Cold application for pain and anxiety reduction following chest tube removal : A systematic review and meta-analysis

Background and Objective: Data on the effects of cold application on reducing pain and anxiety after chest tube removal (CTR) are inconsistent. This study aimed to conduct a systematic review and meta-analysis to evaluate the effects of cold application on pain and anxiety reduction after CTR. Methods: We searched six databases, including Embase, Ovid Medline, Cochrane Library, Scopus, the Index to Taiwan Periodical Literature System, and Airiti Library, to identify relevant articles up to the end of February 2021. We limited the language to English and Chinese and the design to randomized controlled trials (RCTs). All studies were reviewed by two independent investigators. The Cochrane Collaboration’s tool was used to assess the risk of bias, and Review Manager 5.4 was used to conduct the meta-analysis. Results: Ten RCTs with 623 participants were included in the meta-analysis. The use of cold application could effectively reduce immediate pain and had persistent effects on pain after CTR. There were signi�cant effects of cold application on reducing anxiety. The meta-regression showed that a drop in skin temperature to the 13°C target of cold application was signi�cantly more effective for the immediate reduction in pain intensity compared with receiving up to 20 minutes target of cold application. Conclusion: Cold application is a safe and easy-to-administer nonpharmacological method with immediate and persistent effects on pain and anxiety relief after CTR. In particular, skin temperature drops to the 13°C target of cold application were effective for immediate reduction of pain intensity following CTR.


Introduction
A primary goal of chest tube removal (CTR) is the removal of tubes without the introduction of air or contaminants into the pleural space [1,2].The removal of a chest drain is a painful and frightening experience; however, most guidelines regarding CTR do not mention this.The act of removing the chest tube often causes pulling of the endothelial tissue adhered to the chest tube and stimulates intercostal nerves and in amed pleura, all of which can cause pain [3][4][5].A study conducted by Al-Otaibi et al. [6] found that the procedure of removing a chest tube not only causes moderate to severe pain but also increases anxiety.The source of anxiety may be related to fear and worry about the pain caused by the upcoming chest tube removal procedure.[6] Currently, analgesics, including opioid and nonopioid drugs, are routinely prescribed to patients who are about to undergo CTR to alleviate pain during the procedure [6].However, the use of analgesics may cause side effects such as hypoventilation, nausea, allergic reactions, and gastrointestinal bleeding [7].Nonpharmacological interventions for pain related to chest tube removal, including music therapy, aromatherapy, and cold application, have been investigated [4,7,8].Few studies have focused on the effects of music therapy and aromatherapy for reducing pain after CTR.
Cold application is a common nonpharmacological intervention used to relieve the pain caused by CTR [9].Some studies have shown that cold application can also decrease anxiety levels [4,8].The mechanism of cold application mainly involves a slowing of the metabolism in skin tissue, an acceleration of nerve conduction and an increase the pain threshold, thereby reducing pain [10,11].Lee et al. [12] proposed that there was a residual effect of cold application on nerve velocity that could last 30 minutes after the removal of ice.However, the effectiveness of cold application for pain and anxiety level reductions are inconclusive.In addition, the chest tube management guideline does not mention pharmacological or nonpharmacological pain control for chest tube removals [13,14].The aim of the present systematic review and meta-analysis was to evaluate recent RCTs that analyze the effects of cold application on pain and anxiety after CTR.Furthermore, we also explored the effective period of time and target temperature of cold application related to pain relief after CTR.

Search strategy
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [15] (Supplementary Table 1 shows the PRISMA checklist) to explore the e cacy of cold application on pain intensity and anxiety levels in adults after CTR.Six databases, including Embase, Ovid Medline, Cochrane Library, Scopus, the Index to Taiwan Periodical Literature System, and Airiti Library, were systematically searched to identify relevant articles published from 1975 to February 2021.Reference lists of relevant articles were reviewed to identify additional studies.Four main concepts, chest tube removal, cold application, pain, and anxiety search strategy used combination with controlled vocabulary (11 MeSH terms and 5 Emtree terms) and free-text terms (19 synonyms plus truncation symbols) (Supplementary Table 2 shows the search strategy).The study protocol was registered in the PROSPERO international prospective register of systematic review (CRD42021245482).

Eligibility criteria
The inclusion criteria included (1) publications in either the Chinese or English language, (2) randomized controlled trials (3) adults (aged 18 years and over) who had at least one chest tube removed from the pleural or mediastinal spaces in which (4) the experimental group received cold application and usual care and (5) the control group received usual care (or no treatment), and (6) the study outcome must have included a measurement of pain or anxiety.The exclusion criteria were as follows: (1) the experimental and control groups received different analgesic dosages before CTR; or (2) the experimental group received two or more nonpharmacological interventions.

Data extraction and quality assessment
Two reviewers (C.T. Chen and S. H. Tsai) independently extracted and assessed the quality of eligible articles using the Cochrane Collaboration's tool.The seven domains were rated as either low risk, unclear, or high risk [16].Any disagreements were resolved by consensus or consultation with a third author (J.L. Wang).

Data synthesis and analysis
We used Review Manager 5.4 to analyze the effect of cold application on pain intensity and anxiety levels in adults after CTR.The mean difference (MD) and 95% con dence intervals (CIs) were used to analyze continuous outcomes of pain intensity and anxiety level.Heterogeneity was assessed using Cochrane's Q statistic and I-squared [17].If the I 2 value>50% or P value < 0.10 was de ned as statistical heterogeneity, sensitivity analysis with meta-regression was conducted by the software Open MetaAnalyst with a random-effects model [18].A funnel plot was applied to evaluate publication bias.

Result
Literature search A total of 110 articles were retrieved from six electronic databases and websites, and 35 articles were removed due to duplications.After the title, abstract and keywords were reviewed, 52 articles were discarded as not being su ciently relevant, and 5 articles were abstracts for conferences.A total of 16 full-text articles were left for consideration.Eight articles were excluded for the following reasons: non-RCTs (n=3), irrelevant outcomes (n=2), same study reported twice (n=1), study without any report of standard deviation and 95% con dence intervals (n=3), and high risk of bias (n=2).Finally, 10 articles met the inclusion criteria and were included in the qualitative synthesis (Fig 1).
Two studies were rated as having unclear risks of blinding of participants or researchers [8,23], and 8 studies (80%) were rated as having high risks of blinding of participants or researchers [3,4,7,[19][20][21][22]24].Because cold application is a nonpharmacologic therapy, it is di cult to blind both participants and researchers.Two studies were rated as low-risk for the blinding of the outcome assessments [8,19], and 8 studies (80%) were rated as high-risk for the blinding of the outcome assessments [3,4,7,[20][21][22][23][24].All studies (100%) were rated as low-risk for incomplete outcome data, selective reporting, and other biases.The results are depicted in Supplemental Figure 1.

Cold application and immediate pain intensity
Ten studies using the VAS or NRS measurement were included in the meta-analysis to assess pain intensity.Due to high heterogeneity (P < 0.00001, I 2 = 83%), the random effects model was selected.The results showed that cold application signi cantly reduced immediate pain intensity after CTR (MD: 1.32, 95% CI = -1.77 to -0.87, P < 0.00001) (Fig 2a).

Meta-regression of time and temperature target of cold application
Due to the high heterogeneity and variety of cold applications, covariates for meta-regression were divided into time up to 20 minutes and skin temperature drops to the 13°C target of cold application.The results showed that skin temperature drops to the 13°C target of cold application were more effective for the immediate reduction of pain intensity, compared to receiving cold application over a duration up to 20 minutes after CTR (coe cient: -0.979, Std.error 0.376, P= 0.009) (Fig 2b).

Cold application and persistent effects (15 minutes) on pain intensity
Six studies were included in the meta-analysis, and the results revealed that cold applications had signi cantly persistent effects (15 minutes) on pain intensity (MD: -0.50, 95% CI = -0.95 to -0.05, P = 0.03) after CTR (Fig 3).

Publication bias
Funnel plots were investigated through visual inspection to assess the publication bias of the included studies.The shape of the funnel plot showed evidence of obvious symmetry (Supplemental Figure 2).

Discussion
Several randomized studies have discussed the effect of cold application on pain caused by CTR.However, owing to the small sample sizes of the various studies, different strategies of cold application, and different time pain evaluation points considered after CTR, no certain effect of cold application alleviation after CTR can be con rmed.This study is the rst to use a meta-analysis to investigate the effect of cold application on pain caused by CTR.The results of the meta-analysis show that cold application can effectively reduce immediate pain intensity after CTR.This result is similar to those from the two studies conducted by Sajad et al. [20] and Ertug and Ulker [24], respectively.In addition to pain relief after CTR, cold application was also reported to reduce pain before arterial puncture and intramuscular injection, but few studies have been reported [25,26].Cold application can lower the skin tissue temperature, impede the sensory nerve response and nerve conduction speed, and produce anesthetic effects, resulting in analgesia [27].
Currently, there is no consensus on the strategy of cold application regarding pain relief after CTR.Our meta-regression showed that a skin temperature drop to a target of 13°C effectively and immediately reduced the pain intensity following CTR.A study by Lowitzsch et al. [28] found that applying cold application to the skin and causing its temperature to drop to 27°C led to a change in the nerve conduction velocity.When the skin temperature drops to 10°C-15°C, cell metabolism slows, and the anti-in ammatory effect is augmented [27,[29][30][31].If the skin temperature drops to 13.6°C or the cold application lasts 20 minutes, an analgesic effect can then be achieved [12,27,32].Based on the abovementioned research results and arguments, it is recommended to check whether the regional skin temperature has reached 13.6°C when cold application is applied as a method to reduce pain in patients undergoing CTR.If the equipment is not available for checking skin temperature, 20 minute of cold application is recommended before performing CTR [3,20].
In terms of the effect of persistent cold application (15 minutes) on pain after CTR, the meta-analysis shows that there is a signi cant difference in the pain intensity between the experimental group and control group.This result is consistent with the ndings of Mokadem et al. [4] Lee et al. [12] pointed out that even after the cold application is removed, a residual effect reducing the nerve conduction velocity remains, such that analgesia is maintained.
Regarding the effect of cold application on anxiety reduction among patients receiving CTR, the result shows a signi cant difference but high heterogeneity.We supposed that this may be related to different tools, varying time points of anxiety evaluation, and the limited number of 160 participants.The results should be explained with caution.Further studies are required to con rm the effects of cold application on reducing anxiety levels after CTR.
Among the papers included in this systematic literature study, nine out of the ten included studies did not mention whether there were any complications of wound infection or frostbite in the experimental groups in which patients received cold application.Only one study indicated that no side effects were noted [24].According to a systematic literature review by Greenstein [27], if a cold application causes the skin temperature to drop to −5°C or cold is applied for > 30 minutes, temporary or permanent frostbite or nerve damage may occur.Therefore, before and during cold application, it is necessary to closely monitor patients' skin temperature and the application duration.In addition, for patients with a medical history of Raynaud's disease, rheumatoid arthritis, cryoglobulinemia, cold urticaria, arteriosclerosis, or vascular injury, cold application is not recommended owing to contraindication concerns [27,33].

Limitations
This study has some limitations.First, the search strategies were limited to two languages, Chinese and English, and we only included ten studies with small sample sizes, which may affect the precision of our outcomes.Second, various studies have used different cold application strategies combined with different types of medications; therefore, we could not evaluate the effectiveness of different types of cold application on pain intensity in detail, and we do not know if combinations with other relaxation methods help.Third, the initial subjective pain intensity of the participants in all studies was not equal, which may contribute to heterogeneity.Fourth, most of the studies lacked a good concealment and blinding method; therefore, the results should be interpreted with caution.Finally, most eligibility criteria included participants over the age of 18 who underwent cardiothoracic surgery and had at least one chest tube; therefore, the generalization of the results may not be suitable to pediatric or medical patients with CTR.

Conclusion
The results from this meta-analysis revealed that cold application can e ciently reduce pain intensity after CTR.When the skin temperature dropped to the target of 13°C with cold application, the effect was a more immediate reduction in pain intensity following CTR.Cold application is an effective and safe, nonpharmacological strategy that is easy to administer by a healthcare worker.Cold application could be included in the standard nonpharmacological management for reducing pain during CTR.

Declarations
Ethical Approval and Consent to participate Not applicable.

Figure 2 (
Figure 2 (a) Mean difference in the effects of cold application on reducing pain intensity (Visual Analog Scale, VAS; Numerical Rating Scale, NRS) immediately after CTR compared with the control.(b) Bubble plots of covariate meta-regression between time up to 20 minutes and skin temperature drops to the 13°C target of cold application.

Table Table 1
. characteristics of included studies