The Microbiome and Protein Carbamylation: Potential Targets for Protein-Restricted Diets Supplemented with Ketoanalogues in Predialysis Chronic Kidney Disease.

In chronic kidney disease (CKD), metabolic derangements resulting from the interplay between decreasing renal excretory capacity and impaired gut function contribute to accelerating disease progression and enhancing the risk of complications. To protect residual kidney function and improve quality of life in conservatively managed predialysis CKD patients, current guidelines recommend protein-restricted diets supplemented with essential amino acids (EAAs) and their ketoanalogues (KAs). In clinical studies, such an approach improved nitrogen balance and other secondary metabolic disturbances, translating to clinical benefits, mainly the delayed initiation of dialysis. There is also increasing evidence that a protein-restricted diet supplemented with KAs slows down disease progression. In the present review article, recent insights into the role of KA/EAA-supplemented protein-restricted diets in delaying CKD progression are summarized, and possible mechanistic underpinnings, such as protein carbamylation and gut dysbiosis, are elucidated. Emerging evidence suggests that lowering urea levels may reduce protein carbamylation, which might contribute to decreased morbidity and mortality. Protein restriction, alone or in combination with KA/EAA supplementation, modulates gut dysbiosis and decreases the generation of gut-derived uremic toxins associated, e.g., with cardiovascular disease, inflammation, protein energy wasting, and disease progression. Future studies are warranted to assess the effects on the gut microbiome, the generation of uremic toxins, as well as markers of carbamylation.

Manipulation of Nitric Oxide Levels via a Modified Hydroxyethyl Starch Molecule.

INTRODUCTION: Although the improving effect of nitric oxide (NO) donors has experimentally been demonstrated in shock, there are still no NO donor medications clinically available. Thiol-nitrosothiol-hydroxyethyl starch (S-NO-HES) is a novel molecule consisting of NO coupled to a thiolated derivative of hydroxyethyl starch (HES). It was aimed to assess the ability of S-NO-HES to serve as an NO donor under a variety of in vitro simulated physiologic conditions, which might be the first step to qualify this molecule as a novel type of NO donor-fluid. METHODS: We studied the effect of temperature on NO-releasing properties of S-NO-HES in blood, at 34°C, 37°C, and 41°C. Ascorbic acid (Asc) and amylase were also tested in a medium environment. In addition, we evaluated the activity of S-NO-HES in the isolated aortic ring and Langendorff-perfused heart setup. RESULTS: The NO release property of S-NO-HES was found at any temperature. Asc led to a significant increase in the production of NO compared to S-NO-HES incubation (P < 0.05). The addition of amylase together with Asc to the medium further increased the release of NO (P < 0.05). S-NO-HES exerted significant vasodilatory effects on phenylephrine precontracted aortic rings that were dose-dependent (P < 0.01). Furthermore, S-NO-HES significantly increased the heart rate and additionally reduced the duration of the cardiac action potential, as indicated by a reduction of QTc-B values (P < 0.01). CONCLUSIONS: We demonstrated for the first time that the S-NO-HES molecule exhibited its NO-releasing effects. The effectiveness of this new NO donor to substitute NO deficiency under septic conditions or in other indications needs to be studied.

Hydromorphone impurity 2,2-bishydromorphone does not exert mutagenic and clastogenic properties via in silico QSAR prediction and in vitro Ames and micronucleus test.

The opioid agonist hydromorphone is indicated for the management of severe acute and chronic pain given that alternate treatments are insufficient. While the genotoxicity profile of hydromorphone is well investigated, little is known about the genotoxic potential of its impurities. In this study, 2,2-bishydromorphone was tested in silico and in vitro for both its mutagenic potential in an Ames test performed with Salmonella typhimurium and Escherichia coli tester strains up to a maximum concentration of 5 mg per plate in the absence and presence of metabolic activation. Furthermore, it was tested for its ability to induce micronuclei in TK6 cells in a micronucleus test up to a maximum concentration of 500 µg/mL with or without an exogenous metabolic activation system. 2,2-Bishydromorphone did not reveal any potential for inducing mutagenicity or clastogenicity under the conditions of the respective tests and is therefore considered non-mutagenic and non-clastogenic/aneugenic in vitro. These results are in line with negative in silico quantitative structure-activity relationship (QSAR) prediction for 2,2-bishydromorphone mutagenicity and clastogenicity and provide evidence of good correlation of in silico and in vitro data. Conclusively, these studies add important new clinically relevant information on the safety of hydromorphone as the impurity of 2,2-bishydromorphone is proven to be non-mutagenic and non-clastogenic.

Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells.

Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with increased morbidity and mortality. In a murine AKI model induced by ischemia/reperfusion injury (IRI), we show that glutamine significantly decreases kidney damage and improves kidney function. We demonstrate that glutamine causes transcriptomic and proteomic reprogramming in murine renal tubular epithelial cells (TECs), resulting in decreased epithelial apoptosis, decreased neutrophil recruitment, and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Furthermore, the direct modulation of the Tgm2-HSP70 signalosome and reduced Ask1 activation resulted in decreased JNK activation, leading to diminished mitochondrial intrinsic apoptosis in TECs. Glutamine administration attenuated kidney damage in vivo during AKI and TEC viability in vitro under inflammatory or hypoxic conditions.

Co-Administration of Lactulose Crystals with Amoxicillin Followed by Prolonged Lactulose Treatment Promotes Recovery of the Human Gut Microbiome In Vitro.

The validated SHIME model was used to assess the effect of repeated administration of two different lactulose dosages (5 g/d and 10 g/d) on the human gut microbiome during and following amoxicillin-clavulanic acid treatment. First, antibiotic treatment strongly decreased Bifidobacteriaceae levels from 54.4% to 0.6% and from 23.8% to 2.3% in the simulated proximal and distal colon, respectively, coinciding with a marked reduction in butyrate concentrations. Treatment with lactulose enhanced acetate and lactate levels during antibiotic treatment, likely through lactulose fermentation by Lachnospiraceae and Lactobacillaceae. One week after cessation of antibiotic treatment, Bifidobacteriaceae levels re-increased to 20.4% and 7.6% in the proximal and distal colon of the 5 g lactulose/d co-administered unit, as compared with 1.0% and 2.2% in the antibiotic-treated unit, and were even further stimulated upon extension of lactulose administration. Marked butyrogenic effects were observed upon prolonged lactulose supplementation, suggesting the establishment of cross-feeding interactions between Bifidobacteriaceae and butyrate producers. Furthermore, a limited Enterobacteriaceae outgrowth following antibiotic treatment was observed upon dosing with 10 g lactulose/d, indicating inhibition of pathogenic colonization by lactulose following antibiotic therapy. Overall, lactulose seems to be an interesting candidate for limiting the detrimental effects of amoxicillin-clavulanic acid on the human gut microbiome, though further studies are warranted to confirm these findings.

PragmaTic, prospEctive, randomized, controlled, double-blind, mulTi-centre, multinational study on the safety and efficacy of a 6% HydroxYethyl Starch (HES) solution versus an electrolyte solution in trauma patients: study protocol for the TETHYS study.

BACKGROUND: Trauma may be associated with significant to life-threatening blood loss, which in turn may increase the risk of complications and death, particularly in the absence of adequate treatment. Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss to maintain or re-establish hemodynamic stability with the ultimate goal to avoid organ hypoperfusion and cardiovascular collapse. The current study compares a 6% HES 130 solution (Volulyte 6%) versus an electrolyte solution (Ionolyte) for volume replacement therapy in adult patients with traumatic injuries, as requested by the European Medicines Agency to gain more insights into the safety and efficacy of HES in the setting of trauma care. METHODS: TETHYS is a pragmatic, prospective, randomized, controlled, double-blind, multicenter, multinational trial performed in two parallel groups. Eligible consenting adults ≥ 18 years, with an estimated blood loss of ≥ 500 ml, and in whom initial surgery is deemed necessary within 24 h after blunt or penetrating trauma, will be randomized to receive intravenous treatment at an individualized dose with either a 6% HES 130, or an electrolyte solution, for a maximum of 24 h or until reaching the maximum daily dose of 30 ml/kg body weight, whatever occurs first. Sample size is estimated as 175 patients per group, 350 patients total (α = 0.025 one-tailed, power 1-ß = 0.8). Composite primary endpoint evaluated in an exploratory manner will be 90-day mortality and 90-day renal failure, defined as AKIN stage ≥ 2, RIFLE injury/failure stage, or use of renal replacement therapy (RRT) during the first 3 months. Secondary efficacy and safety endpoints are fluid administration and balance, changes in vital signs and hemodynamic status, changes in laboratory parameters including renal function, coagulation, and inflammation biomarkers, incidence of adverse events during treatment period, hospital, and intensive care unit (ICU) length of stay, fitness for ICU or hospital discharge, and duration of mechanical ventilation and/or RRT. DISCUSSION: This pragmatic study will increase the evidence on safety and efficacy of 6% HES 130 for treatment of hypovolemia secondary to acute blood loss in trauma patients. TRIAL REGISTRATION: Registered in EudraCT, No.: 2016-002176-27 (21 April 2017) and ClinicalTrials.gov, ID: NCT03338218 (09 November 2017).

Prospective, randomized, controlled, double-blind, multi-center, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) sOlution versus an Electrolyte solutioN In patients undergoing eleCtive abdominal Surgery: study protocol for the PHOENICS study.

BACKGROUND: Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss and to maintain hemodynamic stability. This study was requested by the European Medicines Agency (EMA) to provide more evidence on the long-term safety and efficacy of HES solutions in the perioperative setting. METHODS: PHOENICS is a randomized, controlled, double-blind, multi-center, multinational phase IV (IIIb) study with two parallel groups to investigate non-inferiority regarding the safety of a 6% HES 130 solution (Volulyte 6%, Fresenius Kabi, Germany) compared with a crystalloid solution (Ionolyte, Fresenius Kabi, Germany) for infusion in patients with acute blood loss during elective abdominal surgery. A total of 2280 eligible patients (male and female patients willing to participate, with expected blood loss ≥ 500 ml, aged > 40 and ≤ 85 years, and ASA Physical status II-III) are randomly assigned to receive either HES or crystalloid solution for the treatment of hypovolemia due to surgery-induced acute blood loss in hospitals in up to 11 European countries. The dosing of investigational products (IP) is individualized to patients' volume needs and guided by a volume algorithm. Patients are treated with IP for maximally 24 h or until the maximum daily dose of 30 ml/kg body weight is reached. The primary endpoint is the treatment group mean difference in the change from the pre-operative baseline value in cystatin-C-based estimated glomerular filtration rate (eGFR), to the eGFR value calculated from the highest cystatin-C level measured during post-operative days 1-3. Further safety and efficacy parameters include, e.g., combined mortality/major post-operative complications until day 90, renal function, coagulation, inflammation, hemodynamic variables, hospital length of stay, major post-operative complications, and 28-day, 90-day, and 1-year mortality. DISCUSSION: The study will provide important information on the long-term safety and efficacy of HES 130/0.4 when administered according to the approved European product information. The results will be relevant for volume therapy of surgical patients. TRIAL REGISTRATION: EudraCT 2016-002162-30 . ClinicalTrials.gov NCT03278548.

Cost-Effectiveness of Propofol (Diprivan) Versus Inhalational Anesthetics to Maintain General Anesthesia in Noncardiac Surgery in the United States.

OBJECTIVES: It is not known whether using propofol total intravenous anaesthesia (TIVA) to reduce incidence of postoperative nausea and vomiting (PONV) is cost-effective. We assessed the economic impact of propofol TIVA versus inhalational anesthesia in adult patients for ambulatory and inpatient procedures relevant to the US healthcare system. METHODS: Two models simulate individual patient pathways through inpatient and ambulatory surgery with propofol TIVA or inhalational anesthesia with economic inputs from studies on adult surgical US patients. Efficacy inputs were obtained from a meta-analysis of randomized controlled trials. Probabilistic and deterministic sensitivity analyses assessed the robustness of the model estimates. RESULTS: Lower PONV rate, shorter stay in the post-anesthesia care unit, and reduced need for rescue antiemetics offset the higher costs for anesthetics, analgesics, and muscle relaxants with propofol TIVA and reduced cost by 11.41 ± 10.73 USD per patient in the inpatient model and 11.25 ± 9.81 USD in the ambulatory patient model. Sensitivity analyses demonstrated strong robustness of the results. CONCLUSIONS: Maintenance of general anesthesia with propofol was cost-saving compared to inhalational anesthesia in both inpatient and ambulatory surgical settings in the United States. These economic results support current guideline recommendations, which endorse propofol TIVA to reduce PONV risk and enhance postoperative recovery.

Hemodilution causes glycocalyx shedding without affecting vascular endothelial barrier permeability in rats.

BACKGROUND: The consequences of acute normovolemic hemodilution (ANH) following different types of fluids on the different components of the glycocalyx and on vascular barrier permeability (VBP) remain unknown. AIM: The aim of the study was to investigate whether the microcirculatory disruption and glycocalyx shedding induced by ANH alters VBP and whether this is affected by the composition and volume of the resuscitation fluid. MATERIALS AND METHODS: Anesthetized Wistar albino rats (n=24) underwent stepwise ANH at hematocrit levels of 35%, 25%, 20%, and 15% induced by the exchange of blood with 6% balanced hydroxyethyl starch (1:1), balanced crystalloid (1:3), and normal saline (NS) (1:3). Glycocalyx-shed products were measured at each level of hemodilution. VBP was reflected in the decay of fluorescence dyes of different molecular size and their plasma retention ratios. Edema was assessed by measuring organ water content and muscle microcirculation by hand-held videomicroscopy. RESULTS: NS caused increased degradation of heparan sulfate and hyaluronan compared with the control group (P=0.003, P=0.004, respectively). Neither VBP nor tissue edema was affected by the fluid used. The total and perfused vessel densities within the microcirculation of muscle tissue decreased at hematocrit 15% in the balanced crystalloid (P=0.02) and NS groups only (P<0.0001, P=0.0003, respectively) compared with baseline. CONCLUSIONS: Balanced colloid solution preserved the glycocalyx layer better than balanced and unbalanced crystalloid solutions while maintaining the microcirculatory function associated with an improved total intravascular volume. Among the fluids tested, NS caused the most microcirculatory alterations. While ANH caused the degradation of glycocalyx components regardless of fluid, it did not disrupt the vascular barrier as indicated by macromolecular leakage. RELEVANCE FOR PATIENTS: The results of this study provide insight into the choice of fluid for optimal perioperative fluid management and the consequences of fluid type on the vascular barrier, glycocalyx, and microcirculation.

Daily Intravenous Infusion of Busulfan Impurity 5 for 4 Days Is Not Associated With Toxic Effects in the Rat.

The alkylating agent busulfan is used in conditioning treatment of chronic myelogenous or granulocytic leukemia prior to stem cell transplantations. Its cytotoxic activity results in primary damage or destruction of hematopoietic cells. While the toxicity of busulfan is well investigated, little is known about the toxic effects of its impurities. In this study, the effect of 4-day intravenous infusion (3 h/d) of 4.8 mg/kg/d busulfan and 0.49, 4.9, and 49 mg/kg/d busulfan impurity 5 (4-((methylsulfonyl)oxy)butyl acetate) was investigated in rats. Whereas busulfan elicited myelotoxic and hepatotoxic effects, no toxic effects were observed in animals receiving the impurity at dosages up to 10 times higher than busulfan. The highest impurity dose of 49 mg/kg/d is therefore considered the no-observed-adverse-effect level of busulfan impurity 5.

Science and fiction in critical care: established concepts with or without evidence?

In the absence of evidence, therapies are often based on intuition, belief, common sense or gut feeling. Over the years, some treatment strategies may become dogmas that are eventually considered as state-of-the-art and not questioned any longer. This might be a reason why there are many examples of "strange" treatments in medical history that have been applied in the absence of evidence and later abandoned for good reasons.In this article, five dogmas relevant to critical care medicine are discussed and reviewed in the light of the available evidence. Dogma #1 relates to the treatment of oliguria with fluids, diuretics, and vasopressors. In this context, it should be considered that oliguria is a symptom rather than a disease. Thus, once hypovolaemia can be excluded as the underlying reason, there is no justification for giving fluids, which may do more harm than good in euvolaemic or hypervolaemic patients. Similarly, there is no solid evidence for forcing diuresis by administering vasopressors and loop diuretics. Dogma #2 addresses the treatment of crush syndrome patients with aggressive fluid therapy using NaCl 0.9%. In fact, this treatment may aggravate renal injury by iatrogenic metabolic acidosis and subsequent renal hypoperfusion. Dogma #3 concerns the administration of NaCl 0.9% to patients undergoing kidney transplantation. Since these patients are usually characterised by hyperkalaemia, the potassium-free solution NaCl 0.9%, containing exclusively 154 mmol/l of sodium and chloride ions each, is often considered as the fluid of choice. However, large volumes of chloride-rich solutions cause hyperchloraemic acidosis in a dose-dependent manner and induce a potassium shift to the extracellular space, thereby increasing serum potassium levels. Thus, balanced electrolyte solutions are to be preferred in this setting. Dogma #4 relates to the fact that enteral nutrition is often withheld for patients with high residual gastric volume due to the theoretical risk of gastro-oesophageal reflux, potentially resulting in aspiration pneumonitis. Despite controversial discussions, there is no clinical data supporting that residual gastric volume should be generally measured, especially not in patients without a gastro-intestinal surgery and/or motility disorders. Clinical evidence rather suggests that abandoning residual gastric volume monitoring does not increase the incidence of pneumonia, but may benefit patients by facilitating adequate enteral feeding. Finally, dogma #5 is about sedating all mechanically ventilated patients because "fighting" against the respirator may cause insufficient ventilation. This concern needs to be balanced against the unwanted consequences of sedation, such as prolonged mechanical ventilation and intensive care unit length of stay as well as increased risk of delirium. Modern concepts based on adequate analgesia and moderate to no sedation appear to be more suitable.In conclusion, dogmas are still common in clinical practice. Since science rather than fiction should govern our actions in intensive care medicine, it is important to remain critical and challenge long established concepts, especially when the underlying evidence is weak or non-existing.

Thinking forward: promising but unproven ideas for future intensive care.

Progress toward determining the true worth of ongoing practices or value of recent innovations can be glacially slow when we insist on following the conventional stepwise scientific pathway. Moreover, a widely accepted but flawed conceptual paradigm often proves difficult to challenge, modify or reject. Yet, most experienced clinicians, educators and clinical scientists privately entertain untested ideas about how care could or should be improved, even if the supporting evidence base is currently thin or non-existent. This symposium encouraged experts to share such intriguing but unproven concepts, each based upon what the speaker considered a logical but unproven rationale. Such free interchange invited dialog that pointed toward new or neglected lines of research needed to improve care of the critically ill. In this summary of those presentations, a brief background outlines the rationale for each novel and deliberately provocative unconfirmed idea endorsed by the presenter.

Differential Effects of Selective and Nonselective Potassium Channel Inhibitors in Ovine Endotoxemic Shock (Macrocirculation) and in a Rat Model of Septic Shock (Microcirculation).

BACKGROUND: Potassium-(K)-channel inhibitors may increase systemic vascular resistance in vasodilatory shock states. OBJECTIVE: The purpose of the present study was to compare the macro- and microvascular effects of the adenosine triphosphate-sensitive K-channel-(KATP)-inhibitor glipizide and the nonselective K-channel inhibitor tetraethylammonium (TEA) in ovine endotoxemic shock and septic shock in rats. DESIGN: Two randomized, controlled laboratory studies. ANIMALS: Thirty female sheep and 40 male Sprague Dawley rats. SETTING: Animal research facility INTERVENTION:: Systemic hemodynamics were analyzed in ovine endotoxemic shock with guideline-oriented supportive therapy. Sheep were allocated to three treatment groups for 12 h: glipizide 10 mg kg·h, TEA 8 mg kg·h, or 0.9% saline. The microvascular effects of each drug were evaluated in septic rats (cecal ligation and puncture model) receiving a 2-h infusion of each study drug: glipizide 20 mg kg·h; TEA 50 mg kg·h, or 0.9% saline, respectively, followed by intravital microscopy of villi microcirculation. RESULTS: Compared with the control group, glipizide infusion increased systemic vascular resistance index and decreased cardiac index and heart rate (HR) in sheep (P < 0.05), whereas TEA infusion decreased HR and resulted in a decreased survival time (P = 0.001). In rats, glipizide infusion resulted in an increase in mean arterial pressure and a decrease in HR compared with baseline measurement (P < 0.05) without relevant effects on the villi microcirculation. TEA decreased HR and decreased capillary perfusion of the villi microcirculation compared with the sham group (P = 0.002). CONCLUSIONS: Selective inhibition of KATP-channels in ovine endotoxemic shock with glipizide partially restored vasomotor tone without exerting harmful effects on intestinal microcirculation in septic shock in rats. On the contrary, nonselective K-channel inhibition with TEA showed deleterious effects in both models, including impaired microcirculation and decreased survival time. Future research on glipizide in vasodilatory shock may be warranted.

Glycocalyx Degradation Is Independent of Vascular Barrier Permeability Increase in Nontraumatic Hemorrhagic Shock in Rats.

BACKGROUND: Glycocalyx shedding after traumatic hemorrhagic or septic shock, as well as different resuscitation fluids, has been causally linked to increased vascular barrier permeability (VBP) resulting in tissue edema. In nontraumatic hemorrhagic shock (NTHS), it remains questionable whether glycocalyx degradation in itself results in an alteration of VBP. The composition of fluids can also have a modulatory effect on glycocalyx shedding and VBP. We hypothesized that the shedding of the glycocalyx during NTHS has little effect on VBP and that the composition of fluids can modulate these effects. METHODS: Fully instrumented Wistar-albino rats were subjected to a pressure-controlled NTHS (mean arterial pressure of 30 mm Hg) for 60 minutes. Animals were fluid resuscitated with Ringer's acetate, balanced hydroxyethyl starch (HES) solution, or 0.9% normal saline to a mean arterial pressure of 80 mm Hg and compared with shams or nonresuscitated NTHS. Glycocalyx shed products were determined at baseline and 60 minutes after fluid resuscitation. Skeletal muscle microcirculation was visualized using handheld vital microscopy. VBP changes were assessed using plasma decay of 3 fluorescent dyes (40- and 500-kDa dextran and 70-kDa albumin), Evans blue dye exclusion, intravital fluorescence microscopy, and determination of tissue edema (wet/dry weight ratio). RESULTS: All glycocalyx shedding products were upgraded as a result of NTHS. Syndecan-1 significantly increased in NTHS (mean difference, -1668; 95% confidence interval [CI], -2336 to -1001; P < .0001), balanced crystalloid (mean difference, -964.2; 95% CI, -1492 to -436.4; P = .0001), and HES (mean difference, -1030; 95% CI, -1594 to -465.8; P = .0001) groups at the end of the experiment compared to baseline. Hyaluronan levels were higher at the end of the experiment in nonresuscitated NTHS (-923.1; 95% CI, -1216 to -630; P = .0001) and balanced crystalloid (-1039; 95% CI, -1332 to -745.5; P = .0001) or HES (-394.2; 95% CI, -670.1 to -118.3; P = .0027) groups compared to controls. Glycocalyx shedding resulted in microcirculation alterations as observed by handheld video microscopy. Total vessel density was altered in the normal saline (mean difference, 4.092; 95% CI, 0.6195-7.564; P = .016) and hemorrhagic shock (mean difference, 5.022; 95% CI, 1.55-8.495; P = .0024) groups compared to the control group, as well as the perfused vessel density and mean flow index. Despite degradation of endothelial glycocalyx, VBP as determined by 4 independent assays remained intact and continued to be so following fluid resuscitation. CONCLUSIONS: NTHS induced glycocalyx shedding and microcirculation alterations, without altering VBP. Fluid resuscitation partially restored the microcirculation without altering VBP. These results challenge the concept that the glycocalyx barrier is a significant contributor to VBP.

The Effect of Propofol and Dexmedetomidine Sedation on Norepinephrine Requirements in Septic Shock Patients: A Crossover Trial.

OBJECTIVES: Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. α-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the α-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock. DESIGN: Prospective open-label crossover study. SETTINGS: University hospital, ICU. PATIENTS: Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between -3 and -4. INTERVENTIONS: An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between -3 and -4 was maintained during the study period. MEASUREMENTS AND MAIN RESULTS: Norepinephrine requirements decreased from 0.69 ± 0.72 µg/kg/min before dexmedetomidine to 0.30 ± 0.25 µg/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 ± 0.36 µg/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 ± 0.2 µg/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 µg/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was -4 (-4 to -3) before, -4 (-4 to -3) during, and -4 (-4 to -4) after dexmedetomidine (p = 0.07). CONCLUSIONS: For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients.

Sole causal therapy worsens outcome as compared to no therapy and combined causal and goal-directed supportive therapy in ovine septic shock.

BACKGROUND: There is clear evidence that early causal therapy improves outcome in sepsis and septic shock, whereas recent studies on supportive hemodynamic therapy have produced very conflictive results. The objective of the present study was to determine whether a supportive hemodynamic therapy guided by clinically relevant invasive monitoring improves survival and organ function in a high-lethality model of septic shock in sheep as compared to sole causal therapy including surgical and antimicrobial treatment. METHODS: Twenty healthy ewes were anaesthetized and instrumented for hemodynamic surveillance. After laparotomy and fecal withdrawal from the caecum, animals were randomly assigned to one of four groups: sham, control, causal and combined therapy. In all groups but the sham group, feces were injected into the peritoneal cavity. Septic shock was defined as mean arterial pressure (MAP) ≤60 mmHg and arterial lactate concentration ≥1.8 mmol·L-1. Animals of the control group received no therapy, while the causal group received broad-spectrum antibiotic therapy and peritoneal lavage. The combined therapy group received causal therapy plus supportive hemodynamic therapy. RESULTS: The sham animals showed no signs of systemic infection, while all other animals developed septic shock with arterial hypotension and lactic acidosis within 4.0 (4.0-6.8) hours. Induction of causal therapy did not impact on haemodynamics as compared to the control group. Notably, 50% of the control animals and none of the causal therapy animals survived the study. Combined therapy stabilized haemodynamics and improved organ function and survival as compared to control and causal therapy groups. CONCLUSIONS: The present data suggest that sole causal sepsis therapy without hemodynamic support worsens outcome even more than natural evolution of sepsis and combined causal and supportive therapy. This underlines the importance of early hemodynamic stabilization in parallel with antibiotic and surgical treatment of the sepsis focus.

Propofol vs. inhalational agents to maintain general anaesthesia in ambulatory and in-patient surgery: a systematic review and meta-analysis.

BACKGROUND: It is unclear if anaesthesia maintenance with propofol is advantageous or beneficial over inhalational agents. This study is intended to compare the effects of propofol vs. inhalational agents in maintaining general anaesthesia on patient-relevant outcomes and patient satisfaction. METHODS: Studies were identified by electronic database searches in PubMed™, EMBASE™ and the Cochrane™ library between 01/01/1985 and 01/08/2016. Randomized controlled trials (RCTs) of peer-reviewed journals were studied. Of 6688 studies identified, 229 RCTs were included with a total of 20,991 patients. Quality control, assessment of risk of bias, meta-bias, meta-regression and certainty in evidence were performed according to Cochrane. Common estimates were derived from fixed or random-effects models depending on the presence of heterogeneity. Post-operative nausea and vomiting (PONV) was the primary outcome. Post-operative pain, emergence agitation, time to recovery, hospital length of stay, post-anaesthetic shivering and haemodynamic instability were considered key secondary outcomes. RESULTS: The risk for PONV was lower with propofol than with inhalational agents (relative risk (RR) 0.61 [0.53, 0.69], p < 0.00001). Additionally, pain score after extubation and time in the post-operative anaesthesia care unit (PACU) were reduced with propofol (mean difference (MD) - 0.51 [- 0.81, - 0.20], p = 0.001; MD - 2.91 min [- 5.47, - 0.35], p = 0.03). In turn, time to respiratory recovery and tracheal extubation were longer with propofol than with inhalational agents (MD 0.82 min [0.20, 1.45], p = 0.01; MD 0.70 min [0.03, 1.38], p = 0.04, respectively). Notably, patient satisfaction, as reported by the number of satisfied patients and scores, was higher with propofol (RR 1.06 [1.01, 1.10], p = 0.02; MD 0.13 [0.00, 0.26], p = 0.05). Secondary analyses supported the primary results. CONCLUSIONS: Based on the present meta-analysis there are several advantages of anaesthesia maintenance with propofol over inhalational agents. While these benefits result in an increased patient satisfaction, the clinical and economic relevance of these findings still need to be addressed in adequately powered prospective clinical trials.

Clinical significance and risk factors for new onset and recurring atrial fibrillation following cardiac surgery - a retrospective data analysis.

BACKGROUND: Although mortality after cardiac surgery has significantly decreased in the last decade, patients still experience clinically relevant postoperative complications. Among others, atrial fibrillation (AF) is a common consequence of cardiac surgery, which is associated with prolonged hospitalization and increased mortality. METHODS: We retrospectively analyzed data from patients who underwent coronary artery bypass grafting, valve surgery or a combination of both at the University Hospital Muenster between April 2014 and July 2015. We evaluated the incidence of new onset and intermittent/permanent AF (patients with pre- and postoperative AF). Furthermore, we investigated the impact of postoperative AF on clinical outcomes and evaluated potential risk factors. RESULTS: In total, 999 patients were included in the analysis. New onset AF occurred in 24.9% of the patients and the incidence of intermittent/permanent AF was 59.5%. Both types of postoperative AF were associated with prolonged ICU length of stay (median increase approx. 2 days) and duration of mechanical ventilation (median increase 1 h). Additionally, new onset AF patients had a higher rate of dialysis and hospital mortality and more positive fluid balance on the day of surgery and postoperative days 1 and 2. In a multiple logistic regression model, advanced age (odds ratio (OR) = 1.448 per decade increase, p < 0.0001), a combination of CABG and valve surgery (OR = 1.711, p = 0.047), higher C-reactive protein (OR = 1.06 per unit increase, p < 0.0001) and creatinine plasma concentration (OR = 1.287 per unit increase, p = 0.032) significantly predicted new onset AF. Higher Horowitz index values were associated with a reduced risk (OR = 0.996 per unit increase, p = 0.012). In a separate model, higher plasma creatinine concentration (OR = 2.125 per unit increase, p = 0.022) was a significant risk factor for intermittent/permanent AF whereas higher plasma phosphate concentration (OR = 0.522 per unit increase, p = 0.003) indicated reduced occurrence of this arrhythmia. CONCLUSIONS: New onset and intermittent/permanent AF are associated with adverse clinical outcomes of elective cardiac surgery patients. Different risk factors implicated in postoperative AF suggest different mechanisms might be involved in its pathogenesis. Customized clinical management protocols seem to be warranted for a higher success rate of prevention and treatment of postoperative AF.

Propofol or benzodiazepines for short- and long-term sedation in intensive care units? An economic evaluation based on meta-analytic results.

PURPOSE: This evaluation compares propofol and benzodiazepine sedation for mechanically ventilated patients in intensive care units (ICUs) in order to identify the potential economic benefits from different payers' perspectives. METHODS: The patient-level simulation model incorporated efficacy estimates from a structured meta-analysis and ICU-related costs from Italy, Germany, France, UK, and the USA. Efficacy outcomes were ICU length of stay (LOS), mechanical ventilation duration, and weaning time. We calculated ICU costs from mechanical ventilation duration and ICU LOS based on national average ICU costs with and without mechanical ventilation. Three scenarios were investigated: 1) long-term sedation >24 hours based on results from randomized controlled trials (RCTs); 2) long-term sedation based on RCT plus non-RCT results; and 3) short-term sedation <24 hours based on RCT results. We tested the model's robustness for input uncertainties by deterministic (DSA) and probabilistic sensitivity analyses (PSA). RESULTS: In the base case, mean savings with propofol versus benzodiazepines in long-term sedation ranged from €406 (95% confidence interval [CI]: 646 to 164) in Italy to 1,632 € (95% CI: 2,362 to 880) in the USA. Inclusion of non-RCT data corroborated these results. Savings in short-term sedation ranged from €148 (95% CI: 291 to 2) in Italy to €502 (95% CI: 936 to 57) in the USA. Parameters related to ICU and mechanical ventilation had a stronger influence in the DSA than drug-related parameters. In PSA, propofol reduced costs and ICU LOS compared to benzodiazepines in 94%-100% of simulations. The largest savings may be possible in the UK and the USA due to higher ICU costs. CONCLUSION: Current ICU sedation guidelines recommend propofol rather than midazolam for mechanically ventilated patients. This evaluation endorses the recommendation as it may lead to better outcomes and savings for health care systems, especially in countries with higher ICU-related costs.