Abnormalities of Coagulation and Fibrinolysis Assessed by Thromboelastometry in an Endotoxic Shock Model in Piglets Treated with Nitric Oxide and Hydrocortisone.

This is an animal model study to investigate changes in hemostasis during endotoxemic shock and to determine whether the combination of inhaled nitric oxide (iNO) + intravenous hydrocortisone had an effect on clot formation and fibrinolysis. iNO selectively decreases pulmonary artery pressure, without affecting cardiac index or systemic vascular resistance; however, the results of studies on the possible consequences of iNO administration on coagulation are inconsistent and require further research. Thirty-four piglets were included. Administering endotoxin caused severe hypodynamic shock. Half of the animals received iNO (30 ppm) + hydrocortisone, starting 3 h after endotoxin infusion and continuing to the end of the study. All animals developed coagulation disorders, manifested by a tendency to hypocoagulation; at the same time, fibrinolysis was impaired. Coagulation and fibrinolysis disorders persisted after endotoxin infusion was discontinued, with worse severity in the animals that died before the study was terminated. Administering iNO + hydrocortisone did not cause further changes in coagulation and fibrinolysis parameters, either during or after the endotoxin challenge, suggesting that potential therapeutic interventions with iNO to lower pulmonary arterial pressure will not affect hemostasis.

[Review of anesthetic technique and 30-day mortality for cholecystectomies based on the Swedish Perioperative Registry]. / Anestesival och 30-dagars- mortalitet vid kolecystektomi.

The Swedish Perioperative Registry (SPOR) offers a unique opportunity for monitoring the peri- and early postoperative processes. It can be utilized for quality monitoring within individual clinics or for epidemiological studies. Combining SPOR's data with organ-specific registries provides a more comprehensive understanding of the overall peri- and early postoperative care and outcomes of surgical procedures. In our example, we present the expected patient profile for gall bladder surgery in Sweden. Inhalation anesthesia is the dominant technique, but Total Intravenous Anesthesia (TIVA) is showing an increasing trend in usage. There are minimal differences between the techniques in terms of early complications, with a mere 8-minute variation in recovery time. The mortality rate for cholecystectomy in Sweden is reassuringly low, with 0.02% of patients passing away within 24 hours and a 30-day mortality rate of 0.13%. As expected, advancing age and higher ASA class increase the risk of mortality within 30 days. Additionally, there is a clear area for improvement identified in increasing the utilization of LÖF's Safe Surgery Checklist.

Anaesthesia practice, quality indices including all-cause 30-day mortality associate to wrist fracture repositioning and surgery in Sweden: A perioperative register-based study 2018-2021.

BACKGROUND: Wrist fracture is one of most common fractures frequently requiring surgical anaesthesia. There is limited information related to the anaesthetic practice and quality including 30-day mortality associated with wrist fracture in Sweden in recent years. AIM: The aim of the present register-based study was to investigate the anaesthesia techniques used and quality indices including 30-day mortality associated with wrist fracture surgery in Sweden during the period 2018-2021. MATERIALS AND METHODS: All fracture repositions, and surgical interventions related to wrist fracture requiring anaesthesia in patients aged >18 years registered in the Swedish Perioperative Register (SPOR) between 2018 and 2021 were included in the analysis. Information on age, ASA class, anaesthesia technique, severe operative events, most reported side-effects during recovery room stay and all-cause 30-day mortality was collected. RESULTS: The data set included 25,147 procedures split into 14,796 females and 10,252 males (missing information n = 99) with a mean age of 52.9 ± 18.7 years and a significant age difference between females and males, 60.3 ± 15.4 and 42.2 ± 17.7 years, respectively. Mean age and ASA class increased during the study period (2018-2021), from 52.8 ± 18.6 to 54.0 ± 18.4 and ASA class 3-5 from 8.1% to 9.4% (p < .001 and p < .041, respectively). General anaesthesia (GA), GA combined with regional anaesthesia (RA), RA with or without sedation and sedation only was used in 41%, 13%, 40% and 6% of procedures, respectively, with minor changes over the study period. Pain at arrival in the recovery room (RR), (3.4%), severe pain during RR stay (2.1%), hypothermia (1.4%), postoperative nausea and vomiting (PONV) (1.2%) and urinary retention (0.5%) were the most reported side-effects during the RR stay. (RA) was associated with significantly lower occurrence of pain and PONV, and shorter RR stay, compared with GA (p < .001). The all-cause 30-day mortality was low (19 of 25,147 (0.08%)) with no differences over the period studied or anaesthetic technique. CONCLUSION: General anaesthesia or general anaesthesia combined with regional anaesthesia are the most used anaesthetic techniques for wrist fracture procedures in Sweden. Recovery room pain, PONV, hypothermia and urinary retention is reported in overall low frequencies, with no change over the period studied, but in lower frequencies for regional anaesthesia. All-cause 30-day mortality was low; 0.08% with no change over time or between anaesthetic techniques. Thus, the present quality review based on SPOR data supports high quality of perioperative anaesthesia care.

[Age, ASA-Physical Status All-Cause 30-Day Mortality Among Caesarean Section in Sweden 2016 to 2022]. / Mammorna blir allt äldre men mortaliteten är betryggande låg.

There is limited research about how age and ASA-physical status (PS) have changed among women undergoing caesarean sections (CS) and how these characteristics have affected all-cause 30-day mortality in Sweden during recent years. The aim of this study was to determine change in age and ASA-PS and impact on all-cause 30-day mortality among CS in Sweden between 2016 and 2022. Data regarding CS performed from 1 Jan 2016 to 30 Jun 2022 were collected from the Swedish Peri-Operative Register (SPOR). The study cohort included 102,965 CS; 44,404 (43.1%) elective, 47,158 (45.8%) emergency and 11,403 (11.1%) crash emergency CS. Age, ASA-PS, 30-day mortality, and year of procedure were primary study variables. Continuous numerical variables were analysed with ANOVA and categorical data with Chi-2-tests or Fishers-exact-test, in SPSS. The mean age for the entire cohort was 32.1 years and increased by 0.8 years (P<0.001). A shift to higher ASA-PS was seen over the study period (P<0.001). The all-cause 30-day mortality rate found was 0.014% (14/102,965). No significant difference was seen in maternal mortality over the study period. Of the 14 mothers who deceased within 30 days, 5 were classified as ASA III-V, the majority were 31-40 years of age and 7 of them underwent emergency CS. Emergency CS decreased (15.2% to 10.1%), use of neuraxial anaesthesia increased and general anaesthesia (GA) decreased. We conclude that CS mothers in Sweden have become older and have higher ASA-PS during the last 6.5 years. Emergency CS have decreased, as has the use of GA. High ASA-PS and CS with a higher degree of urgency were associated with all-cause 30-day mortality. All-cause mortality associated to CS is reassuringly low in Sweden.

Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.

BACKGROUND: In metastatic colorectal cancer (mCRC), acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), was shown to be frequently caused by activating alterations in the RAS genes KRAS or NRAS. To this day, no efficient follow-up treatment option has emerged to treat mCRC in such a setting of resistance. METHODS: To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome reprogramming in an established cellular model of acquired, KRAS-associated CET resistance. RESULTS: This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly, all investigated resistant cell lines displayed upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of traits of progression. Expectedly resistant cell lines displayed increased migration (p < 0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (RNAi) (p < 0.001), ephrin-A1 stimulation (p < 0.001), dasatinib (p < 0.01), or anti-EPHA2 antibody treatment (p < 0.001), identifying it as an actionable target in mCRC with acquired CET resistance. CONCLUSION: These results highlight EPHA2 and its role in mCRC with KRAS-gene mutated acquired CET resistance and support its use as a potential actionable target for the development of future precision medicine therapies.

Pulmonary Vasodilation by Intravenous Infusion of Organic Mononitrites Of 1,2-Propanediol in Acute Pulmonary Hypertension Induced by Aortic Cross Clamping and Reperfusion: A Comparison With Nitroglycerin in Anesthetized Pigs.

INTRODUCTION: Suprarenal aortic cross clamping (SRACC) and reperfusion may cause acute pulmonary hypertension and multiple organ failure. HYPOTHESIS: The organic mononitrites of 1,2-propanediol (PDNO), an nitric oxide donor with a very short half-life, are a more efficient pulmonary vasodilator and attenuator of end-organ damage and inflammation without significant side effects compared with nitroglycerin and inorganic nitrite in a porcine SRACC model. METHODS: Anesthetized and instrumented domestic pigs were randomized to either of four IV infusions until the end of the experiment (n = 10 per group): saline (control), PDNO (45 nmol kg min), nitroglycerin (44 nmol kg min), or inorganic nitrite (a dose corresponding to PDNO). Thereafter, all animals were subjected to 90 min of SRACC and 10 h of reperfusion and protocolized resuscitation. Hemodynamic and respiratory variables as well as blood samples were collected and analysed. RESULTS: During reperfusion, mean pulmonary arterial pressure and pulmonary vascular resistance were significantly lower, and stroke volume was significantly higher in the PDNO group compared with the control, nitroglycerin, and inorganic nitrite groups. In parallel, mean arterial pressure, arterial oxygenation, and fraction of methaemoglobin were similar in all groups. The serum concentration of creatinine and tumor necrosis factor alpha were lower in the PDNO group compared with the control group during reperfusion. CONCLUSIONS: PDNO was an effective pulmonary vasodilator and appeared superior to nitroglycerin and inorganic nitrite, without causing significant systemic hypotension, impaired arterial oxygenation, or methaemoglobin formation in an animal model of SRACC and reperfusion. Also, PDNO may have kidney-protective effects and anti-inflammatory properties.

Organic mononitrites of 1,2-propanediol act as an effective NO-releasing vasodilator in pulmonary hypertension and exhibit no cross-tolerance with nitroglycerin in anesthetized pigs.

PURPOSE: Clinically available intravenous (IV) nitric oxide (NO) donor drugs such as nitroglycerin (GTN) cause systemic hypotension and/or tolerance development. In a porcine model, novel NO donor compounds - the organic mononitrites of 1,2-propanediol (PDNO) - were compared to GTN with regard to pulmonary selectivity and tolerance development. The vasodilatory effects of inorganic nitrite were investigated. MATERIALS AND METHODS: In anesthetized piglets, central hemodynamics were monitored. At normal pulmonary vascular resistance (PVR), IV infusions of PDNO (15-60 nmol kg-1 min-1), GTN (13-132 nmol kg-1 min-1), and inorganic nitrite (dosed as PDNO) were administered. At increased PVR (by U46619 IV), IV infusions of PDNO (60-240 nmol kg-1 min-1) and GTN (75-300 nmol kg-1 min-1) before and after a 5 h infusion of GTN (45 nmol kg-1 min-1) were given. RESULTS: At normal PVR, PDNO (n=12) and GTN (n=7) caused significant dose-dependent decreases in mean systemic and pulmonary arterial pressures, whereas inorganic nitrite (n=13) had no significant effect. At increased PVR, PDNO (n=6) and GTN (n=6) significantly decreased mean systemic and pulmonary pressures and resistances, but only PDNO reduced the ratio between pulmonary and systemic vascular resistances significantly. After the 5 h GTN infusion, the hemodynamic response to GTN infusions (n=6) was significantly suppressed, whereas PDNO (n=6) produced similar hemodynamic effects to those observed before the GTN infusion. CONCLUSION: PDNO is a vasodilator with selectivity for pulmonary circulation exhibiting no cross-tolerance to GTN, but GTN causes non selective vasodilatation with substantial tolerance development in the pulmonary and systemic circulations. Inorganic nitrite has no vasodilatory properties at relevant doses.

Beneficial effects of inhaled nitric oxide with intravenous steroid in an ischemia-reperfusion model involving aortic clamping.

This study evaluated the effects of inhaled nitric oxide (iNO) therapy combined with intravenous (IV) corticosteroids on hemodynamics, selected cytokines, and kidney messenger RNA toll-like receptor 4 (mRNA TLR4) expression in ischemia-reperfusion injury animal model. The primary endpoint was the evaluation of circulatory, respiratory, and renal function over time. We also investigated the profile of selected cytokines and high-mobility group box 1 (HMGB1) protein, as well as renal mRNA TLR4 activation determined by quantitative real-time polymerase chain reaction analysis. Pigs (n = 19) under sevoflurane AnaConDa anesthesia/sedation were randomized and subjected to abdominal laparotomy and alternatively suprarenal aortic cross-clamping (SRACC) for 90 min or sham surgery: Group 1 (n = 8) iNO (80 ppm) + IV corticosteroids (25 mg ×3) started 30 min before SRACC and continued 2 h after SRACC release, followed with decreased iNO (30 ppm) until the end of observation, Group 2 (n = 8) 90 min SRACC, Group 3 (n = 3)-sham surgery. Renal biopsies were sampled 1 hr before SRACC and at 3 and 20 h after SRACC release. Aortic clamping increased TLR4 mRNA expression in ischemic kidneys, but significant changes were recorded only in the control group ( P = 0.016). Treatment with iNO and hydrocortisone reduced TLR4 mRNA expression to pre-ischemic conditions, and the difference observed in mRNA expression was significant between control and treatment group after 3 h ( P = 0.042). Moreover, animals subjected to treatment with iNO and hydrocortisone displayed an attenuated systemic inflammatory response and lowered pulmonary vascular resistance plus increased oxygen delivery. The results indicated that iNO therapy combined with IV corticosteroids improved central and systemic hemodynamics, oxygen delivery, and diminished the systemic inflammatory response and renal mRNA TLR4 expression.

Erratum.

[This corrects the article DOI: 10.1002/mgg3.177.].

CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant congenital disorder characterized by distinctive facial features, broad thumbs and halluces, growth retardation, and a variable degree of cognitive impairment. CREBBP is the major causative gene and mutations in EP300 are the cause of RTS in a minority of patients. In this study, 17 patients with a clinical diagnosis of RTS were investigated with direct sequencing, MLPA, and array-CGH in search for mutations in these two genes. Eleven patients (64.7%) had disease-causing point mutations or a deletion in CREBBP and in one patient (5.9%) a causal de novo frameshift mutation in EP300 was identified. This patient had broad thumbs, mild intellectual disability, and autism. In addition, an inherited missense mutation of uncertain clinical significance was identified in EP300 in one patient and his healthy father, and three patients had intronic nucleotide changes of uncertain clinical significance in CREBBP. Snoring and sleep apnea were common in both groups and four of the patients' mothers had preeclampsia during pregnancy. Importantly, difficulties associated with anesthesia were frequently reported and included delayed or complicated emergency in 53.3% of patients.

Organ dysfunction among piglets treated with inhaled nitric oxide and intravenous hydrocortisone during prolonged endotoxin infusion.

OBJECTIVE: It has previously been shown that a combination of inhaled nitric oxide (iNO) and intravenous (IV) steroid attenuates endotoxin-induced organ damage in a 6-hour porcine endotoxemia model. We aimed to further explore these effects in a 30-hour model with attention to clinically important variables. DESIGN: Randomized controlled trial. SETTING: University animal laboratory. SUBJECTS: Domestic piglets (n = 30). INTERVENTIONS: Animals were randomized into 5 groups (n = 6 each): 1) Controls, 2) LPS-only (endotoxin/lipopolysaccharide (LPS) infusion), 3) LPS + iNO, 4) LPS + IV steroid, 5) LPS + iNO + IV steroid. MEASUREMENTS AND MAIN RESULTS: Exposure to LPS temporarily increased pulmonary artery mean pressure and impeded renal function with elevated serum creatinine and acidosis compared to a control group over the 30-hour study period. Double treatment with both iNO and IV steroid tended to blunt the deterioration in renal function, although the only significant effect was on Base Excess (p = 0.045). None of the LPS + iNO + IV steroid treated animals died during the study period, whereas one animal died in each of the other LPS-infused groups. CONCLUSIONS: This study suggests that combined early therapy with iNO and IV steroid is associated with partial protection of kidney function after 30 hours of experimental LPS infusion.

Prolonged exposure to inhaled nitric oxide does not affect haemostasis in piglets.

OBJECTIVE: To examine possible adverse effects on haemostasis from prolonged exposure to inhaled nitric oxide (iNO). DESIGN AND SETTING: Blinded, randomised, experimental animal study in a university animal laboratory. INTERVENTIONS: Anaesthetised and intubated piglets received central venous, arterial, and transabdominal urinary catheters. Twelve piglets were studied with triggered pressure support ventilation breathing with an air-oxygen mixture for 30 h with nitric oxide (NO), 40 parts per million (ppm) (n = 6) or without NO gas (n = 6) added. The tests of platelet function were assessed in a separate 1-h experiment in which 12 additional animals were blindly randomised to receive intravenous acetylsalicylic acid (ASA) (n = 7) or placebo (n = 5). MEASUREMENTS AND RESULTS: All 12 animals were clinically stable during the study period of 30 h. Haemostasis was assessed in terms of bleeding time and platelet function by Adeplat-S, reflecting platelet adhesion. Prothrombin fragment 1 + 2, fibrin D-dimer, tissue plasminogen activator and prothrombin complex were measured to investigate whether inhaled NO (iNO) had any effects on thrombin formation, fibrin formation, fibrinolysis or coagulation. All parameters including bleeding time and Adeplat-S were unaffected by iNO. ASA significantly increased bleeding time, but did not affect Adeplat-S. Nitrate in plasma and NOx (nitrate and nitrite) in urine increased significantly in pigs receiving iNO compared with controls. CONCLUSIONS: Prolonged exposure to iNO at 40[Symbol: see text]ppm did not affect bleeding time or coagulation parameters in healthy piglets. The findings do not support the hypothesis that iNO increases the risk of bleeding in humans.