Multidisciplinary Cooperation Alleviates Postoperative Pain after Elective Craniotomies: A Prospective Randomized Controlled Study of Neurosurgical Enhanced Recovery After Surgery (ERAS) program

Objective: To prospectively evaluate the efficacy of neurosurgical enhanced recovery after surgery (ERAS) protocol on the management of postoperative pain after elective craniotomies. Methods: This randomised controlled trial was conducted in the neurosurgical center of Tangdu Hospital (Fourth Military Medical University, Xi’an, China). A total of 129 patients undergoing craniotomies between October 2016 and July 2017 were enrolled in a randomized clinical trial comparing ERAS protocol and conventional care. The primary outcome was the postoperative pain score assessed by a verbal numerical rating scale (NRS). Results: Patients in the ERAS group had a significant reduction in postoperative pain score on POD 1 compared to patients in the control group (mean NRS 3.12 vs. 4.44, OR 0.0968, 95% CI 0.3299 to 2.317, p = 0.010). More patients (n = 44, 68.8%) in the ERAS group experienced mild pain (NRS: 1 to 3) on POD1 compared with patients (n = 23, 35.4%) in the control group (p < 0.05). A significant reduction in pain score was observed on POD 2 and POD 3 in the ERAS group compared with that in the control group (POD2: mean NRS 2.85 vs. 4.32, OR 0.2628, 95% CI 0.5619 to 2.379, p=0.002. POD3: mean NRS 2.32 vs. 4.03, OR 0.1468, 95% CI 0.9537 to 2.458, p < 0.001, respectively). In addition, the median postoperative length of hospital stay was significantly decreased with the incorporation of ERAS protocol compared to the controls (ERAS: 4 days, control: 7 days, P<0.001). Conclusion: Implementation of the neurosurgical ERAS protocol for elective craniotomy patients have significant benefits in alleviating postoperative pain and enhancing recovery after surgery compared to the conventional care. Further evaluation of this protocol in larger, multi-center studies is warranted.


Introduction
With the increasing public expectations for high quality and efficient healthcare, there is a trend that more clinicians, especially neurosurgeons, are making efforts to optimize patient outcomes by addressing pre-, peri-, and post-operative factors 1,2 . Enhanced recovery after surgery (ERAS) protocols primarily aim at optimizing outcomes, increasing patient satisfaction, and reducing health care costs 3 . In the recent decades, a number of standardized ERAS protocols have been implemented across the entire perioperative period [4][5][6][7][8] . Conventional perioperative care protocol is typically related to extensive preoperative preparation, significant surgical stress and prolonged time of functional recovery. Excessive adverse effects may increase the risks of cerebrovascular complications, nutrient malabsorption and delayed convalescence in surgical patients 9 .
On the other hand, with the development of perioperative pathophysiology, the concept of ERAS has been established to standardize clinical practice, improve functional capacity after surgery, speed up the patients' rehabilitation, reduce postoperative length of stay (LOS), reduce medical cost, and improve the patients' satisfaction 10,11 .
When making the decision on whether to adopt a new comprehensive protocol in elective craniotomies, the neurosurgeons must consider the quality & safety of the procedure and risk tolerance. Moreover, the quality improvement methods should raise the degree of patients' perceived comfortableness. For elective craniotomies, the key indicator is postoperative pain. Acute pain is common during the postoperative period, and is associated with complications and adverse outcomes. To date, there is controversy in the literature regarding the evaluation of pain and its intensity in patients undergoing neurosurgical procedures 12,13 . Moreover, different types of pain therapy have been advocated for the same neurosurgical procedure based on clinicians' personal or institutional preference [13][14][15] . To our knowledge, no well designed study has been conducted to compare the effect on perioperative verbal NRS scores of ERAS program with the conventional surgery protocol.
Although there are a few studies to evaluate new protocols for elective spinal and peripheral nerve surgery, the quality and safety outcomes of those programs have not been well described 9, 10 . Recently, our group have developed a multi-disciplinary neurosurgical ERAS protocol for craniotomies based on the best available evidence 1,16,17   The exclusion criteria comprised of (1) non-brain tumor patients, such as severe craniocerebral injury leading to bilateral mydriasis, unstable vital signs; (2) children (patients less than 18 years), awake craniotomy; (3) patients with severe spinal cord shock; (4) other trauma caused by preoperative cardiac arrest, combined with severe limb fractures or thoracic and abdominal injury; (5) infection or inflammation in the surgical area; (6) serious comorbidities (blood system, respiratory system, digestive system, etc.) patients; (7) patients with severe heart disease (such as coronary heart disease, myocardial infarction, etc.); (8) Patients with ULN and / or renal function (Cr)> 1.5 times ULN with liver function (ALT, AST)> 2 times; (9) patients with mental illness or severe mental illness; (10) Women who have a childcare plan within 6 months of pregnancy or breastfeeding; (11) Other patients who were considered unsuitable for inclusion in the study.

Patient enrolment
Research assistants (RAs) consulted duty nurses daily to identify all new admissions as potential study participants. After confirming eligibility and obtaining consent, RAs collected patient characteristics data including demographic information (age, sex), admission diagnosis, preoperative co-morbidity status (American association of anesthesiologists grades, ASA grades) and other presenting physical characteristics (smoking, diabetes, motion sickness, hypertensive disease, etc.). Data about the details of operations like types of operation, lesion locations (supratentorial superficial lesion, supratentorial deep-seated lesion or infratentorial lesion) were also assessed. All data were collected on a secure, web-based program.

Randomisation
After obtaining informed consents, patients were prospectively randomized into two groups (1:1 ration) by simple randomization procedures (computerized random numbers) by the research coordinator. A total of 65 patients were allocated to control group who received the conventional perioperative care, whereas 64 patients were allocated to ERAS group who received care according to the neurosurgical ERAS protocol. Due to the requirement for active patient participation, it was not possible to perform the study with blinded participants and care providers. Only those who collected and assessed outcomes were blinded to the allocation.

Outcome measurements
The primary outcome of this study was the score of postoperative pain related NRS. The verbal NRS ranges from 0 to 10 (0 represents no pain and 10 represents the worst pain).
Postoperative NRS of surgical site pain was assessed on postoperative day (POD) 1 and repeated daily until the patient had no complaint of pain or was discharged.

Statistical analysis
Data were collected during the hospitalization and at the 4-month follow-up after hospital discharge. Descriptive statistics of ERAS group and control group were compared for all relevant patient characteristics. A sample size of at least 60 patients per arm was calculated to have a power of 80% and a significance of 5%. To compensate for potential dropouts, 129 patients were enrolled. Continuous data with a normal distribution were statistically tested for group differences using chi-square test and Fisher's exact text. The statistical analysis was performed with SPSS software (Ver. 19, IBM Corp., Armonk, NY). A P value of <0.05 was considered to be statistically significant.

Baseline characteristics
A total of 129 patients (64 patients from ERAS group and 65 patients from control group) patients were enrolled in this study and were preoperatively randomized to one of two groups: ERAS group and control group. Patient characteristics are shown in Table 1.
Demographic and clinical features were not significantly different between the intervention and control groups. All patients in both groups underwent elective craniotomies by the same experienced neurosurgical team. Final analysis compared 64 ERAS group patients with 65 control group patients (Figure 1).. In both groups, the proportion of female patients was higher than that of male patients, but there was no significant gender difference between two groups. The relevant details of surgery and outcomes are also shown in Table 1. There was no significant difference in categories of indications for operations. Patients who met the inclusion criteria were included in the study and presented with common neurological deficits. The location of lesions has no significant difference between the groups, and every patient went through a standardized surgical procedure as mentioned previously.
The assessment of postoperative surgical pain Primary outcome measurements are shown in Table 2  Analgesic medication administration and other secondary outcomes The analgesics were administered to relieve postoperative pain depending on the assessment and decision of the attending team. The analgesics were divided into three categories (WHO classification of pain treatment, Table 3).. The analgesic medication used in the ERAS group and control group are shown in Table 4. In general, the number of patients receiving WHO Class I -WHO Class III medication was not significantly different between two groups (ERAS group: n = 15, 23.4% vs. control group: n = 22, 33.8%, P = 0.356). On POD 1, the percentage of patients receiving WHO Class I analgesic medication was 14.1% in the ERAS group vs. that of 12.3% in the control group. The percentage of patients receiving WHO Class II analgesic medication was 4.7% in the ERAS group vs. that of 13.8% in the control group. The number of patients receiving WHO Class III analgesic medication was 4.7% in the ERAS group vs. that of 7.7% in the control group.
Other secondary outcome measurements are shown in Table 4. The median of total hospital LOS was significant reduced from 13 days in the control group to 10 days in the ERAS group (P = 0.004). The median of postoperative LOS was also significant reduced from 7 days in the control group to 4 days in the ERAS group (P < 0.001). In addition, the total cost of hospitalization was RMB 52424 (range: 33652-118965) in the ERAS group and RMB 64462 (range: 39973-141216) in the control group (P < 0.001).

Postoperative Complications and Re-admission
Postoperative complications are listed in Table 5 Recently we have implemented a new multidisciplinary, evidence-based, neurosurgical ERAS program for elective craniotomy patients in a single center 22 .
Optimization of pain management is a key element of ERAS protocol. Till now, there is no consensus regarding the pain management and analgesic regimen for post-craniotomy pain 23 . NRS is one of the most frequently used standardized methods to evaluate postoperative pain. In our study, in spite of the treatment of postoperative pain with analgesics, over 64.6 % of the patients suffered from moderate-severe pain in the control group. This is consistent with some previous reports on the prevalence of postcraniotomy pain 24-27 , though nurses and physicians tried to treat the patients with best efforts. Our data showed that patients in the ERAS group had a statistically significant reduction in pain score on POD 1-POD 3 compared to patients in the control group. Moreover, the incidence of moderate pain on POD 1 reduced with the implementation of the ERAS protocol, and the patients had shorter duration of pain complaint than those in the control group ( Table 2).. These results suggested that the successful implementation of the neurosurgical ERAS protocol could reduce the probability of suffering with severe pain after elective craniotomies.
There is an intense debate on whether the ERAS program reduces pain after elective craniotomies. The main finding of this study was a trend for less pain in the ERAS group patients. We speculate that the findings of reduced pain in this study may be related to some interventions included in the ERAS protocol such as smoking cessation, incisional local anesthetic blocks and additional use of acetaminophen/NSAIDs. In addition, multidisciplinary collaboration also reduces patient discomfort, speeds up wound healing, and thus reduces the degree and duration of postoperative pain. Firstly, one of the main interventions in ERAS protocol is smoking cessation. Smoking has been known to be harmful to overall health, and cigarette smoking may also associated with a worse surgical outcome and prognosis in patients undergoing craniotomy. Some studies indicate that smoking cessation may reduce postoperative complications following craniotomy 28 .
Secondly, numerous studies have shown that scalp infiltration in patients undergoing craniotomies play crucial roles in post-craniotomy pain management 29-33 . Accordingly, scalp infiltration with ropivacaine or bupivacaine in the ERAS protocol may reduce the incidence and severity of postoperative pain, which has also been shown in other studies 23,34 . The mechanisms underlying the beneficial effects of local anesthetic blocks include a reduction in the inflammatory and stress response associated with surgery, lower levels of angiogenesis, a decrease in the requirements of volatile anesthetics and minimization or avoidance of opioid 35 . Thirdly, non-opioid analgesics including acetaminophen or non-steroidal anti-inflammatory drugs were administrated according to the pain degree of patient postoperative NRS. Evidence showed that morphine was less effective for pain relief in craniotomy patients 36, 37 . Therefore, postoperative morphine and equivalent opioids were not routinely prescribed due to their limited effect and wide ranges of side-effects for mild or moderate pain. The low dose consuming non-opioid analgesics can also reduce opioid consumption by 35-50%, and alleviate persistent pain without significant adverse effects 38-42 . In our study, most patient showed mild pain (NRS 1-3) on POD 1, and more patients showed shortened pain duration time (1-2d) in the ERAS group ( Table 2).. There was no statistical difference in analgesic medication administration between the two groups (p = 0.356, Table 4).. These results supported the effectiveness of pain management protocol in the ERAS group, which had also improved the medical recovery of patients.
Hospital stay relies on various factors, which may be modified to a certain extent by the effect of perioperative care 43 . Total hospital LOS and postoperative LOS was evaluated between the ERAS group and the control group ( Table 4) In addition, the current ERAS protocol incorporates nutritional interventions including preoperative carbohydrate loading and early restoration of oral solid food postoperatively, which may have a profound impact on the enhanced recovery. Such interventions were shown to alleviate muscle loss and improve organ function such as pulmonary function in addition to improve glucose homeostasis and insulin resistance 46,47 . These beneficial effects may also correlate with a reduction in both hospital LOS and postoperative LOS in patients participating in an ERAS program for major surgeries including craniotomies 47,48 .
We monitored all patients for postoperative complications and re-admission rates, and none of the patients had suffered from raised intracranial pressure, recraniotomy, mental status changes (needs for emergent imaging), diabetes insipidus and toxic epidermal necrolysis (due to phenytoin) in the ERAS group ( Table 5).. However, 4 patients in the ERAS group had serial blood sugar levels >200 mg/dL intraoperatively which lasted for 3 days postoperatively and required insulin therapy. Limited by our case number, the current results may not reflect the influences of the ERAS protocol in this respect. To summarize, the postoperative complications and re-admission rate in the ERAS group was not increased as compared to that in the control group, while postoperative pain of patients was reduced significantly.
There are several limitations of the current study. First, subgroup analysis may be needed to perform with all consecutive patients within the ERAS group and conventional care protocol. Postoperative pain management is embedded in a multidisciplinary cooperation and the impact of pain management on recovery, pain relief, and length of stay needs to be interpreted in this context. Second, though postoperative pain was significantly reduced in the ERAS group, the use of opioid analgesics was not significantly decreased in the ERAS group compared to the control group. It is possible that expectations on the part of both the patients and researchers may cause bias towards a more favorable NRS score in the ERAS group since this study was not blinded. This limitation in interpretating the results of this study should be noted. Third, little information was assessed in-depth regarding the specific characteristics of targeted patient populations, which may be investigated in further studies. As mentioned in the Methods section, the ERAS pathway has been continuously adapted and updated during the study period to avoid the bias of various perioperative care pathways and unbalanced interventions.

Conclusion
In conclusion, we have assessed the effect of an ERAS protocol for elective craniotomies, which includes a series of interventions, on alleviating postoperative pain and enhancing recovery after surgery. The results of this study confirmed the efficacy of the ERAS protocol for pain management after elective craniotomies. Moreover, the ERAS protocol also reduced total / postoperative hospital LOS and the total cost of medical care. There is an urgent need for larger multi-center studies to further evaluate this protocol in the targeted patient population. Declarations manuscript. All authors revised the manuscript and provided feedback and comments.

Patient consent
This article does not contain personal medical information about an identifiable living individual, and therefore does not require the patient's explicit consent before we can publish it.

Ethics approval
The study was approved by the Ethical Committee of Tangdu Figure 1 Flow diagram of CONSORT study design. Randomized controlled trial comparing ERAS group versus control group for elective craniotomies.