Ultrasound-enabled topical anesthesia for pain reduction of phlebotomy for whole blood donation
Supported by Echo Therapeutics, Inc.
Christopher P. Stowell, MD, PhD, Director, Blood Transfusion Service, GRJ 148, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114; e-mail: firstname.lastname@example.org.
BACKGROUND: Ultrasound-facilitated delivery of topical anesthetics has been used to achieve effective anesthesia within 5 minutes for venipuncture and the insertion of intravenous access devices, but has never been studied for blood donation.
STUDY DESIGN AND METHODS: This study was a single-center, prospective, randomized, sham treatment–controlled, single-blinded clinical evaluation. Repeat donors were randomly assigned to undergo treatment with ultrasound and topical anesthetic or sham ultrasound and placebo anesthetic before phlebotomy for whole blood donation. The primary outcome measures were pain assessments using the Verbal Categorical Scale (VCS) and the Visual Analogue Scale and the assessment of skin irritation at the target site.
RESULTS: One-hundred subjects were enrolled and all completed the study. Compared to the sham/placebo control group, donors receiving ultrasound/anesthetic had lower pain scores on the VCS (1.81 ± 0.67 vs. 2.17 ± 0.68; p = 0.01) and Visual Analog Scale (17.2 ± 15.5 vs. 27.6 ± 19.5; p = 0.006). The proportion of subjects in the treatment group who experienced skin irritation (8%) was similar to that in the control group (2%; p = 0.20).
CONCLUSION: Ultrasound-enhanced delivery of topical anesthetic was demonstrated to be a safe means of quickly achieving clinically meaningful reduction in the pain of phlebotomy for whole blood donation compared to sham/placebo treatment.
Visual Analogue Scale
Verbal Categorical Scale.
Topical anesthetics have been used to reduce the pain of phlebotomy, the insertion of intravenous access devices (IVs), injections, immunization, and other procedures. Eutectic mixtures of local anesthetics, such as EMLA cream, which contains lidocaine and prilocaine, have been used for more than a decade but require a minimum application time of 1 hour to achieve effective anesthesia.1 A formulation of lidocaine in a liposome carrier is effective in only 30 minutes and has been shown to reduce the pain of venipuncture2 and IV insertion.3-5 The onset of anesthesia is delayed by the time required for the topical anesthetic to diffuse through the outer layers of the skin. Iontophoresis has been used to accelerate penetration of topical anesthetics. It was shown to reduce the time for anesthesia to 7 to 15 minutes6 and was effective in decreasing the pain of IV insertion in children and adults.7,8 However, it has also been associated with various local side effects such as skin irritation and burns.9-11 With laser treatment of the skin, anesthesia with topical lidocaine was achieved in only 5 minutes in children and adults before venipuncture and IV insertion but was associated with skin irritation in some patients.12-14 Delivery of a eutectic mixture of lidocaine and tetracaine has also been accelerated using a controlled heating device.15
More recently, ultrasound has been used to accelerate the delivery of topical anesthetics. The application of low-frequency ultrasound at the skin surface causes cavitation which disrupts the lipid layers of the stratum corneum forming temporary pores, which facilitate distribution of the topical anesthetic to the subepidermal layers.16 The presence of a surfactant, such as sodium lauryl sulfate, acts synergistically with the ultrasound energy and further enhances the permeability of the skin to the anesthetic.17,18 This technique has been shown to decrease the onset of anesthesia with EMLA from 60 minutes to 5 minutes.19 In randomized, controlled trials, two in children20,21 and one in adults in the emergency room,22 ultrasound-enhanced delivery of 4 percent lidocaine in a liposome carrier was found to reduce pain scores significantly and was well tolerated.
In contrast, there have been very few studies of the use of topical anesthetics for blood donation where relatively large bore needles are typically used (16 g for whole blood donation; 17-18 g for apheresis donation).23-25 The prolonged application times that are required for the topical anesthetics currently available make them impractical in most donation settings. However, achieving an analgesic effect within 5 minutes with a combination of ultrasound and a topical anesthetic would be much more compatible with the work flow in a donor center. This study was undertaken to determine whether ultrasound-facilitated delivery of topical anesthetic was effective in reducing the pain associated with whole blood donation.
MATERIALS AND METHODS
This study was a single-center, prospective, randomized, sham ultrasound/placebo-controlled, single-blinded clinical evaluation that was reviewed and approved by the hospital's institutional review board. After giving written, informed consent, subjects were randomly assigned to undergo treatment of the target phlebotomy site with ultrasound and topical anesthetic or sham ultrasound and placebo before phlebotomy for whole blood donation. After donation, a research associate administered two pain assessment tools and a short questionnaire and assessed the treated area. Local reaction at the treatment site was also assessed the following day by a telephone call from the research associate.
Setting and population
This study was conducted in a hospital-based blood donor center. Consecutive, repeat, volunteer, allogeneic donors who had been accepted for whole blood donation were approached by a research associate who described the study and obtained informed consent. Potential subjects were excluded if they had participated in any other clinical studies within the previous month, were pregnant (by virtue of their exclusion from donation), had an implanted pacemaker or defibrillator, or had a history of hypersensitivity to sodium lauryl sulfate, topical anesthetics, or medical adhesives.
Subjects who were enrolled in the study underwent baseline screening that included several questions about skin characteristics and attitudes about blood donation. Randomization was performed by a third party before initiation of the study, and sealed envelopes were prepared, numbered, and used in a consecutive manner so that each subject was assigned to a study group after informed consent had been obtained. Consented whole blood donors enrolled and randomized to the control arm of the study had the target site for venipuncture pretreated with sham ultrasound and anesthetic placebo. Subjects randomized to the treatment arm of the study had the target site treated with ultrasound followed by the application of 4 percent lidocaine topical cream. After the treatment of the venipuncture site with ultrasound/sham, the anesthetic/placebo was applied and left in place for 5 minutes. The topical agent was then wiped away and the target site prepared by the usual arm preparation protocol for venipuncture. The phlebotomist and subject were blinded to the study treatment; however, the research associate who administered the treatment or placebo/sham was not. After donation, the same research associate administered the following assessments. The research associate directed the subject to respond to two pain assessment instruments: the Visual Analogue Scale (VAS; scale from 0 mm = “no pain” to 100 mm = “severe pain”) and the Verbal Categorical Scale (VCS; 1 = no pain; 2 = mild pain; 3 = moderate pain; 4 = severe pain) and a questionnaire (see Appendix 1, available as supporting information in the online version of this article). The research associate assessed the treatment area by comparison with a series of photographs showing different grades of skin reaction. The research associate also explained the procedure for assessing skin reaction and gave each subject a card with the same grading photographs. The research associate called each subject within 48 hours of the intervention to obtain information about delayed skin reactions to the treatment. Information about adverse events was also recorded.
The study medication was L.M.X.4 (4% lidocaine in a liposome carrier; Ferndale Laboratories, Inc., Ferndale, MI) which is available over the counter. The placebo was hand lotion (Curel Daily Moisture Therapy Lotion, Curel, Cincinnati, OH), chosen for its resemblance to L.M.X.4 and repackaged in the same aluminum pouch as the L.M.X.4 from Ferndale Laboratories.
The ultrasound device (SonoPrep skin permeation system, Echo Therapeutics, Franklin, MA) consists of a microprocessor-controlled ultrasonic generator, a reusable hand piece, a reference electrode, and a disposable, single-use, coupling media cartridge containing a solution of sodium lauryl sulfate.26 During operation, the device measures electrical conductivity of the target site, which correlates with the extent of skin permeability. Via an electrical feedback mechanism, the ultrasound device automatically turns off when the skin conductivity measurement reaches a specific level, thus producing a consistent degree of skin permeability.27,28 The system has been cleared by the US Food and Drug Administration for the applications of electrophysiology and transdermal delivery of topical anesthetic.
Outcomes and statistical analysis
The predetermined primary endpoints were pain assessments using the VCS and the VAS and the assessment of skin irritation at the target site. The VCS and VAS have been validated and are widely accepted as standard measures of pain intensity.29-31 With 50 subjects enrolled per arm, the study was adequately powered to have a more than 99 percent probability of detecting a difference of 20 mm on the 0- to 100-mm VAS at the 5 percent level of significance in a two-sided test, assuming a standard deviation of 20 mm.
VCS scores were converted to an ordinal 4-point scale by assigning numbers 1 to 4 to responses, none, mild, moderate, and severe, respectively. The resulting VCS scores were compared between treatment groups using a Wilcoxon (Mann-Whitney) two-sample test at a 5 percent level of significance. In addition, the number and percentage of subjects who reported moderate or severe pain experienced with the needlestick from this donation were summarized and compared between treatment groups with a two-sided Fisher's exact test. The mean VAS scores after whole blood donation were compared between treatment groups using a Wilcoxon (Mann-Whitney) two-sample test at a 5 percent level of significance. In addition, the number and percentage of subjects with VAS scores of 30 or less in each treatment group were compared using a two-sided Fisher's exact test at 5 percent level of significance. The proportions of subjects experiencing any skin irritation at the treatment site were compared using a two-sided Fisher's exact test at a 5 percent level of significance. The secondary endpoints were the responses to the short pain assessment questionnaire administered after phlebotomy. The responses were compared individually between treatment groups using a two-sided Fisher's exact test at a 5 percent level of significance. No adjustments were made for multiple comparisons.
Study subject disposition
A total of 100 subjects were enrolled and randomly assigned, all of whom received sham/placebo or treatment, were phlebotomized, and completed the postphlebotomy pain assessment and questionnaire, hence also meeting the criteria for being evaluable (see Table 1). Analyses were conducted on the intention-to-treat population. Of these 100 subjects, 12 (5 in the control group and 7 in the active treatment group) could not be reached to complete the telephone safety assessment. There were two protocol violations: 2 subjects who were randomly assigned to receive sham/placebo treatment underwent sham ultrasound treatment but then received the anesthetic cream. Since the topical agent requires 30 minutes to achieve full anesthesia, it is unlikely to have affected the outcome; however, these two subjects were included in the sham/placebo, intention-to-treat population. The needle was not introduced at the treatment site in 3 patients in the sham/placebo group and 5 patients in the treatment arm. These patients were also included in the intention-to-treat population. The mean duration of the ultrasound treatment (10.8 ± 5.2 sec) was the same as the mean duration of the sham ultrasound (10.8 ± 2.9 sec).
Table 1. Subject disposition in the study*
|Number randomly assigned||51 (100)||49 (100)|
|Number treated||51 (100)||49 (100)|
|Number evaluable†||51 (100)||49 (100)|
|Number completed||46 (90)||42 (86)|
|Number discontinued||5 (10)||7 (14)|
|Reason for discontinuation|| || |
| Enrolled but not treated||0 (0)||0 (0)|
| Lost to follow-up (safety assessment)||5 (10)||7 (14)|
| Other||0 (0)||0 (0)|
|Number excluded from analysis||0 (0)||0 (0)|
Demographic and baseline characteristics of study populations
The demographic and baseline characteristics of the two groups of study subjects are summarized in Tables 2 and 3. The two groups were similar with respect to all of these characteristics, including skin type and history of dermatologic disease, easy bruising, and sun sensitivity. There was also no difference with respect to attitudes toward the pain associated with phlebotomy for whole blood donation. It is notable that when asked about the needlestick for donation, 86 to 92 percent of these repeat donors said that they “don't mind a bit” or associated it with “a little bit of discomfort” and that 92 to 96 percent claimed that the needlestick had no effect on their willingness to donate blood. There was a difference in how subjects in the two groups assessed the relative painfulness of the needlestick to withdraw the unit of blood versus the fingerstick for performing the hemoglobin/hematocrit tests; however, the difference was not significant.
Table 2. Demographic and baseline characteristics*
|Gender|| || |
|Age (years)||43 (18-75)||48 (22-66)|
|Weight (kg)||77 (53-132)||79 (46-122)|
|Height (cm)||173 (152-187)||172 (154-188)|
|Body mass index (kg/m2)||26 (20-39)||26 (18-42)|
Table 3. Baseline dermatologic characteristics and donation attitudes
|History of easy bleeding or bruising (yes)||2 (4)||2 (4)|
|History of any dermatologic (skin) disease (yes)||5 (10)||3 (6)|
|Description of skin|| || |
| Always burns, never tans||4 (8)||3 (6)|
| Always burns, tans minimally||6 (12)||12 (24)|
| Burns moderately, tans gradually||16 (31)||15 (31)|
| Burns minimally, always tans well||16 (31)||11 (22)|
| Rarely burns, tans profusely||5 (10)||6 (12)|
| Never burns, normally deeply pigmented||4 (8)||1 (2)|
|Description of skin type|| || |
| Oily||8 (16)||6 (12)|
| Normal||32 (63)||29 (59)|
| Dry||7 (14)||13 (27)|
| Combination||2 (4)||1 (2)|
|Feeling about the needlestick for blood donation|| || |
| Don't mind a bit||21 (41)||16 (33)|
| A little bit of discomfort||23 (45)||29 (59)|
| A lot of discomfort||6 (12)||4 (8)|
| Painful||1 (2)||0 (0)|
| Very painful||0 (0)||0 (0)|
|Effect of needlestick on your willingness to donate blood|| || |
| No effect||47 (92)||47 (96)|
| Slight effect||4 (8)||2 (4)|
| Some effect||0 (0)||0 (0)|
| Significant effect||0 (0)||0 (0)|
| Major effect||0 (0)||0 (0)|
|Next plan to donate blood|| || |
| In the next month||2 (4)||5 (10)|
| Between 2 and 3 months||28 (55)||25 (51)|
| In the next 6 months||6 (12)||2 (4)|
| Not sure||15 (29)||17 (35)|
|Which one is more painful|| || |
| Fingerstick||19 (37)||23 (47)|
| Needlestick||28 (55)||18 (37)|
The primary comparison of VCS pain scores between groups revealed a significant difference (p = 0.05; Table 4). Collapsing the categories to examine the proportion of patients in each group who reported moderate or severe pain showed that 7 of 49 patients (14%) in the treatment group reported moderate or severe pain, compared to 15 of 51 (29%) in the sham/placebo group (p = 0.09). In addition, the proportion of subjects with no pain (16/49; 33%) in the treatment group was significantly higher (p = 0.03) than that in the sham/placebo group (7/51; 14%). When the VCS rating was converted into a continuous score, the mean VCS score in the sham/placebo group was significantly higher than that of the treatment group (p = 0.01).
Table 4. Summary of primary outcomes
|Verbal response scale (VCS), n (%)|| || || || |
| None||7 (14)||16 (33)|| ||0.05*|
| Mild||29 (57)||26 (53)||NA|| |
| Moderate||14 (27)||7 (14)|| || |
| Severe||1 (2)||0 (0)|| || |
|Number (%) of subjects reporting no pain in the VCS||7 (14)||16 (33)||−2.4% to −35.1%||0.03*|
|Number (%) of subjects reporting moderate or severe pain in the VCS||15 (29)||7 (14)||−1.4% to 31.9%||0.09*|
|Mean (SD) level of pain from VCS in a continuous scale||2.17 (0.68)||1.81 (0.67)||−0.63 to −0.09||0.01†|
|Mean (SD) level of pain (0-100 mm) from VAS||27.6 (19.5)||17.2 (15.5)||−17.4 to −3.39||0.006†|
|Number (%) of subjects reporting pain ≤ 30 from VAS||37 (47)||41 (53)||−28.1% to 5.5%||0.22*|
|Number (%) of subjects reporting any redness at the target site on the day of donation||1 (2)||4 (8)||−17.9% to 3.4%||0.20*|
The mean VAS score in the sham/placebo group (27.6 + 19.5) was significantly higher than that of the treatment group (17.2 + 15.5; p = 0.006). However, the proportion of subjects reporting a pain score 30 or less (considered mild pain) was not significantly different between treatment groups (p = 0.22).
Table 5 summarizes the secondary efficacy outcomes, which were responses to the postdonation questionnaire. There were no significant differences in the responses to any of the questions. However, the responses to the question asking the subjects to compare the pain associated with the needlestick in this study to those experienced with previous donations were notable. Twenty-four (49%) subjects in the treatment group reported that the study needlestick was less painful as compared to only 15 subjects (29%) in the sham/placebo group, although the difference was not significant. Although subjects in the treatment group were more likely to respond that the pain associated with the study donation was less than that experienced previously, they were no more likely to request this predonation treatment than the control group, nor did it appear to affect their willingness to give blood.
Table 5. Summary of secondary efficacy outcomes
|Pain associated with the needlestick in this experience compared to previous blood donations = “less”||15 (29)||24 (49)||−37.5% to −0.3%||0.06|
|Rating of sensation of the treatment = “uncomfortable,”“painful”||0 (0)||1 (2)||−10.7% to 5.1%||0.49|
|Rating of sensation of the treatment compared to the needlestick = “much less painful than the needle stick,”“less painful than the needle stick”||51 (100)||47 (96)||−3.2% to 13.8%||0.23|
|Likelihood of requesting this pretreatment prior to subject's next donation = “very likely”||0 (0)||0 (0)||NA||NA|
|Effect of this pretreatment on subject's willingness to give blood = “somewhat more willing,”“definitely be more willing”||3 (6)||2 (4)||−8.7% to 12.5%||1.00|
More subjects in the treatment group experienced minor redness at the treatment site on the day of donation or the following day, although the difference was not significant (control, 2%; treatment, 8%; p = 0.20; see Table 4). There was only one adverse event in the study and no serious adverse events. One subject who had been randomly assigned to the sham/placebo group experienced some itching at the site which resolved without sequelae.
The objective of this study was to evaluate the safety and efficacy of ultrasonically facilitated delivery of a readily available topical anesthetic in blood donors. The primary endpoints were pain assessments using the VCS and VAS and the assessment of skin irritation. Mean pain assessment scores were lower in the treatment group compared to the sham/placebo group using both the VAS and the VCS. Dichotomizing the VCS categorical measures showed that the proportion of individuals reporting no pain after venipuncture was doubled in the presence of active treatment compared to sham treatment. Similarly, the proportion of patients reporting moderate or severe pain was approximately doubled in the sham/placebo compared to the treatment group (although these nonprespecified categorical approaches to analyzing the VCS were not significant).
There were no safety concerns that emerged during this study. There was a nonsignificant increase in the number of subjects in the treatment arm who experienced minor redness at the target site and one adverse event in a subject in the sham/placebo arm.
Although subjects in the treatment arm reported decreased pain when comparing the study phlebotomy to previous blood donations, they responded that they would not request it for subsequent donations, nor did they believe it would have much effect on their willingness to donate blood and in this regard were no different than the donors who received the sham/placebo treatment. However, in the pretreatment questionnaire, the donors enrolled in this study also claimed that the needlestick pain was minor and did not have a strong influence on their willingness to donate blood. The indifference to needle-stick pain in the study population of repeat, whole blood donors might reflect a self-selection bias if people who find phlebotomy to be painful are less likely to donate blood voluntarily or to become repeat donors. It has been observed that experienced blood donors assign lower scores to venipuncture pain than do less experienced (≤1 donation) donors.32 In a study in preoperative autologous blood donation,22 those donors who assigned a relatively low pain scale rating to a reference (untreated) donation also showed little difference in pain ratings between blinded EMLA and placebo-pretreated venipunctures. However, donors who assigned relatively high pain scale ratings to the reference donation also rated the EMLA-pretreated venipuncture as significantly less painful than the placebo pretreated venipuncture. It is possible to attribute the low pain scores observed in the present study population of repeat blood donors, and the associated small treatment effect, to stoicism. However, an equally plausible explanation is that some individuals experience less pain from needlestick than others; hence there is little improvement to be gained by treatment to reduce pain in that population.
The response of nondonors to less painful phlebotomy might be quite different than that of experienced donors, however. It is conceivable that for potential donors who are fearful of the pain of needlestick, or who have had a painful experience in the past, the option for pain mitigation might persuade them to donate. However, very little work has been done to assess the effect of pain on the behavior of blood donors. Several studies have correlated reduced donor return rates to donation adverse events33,34 and anxiety.35 However, phlebotomy-related adverse events such as bruising and arm pain had little effect on return rates compared to other types of events such as fatigue and vasovagal responses.33,36
There were several limitations to this study, one of which was the single-blind design. The optimal approach would have been to blind the person performing the treatment or to use a blinded “third-party” assessor. Assessor bias may have been somewhat mitigated by the fact that the VAS, VCS, and questionnaires were filled out directly by each study subject. A second limitation was the lack of previous validation of the postdonation questionnaire (used for the secondary outcomes) and its apparent lack of discriminatory power in a repeat donor population in which pain does not appear to be a major factor affecting donation behavior.
In this study, ultrasound-enhanced delivery of topical anesthetic was demonstrated to be a safe and well-tolerated means to provide clinically and statistically meaningful reduction in the pain of phlebotomy for whole blood donation at 5 minutes compared to sham/placebo treatment, based on multiple methods of measuring pain intensity. The combination of ultrasound and local anesthetic continues to be the only available approach that appears to provide effective anesthesia for most patients within a few minutes. This is a promising technology that deserves further investigation.
APPENDIX 1—POSTPHLEBOTOMY QUESTIONNAIRE
- 1How did the pain associated with the needlestick in this experience compare with other times you have donated blood?
- □About the same
- 2How would you describe the sensation of the treatment?
- □No sensation
- 3How did the sensation of the treatment compare to the needlestick?
- □Much less painful than the needlestick
- □Less painful than the needlestick
- □About the same as the needlestick
- □More painful than the needlestick
- 4If this pretreatment were available, how likely would you be to request it prior to your next donation?
- □Not likely
- □Somewhat likely
- □Very likely
- 5If this pretreatment were available, what effect would it have on your willingness to give blood?
- □Would have no effect
- □Would be somewhat more willing to donate blood
- □Would definitely be more willing to donate blood
- 6How soon do you think you will give blood again?
- □Don't know
- □Within 6 months
- □Within 3 months
- □Within 1 month