1. Introduction
noxaparin sodium is one of the Low Molecular Weight Heparin (LMWH) anticoagulants. Since the development of LMWHs in 1980, they were pillars of the treatment and prevention of ischemic heart diseases [1]. Enoxaparin has many benefits over regular heparin. High bioavailability and low binding to plasma proteins make the response dose predictable without the need for plasma monitoring. It also has a higher inhibitory of enoxaparin into the abdomen could lead to spontaneous retroperitoneal bleeding and hematoma and damage to the renal veins and suggested that the injection be done on the outside of the arm [31]. Annersten and William (2005) and Julia Domiciana et al. (2013) examined the enoxaparin injection technique in a meta-analysis. They concluded that more research is needed because the subjects of different studies are heterogeneous and the injection techniques are also different, so the scientific basis for the injection techniques is weak and needs more research [32].
Subcutaneous injection of enoxaparin in the abdomen or arm seems to be more based on routine form than scientific evidence [29]. There are still no detailed recommendations on the timing and location of enoxaparin subcutaneous injection in pharmaceutical books and articles. At present, 10-s injections are used as a conventional method and as a control method in comparison with other methods of changing the duration. Research has shown that rapid injection of the drug causes tissue damage and rupture of blood vessels at the injection site, as well as leakage of the drug into the surrounding tissue and causes pain, bleeding, and bruising [11, 12]. Studies conducted so far have reported contradictory results on various interventions (application of cold, application of heat, etc.) and its effect on the incidence, size of bruises, and pain intensity due to injection. Also, few studies on the effect of time and place of enoxaparin injection on severe pain and bruising as two important variables have reported different and contradictory results. Clinical nursing resources have not mentioned a specific time and place and there is a lack of information in this regard. According to the research results, one of the most scientific clinical measures is changing the duration and the injection site subcutaneously. This can affect the size of the bruise and the pain on the injection site. Therefore, this study was performed to compare the effect of duration and location of subcutaneous injection of enoxaparin on pain intensity and bruise size of patients admitted to the cardiac care units of Zahedan City teaching hospitals in 2019.
2. Materials and Methods
This study is a randomized clinical trial with two intervention parallel groups and is single-blind. This is a comparative study of the technique and location of the subcutaneous injection of enoxaparin on the size of bruise and pain intensity at the injection site. The study was done in patients admitted to the cardiac care units of Zahedan City teaching hospitals in 2019. The participants were selected from patients admitted to the CCU (coronary care unit) and PCCU (progressive coronary care unit). The samples were selected by purposeful sampling method and according to the inclusion criteria, then they were randomly assigned to one of the two intervention groups. In the first group, enoxaparin was injected subcutaneously in the abdomen and arm according to the doctor’s prescription (40 or 60 mg) for 30 seconds. In this method, after the needle enters the subcutaneous space, enoxaparin was injected for 30 seconds and the needle was immediately pulled out of the tissue. In the second group, according to the doctor’s prescription (40 or 60 mg), enoxaparin was injected subcutaneously in the abdomen and arm by 15+5 seconds method. In this method, after the needle entered the subcutaneous space, enoxaparin was injected for 15 seconds and then, the needle was remained in the subcutaneous space for 5 seconds and then removed. Because of the small number of study variables, we used the formula for comparing means for two independent communities. Also, based on similar studies [33], taking into account the test power of 90%, reliability of 99%, and the probability of falling sample size of 20%, a total of 30 patients were selected for each group.



The inclusion criteria were age range of 40-75 years, no neuromuscular disease, or known skin disease and coagulation disorder, no type 1 or type 2 insulin-treated diabetes, no swelling, sores, scratches, redness in the injection site, and a body mass index of between 18.5 and 30. The exclusion criteria included death, discharge before 48 hours, intravenous anticoagulation for any reason, and need for subcutaneous injection other than enoxaparin in the abdomen and arms. For each patient, two subcutaneous injections were performed with the same technique in the abdomen and arm. The site of subcutaneous injection in the abdominal area was in the anterior wall and the left side of the abdomen at a distance of 5 cm from the umbilicus and the arm site of subcutaneous injection was in the left arm around the middle and outside of the arm. All drugs were pre-filled syringes of enoxaparin with volumes of 0.4 or 0.6 mL, with needle number 27 with 0.2 mL of air (airlock) (Sanofi-Aventis Pharmaceutical Company of France). Throughout the skin creasing technique, the needle was inserted and exited at a 90-degree angle and no aspiration was performed.
A stopwatch with the Q&Q brand (model HS43, made in Japan) was used to accurately measure the duration of subcutaneous injection. Pain intensity was determined immediately after each injection and the greatest amount of bruising was determined 24 and 48 hours after each injection. To accurately examine the size of the bruise, after the injection with a waterproof marker, a circle with a radius of 5 cm was drawn around the injection site to avoid selecting that area again for subsequent injections and to identify the area for bruising. The patient was also asked not to rub, scratch, or manipulate the injection site. To avoid bias, all injections were performed by the researcher. Pain and bruising were also measured with the help of a researcher who was unaware of the injection technique. The standard safe injection protocol was implemented for all research units [34]. The data collection tool was a form consisting of 3 parts. In the first part, demographic and disease information was collected in a form prepared by the researcher (corresponding author). The second and third parts of the instrument included visual analog scale and bruise size recording form using a transparent millimeter ruler, which was completed by an uninformed researcher with the injection technique. Visual Analog Scale (VAS) is the use of a graduated 10-cm line that scores ten for the most severe pain and zero for painless. The amount of pain is determined by the patient on the line [35].
The visual pain measuring tool is the most widely used pain measuring tool in the world. In addition to validity and reliability, the most important feature of this tool is its ease of use. The validity and reliability of this instrument have been confirmed in several studies abroad [36] and in Iran, the reliability of this scale has been confirmed with a correlation coefficient of r=0.88 [37]. The collected data were coded and entered into SPSS V. 21 and analyzed. First, the frequency, percentage, and Mean±SD of the variables were determined using descriptive statistics. To analyze the data, first, the data adherence to the normal distribution was examined using the Kolmogorov-Smirnov test, which was found to follow the normal distribution, and therefore, the independent t-test and paired t-test were used to analyze the data. The independent t-test was used to compare the mean pain intensity and bruise size between the two groups and the paired t-test was used to compare the mean pain intensity and bruise size of a patient in two areas. The Chi-square test was also used to compare the frequency of qualitative variables between the two groups. The significance level in this study is less than 0.05.
3. Results
The number of participants in this study was 60. The minimum age of the subjects was 42 and the maximum age was 75 years. The Mean±SD age was 62.86±6.41 in the 30-s injection group and 62.03±7.54 in the 15+5-s injection group. In terms of gender, 46.7% of the patients in the 30-s injection group were men and 53.3% were women. In the injection group of 15+5 s, 52% were men and 48% were women. All patients in both groups were married. The results of the statistical test showed that the two intervention groups were homogeneous in terms of gender, marital status, level of education, inpatient ward, and medical diagnosis (Table 1). 

The highest rate of pain intensity was reported in the 15+5-s technique at the arm with a score of 6. The largest bruise size was 10 mm in the abdomen and 30 mm in the arm 48 hours after injection with the 30-s injection technique. Also, the largest bruise size was 18 mm in the abdomen and 36 mm in the arm 48 hours after injection with the 15+5-s technique.
The independent t-test showed that the mean pain intensity of subcutaneous injection in the abdomen and arm in the 30-s method was significantly lower than the 15+5-s method (P<0.001) (Table 2).

The independent t-test showed that the mean bruise size of both injection sites (abdomen and arm) after 24 hours in the injection group of 30-s was significantly lower than the injection group of 15+5-s (P<0.001). 
The result of the paired t-test showed that in the injection method of 15+5-s, the average size of bruises 24 hours after injection at the injection site of the abdomen was not significantly different from the injection site of the arm (P = 0.144) (Table 3). 

The independent t-test showed that the mean size of bruising at the injection site of the abdomen and arm after 48 hours in the injection group of 30-s compared to the injection group of 5+15-s were significantly lower (P=0.004 and P =0.061, respectively). The results of the paired t-test showed that in the 30-s injection method, the average size of bruises 48 hours after injection at the injection site of the abdomen was significantly lower than the injection site of the arm (P<0.001). Also, the results of the paired t-test showed that the mean size of bruising 48 hours after the injection in the abdomen compared to the injection site in the arm, in the method of 15+5-s was not significantly different (P=0.134) (Table 4). 

4. Discussion
This study aimed to compare the effect of duration and location of subcutaneous injection of enoxaparin on pain intensity and bruise size of the patients admitted to the cardiac care units of Zahedan City teaching hospitals in 2019. It was found that the 30-s injection method leads to less bruising in the abdomen and arm than the 15+5-s injection method. Also, bruising was less in the abdomen than in the arm 24 and 48 hours after injection. The results showed that subcutaneous injection of enoxaparin with 30-s method leads to less pain in both abdomen and arm. Also, the average intensity of abdominal pain is lower than the arm.
 Regarding the relationship between subcutaneous injection technique and pain intensity and bruising size, Dad Ain et al. reported that increasing the injection time (30-s injection) reduces pain and bruise size [20]. Khani Jeyhoni also reported that increasing the time (injection of 30 seconds) reduced the bruise size [38]. Also, studies conducted abroad, including Chan (2001) showed that the 30-s injection method would cause less bruising and pain in the injection site [9]. Zaybak also reported that a 30-s injection resulted in less bruising and less pain, compared with the 10-s technique [21]. Balci Akpinar also reported that bruising occurred less at 30 s and 10+10-s (10 seconds injection and 10 seconds delay in needle exit) than the 10-s injection method [39]. The results of these studies, which examined the variables of pain and bruising, are consistent with the results of the present study. Poor Safar et al. reported that injection for 10 seconds compared to 20 seconds would reduce the bruising size by controlling the effects of interfering variables [40]. Rahmani Anaraki et al. reported in their study that subcutaneous injection of 10 seconds and 10+10 seconds in the abdomen had no effect on pain intensity and bruising size 24, 48, and 72 hours after the injection [40]. The results of the Chenicek et al. study showed no significant difference between pain intensity and bruise size in the two methods of injection of 30 and 10 seconds in the abdomen [41]. The results of Nevin Kuzu (2001) also showed that the 30-s injection with the application of a cold pad on the abdomen has no effect on the size of the bruise, but reduces the pain at the injection site [42]. These results are not consistent with the results of the present study in domestic and foreign studies.
 Because of the small size of samples, studied patients in different wards, the fixed-dose of the drug, or interventions before, during, or after injection, the results of some studies are inconsistent with that of the present study. Because this study is the first study in Iran to compare the severity of pain and bruising size of the subcutaneous injection of enoxaparin in the abdomen and arm, we were reviewed and compared our results with the results of other studies. 
Jarnocolado et al. (2017) in a study compared the incidence of side effects of subcutaneous injection of enoxaparin (bruising and hematoma) in the arm and abdomen. They reported that the average size of bruises 72 hours after injection in the abdomen is significantly smaller than that in the arm. Also, there was no significant difference between demographic information, clinical variables, and body mass index between study groups [25], which is consistent with the results of the present study. Poor Ghaznin et al. examined the effect of four enoxaparin injection techniques in both the abdomen and thigh and reported that the average intensity of pain in the abdomen is lower than that in the thigh. Also, there is no significant difference between the frequency and size of bruises at the injection site of the abdomen and thigh [30]. Zaraatkar et al. also reported that subcutaneous injection of heparin with the same technique did not affect bruising at the three injection sites of the abdomen, thigh, and arm, but the intensity of pain at the injection site is most decreasing in the abdomen, then thigh, and finally arm [43]. In the mentioned study, the injection technique, the type of patients, and other variables were not mentioned as effective factors in the severity of pain and the size of bruises at the subcutaneous injection site, and this point can negatively affect the significance and generalization of results. Fahs and Kinney also showed no significant difference between the abdomen and thigh regarding the frequency and size of bruising at the injection site [29]. However, Da Silva et al. (2002) reported severe hematoma in the thigh relative to the arm and severe hematoma in the arm compared to the abdomen [44]. 
Hematoma in the abdomen, arm, and thigh can be due to the mobility of patients, which was not mentioned in Da Silva’s research. The present study, like other studies, has some limitations. One of the study limitations was related to the samples. We included only the patients who were admitted to the cardiac care units in Zahedan City teaching hospitals, thus reducing the ability to generalize the study results to the entire patient population. Pain is a mental experience, and the researcher should have recorded what the patients reported. This subjective data may lead to a possible bias in the results. Using the same patient for both injections also allows the participant to predict and determine the severity of pain ahead of schedule for the second injection. Therefore, it is recommended that similar studies be performed on different patient groups and more centers, as well as using one injection for each patient.
5. Conclusion
The results of the present study showed that by increasing the time of subcutaneous injection of enoxaparin (30 seconds injection technique) compared to the routine method of subcutaneous injection in 10 seconds, the pain intensity and bruising would significantly decrease. It was also found that subcutaneous injection of enoxaparin in the abdomen and the use of the 30-s injection technique resulted in less pain and smaller bruising than the subcutaneous injection of enoxaparin in the arm. Further studies are suggested to confirm these results.
Ethical Considerations
Compliance with ethical guidelines
In this study, all the rules and regulations of ethics have been observed, including the confidentiality of information, the right to withdraw the study, and obtaining the consent of the participants. Researchers have complied with all ethical codes related to research on human specimens and obtained the necessary permits from the competent authorities. They have also received the code of ethics from the Research Ethics Committee of Zahedan University of Medical Sciences and the National Committee for Ethics in Biomedical Research (Code: IRZAUMS.REC.1397.415). It should be noted that this study has been registered in the International Center for Clinical Trials of Iran (under the number IRCT20150106020581N2) and all the instructions were approved by the Ethics Committee of Zahedan University of Medical Sciences.
Funding
This article was extracted from the Master’s thesis of the first author approved by the Research Council of Graduate Studies of the School of Nursing and Midwifery of Zahedan University of Medical Sciences No. 8907 and was conducted with the financial support of the Research Vice-Chancellor of the School of Nursing and Midwifery of Zahedan University of Medical Sciences.
Authors' contributions
All authors contributed equally in preparing all parts of the research.
Conflicts of interest
The authors of this article declared no conflict of interest.
Acknowledgements
The authors consider it necessary to express their gratitude to the School of Nursing and Midwifery as well as the financial support of the Research Vice-Chancellor of the School of Nursing and Midwifery of Zahedan University of Medical Sciences. The authors also express their gratitude to the officials and staff of Zahedan City teaching hospitals who assisted the authors in conducting this research. Special thanks to the hospitalized patients who participated in this study with interest and sincerity.