Home Medicine Prospective, double blind, randomized, controlled trial comparing vapocoolant spray versus placebo spray in adults undergoing intravenous cannulation
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Prospective, double blind, randomized, controlled trial comparing vapocoolant spray versus placebo spray in adults undergoing intravenous cannulation

  • Sharon E. Mace EMAIL logo
Published/Copyright: October 1, 2017
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 17 Issue 1

Abstract

Objectives

Painful diagnostic and therapeutic procedures are common in the health care setting. Eliminating, or at least, minimizing the pain associated with various procedures should be a priority. Although there are many benefits of providing local/topical anesthesia prior to performing painful procedures, ranging from greater patient/family satisfaction to increased procedural success rates; local/topical anesthetics are frequently not used. Reasons include the need for a needlestick to administer local anesthetics such as lidocaine and the long onset for topical anesthetics. Vapocoolants eliminate the risks associated with needlesticks, avoids the tissue distortion with intradermal local anesthetics, eliminates needlestick pain, have a quick almost instantaneous onset, are easy to apply, require no skills or devices to apply, are convenient, and inexpensive. The aims of this study were to ascertain if peripheral intravenous (PIV) cannulation pain would be significantly decreased by using a vapocoolant (V) versus sterile water placebo (S) spray, as determined by a reduction of at least >1.8 points on numerical rating scale (NRS) after vapocoolant versus placebo spray, the side effects and incidence of side effects from a vapocoolant spray; and whether there were any long term visible skin abnormalities associated with the use of a vapocoolant spray.

Materials and methods

Prospective, randomized, double-blind controlled trial of 300 adults (ages 18-80) requiring PIV placement in a hospital ED, randomized to S(N = 150)or V(N = 150) prior to PIV. Efficacy outcome was the difference in PIV pain: NRS from 0 (none) to worst (10). Safety outcomes included a skin checklist for local adverse effects (i.e., redness, blanching, edema, ecchymosis, itching, changes in skin pigmentation), vital sign (VS) changes, and before/after photographs of the PIV site.

Results

Patient demographics (age, gender, race), comorbidity, medications, and vital signs; and PIV procedure variables (e.g., IV needle size, location, number of IV attempts, type and experience of healthcare provider performing the IV) were not significantly different for the two groups. Median (interquartile range) PIV pain was 4 (2,7) (S) and 2 (0,4) (V) (P< 0.001). Skin checklist revealed minimal erythema: S 0% (N = 0/150), V: 2.7% (4/150), which resolved within 5min, and no blanching, skin pigmentation changes, itching, edema, or ecchymosis. Photographs at 5-10 min revealed no visible skin changes in any patient (N=300), vapocoolant (N = 150) or placebo groups (N = 150). Complaints (N = 26) were coolness/cold feeling S 8.7% (N = 13), V 7.3% (N = 11), coolness/numbness S 0% (N =0), V 0.7% (N =1), and burning S 0.7% (N =1), V 0 (0%). Patient acceptance of the vapocoolant spray was high: 82% (123/150) of the patients stated they would use the spray in the future, while only 40.7% (61/150) of the placebo group stated they would use the placebo spray in the future.

Conclusions and Implications

Vapocoolant spray significantly decreased peripheral intravenous cannulation pain in adults versus placebo spray and was well tolerated with minor adverse effects that resolved quickly. There were no significant differences in vital signs and no visible skin changes documented by photographs taken within 5-10 min postspray/PIV.

Keywords: Vapocoolant; Topical anesthetics; Intravenous cannulation; Procedural pain; Pain relief

1 Introduction

Painful diagnostic and therapeutic procedures are frequently performed in the emergency department (ED) [1,2]. Suboptimal pain management or oligoanesthesia has been noted as “a problem for emergency medicine” [3]. Failure to adequately treat pain has significant short-term and long-term consequences [4,5]. This oligoanesthesia [6,7,8] extends to painful procedures [9,10,11]. Health care providers frequently fail to provide adequate anesthesia prior to painful procedures even when patients and families indicate that they would like to receive analgesia before painful procedures including needlestick procedures [1,9,10,11,12,13].

Benefits of adequate analgesia include increased patient/family satisfaction and increased procedural success [6,14,15,16]. Yet topical anesthesia prior to procedures is underused [10,11,14].

Topical skin refrigerants, or vapocoolants, have some advantages over other options for local anesthesia including eliminates the risk of needlestick injury, avoids tissue distortion, avoids the pain of intradermal anesthetics, rapid almost instantaneous onset (some topical analgesic creams take up to an hour to achieve clinically significant pain relief), easy to apply, no need for devices for administration (which have been associated with delayed local soreness and edema), less administration time, greater staff convenience, decreased ED length of stay, and is inexpensive [1,5,10,17,18,19,20,21].

This study sought to determine the efficacy and safety of a vapocoolant spray in adults undergoing peripheral intravenous cannulation (PIV). We hypothesized that pain of PIV would be at least 1.8 points lower after vapocoolant spray compared to placebo spray and that there would be no permanent visible changes associated with the use of a vapocoolant spray [22,23].

2 Materials and methods

Thus study, termed IMPACT PAIN II for “IMproved PAtient Comfort Trial: Pain Assessment in Intravenous CaNnulation” was an investigator-initiated study supported by a research grant from the Gebauer Company. The sponsor had no involvement in the study other than funding and supplying the spray cans used for the administration of the placebo spray and the vapocoolant spray.

2.1 Study design and setting

This was a prospective, double blind, randomized controlled efficacy and safety trial conducted at an urban, academic, tertiary care referral hospital conducted from August 2012 to December 2014. The study was approved by the institutional review board and all patients gave written informed consent.

2.2 Study population

Adults (ages 18-80 years) undergoing peripheral intravenous cannulation (PIV) in the ED were eligible for enrollment in the study. Inclusion criteria were: patient undergoing PIV, mentally competent patient able to understand the consent form, and clinically stable. Patients were excluded from the study if any of the following criteria were met: allergy to the spray components (e.g. 1,1,1,3,3-pentafluoropropane or 1,1,1,2-tetrafluoroethane), critically ill or unstable, extremes of age (pediatric <18 years or elderly geriatric >80 years), pregnant, previous experience with any vapocoolant spray, PIV site located in area of compromised blood supply, PIV site located in area of insensitive skin, patient intolerant of cold or with hypersensitivity to cold, and patient unwilling to give consent. Examples of PIV sites located in areas of compromised blood supply would include patients with peripheral vascular disease, gangrene, Raynaud’s disease or Buerger’s disease. Examples of patients with insensate or abnormal sensation of the skin would include patients with a peripheral neuropathy. None of the patients recently received an analgesic (such as an opioid) prior to the venipuncture. Informed written consent was obtained from all subjects.

This was a convenience sample since patients were enrolled when the ED research staff was available, e.g. day and evening shifts on weekdays and weekends. The ED research staff members conducting the study were not involved in the care of the patient or in starting the PIV line. The primary researcher was not present and not involved in patient enrollment or data analysis. A research assistant approached the patient if the patient was in the appropriate age range (18-80 years) and if the patient was clinically stable (e.g. not in shock or respiratory distress or had no alteration of mental status), and obtained informed written consent.

The past medical history including comorbidities, current medications and characteristics of the PIV itself were listed in order to determine if the patient populations for the two groups were well matched at baseline since comorbidity and medication use, and the PIV itself could possibility affect the difficulty of the PIV procedure and the response to the pain of the PIV.

Patients were randomized to either sterile water placebo spray (Nature’s Tears ) or to vapocoolant spray (1,1,1,3,3-pentafluoropropane and 1,1,1,2-tetrafluoroethane) (Gebauer’s Pain Ease® Medium Stream). The application of the spray in all patients was completed by one of two trained research assistants whose job was to enroll patients and to standardize administration of the topical spray. After prepping and cleansing the PIV site, the spray was applied in the same manner for all patients, both placebo and vapocoolant subjects, as recommended by the manufacturer. The specific technique of spray application for both the placebo spray and the vapocoolant spray was: hold the can 3-7 in from the PIV site, spray onto the PIV site steadily 4-10 s or until the skin begins turning white, whichever comes first (the anesthetic effect is complete at this time), then, immediately perform the IV needlestick for the IV line. There is about a one minute time frame to complete the PIV cannulation since the topical anesthetic lasts only about one minute.

The spray cans were not identified as to whether they were the placebo spray or the vapocoolant spray and thus, were blinded to both the subjects, the research assistants applying the spray and the health care providers performing the PIV. The actual PIV was done by the ED staff and not by the two research associates.

Randomization was accomplished utilizing a computer random number generator with block randomization using randomly varied block sizes of 20 or 30. The spray cans were supplied from outside the ED in varied block sizes such that the randomization was not done by or knowledgeable to the ED research staff performing the actual patient enrollment and data collection in order to maintain allocation concealment.

2.3 Data collection and processing

All data was collected by trained research associates who had no patient care duties. Their research duties included patient enrollment, data recording and application of the spray. They recorded on standardized case report forms: the demographics, PIV procedural data, vital signs (completed by ED nursing staff), clinical variables (from the electronic medical record), all side effects/complications, and pain scales (e.g. numeric rating scale [NRS]) as reported by the patients: NRS immediately post spray/pre PIV cannulation, and NRS for the pain of PIV cannulation. They completed the standardized checklist and took before and after photographs of the IV site to document any visible skin changes.

All data was entered into a REDCap database and then analyzed using R software (version 3.1.1) by a biostatistician. Continuous variables were summarized using means with variability assessed using standard deviations. Categorical variables were summarized as counts and percentages. Tests for differences of continuous variables were done using Welch 2-sample t-tests or Wilcoxon’s rank-sum tests. Tests on categorical variables were done using either Pearson’s chi-squared tests with Yates continuity correction or Fisher’s exact test for count data. Significance was at P < 0.05 and the results of testing were given by P-values and/or confidence intervals.

2.4 Outcome measures

The primary efficacy outcome was the pain of PIV on a verbal NRS scale ranging from 0 (none) to 10 (worst). The primary safety measures were the documentation of any and all adverse effects/complications and vital signs. Secondary safety measures included a skin checklist for any changes (rated none, mild, moderate, severe) of the skin: redness, blanching or pallor, changes in skin pigmentation, itching, edema, or other (such as ecchymosis) done immediately post spay, NRS post spray/pre PIV, and photographs of the PIV site done pre and 5-10 min post application of the spray/post PIV for any visible skin changes.

According to previous studies, a change in NRS of 1.3 or greater is deemed clinically significant [22,23], while a previous pediatric IV study found a difference of 18 on a 0-100 mm VAS scale between placebo vs. vapocoolant spray [16]. Therefore, we decided to use a decrease of >1.8 on the NRS since this would include the meaningful difference. To detect a decrease of 1.8 on the NRS, a sample size of 277 was chosen, assuming a 2-tailed test, power of 80%, and type I error rate of 0.05. The sample size was increased to 300 (150 per group) to compensate for potential dropouts or protocol deviations.

3 Results

3.1 Study subjects

Of the 544 patients recruited to the study, 300 consented, were randomized and received their allocated treatment: 150 patients received sterile water spray (placebo arm) and 150 patients received vapocoolant spray (treatment arm) (Fig. 1). For all 300 study subjects, the mean age (±SD) was 42.8 (±16.6) years (range 18-80 years), with 120 males and 180 females: 150 African-Americans, 137 Caucasians, and 13 other. The patients in the two study arms had similar baseline characteristics with no significant differences in any of the demographic variables (age, gender, race); or clinical characteristics (comorbidities, or medications) (Table 1). The characteristics of the PIV itself were similar between the two groups with no significant differences in PIV location, PIV needle gauge, PIV success rate, number of PIV attempts, difficulty of PIV, or with the health care providers performing the PIV (years’ experience and role in ED) except for spray time: 7.5 (V) vs. 10 s (S). The procedure (e.g. PIV) was performed in <1 min in all patients (Table 2).

Fig. 1 Participant flow diagram according to the consolidated standards of reporting trial guidelines.
Fig. 1

Participant flow diagram according to the consolidated standards of reporting trial guidelines.

Table 1

Patient demographics, clinical variables, vital signs.

Placebo saline spray (N = 150 patients) Vapocoolant spray (N = 150 patients) P-value All patients (N =300 patients)
Demographics
 Age (years): mean (±SD) 42.7 (± 16.6) 43.0 (± 16.6) 0.91 42.8 (±16.6)
 Gender: number of patients (%) Male 64 (42.7%) Male 56 (37.3%) 0.41 Male 120 (40%)
  Female 86 (57.3%) Female 94 (62.7%) Female 180 (60%)
 Race: number of patients (%) African-American 73 African-American >0.99 African-American
  (48.7%) 77 (51.3%) 150 (50%)
  Caucasian 68 (45.3%) Caucasian 69 Caucasian 137
  Other 9 (6%) (46.0%) (45.7%)
  Other 4 (2.7%) Other 13 (4.3%)
Comorbidity
 Hypertension 65 (43.3%) 65 (43.3%) >0.99 130 (43.3%)
 Diabetes 35 (23.3%) 34 (22.7%) >0.99 69 (23%)
 COPD 11 (7.3%) 11 (7.3%) >0.99 22 (7.3%)
 Cancer 22 (14.7%) 20 (13.3%) 0.87 42 (14.3%)
 Current chemotherapy 4 (2.7%) 2 (1.3%) 0.68 6 (2%)
 Past chemotherapy 5 (3.33%) 3 (2%) 0.72 8 (2.7%)
 Current radiation therapy 0 (0%) 2 (1.3%) 0.67 2 (1%)
 Past radiation therapy 6 (4%) 3 (2%) 0.50 9 (3%)
 Status post mastectomy 1 (0.7%) 4 (2.7%) 0.37 5 (1.7%)
 Obesity 21 (14%) 35 (23.3%) 0.54 56 (18.7%)
 Renal disease 5 (3.3%) 7 (4.7%) 0.77 12 (4%)
 Hemodialysis 4 (2.7%) 3 (2%) >0.99 7 (2.3%)
 Sickle cell disease 2 (1.3%) 1 (0.7%) >0.99 3 (1%)
 Grave’s disease 0 (0%) 1 (0.7%) >0.99 1 (0.3%)
 Gout 6 (4%) 8 (5.3%) 0.78 14 (4.7%)
 Osteoarthritis 9 (6%) 11 (7.3%) 0.82 20 (6.7%)
 Rheumatoid arthritis 5 (3.3%) 7 (4.7%) 0.77 12 (4%)
 Systemic lupus erythromatosis 6 (4.0%) 1 (0.7%) 0.13 7 (2.3%)
 Sarcoidosis 1 (0.7%) 0 (0%) >0.99 1 (0.3%)
 Scleroderma 1 (0.7%) 0 (0%) >0.99 1 (0.3%)
 Polymyositis 1 (0.7%) 0 (0%) >0.99 1 (0.3%)
 Spondyloarthropathy 1 (0.7%) 1 (0.7%) >0.99 2 (0.7%)
 Other rheumatologic disorders 2 (1.3%) 3 (2%) >0.99 5 (1.7%)
 GI disorders: Crohn’s 1 (0.7%) 1 (0.7%) >0.99 2 (0.7%)
 GI disorders: celiac disease 1 (0.7%) 0 (0%) >0.99 1 (0.3%)
 Multiple sclerosis 2 (1.3%) 1 (0.7%) >0.99 3 (1%)
 History of blood clot in upper 4 (2.7%) 4 (2.7%) >0.99 4 (2.7%)
extremity
 IV drug use 3 (2%) 0 (0%) 0.25 3 (1%)
 Dehydration in last 72 h 23 (15.3%) 26 (17.3%) 0.75 49 (16.3%)
 Surgery in last 30 days 9 (6%) 13 (8.7%) 0.51 22 (7.3%)
Medications
 Acetaminophen 18 (12%) 18 (12%) >0.99 36 (12%)
 Opioids (acetaminophen-oxycodone 34 (22.7%) 33 (22%) >0.99 67 (22.3%)
 or acetaminophen-hydrocodone)
 Nonsteroidal anti-inflammatory 25 (16.7%) 28 (18.7%) 0.76 53 (17.7%)
 drugs (NSAIDS)
 Anticonvulsants 17 (11.3%) 12 (8%) 0.43 29 (9.7%)
 Antidepressants 14 (9.3%) 18 (12%) 0.57 32 (10.7%)
 Benzodiazepines 13 (8.7%) 10 (6.7%) 0.66 23 (7.7%)
 Corticosteroids (e.g. prednisone) 9 (6%) 9 (6%) >0.99 9 (6%)
Vital signs
 Blood pressure: systolic (mm Hg), 139.1 (±24.0) 135.7 (±21.9) 0.20 137.4 (±23.0)
mean (±SD)
 Blood pressure: diastolic (mm Hg), 80.0 (±15.0) 78.0 (±15.3) 0.26 79.0 (±15.2)
mean (±SD)
 Heart rate (beats/min) 84.5 (±15.8) 85.7 (±16.4) 0.52 85.1 (±16.1)
 Respiratory rate (breaths/min) 18.0 (±1.9) 18.3 (±2.6) 0.29 18.2 (±2.3)

Table 2

Characteristics ofthe peripheral intravenous cannulation procedure.

Placebo spray (N = 150 patients) Vapocoolant spray (N = 150 patients) P-value All patients (N =300 patients)
Needle size 0.20
 18 gauge 39 (26%) 35 (23.3%) 74 (24.7%)
 20 gauge 100 (66.7%) 103 (68.7%) 203 (67.6%)
 22 gauge 11 (7.3%) 12 (8%) 23 (7.7%)
Location of PIV 0.16
 Hand 5 (3.3%) 8 (5.3%) 13 (4.3%)
 Antecubital fossa 88 (58.6%) 94 (62.7%) 182 (61%)
 Forearm 50 (33.3%) 44 (29.3%) 94 (31.3%)
 Wrist 7 (4.7%) 4 (2.7%) 11 (3.7%)
Total number of PIV attempts 0.58
 One 114 (76%) 124 (82.7%) 238 (79.3%)
 Two 27 (18%) 17 (11.3%) 44 (14.7%)
 Three 5 (3.3%) 7 (4.7%) 12 (4%)
 Four 4 (2.7%) 1 (0.7%) 5 (1.7%)
 Five 0 (0%) 1 (0.7%) 1 (0.3%)
Job description of healthcare provider starting the PIV 0.97
 Paramedic 91 (60.7%) 89 (59.3%) 179 (59.7%)
 Registered nurse 58 (38.7%) 60 (40%) 117 (39%)
 Licensed practical nurse 1 (0.7%) 1 (0.7%) 2 (0.7%)
Number years experience of individual performing the PIV, mean ±SD [95% CI] [95% CI] 0.83 [95% CI]
 0-2 years 13 (8.7%) 11 (7.3%) 24 (8%)
 3-5 years 34 (23.3%) 38 (25.3%) 72 (24%)
 5-10 years 47 (31.3%) 51 (34%) 99 (33%)
 10+ years 56 (37.3%) 50 (33.3%) 106 (35.3%)
Patient question
 Would you use this spray for future IVs? 61 (49.7%) 123 (82%) <0.001 184 (61.3%)
 Spray time seconds median [P25, P75] 10 [8,10] 7.5 [6,10] <0.001 10 [7,10]

3.2 Results: efficacy

The median NRS interquartile range (IQR) for PIV cannulation pain was 4 (2-7) for the placebo spray group vs. 2 (0-4) for the vapocoolant spray group (P< 0.001) (Fig. 2). Over one-third (35% = 52/150) of the patients in the vapocoolant group reported no pain (NRS = 0) for their IV start compared with 8.7% (13/150) for the placebo group (P< 0.001) (Fig. 3).

Fig. 2 The pain of peripheral intravenous cannulation (PIV) on numeric rating scale (NRS): box and whisker plots of NRS for the placebo spray and the vapocoolant spray. The median is the center line, the boxes are the 25th to 75th percentile and the triangle is the mean.
Fig. 2

The pain of peripheral intravenous cannulation (PIV) on numeric rating scale (NRS): box and whisker plots of NRS for the placebo spray and the vapocoolant spray. The median is the center line, the boxes are the 25th to 75th percentile and the triangle is the mean.

Fig. 3 Frequencies of the numeric rating scale (NRS) for the placebo spray and the vapocoolant spray for all the points (0 to 10) on the NRS.
Fig. 3

Frequencies of the numeric rating scale (NRS) for the placebo spray and the vapocoolant spray for all the points (0 to 10) on the NRS.

3.3 Results: safety

There were no significant differences in vital signs between the two groups (Table 1). There were 26 complaints (Table 3). In the placebo group, 13 (8.7%) complained of coolness/cold feeling, and 1 (0.7%) had burning at the site. In the vapocoolant group, 11 (7.3%) complained of coolness/cold feeling and 1 (0.7%) complained of coolness and numbness. There were no serious side effects/adverse events or complications and minor adverse effects, such as redness of the skin, resolved in <5 min.

Table 3

Patient comments: side effects.

Side effect Placebo spray (N =150) Vapocoolant spray (N = 150) P-value
Coolness/cold feeling 13 (8.7%) 11 (7.3%) 0.63
Coolness and numbness 0 (0%) 1 (0.7%) >0.99
Burning 1 (0.7%) 0 (0%) >0.99
No comment 136 (90.7%) 138 (92%) >0.99

The skin checklist completed immediately post spray revealed minimal redness in 4 patients in the vapocoolant group (4/150 = 2.7%), which resolved within 5 min post spray application/post PIV and no redness in the saline placebo group. There was no blanching, skin pigmentation changes, itching, edema, bruising, or other visible skin changes reported for either group (Table 4).

Table 4

Skin checklist: immediately postspray.

Placebo spray (N = 150 patients) Vapocoolant spray (N = 150 patients) P-value
Redness 0.13
 None 150 146 (97.3%)
 Minimal 0 4 (2.7%)
 Moderate 0 0
 Severe 0 0
Blanching
 None 150 150 >0.99
 Minimal 0 0
 Moderate 0 0
 Severe 0 0
Changes in skin pigmentation
 None 150 150 >0.99
 Mild 0 0
 Moderate 0 0
 Severe 0 0
Itching
 None 150 150 >0.99
 Mild 0 0
 Moderate 0 0
 Severe 0 0
Edema
 None 150 150 >0.99
 Mild 0 0
 Moderate 0 0
 Severe 0 0
Other >0.99
 None 0 0
 Mild 0 0
 Moderate 0 0
 Severe 0 0

Immediately post spray/pre PIV cannulation, the median NRS was the same for the placebo spray and for the vapocoolant spray at 0 and the IQR was between 0 and 0 for the placebo spray and 0 and 2 for the vapocoolant spray (P< 0.001). Patients were asked “Would you want to use this spray for future IVs?” Of the vapocoolant group, 82% (123/150) responded affirmatively versus 40.7% (61/150) of the placebo group (P< 0.001) (Table 2). Before-and-after photographs of the spray/PIV site revealed no visible skin changes in any of the patients no matter what the gender, ethnicity, or age and no matter whether they received the placebo or vapocoolant spray.

4 Discussion

Painful diagnostic and therapeutic medical procedures, especially needlestick procedures, are frequently performed in the ED [1,11,13,14]. Unfortunately, health care providers frequently fail to provide adequate analgesia prior to painful procedures, even when patients indicated that they would like to receive analgesia before painful procedures including needlestick procedures [6]. Vapocoolants, also known as topical skin refrigerants, have some advantages over other options for local anesthesia including avoids the risk of needlestick injury and the pain of the needlestick injection of intradermal local anesthetics, rapid almost instantaneous onset (some topical creams take up to an hour for effect), easy to apply (no need for devices for application) and is inexpensive. Recent evidence from both human and animal studies indicates that topical refrigerant sprays are safe, e.g. have no lasting skin abnormalities with proper application and no effect on the microcirculation [21,24].

This prospective, double-blind, randomized, placebo-controlled trial demonstrated a significant decrease in the acute pain of PIV cannulation in adult ED patients after application of topical vapocoolant spray (1,1,1,3,3-pentafluoropropane and 1,1,1,2-tetrafluoroethane) compared with placebo spray and safety with no visible skin abnormalities 5-10 min after spray application. Other studies have considered the issue of skin sterility with application of a vapocoolant spray and concluded there was no increased risk of infection when a topical vapocoolant spray was used [25,26]. The analgesic effect of vapocoolants is thought to be via rapid cooling [27] by decreasing “both initiation and conduction impulses in surrounding (peripheral) sensory nerve”, thereby interrupting the nocioceptive input into the spinal cord and raising the pain threshold [28]. In an animal study, cryotherapy or cold therapy increases the pain threshold and decreases the nerve conduction velocity [29]. Vapocoolant sprays are thought to produce “the sensation of cooling and analgesia through activation of transient receptor potential (TRP) ion channels in cold-sensitive peripheral sensory neurons” [30].

This study is unique in several respects. This is the first large (N = 300) prospective, double-blind, randomized controlled trial in an ED patients, which looked at both safety and efficacy. By comparison, an earlier study that used health care provider volunteers, had a much smaller N (only 38 volunteers) and was in a non-acute care setting (healthy volunteers, not actual ED patients), used a different vapocoolant spray (e.g. ethyl chloride), and did not address the safety issue. However, they also found a decrease in pain of PIV cannulation with the use of a vapocoolant spray: verbal NRS (median, IQR) scores were placebo (sterile water spray) 4 (2-5) vs. ethyl chloride spray 2 (1-4) [31].

A study in a different age group, children (ages 6-12 years) in a Canadian pediatric ED also found a significant decrease in the pain of PIV cannulation with the use of the 1,1,1,3,3-pentafluoropropane and 1,1,1,2-tetrafluoroethane spray compared to a placebo saline spray: (mean difference 19 mm, 95% confidence interval [CI] 6-32 mm, P<0.01) using a 100-mm color visual analogue scale. Moreover, the first attempt PIV cannulation success rate was significantly greater for the vapocoolant spray (85%) than placebo spray (62.5%) (mean difference 22.5%, 95% CI 3.2-39.9%, P = 0.03). The number needed to treat to prevent one cannulation failure was 5 [16].

Another smaller non-blinded Australian study using a different vapocoolant; COLD spray ; a mixture of propane, butane and pentane; in adult ED patients comparing subcutaneous lidocaine vs. COLD spray also found significantly greater PIV success rates for the COLD spray group (83.6%) vs. lidocaine group (67.3%) (P= 0.005) and a significantly decreased pain of PIV insertion (P < 0.001) with the COLD spray [19].

The pain of PIV cannulation in our trial is similar to that reported in other studies. The study from Scotland that compared 3 groups: no treatment, intradermal lidocaine and ethyl chloride for PIV cannulation on a 0-10 VAS scale in adult females undergoing outpatient gynecologic surgery found the pain of PIV insertion with no treatment was 3.8 ±2.1 (mean ±SD) vs. ethyl chloride group 1.8 ±1.5 (mean ±SD) (P < 0.001). Intradermal lidocaine also significantly decreased the pain of PIV insertion, but with significantly decreased vein visibility and decreased ease of cannulation compared to the no treatment or ethyl chloride groups (P < 0.001) [18]. Comparatively, the pain of PIV cannulation for our placebo group was 4.3 ± 3.0 (mean ± SD) and median (IQR) 4 (2, 7) versus the vapocoolant group 2.3 ±2.4 (mean ±SD) and median (IQR) 2 (0,4) (Fig. 2).

5 Limitations

This study has several limitations. Although we did include a wide age range of adults, ages 18-80 years, we did not evaluate children or “older” geriatric patients (>80 years), we evaluated only one needlestick procedure and we used one formulation of vapocoolant spray. This was done to standardize our methodology, but may limit our generalizability, although other studies suggest that our findings may be generalizable to other patient populations, other needlestick procedures, and other vapocoolant sprays [16,32,33,34,35].

Our study is consistent with the study in a pediatric ED that also found significantly decreased PIV cannulation pain and a higher PIV success rate in children with the use of a vapocoolant spray compared to a placebo spray [16]. Other research documented significantly decreased pain for various other needlestick procedures including immunizations in both children [32] and in adults [15,33] and as a pre-injection anesthetic [34,35]. These studies [15,16,32,33,34,35] used the same formulation, 1,1,3,3-pentafluoropropane and 1,1,1,2-tetrafluoroethane, of vapocoolant spray that we used in our clinical trial. Studies using other vapocoolant sprays e.g. ethyl chloride, or a propane/butane/pentane blend, have also found that these formulations decrease needlestick pain in adults [18,19,36,37,38].

In these studies and our study, the proper application of the vapocoolant spray as described in the methodology was followed. The importance of appropriate spray application: adequate spray time, proper height or distance from the site, etc. cannot be overlooked [28]. A few studies that found conflicting results failed to adhere to the recommended technique of application [28,39,40,41,42] and this has been cited as a possible reason for lack of efficacy of the vapocoolant spray in these studies [16,19,21,37].

Vapocoolant sprays last a short time, so the health care provider performing the needlestick procedure should have all the supplies readily available. This may be difficult in a busy ED. If the health care practitioner has to leave the patient and go and retrieve needed supplies, this allows the efficacy of the vapocoolant spray to wane. However, this should not be an issue, since the vapocoolant spray may be reapplied as often as needed.

The spray containers were identical (indistinguishable) and thus, blinded. The spray cans were masked and were stored together at the same (e.g. room temperature). Moreover, unmasking of the spray cans was not done until the study was over (e.g. enrollment ended and all data collection was completed). Although we sought to maintain blinding through obscuring aerosol containers, keeping the containers at the same temperature, and directing treatment sprays away from patients’ and health care providers faces to avoid visual cues and olfactory detection, we cannot prove effective blinding.

There may be a difference in sensation on the skin between the vapocoolant spray and the placebo spray, which may lead to a bias. Patients could only be enrolled once in the study to avoid previous experience with this specific vapocoolant spray and because patients never had prior experience with a vapocoolant spray (or placebo spray) as a topical anesthetic in the past, he/she would be “naíve” and would not know what a vapocoolant spray (or placebo spray) would feel like, so it is unlikely that the patient responses would be biased. Since we did not want to influence the patient’s response, we did not give them any pre-information about the sprays except that one was a placebo spray and one was the treatment spray.

We did collect details regarding the patients and the health care providers performing the procedures in order to document that the placebo and vapocoolant groups were similar at baseline and that the actual procedure of PIV cannulation was not significantly different between the two groups.

In summary, this prospective, double-blind, randomized controlled trial suggests that a topical vapocoolant spray (1,1,1,3,3-pentafluoropropane and 1,1,1,2-tetrafluoroethane) is not only effective in significantly relieving the pain of PIV cannulation in adults in the ED, but was also well tolerated with a majority of patients indicating they would use the vapocoolant spray in the future.

This vapocoolant spray appears to be safe with only a few minor adverse effects that resolved quickly (within 5-10 min), and had no lasting visible skin abnormalities. This is consistent with an animal study that found no microcirculatory effects (e.g., no significant changes in vessel diameter and inflammatory markers) [24].

6 Implications

The use of topical skin refrigerants or vapocoolants has numerous advantages: rapid onset, easy application, inexpensive, avoids needlestick injury, eliminates intradermal injection pain, increases procedural success rates, and improves patient satisfaction. Given the frequency of needlestick procedures in the health care setting, not just in the emergency department but throughout the hospital: on the inpatient floors and the operating room, in clinics and offices, and outpatient surgery centers: topical refrigerant sprays have wide applicability and likely, increased usage in the future.

Highlights

  • Vapocoolant spray significantly decreased the pain of intravenous cannulation.

  • There were no complications or adverse events.

  • Minor side effects that occurred in a few patients resolved quickly.

  • No visible skin abnormalities were present 5–10 min after spray application.

Department of Emergency Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Faculty MetroHealth Medical Center/Cleveland Clinic Emergency Medicine Residency, Cleveland, OH, United States

☆ Presentations: American College of Emergency Physicians, October 2013, Seattle, WA. American Society of Regional Anesthesia and Pain Medicine, April 2014, Chicago, IL.Society of Academic Emergency Medicine, May 2014, Dallas, TX. American College of Emergency Physicians, October 2014, Chicago, IL. International Conference on EmergencyMedicine, April 2016, Capetown, South Africa. Society of Academic Emergency Medicine, May 2016, New Orleans, LA.

  1. Ethical issues: The study was approved by the Institutional Review Board (IRB).

    Written informed consent was obtained from all subjects.

    The study protocol was registered at ClinicalTrials.gov (NCT01670487).

  2. Conflict of interest: Thus study was an investigator-initiated study supported by a research grant from the Gebauer Company. The sponsor had no involvement in the study other than funding and supplying the spray cans used for the administration of the placebo spray and the vapocoolant spray.

Acknowledgement

I would like to thank Mr. Benjamin Nutter, the Section of Biostatistics, Quantitative Health Sciences for his statistical analysis of the data.

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Received: 2017-04-29
Revised: 2017-06-07
Accepted: 2017-06-10
Published Online: 2017-10-01
Published in Print: 2017-10-01

© 2017 Scandinavian Association for the Study of Pain

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https://doi.org/10.1016/j.sjpain.2017.06.002
Keywords for this article
Vapocoolant; Topical anesthetics; Intravenous cannulation; Procedural pain; Pain relief

Articles in the same Issue

  1. Observational study
  2. Perceived sleep deficit is a strong predictor of RLS in multisite pain – A population based study in middle aged females
  3. Clinical pain research
  4. Prospective, double blind, randomized, controlled trial comparing vapocoolant spray versus placebo spray in adults undergoing intravenous cannulation
  5. Clinical pain research
  6. The Functional Barometer — An analysis of a self-assessment questionnaire with ICF-coding regarding functional/activity limitations and quality of life due to pain — Differences in age gender and origin of pain
  7. Clinical pain research
  8. Clinical outcome following anterior arthrodesis in patients with presumed sacroiliac joint pain
  9. Observational study
  10. Chronic disruptive pain in emerging adults with and without chronic health conditions and the moderating role of psychiatric disorders: Evidence from a population-based cross-sectional survey in Canada
  11. Educational case report
  12. Management of patients with pain and severe side effects while on intrathecal morphine therapy: A case study
  13. Clinical pain research
  14. Behavioral inhibition, maladaptive pain cognitions, and function in patients with chronic pain
  15. Observational study
  16. Comparison of patients diagnosed with “complex pain” and “somatoform pain”
  17. Original experimental
  18. Patient perspectives on wait times and the impact on their life: A waiting room survey in a chronic pain clinic
  19. Topical review
  20. New evidence for a pain personality? A critical review of the last 120 years of pain and personality
  21. Clinical pain research
  22. A multi-facet pain survey of psychosocial complaints among patients with long-standing non-malignant pain
  23. Clinical pain research
  24. Pain patients’ experiences of validation and invalidation from physicians before and after multimodal pain rehabilitation: Associations with pain, negative affectivity, and treatment outcome
  25. Observational study
  26. Long-term treatment in chronic noncancer pain: Results of an observational study comparing opioid and nonopioid therapy
  27. Clinical pain research
  28. COMBAT study – Computer based assessment and treatment – A clinical trial evaluating impact of a computerized clinical decision support tool on pain in cancer patients
  29. Original experimental
  30. Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain
  31. Editorial comment
  32. Spatial summation of pain and its meaning to patients
  33. Original experimental
  34. Effects of validating communication on recall during a pain-task in healthy participants
  35. Original experimental
  36. Comparison of spatial summation properties at different body sites
  37. Editorial comment
  38. Behavioural inhibition in the context of pain: Measurement and conceptual issues
  39. Clinical pain research
  40. A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis
  41. Editorial comment
  42. Quantitative sensory tests (QST) are promising tests for clinical relevance of anti–nociceptive effects of new analgesic treatments
  43. Educational case report
  44. Pregabalin as adjunct in a multimodal pain therapy after traumatic foot amputation — A case report of a 4-year-old girl
  45. Editorial comment
  46. Severe side effects from intrathecal morphine for chronic pain after repeated failed spinal operations
  47. Editorial comment
  48. Opioids in chronic pain – Primum non nocere
  49. Editorial comment
  50. Finally a promising analgesic signal in a long-awaited new class of drugs: TRPV1 antagonist mavatrep in patients with osteoarthritis (OA)
  51. Observational study
  52. The relationship between chronic musculoskeletal pain, anxiety and mindfulness: Adjustments to the Fear-Avoidance Model of Chronic Pain
  53. Clinical pain research
  54. Opioid tapering in patients with prescription opioid use disorder: A retrospective study
  55. Editorial comment
  56. Sleep, widespread pain and restless legs — What is the connection?
  57. Editorial comment
  58. Broadening the fear-avoidance model of chronic pain?
  59. Observational study
  60. Identifying characteristics of the most severely impaired chronic pain patients treated at a specialized inpatient pain clinic
  61. Editorial comment
  62. The burden of central anticholinergic drugs increases pain and cognitive dysfunction. More knowledge about drug-interactions needed
  63. Editorial comment
  64. A case-history illustrates importance of knowledge of drug-interactions when pain-patients are prescribed non-pain drugs for co-morbidities
  65. Editorial comment
  66. Why can multimodal, multidisciplinary pain clinics not help all chronic pain patients?
  67. Topical review
  68. Individual variability in clinical effect and tolerability of opioid analgesics – Importance of drug interactions and pharmacogenetics
  69. Editorial comment
  70. A new treatable chronic pain diagnosis? Flank pain caused by entrapment of posterior cutaneous branch of intercostal nerves, lateral ACNES coined LACNES
  71. Clinical pain research
  72. PhKv a toxin isolated from the spider venom induces antinociception by inhibition of cholinesterase activating cholinergic system
  73. Clinical pain research
  74. Lateral Cutaneous Nerve Entrapment Syndrome (LACNES): A previously unrecognized cause of intractable flank pain
  75. Editorial comment
  76. Towards a structured examination of contextual flexibility in persistent pain
  77. Clinical pain research
  78. Context sensitive regulation of pain and emotion: Development and initial validation of a scale for context insensitive avoidance
  79. Editorial comment
  80. Is the search for a “pain personality” of added value to the Fear-Avoidance-Model (FAM) of chronic pain?
  81. Editorial comment
  82. Importance for patients of feeling accepted and understood by physicians before and after multimodal pain rehabilitation
  83. Editorial comment
  84. A glimpse into a neglected population – Emerging adults
  85. Observational study
  86. Assessment and treatment at a pain clinic: A one-year follow-up of patients with chronic pain
  87. Clinical pain research
  88. Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of L-4-chlorokynurenine in healthy volunteers
  89. Clinical pain research
  90. Prevalence and characteristics of chronic pain: Experience of Niger
  91. Observational study
  92. The use of rapid onset fentanyl in children and young people for breakthrough cancer pain
  93. Original experimental
  94. Acid-induced experimental muscle pain and hyperalgesia with single and repeated infusion in human forearm
  95. Original experimental
  96. Swearing as a response to pain: A cross-cultural comparison of British and Japanese participants
  97. Clinical pain research
  98. The cognitive impact of chronic low back pain: Positive effect of multidisciplinary pain therapy
  99. Clinical pain research
  100. Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia
  101. Topical review
  102. Targeting cytokines for treatment of neuropathic pain
  103. Original experimental
  104. What constitutes back pain flare? A cross sectional survey of individuals with low back pain
  105. Original experimental
  106. Coping with pain in intimate situations: Applying the avoidance-endurance model to women with vulvovaginal pain
  107. Clinical pain research
  108. Chronic low back pain and the transdiagnostic process: How do cognitive and emotional dysregulations contribute to the intensity of risk factors and pain?
  109. Original experimental
  110. The impact of the Standard American Diet in rats: Effects on behavior, physiology and recovery from inflammatory injury
  111. Educational case report
  112. Erector spinae plane (ESP) block in the management of post thoracotomy pain syndrome: A case series
  113. Original experimental
  114. Hyperbaric oxygenation alleviates chronic constriction injury (CCI)-induced neuropathic pain and inhibits GABAergic neuron apoptosis in the spinal cord
  115. Observational study
  116. Predictors of chronic neuropathic pain after scoliosis surgery in children
  117. Clinical pain research
  118. Hospitalization due to acute exacerbation of chronic pain: An intervention study in a university hospital
  119. Clinical pain research
  120. A novel miniature, wireless neurostimulator in the management of chronic craniofacial pain: Preliminary results from a prospective pilot study
  121. Clinical pain research
  122. Implicit evaluations and physiological threat responses in people with persistent low back pain and fear of bending
  123. Original experimental
  124. Unpredictable pain timings lead to greater pain when people are highly intolerant of uncertainty
  125. Original experimental
  126. Initial validation of the exercise chronic pain acceptance questionnaire
  127. Clinical pain research
  128. Exploring patient experiences of a pain management centre: A qualitative study
  129. Clinical pain research
  130. Narratives of life with long-term low back pain: A follow up interview study
  131. Observational study
  132. Pain catastrophizing, perceived injustice, and pain intensity impair life satisfaction through differential patterns of physical and psychological disruption
  133. Clinical pain research
  134. Chronic pain disrupts ability to work by interfering with social function: A cross-sectional study
  135. Original experimental
  136. Evaluation of external vibratory stimulation as a treatment for chronic scrotal pain in adult men: A single center open label pilot study
  137. Observational study
  138. Impact of analgesics on executive function and memory in the Alzheimer’s Disease Neuroimaging Initiative Database
  139. Clinical pain research
  140. Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [11C]-D-deprenyl PET/CT
  141. Original experimental
  142. Developing a model for measuring fear of pain in Norwegian samples: The Fear of Pain Questionnaire Norway
  143. Topical review
  144. Psychoneuroimmunological approach to gastrointestinal related pain
  145. Letter to the Editor
  146. Do we need an updated definition of pain?
  147. Narrative review
  148. Is acetaminophen safe in pregnancy?
  149. Book Review
  150. Physical Diagnosis of Pain
  151. Book Review
  152. Advances in Anesthesia
  153. Book Review
  154. Atlas of Pain Management Injection Techniques
  155. Book Review
  156. Sedation: A Guide to Patient Management
  157. Book Review
  158. Basics of Anesthesia
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