A double-blind, randomised, placebo-controlled trial comparing intrathecal bupivacaine with bupivacaine plus morphine to reduce delirium in patients with hip fractures-Salmon-Mind trial study protocol.

Background: Surgical treatment of proximal femur fractures is complicated by postoperative delirium in about one-third of patients. Pain and opioid consumption are modifiable factors that may influence the incidence of delirium.1 An intrathecal injection of morphine may lead to a reduction in postoperative pain and reduced systemic opioid consumption. In current practice, the addition of morphine to intrathecal anaesthesia is commonly used but depends on the anaesthesiologist's preference. Recently, a retrospective study found that intrathecal morphine was independently associated with a lower incidence of delirium. However, this has to be confirmed in a prospective, randomised study. We hypothesise that using intrathecal morphine reduces postoperative pain and opioid consumption during the first 48 h after surgery and reduces the incidence of delirium during hospital admission. We also seek additional evidence of the association between neuronal injury (delirium) and neurofilament light in serum of patients with proximal femur fractures. Objective: The primary objective is to compare the incidence of delirium. The secondary objectives are to compare pain scores, systemic opioid consumption, and (opioid-related) side-effects. The tertiary objective is to test the association between intrathecal morphine and neurofilament light as a marker of neuronal injury. Study design: A double-blind, randomised, placebo-controlled intervention study is proposed. Study population: All patients with a proximal femur fracture who are scheduled for surgery under spinal anaesthesia. Intervention: The intervention is the addition of morphine 100 µg to the intrathecal injection for spinal anaesthesia. The intervention group will receive a mixture of bupivacaine 10 mg and morphine 100 µg. The control group will receive bupivacaine 10 mg. Clinical trial registration: EU Clinical Trials Register: EudraCT number 2020-002143-27.

Prevention and Treatment of Neuraxial Morphine-Induced Pruritus: A Scoping Review.

The addition of morphine to neuraxial anaesthesia leads to improved postoperative analgesia and lower opioid consumption, but is often accompanied by pruritus. Studies on preventing or treating pruritus show contradictory results. Our objective was to identify effective drugs for the prevention or treatment of pruritus by a scoping review of clinical trials. A systematic literature search was conducted in PubMed, Embase and Web of Science. We identified clinical trials investigating the prevention or treatment of neuraxial morphine-induced pruritus in adults. Systematic reviews and meta-analyses were screened for eligible studies. One-hundred-and-four articles were included covering 13 pharmacological groups. We conclude that dopamine antagonists, µ-opioid agonist/antagonists and neuraxial or orally administered µ-opioid antagonists prevent pruritus caused by neuraxial morphine regardless of the timing of administration. In the reviewed literature, 5HT3-antagonists prevent neuraxial morphine-induced pruritus when administered before morphine administration. For the treatment of neuraxial morphine-induced pruritus, only nalbuphine appears to be consistently effective. More research is needed to find the most effective doses and the optimal timing of the effective medication.

Measurement of drug concentration and bacterial contamination after diluting morphine for intrathecal administration: an experimental study.

BACKGROUND: Low concentrations of morphine are required for safe dosing for intrathecal injections. Sometimes, manual dilution of morphine is performed to achieve these low concentrations, but risks dilution errors and bacterial contamination. The primary goal was to compare the concentrations of morphine and bupivacaine between four groups of syringes. The secondary goal was to investigate the difference in contamination rate between these groups. METHODS: Twenty-five experienced anesthesia providers were asked to prepare a mixture of bupivacaine 2.0 mg/ml and morphine 60 µg/ml using 3 different methods as clean and precise as possible. The fourth method used was the aspiration of ampoules prepared by the pharmacy. The concentrations of morphine and bupivacaine were measured by High-Pressure Liquid Chromatography (HPLC). The medication was cultured for bacterial contamination. RESULTS: Group 1 (median 60 µg/ml; 95% CI: 59-110 µg/ml) yielded 3 outliers above 180 µg/ml morphine concentration. Group 2 (76 µg/ml; 95% CI: 72-80 µg/ml) and 3 (69 µg/ml; 95% CI: 66-71 µg/ml) were consistently higher than the target concentration of 60 µg. The group "pharmacy" was precise and accurate (59 µg/ml; 95% CI: 59-59 µg/ml). Group 2 and "pharmacy" had one contaminated sample with a spore-forming aerobic gram-positive rod. CONCLUSION: Manually diluted morphine is at risk for deviating concentrations, which could lead to increased side-effects. Medication produced by the hospital pharmacy was highly accurate. Furthermore, even when precautions are undertaken, contamination of the medication is a serious risk and appeared to be unrelated to the dilution process.

Intrathecal Morphine for Laparoscopic Segmental Colonic Resection as Part of an Enhanced Recovery Protocol: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Management of postoperative pain after laparoscopic segmental colonic resections remains controversial. We compared 2 methods of analgesia within an Enhanced Recovery After Surgery (ERAS) program. The goal of the study was to investigate whether administration of intrathecal bupivacaine/morphine would lead to an enhanced recovery. METHODS: A single-center, randomized, double-blind controlled trial was performed (NL43488.101.13). Patients scheduled for laparoscopic segmental intestinal resections were considered. Exclusion criteria were patients in whom contraindications to spinal anesthesia were present, conversion to open surgery, and gastric and rectal surgery. The intervention group received single-shot intrathecal bupivacaine/morphine (12.5 mg/300 µg), with an altered dose for older patients. The control group received a sham procedure and a bolus of piritramide (0.1 mg/kg). Both groups received standardized general anesthesia and a patient-controlled intravenous analgesia pump as postoperative analgesia. All patients were treated according to an ERAS protocol. A decrease in days to "fit for discharge" was the primary outcome. RESULTS: Fifty-six patients were enrolled. Intervention group patients were fit for discharge earlier (median of 3 vs 4 days, P = 0.044). Furthermore, there was a significant decrease in opioid use and lower pain scores on the first postoperative day in the intervention group. There were no differences in adverse events (except for more pruritus), time to mobilization, fluid administration, or patient satisfaction. CONCLUSIONS: This randomized controlled trial shows that intrathecal morphine is a more effective method of postoperative analgesia in laparoscopic surgery than intravenous opioids within an ERAS program. Recovery is faster and less painful with intrathecal morphine. Other studies have confirmed these results, although data on faster recovery are new and require confirmation in future trials. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT02284282.