% lidocaine with epinephrine at a 1:200,000 ratio and sodium bicarbonate at a 20:3 ratio (69 ml) with additional normal saline (111 ml). Treatment IV: 400-600ml (368.5-537.5mg) 1% lidocaine with epinephrine at a 1:200,000 ratio and sodium bicarbonate at a 20:3 ratio (115 ml) with additional normal saline (1000 ml).
Outcomes Pain intensity measured using VAS. Patient preference of intervention reported. No withdrawals.
Notes Group I excluded because healthy volunteers. Group III participants given IV diazepam to be sedated prior to injection. Results were reported as bar graphs, not numeric data, so we abstracted the values from the graphs and pooled the data from the 3 groups.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "A randomized double blind, randomized controlled trial ....". Comment: Unclear method of randomization.
Allocation concealment? Unclear Unclear method of allocation concealment.
Blinding? All outcomes Unclear Unclear method of blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Sapin 1991
Methods Crossover double-blind RCT.
Participants Adults receiving bilateral cardiac catheterization with femoral approach. n = 20.
Interventions Control: 15-20 ml (150-200 mg) 1% lidocaine. Treatment: 15-20 ml (146-194 mg) 1% lidocaine with sodium bicarbonate at approximately 200:6 ratio
Outcomes Pain intensity measured using linear numeric scale from 0 to 10. Patient preference also reported. No withdrawals.
Notes All participants received 25-50 mg diphenhydramine and up to 5 mg diazepam 1 hour prior to the procedure.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "The lidocaine solution used and the site of injection were randomized in a double blinded manner". Comment: Unclear method of randomization.
Allocation concealment? Yes Quote: "Lidocaine solution was prepared in bulk by the hospital pharmacy". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "10-15 ml of the blinded anaesthetic was infiltrated slowly". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Steinbrook 1993
Methods Parallel double-blind RCT.
Participants 184 adults requiring IV cannulation prior to surgery. Buffered group n = 89. Control n = 95.
Interventions Control: 0.1-0.2ml (1-2mg) 1% lidocaine. Treatment: 0.1-0.2ml (0.91-1.82mg) 1% lidocaine with sodium bicarbonate at a 10:1 ratio.
Outcomes Pain intensity measured using VAS. No withdrawals.
Notes Results converted to 0 to 10 scale by review team.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "Randomized, double blind study". Comments: Unclear method of randomization.
Allocation concealment? Yes Quote: "Multidose vials with or without the random addition of 5 mEq od NaHCO were prepared daily by the pharmacy". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Neither the individual performing the injection and catheterization nor the patients were aware of the composition of the local anaesthetic". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Vossinakis 2004
Methods Crossover double-blind RCT.
Participants Adults receiving bilateral open carpal tunnel decompression. People with known allergy to lidocaine and pregnant or breastfeeding women were excluded. n = 21.
Interventions Control: 15 ml (150 mg) 1% lidocaine with epinephrine at 1:200000 ratio. Treatment: 15 ml (125 mg) 1% lidocaine with epinephrine at 1:200000 ratio with 8.4% sodium bicarbonate at 5:1 ratio.
Outcomes Pain intensity measured using VAS. Patient preference also reported. No withdrawals.
Notes  
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "Randomization of the order of use of the two solutions was performed using sealed envelopes stating the type of solution for the first procedure for each patient". Comment: Adequate sequence randomization.
Allocation concealment? Yes Quote: "The solutions were prepared immediately preoperatively and administered by an assistant who withheld the information until completion of the statistical analysis". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "The order of these two anaesthetics was randomized and neither the patient nor the operating surgeon knew which type of solution was injected in each hand". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Watts 2003
Methods Parallel double-blind RCT.
Participants 64 adults receiving open carpal tunnel decompression. Buffered group n = 32. Control n = 32.
Interventions Control: 5.5 ml (100 mg) of 2% lidocaine with 0.9% normal saline at 10:1 ratio. Treatment: 5.5 ml (100 mg) of 2% lidocaine with 8.6% sodium bicarbonate at 10:1 ratio.
Outcomes Pain intensity measured using VAS and descriptive scales. Anxiety about receiving injection again also reported. No withdrawals.
Notes Results converted to 0 to 10 scale by review team.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "On recruitment they were allocated a study number. Allocation of study numbers to the case or control group was performed by block randomization". Comment: Adequate sequence randomization.
Allocation concealment? Yes Quote: "The hospital pharmacy provided syringes containing solutions...prepared on the day of operation". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "The syringes were labelled with the patient's study number only, in order to blind the investigators to the nature of the solution used". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Unclear No data on baseline similarity between groups. Free of other bias.
Yiannakopoulos 2004
Methods Parallel double-blind RCT.
Participants 42 adults receiving open carpal tunnel decompression. Buffered group n = 22. Control group n = 20.
Interventions Control: 10 ml (90 mg) 1% lidocaine with 0.9% saline at a 9:1 ratio Treatment 10 ml (90 mg) 1% lidocaine with 8.4% sodium bicarbonate at a 9:1 ratio.
Outcomes Pain intensity measured using VAS. Patient satisfaction reported based on whether patient would be willing to receive the same injection in the other wrist, should they need it. No withdrawals.
Notes Author was contacted for blinding and randomization information. Author responded they used a random number table and the study was double blind. Results from a third study arm testing warmed, alkalinized lidocaine were excluded.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Random numbers table (information was given to us by contacting the author).
Allocation concealment? Unclear B - Unclear.
Blinding? All outcomes Yes Study was double blinded.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Younis 2004
Methods Crossover double-blind RCT.
Participants 85 adults undergoing bilateral vasectomy.
Interventions Patients received either commercial xylocaine 1% with 1:200,000 adrenaline, or buffered preparation with the addition of 0.5 ml sodium bicarbonate. Patients were randomly allocated to one of the four possible procedural groups:
  • 1.
    buffered preparation into left side first and commercial into right side,
  • 2.
    buffered preparation into right side first and commercial into left side,
  • 3.
    commercial preparation into left side first and buffered into right side,
  • 4.
    commercial preparation into right side first and buffered into left side.
Outcomes Pain intensity at infiltration and at procedure using a 0-10 visual analogue scale.
Notes We calculated mean and standard error (SE) using the data provided by the study.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Yes Quote: "Patients were randomly allocated to one of the four possible procedural groups from sealed instructions". Comment: Adequate sequence generation.
Allocation concealment? Yes Quote: "The scrub nurse was responsible for opening the instructions, ensuring that the correct preparation was given to the surgeon...". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "..ensuring that both surgeon and patient were blind to the type of preparation". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.
Yuen 1999
  1. ED: emergency department

  2. HT: hyperthermia treatment

  3. IV: intravenous

  4. RCT: randomized controlled trial

  5. SEM: standard error of the mean

  6. VAS: visual analogue scale

  7. XRT: radiation

Methods Crossover double-blind RCT.
Participants Adults receiving bilateral eyelid procedures, n = 10.
Interventions Control: 6 ml of 2% lidocaine with epinephrine at a 1:100,000 ratio. Treatment: 6 ml of 2% lidocaine with epinephrine at a 1:100,000 ratio and 8.4% sodium bicarbonate at a 9:2 ratio.
Outcomes Pain intensity measured using a 5-point descriptive scale. Patient preference was also reported. No withdrawals. Buffered lidocaine less painful than unbuffered lidocaine.
Notes Measure of dispersion not reported. Exact P values were not reported. The study was not included in the meta-analysis for pain intensity.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation? Unclear Quote: "Patients were randomized into one of three experimental groups". Comment: Unclear method of sequence generation.
Allocation concealment? Yes Quote: "Injection solutions were prepared by an assistant before surgery". Comment: Adequate allocation concealment.
Blinding? All outcomes Yes Quote: "Neither the surgeon nor the patient were aware of which solutions were being used". Comment: Adequate blinding.
Incomplete outcome data addressed? All outcomes Yes The study is a short term study and no incomplete data were addressed.
Free of selective reporting? Yes Free of selective reporting.
Free of other bias? Yes Free of other bias.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
  1. RCT: randomized controlled trial

Acosta 1997 Not a double-blinded RCT.
Ball 2006 Not randomized.
Barnett 1992 Unit of analysis was not the individual but the number of "fields treated".
Bartfield 1992 Healthy volunteers as subjects.
Benlabed 1990 Improper interventions.
Bowles 1995 Healthy volunteers as subjects.
Brown 2004 Improper interventions.
Burns 2006 Healthy volunteers as subjects.
Capogna 1993 Improper outcomes.
Christoph 1988 Healthy volunteers as subjects.
Connelly 1996 Not randomized.
DiFazio 1986 Improper outcomes.
Eccarius 1990 Improper randomizations.
Elhakim 1998 Improper outcomes.
Farrell 1995 Healthy volunteers as subjects.
Friedman 1997 Healthy volunteers as subjects.
Gaggero 1995 Improper outcomes.
Gormley 1995 Improper outcomes.
Hinshaw 1995 Improper interventions.
Iwama 2001 Healthy volunteers as subjects and improper outcomes.
Jones 1998 Improper interventions.
Kelsaka 2006 Improper outcomes.
Koscielniak-Nielsen Improper interventions.
Larson 1991 Healthy volunteers as subjects.
Long 1991 Healthy volunteers as subjects.
Lugo-Janer 1993 Not a double-blinded RCT.
Manka 1991 Outcome assessed by third party observer.
Marica 2002 Healthy volunteers as subjects.
Matsumoto 1994 Not randomized.
McGlone 1990 Healthy volunteers as subjects.
McKay 1987 Healthy volunteers as subjects.
Metzinger 1992 Improper interventions.
Minasian 2000 Improper interventions.
Moharib 2002 Improper interventions.
Moreno-Jimenez 2008 Unit of analysis was not the individual but the site of infiltration.
Nevarre 1998 Healthy volunteers as subjects.
Ng 1999 Improper interventions.
Ong 2000 Not a double-blinded RCT.
Ozer 2005 Improper interventions.
Palmon 1998 Healthy volunteers as subjects.
Parham 1996 Healthy volunteers as subjects.
Primosch 1996 Healthy volunteers as subjects.
Redd 1990 Healthy volunteers as subjects.
Ririe 1997 Improper outcomes.
Roberts 1993 Improper interventions.
Ruegg 2009 The study is not included in the analysis because for the period of time of interest (at time of skin injection) authors did not report mean difference between paired observations or the P value for this specific point in time.
Scarfone 1998 Healthy volunteers as subjects.
Schooff 1998 Not a double-blinded RCT.
Stang 1997 Outcome assessed by third party observer.
Stewart 1989 Not randomized.
Stewart 1990 Not randomized.
Tanaka 2001 Healthy volunteers as subjects.
Yang 2006 Not a double-blinded RCT.
Zehetmayer 1997 Improper interventions.

Characteristics of studies awaiting assessment [ordered by study ID]

Da Fonseca 2009
Methods RCT.
Participants 25 patients undergoing upper blepharoplasty.
Interventions Control intervention: 2% lidocaine with 1:100,000 epinephrine. Treatment intervention: 2% lidocaine with 1:100,000 epinephrine buffered 9:1 with 8.4% sodium bicarbonate.
Outcomes Pain on injection using a 4-point pain scale.
Notes The study is in Spanish.
Jaichandran 2010
Methods RCT.
Participants 200 patients undergoing cataract surgery.
Interventions Group A: warmed plain lidocaine. Group B: alkalinized plain lidocaine. Group C: warmed and alkalinized lidocaine. Control Group: Plain lidocaine at room temperature.
Outcomes Pain of injection. Efficacy of anaesthetic solution.
Notes  
Narvaez 2010
Methods RCT.
Participants 39 patients undergoing combined upper eyelid blepharoplasty and levator advancement ptosis repair surgery with local anaesthesia.
Interventions Control intervention: Plain lidocaine with epinephrine. Treatment intervention: Buffered lidocaine with epinephrine.
Outcomes Short term complications.
Notes  

Data and analyses

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES
Table Comparison 1.. Mean pain difference in parallel-group studies by presence of epinephrine
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean difference in parallel studies with and without epinephrine 9 685 Mean Difference (IV, Random, 95% CI) -0.95 [-1.42, -0.49]
1.1 Without epinephrine 8 645 Mean Difference (IV, Random, 95% CI) -0.93 [-1.41, -0.45]
1.2 With epinephrine 1 40 Mean Difference (IV, Random, 95% CI) -1.30 [-2.54, -0.06]
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Figure Analysis 1.1. Comparison 1 Mean pain difference in parallel-group studies by presence of epinephrine, Outcome 1 Mean difference in parallel studies with and without epinephrine.

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Table Comparison 2.. Mean pain difference in parallel-group studies by pH of solution
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain difference in parallel studies by pH of solution 7 605 Mean Difference (IV, Random, 95% CI) -0.98 [-1.49, -0.47]
1.1 Buffered pH < 7.35 3 180 Mean Difference (IV, Random, 95% CI) -1.24 [-2.04, -0.44]
1.2 Buffered pH >=7.35 4 425 Mean Difference (IV, Random, 95% CI) -0.81 [-1.46, -0.15]
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Figure Analysis 2.1. Comparison 2 Mean pain difference in parallel-group studies by pH of solution, Outcome 1 Mean pain difference in parallel studies by pH of solution.

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Table Comparison 3.. Mean pain difference in crossover studies by presence of epinephrine
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain difference in crossover studies with and without epinephrine 10   Mean pain difference (Random, 95% CI) -1.98 [-2.62, -1.34]
1.1 Without epinephrine 4   Mean pain difference (Random, 95% CI) -1.15 [-1.67, -0.63]
1.2 With epinephrine 6   Mean pain difference (Random, 95% CI) -2.46 [-3.20, -1.72]
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Figure Analysis 3.1. Comparison 3 Mean pain difference in crossover studies by presence of epinephrine, Outcome 1 Mean pain difference in crossover studies with and without epinephrine.

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Table Comparison 4.. Mean pain difference in crossover studies by pH of solution
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain difference in crossover studies by pH of solution 10   Mean pain difference (Random, 95% CI) -1.98 [-2.62, -1.34]
1.1 Buffered pH < 7.35 6   Mean pain difference (Random, 95% CI) -1.70 [-2.19, -1.22]
1.2 Buffered pH >=7.35 4   Mean pain difference (Random, 95% CI) -2.44 [-3.96, -0.92]
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Figure Analysis 4.1. Comparison 4 Mean pain difference in crossover studies by pH of solution, Outcome 1 Mean pain difference in crossover studies by pH of solution.

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Table Comparison 5.. Preference
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Preference in cross over studies 8   Odds ratio (Random, 95% CI) 3.01 [2.19, 4.15]
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Figure Analysis 5.1. Comparison 5 Preference, Outcome 1 Preference in cross over studies.

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Table Comparison 6.. Effect of risk of bias on mean pain intensity in parallel-group studies (low risk versus high risk)
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain difference 9 685 Mean Difference (IV, Random, 95% CI) -0.95 [-1.42, -0.49]
1.1 Low risk of bias 5 463 Mean Difference (IV, Random, 95% CI) -0.30 [-0.41, -0.19]
1.2 High risk of bias 4 222 Mean Difference (IV, Random, 95% CI) -1.54 [-2.39, -0.68]
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Figure Analysis 6.1. Comparison 6 Effect of risk of bias on mean pain intensity in parallel-group studies (low risk versus high risk), Outcome 1 Mean pain difference.

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Table Comparison 7.. Effect of volume on mean pain intensity in parallel-group studies
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain intensity in parallel studies 9 685 Mean Difference (IV, Random, 95% CI) -0.95 [-1.42, -0.49]
1.1 Low volume 4 364 Mean Difference (IV, Random, 95% CI) -0.97 [-1.58, -0.36]
1.2 High volume 5 321 Mean Difference (IV, Random, 95% CI) -0.94 [-1.88, 0.01]
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Figure Analysis 7.1. Comparison 7 Effect of volume on mean pain intensity in parallel-group studies, Outcome 1 Mean pain intensity in parallel studies.

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Table Comparison 8.. Effect of volume on mean pain intensity in crossover studies
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain difference in crossover studies 10   Mean pain difference (Random, 95% CI) -1.98 [-2.62, -1.34]
1.1 Low volume 2   Mean pain difference (Random, 95% CI) -0.97 [-1.57, -0.37]
1.2 High volume 8   Mean pain difference (Random, 95% CI) -2.22 [-2.87, -1.58]
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Figure Analysis 8.1. Comparison 8 Effect of volume on mean pain intensity in crossover studies, Outcome 1 Mean pain difference in crossover studies.

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Table Comparison 9.. Effect of type of procedure on mean pain intensity in parallel-group studies
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain intensity by type of procedure 9 685 Mean Difference (IV, Random, 95% CI) -0.95 [-1.42, -0.49]
1.1 Intravenous cannulation 3 314 Mean Difference (IV, Random, 95% CI) -0.60 [-0.91, -0.28]
1.2 Nerve block or insertion of epidural catheter 3 130 Mean Difference (IV, Random, 95% CI) -1.36 [-2.43, -0.30]
1.3 Small surgical procedures 3 241 Mean Difference (IV, Random, 95% CI) -0.98 [-2.28, 0.32]
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Figure Analysis 9.1. Comparison 9 Effect of type of procedure on mean pain intensity in parallel-group studies, Outcome 1 Mean pain intensity by type of procedure.

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Table Comparison 10.. Effect of type of procedure on mean pain intensity in crossover studies
Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Mean pain intensity by type of procedure 10   (Random, 95% CI) 0.14 [0.07, 0.26]
1.1 Intravenous cannulation 1   (Random, 95% CI) 0.33 [0.14, 0.82]
1.2 Nerve block or insertion of epidural catheter 2   (Random, 95% CI) 0.28 [0.08, 0.91]
1.3 Small surgical procedures 7   (Random, 95% CI) 0.10 [0.05, 0.20]
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Figure Analysis 10.1. Comparison 10 Effect of type of procedure on mean pain intensity in crossover studies, Outcome 1 Mean pain intensity by type of procedure.

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Appendices

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Appendix 1. Search strategy for MEDLINE (Ovid SP)

1. exp Lidocaine/ or Anesthetics/ or Anesthetics, Local/

2. (lidocain* or lignocain* or xylocaine).mp. or an?esthetic*.ti,ab.

3. 1 or 2

4. (pain* adj3 inject*).mp. or (pain* or nociception* or inject*).ti,ab.

5. exp Pain/ or exp Pain Measurement/ or Injections/

6. 4 or 5

7. exp Sodium Bicarbonate/ or exp Bicarbonates/ or exp Hydrogen-Ion Concentration/

8. (neutral* or bicarb* or alkalin* or pH).mp.

9. 8 or 7

10. 6 and 3 and 9

11. ((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (animals not (humans and animals)).sh.

12. 11 and 10

Appendix 2. Search strategy for CENTRAL (The Cochrane Library)

#1 MeSH descriptor Lidocaine explode all trees

#2 MeSH descriptor Anesthetics explode all trees

#3 MeSH descriptor Anesthetics, Local explode all trees

#4 lidocain* or lignocain* or xylocaine or (an?esthetic*):ti,ab

#5 (#1 OR #2 OR #3 OR #4)

#6 MeSH descriptor Pain explode all trees

#7 MeSH descriptor Pain Measurement explode all trees

#8 MeSH descriptor Injections, this term only

#9 (pain* near inject*) or (pain* or nociception* or inject*):ti,ab

#10 (#6 OR #7 OR #8 OR #9)

#11 MeSH descriptor Sodium Bicarbonate explode all trees

#12 MeSH descriptor Bicarbonates explode all trees

#13 MeSH descriptor Hydrogen-Ion Concentration explode all trees

#14 neutral* or bicarb* or alkalin* or pH

#15 (#11 OR #12 OR #13 OR #14)

#16 (#5 AND #10 AND #15)

Appendix 3. Search strategy for EMBASE (Ovid SP)

1. exp Lidocaine/ or exp local-anesthetic-agent/ or exp anesthetic-agent/

2. (lidocain* or lignocain* or xylocaine).mp. or an?esthetic*.ti,ab.

3. 1 or 2

4. exp pain/ or exp nociception/ or exp Pain Assessment/ or Sensory system examination/ or exp injection pain/ or injection/

5. (pain* adj3 inject*).mp. or (pain* or nociception* or inject*).ti,ab.

6. 4 or 5

7. exp bicarbonate/ or exp pH/

8. (neutral* or bicarb* or alkalin* or pH).mp.

9. 8 or 7

10. 6 and 3 and 9

11. (RANDOMIZED-CONTROLLED-TRIAL/ or RANDOMIZATION/ or CONTROLLED-STUDY/ or MULTICENTER-STUDY/ or PHASE-3-CLINICAL-TRIAL/ or PHASE-4-CLINICAL-TRIAL/ or DOUBLE-BLIND-PROCEDURE/ or SINGLE-BLIND-PROCEDURE/ or (RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or VOLUNTEER* or ((SINGL* or DOUBL* or TREBL* or TRIPL*) adj3 (BLIND* or MASK*))).ti,ab.) not (animals not (humans and animals)).sh.

12. 11 and 10

Appendix 4. Search strategy for LILACS (BIREME)

("LIDOCAINE" or "LIDOCAINES" or "LIGNOCAINE" or "Local anesthesia" ) and ("injections" or "Buffered solution$" or "Pain" or "alkalization")

Appendix 5. Search strategy for CINAHL (EBSCOhost)

S1 (MM "Lidocaine")

S2 (MH "Anesthetics") or (MM "Anesthetics, Local+") S3 TX lidocain* or lignocain* or xylocaine or an?esthetic*

S4 S1 or S2 or S3

S5 (MM "Pain+")

S6 (MM "Pain Measurement")

S7 (MH "Injections")

S8 TX (pain* and inject*) or pain* or nociception*

S9 S5 or S6 or S7 or S8 S10 (MM "Sodium Bicarbonate") or (MM "Bicarbonates+")

S11 (MM "Hydrogen-Ion Concentration+")

S12 TX neutral* or bicarb* or alkalin* or pH

S13 S10 or S11 or S12

S14 S4 and S9 and S13

Appendix 6. Search strategy for ISI Web of Science

#1TS=(lidocain* or lignocain* or xylocaine or anesthetic* or anaesthetic*)

#2TS=(pain* SAME inject*) or TS=(pain* or nociception* or inject*)

#3TS=(neutral* or bicarb* or alkalin* or pH)

#4#3 AND #2 AND #1

#5TS=(RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or VOLUNTEER*) or TS=((SINGL* or DOUBL* or TREBL* or TRIPL*) SAME (BLIND* or MASK*))

#6#5 AND #4

Contributions of authors

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Conceiving the review: Jana Hudcova (JH), Roman Schumann (RS)

Co-ordinating the review: M Soledad Cepeda (MSC), Aikaterini Tzortzopoulou (AT), Michael Thackrey (MT)

Undertaking manual searches: MT, JH, Preeti Arora (PA)

Screening search results: MT, JH, PA

Organizing retrieval of papers: MT, JH, PA

Screening retrieved papers against inclusion criteria: MT, AT, JH, PA, MSC

Appraising quality of papers: MT, AT, JH, PA, MSC

Abstracting data from papers: MT, AT, JH, PA, MSC

Writing to authors of papers for additional information: MT, JH

Providing additional data about papers: MT, AT, JH, MSC

Obtaining and screening data on unpublished studies: MT, JH

Data management for the review: MT, MSC

Entering data into Review Manager (RevMan 5.0): MT, MSC, AT

RevMan statistical data: MSC

Other statistical analysis not using RevMan: MSC

Double entry of data: data entered by person one, MT; data entered by person two, MSC

Interpretation of data: MSC, AT

Statistical inferences: MSC

Writing the review: MSC, AT, MT, RS

Securing funding for the review:

Performing previous work that was the foundation of the present study:

Guarantor for the review (one author): MSC

Persons responsible for reading and checking review before submission: MSC, AT, MT, RS, JH

Declarations of interest

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

The review was performed when M Soledad Cepeda was working full time as Professor of Anesthesiology at Tufts University, School of Medicine. Since February 25th 2008, M Soledad Cepeda has been working for Johnson & Johnson. Professor Cepeda is still holding her academic appointment at Tufts University School of Medicine. Johnson & Johnson does not produce local anaesthetics products.  

A Tzortzopoulou, M Thackrey, P Arora Gandhi, J Hudcova and R Schumann do not have any potential conflict of interest.

Differences between protocol and review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES

Dr Tzortzopoulou Aikaterini joined the review and became the contact author. No changes were made in the way we performed the review.

Dr Preeti Arora is now known as Dr Preeti Arora Gandhi.

REFERENCES

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. REFERENCES
  • References to studies included in this review
  • Bartfield 1993 {published data only}
  • * Bartfield JM, Ford DT, Homer PJ. Buffered versus plain lidocaine for digital nerve blocks. Annals of Emergency Medicine 1993;22(2):216-9. [MEDLINE: 8381259]
  • Carvalho 2007a {published data only}
  • Carvalho B, Fuller A, Brummel C, Cohen SE. Local infiltration of epinephrine-containing lidocaine with bicarbonate reduces superficial bleeding and pain during labor epidural catheter insertion: a randomized trial. International Journal of Obstetric Anesthesia 2007;16:116-21. [MEDLINE: 17276670]
  • Carvalho 2007b {published data only}
  • Carvalho B, Fuller A, Brummel C, Cohen S. Local infiltration of epinephrine-containing lidocaine with bicarbonate reduces superficial bleeding and pain during labor epidural catheter insertion: a randomized trial. International Journal of Obstetric Anesthesia 2007;16:116-21. [MEDLINE: 17276670]
  • Cornelius 1996 {published data only}
  • * Cornelius P, Kendall J, Meek S, Rajan R. Alkalinisation of lignocaine to reduce the pain of digital nerve blockade. Journal of Accident & Emergency Medicine 1996;13(5):339-40. [MEDLINE: 8894861]
  • Ernst 1996 {published data only}
  • Ernst AA, Marvez-Valls E, Nick TG, Wahle M. Comparison trial of four injectable anesthetics for laceration repair. Academic Emergency Medicine 1996;3:228-33. [MEDLINE: 8673778]
  • Fatovich 1999 {published data only}
  • Fatovich DM, Jacobs IG. A randomized controlled trial of buffered lidocaine for local anesthetic infiltration in children and adults with simple lacerations. The Journal of Emergency Medicine 1999;17:223-8. [MEDLINE: 10195475]
  • Fitton 1996 {published data only}
  • * Fitton AR, Ragbir M, Milling MA. The use of pH adjusted lignocaine in controlling operative pain in the day surgery unit: a prospective, randomised trial. British Journal of Plastic Surgery 1996;49(6):404-8. [PUBMED: 8881789]
  • Gershon 1991 {published data only}
  • Gershon RY, Mokriski BK, Matjasko MJ. Intradermal anesthesia and comparison of intravenous catheter gauge. Anesthesia and Analgesia 1991;73(4):469-70. [MEDLINE: 1654756]
  • Martin 1990 {published data only}
  • * Martin AJ. pH-adjustment and discomfort caused by the intradermal injection of lignocaine.[erratum appears in Anaesthesia 1991 Mar;46(3):242]. Anaesthesia 1990;45(11):975-8. [MEDLINE: 2174653]
  • Masters 1998 {published data only}
  • * Masters JE. Randomised control trial of pH buffered lignocaine with adrenaline in outpatient operations. British Journal of Plastic Surgery 1998;51(5):385-7. [MEDLINE: 9771366]
  • Metzinger 1994 {published data only}
  • Metzinger SE, Rigby PL, Bailey DJ, Brousse RG. Local anesthesia in blepharoplasty: a new look?. Southern Medical Journal 1994;87:225-7. [MEDLINE: 8115888]
  • Nakayama 2001a {published data only}
  • Nakayama M, Munemura Y, Kanaya N, Tsuchida H, Namiki A. Efficacy of alkalinized lidocaine for reducing pain on intravenous and epidural catheterization. Journal of Anesthesia 2001;15:201-3. [MEDLINE: 14569436]
  • Nakayama 2001b {published data only}
  • Nakayama M, Munemura Y, Kanaya N, Tsuchida H, Namiki A. Efficacy of alkalinized lidocaine for reducing pain on intravenous and epidural catheterization. Journal of Anesthesia 2001;15:201-3. [MEDLINE: 14569436]
  • Nelson 1995 {published data only}
  • * Nelson AL. Neutralizing pH of lidocaine reduces pain during Norplant system insertion procedure. Contraception 1995;51(5):299-301. [MEDLINE: 7628204]
  • Nuttall 1993 {published data only}
  • * Nuttall GA, Barnett MR, Smith RL 2nd, Blue TK, Clark K, Payton BW. Establishing intravenous access: a study of local anesthetic efficacy. Anesthesia and Analgesia 1993;77(5):950-3. [MEDLINE: 8214733]
  • Orlinsky 1992 {published data only}
  • * Orlinsky M, Hudson C, Chan L, Deslauriers R. Pain comparison of unbuffered versus buffered lidocaine in local wound infiltration. Journal of Emergency Medicine 1992;10(4):411-5. [MEDLINE: 1430977]
  • Richtsmeier 1995 {published data only}
  • * Richtsmeier AJ, Hatcher JW. Buffered lidocaine for skin infiltration prior to hemodialysis. Journal of Pain and Symptom Management 1995;10(3):198-203. [MEDLINE: 7629414]
  • Samdal 1994 {published data only}
  • * Samdal F, Arctander K, Skolleborg KC, Amland PF. Alkalisation of lignocaine-adrenaline reduces the amount of pain during subcutaneous injection of local anaesthetic. Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery 1994;28(1):33-7. [MEDLINE: 8029650]
  • Sapin 1991 {published data only}
  • * Sapin P, Petrozzi R, Dehmer GJ. Reduction in injection pain using buffered lidocaine as a local anesthetic before cardiac catheterization. Catheterization and Cardiovascular Diagnosis 1991;23(2):100-2. [MEDLINE: 2070391]
  • Steinbrook 1993 {published data only}
  • * Steinbrook RA, Hughes N, Fanciullo G, Manzi D, Ferrante FM. Effects of alkalinization of lidocaine on the pain of skin infiltration and intravenous catheterization. Journal of Clinical Anesthesia 1993;5(6):456-8. [MEDLINE: 8123269]
  • Vossinakis 2004 {published data only}
  • * Vossinakis IC, Stavroulaki P, Paleochorlidis I, Badras LS. Reducing the pain associated with local anaesthetic infiltration for open carpal tunnel decompression. Journal of Hand Surgery - British Volume 2004;29(4):399-401. [MEDLINE: 15234509]
  • Watts 2003 {published data only}
  • * Watts AC, Gaston P, Hooper G. Randomized trial of buffered versus plain lidocaine for local anaesthesia in open carpal tunnel decompression. Journal of Hand Surgery - British Volume 2004;29(1):30-1. [MEDLINE: 14734066]
  • Yiannakopoulos 2004 {published and unpublished data}
  • * Yiannakopoulos CK. Carpal ligament decompression under local anaesthesia: the effect of lidocaine warming and alkalinisation on infiltration pain. Journal of Hand Surgery - British Volume 2004;29(1):32-4. [MEDLINE: 14734067]
  • Younis 2004 {published data only}
  • * Younis I, Bhutiani RP. Taking the 'ouch' out - effect of buffering commercial xylocaine on infiltration and procedure pain - a prospective, randomised, double-blind, controlled trial. Annals of the Royal College of Surgeons of England 2004;86:273-17. [MEDLINE: 15140310]
  • Yuen 1999 {published data only}
  • Yuen VH, Dolman PJ. Comparison of three modified lidocaine solutions for use in eyelid anesthesia. Ophthalmic Plastic & Reconstructive Surgery 1999;15(2):143-7. [MEDLINE: 10189646]
  • References to studies excluded from this review
  • Acosta 1997 {published data only}
  • Acosta AE. Clinical parameters of tumescent anesthesia in skin cancer reconstructive surgery. A review of 86 patients. Archives of Dermatology 1997;133(4):451-4. [MEDLINE: 9126008]
  • Ball 2006 {published data only}
  • Ball EL, Sanjay P, Woodward A. Comparison of buffered and unbuffered local anaesthesia for inguinal hernia repair: a prospective study. Hernia 2006;10:175-8. [MEDLINE: 16424994]
  • Barnett 1992 {published data only}
  • Barnett TA, Kapp DS. Reduction of pain and local complications when buffered lidocaine solution is used as a local anesthetic in conjunction with hyperthermia treatments: results of a randomized trial. International Journal of Radiation Oncology, Biology, Physics 1992;23(3):585-91. [MEDLINE: 1612959]
  • Bartfield 1992 {published data only}
  • Bartfield JM. Homer PJ. Ford DT. Sternklar P. Buffered lidocaine as a local anesthetic: an investigation of shelf life. Annals of Emergency Medicine 1992;21(1):16-9. [MEDLINE: 1539881]
  • Benlabed 1990 {published data only}
  • Benlabed M, Jullien P, Guelmi K, Hamza J, Bonhomme L, Benhamou D. Alkalinization of 0.5% lidocaine for intravenous regional anesthesia. Regional Anesthesia 1990;15(2):59-60. [MEDLINE: 2176097]
  • Bowles 1995 {published data only}
  • * Bowles WH, Frysh H, Emmons R. Clinical evaluation of buffered local anesthetic. General Dentistry 1995;43(2):182-4. [MEDLINE: 7590153]
  • Brown 2004 {published data only}
  • Brown D. Local anesthesia for vein cannulation: a comparison of two solutions. Journal of Infusion Nursing 2004;27(2):85-8. [MEDLINE: 15085035]
  • Burns 2006 {published data only}
  • * Burns CA, Ferris G, Feng C, Cooper JZ, Brown MD. Decreasing the pain of local anesthesia: a prospective, double-blind comparison of buffered, premixed 1% lidocaine with epinephrine versus 1% lidocaine freshly mixed with epinephrine. Journal of the American Academy of Dermatology 2006;54(1):128-31. [MEDLINE: 16384767]
  • Capogna 1993 {published data only}
  • * Capogna G, Celleno D, Costantino P, Muratori F, Sebastiani M, Baldassini M. Alkalinization improves the quality of lidocaine-fentanyl epidural anaesthesia for caesarean section. Canadian Journal of Anaesthesia 1993;40(5 Pt 1):425-30. [MEDLINE: 8390329]
  • Christoph 1988 {published data only}
  • * Christoph RA, Buchanan L, Begalla K, Schwartz S. Pain reduction in local anesthetic administration through pH buffering. Annals of Emergency Medicine 1988;17(2):117-20. [MEDLINE: 2827545]
  • Connelly 1996 {published data only}
  • Connelly NR, Leonard R. Discomfort associated with regional anesthetic placement in obstetrics: does alkalinization help?. International Journal of Obstetric Anesthesia 1996;5:89-91. [MEDLINE: 15321358]
  • DiFazio 1986 {unpublished data only}
  • DiFazio CA, Carron H, Grosslight KR, Moscicki JC, Bolding WR, Johns RA. Comparison of pH-adjusted lidocaine solutions for epidural anesthesia. Anesthesia and Analgesia 1986;65:760-4. [MEDLINE: 3717616]
  • Eccarius 1990 {published data only}
  • * Eccarius SG, Gordon ME, Parelman JJ. Bicarbonate-buffered lidocaine-epinephrine-hyaluronidase for eyelid anesthesia. Ophthalmology 1990;97(11):1499-501. [MEDLINE: 2255521]
  • Elhakim 1998 {published data only}
  • Elhakim M, Magady M, Seuam A, Mostafa BE. Alkalinization of lidocaine for multiple level infiltration after tonsillectomy in children. Acta Anaesthesiologica Italica 1998;49:191-5.
  • Farrell 1995 {published data only}
  • Farrell HA, Waldman SR, Campbell JP, Jones RO. Duration of buffered lidocaine versus unbuffered lidocaine: a double-blind, randomized prospective study. Ear, Nose, & Throat Journal 1995;74:416-8. [MEDLINE: 7628332]
  • Friedman 1997 {published data only}
  • * Friedman HE, Jules KT, Springer K, Jennings M. Buffered lidocaine decreases the pain of digital anesthesia in the foot. Journal of the American Podiatric Medical Association 1997;87(5):219-23. [MEDLINE: 9158315]
  • Gaggero 1995 {published data only}
  • * Gaggero G, Meyer O, Van Gessel E, Rifat K. Alkalinization of lidocaine 2% does not influence the quality of epidural anaesthesia for elective caesarean section. Canadian Journal of Anaesthesia 1995;42(12):1080-4. [MEDLINE: 8595681]
  • Gormley 1995 {published data only}
  • * Gormley WP, Hill DA, Murray JM, Fee JP. The effect of alkalinisation of lignocaine on axillary brachial plexus anaesthesia. Anaesthesia 1996;51(2):185-8. [MEDLINE: 8779380]
  • Hinshaw 1995 {published data only}
  • Hinshaw KD, Fiscella R, Sugar J. Preparation of pH-adjusted local anesthetics. Ophthalmic Surgery 1995;26(3):194-9. [MEDLINE: 7651682]
  • Iwama 2001 {published data only}
  • Iwama H, Ohmori S, Kaneko T, Watanabe K. Water-diluted local anesthetic for trigger-point injection in chronic myofascial pain syndrome: evaluation of types of local anesthetic and concentrations in water. Regional Anesthesia and Pain Medicine 2001;26(4):333-6. [MEDLINE: 11464352]
  • Jones 1998 {published data only}
  • Jones JS, Plzak C, Wynn BN, Martin S. Effect of temperature and pH adjustment of bupivacaine for intradermal anesthesia. The American Journal of Emergency Medicine 1998;16:117-20. [MEDLINE: 9517682]
  • Kelsaka 2006 {published data only}
  • Kelsaka E, Guldpgus F, Sarihasan B, Tepe S. Comparison of EMLA and lidocaine with or without sodium bicarbonate in prevention of spinal needle insertion pain. Anestezi Dergisi 2006;14:76-9.
  • Koscielniak-Nielsen {published data only}
  • * Koscielniak-Nielsen ZJ, Stens-Pedersen HL, Kjaerbo EJ. Intra-arterial regional anaesthesia for hand surgery with alkalinized 0.5% lignocaine. Acta Anaesthesiologica Scandinavica 1995;39(8):1048-52. [MEDLINE: 8607307]
  • Larson 1991 {published data only}
  • Larson PO, Ragi G, Swandby M, Darcey B, Polzin G, Carey P. Stability of buffered lidocaine and epinephrine used for local anesthesia. The Journal of Dermatologic Surgery and Oncology 1991;17:411-4. [MEDLINE: 2030202]
  • Long 1991 {published data only}
  • * Long CC, Motley RJ, Holt PJ. Taking the 'sting' out of local anaesthetics. British Journal of Dermatology 1991;125(5):452-5. [MEDLINE: 1751351]
  • Lugo-Janer 1993 {published data only}
  • * Lugo-Janer G, Padial M, Sanchez JL. Less painful alternatives for local anesthesia. Journal of Dermatologic Surgery & Oncology 1993;19(3):237-40. [MEDLINE: 8383150]
  • Manka 1991 {published data only}
  • * Manka RL, Gast TJ. Sodium bicarbonate reduces pain associated with ophthalmic nerve blocks. Refractive & Corneal Surgery 1991;7(2):186-7. [MEDLINE: 1645990]
  • Marica 2002 {published data only}
  • * Marica LS, O'Day T, Janosky JE, Nystrom EU. Chloroprocaine is less painful than lidocaine for skin infiltration anesthesia. Anesthesia and Analgesia 2002;94(2):351-4. [MEDLINE: 11812697]
  • Matsumoto 1994 {published data only}
  • * Matsumoto AH, Reifsnyder AC, Hartwell GD, Angle JF, Selby JB Jr, Tegtmeyer CJ. Reducing the discomfort of lidocaine administration through pH buffering. Journal of Vascular and Interventional Radiology 1994;5(1):171-5. [MEDLINE: 8136599]
  • McGlone 1990 {published data only}
  • * McGlone R, Bodenham A. Reducing the pain of intradermal lignocaine injection by pH buffering. Archives of Emergency Medicine 1990;7(2):65-8. [MEDLINE: 2390155]
  • McKay 1987 {published data only}
  • * McKay W, Morris R, Mushlin P. Sodium bicarbonate attenuates pain on skin infiltration with lidocaine, with or without epinephrine. Anesthesia and Analgesia 1987;66(6):572-4. [MEDLINE: 3034106]
  • Metzinger 1992 {published data only}
  • Metzinger SE, Bailey DJ, Boyce RG, Lyons GD. Local anesthesia in rhinoplasty: a new twist?. Ear, Nose, & Throat Journal 1992;71:405-6. [MEDLINE: 1330485]
  • Minasian 2000 {published data only}
  • * Minasian MC, Ionides AC, Fernando R, Davey CC. Pain perception with pH buffered peribulbar anaesthesia: a pilot study. British Journal of Ophthalmology 2000;84(9):1041-4. [MEDLINE: 10966962]
  • Moharib 2002 {published data only}
  • * Moharib MM, Mitra S, Rizvi SG. Effect of alkalinization and/or hyaluronidase adjuvancy on a local anesthetic mixture for sub-Tenon's ophthalmic block. Acta Anaesthesiologica Scandinavica 2002;46(5):599-602. [MEDLINE: 12027856]
  • Moreno-Jimenez 2008 {published data only}
  • Moreno-Jimenez S, Ibarra Rangel A, Loaeza Zarate C, Gutierrez Aceves GA, Celis MA, Terrazo-Lluch J, et al.Comparative study between different dilutions of lidocaine-sodium bicarbonate in local infiltration to the positioning of the stereotactic frame [Spanish]. Archivos de Neurociencias 2008;13(1):3-7. [: CINAHL: 2009954294; : ISSN: 1028-5938]
  • Nevarre 1998 {published data only}
  • Nevarre DR, Tzarnas CD. The effects of hyaluronidase on the efficacy and on the pain of administration of 1% lidocaine. Plastic and Reconstructive Surgery 1998;101(2):365-9. [MEDLINE: 9462768]
  • Ng 1999 {published data only}
  • Ng HN, Sim KM, Boey SK. Bone marrow harvesting using EMLA (eutectic mixture of local anaesthetics) cream, local anaesthesia and patient-controlled analgesia with alfentanil. Bone Marrow Transplantation 1999;23(9):941-5. [MEDLINE: 10338051]
  • Ong 2000 {published data only}
  • Ong EL, Lim NL, Koay CK. Towards a pain-free venepuncture. Anaesthesia 2000;55:260-2. [MEDLINE: 10671845]
  • Ozer 2005 {published data only}
  • Ozer H, Solak S, Oguz T, Ocguder A, Colakoglu T, Babacan A. Alkalinisation of local anaesthetics prescribed for pain relief after surgical decompression of carpal tunnel syndrome. Journal of Orthopaedic Surgery 2005;13(3):285-9. [MEDLINE: 16365493]
  • Palmon 1998 {published data only}
  • * Palmon SC, Lloyd AT, Kirsch JR. The effect of needle gauge and lidocaine pH on pain during intradermal injection. Anesthesia and Analgesia 1998;86(2):379-81. [MEDLINE: 9459252]
  • Parham 1996 {published data only}
  • * Parham SM, Pasieka JL. Effect of pH modification by bicarbonate on pain after subcutaneous lidocaine injection. Canadian Journal of Surgery 1996;39(1):31-5. [MEDLINE: 8599788]
  • Primosch 1996 {published data only}
  • Primosch RE, Robinson L. Pain elicited during intraoral infiltration with buffered lidocaine. American Journal of Dentistry 1996;9(1):5-10. [MEDLINE: 9002806]
  • Redd 1990 {published data only}
  • * Redd DA, Boudreaux AM, Kent RB 3rd. Towards less painful local anesthesia. Alabama Medicine 1990;60(4):18-9. [MEDLINE: 2281830]
  • Ririe 1997 {published data only}
  • Ririe DG, Walker FO, James RL, Butterworth J. Effect of alkalinization of lidocaine on median nerve block. British Journal of Anaesthesia 2000;84:163-8. [MEDLINE: 10743447]
  • Roberts 1993 {published data only}
  • * Roberts JE, MacLeod BA, Hollands RH. Improved peribulbar anaesthesia with alkalinization and hyaluronidase. Canadian Journal of Anaesthesia 1993;40(9):835-8. [MEDLINE: 8403178]
  • Ruegg 2009 {published data only}
  • Ruegg TA. Use of buffered lidocaine in bone marrow biopsies: A randomized, controlled trial. Oncology Nursing Forum 2009;36(1):52-60.
  • Scarfone 1998 {published data only}
  • * Scarfone RJ, Jasani M, Gracely EJ. Pain of local anesthetics: rate of administration and buffering. Annals of Emergency Medicine 1998;31(1):36-40. [MEDLINE: 9437339]
  • Schooff 1998 {published data only}
  • * Schooff M. Lessening the pain of lidocaine injection. Journal of Family Practice 1998;46(4):279. [MEDLINE: 9564364]
  • Stang 1997 {published data only}
  • Stang HJ, Snellman LW, Condon LM, Conroy MM, Liebo R, Brodersen L, et al.Beyond dorsal penile nerve block: a more humane circumcision. Pediatrics 1997;100(2):E3. [MEDLINE: 9233974]
  • Stewart 1989 {published data only}
  • * Stewart JH, Cole GW, Klein JA. Neutralized lidocaine with epinephrine for local anesthesia. Journal of Dermatologic Surgery and Oncology 1989;15(10):1081-3. [MEDLINE: 2794204]
  • Stewart 1990 {published data only}
  • * Stewart JH, Chinn SE, Cole GW, Klein JA. Neutralized lidocaine with epinephrine for local anesthesia--II. Journal of Dermatologic Surgery & Oncology 1990;16(9):842-5. [MEDLINE: 2168907]
  • Tanaka 2001 {published data only}
  • Tanaka PP, Tambara EM, Almeida MA, Sepulcri RP. Pain intensity after subcutaneous injection of lidocaine or lidocaine-sodium bicarbonate association. Revista Brasileira de Anestesiologia 2001;51:37-42.
  • Yang 2006 {published data only}
  • Yang CH, Hsu HC, Shen SC, Juan WH, Hong HS, Chen CH. Warm and neutral tumescent anesthetic solutions are essential factors for a less painful injection. Dermatologic Surgery 2006;32:1119-22. [MEDLINE: 16970691]
  • Zehetmayer 1997 {published data only}
  • Zehetmayer M, Rainer G, Turnheim K, Skorpik C, Menapace R. Topical anesthesia with pH-adjusted versus standard lidocaine 4% for clear corneal cataract surgery. Journal of Cataract & Refractive Surgery 1997;23(9):1390-3. [MEDLINE: 9423913]
  • References to studies awaiting assessment
  • Da Fonseca 2009 {published data only}
  • Da Fonseca NL, Lucci LMD, Badessa Mpsg, Rehder Jrcl. Comparison of two modified lidocaine solutions for local anesthesia in blepharoplasty [Comparacao entre duas solucoes modificadas de lidocaina para uso em anestesia local na blefaroplastia]. Arquivos Brasileiros De Oftalmologia 2009;72(2):211-4.
  • Jaichandran 2010 {published data only}
  • Jaichandran V, Vijaya L, George RJ, InderMohan B. Peribulbar anesthesia for cataract surgery: effect of lidocaine warming and alkalinization on injection pain, motor and sensory nerve blockade. Indian Journal of Ophthalmology 2010;58(2):105-8.
  • Narvaez 2010 {published data only}
  • Narvaez J, Wessels I, Bacon G, Chin VR, Baqai WK, Zimmerman GJ. Prospective randomized evaluation of short-term complications when using buffered or unbuffered lidocaine 1% with epinephrine for blepharoplasty surgery. Ophthalmic Plastic and Reconstructive Surgery 2010;26(1):33-5.
  • Additional references
  • Bartfield 1992
  • Bartfield JM, Homer PJ, Ford DT, Sternklar P. Buffered lidocaine as a local anesthetic: an investigation of shelf life. Annals of Emergency Medicine 1992;21(1):16-9. [MEDLINE: 1539881]
  • Berlin 1997
  • Berlin JA. Does blinding of readers affect the results of meta-analyses? University of Pennsylvania Meta-analysis Blinding Study Group [letter]. Lancet 1997;350:185-6.
  • Brogan 1995
  • Brogan GX Jr, Giarrusso E, Hollander JE, Cassara G, Maranga MC, Thode HC. Comparison of plain, warmed, and buffered lidocaine for anesthesia of traumatic wounds. Annals of Emergency Medicine 1995;26(2):121-5. [MEDLINE: 7618771]
  • Burns 2006
  • Burns CA, Ferris G, Feng C, Cooper JZ, Brown MD. Decreasing the pain of local anesthesia: a prospective, double-blind comparison of buffered, premixed 1% lidocaine with epinephrine versus 1% lidocaine freshly mixed with epinephrine. Journal of the American Academy of Dermatology 2006;54(1):128-31.
  • Cepeda 2003
  • Cepeda MS, Africano JM, Polo R, Alcala R, Carr DB. What decline in pain intensity is meaningful to patients with acute pain?. Pain 2003;105:151-7.
  • Colaric 1998
  • Colaric KB, Overton DT, Moore K. Pain reduction in lidocaine administration through buffering and warming. The American Journal of Emergency Medicine 1998;16(4):353-6. [MEDLINE: 9672449]
  • Corbett 2005
  • Corbett IP, Ramacciato JC, Groppo FC, Meechan JG. A survey of local anaesthetic use among general dental practitioners in the UK attending postgraduate courses on pain control. British Dental Journal 2005;199(12):784-7.
  • Elbourne 2002
  • Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31:140-9.
  • Gaggero 1995
  • Gaggero G, Meyer O, Van Gessel E, Rifat K. Alkalinization of lidocaine 2% does not influence the quality of epidural anaesthesia for elective caesarean section. Canadian Journal of Anaesthesia 1995;42(12):1080-4. [MEDLINE: 8595681]
  • Haas 1995
  • Haas DA, Lennon D. Local anesthetic use by dentists in Ontario. Journal (Canadian Dental Association) 1995;61(4):297-304.
  • Higgins 2003
  • Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
  • Higgins 2005
  • Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]. In: The Cochrane Library, Issue 3, 2005. Chichester, UK: John Wiley & Sons, Ltd.
  • Issberner 1996
  • Issberner U, Reeh PW, Steen KH. Pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia?. Neuroscience Letters 1996;208(3):191-4.
  • Koeppe 2005
  • Koeppe T, Constantinescu MA, Schneider J, Gubisch W. Current trends in local anesthesia in cosmetic plastic surgery of the head and neck: results of a German national survey and observations on the use of ropivacaine. Plastic and Reconstructive Surgery 2005;115(6):1723-30.
  • Larson 1991
  • Larson PO, Ragi G, Swandby M, Darcey B, Polzin G, Carey P. Stability of buffered lidocaine and epinephrine used for local anesthesia. The Journal of Dermatologic Surgery and Oncology 1991;17(5):411-4. [MEDLINE: 2030202]
  • Liu 1995
  • Liu S, Carpenter RL, Chiu AA, McGill TJ, Mantell SA. Epinephrine prolongs duration of subcutaneous infiltration of local anesthesia in a dose-related manner. Correlation with magnitude of vasoconstriction. Regional Anesthesia 1995;20(5):378-84. [MEDLINE: 8519713]
  • McKay 1987
  • McKay W, Morris R Mushlin P. Sodium bicarbonate attenuates pain on skin infiltration with lidocaine, with or without epinephrine. Anesthesia and Analgesia 1987;66:572-4.
  • Mosby 2006
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