Effect of intraoperative remimazolam on postoperative sleep quality in elderly patients after total joint arthroplasty: a randomized control trial.

PURPOSE: To investigate the effect of intraoperative remimazolam sedation on postoperative sleep quality in elderly patients after total joint arthroplasty. METHODS: Between May 15, 2021 and March 26, 2022, 108 elderly patients (age ≥ 65 years) who received total joint arthroplasty under neuraxial anesthesia were randomized into remimazolam group (a loading dose of 0.025-0.1 mg/kg and followed by an infusion rate of 0.1-1.0 mg/kg/h till end of surgery) or routine group (sedation was given on patient's requirement by dexmedetomidine 0.2-0.7 µg/kg/h). Primary outcome was the subjective sleep quality at surgery night which was evaluated by Richards Campbell Sleep Questionnaire (RCSQ). Secondary outcomes included RCSQ scores at postoperative first and second nights and numeric rating scale pain intensity within first 3 days after surgery. RESULTS: RCSQ score at surgery night was 59 (28, 75) in remimazolam group which was comparable with 53 (28, 67) in routine group (median difference 6, 95% CI - 6 to 16, P = 0.315). After adjustment of confounders, preoperative high Pittsburg sleep quality index was associated worse RCSQ score (P = 0.032), but not remimazolam (P = 0.754). RCSQ score at postoperative first night [69 (56, 85) vs. 70 (54, 80), P = 0.472] and second night [80 (68, 87) vs. 76 (64, 84), P = 0.066] were equivalent between two groups. Safety outcomes were comparable between the two groups. CONCLUSIONS: Intraoperative remimazolam did not significantly improve postoperative sleep quality in elderly patients undergoing total joint arthroplasty. But it is proved to be effective and safe for moderate sedation in these patients. CLINICAL TRIAL NUMBER AND REGISTRY URL: ChiCTR2000041286 ( www.chictr.org.cn ).

Impact of Dexmedetomidine on Long-term Outcomes After Noncardiac Surgery in Elderly: 3-Year Follow-up of a Randomized Controlled Trial.

OBJECTIVES: The aim was to compare the long-term outcomes of low-dose dexmedetomidine versus placebo in a randomized controlled trial (ChiCTR-TRC-10000802). BACKGROUND: Low-dose dexmedetomidine infusion decreased delirium occurrence within 1 week after surgery in elderly admitted to the intensive care unit (ICU) after noncardiac surgery, but the long-term outcome of this intervention is unknown. METHODS: Patients or their family members were telephone-interviewed for a 3-year follow-up data collection of survival, cognitive function assessed with the modified Telephone Interview for Cognitive Status, and quality of life evaluated with the World Health Organization Quality of Life. RESULTS: Of the 700 patients, 23 (3.3%) were lost at 3-year follow-up. The 3-year overall survival was not statistically different between the dexmedetomidine and placebo groups [114 deaths vs 122/350; hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.68-1.13, P = 0.303]. The survival rates at 6 months, 1 year, and 2 years were significantly higher in the dexmedetomidine than in the placebo group (rate difference of 5.2%, 5.3%, and 6.7% respectively; all P < 0.05). The remaining 98.4% (434/441) 3-year survivors, the dexmedetomidine group, had significantly better cognitive function (mean difference 4.7, 95% CI 3.8-5.6, P < 0.0001) and quality of life (physical domain: 13.6 [10.6-16.6]; psychological domain: 15.2 [12.5-18.0]; social relationship domain: 8.1 [5.5-10.7]; environment domain: 13.3 [10.9-15.7]; all P < 0.0001) than in the placebo group. CONCLUSIONS: For elderly admitted to ICU after noncardiac surgery, low-dose dexmedetomidine infusion did not significantly change 3-year overall survival, but increased survival up to 2 years, and improved cognitive function and quality of life in 3-year survivors.

Handover of anesthesia care is associated with an increased risk of delirium in elderly after major noncardiac surgery: results of a secondary analysis.

In patients undergoing major surgery, complete handover of intraoperative anesthesia care is associated with adverse postoperative outcomes including high mortality and more major complications. The purpose of this study was to explore the association between the intraoperative complete handover between anesthesiologists and the occurrence of postoperative delirium. This was a secondary analysis of the database of a previously published clinical trial. Seven hundred patients aged 65 years or older, who were admitted to the intensive care unit after noncardiac surgery, were included. Delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit twice daily during the first 7 postoperative days. Other postoperative outcomes were also monitored. The association between the intraoperative complete handover of anesthesia care and the development of postoperative delirium was analyzed with a logistic regression model. Of the 700 enrolled patients, 111 (15.9%) developed postoperative delirium within 7 days. After correction for confounding factors, intraoperative complete handover between anesthesiologists was associated with an increased risk of postoperative delirium (OR 1.787, 95% CI 1.012-3.155, P = 0.046). Patients with intraoperative complete handover also had higher incidence of non-delirium complications (P = 0.003) and stayed longer in hospital after surgery (P = 0.002). For elderly patients admitted to the intensive care unit after noncardiac surgery, intraoperative complete handover of anesthesia care was associated with an increased risk of postoperative delirium. Chinese Clinical Trial Registry ( http://www.chictr.org.cn ): ChiCTR-TRC-10000802.

Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery. METHODS: We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0·1 µg/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-10000802. FINDINGS: Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0·35, 95% CI 0·22-0·54; p<0·0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0·50, 0·32-0·78; p=0·002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0·44, 0·26-0·75; p=0·002). Occurrence of hypotension and bradycardia did not differ between groups. INTERPRETATION: For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe. FUNDING: Braun Anaesthesia Scientific Research Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China.

Parecoxib Supplementation to Morphine Analgesia Decreases Incidence of Delirium in Elderly Patients After Hip or Knee Replacement Surgery: A Randomized Controlled Trial.

BACKGROUND: Severe pain and high-dose opioids are both associated with increased risk of postoperative delirium. The authors investigated whether parecoxib-supplemented IV morphine analgesia could decrease the incidence of delirium in elderly patients after total hip or knee replacement surgery. METHODS: In a randomized, double-blind, 2-center trial, patients of 60 years or older who underwent elective total hip or knee replacement surgery were assigned in a 1:1 ratio to receive either parecoxib (40 mg at the end of surgery and then every 12 hours for 3 days) or placebo (normal saline). All patients received combined spinal-epidural anesthesia during surgery and IV morphine for postoperative analgesia. The primary outcome was the incidence of delirium within 5 days after surgery. RESULTS: Between January 2011 and May 2013, 620 patients were enrolled and were included in the intention-to-treat and safety analyses. The incidence of delirium was significantly reduced from 11.0% (34/310) with placebo to 6.2% (19/310) with parecoxib (relative risk 0.56, 95% confidence interval 0.33-0.96, P = .031). The severity of pain and the cumulative consumptions of morphine at 24, 48, and 72 hours after surgery were significantly lower with parecoxib than with placebo (all P < .001), although the differences were small. There was no difference in the incidence of postoperative complications between the 2 groups (12.3% [38/310] with placebo versus 11.6% [36/310] with parecoxib; P = .80). CONCLUSIONS: For low-risk elderly patients undergoing elective total hip or knee replacement surgery, multidose parecoxib supplemented to IV morphine decreased the incidence of postoperative delirium without increasing adverse events.

Low-dose Dexmedetomidine Improves Sleep Quality Pattern in Elderly Patients after Noncardiac Surgery in the Intensive Care Unit: A Pilot Randomized Controlled Trial.

BACKGROUND: Patients admitted to the intensive care unit (ICU) after surgery often develop sleep disturbances. The authors tested the hypothesis that low-dose dexmedetomidine infusion could improve sleep architecture in nonmechanically ventilated elderly patients in the ICU after surgery. METHODS: This was a pilot, randomized controlled trial. Seventy-six patients age 65 yr or older who were admitted to the ICU after noncardiac surgery and did not require mechanical ventilation were randomized to receive dexmedetomidine (continuous infusion at a rate of 0.1 µg kg h; n = 38) or placebo (n = 38) for 15 h, i.e., from 5:00 PM on the day of surgery until 8:00 AM on the first day after surgery. Polysomnogram was monitored during the period of study-drug infusion. The primary endpoint was the percentage of stage 2 non-rapid eye movement (stage N2) sleep. RESULTS: Complete polysomnogram recordings were obtained in 61 patients (30 in the placebo group and 31 in the dexmedetomidine group). Dexmedetomidine infusion increased the percentage of stage N2 sleep from median 15.8% (interquartile range, 1.3 to 62.8) with placebo to 43.5% (16.6 to 80.2) with dexmedetomidine (difference, 14.7%; 95% CI, 0.0 to 31.9; P = 0.048); it also prolonged the total sleep time, decreased the percentage of stage N1 sleep, increased the sleep efficiency, and improved the subjective sleep quality. Dexmedetomidine increased the incidence of hypotension without significant intervention. CONCLUSIONS: In nonmechanically ventilated elderly patients who were admitted to the ICU after noncardiac surgery, the prophylactic low-dose dexmedetomidine infusion may improve overall sleep quality.

Epidural morphine improves postoperative analgesia in patients after total knee arthroplasty: A randomized controlled trial.

BACKGROUND: Patients after total knee arthroplasty (TKA) often develop moderate to severe pain. This study compared the analgesic effect of low-dose epidural morphine vs. a comparable saline injection in patients following TKA surgery. METHODS: This randomized, double-blinded, and placebo-controlled trial was conducted in a tertiary hospital in Beijing between July 1, 2017 and May 30, 2018. One hundred and ten patients following TKA under combined spinal-epidural anesthesia were randomized to receive either epidural morphine (2 mg diluted to 5 ml normal saline, the epidural morphine group) or placebo (5 ml normal saline, the placebo group). For all patients, single-injection femoral nerve block was performed, and a supplementary patient-controlled intravenous analgesia pump was provided. The severity of pain was assessed with the numerical rating scale (NRS, an 11-point scale where 0 = no pain and 10 = the worst pain) at 6, 12, 24, 36, and 48 hours after surgery. The primary endpoint was moderate to severe pain (NRS pain score ≥4) within 48 hours after surgery. RESULTS: The percentage with moderate to severe pain within 48 hours was lower in the epidural morphine group than in the placebo group (58.2% [32/55] with epidural morphine vs. 76.4% [42/55] with placebo; OR 0.43, 95% CI 0.19-0.98; p = 0.042). Furthermore, the cumulative morphine consumption within 48 hours was lower (18.4±6.1 mg vs. 22.4±7.3 mg; p = 0.002) whereas the mental component summary score of 30-day quality of life was higher (63.8±2.9 vs. 61.9±4.2; p = 0.008) in the epidural morphine group than in the placebo group. CONCLUSIONS: For patients following TKA, the addition of epidural morphine to single-injection femoral nerve block improves the quality of analgesia within 48 hours, without increasing adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT03203967.

Preoperative severe hypoalbuminemia is associated with an increased risk of postoperative delirium in elderly patients: Results of a secondary analysis.

PURPOSE: To explore the association between the severity of preoperative hypoalbuminemia and the occurrence of postoperative delirium. MATERIALS AND METHODS: This was a secondary analysis of the database from a previously conducted clinical trial. 700 elderly patients (age ≥65years) who were admitted to intensive care unit (ICU) after noncardiac surgery were included. Delirium was assessed with the Confusion Assessment Method for the ICU twice daily during the first 7days postoperatively. Other outcomes were also monitored. The relationship between preoperative albumin level and postoperative delirium were analyzed using a logistic regression model. RESULTS: 111 of 700 patients (15.9%) developed postoperative delirium. When compared with normal albumin level (>40.0g/L), severe (≤30.0g/L: OR 2.727, 95% CI 1.283-5.797, P=0.009), but not mild (35.1-40.0g/L: OR 1.175, 95% CI 0.679-2.032, P=0.565) or moderate (30.1-35.0g/L: OR 1.674, 95% CI 0.897-3.122, P=0.105) hypoalbuminemia was associated with an increased risk of postoperative delirium. Preoperative severe hypoalbuminemia was also associated with prolonged mechanical ventilation, increased non-delirium complications, and prolonged ICU and hospital stay after surgery. CONCLUSIONS: Preoperative severe hypoalbuminemia (≤30.0g/L) was associated with an increased risk of postoperative delirium and worse outcomes. TRIAL REGISTRATION: Chinese Clinical Trial Registry, www.chictr.org.cn, ChiCTR-TRC-10000802.

Astragalus polysaccharide promotes the release of mature granulocytes through the L-selectin signaling pathway.

BACKGROUND: This study aims to investigate the leukogenic effect of astragalus polysaccharide (APS), to compare its effect of increasing the numbers of mature granulocytes with that of granulocyte colony-stimulating factor (G-CSF), and to investigate the mechanism. METHODS: Rats were arbitrarily grouped into four groups (control, cyclophosphamide (CTX), CTX + APS, and CTX + G-CSF groups), and each group was then arbitrarily divided into five subgroups according to the time period since CTX infusion (0, 4, 7, 10, and 14 days). The expression of leukocyte selectin (L-selectin), its ligand, and shedding-related protease on granulocytes was analyzed. Leukocyte counts were obtained. Chemotactic capacity of polymorphonuclear leukocytes (PMNLs) was assessed. RESULTS: Both APS and G-CSF restored the expression of L-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), CD11b/CD18, and ADAM17 to normal levels (P > 0.05 vs. control group on each time point), with APS eliciting a greater effect than G-CSF (P = 0.005 on day 7, P < 0.001 on day 10 and 14 for L-selectin; P = 0.038 on day 7, P = 0.001 on day 10, P < 0.001 on day 14 for PSGL-1; P < 0.001 on day 7, 10 and 14 for ADAM17; P < 0.001 on day 7, 10, and 14 for CD11b/CD18). The percentages of the bands and segmented bone marrow (BM) cells in myeloid neutrophils were higher in the CTX + APS group than in the CTX group on day 7 (P = 0.030) and reached normal levels on day 10 (P = 0.547) and 14 (P = 0.431) vs. control group. The ability of APS to increase numbers of PMNLs in peripheral blood after chemotherapy was significantly superior to that of G-CSF 7 days after chemotherapy (P = 0.029 on day 10, P = 0.006 on day 14). Moreover, APS more significantly improved the chemotactic ability of PMNLs among mature BM granulocytes and peripheral blood neutrophils after chemotherapy than did G-CSF (P < 0.001 on day 7, P = 0.001 on day 10 and P = 0.005 on day 14). CONCLUSIONS: APS promoted the differentiation and chemotactic ability of BM granulocytes via the L-selectin signaling pathway.

[A mouse model of myelofibrosis induced by high dose of recombinant human erythropoietin].

Tn order to set up a mouse model of myelofibrosis (MF) induced with high dose recombinant human erythropoietin (rhEPO). 60 mice were collected and divided into EPO and control groups, the former was injected with rhEPO and the latter with normal saline intraperitoneally. 5 mice from each group were executed on day 6, 30, 60, 90, 120 and 150 respectively. Their WBC count, Hb level, MCV, RDW and platelet amount were measured by automatic blood cell analyzer; CD34(+) cell ratio in bone marrow were analyzed by flow cytometry; liver and spleen coefficients were measured; pathological changes of liver, spleen, femur were observed by HE staining and reticular fibers staining; cortex thickness, femoral canal diameter and lumbar spine density were determined by computerized tomography (CT). The results indicated that as compared with normal control group in EPO induced group, WBC count was increased slightly in whole period, but without statistic significance (p > 0.05), Hb level and RDW increased at day 6 and 30 significantly (p < 0.05), MCV increased at day 6 significantly (p < 0.05), but platelet amount decreased significantly at all time points (p < 0.05). Most mice in EPO-induced group had hepatomegalia and their liver and spleen coefficient increased significantly at day 60 (p < 0.05), while most mice had splenomegaly and its coefficient was increased significantly at all time-points (p < 0.05). CD43(+) cell ratio of EPO group increased significantly in whole period (p < 0.05). CT scanning displayed femoral cortical thickening, medulla canal narrowing and lumbar spine density increasing at day 150, meanwhile, HE staining and reticular fiber staining showed the fatty degeneration or vacuolization in liver, splenomegaly with megakaryocytic proliferation, femur bone marrow fibrosis and osteosclerosis. It is concluded that the mouse induced by high dose of rhEPO displays the myelofibrosis associated with splenic extramedullary hemopoiesis, and this study is useful to establish a practical MF model, and to explore its pathological mechanism.

Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of pemetrexed plus cisplatin/carboplatin in locally advanced or metastatic non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy. METHODS: Fifty-three locally advanced or metastatic non-small cell lung cancer patients previously treated with platinum-based chemotherapy received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin area under the curve (AUC) 5 every 21 days, with dexamethasone, folic acid and vitamin B12 being administered. RESULTS: Median age was 52 years. Eastern Cooperative Oncology Group (ECOG) performance status was 0-2. Thirty-eight patients had stage IV tumors. Thirty-seven patients had adenocarcinoma (including 6 alveolar carcinoma patients), and fourteen patients had squamous cell carcinoma. Thirty-four patients were treated in second line, 15 in third line, and 4 in fourth line. Seven patients (13.2%) showed partial response; Thirty-six (67.9%) had stable disease. The median progression free survival time was 6.0 months and the median overall survival time was 10.0 months. The 1-year survival rate was 40.9%. Five (9.4%) and four (7.5%) patients experienced grade 3 or 4 leukopenia and thrombocytopenia, respectively. Nonhematological toxicities included grade 3 nausea/vomiting in 1 patient (1.9%), grade 3 rash in 1 patient, grade 4 diarrhea in 1 patient (1.9%) and grade 4 creatinine increase in 1 patient (1.9%). CONCLUSION: Locally advanced or metastatic NSCLC patients previously treated with platinum-based chemotherapy could benefit from pemetrexed plus cisplatin/carboplatin chemotherapy with tolerable adverse events.

[Intra-bone marrow infusion of human cord blood hematopoietic stem/progenitor cells improves hematopoietic reconstitution in NOD-SCID mice].

The purpose of this study was to explore the effect of intra-bone marrow infusion (iBMI) of cord blood (CB)-derived hematopoietic stem/progenitor cells (HS/PCs) on human hematopoietic reconstitution in xenotransplanted NOD-SCID mouse model. Aliquots containing 5 x 10(5) CB CD34(+) cells were transplanted into sublethally irradiated NOD-SCID mouse via intravenous infusion (iVI) or iBMI routes. 64 female NOD-SCID mice were divided randomly into 3 groups: iBMI group, iVI group and negative control group. The engraftment levels of human hematopoietic cells at 3, 5 and 8 weeks after xenotransplantation were detected by fluorescence-activated cell sorter (FACS), polymerase chain reaction (PCR), immunohistochemistry and HPC colony formation assay, and long-term hematopoietic reconstitution capacity of HSC was tested by secondary transplantation. The results showed that the percentages of human CD45(+) cells in bone marrow, peripheral blood and spleen of recipient in iBMI group at 8 weeks after xenotransplantation were significantly higher than those in iVI group (p < 0.05). HS/PCs given through both iVI and iBMI methods had the ability of multilineage differentiation, the percentages of CD45(+)CD19(+) cells, CD45(+)CD33(+) cells, CD45(+)CD56(+) cells and CD45(+)CD34(+) cells of recipient bone marrow in iBMI group at 8 weeks after xenotransplantation were significantly higher than those in iVI group (p < 0.05), while other lineages in iBMI group were also higher than that in iVI group (p > 0.05). alpha-satellite-specific fragment of human chromosome 17 could be detected by PCR in liver, spleen, lung, peripheral blood and bone marrow cells of long-term survival recipients in both iVI and iBMI groups. Human CD45 antigen could be detected by immunohistochemical method in spleen, liver and lung of recipients in iBMI group at 8 weeks after xenotransplantation. Total colony count in iBMI group at 8 weeks after xenotransplantation was significantly higher than that in iVI group (p < 0.05). alpha-satellite-specific fragment of human chromosome 17 could be detected in all above organs of both group recipients at 6 weeks after secondary xenotransplantation. It is concluded that iBMI of CB CD34(+) cells improves hematopoietic reconstitution in xenotransplanted NOD-SCID mouse model.