Application of preoperative assessment of pain induced by venous cannulation in predicting postoperative pain in patients under laparoscopic nephrectomy: a prospective study

Backgroud: Postoperative pain is the most prominent concern among surgical patients. It has previously been reported that venous cannulation-induced pain (VCP) can be used to predict postoperative pain after laparoscopic cholecystectomy within 90 mins in the recovery room. Its potential in predicting postoperative pain in patients with patient-controlled intravenous analgesia (PCIA) is worth establishing. The purpose of this prospective study was to investigate the application of VCP in predicting postoperative pain in patients with PCIA during the first 24 h after laparoscopic nephrectomy. Methods: 120 patients scheduled for laparoscopic nephrectomy. A superficial vein on the back of the hand was cannulated with a standard-size peripheral venous catheter (1.1×3.2 mm) by a nurse in the preoperative areas.Then the nurse recorded the VAS 1 Correspondence: 282243756@qq.com Department of Anesthesiology, the First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, China score associated with this procedure estimated by patients, and dichotomized the patients into low response group (VAS scores < 2.0) or high response group (VAS scores ≥ 2.0). After general anesthesia and surgery, all the patients received the patient-controlled intravenous analgesia (PCIA) with sufentanil. The VAS scores at rest and on coughing at 2 h, 4 h, 8 h, 12 h, 24 h, the effective number of presses and the number of needed rescue analgesia within 24 h after surgery were recorded. Results: Peripheral venous cannulation-induced pain score was significantly correlated with postoperative pain intensity at rest (rs = 0.64) and during coughing (rs = 0.65), effective times of pressing (rs = 0.59), additional consumption of sufentanil (rs = 0.58). Patients with venous cannulation-induced pain intensity ≥ 2.0 VAS units reported higher levels of postoperative pain intensity at rest (P < 0.0005) and during coughing (P < 0.0005), needed more effective times of pressing (P < 0.0005) and additional consumption of sufentanil (P < 0.0005), and also needed more rescue analgesia (P = 0.01) during the first 24 h. The odds of risk for moderate or severe postoperative pain (OR 3.5, 95% CI 1.3-9.3) was significantly higher in patients with venous cannulation-induced pain intensity ≥ 2.0 VAS units compared to those < 2.0 VAS units. Conclusions: Preoperative assessment of pain induced by venous cannulation can be used to predict postoperative pain intensity in patients with PCIA during the first 24 h after laparoscopic nephrectomy. Trial registration:We registered this study in a Chinese Clinical Trial Registry (ChiCTR) center on July 6 2019 and received the registration number: ChiCTR1900024352.


Trial registration: We registered this study in a Chinese Clinical Trial Registry
(ChiCTR) center on July 6 2019 and received the registration number: ChiCTR1900024352.

Background
Postoperative pain is the most prominent concern among surgical patients. If not adequately controlled, it will affect postoperative rehabilitation, health-related quality of life, and may develop into persistent long-term pain [1][2][3].
Current postoperative pain management strategies apply a standardized， one-size-fits-all approach to all patients. These standardized protocols are not suitable for the significant difference in patient's pain and may lead to insufficient analgesia in patients with high analgesic needs, or excessive analgesia, which is accompanied by increasing analgesic-related side effects. The ability to preoperative predict who is at risk for developing moderate or severe postoperative pain might allow anaesthetists to optimize pain management by offering personalized, stratified or targeted analgesic treatment protocols. Preoperative pain prediction methods are highly relevant in this regard.
Numerous studies have tried to identify patients who are at risk for postoperative pain in the preoperative period and evaluated the role of psychological factors and experimental pain tests or quantitative sensory tests (QST) [4][5][6][7][8]. However, none of those prediction methods has been used as a routine for prediction of postoperative pain, mainly because expensive equipment, much time and effort are required outside routine preoperative procedures.
Peripheral venous cannulation, a routine procedure of preoperative preparation, induced pain intensity could be assessed easily and rapidly before surgery without specific equipment or training. It was recently shown that peripheral venous cannulation-induced pain (VCP) intensity could be used to predict the risk of postoperative pain. Patients with VCP score at or above 2.0 VAS units reported higher levels of acute postoperative pain intensity and more often have moderate or severe postoperative pain within 90 mins in the recovery room [9]. Its potential in predicting postoperative pain in patients with patient-controlled intravenous analgesia (PCIA) is worth establishing. The purpose of this study was to test if peripheral VCP intensity can be used to predict the risk for pain in patients with PCIA during the first 24 h after laparoscopic nephrectomy. Patients with the following conditions were excluded: severe heart, lung and metabolic diseases, hepatic or renal dysfunction, a history of neuromuscular system disease, mental illness, and a tendency to malignant hyperthermia, preoperative existing pain, long-term use of sedative and analgesic drugs (> 3 months), drug or alcohol abusers, or severe hypertension, poor understanding or communication difficulty, failed venous cannulation, changed in surgical approach (from laparoscopic to open surgery, the operative time over than 3 h, failed to complete the data collection.

Preoperative pain assessment
An anaesthetist visited the patients the day before surgery, described the visual Then the nurse recorded the VAS score estimated (on a horizontal VAS ruler, their maximum pain score associated with this procedure) by the patients, and dichotomized the patients into low response group (VCP score < 2.0 VAS units) or high response group (VCP score ≥ 2.0 VAS units). The nurse was aware of whether the patient was to take part in the study.

Anaesthesia
All patients were anaesthetized by anaesthetists who were blinded to study and did not participate in data collection. Once in the operating room, the standardized monitoring of ECG, SpO2, noninvasive blood pressure was established. Before the induction of anaesthesia, the patients were given IV Penehyclidine Hydrochloride 0.5 mg, and a loading dose of dexmedetomidine with 0.5 μg kg -1 was infused over 10 minutes. The bispectral index (BIS) was used to monitor the depth of anaesthesia.
Then anaesthesia was induced with midazolam 2 mg, sulfentanil 0.5 μg kg -1 , etomidate 2-3 mg kg -1 . Cisatracurium 0.2 mg kg -1 was given to facilitate endotracheal intubation. Anaesthesia was maintained with sevoflurane (1-2%), remifentanil 0.1-0.3 μg kg -1 min -1 . The cisatracurium was used to provide a satisfactory level of muscle relaxation. The BIS value was maintained between 40 to 60. The pneumoperitoneum pressure with carbon dioxide was set at 13-15 mmHg, and the EtCO2 was maintained at 35 to 45 mmHg. Thirty minutes before the end of the surgery, sulfentanil 10 μg and flurbiprofen axetil 100 mg were given as postoperative analgesia, and tropisetron 5 mg was given to prevent postoperative nausea and vomiting. At the end of the surgery, sevoflurane and remifentanil were stopped. Immediately after surgery, the PCIA pump was attached to the peripheral venous line by the anaesthetist. Then the patients were sent to the post anaesthetic care unit for anaesthetic resuscitation. All patients were sent to the general ward after being fully awake. Upon arrival in the general ward, all the patients were once again instructed on the use of the PCIA pump and VAS.

Postoperative analgesia regimen
The PCIA with sulfentanil regimen was applied to 48 h after surgery. The PCIA regimen consisted of sulfentanil 3.0 μg kg -1 and 5 mg tropisetron, mixed with 0.9% normal saline to a total volume of 150 ml. The PCIA was programmed to deliver a 2 ml bolus on demand, with a lock-out interval of 10 min, and a background infusion rate of 2 ml h -1 . In the ward, patients pressed PCA when VAS score at rest > 3.0. If patients still reported pain or the VAS scores ≥ 4.0, supplemental rescue boluses of intravenous flurbiprofen axetil injection of 50 mg were administered. The complete history of continuous infusion, bolus infusion, and bolus demand for the PCIA device was downloaded after surgery.

Outcome variables measures and data collection
The study outcomes variables and the vital parameters were recorded at 2, 4, 8, 12 and 24 hours after surgery. During the studied period, pain intensity, sulfentanil consumption, pressing times of the PCIA, and the number of rescue analgesia were recorded at above time points. Overall satisfaction index of the patients was recorded at 24 h. Pain intensity was assessed with VAS at rest and during coughing.
The primary outcome was maximum postoperative pain scores at rest and during coughing within the first 24 h. The secondary outcome was effective times of pressing, additional consumption of sulfentanil and satisfaction index at 24 h. Also, the number of rescue analgesia within the first 24 h was also measured.
Postoperative data collector was blinded to the preoperative peripheral venous cannulation-induced pain score of the patients.

Sample size and statistical analyses
The sample size was based on a pilot experiment of 20 cases (8 patients with VCP score ≥ 2.0 VAS units), with a primary outcome for maximum postoperative pain at rest within 24 h. The mean maximum postoperative pain score (VAS) at rest was 3.9 (± 1.3) in high response group. Therefore, in order to show a 20% difference between the high response group and low response group, the number of patients in each group was 41 (α=0.05, β=0.8). Since the groups are unequal, and assuming a 40% of patients with VCP score ≥ 2.0 VAS units, 120 patients were primarily included (48 patients with VCP score ≥ 2.0 VAS units and 72 patients with VCP score < 2.0 VAS units ) allow for up to 15% dropouts.
The IBM SPSS version 22.0 software packages were used for statistical analyses.
The normality of the continuous data was tested by the Shapiro-Wilk test. Normally distributed continuous variables were expressed as mean ± SD and compared between groups using a two-sample Student t-test. IF the distribution was not normal, the median with inter-quartile range (IQR) were expressed, and a Mann-Whitney U-test was used. Categorical data were expressed as frequency (n) and percentage (%) and were statistically tested using the chi-square or Fisher's exact test. Correlations between variables were assessed with Spearman's rank correlation coefficients.
Logistic regression analysis was used to evaluate the predictive abilities of cannulation-induced pain intensity. All P values < 0.05 were considered to be statistically significant.

Results
A total of 139 patients undergoing laparoscopic nephrectomy were screened between August and October 2019, of which 19 were excluded because they did not meet the inclusion criteria, refused to participate in the trial, and failed venous cannulation. Among the remaining 120 patients, some were eliminated due to transferred to ICU, converted to open surgery, surgery duration over three hours, or incomplete recording, and 106 study patients were available for analysis (Fig. 1).
Patients' demographic characteristics and perioperative data are shown in Table 1. Bivariate correlations between peripheral venous cannulation-induced pain score and outcome variables are shown in Fig. 2 and Table 2. Postoperative maximum pain score at rest (rs = 0.64, P < 0.001) ( Fig. 2A), postoperative maximum pain score during coughing (rs = 0.65, P < 0.001) (Fig. 2B), effective times of pressing (rs = 0.59, P< 0.001), additional consumption of sulfentanil (rs = 0.58, P < 0.001) were statistically significantly correlated with peripheral venous cannulation-induced pain score, respectively.  Patients' demographic characteristics and perioperative data between the two groups are shown in Table 3. There were no significant differences in age, gender, BMI, ASA, history of surgery, type of surgery, approaches of surgery, duration of anaesthesia and surgery, consumption of remifentanil between the two groups.    (Table 5).

Discussion
This study shows that peripheral venous cannulation-induced pain score is positively correlated with postoperative maximum pain and addition consumption of sulfentanil during the first 24 h after laparoscopic nephrectomy. Patients with VCP score ≥ 2.0 VAS units are more likely to report higher postoperative pain scores and additional consumption of sulfentanil. Furthermore, patients with VCP score ≥ 2.0 VAS units have a 3.5 times higher risk for moderate or severe postoperative pain.
Peripheral venous cannulation, is a routine practice before surgery, has been reported by patients to be painful. The pain intensity is associated with cannula site, cannula size, failed venipuncture attempts and process times [10,11]. In the present study, we did not include patients with failed venipuncture, and this procedure was performed by the experienced nurse with same diameter puncture needle on the same site. The results showed that the median level of pain intensity associated with venous cannulation on the hand was 1.8 VAS units, which was close to current study proposed the cut-off level of the VCP (2.0 VAS units). Furthermore, the cut-off level of the VCP was found to be 2.0 VAS units in predicting postoperative pain in Persson et al. Study [9]. Another study reported that 2.0 VAS units represented a more reasonable cut-off level of VCP for prediction of postoperative pain [12].  [13] study used VCP score to predict pain during childbirth in a cohort of 50 women admitted for induction of labour and found that intense pain upon intravenous cannulation predicted an earlier request for epidural analgesia during the course of induction of labour. A recently study [12] evaluated the usefulness of VCP score in 4 categories surgery (presumed to with hardly any postoperative pain, slight, moderate and severe levels of postoperative pain) and reported that the method of VCP score was only statistically significant in the patients subjected to surgery presumed to result in moderate levels of postoperative pain.
Numerous studies have been developed to predict postoperative pain in the last decade. The pain intensity of QST stimuli, including pressure, electric, and thermal stimulus, have been reported to correlate with the intensity of postoperative pain [6][7][8][14][15][16][17]. Werner et al. [18] reported that QST assessments might predict up to 54% of the variance in the postoperative pain experience. The predictive ability of the tests is much higher than previously reported for single-factor analyses of demographics and psychologic factors. However, these methods may be time-consuming and not necessarily available in a fast-paced clinical environment.
The VCP assessment is easy to perform, timely and rapid clinical test and requires no special equipment.
Our finding has important clinical implications since the management of postoperative pain remains an ongoing challenge. Due to the individual variability in opioids response, and the potential side effects such as nausea and vomiting, pruritus and respiratory depression, being able to preoperative identify patients with lower pain thresholds and potentially higher analgesic requirements is essential. Using peripheral VCP intensity as a predictor for patients tend to experience moderate or severe postoperative pain, may allow anaesthetists more convenient to adjust opioids dose to optimize postoperative pain management.
There are some limitations to the present study. Known risk factors of postoperative pain are female gender, lower age, preoperative pain, intraoperative factors and psychological factors, and so on [8,[19][20][21]. Furthermore, it was reported that psychological factors were correlated with venous cannulation-induced pain score [22]. This study did not take psychological factors into account. The psychological variables may affect the levels of postoperative pain and venous cannulation-induced pain score. Besides, this method did not be evaluated in other surgical patients.

Conclusions
In conclusion, peripheral venous cannulation-induced pain score was associated

Funding
The authors received no funding for this study.

Availability of data and materials
The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

Authors' contributions
FP contributions to the study concept and design, acquisition of data, analysis and interpretation of data, drafting and revising the manuscript. YSL contributions to the study design, acquisition of data. YQA contributions to the study concept and design. JJY helped revise the manuscript. YPW contribution to the study concept and design, analysis and interpretation of data, revising the manuscript. All authors read and approved of the final manuscript.

This study was approved by the Institutional Scientific Research and Clinical Trials Ethics
Committee of the First Affiliated Hospital of Zhengzhou University on June 12, 2019. This study was also registered at chictro.org (ChiCTR1900024352). Written informed consent was obtained from all of the participants.

Consent for publication
Not applicable.