Simvastatin attenuates sepsis-induced blood-brain barrier integrity loss.

BACKGROUND: Systemic inflammation and oxidative stress are crucial in mediating blood-brain barrier (BBB) integrity loss during sepsis. Simvastatin possess potent anti-inflammation and antioxidation capacity. We sought to elucidate whether an acute bolus of simvastatin could mitigate BBB integrity loss in a rodent model of polymicrobial sepsis. METHODS: A total of 96 adult male rats (200-250 g) were randomized to receive cecal ligation and puncture (CLP), CLP plus simvastatin, sham operation, or sham operation plus simvastatin (n = 24 in each group). After maintaining for 24 h, BBB integrity in the surviving rats was determined. RESULTS: CLP significantly induced BBB integrity loss, as grading of Evans blue staining of the brains, BBB permeability to Evans blue dye, and brain edema levels in rats receiving CLP were significantly higher than those receiving sham operation. In contrast, grading of Evans blue staining (P = 0.020), BBB permeability to Evans blue dye (P = 0.031), and brain edema levels (P = 0.009) in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP alone. Tight junction proteins claudin-3 and claudin-5 in endothelial cells are major structural components of BBB. Our data revealed that concentrations of claudin-3 and claudin-5 in rats receiving CLP were significantly lower than those receiving CLP plus simvastatin (P = 0.010 and 0.007). Immunohistochemistry further revealed significant fragmentation of claudin-3 and claudin-5 in rats receiving CLP. Moreover, levels of claudin-3 and claudin-5 fragmentation in rats receiving CLP plus simvastatin were significantly lower than those receiving CLP. CONCLUSIONS: Simvastatin mitigates BBB integrity loss in a rodent model of polymicrobial sepsis.

Anti-inflammation effects of naloxone involve phosphoinositide 3-kinase delta and gamma.

BACKGROUND: Phosphoinositide 3-kinase (PI3K) delta and gamma (the p110δ and p110γ isoforms of PI3K) actively participate in the process of inflammation. We sought to elucidate the possible roles of PI3Kδ and PI3Kγ in mediating the anti-inflammation effects of naloxone. MATERIALS AND METHODS: Murine macrophages were treated with endotoxin, endotoxin plus naloxone, or endotoxin plus naloxone plus the PI3K inhibitors (the PI3Kδ inhibitor IC87114, the PI3Kγ inhibitor AS252424, or IC87114 plus AS252424) and denoted as the LPS, LPS + N, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS group, respectively. Differences in inflammatory molecules and levels of nuclear factor-κB (NF-κB) activation and Akt activation (indicator of PI3K activity) among these groups were compared. RESULTS: The concentrations of inflammatory molecules (macrophage inflammatory protein 2, tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2/prostaglandin E2) and the levels of NF-κB activation (p-NF-κB p65 and p-inhibitor-κB concentrations and NF-κB-DNA binding activity) of the LPS + N group were significantly lower than those of the LPS group (all P < 0.001). These data confirmed the anti-inflammation effects of naloxone. Moreover, the anti-inflammation effects of naloxone could be counteracted by the inhibitors of PI3Kδ and PI3Kγ, as the concentrations of inflammatory molecules and the levels of NF-κB activation of the LPS + N group were significantly lower than those of the LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). In contrast, the concentration of phosphorylated Akt of the LPS + N group was significantly higher than those of the LPS, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). CONCLUSIONS: PI3Kδ and PI3Kγ play crucial roles in mediating the anti-inflammation effects of naloxone.

Agreement of cardiac output measurement between pulse contour analysis and thermodilution in various body positions: a porcine study.

BACKGROUND: We elucidated the effects of various body positions on the agreement of cardiac output (CO) measurement between pulse contour analysis with the PiCCO monitor and thermodilution with pulmonary artery catheterization. METHODS: Fifteen anesthetized and mechanically ventilated pigs (40 ± 2 kg) were sequentially placed in various positions to facilitate simultaneous CO measurement. Between-methods agreement was assessed using the Bland-Altman method. Trending ability was assessed using Pearson product-moment correlation coefficient analysis. RESULTS: In supine, reverse Trendelenburg, Trendelenburg, and left lateral decubitus (lateral) positions, CO measured by these two methods was comparable (4.9 ± 1.5 versus 4.6 ± 1.6 L/min, 4.6 ± 2.2 versus 4.8 ± 1.8 L/min, 5.1 ± 2.1 versus 4.9 ± 2.1 L/min, and 5.4 ± 1.8 versus 5.0 ± 1.6 L/min; all P > 0.05). Mean bias between methods and limits of agreement (percentage error) were 0.3 ± 2.9 L/min (61%), -0.3 ± 3.3 L/min (71%), 0.1 ± 4.1 L/min (77%), and 0.5 ± 3.7 L/min (71%). Directional changes of paired CO revealed 66% (reverse Trendelenburg), 57% (Trendelenburg), and 66% (lateral) concordance. The correlation coefficient (r(2)) was 0.199, 0.127, and 0.108. For paired CO ≤6 L/min, mean bias between methods and limits of agreement (percentage error) were 0.2 ± 1.0 L/min (25%), -0.1 ± 1.0 L/min (28%), 0.2 ± 1.1 L/min (29%), and 0.5 ± 0.9 L/min (23%). Directional changes of paired CO revealed 84% (reverse Trendelenburg), 76% (Trendelenburg), and 65% (lateral) concordance. The correlation coefficient (r2) was 0.583, 0.626, and 0.213. CONCLUSIONS: The mean CO measured by pulse contour analysis and thermodilution did not agree well in various body positions. Moreover, the measurements tended to trend differently in response to positional changes. For paired CO ≤6 L/min, however, the between-methods agreement and the trending ability improved significantly.

Effects of opioids administered via intravenous or epidural patient-controlled analgesia after caesarean section: A network meta-analysis of randomised controlled trials.

Background: Post-caesarean section analgesia is important physiologically and psychologically for both mothers and infants. Patient-controlled analgesia is a well-established method of administering opioids for postoperative pain. However, to date, no study has systematically investigated the effects of opioids administered through intravenous patient-controlled analgesia (IVPCA) or patient-controlled epidural analgesia (PCEA) in parturients who have undergone caesarean section. Methods: This systematic review and network meta-analysis aimed to evaluate the analgesic and adverse effects of opioids administered via IVPCA or PCEA in parturients who have undergone a caesarean section. PubMed, Embase, Scopus, Web of Science, and Cochrane Library were searched from inception through 02 10, 2022 for relevant records. Randomised controlled trials (RCTs) that compared opioids administered via IVPCA or PCEA and reported outcomes of interest were included. Studies were excluded if the solution for patient-controlled analgesia contained antiemetics and/or other analgesics in addition to opioids. The methodological quality of RCTs was assessed using the revised Cochrane Risk of Bias Tool. Summary data were extracted from each eligible study. The primary outcome was pain intensity, and the secondary outcomes were opioid-related adverse effects. Frequentist network meta-analyses were performed using a contrast-based random-effects model. This study is registered with PROSPERO, CRD42021254040. Findings: Twenty-three studies with 2589 parturients were included. Compared with IVPCA morphine as a reference treatment, PCEA fentanyl had better analgesic effects at 4 h (mean difference [MD] in the visual analogue scale score, -0.75; 95% confidence interval [CI] [-1.16, -0.34]) and 8 h (MD, -0.93; 95% CI [-1.57, -0.28]) and yielded lower odds of developing nausea/vomiting (odds ratio [OR], 0.27; 95% CI [0.09, 0.80]) and sedation/drowsiness (OR, 0.22; 95% CI [0.11, 0.45]). However, PCEA fentanyl may be more likely to cause pruritus than IVPCA treatments. Interpretation: Considering the analgesic efficacy; opioid-induced nausea, vomiting, and sedation; and the well-being of breastfed infants, PCEA fentanyl may be the treatment of choice for post-caesarean section analgesia. Funding: The Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (TCRD-TPE-111-27).

Effects of Short-Acting Opioids on Intraocular Pressure during General Anesthesia: Systematic Review and Network Meta-Analysis.

Intraocular pressure (IOP) is crucial to the well-being of eyes. During anesthesia, the administration of succinylcholine and endotracheal intubation are associated with an increase in IOP, which may be attenuated by short-acting opioids. However, the drug of choice among the commonly used short-acting opioids is unclear. This study aimed to evaluate the effects of fentanyl, sufentanil, alfentanil, and remifentanil on IOP measured after the administration of succinylcholine and after endotracheal intubation in patients undergoing general anesthesia. Five databases were searched. Randomized controlled trials (RCTs) that compared short-acting opioids and reported at least one of the clinical outcomes of interest were included. Nine RCTs with 357 patients were included. Remifentanil (1 µg kg-1) more effectively alleviated the increase in IOP than the placebo after the administration of succinylcholine [mean difference (MD) of IOP, -3.64; confidence interval (CI), -5.47 to -1.81 and after endotracheal intubation (MD, -9.71; CI, -11.91 to -7.51). Remifentanil (1 µg kg-1) ranked the best in terms of both attenuating the increase in IOP after the administration of succinylcholine [surface under the cumulative ranking curve (SUCRA), 0.91; normalized entropy (NE), 0.47; and after endotracheal intubation (SUCRA, 0.89; NE, 0.54) among all of the treatments. Remifentanil (1 µg kg-1) should be considered the drug of choice in the circumstances where increased IOP is a great concern.

Dimethyl Sulfoxide Attenuates Acute Lung Injury Induced by Hemorrhagic Shock/Resuscitation in Rats.

Inflammation following hemorrhagic shock/resuscitation (HS/RES) induces acute lung injury (ALI). Dimethyl sulfoxide (DMSO) possesses anti-inflammatory and antioxidative capacities. We sought to clarify whether DMSO could attenuate ALI induced by HS/RES. Male Sprague-Dawley rats were allocated to receive either a sham operation, sham plus DMSO, HS/RES, or HS/RES plus DMSO, and these were denoted as the Sham, Sham + DMSO, HS/RES, or HS/RES + DMSO group, respectively (n = 12 in each group). HS/RES was achieved by drawing blood to lower mean arterial pressure (40-45 mmHg for 60 min) followed by reinfusion with shed blood/saline mixtures. All rats received an intravenous injection of normal saline or DMSO immediately before resuscitation or at matching points relative to the sham groups. Arterial blood gas and histological assays (including histopathology, neutrophil infiltration, and lung water content) confirmed that HS/RES induced ALI. Significant increases in pulmonary expression of tumor necrosis factor-α (TNF-α), malondialdehyde, nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) confirmed that HS/RES induced pulmonary inflammation and oxidative stress. DMSO significantly attenuated the pulmonary inflammation and ALI induced by HS/RES. The mechanisms for this may involve reducing inflammation and oxidative stress through inhibition of pulmonary NF-κB, TNF-α, iNOS, and COX-2 expression.