Postoperative acute kidney injury after volatile or intravenous anesthesia: a meta-analysis.

Postoperative acute kidney injury (AKI) is a common complication after surgery. The pathophysiology of postoperative AKI is complex. One potentially important factor is anesthetic modality. We, therefore, conducted a meta-analysis of the available literature regarding anesthetic modality and incidence of postoperative AKI. Records were retrieved until January 17, 2023, with the search terms ("propofol" OR "intravenous") AND ("sevoflurane" OR "desflurane" OR "isoflurane" OR "volatile" OR "inhalational") AND ("acute kidney injury" OR "AKI"). A meta-analysis for common effects and random effects was performed after exclusion assessment. Eight records were included in the meta-analysis with a total of 15,140 patients (n = 7,542 propofol and n = 7,598 volatile). The common and random effects model revealed that propofol was associated with a lower incidence of postoperative AKI compared with volatile anesthesia [odds ratio: 0.63 (95% confidence interval: 0.56-0.72) and 0.49 (95% confidence interval: 0.33-0.73), respectively]. In conclusion, the meta-analysis revealed that propofol anesthesia is associated with a lower incidence of postoperative AKI compared with volatile anesthesia. This may motivate choosing propofol-based anesthesia in patients with increased risk of postoperative AKI due to preexisting renal impairment or surgery with a high risk of renal ischemia.NEW & NOTEWORTHY This study analyzed the available literature on anesthetic modality and incidence of postoperative AKI. The meta-analysis revealed that propofol is associated with lower incidence of AKI compared with volatile anesthesia. It might therefore be considerable to use propofol anesthesia in surgeries with increased susceptibility for developing renal injuries such as cardiopulmonary bypass and major abdominal surgery.

Renal mitochondrial dysfunction in ovine experimental sepsis-associated acute kidney injury.

Sheep develop sepsis-associated acute kidney injury (SA-AKI) during experimental sepsis despite normal to increased renal oxygen delivery. A disturbed relation between oxygen consumption (V̇o2) and renal Na+ transport has been demonstrated in sheep and in clinical studies of AKI, which could be explained by mitochondrial dysfunction. We investigated the function of isolated renal mitochondria compared with renal oxygen handling in an ovine hyperdynamic model of SA-AKI. Anesthetized sheep were randomized to either an infusion of live Escherichia coli with resuscitative measures (sepsis group; n = 13 animals) or served as controls (n = 8 animals) for 28 h. Renal V̇o2 and Na+ transport were repeatedly measured. Live cortical mitochondria were isolated at baseline and at the end of the experiment and assessed in vitro with high-resolution respirometry. Sepsis markedly reduced creatinine clearance, and the relation between Na+ transport and renal V̇o2 was decreased in septic sheep compared with control sheep. Cortical mitochondrial function was altered in septic sheep with a reduced respiratory control ratio (6.0 ± 1.5 vs. 8.2 ± 1.6, P = 0.006) and increased complex II-to-complex I ratio during state 3 (1.6 ± 0.2 vs. 1.3 ± 0.1, P = 0.0014) mainly due to decreased complex I-dependent state 3 respiration (P = 0.016). However, no differences in renal mitochondrial efficiency or mitochondrial uncoupling were found. In conclusion, renal mitochondrial dysfunction composed of a reduction of the respiratory control ratio and an increased complex II/complex I relation in state 3 was demonstrated in an ovine model of SA-AKI. However, the disturbed relation between renal V̇o2 and renal Na+ transport could not be explained by a change in renal cortical mitochondrial efficiency or uncoupling.NEW & NOTEWORTHY We studied the function of renal cortical mitochondria in relation to oxygen consumption in an ovine model of sepsis with acute kidney injury. We demonstrated changes in the electron transport chain induced by sepsis consisting of a reduced respiratory control ratio mainly by a reduced complex I-mediated respiration. Neither an increase in mitochondrial uncoupling nor a reduction in mitochondrial efficiency was demonstrated and cannot explain why oxygen consumption was unaffected despite reduced tubular transport.

Plasma cytokine levels in spinal surgery with sevoflurane or total intravenous propofol anesthesia - A post hoc analysis of a randomized controlled trial.

Surgical tissue trauma stimulates an inflammatory response resulting in increased levels of cytokines which could contribute to acute kidney injury (AKI). It is not clear if anesthetic modality affects this response. We aimed to investigate the role of anesthesia in a healthy surgical population on the inflammatory response and the correlation to plasma creatinine. This study is a post hoc analysis of a published randomized clinical trial. We analyzed plasma from patients who underwent elective spinal surgery randomized to either total intravenous propofol anesthesia (n = 12) or sevoflurane anesthesia (n = 10). The plasma samples were collected before anesthesia, during anesthesia, and 1 h after surgery. Plasma cytokine levels after surgery were analyzed for correlations with duration of surgical insult and change in plasma creatinine concentration. The cytokine interleukin-6 (IL-6) was increased after surgery compared with preoperatively. IL-6 was higher in the sevoflurane group than the propofol group after surgery. No patient developed AKI, but plasma creatinine was increased postoperatively in the sevoflurane group. There was a significant association between surgical time and plasma IL-6 postoperatively. No significant correlation between change in plasma creatinine and IL-6 was detected. The cytokines IL-4, IL-13, Eotaxin, Interferon γ-Induced Protein 10 (IP-10), Granulocyte Colony-Stimulating Factor (G-CSF), Macrophage Inflammatory Protein-1ß (MIP-1ß), and Monocyte Chemoattractant Protein 1 (MCP-1) were lower postoperatively than before surgery independent of anesthetic modality. This post hoc analysis revealed that plasma IL-6 was increased after surgery and more so in the sevoflurane group than the propofol group. Postoperative plasma IL-6 concentration was associated with surgical time.

Oxygen saturation in intraosseous sternal blood measured by CO-oximetry and evaluated non-invasively during hypovolaemia and hypoxia - a porcine experimental study.

PURPOSE: This study intended to determine, and non-invasively evaluate, sternal intraosseous oxygen saturation (SsO2) and study its variation during provoked hypoxia or hypovolaemia. Furthermore, the relation between SsO2 and arterial (SaO2) or mixed venous oxygen saturation (SvO2) was investigated. METHODS: Sixteen anaesthetised male pigs underwent exsanguination to a mean arterial pressure of 50 mmHg. After resuscitation and stabilisation, hypoxia was induced with hypoxic gas mixtures (air/N2). Repeated blood samples from sternal intraosseous cannulation were compared to arterial and pulmonary artery blood samples. Reflection spectrophotometry measurements by a non-invasive sternal probe were performed continuously. RESULTS: At baseline SaO2 was 97.0% (IQR 0.2), SsO2 73.2% (IQR 19.6) and SvO2 52.3% (IQR 12.4). During hypovolaemia, SsO2 and SvO2 decreased to 58.9% (IQR 16.9) and 38.1% (IQR 12.5), respectively, p < 0.05 for both, whereas SaO2 remained unaltered (p = 0.44). During hypoxia all saturations decreased; SaO2 71.5% (IQR 5.2), SsO2 39.0% (IQR 6.9) and SvO2 22.6% (IQR 11.4) (p < 0.01), respectively. For hypovolaemia, the sternal probe red/infrared absorption ratio (SQV) increased significantly from baseline (indicating a reduction in oxygen saturation) + 5.1% (IQR 7.4), p < 0.001 and for hypoxia + 19.9% (IQR 14.8), p = 0.001, respectively. CONCLUSION: Sternal blood has an oxygen saturation suggesting a mixture of venous and arterial blood. Changes in SsO2 relate well with changes in SvO2 during hypovolaemia or hypoxia. Further studies on the feasibility of using non-invasive measurement of changes in SsO2 to estimate changes in SvO2 are warranted.

Renal function during sevoflurane or total intravenous propofol anaesthesia: a single-centre parallel randomised controlled study.

BACKGROUND: The choice of anaesthetic may influence regulation of renal perfusion and function. We investigated renal function in patients anaesthetised with propofol or sevoflurane before surgery and postoperatively. METHODS: Patients with ASA physical status 1-2 planned for spinal surgery were randomised to propofol or sevoflurane anaesthesia. Blood and urine were collected before anaesthesia, during anaesthesia (before surgery), during postoperative care, and the day after surgery. RESULTS: Twenty-seven patients completed the study protocol (average age, 51 yr; average BMI, 28 kg m-2) and 11 were women. Urine output and sodium excretion were lower during sevoflurane anaesthesia (n=14) than during propofol anaesthesia (n=13) (0.3 vs 1.1 ml kg-1 h-1 [P=0.01] and 2.6 vs 6.0 mmol h-1 [P=0.04], respectively). Urinary potassium excretion was lower during anaesthesia than after, without intergroup difference (2.3 vs 5.7 mmol h-1, P<0.001). Sevoflurane anaesthesia increased plasma renin compared with baseline (138 vs 23 mIU L-1, P<0.001) and propofol anaesthesia (138 vs 27 mIU L-1, P=0.008). Plasma arginine-vasopressin did not change significantly during anaesthesia, but was elevated postoperatively compared with baseline irrespective of anaesthetic (21 vs 12 ng L-1, P=0.02). Sevoflurane caused higher postoperative plasma creatinine than propofol (83 vs 66 mmol L-1, P=0.01). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not change significantly in either group. CONCLUSIONS: Sevoflurane anaesthesia reduced urine output and sodium excretion and increased plasma renin compared with propofol anaesthesia. The impact of this on acute kidney injury and fluid resuscitation during surgery warrants further investigation. CLINICAL TRIAL REGISTRATION: EudraCT: 2017-001646-10; Clinicaltrials.gov: NCT0333680.

Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs.

Angiotensin II (ANG II) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma ANG II levels and is associated with increased risk of acute kidney injury. We hypothesized that ANG II antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared, and randomized to intravenous losartan (1.5 mg·kg-1·h-1, n = 8) or an equal volume of intravenous Ringer acetate (vehicle-treated, n = 8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial pressure of <50 mmHg for 30 min. Plasma ANG II levels, hemodynamics and oxygenation were assessed 60 min prehemorrhage, 30-min after the start of hemorrhage, and 60 min posthemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma ANG II levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, ANG II antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.

Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats.

About one-third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease, including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (sarafotoxin 6c for 30-40 min; 0.78 pmol/h directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague-Dawley rats administered streptozotocin (55 mg/kg) 2 wk before the acute experiments. Intrarenal activation of ETB-R improved oxygenation in the hypoxic diabetic kidney. However, the effects on diabetes-induced increased kidney oxygen consumption could not explain the improved oxygenation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery without increasing glomerular filtration or tubular sodium load. In conclusion, increased ETB-R signaling in the diabetic kidney improves intrarenal tissue oxygenation due to increased oxygen delivery secondary to increased renal blood flow.

Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice.

Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease to be the causal mechanism. To establish whether hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared with normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia 3 days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.

Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery.

AIMS/HYPOTHESIS: Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown. METHODS: The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes. RESULTS: Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals. CONCLUSIONS/INTERPRETATION: Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.

Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats.

Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na(+)-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na(+) transport efficiency [tubular Na(+) transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary Po2 in both control and diabetic kidneys during the inhibition of proximal Na(+) reabsorption suggests the redistribution of active Na(+) transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes.

One-third of diabetes mellitus patients develop diabetic nephropathy, and with underlying mechanisms unknown it is imperative that diabetic animal models resemble human disease. The present study investigated the susceptibility to develop diabetic nephropathy in four commonly used and commercially available mouse strains with type 1 diabetes to determine the suitability of each strain. Type 1 diabetes was induced in C57Bl/6, NMRI, BALB/c, and 129Sv mice by alloxan, and conscious glomerular filtration rate, proteinuria, and oxidative stress levels were measured in control and diabetic animals at baseline and after 5 and 10 wk. Histological alterations were analyzed using periodic acid-Schiff staining. Diabetic C57Bl/6 displayed increased glomerular filtration rate, i.e., hyperfiltration, whereas all other parameters remained unchanged. Diabetic NMRI developed the most pronounced hyperfiltration as well as increased oxidative stress and proteinuria but without glomerular damage. Diabetic BALB/c did not develop hyperfiltration but presented with pronounced proteinuria, increased oxidative stress, and glomerular damage. Diabetic 129Sv displayed proteinuria and increased oxidative stress without glomerular hyperfiltration or damage. However, all strains displayed intrastrain correlation between oxidative stress and proteinuria. In conclusion, diabetic C57Bl/6 and NMRI both developed glomerular hyperfiltration but neither presented with histological damage, although NMRI developed low-degree proteinuria. Thus these strains may be suitable when investigating the mechanism causing hyperfiltration. Neither BALB/c nor 129Sv developed hyperfiltration although both developed pronounced proteinuria. However, only BALB/c developed detectable histological damage. Thus BALB/c may be suitable when studying the roles of proteinuria and histological alterations for the progression of diabetic nephropathy.

Repetitive measurements of intrarenal oxygenation in vivo using L band electron paramagnetic resonance.

Intrarenal oxygenation is heterogeneous with oxygen levels normally being highest in the superficial cortex and lowest in the inner medulla. Reduced intrarenal oxygenation has been implied in the pathology of several kidney diseases. However, there is currently no method available to repetitively monitor regional renal oxygenation using minimally invasive procedures. We therefore evaluated implantable lithium phthalocyanine (LiPc) probes, which display a close correlation between EPR line width and oxygen availability.LiPc probes were implanted in the kidney cortex and medulla in the same mouse and EPR spectra were acquired using a L band scanner during inhalation of air (21 % oxygen) or a mixture of air and nitrogen (10 % oxygen). In order to separate the signals from the two probes, a 1 G/cm gradient was applied and the signals were derived from 40 consecutive sweeps. Peak-to-peak comparison of the EPR line was used to convert the signal to an approximate oxygen tension in MATLAB. Kidney cortex as well as medullary oxygenation was stable over the 45 day period (cortex 56 ± 7 mmHg and medulla 43 ± 6 mmHg). However, 10 % oxygen inhalation significantly reduced oxygenation in both cortex (56 ± 6 to 34 ± 2 mmHg n = 15 p < 0.05) and medulla (42 ± 5 to 29 ± 3 mmHg n = 7 p < 0.05).In conclusion, L band EPR using LiPc probes implanted in discrete intrarenal structures can be used to repetitively monitor regional renal oxygenation. This minimally invasive method is especially well suited for conditions of reduced intrarenal oxygenation since this increases the signal intensity which facilitates the quantification of the EPR signal to absolute oxygenation values.

Immuno-Modulatory Effects of Dexamethasone in Severe COVID-19-A Swedish Cohort Study.

Dexamethasone (Dex) has been shown to decrease mortality in severe coronavirus disease 2019 (COVID-19), but the mechanism is not fully elucidated. We aimed to investigate the physiological and immunological effects associated with Dex administration in patients admitted to intensive care with severe COVID-19. A total of 216 adult COVID-19 patients were included-102 (47%) received Dex, 6 mg/day for 10 days, and 114 (53%) did not. Standard laboratory parameters, plasma expression of cytokines, endothelial markers, immunoglobulin (Ig) IgA, IgM, and IgG against SARS-CoV-2 were analyzed post-admission to intensive care. Patients treated with Dex had higher blood glucose but lower blood lactate, plasma cortisol, IgA, IgM, IgG, D-dimer, cytokines, syndecan-1, and E-selectin and received less organ support than those who did not receive Dex (Without-Dex). There was an association between Dex treatment and IL-17A, macrophage inflammatory protein 1 alpha, syndecan-1 as well as E-selectin in predicting 30-day mortality. Among a subgroup of patients who received Dex early, within 14 days of COVID-19 debut, the adjusted mortality risk was 0.4 (95% CI 0.2-0.8), i.e., 40% compared with Without-Dex. Dex administration in a cohort of critically ill COVID-19 patients resulted in altered immunological and physiologic responses, some of which were associated with mortality.

Effect of controlled hypotensive hemorrhage on plasma sodium levels in anesthetized pigs: An exploratory study.

Perioperative hyponatremia, due to non-osmotic release of the antidiuretic hormone arginine vasopressin, is a serious electrolyte disorder observed in connection with many types of surgery. Since blood loss during surgery contributes to the pathogenesis of hyponatremia, we explored the effect of bleeding on plasma sodium using a controlled hypotensive hemorrhage pig model. After 30-min baseline period, hemorrhage was induced by aspiration of blood during 30 min at mean arterial pressure <50 mmHg. Thereafter, the animals were resuscitated with retransfused blood and a near-isotonic balanced crystalloid solution and monitored for 180 min. Electrolyte and water balances, cardiovascular response, renal hemodynamics, and markers of volume regulation and osmoregulation were investigated. All pigs (n = 10) developed hyponatremia. All animals retained hypotonic fluid, and none could excrete net-free water. Urinary excretion of aquaporin 2, a surrogate marker of collecting duct responsiveness to antidiuretic hormone, was significantly reduced at the end of the study, whereas lysine vasopressin, i.e., the pig antidiuretic hormone remained high. In this animal model, hyponatremia developed due to net positive fluid balance and generation of electrolyte-free water by the kidneys. A decreased urinary aquaporin 2 excretion may indicate an escape from antidiuresis.

Anesthesia and the renal sympathetic nervous system in perioperative AKI.

Approximately 7% of patients undergoing non-cardiac surgery with general anesthesia develop postoperative acute kidney injury (AKI). It is well-known that general anesthesia may have an impact on renal function and water balance regulation, but the mechanisms and potential differences between anesthetics are not yet completely clear. Recently published large animal studies have demonstrated that volatile (gas) anesthesia stimulates the renal sympathetic nervous system more than intravenous propofol anesthesia, resulting in decreased water and sodium excretion and reduced renal perfusion and oxygenation. Whether this is the case also in humans remains to be clarified. Increased renal sympathetic nerve activity may impair renal excretory function and oxygenation and induce structural injury in ischemic AKI models and could therefore be a contributing factor to AKI in the perioperative setting. This review summarizes anesthetic agents' effects on the renal sympathetic nervous system that may be important in the pathogenesis of perioperative AKI.

Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients.

PURPOSE: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival. METHODS: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure. RESULTS: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively. CONCLUSION: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.

Role of Renal Sympathetic Nerve Activity in Volatile Anesthesia's Effect on Renal Excretory Function.

Regulation of fluid balance is pivotal during surgery and anesthesia and affects patient morbidity, mortality, and hospital length of stay. Retention of sodium and water is known to occur during surgery but the mechanisms are poorly defined. In this study, we explore how the volatile anesthetic sevoflurane influences renal function by affecting renal sympathetic nerve activity (RSNA). Our results demonstrate that sevoflurane induces renal sodium and water retention during pediatric anesthesia in association with elevated plasma concentration of renin but not arginine-vasopressin. The mechanisms are further explored in conscious and anesthetized ewes where we show that RSNA is increased by sevoflurane compared with when conscious. This is accompanied by renal sodium and water retention and decreased renal blood flow (RBF). Finally, we demonstrate that renal denervation normalizes renal excretory function and improves RBF during sevoflurane anesthesia in sheep. Taken together, this study describes a novel role of the renal sympathetic nerves in regulating renal function and blood flow during sevoflurane anesthesia.

Pre-treatment with the angiotensin receptor 1 blocker losartan protects renal blood flow and oxygen delivery after propofol-induced hypotension in pigs.

Hypotensive events are strongly correlated to the occurrence of perioperative acute kidney injury, but the underlying mechanisms for this are not completely elucidated. We hypothesised that anaesthesia-induced hypotension causes renal vasoconstriction and decreased oxygen delivery via angiotensin II-mediated renal vasoconstriction. Pigs were anaesthetised, surgically prepared and randomised to vehicle/losartan treatment (0.15 mg*kg-1). A deliberate reduction in arterial blood pressure was caused by infusion of propofol (30 mg*kg-1) for 10 min. Renal function and haemodynamics were recorded 60 min before and after hypotension. Propofol induced hypotension in all animals (p < 0.001). Renal blood flow (RBF) and renal oxygen delivery (RDO2) decreased significantly regardless of treatment but more so in vehicle-treated compared to losartan-treated (p = 0.001, p = 0.02, respectively). During recovery RBF and RDO2 improved to a greater extent in the losartan-treated compared to vehicle-treated (+ 28 ml*min-1, 95%CI 8-50 ml*min-1, p = 0.01 and + 3.1 ml*min-1, 95%CI 0.3-5.8 ml*min-1, p = 0.03, respectively). Sixty minutes after hypotension RBF and RDO2 remained depressed in vehicle-treated, as renal vascular resistance was still increased (p < 0.001). In losartan-treated animals RBF and RDO2 had normalised. Pre-treatment with losartan improved recovery of renal blood flow and renal oxygen delivery after propofol-induced hypotension, suggesting pronounced angiotensin II-mediated renal vasoconstriction during blood pressure reductions caused by anaesthesia.

ß-Cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome.

Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 µg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into ß-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.