Does a combined intravenous-volatile anesthesia offer advantages compared to an intravenous or volatile anesthesia alone

$\bf Background$ In anesthesia, additive drug interactions are used for reducing dose and dose-dependent side-effects. The combination of propofol with volatile anesthetics is rather unusual but might have advantages compared to the single use regarding PONV, time to extubation, movement during surgery and postoperative pain perception. $\bf Methods$ We searched PubMed, Scopus, Web of Science, and CENTRAL for relevant studies comparing combined intravenous volatile anesthesia with total intravenous or balanced anesthesia. The studies identified were summarized in a meta-analysis with the standardized mean difference or risk ratio as the effect size. $\bf Results$ Ten studies provided data. The risk for PONV in the recovery room was significantly reduced for a combined anesthesia compared to a balanced anesthesia (RR 0.657, CI 0.502–0.860, $\it p$-value 0.002). There was no significant difference detected either in the time to extubation or in pain perception. Movement during surgery was significantly reduced for a combined compared to a total intravenous anesthesia (RR 0.241, CI 0.135–0.428, $\it p$-value 0.000). $\bf Conclusions$ The combination of propofol and volatiles may have some advantages in the early occurrence of PONV compared to a balanced anesthesia. To sufficiently evaluate potential advantages of a combination of volatiles and propofol further high-quality trials are needed

Resveratrol therapy improves liver function via estrogen-receptors after hemorrhagic shock in rats

$\bf Background:$ Resveratrol may improve organ dysfunction after experimental hemorrhagic or septic shock, and some of these effects appear to be mediated by estrogen receptors. However, the influence of resveratrol on liver function and hepatic microcirculation after hemorrhagic shock is unknown, and a presumed mediation via estrogen receptors has not been investigated in this context. $\bf Methods:$ Male Sprague-Dawley rats (200-300g, n = 14/group) underwent hemorrhagic shock for 90 min (MAP 35$\pm$5 mmHg) and were resuscitated with shed blood and Ringer's solution. Animals were treated intravenously with vehicle (1% EtOH), resveratrol (0.2 mg/kg), the unselective estrogen receptor antagonist ICI 182,780 (0.05 mg/kg) or resveratrol + ICI 182,780 prior to retransfusion. Sham-operated animals did not undergo hemorrhage but were treated likewise. After 2 hours of reperfusion, liver function was assessed either by plasma disappearance rate of indocyanine green ($PDR_{ICG}$) or evaluation of hepatic perfusion and hepatic integrity by intravital microscopy, serum enzyme as well as cytokine levels. $\bf Results:$ Compared to vehicle controls, administration of resveratrol significantly improved PDRICG, hepatic perfusion index and hepatic integrity after hemorrhagic shock. The co-administration of ICI 182,780 completely abolished the protective effect only with regard to liver function. $\bf Conclusions:$ This study shows that resveratrol may improve liver function and hepatocellular integrity after hemorrhagic shock in rats; estrogen receptors mediate these effects at least partially

Impact of carbohydrate-reduced nutrition in septic patients on ICU

$\bf Introduction$ Sepsis is defined as detrimental immune response to an infection. This overwhelming reaction often abolishes a normal reconstitution of the immune cell homeostasis that in turn increases the risk for further complications. Recent studies revealed a favourable impact of ketone bodies on resolution of inflammation. Thus, a ketogenic diet may provide an easy-to-apply and cost-effective treatment option potentially alleviating sepsis-evoked harm. This study is designed to assess the feasibility, efficiency and safety of a ketogenic diet in septic patients. $\textbf {Methods and analysis}$ This monocentric study is a randomised, controlled and open-label trial, which is conducted on an intensive care unit of a German university hospital. As intervention enteral nutrition with reduced amount of carbohydrates (ketogenic) or standard enteral nutrition (control) is applied. The primary endpoint is the detection of ketone bodies in patients’ blood and urine samples. As secondary endpoints, the impact on important safety-relevant issues (eg, glucose metabolism, lactate serum concentration, incidence of metabolic acidosis, thyroid function and 30-day mortality) and the effect on the immune system are analysed. $\textbf {Ethics and dissemination}$ The study has received the following approvals: Ethics Committee of the Medical Faculty of Ruhr-University Bochum (No. 18-6557-BR). Results will be made available to critical care survivors, their caregivers, the funders, the critical care societies and other researchers by publication in a peer-reviewed journal

Therapeutic suggestions during general anesthesia reduce postoperative nausea and vomiting in high-risk patients

Postoperative nausea and vomiting (PONV) are one of the most adverse events after general anesthesia, a distressing experience, and pose a risk to the patient. Despite advances in drug prophylaxis and PONV treatment, the incidence remains high and additional non-pharmacological treatments are needed. In this $\textit {post hoc}$ analysis of a recently published double-blind multicenter randomized controlled trial on the efficacy of intraoperative therapeutic suggestions on postoperative opioid dosage, we analyzed the effects of intraoperative therapeutic suggestions on PONV. We focus on patients with a high risk of PONV (Apfel risk score of 3–4) and distinguished early (first two postoperative hours) and delayed PONV (2–24 h). A total of 385 patients with a moderate or high risk for PONV were included. The incidence of early and delayed PONV was reduced (22.7–18.3 and 29.9–24.1%, respectively), without statistical significance, whereas in high-risk patients ($\it n$ = 180) their incidence was nearly halved, 17.2 vs. 31.2% ($\it p$ = 0.030) and 20.7 vs. 34.4% ($\it p$ = 0.040), corresponding to a number needed to treat of 7 to avoid PONV. In addition, there was a significant reduction in PONV severity. In a multivariate logistic regression model, assignment to the control group (OR 2.2; 95% CI: 1.1–4.8) was identified as an independent predictor of the occurrence of early PONV. Our results indicate that intraoperative therapeutic suggestions can significantly reduce the incidence of PONV in high-risk patients. This encourages the expansion of therapeutic suggestions under general anesthesia, which are inexpensive and virtually free of side effects

The impact of the COVID-19 pandemic on non-COVID induced sepsis survival

$\bf Background:$ The COVID-19 pandemic has taken a toll on health care systems worldwide, which has led to increased mortality of different diseases like myocardial infarction. This is most likely due to three factors. First, an increased workload per nurse ratio, a factor associated with mortality. Second, patients presenting with COVID-19-like symptoms are isolated, which also decreases survival in cases of emergency. And third, patients hesitate to see a doctor or present themselves at a hospital. To assess if this is also true for sepsis patients, we asked whether non-COVID-19 sepsis patients had an increased 30-day mortality during the COVID-19 pandemic. $\bf Methods:$ This is a post hoc analysis of the SepsisDataNet.NRW study, a multicentric, prospective study that includes septic patients fulfilling the SEPSIS-3 criteria. Within this study, we compared the 30-day mortality and disease severity of patients recruited pre-pandemic (recruited from March 2018 until February 2020) with non-COVID-19 septic patients recruited during the pandemic (recruited from March 2020 till December 2020). $\bf Results:$ Comparing septic patients recruited before the pandemic to those recruited during the pandemic, we found an increased raw 30-day mortality in sepsis-patients recruited during the pandemic (33% vs. 52%, $\it p$ = 0.004). We also found a significant difference in the severity of disease at recruitment (SOFA score pre-pandemic: 8 (5 - 11) vs. pandemic: 10 (8 - 13); $\it p$ < 0.001). When adjusted for this, the 30-day mortality rates were not significantly different between the two groups (52% vs. 52% pre-pandemic and pandemic, $\it p$ = 0.798). $\bf Conclusions:$ This led us to believe that the higher mortality of non-COVID19 sepsis patients during the pandemic might be attributed to a more severe septic disease at the time of recruitment. We note that patients may experience a delayed admission, as indicated by elevated SOFA scores. This could explain the higher mortality during the pandemic and we found no evidence for a diminished quality of care for critically ill sepsis patients in German intensive care units

The aquaporin 3 polymorphism (rs17553719) is associated with sepsis survival and correlated with IL-33 secretion

Sepsis is a common life-threatening disease caused by dysregulated immune response and metabolic acidosis which lead to organ failure. An abnormal expression of aquaporins plays an important role in organ failure. Additionally, genetic variants in aquaporins impact on the outcome in sepsis. Thus, we investigated the polymorphism (rs17553719) and expression of aquaporin-3 ($\it AQP3$) and correlated these measurements with the survival of sepsis patients. Accordingly, we collected blood samples on several days (plus clinical data) from 265 sepsis patients who stayed in different ICUs in Germany. Serum plasma, DNA, and RNA were then separated to detect the promotor genotypes of $\it AQP3$ mRNA expression of AQP3 and several cytokines. The results showed that the homozygote CC genotype exhibited a significant decrease in 30-day survival (38.9%) compared to the CT (66.15%) and TT genotypes (76.3%) ($\it p$ = 0.003). Moreover, $\it AQP3$ mRNA expression was significantly higher and nearly doubled in the CC compared to the CT ($\it p$ = 0.0044) and TT genotypes ($\it p$ = 0.018) on the day of study inclusion. This was accompanied by an increased IL-33 concentration in the CC genotype (day 0: $\it p$ = 0.0026 and day 3: $\it p$ = 0.008). In summary, the C allele of the $\it AQP3$ polymorphism (rs17553719) shows an association with increased $\it AQP3$ expression and IL-33 concentration accompanied by decreased survival in patients with sepsis

The distinctive activation of toll-like receptor 4 in human samples with sepsis

Clinical success of Toll-Like receptor-4 (TLR-4) antagonists in sepsis therapy has thus far been lacking. As inhibition of a receptor can only be useful if the receptor is active, stratification of patients with active TLR-4 would be desirable. Our aim was to establish an assay to quantify phosphorylated TLR-4 using the proximity ligation assay (PLA). HEK293 TLR4/MD2/CD14 as well as THP-1 cells were stimulated with LPS and the activation of TLR-4 was measured using the PLA. Furthermore, peripheral blood mononuclear cells (PBMCs) from 25 sepsis patients were used to show the feasibility of this assay in clinical material. Activation of TLR-4 in these samples was compared to the PBMCs of 11 healthy individuals. We could show a transient activation of TLR-4 in both cell lines. Five min after the LPS stimulation, the signal increased 6.7-fold in the HEK293 cells and 4.3-fold in the THP-1 cells. The assay also worked well in the PBMCs of septic patients. Phosphorylation of TLR-4 at study inclusion was 2.9 times higher in septic patients compared to healthy volunteers. To conclude, we established a diagnostic assay that is able to quantify the phosphorylation of TLR-4 in cell culture and in clinical samples of sepsis patients. This makes large-scale stratification of sepsis patients for their TLR-4 activation status possible

Methazolamide reduces the AQP5 mRNA expression and immune cell migration

Sepsis is a life-threatening condition caused by the dysregulated host response to infection. Novel therapeutic options are urgently needed and aquaporin inhibitors could suffice as aquaporin 5 $\it (Aqp5)$ knockdown provided enhanced sepsis survival in a murine sepsis model. Potential AQP5 inhibitors provide sulfonamides and their derivatives. In this study, we tested the hypothesis that sulfonamides reduce AQP5 expression in different conditions. The impact of sulfonamides on AQP5 expression and immune cell migration was examined in cell lines REH and RAW 264.7 by qPCR, Western blot and migration assay. Subsequently, whether furosemide and methazolamide are capable of reducing AQP5 expression after LPS incubation was investigated in whole blood samples of healthy volunteers. Incubation with methazolamide ($10^{−5}$ M) and furosemide ($10^{−6}$ M) reduced $\it AQP5$ mRNA and protein expression by about 30% in REH cells. Pre-incubation of the cells with methazolamide reduced cell migration towards SDF1-$\alpha$ compared to non-preincubated cells to control level. Pre-incubation with methazolamide in PBMCs led to a reduction in LPS-induced $\it AQP5$ expression compared to control levels, while furosemide failed to reduce it. Methazolamide appears to reduce $\it AQP5$ expression and migration of immune cells. However, after LPS administration, the reduction in $\it AQP5$ expression by methazolamide is no longer possible. Hence, our study indicates that methazolamide is capable of reducing $\it AQP5$ expression and has the potential to be used in sepsis prophylaxis

Human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis

$\bf Background$ Sepsis is one of the leading causes of death. Treatment attempts targeting the immune response regularly fail in clinical trials. As HCMV latency can modulate the immune response and changes the immune cell composition, we hypothesized that HCMV serostatus affects mortality in sepsis patients. $\bf Methods$ We determined the HCMV serostatus (i.e., latency) of 410 prospectively enrolled patients of the multicenter SepsisDataNet.NRW study. Patients were recruited according to the SEPSIS-3 criteria and clinical data were recorded in an observational approach. We quantified 13 cytokines at Days 1, 4, and 8 after enrollment. Proteomics data were analyzed from the plasma samples of 171 patients. $\bf Results$ The 30-day mortality was higher in HCMV-seropositive patients than in seronegative sepsis patients (38% vs. 25%, respectively; $\it p$ = 0.008; HR, 1.656; 95% CI 1.135–2.417). This effect was observed independent of age ($\it p$ = 0.010; HR, 1.673; 95% CI 1.131–2.477). The predictive value on the outcome of the increased concentrations of IL-6 was present only in the seropositive cohort (30-day mortality, 63% vs. 24%; HR 3.250; 95% CI 2.075–5.090; $\it p$ < 0.001) with no significant differences in serum concentrations of IL-6 between the two groups. Procalcitonin and IL-10 exhibited the same behavior and were predictive of the outcome only in HCMV-seropositive patients. $\bf Conclusion$ We suggest that the predictive value of inflammation-associated biomarkers should be re-evaluated with regard to the HCMV serostatus. Targeting HCMV latency might open a new approach to selecting suitable patients for individualized treatment in sepsis