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Background: Epidural analgesia (EA) has been the standard of care after major abdominal surgery for many years. This study aimed to correlate EA with postoperative complications, short- and long-term mortality in patients with and without EA after open surgery (OS) and minimally invasive surgery (MIS) for colorectal cancer. Methods: Patient, clinical and outcome data were obtained from the Swedish Colorectal Cancer Registry and the Swedish Perioperative Registry. All adult patients diagnosed with colorectal cancer without metastases who underwent elective curative MIS or OS for colorectal cancer between January 2016 and December 2018 and who had data recorded in both registries, were included in the study. Data were analyzed for OS and MIS procedures separately. A Poisson regression model was used to investigate the association between EA and the outcomes of interest. Results: Five thousand seven hundred sixty-two patients were included in the study, 2712 in the MIS and 3050 patients in the OS group. After adjusting for patient specific and clinically relevant variables in the regression model, no statistically significant difference in risk for complications; 30-day, 90-day, and up to 3-year mortality following either MIS or OS could be detected between the EA+ and EA-cohorts. Conclusions: In this large study cohort, EA as part of the comprehensive care provided was not associated with a reduction in postoperative complications risk or improved 30-day, 90-day, or 3-year survival after MIS or OS for colorectal cancer., Funding Agency:ALF funding Region Örebro County OLL-880951, Epidural Analgesia for Colorectal Cancer Surgery: Experimental and Clinical studies

Background P. aeruginosa possesses antibiotic resistance, making treatment difficult. Polyclonal anti-P. aeruginosa IgY-antibodies (Pa-IgY) have antibacterial effects, but have not been studied in large animal pneumonia. Objectives To test if Pa-IgY decreases the concentration of P. aeruginosa in bronchoalveolar lavage in experimental porcine pneumonia over 27 hours. Method Norwegian landrace pigs were anesthetized, mechanically ventilated, and subject to invasive monitoring. The animals were randomized to receive either P. aeruginosa (control, n = 12) or P aeruginosa + Pa-IgY antibodies with a repeated dose of Pa-IgY after 12 hours (intervention, n = 12) in the right lower pulmonary lobe. Bronchoalveolar lavage (BAL) cultures and physiological measurements were obtained repeatedly for 27 hours after which the pigs were sacrificed. Results BAL bacterial concentration increased in both groups and peaked at 107.28 ± 100.21 CFU/mL in the intervention group vs 107.36 ± 100.50 CFU/mL in the control group (n.s.). BAL bacterial concentration decreased during the experiment to 105.35 ± 100.39 CFU/mL in the intervention group vs 105.19 ± 100.37 in the control group (n.s.). The intervention group had lower heart rate (P

The SSAI fully supports the suspension of hydroxyethyl-starch solutions commissioned by the European Medicines Agency

Background: Isoflurane is a common anesthetic agent used in human surgery and in animal models of sepsis. It has been suggested to have beneficial anti-inflammatory properties and to protect kidney function. Here, we investigated the effect of isoflurane on the development of kidney injury and dysfunction during 48-h endotoxemia in sheep. Methods: Before the experiments, the sheep (n=16) were surgically equipped with transit-time flowprobes around the renal, femoral and superior mesenteric artery. The animals were randomized to either be anesthetized with isoflurane and mechanically ventilated or to remain conscious while they received intravenous Escherichia coli lipopolysaccharide (LPS) for 48 h (25 ng/kg/min). In two animals in each group, the LPS was excluded to investigate any effect of isoflurane per se over time. Results: Endotoxemia caused cardiovascular changes typical for hyperdynamic sepsis and, although renal hyperemia occurred, impaired renal function in both groups. Compared with conscious animals, isoflurane significantly (P

Background Microcirculatory dysfunction is a common feature of sepsis. The potent vasoconstrictor endothelin (ET) is released in sepsis and endotoxemia, potentially contributing to sepsis-induced microcirculatory failure. In this study we tested the hypothesis that mixed ET receptor antagonism with tezosentan would improve splanchnic microcirculatory blood flow in acute porcine endotoxemia. Materials and methods Sixteen anesthetized and mechanically ventilated pigs received an infusion of endotoxin for 300 min. After 120 min eight pigs received a bolus dose of tezosentan 1 mg/kg followed by an infusion of tezosentan of 1 mg/kg/h throughout the experiment. Eight pigs served as endotoxin controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and in the ileal and colon mucosa. PCO2 in the ileal mucosa was measured by air tonometry and portal vein flow by an ultrasonic flow probe. Results Endotoxin administration induced a state of shock with impaired splanchnic microcirculatory blood flow. Microcirculation in the mucosa of the colon and ileum and mucosal-arterial PCO2 gap were improved by tezosentan. Portal vein flow was increased, but hepatic microcirculatory blood flow was not significantly improved. Tezosentan preserved cardiac index and decreased pulmonary capillary wedge pressure compared to controls, without causing any differences in the heart rate or mean arterial blood pressure response. Tezosentan also distinctly improved pH and arterial lactate values. Conclusions The findings of this study indicate that ET is involved in the microcirculatory dysfunction seen in the ileal and colon mucosa in early endotoxemia. Moreover, this detrimental effect was counteracted by i.v. administration of the mixed ET receptor antagonist tezosentan.

We investigated the possible differences in epidemiology, clinical course, management, and outcome between early and late occurrence of shock using data from the Sepsis Occurrence in Acutely Ill Patients Study, a large European multicenter study, which prospectively collected data from all adult intensive care unit (ICU) patients admitted to a participating center within a 2-week period in 2002. Shock was defined as hemodynamic compromise necessitating the administration of vasopressor agents. Early and late shock were defined as onset of shock within the first 2 days in the ICU or later, respectively. Of 3,147 patients, 1,058 (33.6%) had shock at any time, of whom 462 (43.7%) had septic shock. Patients with late shock had a higher incidence of respiratory (87.4 vs. 69.7%, P < 0.001) and hepatic (15.5 vs. 8.7%, P < 0.05) failure, and more often received dopamine (44.7% vs. 34.5%, P < 0.05) and albumin (31.1% vs. 20.3%, P < 0.001) than patients who developed shock early. Intensive care unit and hospital mortality rates were greater in patients who developed shock late, rather than early (52.4% vs. 36.8% and 55.3% vs. 43%, respectively, P < 0.02). In a multivariable analysis, late shock was associated with an independent risk of higher ICU mortality in shock patients (odds ratio, 2.6; 95% confidence interval, 1.6-4.3, P < 0.001). These observations have important implications in establishing individual prognosis as well as in the design and interpretation of clinical trials.

During progressive blood loss several mechanisms act in concert to compensate for the reduced intravascular volume with the overall aim to provide sufficient blood supply to vital organs. The hemodynamic responses in this situation follow a characteristic course of events in conscious individuals with an initial phase of largely maintained blood pressure and tachycardia followed by an abrupt fall in pressure, accompanied by bradycardia and widespread inhibition of sympathetic nervous activity when 20–30% of the blood volume is lost. Our research has focussed on Na + and angiotensin II effects on the brain for the cardiovascular compensatory mechanisms in response to hypotensive hemorrhage in sheep. We have found that intracerebroventricular infusion of hypertonic NaCl solution improves the tolerance to blood loss, i.e., increases the amount of blood loss needed to induce hypotension. Inhalation anesthesia abolished this effect of the infusion. Similarly, corresponding infusions of angiotensin II also increased the resistance to blood loss in conscious animals only, although accompanied by different hemodynamic compensatory mechanisms. The effects of intracerebroventricular hypertonic NaCl infusion on cardiovascular compensation during hemorrhage are similar to those achieved with treatment of hemorrhagic shock with intravenous infusions of small volumes of hypertonic NaCl solutions. We therefore suggest that a substantial part of the beneficial effect of that treatment is mediated via direct effects of the hypernatremia on the brain. These observations also illustrate the need for further elucidation of more possible influences on autonomic functions by increased Na + concentration which, together with hypovolemia, is a hallmark of dehydration.

Background: Ethyl pyruvate has been shown to possess anti-inflammatory and free radical scavenging properties. However, the haemodynamic effects of ethyl pyruvate have not been studied in detail. We investigated the systemic, regional and microcirculatory haemodynamic and metabolic effects of resuscitation with Ringer’s ethyl pyruvate solution (REPS) vs. Ringer’s acetate (RA) in an acute model of porcine endotoxaemic shock. Methods: Fourteen anaesthetized pigs received an infusion of endotoxin that was increased stepwise over 30 min to a rate of 2.5 μg/kg/h. After 60 min of endotoxaemia, the animals were resuscitated with either ethyl pyruvate 40 mg/kg, given as REPS, or the equivalent volume of RA, administered over 10 min. Thereafter, an infusion of either ethyl pyruvate 40 mg/kg/h, given as REPS, or the equivalent volume of RA, was started, and the maintenance fluid was reduced so that the total amount of fluid given was kept constant. The experiment was terminated after 300 min of endotoxaemia. Results: Endotoxin infusion led to a hypodynamic state that was reversed by fluid resuscitation after 60 min. Progressive deterioration ensued and, after 300 min, all animals were again hypodynamic. No differences in response to treatment were found between the groups with regard to systemic haemodynamics, renal artery or portal vein flow or microcirculatory flow in the liver, kidney, ileal serosa or mucosa. Metabolic acidosis and increased arterial blood lactate developed in both groups, but, in the REPS group, the base excess was significantly lower from 150 min and the anion gap was significantly higher at 150 and 210 min. Conclusion: We could not demonstrate any difference between REPS and RA for resuscitation in this model of acute porcine endotoxaemic shock.

The effects of hypertonic saline/dextran (HSD) on hemodynamics and on rebleeding were studied during an uncontrolled intra-abdominal hemorrhage combined with a high-energy gunshot wound (GSW) in the hind limb of anesthetized swine. The GSW had instant effects on the central hemodynamics, which were aggravated when the internal hemorrhage was induced. Compared with baseline, cardiac output decreased to about 42%, mean arterial pressure decreased to 52 +/- 4%, and mean flow rates in the splanchnic region, in the upper aorta, and in the kidney decreased to 51 to 15%. The injection of HSD at 10 minutes was followed by a prompt increase in blood flow rates, but rebleeding occurred in five of eight animals, although only two died. In conclusion, GSW induced instant changes in hemodynamics at distance from the injury. When HSD treatment was given in a bolus injection, rebleeding occurred in five of eight animals, although the second hemorrhage became fatal in only one animal.

Background: There is little epidemiologic data on sepsis, particularly in areas of low antibiotic resistance. Here we report a prospective observational study of severe sepsis and septic shock in patients admitted to the Intensive Care Unit (ICU) at Karolinska University Hospital, Sweden. We aimed to evaluate short- and long-term mortality, and risk factors for sepsis-related death. A second aim was to investigate patient care in relation to gender. Methods: One hundred and one patients with severe sepsis and septic shock, admitted to the ICU between 2005 and 2009, were prospectively enrolled in the study. Defined primary endpoints were day 28, hospital, and 1-year mortality. Risk factors for sepsis-related death was evaluated with a multivariate analysis in a pooled analysis with two previous sepsis cohorts. In the subset of patient admitted to the ICU through the emergency department (ED), time to clinician evaluation and time to antibiotics were assessed in relation to gender. Results: In the septic cohort, the day 28, hospital, and 1-year mortality rates were 19, 29, and 34%, respectively. Ninety-three percent of the patients received adequate antibiotics from the beginning. Multi-resistant bacteria were only found in three cases. Among the 43 patients admitted to the ICU through the ED, the median time to antibiotics was 86 min (interquartile range 52–165), and overall 77% received appropriate antibiotics within 2 h. Female patients received antibiotics significantly later compared to male patients (p = 0.047). Conclusion: The results demonstrate relatively low mortality rates among ICU patients with severe sepsis/septic shock, as compared to reports from outside Scandinavia. Early adequate antibiotic treatment and the low incidence of resistant isolates may partly explain these findings. Importantly, a gender difference in time to antibiotic therapy was seen.

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal hyperinflammatory syndrome characterized by fever, hepatosplenomegaly, cytopenia, and in some cases hemophagocytosis. Here, we describe the mutation analysis, clinical presentation, and functional analysis of natural killer (NK) cells in patients with mutations in STXBP2 encoding Munc18-2, recently associated with familial HLH type 5. The disease severity among 11 persons studied here was highly variable and, accordingly, age at diagnosis ranged from 2 months to 17 years. Remarkably, in addition to typical manifestations of familial HLH (FHL), the clinical findings included colitis, bleeding disorders, and hypogammaglobulinemia in approximately one-third of the patients. Laboratory analysis revealed impairment of NK-cell degranulation and cytotoxic capacity. Interleukin-2 stimulation of lymphocytes in vitro rescued the NK cell–associated functional defects. In conclusion, familial HLH type 5 is associated with a spectrum of clinical symptoms, which may be a reflection of impaired expression and function of Munc18-2 also in cells other than cytotoxic lymphocytes. Mutations in STXBP2 should thus also be considered in patients with clinical manifestations other than those typically associated with HLH.

The incidence of fungal infections in hospitalized patients has increased, and due to demographic changes and increasingly advanced medical methods, the intensive care units (ICU) have emerged as epicentres for fungal infections. The aim of the present study was to investigate Candida colonization pattern and colonization index (CI), in combination with other risk factors and its relation to invasive candida infection (ICI), in 59 consecutive patients with at least 7 d length of stay (LOS) at a multidisciplinary ICU. Surveillance samples were collected on d 7 and then weekly during the ICU stay. In addition, immunological status was monitored by measuring the histocompatibility leukocyte antigen-DR (HLA-DR). In the present study with a patient population burdened by several risk factors for ICI, 17% acquired an invasive infection. Overall ICU mortality was 30%. We could demonstrate that both a high colonization index and recent extensive gastroabdominal surgery were significantly correlated with ICI, while a decreased level of HLA-DR (or = 70%) was not predictive for ICI in this high-risk population. The results indicate that ICU patients exposed to extensive gastroabdominal surgery would benefit from early antifungal prophylaxis.

Background: Hypertonic saline/dextran (HSD) has been shown to have beneficial effects in haemorrhagic shock. These effects, with improved haemodynamics and organ perfusion, would in theory also be of benefit in septic shock. However, this is less studied. We have therefore further evaluated the effect of additional treatment with HSD in a porcine endotoxin shock model. Methods: Sixteen anaesthetized pigs were used. A continuous infusion of endotoxin (LPS EC) was increased stepwise during 30 min to a rate of 5 µg/kg/h. The infusion was discontinued after 3 h and the animals were observed for another 2 h. The animals received continuous basal fluid resuscitation with isotonic Ringer's glucose 2.5% at a rate of 20 ml/kg/h throughout the experiment. After 1 h of endotoxin infusion, the animals were randomized to additional treatment with HSD, 4 ml/kg over 5 min, or the same volume of isotonic saline. Every 30 min, haemodynamics and mixed venous saturation (SvO2) were measured via a pulmonary artery catheter. Regional blood flow rates were measured continuously by perivascular ultrasonic flow probes. The metabolic response was measured by arterial blood gas analysis. Results: The endotoxin put all animals into a progressive hypodynamic circulatory shock during the experiment. Treatment with HSD improved survival rate to 8/8 compared with controls 3/8. There was a transient circulatory recovery with improved central and regional haemodynamics, accompanied by stabilized metabolic response. Conclusion: Treatment with additional HSD improves survival in an early phase of endotoxin shock. Generally improved haemodynamics and oxygenation of peripheral tissues are suggested as possible mechanisms.

Background: Hypothermia is considered harmful in trauma patients. In surgery, hypothermia is occasionally used to reduce metabolism and protect the brain. Recent studies in animals have also shown protective effects of hypothermia in hemorrhagic shock. The aim of this study was to evaluate the metabolic and endocrine effects of induced hypothermia in hemorrhagic shock. Methods: Half of the individually calculated blood volume was removed from 17 anesthetized piglets. They were then randomized to normothermia or hypothermia and followed for 4 hours after hemorrhage. Results: In the hypothermic pigs, arterial Po 2 increased from 10.3 ± 0.7 to 16.4 ± 0.9 kPa, but it remained unchanged in the normothermic group. The serum levels of potassium increased from 3.9 ± 0.2 to 5.0 ± 0.2 mmol/L in the normothermic group. In the hypothermic pigs, the potassium levels temporarily decreased from 3.8 ± 0.1 to 3.0 ± 0.1 mmol/L but then returned to baseline levels. The levels of serum catecholamines surged in both groups during hemorrhage. They remained elevated in normothermic pigs but declined in the hypothermic group. Conclusion: In porcine hemorrhagic shock, induced hypothermia increases arterial oxygen tension and stabilizes serum levels of potassium and catecholamines.