Pain During Venous Cannulation
A randomized controlled study of the efficacy of local anesthetics
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Background: The pain of venous puncture for the cannulation of peripheral veins is disturbing to many patients. This is the first clinical trial of the efficacy of local anesthesia in comparison to placebo (no pretreatment) in a control group, as a function of the size of the cannula.
Methods: A randomized, controlled trial of fully factorial design was performed to study pain during venipuncture after local anesthesia either with intradermally injected lidocaine or with a vapocoolant spray, in comparison to placebo. A standardized protocol was used for structured communication with the patient to provide the greatest feasible degree of patient blinding (trial registration number DRKS00010155). The primary endpoints were the subjective discomfort of the patient during preparation and puncture of a vein of the dorsum of the hand, assessed on a numerical rating scale (NRS) from 0 (no discomfort) to 10 (unbearable discomfort), and the rate of unsuccessful puncture.
Results: The intention-to-treat analysis of all 450 patients revealed that the reported degree of pain during venipuncture depended to a large extent on the caliber of the chosen venous cannula. For a 17-gauge (17G) cannula, both the vapocoolant spray (NRS = 2.6 ± 1.3) and lidocaine (NRS = 3.5 ± 2.2) lessened the discomfort due to venipuncture compared to control treatment (5.0 ± 1.5). The effect of vapocoolant spray compared to the control was both clinically relevant and statistically significant (p <0.0001). When a smaller 20G cannula was used, however, vapocoolant spray improved discomfort by only 0.8 NRS points, which, though still statistically significant (p = 0.0056), was no longer clinically relevant. The rate of unsuccessful puncture was higher after lidocaine pretreatment (12.7%) than after either vapocoolant spray (4.7%; p = 0.0066) or no pretreatment (4.0%; p = 0.0014).
Conclusion: Local anesthesia can be recommended before venipuncture only if a large cannula is used (e.g., ≥ 17G). Vapocoolant spray may be at least as useful as lidocaine injection; it prevents pain to a similar extent and is associated with a lower rate of unsuccessful puncture.
Inserting a cannula into a vein is a routine procedure, which in some patients may none the less cause discomfort (1, 2). Surveys, editorials, and systematic reviews on this topic imply that local anesthesia is applied to the venipuncture sites on a regular basis in children, but this is handled rather inconsistently in adults (3–7). In a survey among anesthetists in the UK, the doctors reported that they administered a local anesthetic for venipuncture in cases where the cannula size exceeded 18 G. However, fewer than half of surgeons or specialists in internal medicine followed this practice (6). According to a survey of 71 hospital doctors, 35% occasionally administered a local anesthetic—mostly lidocaine—before venous cannulation (7). Doctors‘ reasons for not doing so included the amount of time it takes (45%), a lacking need/indication (35%), and the worry that venous cannulation might be more difficult as a result of this practice (21%).
Application of a spray-on cooling agent produces temporary anesthesia at the puncture site. Mixtures of short-chain alkanes are the main substances used in this setting; in the past, various chlorofluorocarbons were also used. Using such vapocoolant sprays before venipuncture has shown inconsistent results in different studies (1, 8–13); methodological reasons do not explain this lack of homogeneity (4).
By contrast, numerous studies have consistently found that intradermal or subcutaneous application of a local anesthetic—for example, lidocaine solution 1–2%—reduces puncture-related pain (1, 8–10, 14, 15). A recent network meta-analysis directly or indirectly compared lidocaine application with 16 further analgetic interventions before peripheral venipuncture and found that 2% lidocaine was most effective (5). However, this procedure is time-consuming (7); it can result in a higher rate of puncture failures (15, 16), and of itself causes pain (8–10, 16).
It is especially for this reason that the present comparison of different methods aiming to reduce discomfort during venous cannulation does not look at the insertion of the venous cannula in isolation but considers the entire procedure from the moment of applying the tourniquet to the first cannulation attempt. As previous studies rarely considered the importance of the cannula size, we will compare two different cannula sizes in order to determine the optimal pre-treatment of the puncture site. We combined this research question with the rate of failed first attempts at venipuncture.
The study was conducted in 450 inpatients of legal age at Marburg University Medical Center as a monocenter, prospective blinded intervention study with a passive control group (study registration number: DRKS00010155). After arriving in the operating room area, patients having elective surgery were allocated according to instructions from a sealed, non-transparent envelope (randomization on the basis of random numbers from www.random.org) to one of 6 treatment groups consisting of 75 patients each. These comprised all possible combinations (full factorial design) of the two cannula sizes under study (17 Gauge[G] versus 20 G) and the three options for local pre-treatment of the venipuncture site (intracutaneous injection using 0.1–0.3 mL lidocaine solution 2%; vapocoolant spray applied for about 2 seconds from a distance of about 5 cm until the environmental moisture starts forming ice crystals; alcohol-based disinfectant as control). The venipuncture site was always on the dorsum of the hand. During the procedure, doctor and patient communicated in a structured and standardized way, with the patient blinded as well as possible. A third person supervised the blinding (details on the exact proceedings are in the eMethods).
Following the first cannulation attempt, and independently of whether this was successful or unsuccessful, patients rated their level of discomfort caused by the entire venipuncture process (from the moment of applying the tourniquet) on an 11-point numerical rating scale (NRS: 0–10, 0 = no discomfort, 10 = intolerable discomfort). Taken together with the number of failed attempts at venipuncture, this patient assessment was the primary outcome measure of the study. The NRS discomfort was analyzed initially by using multifactorial analysis of variance (ANOVA) as a global test. If this showed significant between-group differences at the 5% level, the Tukey-Kramer test was used to assess the effect of the cannula size (17 G versus 20 G) and the local preparation for venipuncture (control versus lidocaine versus vapocoolant spray). The estimated case number was based on the endpoint “failed venipuncture attempt,“ because—owing to the dichotomous characteristic value—this placed the highest demand in terms of case numbers required. On the basis of older publications (1, 8, 10), we estimated by using weighted mean values the increase in the rate of failed venipuncture attempts, especially after lidocaine injection, to be 16 percentage points; this estimate was confirmed by a more recent study (16). A two-tailed chi-square test can confirm such a difference (effect size ω = 0.30) in the setting of a 5% alpha error and statistical power of 90% and 141 patients per group, while assuming that the cannula size is an independent factor. Because of expected study dropouts, the group size was increased to 150 patients per intervention. This case number is large enough to confirm differences between groups in the subjective discomfort assessed by the patients (ranked scaled NRS), which is considered as significant upwards at a value of roughly 1 point on the NRS (17–19).
Secondary endpoints of the study were the time required for the venipuncture; this included the respective specific preparation measures taken for administering local anesthesia to the venipuncture site. Furthermore, postoperative skin reactions were documented and described. A total of 5 anesthetists undertook patient recruitment over a time period of 3–6 months respectively. Recruitment started in May 2005 and took 42 months. A second, subsequent study, which investigated pain reduction in cannulation of the radial artery, used similar methods (20).
Figure 1 shows the distribution of the 450 patients and their allocation to the 6 groups of 75 patients each, as well as the number of and reasons for the 8 cases of non-adherence to the study protocol (flow chart). Because of this small number the results of the per-protocol analysis (n=442) hardly differed from the intention-to-treat analysis (n=450). Therefore, only the data of the latter is shown. Patients‘ biometric data and the distribution of the 5 participating doctors were comparable in all groups (
When patients subjectively rated the discomfort caused by the entire venipuncture procedure, we found that the gauge of the venous cannula used significantly affected patients‘ ratings, as did the kind of pre-treatment of the venipuncture site (P<0.0001 for both). Figure 2 shows the data as percentiles. The Table shows arithmetic
Effect of cannula size
Venipuncture using a 17G venous cannula was rated across all intervention groups as significantly more uncomfortable than when a small 20G cannula was used (NRS-17G: 3.8 ± 2.1; NRS-20G: 2.7 ± 1.5; P<0.0001). Differences were greater—2 points—in the control group than in the two active intervention groups (lidocaine: 0.6; vapocoolant spray: 0.5). The difference between groups in the last two comparisons still reach statistical significance but are no longer clinically relevant.
Effects of local pre-treatment
When looking at means across all cannula sizes, controls without pre-treatment gave the entire procedure of venipuncture a mean NRS rating of 4.0 ± 1.7. A preceding lidocaine injection improved this to 3.2 ± 2.0 (P = 0.0002 versus controls). This reduction, however, missed the minimum target of 1 point on the NRS that was defined as clinically relevant. Vapocoolant spray, with a rating of 2.4 +/- 1.3 achieved a statistical significant (P<0.0001) and a clinically relevant improvement when compared to control. Compared with the lidocaine group, the improvement reached statistical significance (P=0.0002) but was clinically not relevant, with an NRS difference of 0.8 points.
Interactions between pre-treatment and cannula size
The interaction term of the ANOVA (P<0.0001) indicated a significant interaction between cannula size and the type of local preparation for venipuncture. Closer analysis and post hoc testing in the subgroups showed that the beneficial effects of both forms of local anesthesia reached statistical significance (P values between 0.0001 and 0.0047) as well as clinical relevance only when the larger 17G venous cannulas were used. No significant effects were observed for intradermal or subcutaneous lidocaine application before venipuncture using 20G venous cannulas. Improvements in patients‘ subjective ratings of their discomfort after preceding application of vapocoolant spray reached statistical significance (P=0.0056), but absolute improvement of 0.8 NRS points was too slight to reach genuine clinical relevance.
Failed venipuncture attempts
Over the course of the study, 32 failed venipuncture attempts occurred (7.1%). More than half of these (n=19) occurred in the lidocaine group (Table). This accumulation reached statistical significance compared with patients receiving vapocoolant spray (P=0.0066) or those who did not receive any pre-treatment (P=0.0014).
Without any additional preparation of the venipuncture site, the procedure took 50 (95% confidence interval [48; 52]) seconds, as measured from applying the tourniquet to completion of the venipuncture. Administering vapocoolant spray does not prolong the procedure notably (51 [49; 52] seconds; P=0.82). In the lidocaine group, however, cannulation times increased on average by approximately half a minute to 75 seconds ([73; 78]; P<0.0001) (Table).
Except for small hematomata, caused by failed venipuncture attempts or when removing the venous cannula, mild erythema at the venipuncture site was observed in 32 patients in the cooling anesthesia group. In most cases (n=27) this had disappeared by the following day. Only 5 patients experienced skin changes for up to five days. Particular treatment for the observed skin changes was not required.
This clear result regarding the relevance of the size of the venous cannula used enables us to confirm a suspicion that has often been voiced but never consistently shown in studies up to the present. Local anesthetic pre-treatment of the venipuncture site on the dorsum of the hand is indicated when using venous cannulas from a size of 18G (6). Without such preparation, half of our patients rated the subjective stress/discomfort caused by a 17G venous cannula to be 5 NRS points or more, 10% even rated it at 7 points or more. Langham et al. showed even higher scores: 5.7 NRS points for 18G venous cannulas placed on the dorsum of the hand (21). Further studies observed lower scores (NRS 2.8–4.5), but the puncture site was not defined (1, 11, 22) or the results were not differentiated by cannula size (9, 22).
In view of such high levels of pain and impairment/discomfort, patients‘ scores can be improved by using intradermal lidocaine injection or vapocoolant spray to a statistically significant and clinically relevant degree. Furthermore, it is obvious that patients‘ stress—and therefore the probable benefit of this intervention—will increase if cannula sizes larger than 17G are used.
The situation for smaller cannulas (20G and smaller) is very different: The statistically significant effect of cryoanesthesia seems clinically not relevant, as it is 0.75 points on the NRS and thus just misses the measuring method‘s ability to discriminate (17, 18). This result is consistent with the results of a meta-analysis of the benefits of cryoanesthesia before venipuncture (3). Across all studies, venipuncture using smaller cannula sizes (22G and smaller) (10/100 points) reduced pain in children, but did not reach statistical significance. With the exception of one study (9), exclusively 20G venous cannulas were used in adults as well. Compared with one venipuncture without pre-treatment, the meta-analysis found a pooled reduction in pain at the 10/100 level; because of a larger total number of cases than in the preceding comparison, this reached statistical significance (3). Compared with genuine placebo treatment, the pain reduction of 12/100 points did not reach significance any longer. A limitation of this meta-analysis is the pooling of studies in which different sizes of venous cannulae were used for the purpose of venipuncture in different areas of the body. Furthermore, the range of different vapocoolant sprays used was wide. On the face of it it may seem irrelevant which substances were used to produce the evaporation chill. However, it is crucial to hit the desired venipuncture site precisely by using a brief puff of the spray. Different preparations differ widely in this respect, as they were mostly conceived for use on larger areas of the body, for example, for joints.
The question of which method yields better results before inserting a 17G (or larger) venous cannula cannot be decided on the basis of patients‘ ratings alone. In the direct comparison, vapocoolant is superior to lidocaine injection (P=0.0047), but the difference of 0.9 NRS points fails ever so slightly the criterion for clinical relevance. The results are therefore comparable with those from a follow-up study of the cannulation of the radial artery (20). After intradermal or subcutaneous injection of lidocaine, the rate of failed venipuncture attempts increased significantly and more than doubled—probably because of the poorer differential of the vein‘s contour. Overall, the outcome is in favor of cryoanesthesia, especially as it is easy to conduct and no long-term adverse effects have been confirmed if it is applied correctly.
Limitations of the study
An additional aspect that causes lidocaine injection to appear in a less favorable light is the methodological handling of a failed venipuncture. The affected patients gave their scores before the required follow-up puncture, which might have had a negative influence on the overall assessment.
Furthermore, the lack of genuine blinding of patients is a central problem of this study, which is also the case for all other, comparable studies. In most studies, patients were asked to close their eyes during the venipuncture process, which entails the risk of de-blinding in the truest sense of the word. In our study, we tried to minimize this risk by using a neutral observer. This observer ensured during the entire procedure that the patients were neither able to see the preparations nor the procedure itself, and that standardized communication was adhered to. This helped identify a protocol violation in 8 patients (Figure 1). Adding a third group (vapocoolant spray) increased the challenge of concealing the type of intervention from patients. We used strictly standardized communication with patients to inform them about the application of vapocoolant spray or the application of alcohol-based disinfectant spray without mentioning which of the two was actually applied. The lidocaine injection and the actual venipuncture were also announced using the exact identical wording, again without unveiling which of the two was actually applied. However, patients in whom vapocoolant spray had been used in the past would have been able to distinguish the less intensive sensation of cold owing to the evaporation of alcohol from the strong cooling sensation of the alkane spray. Ultimately, as in comparable studies, it remains unclear whether the efforts involved in blinding patients to their treatment were actually successful.
In principle, patients who think they are in an intervention group can be expected to be more prone to making a better judgement of the subjective discomfort caused by the venipuncture. This should be borne in mind when interpreting the data.
The size selection of the venous cannulas used is based on the fact that in our hospital, 18G cannulas are used most often, according to data from the local resource/materials management. The selection of a larger or smaller caliber was intended to improve the results‘ ability to discriminate. 17G and 20G are therefore representative for “large“ and “small“ cannula diameters.
The present results underline the indication for local anesthetic pre-treatment if a venous cannula of 17G or larger is inserted on the dorsum of the hand. Cryoanesthesia may offer advantages in this setting, compared with the thus far more common lidocaine infiltration, in terms of condition of the puncture site, effectiveness, and simplified processes. In smaller venous cannulas (20G and smaller), positive effects are statistically significant. However, these are small and clinically not relevant.
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 13 October 2016, revised version accepted on
12 June 2017.
Translated from the original German by Birte Twisselmann, PhD.
Prof. Dr. med. Leopold Eberhart
Klinik für Anästhesie und Intensivtherapie
Baldingerstr., 35033 Marburg, Germany
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