Effectiveness of ESPITO analgesia in enhancing recovery in patients undergoing open radical cystectomy when compared to a contemporaneous cohort receiving standard analgesia: an observational study

Introduction

Open Radical Cystectomy (ORC) with pelvic node dissection and urinary diversion is the current treatment of choice for many muscle invasive and high-risk non-muscle invasive bladder cancers [1]. The extensive tissue dissection is associated with prolonged length of hospital stay and high overall morbidity. The median length of hospital stay following ORC in the United Kingdom is 11 days [2]. Postoperative paralytic ileus (POI) is a major factor in the delayed recovery and hospital discharge following ORC [3]. The incidence of POI is reported to be 23–40% [4], [5].

Current practice in the United Kingdom is largely based on enhanced recovery programme (ERP) recommended by the British Association of Urological Surgeons (BAUS) [6]. The main thrust of ERP in radical cystectomy is to avoid POI. Modifiable factors implicated in the development of POI include opioid medication, nasogastric tube placement, mechanical bowel preparation, fluid overload causing bowel odema, postoperative nausea and vomiting and poorly controlled postoperative pain. However, opioids are recognised to play a prominent role in the development of POI and most ERP recommend multimodal opioid-sparing analgesia (MOSA) [3], [4], [5].

The analgesic technique of choice recommended by the British, European and American urological societies is thoracic epidural analgesia (TEA) [6], [7], [8], [9]. However, there is an on-going trend moving away from TEA [10], [11]. Alternative analgesic regimens include rectus sheath analgesia and wound infusion analgesia (WIA) [12], [13]. Although these techniques can provide effective somatic analgesia, they rely on systemic morphine to provide visceral analgesia in the postoperative period (patient controlled analgesia with morphine, PCA with morphine). In opioid naïve individuals, even a small amount of systemic morphine in the postoperative period could impair recovery of bowel function. Analgesia following ORC is recognised as one area where further research has been recommended [8].

We have previously described a novel technique, Erector Spinae Plane and Intrathecal opioid (ESPITO) analgesia in patients undergoing open radical cystectomy [14]. ESP infusion provides analgesia via paravertebral block and the technique has been termed paravertebral by proxy [15]. The combination of continuous paravertebral block and single shot intrathecal opioid provide pre-emptive analgesia, sympathetic blockade, intraoperative analgesia as well as adequate postoperative analgesia. There is early evidence that paravertebral block could suppress stress response to surgery and the resultant sympathetic blockade may provide visceral analgesia [16], [17]. We have observed that addition of intrathecal diamorphine provides cover for the intense but short lasting (18–24 h) visceral pain that accompanies the extensive pelvic dissection during ORC [14].

The authors present a prospective study on the effectiveness of ESPITO analgesia in reducing the incidence of postoperative ileus and the length of hospital stay when compared to a contemporaneous control group receiving standard analgesia in patients undergoing ORC with ileal conduit (IL).

Methods

After obtaining approval from the research ethics committee (REC, 17/YH/0380) and written informed consent from the patients, we included all ASA I-III patients scheduled for elective ORC and IL formation under a single surgeon (BLJ) in an observational trial between November 2017 and May 2019 (ESPITO group). Ethics committee approval (17/YH/0380) was also obtained for collection of retrospective outcome data on a contemporaneous cohort of ORC patients receiving standard analgesia during the study period (control group). Both groups received broadly similar components of enhanced recovery protocol (ERP) (Table 1).

In addition, ESPITO group recived prophylactic metaraminol infusion for the first 24 h after surgery and prophylactic dexamethasone during surgery to offset intrathecal bupivacaine induced hypotension and intrathecal opioid induded emesis respectively.

Exclusion criteria included patients undergoing ORC and Studer pouch formation, ORC and Indiana pouch formation, salvage cystectomy or patients in whom ERP was not adhered.

The primary outcome was the incidence of postoperative ileus (POI). POI was defined as ‘Intolerance of solid food at the fifth postoperative day with the need to hold oral nutrition because of bloating, nausea and vomiting requring the placement of a nasogastric tube and commencement of intravenous fluid administration’ [18]. We have used a modified version of the definition of POI by Shabsigh et al. [18], [19]. We have not included anti-emetic medication in the definition as the patients in this study received prophylactic anti-emetics for upto five days as part of ERP.

The secondary outcomes included day of bowel opening (bowel evacuation), 72 h intravenous tramadol consumption (rescue analgesia), length of hospital stay (LOS) and 90-day mortality.

Results

Over the study period, 63 patients underwent ORC and IL formation at our centre. Twenty-five patients received ESPITO analgesia and 31 patients received standard analgesia (control arm) within an enhanced recovery programme. Seven patients in the control arm were excluded due to non-compliance with ERP. In the control arm, 14 patients received TEA (45%, 14/31) while 17 patients received WIA with PCA (55%, 17/31).

The patient characteristics for each group are summarised in Table 2. There were no significant differences in the age, gender, BMI or ASA (Table 2). All patients received intraoperative cardiac output monitoring, goal directed fluid therapy, prophylactic anti-emetic administration and normothermia during the surgery.

The 72 h postoperative intravenous fluid consumption (mean ± SD, litres) was greater in the control analgesia group when compared to ESPITO group (4.8 ± 1.4 vs. 3.9 ± 1.1, p=0.008). ESPITO group received metaraminol infusion for the first 24 h after surgey and this may have played a role in reducing intravenous fluid use.

ESPITO analgesia was associated with a significant reduction in the incidence of POI (16 [4/25] vs. 65% [20/31], p<0.001) when compared to standard analgesia (Table 3).

ESPITO analgesia was also associated with significant reduction in key recovery outcomes including time to first open bowel (4.4 ± 2.3 vs. 6.6 ± 2.3, p<0.001) and median (IQR) LOS (7[6, 12] vs. 10[8, 15], p<0.007). Tramadol consumption (rescue analgesia in milligram, median [IQR]) was not significantly different between the two groups (100[0, 150] vs. 100[0, 250], p 0.69). The 90-day mortality in the ESPITO group was nil while in the control groups, it was 6.4% (2/31).

ESP catheter(s) insertion and intrathecal opioid administration was successfully performed in all patients. There was no therapeutic failure of ESPITO analgesia.

Complications in the ESPITO group included catheter displacement in three patients requiring re-siting of the catheters on the ward. In one patient, part of the catheter was accidentally retained during catheter removal on the ward. There may have been partial shearing of the cathter during subcutaneous tunnelling at the time of insertion. The patient was followed up for a year without any further complication.

Therapeutic failure in TEA was 36% (5/14) requiring the addition of PCA with morphine within 48 h after surgery. As a result, 71% of patients in the control group (22/31) received systemic morphine. The mean 72 h morphine consumption was 84 mg. There was no specific complication from wound catheter insertion.

Discussion

Continuous erector spinae plane infusion and single shot intrathecal opioid (ESPITO) analgesia significantly reduced the incidence of POI by 75%, thereby enabling a 30% reduction in the LOS when compared to standard analgesia in a cohort of patients undergoing ORC and IL formation. ESPITO analgesia avoided the need for both TEA and systemic morphine (PCA with morphine). POI has been recognised as one of the principal reasons for prolonged length of stay following radical cystectomy [5], [19]. The incidence of POI is quoted as 23–40% [4], [5]. In the ESPITO group, POI was 16% (4/25). However, in the control group where 71% (22/31) of patients received systemic morphine, the incidence of POI was 65%. Systemic morphine has been recognised as the predominant cause of POI [8]. We used a modified version of the original definition of POI by Shabsigh et al. [18], [19]. We did not use pragmatic outcomes including first day to pass stool as the primary outcome. We have observed patients who passed flatus on day 1 or day 2 develop POI on day 5, delaying their recovery and subsequent discharge. Patients receiving TEA may report passing flatus on day 1. However, if TEA fails within the first 72 h and patients receive rescue analgesia with systemic morphine, they are likely to develop POI by day 5. Absence of POI at day 5 appears to be a more sensitive indicator of bowel recovery than first day of passing flatus.

Urinary diversion utilises a segment of bowel to create an ileal conduit in most cases of ORC. This requires extensive viseral dissection that results in significant but short lived (24–36 h) post operative visceral pain [14]. Intrathecal opioids provide visceral analgesia during the first 24 h and its adverse effect on the bowel function probably coincides with the effect of surgery handling on bowel motility. Thus, avoiding systemic morphine in the postoperative period prevents further bowel dysfunction allowing earlier return of bowel motility.

Analgesia following ORC is recognised as one area where further research has been recommended [8]. Although TEA can provide optimal analgesia and enhances bowel motility, the associated side effects have been shown to hinder early mobilisation with subsequent delayed recovery [23], [24]. Hypotension following TEA can result in significant intravenous fluid administration. In an internal audit, we found that patients receiving TEA received an average of over 6 L (4.6–8.2 L) of intravenous fluid in the first 72 h following surgery [14]. In the control group, despite adhering to the ERP, patients received over 4 L of crystalloids in the first 72 h after surgery. Therapeutic failure with TEA is a major issue as these patients receive systemic morphine as rescue analgesia. Reported failure rate of TEA is between 30 and 40% [23], [24]. In our cohort, 36% of TEA patients (5/14) were on PCA with morphine (rescue analgesia) within 48 h of surgery. There is an inherent delay in early mobilisation of patients who receive TEA probably due to fear of falls as a result of hypotension as well as lower limb motor block. In our cohort, ESPITO analgesia avoided the need for TEA.

Alternative regional anaesthetic techniques that have gained popularity include rectus sheath analgesia and wound infusion analgesia (WIA). However, these techniques require supplemental analgesia with systemic morphine [12], [13]. In the control group, 17 patients (55%, 17/31) received WIA. The 72 h mean (SD) morphine consumption was 92.6 (98.1) mg and the incidence of POI was 71% (12/17).

We have previously shown that ESP analgesia has wide applicability in patients undergoing open abdominal surgery including liver resection, radical nephrectomy and inferior vena cava exploration and laparotomy [20]. ESP infusion provides excellent somatic analgesia and some visceral analgesia. However, in patients undergoing ORC, ESP analgesia is unable to provide sufficient visceral analgesia and therefore relies on systemic morphine for visceral analgesia [14], [20]. Combining ESP infusion with intrathecal opioids (ESPITO) provides adequate somatic as well as visceral analgesia thereby completely avoiding systemic morphine in the postoperative period. The rationale of using intrathecal bupivacaine was to provide intense intraoperative pre-emptive analgesia, attenuate surgery-induced stress response and reduce intraoperative blood loss.

Open radical cystectomy carries significant morbidity as well as mortality. The 90-day mortality in the UK after ORC is 5.1% [25]. In ESPITO group, the 90-day mortality from factors related to the surgical procedure was 0%. Perhaps, avoiding systemic morphine may have played a role. We were unable to avoid opioids completely in the postoperative period as tramadol was used for rescue analgesia. Although tramadol has opioid receptor activity, it causes less impairment of bowel function when compared to morphine [26].

The authors are aware of the significant limitations of this open label, observational non-randomised study. The objective was to collect data to inform the design of a substantive randomised controlled trial.

In conclusion, ESPITO analgesia has the potential to avoid systemic morphine as well as epidural analgesia thereby enhancing bowel recovery when compared to standard analgesia in patients undergoing open radical cystectomy.