Postoperative effects and complications of intrathecal morphine compared to epidural analgesia in patients undergoing intracorporeal robot-assisted radical cystectomy: a retrospective study

This study is a single-center retrospective study performed at the Rijnstate hospital in Arnhem, The Netherlands: a large teaching hospital and a center of referral for RARC-procedures. This manuscript adheres to the applicable STROBE guidelines. Prior to October 2020, all patients scheduled for a RARC-procedure received EDA, as recommended according to the Enhanced Recovery After Surgery (ERAS) guidelines for radical cystectomies [4]. In October 2020, intrathecal bupivacaine/morphine became the analgesic technique of choice, based on results demonstrated by other laparoscopic procedures in our hospital. No changes in clinical practice occurred during the study period.

The study was in accordance with the declaration of Helsinki and approved of by the hospital’s institutional review board on 21 January 2021 (Rijnstate Lokale Haalbaarheidscommissie, reference number 2020–1780). No written informed consent was required, since a retrospective study does not fall under the Medical Research involving Human Subjects Act (Dutch WMO-act). Per hospital policy, patients were informed that all clinical data can be used for retrospective analyses and patients were given the opportunity to oppose to the use of data. All patients were scheduled for RARC with or without pelvic lymph node dissection and with construction of a cutaneous uretero-ileostomy according to Bricker, in the time period of January 2019 until April 2021. Exclusion criteria were primary open surgery and the absence of neuraxial analgesia. The intrathecal cohort was determined by the time between change of practice and the time of evaluation (October 2020-April 2021). The epidural cohort was arbitrarily set on January 2019-October 2020, with the consideration of including sufficient patients, but without setting a too wide timeframe, so that unknown confounders could affect the research.

Standard care

Patients were allowed enteral nutrition up to six hours prior to surgery and clear drinks up to two hours. No sedative premedication was administered and 2000 mg cefazolin and 500 mg metronidazole were administered intravenously as surgical site infection prophylaxis.

Both epidural and intrathecal analgesia were administered immediately prior to induction of anesthesia. For EDA, the patient was placed in the sitting position and the preference of the anesthesiologist determined the level and method of placement and the depth of catheter insertion. Typically, a level between thoracic 6 and 10 was preferred and the catheter was placed between 3 to 5 cm into the epidural space. A loading dose was administered at the anesthesiologist’s discretion. As maintenance regimen, a mixture of bupivacaine 1.25 mg/ml and sufentanil 1 mcg/ml was administered continuously between 6 and 12 ml/h. Intrathecal analgesia was administered with a 25- or 27-gauge needle (Pencan; Braun Melsungen AG, Melsungen, Germany), inserted at the lowest lumbar level possible until cerebrospinal fluid was obtained. Three to 5 ml of a pharmaceutically prepared mixture of bupivacaine 2.5 mg/ml and morphine 60 mcg/ml was administered, depending on the preference of the anesthesiologist.

Both groups received standardized general anesthesia, using 0.2 mcg/kg sufentanil, 2 mg/kg propofol and 0.6 mg/kg rocuronium. Subsequently their trachea was intubated, and the patient was positioned in the supine position. Anesthesia was maintained with continuous propofol or sevoflurane, depending on the preference of the anesthesiologist. In case of ventilator dyssynchrony or abdominal wall contraction, 10 mcg of intravenous rocuronium were given. When there was a greater than 10% increase in heart rate or blood pressure, 10 mcg of intravenous sufentanil were administered. Vasoactive medication (phenylephrine, ephedrine or norepinephrine) and fluid administration were given at the discretion of the attending anesthesiologist. Typically, a positive fluid balance of 1000–1500 ml was targeted. Prior to surgery, a transurethral catheter was inserted, the operative field was disinfected and covered in sterile drapes. Pneumoperitoneum up to a pressure of 15 mmHg was achieved by CO2-insufflation through a 12 mm camera trocar that was inserted via a periumbilical incision. Three 8 mm robotic trocars, a 15 mm and 5 mm trocar were then inserted before intra-abdominal pressure was decreased to 12 mmHg. The patient was placed in Trendelenburg position at 25 to 30 degrees and after the robot surgery system (Da Vinci Xi System, Intuitive Surgical, Sunnyvale, CA, USA) was docked, surgery started. In female patients, the urinary bladder, uterus, ovaries and ventral part of vaginal wall were resected. In male patients, urinary bladder and prostate were removed. After the radical cystectomy, pelvic lymphadenectomy was performed if indicated and an intracorporeal ileal conduit was constructed. The specimen bag was removed transvaginally in female patients or with a mini-laparotomy in male cases, after which the urostomy was created.

All patients received 1000 mg paracetamol at the start of surgery. Furthermore, patients received 1000 mg metamizole, 0.625 mg dehydrobenzperidol, 4 mg dexamethasone and/or 4 mg ondansetron at the discretion of the attending anesthesiologist.

After surgery, the patient was transferred to the Post Anesthesia Care Unit (PACU) for at least 30 min of observation. If patients required norepinephrine or there was an indication for intensive postoperative monitoring (such as, but not limited to, obstructive sleep apnea, severe heart failure or severe pulmonary compromise) they were admitted to the PACU, Medium Care or Intensive Care Unit for the first postoperative night. The unit of admission depended on availability.

In the epidural cohort, postoperative analgesia consisted of paracetamol 1000 mg four times daily and epidural bupivacaine 1.25 mg/ml and sufentanil 1 mcg/ml at a rate of 6–12 ml/hr. In the case of refractory postoperative pain, intravenous morphine was allowed in 2.5 mg increments. When patients with an epidural catheter were transferred to the ward, they were visited by nursing staff of the acute pain services daily to assure correct use of the epidural catheter and to answer questions from the ward if needed. At the third postoperative day, the epidural medication was stopped. If the pain was acceptable, the epidural catheter was removed and oxycodone 5–10 mg extended release was available up to three times daily if needed.

For the intrathecal morphine group, postoperative analgesia consisted of paracetamol 1000 mg four times daily, naproxen 250 mg three times daily and oxycodone 5–10 mg extended release up to three times daily if needed. Ondansetron 4 mg and haloperidol 1 mg was available for nausea and pruritus.

If pain was unresolved beyond this protocol, physicians could prescribe a Patient Controlled Analgesia (PCA)-pump if analgesia was unsatisfactory, or tramadol if the pain was deemed too mild for oxycodone.

Data extraction and outcomes

Data were retrospectively extracted from the electronic patient data system (Hix 6.1, Chipsoft, Amsterdam, The Netherlands) and consisted of baseline characteristics (gender, weight, height, age, indication for surgery, medical history and ASA-classification), surgical characteristics (duration of surgery, estimated blood loss, type of urinary diversion and the need for conversion to an open procedure), anesthesia characteristics (type and specifics of analgesic method, intra-operative medication administration, fluid administration and dose and duration of vasopressors) and post-operative characteristics (admission to PACU, MCU or ICU and duration of admission, amount of fluid administration over the first two days and number of fluid challenges, urine production, blood transfusion, first day out of bed, first day of defecation, first day of enteral nutrition, length of hospital stay (LOS), time to fit for discharge (FFD) and re-admission to hospital within seven days after discharge). Postoperative pain characteristics consisted of the use of paracetamol and NSAIDs, duration of EDA, level of insertion, the dose of epidural medication, the reason for catheter removal, systemic morphine equivalent (ME) consumption over the first seven days, pain-scores on an 11-point Numeric Rating Scale (NRS; 0 is no pain, 10 is worst pain imaginable) over the first three days and occurrence of nausea, pruritus, hypotension (defined as Mean Arterial Pressure < 65 mmHg), respiratory depression (defined as a respiratory rate less than six breaths per minute), desaturation (defined as SpO2 < 90%) and motor blockade. The ME consumptions was converted with ratio of 1.0 for intravenous morphine, a ratio of 0.75 for oxycodone and 0.1 for tramadol. If a PCA-pump was provided to a patient, a ME consumption of 15 mg was assumed for that day, since the exact morphine consumption was not documented or retrievable. Pain scores on a NRS were measured once during every shift (day, evening and night) and when NRS was noted more than once, the highest value per shift was used to calculate a daily mean NRS. When NRS was higher than seven, it was registered as severe pain. The charts were reviewed for occurrence of complications and were classified according to the Clavien-Dindo classification. The following complications were defined: bradypnea, desaturation and infection (defined as a fever for which antibiotics were initiated and/or a rise in CRP together with a positive blood culture).

Fit for discharge (FFD) was defined as adequate analgesia with oral medication, hemodynamic stability, sufficient oral intake, passage of flatus and the capability of personal hygiene maintenance.

Statistical analysis

Data were described as n(%) for categorical data or median (IQR)[range] for continuous data. All data were checked for normality by using a Kolmogorov–Smirnov test. Categorical data were analyzed with a Chi-squared test or a Fishers' exact test where appropriate. Continuous data were analyzed by using a Mann–Whitney-U-test. Correlations between continuous variables were tested with a Spearman Rho-test. Propensity Score Matching used a binary logistic regression in which the odds for inclusion in the epidural or intrathecal group was the dependent variable and gender, BMI, ASA-classification and age were the independent variables. P < 0.05 was considered statistically significant. SPSS 26.0 (IBM, Armonk, NY, USA) was used for the analysis.

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