Adjusting Acute Kidney Injury Kidney Disease: Improving Global Outcomes Urine Output Criterion for Predicted Body Weight Improves Prediction of Hospital Mortality.

BACKGROUND: Based on the Kidney Disease: Improving Global Outcomes (KDIGO) definitions, urine output, serum creatinine, and need for kidney replacement therapy are used for staging acute kidney injury (AKI). Currently, AKI staging correlates strongly with mortality and can be used as a predictive tool. However, factors associated with the development of AKI may affect its predictive ability. We tested whether adjustment for predicted (versus actual) body weight improved the ability of AKI staging to predict hospital mortality. METHODS: A total of 3279 patients who had undergone cardiac surgery in a university hospital were retrospectively analyzed. AKI was staged according to KDIGO criteria (standard staging) and after adjustment for hourly urine output adjusted by predicted body weight for each patient and each day of their hospital stay. RESULTS: The incidence of AKI (all stages) was 43% (predicted body weight adjusted) and 50% (standard staging), respectively ( P < .001). In sensitivity-specificity analyses for predicting hospital mortality, the area under the curve was significantly higher after adjustment for predicted body weight than with standard staging ( P = .002). CONCLUSIONS: Compared to standard staging, adjustment of urine output for predicted body weight increases the specificity and improves prediction of hospital mortality in patients undergoing cardiac surgery.

Population pharmacokinetics of vancomycin in patients with external ventricular drain-associated ventriculitis.

BACKGROUND: To determine the distribution of vancomycin into the cerebrospinal fluid (CSF) in patients with external ventricular drain (EVD)-associated ventriculitis, the pharmacokinetics of vancomycin were evaluated and covariate relationships explored. METHODS: For the population pharmacokinetic model patients were recruited in a neurocritical care unit at the University Hospital of Muenster in the period between January 2014 and June 2015. All patients had a clinical evidence of EVD-associated ventriculitis. Population pharmacokinetic analysis of vancomycin was performed using NONMEM. RESULTS: A total of 184 blood and 133 CSF samples were collected from 29 patients. The final population pharmacokinetic model is a three-compartment model with linear elimination. Creatinine clearance (ClCr ) and CSF-lactate were detected as significant covariates, showing that the total vancomycin plasma clearance (Cl) depends on ClCr and furthermore the clearance (Cldif ) between the central and CSF compartment correlates with CSF lactate concentration. Based on the final model, the following values were estimated by NONMEM: Cl = 5.15 L/h, Q (intercompartmental clearance) = 3.31 L/h, Cldif  = 0.0031 L/h, Vcentral  = 42.1 L, VCSF  = 0.32 L and the value of Vperipheral was fixed to 86.2 L. With the developed pharmacokinetic model, area under the curve (AUC) values as well as CSF trough levels were simulated. CONCLUSION: Based on our analysis, the dosing of vancomycin should be referred to the degree of inflammation (derived from the CSF lactate concentration) and renal function (derived from ClCr ).

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.

Resuscitation with Hydroxyethyl Starch Maintains Hemodynamic Coherence in Ovine Hemorrhagic Shock.

BACKGROUND: Fluid resuscitation in hemorrhagic shock aims to restore hemodynamics and repair altered microcirculation. Hemodynamic coherence is the concordant performance of macro- and microcirculation. The present study on fluid therapy in hemorrhagic shock hypothesized that the choice of fluid (0.9% sodium chloride [saline group] or balanced 6% hydroxyethyl starch 130/0.4 [hydroxyethyl starch group]) impacts on hemodynamic coherence. METHODS: After instrumentation, 10 sheep were bled up to 30 ml/kg body weight of blood stopping at a mean arterial pressure of 30 mmHg to establish hemorrhagic shock. To reestablish baseline mean arterial pressure, they received either saline or hydroxyethyl starch (each n = 5). Hemodynamic coherence was assessed by comparison of changes in mean arterial pressure and both perfused vessel density and microvascular flow index. RESULTS: Bleeding of 23 ml/kg blood [21; 30] (median [25th; 75th percentile]) in the saline group and 24 ml/kg [22; 25] (P = 0.916) in the hydroxyethyl starch group led to hemorrhagic shock. Fluid resuscitation reestablished baseline mean arterial pressure in all sheep of the hydroxyethyl starch group and in one sheep of the saline group. In the saline group 4,980 ml [3,312; 5,700] and in the hydroxyethyl starch group 610 ml [489; 615] of fluid were needed (P = 0.009). In hemorrhagic shock perfused vessel density (saline from 100% to 83% [49; 86]; hydroxyethyl starch from 100% to 74% [61; 80]) and microvascular flow index (saline from 3.1 [2.5; 3.3] to 2.0 [1.6; 2.3]; hydroxyethyl starch from 2.9 [2.9; 3.1] to 2.5 [2.3; 2.7]) decreased in both groups. After resuscitation both variables improved in the hydroxyethyl starch group (perfused vessel density: 125% [120; 147]; microvascular flow index: 3.4 [3.2; 3.5]), whereas in the saline group perfused vessel density further decreased (64% [62; 79]) and microvascular flow index increased less than in the hydroxyethyl starch group (2.7 [2.4; 2.8]; both P < 0.001 for saline vs. hydroxyethyl starch). CONCLUSIONS: Resuscitation with hydroxyethyl starch maintained coherence in hemorrhagic shock. In contrast, saline only improved macro- but not microcirculation. Hemodynamic coherence might be influenced by the choice of resuscitation fluid.

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.

A new complimentary web-based tool for manual analysis of microcirculation videos: Validation of the Capillary Mapper against the current gold standard AVA 3.2.

OBJECTIVE: The aim of the current study was to compare a newly developed web-based freely accessible software program for manual analysis of the microcirculation, the Capillary Mapper (CM), with AVA 3.2 software (AVA; MicroVision Medical B.V., Amsterdam, The Netherlands), which is the current gold standard for analysis of microcirculation videos. METHODS: A web-based software program was developed, which enables manual analysis of videos of the microcirculation to be carried out according to recommendations of the 2018 consensus conference. A set of 50 high quality microcirculation videos was analyzed with AVA and CM with respect to total vessel density, perfused vessel density, proportion of perfused vessels, and the microvascular flow index. RESULTS: Comparison of the mean values derived from manual analysis with CM and AVA revealed no significant differences in microcirculatory variables. Analysis according to Bland and Altman revealed an acceptable bias between manual analysis with the CM and AVA for all variables tested with sufficient limits of agreement. The analysis of intraclass correlation showed "excellent" agreement for all microcirculatory variables analyzed. CONCLUSIONS: The newly developed CM was successfully validated for manual analyses of microcirculation videos against the current gold standard, the software AVA 3.2.

Feasibility of optical coherence tomography angiography to assess changes in retinal microcirculation in ovine haemorrhagic shock.

BACKGROUND: This study aimed to investigate the feasibility of optical coherence tomography angiography (OCT-A) for quantitative analysis of flow density to assess changes in retinal perfusion in an experimental model of haemorrhagic shock. METHODS: Haemorrhagic shock was induced in five healthy, anaesthetized sheep by stepwise blood withdrawal of 3 × 10 ml∙kg- 1 body weight. OCT-A imaging of retinal perfusion was performed using an OCT device. Incident dark-field illumination microscopy videos were obtained for the evaluation of conjunctival microcirculation. Haemodynamic variables and flow density data in the OCT angiogram were analysed before and during progressive haemorrhage resulting in haemorrhagic shock as well as after fluid resuscitation with 10 ml∙kg- 1 body weight of balanced hydroxyethyl starch solution (6% HES 130/0.4). Videos of the conjunctival microcirculation were recorded at baseline, in haemorrhagic shock, and after resuscitation. Data are presented as median with interquartile range. Comparisons between time points were made using Friedman's test and the degree of correlation between two variables was expressed as Spearman's rank correlation coefficient. RESULTS: Mean arterial pressure and cardiac index (CI) decreased and lactate concentration increased after induction of shock, and haemodynamics recovered after resuscitation. The flow density in the superficial retinal OCT angiogram decreased significantly after shock induction (baseline 44.7% (40.3; 50.5) vs haemorrhagic shock 34.5% (32.8; 40.4); P = 0.027) and recovered after fluid resuscitation (46.9% (41.7; 50.7) vs haemorrhagic shock; P = 0.027). The proportion of perfused vessels of the conjunctival microcirculation showed similar changes. The flow density measured using OCT-A correlated with the conjunctival microcirculation (perfused vessel density: Spearman's rank correlation coefficient ρ = 0.750, P = 0.001) and haemodynamic parameters (CI: ρ = 0.693, P < 0.001). CONCLUSIONS: Retinal flow density, measured using OCT-A, significantly decreased in shock and recovered after fluid therapy in an experimental model of haemorrhagic shock. OCT-A is feasible to assess changes in retinal perfusion in haemorrhagic shock and fluid resuscitation.

Provision of physiological data and reference values in awake and anaesthetized female sheep aged 6-12 months.

OBJECTIVE: To provide physiological data and reference values in awake and anaesthetized sheep aged 6-12 months. STUDY DESIGN: Descriptive study. ANIMALS: Data from 260 female sheep of the species Ovis orientalis aries aged 6-12 months were extracted from 10 experimental trials. METHODS: Data from pulmonary arterial thermodilution in awake (cohort 1; n = 109) and anaesthetized animals (cohort 2; n = 81), and transpulmonary thermodilution in anaesthetized animals (cohort 3; n = 70) were analysed. General anaesthesia was induced by intramuscular injection of S-ketamine and midazolam and maintained by inhaled isoflurane. Standard laboratory variables (blood gas and clinical chemistry) were assessed. RESULTS: A total of 7553 single data entries from 260 healthy sheep were included. Measurement errors or invalid data documentation meant that 313 data entries (4.1%) were excluded. A small confidence interval for median values was calculated for nearly all variables. The median body weight was 39.8 kg (2.5-97.5th percentile 30.6-48.1 kg). A set of reference values (2.5-97.5th percentiles) is provided for common cardiopulmonary and laboratory variables. Compared to awake animals, haemodynamic variables were markedly influenced by anaesthesia, as reflected by a considerably lower stroke volume index in anaesthetized sheep. There were also differences in stroke volume index between the cohorts of pulmonary artery and transpulmonary thermodilution. CONCLUSIONS AND CLINICAL RELEVANCE: The present work presents a large and consistent database of a variety of physiological variables measured in healthy juvenile female sheep. The data appear to be robust and allow the establishment of standardized inclusion criteria for experimental studies and may help to better evaluate past, present and future research. Differences between pulmonary artery and transpulmonary thermodilution should be assessed in future studies.

Impact of human albumin infusion on organ function in orthotopic liver transplantation--a retrospective matched-pair analysis.

BACKGROUND: The purpose of this study was to retrospectively analyze the impact of human albumin (HA) substitution on organ function in patients undergoing orthotopic liver transplantation (OLT). METHODS: We retrospectively analyzed chart data of 15 hypoalbuminemic patients who received continuous infusion of HA (100 g/d) for seven d following OLT and matched them with 15 control patients for severity scores at admission. Primary endpoint was a difference in mean "sequential organ failure assessment" (SOFA) score during 14 d following OLT. Secondary endpoints included SOFA subscores, length of intensive care unit (ICU) stay, ICU mortality, one-yr mortality, fluid balance, colloid osmotic pressure (COP), serum albumin, and total protein concentrations. RESULTS: Substitution of HA was associated with a lower mean SOFA score as compared to control (11.0 ± 3.6 vs. 13.4 ± 3.7; p < 0.001). Patients treated with HA also exhibited lower cardiovascular SOFA subscore and higher COP, serum albumin, and total protein concentrations. There were no significant differences in fluid balance, length of ICU stay, ICU mortality, or one-yr mortality. CONCLUSIONS: The present data suggest that continuous infusion of HA may preserve cumulative organ function (as measured by SOFA score) with emphasis on cardiovascular function in patients following OLT.

The race against the "septic shark".

Great white sharks are responsible for about 10 cases of death annually worldwide, as compared with millions of deaths caused by sepsis. However, the basic principles of avoiding shark attacks and fighting sepsis seem to be similar: avoidance, attention, and speed, if necessary. The present review discusses the current status of the systemic inflammatory response syndrome (SIRS) criteria, which are actually content for discussion because of their low specificity. Current data suggest that one in eight patients with severe sepsis does not fulfill the SIRS criteria and is consequently missed, and therefore the calls for new definitions of sepsis are getting louder. Furthermore, the need for early treatment of sepsis and fast admission to an intensive care unit (ICU) with experienced stuff is reviewed as well as the early and appropriate initiation of therapy, namely antibiotic and volume therapy. A key feature is the analysis of the studies from the so-called "Sepsis Trilogy" (ProCESS, ARISE, and ProMiSe studies), with a focus on the status of early goal-directed therapy (EGDT). The authors of the "Sepsis Trilogy" concluded that there is no benefit regarding survival in septic patients by using EGDT as compared with standard therapy. However, the low mortality of the control groups within the "Sepsis Trilogy" studies as compared with the Rivers et al. study from 2001 leads to the conclusion that there has been an improvement in the therapy of septic patients, most probably due to the early initiation of therapy as a kind of "standard" in sepsis therapy. Finally, the phenomenon of a "large trial disease" is discussed, exemplary in a trial which investigated the maintenance of the "right" mean arterial pressure in sepsis patients. Even if the result of a large randomized trial might be that there is no difference between two study groups, the real exercise is to identify the patient collectives who might benefit or experience harm due to an intervention. In summary, as compared with swimming in dangerous waters, high attention is needed in handling septic patients. Once an attack has occurred, speed is of utmost importance (i.e., initiation of therapy and admission to the ICU) because it appears logical that time is critical in septic patients This may have resulted in the implementation of early (goal-directed) treatment as a "standard" in the treatment of sepsis with significant improvement in survival.

Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study.

OBJECTIVE: ß-blocker therapy may control heart rate and attenuate the deleterious effects of ß-stimulating catecholamines in septic shock. However, their negative chronotropy and inotropy may potentially lead to an inappropriately low cardiac output, with a subsequent compromise of microvascular blood flow. The purpose of the present pilot study was to investigate the effects of reducing heart rate to less than 95 beats per minute in patients with septic shock using the ß-1 adrenoceptor blocker, esmolol, with specific focus on systemic hemodynamics and the microcirculation. DESIGN: Prospective, observational clinical study. SETTING: Multidisciplinary ICU at a university hospital. MEASUREMENTS AND MAIN RESULTS: After 24 hours of initial hemodynamic optimization, 25 septic shock patients with a heart rate greater than or equal to 95 beats per minute and requiring norepinephrine to maintain mean arterial pressure greater than or equal to 65 mm Hg received a titrated esmolol infusion to maintain heart rate less than 95 beats per minute. Sublingual microcirculatory blood flow was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 24 hours after esmolol administration. Heart rates targeted between 80 and 94 beats per minute were achieved in all patients. Whereas cardiac index decreased (4.0 [3.5; 5.3] vs 3.1 [2.6; 3.9] L/min/m; p<0.001), stroke volume remained unchanged (34 [37; 47] vs 40 [31; 46] mL/beat/m; p=0.32). Microcirculatory blood flow in small vessels increased (2.8 [2.6; 3.0] vs 3.0 [3.0; 3.0]; p=0.002), while the heterogeneity index decreased (median 0.06 [interquartile range 0; 0.21] vs 0 [0; 0]; p=0.002). PaO2 and pH increased while PaCO2 decreased (all p<0.05). Of note, norepinephrine requirements were significantly reduced by selective ß-1 blocker therapy (0.53 [0.29; 0.96] vs 0.41 [0.22; 0.79] µg/kg/min; p=0.03). CONCLUSIONS: This pilot study demonstrated that heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular blood flow, and a reduction in norepinephrine requirements.

Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial.

IMPORTANCE: ß-Blocker therapy may control heart rate and attenuate the deleterious effects of ß-adrenergic receptor stimulation in septic shock. However, ß-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting ß-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P < .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 µg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 µg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P < .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01231698.

Fluid therapy in critical illness: a special focus on indication, the use of hydroxyethyl starch and its different raw materials.

PURPOSE OF REVIEW: Fluid therapy is a complex intervention with insufficient resuscitation, as well as overinfusion and fluid accumulation being associated with adverse outcomes. Early goal-directed therapy with later conservative fluid management (i.e. prevention of positive fluid balance and weight gain) appears to markedly improve the survival of patients with severe sepsis. The impact of colloids in resuscitation of patients with sepsis has been the topic of several recently published studies. The purpose of the present review is to outline the indication of fluid administration in critically ill patients, discuss the recent findings of trials involving hydroxyethyl starch (HES) solutions and highlight the impact of different raw materials for HES synthesis. RECENT FINDINGS: Pragmatic trials of modern HES solutions versus crystalloids in critically ill patients show either no difference or adverse outcomes associated with HES infusion. However, fluid therapy was not protocolized in most of these studies and probably associated with overinfusion and hemodilution. Data on the use of waxy maize-derived 6% HES 130/0.4 during early goal-directed therapy show no evidence for harm and an improvement in microvascular blood flow. In addition, experimental data suggest that waxy maize-derived 6% HES 130/0.4 may have different biological effects compared to potato-derived 6% HES 130/0.42 with potentially reduced pulmonary inflammation. SUMMARY: Adverse effects of fluid resuscitation in critically ill patients appear to be a consequence of dose and timing rather than the type of fluid itself. Modern waxy maize-derived 6% HES 130/0.4 may have advantages over crystalloids in the very early course of the disease. Clinical trials of early, goal-directed and protocolized therapy with innovative endpoints of resuscitation comparing balanced crystalloids and balanced, waxy maize-derived 6% HES 130/0.4 as the initial resuscitation fluid are warranted.

A model of porcine polymicrobial septic shock.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Mortality of patients with sepsis is high and largely unchanged throughout the past decades. Animal models have been widely used for the study of sepsis and septic shock, but translation into effective treatment regimes in the clinic have mostly failed. Pigs are considered as suitable research models for human diseases due to their high comparability and similarity to human anatomy, genetics, and the immune system. We here evaluated the previously reported models of septic shock in pigs and established a novel model of polymicrobial sepsis that meets the clinical criteria of septic shock in pigs. MATERIALS AND METHODS: The literature search was performed using the keywords "pig", "sepsis" and "septic shock". For the establishment of septic shock in n = 10 German landrace pigs, mechanical ventilation was initiated, central venous and arterial lines and invasive hemodynamic monitoring via pulse contour cardiac output measurement (PiCCO) established. Peritoneal polymicrobial faecal sepsis was induced by application of 3 g/kg body weight faeces into the abdominal cavity. Septic shock was defined according to the third international consensus definitions (Sepsis-3). Upon shock, pigs underwent the 1-h bundle for the treatment of human sepsis. Cytokine levels were measured by ELISA. RESULTS: Published porcine sepsis models exhibited high methodological variability and did not meet the clinical criteria of septic shock. In our model, septic shock developed after an average of 4.8 ± 0.29 h and was associated with a reproducible drop in blood pressure (mean arterial pressure 54 ± 1 mmHg) and significant hyperlactatemia (3.76 ± 0.65 mmol/L). Septic shock was associated with elevated levels of interleukin-6 (IL6) and initial cardiac depression followed by a hyperdynamic phase with significant loss of systemic vascular resistance index after initial resuscitation. In addition, organ dysfunction (acute kidney injury) occurred. CONCLUSIONS: We here established a model of septic shock in pigs that meets the clinical criteria of septic shock utilized in human patients. Our model may thus serve as a reference for clinically relevant sepsis research in pigs.

Fluid resuscitation in patients with traumatic brain injury: what is a SAFE approach?

PURPOSE OF REVIEW: In patients with traumatic brain injury (TBI), dysfunction of the neurovascular unit ('blood-brain barrier') is a common finding, resulting in maldistribution of water and osmoles within the brain. The purpose of the present article is to review the underlying physiology of osmolality and fluid therapy in TBI. RECENT FINDINGS: The findings of the 'Saline versus Albumin Fluid Evaluation' study suggest that infusion of colloidal solutions is associated with adverse outcomes as compared with sole crystalloid infusion in patients suffering from TBI. Comparison of calculated osmolarity and measured in-vitro osmolality suggests that human albumin solutions, Hartmann's solution, and, to a lesser extent, gelatine preparations are hypo-osmolar, and may, therefore, increase brain volume and intracranial pressure. SUMMARY: In the context of the published literature on this topic, it appears that the osmolality of an infusion solution rather than the colloid osmotic pressure per se represents the key determinant in the pathogenesis of cerebral edema formation.

Effects of balanced crystalloid vs. 0.9% saline-based vs. balanced 6% tetrastarch infusion on renal function and tubular integrity in ovine endotoxemic shock.

OBJECTIVE: Conflicting data exist on the renal effects of hydroxyethyl starch preparations. The aim of the present study was to evaluate the impact of balanced crystalloids, as well as 0.9% saline-based and balanced 6% tetrastarch solutions, on renal function and ultrastructural morphologic correlates of acute kidney injury in an established model of ovine endotoxemic shock. DESIGN: Randomized, controlled, experimental study. SETTING: Animal research facility of a university hospital. SUBJECTS: A total of 31 awake instrumented sheep. INTERVENTIONS: The animals were subjected to continuous endotoxin infusion (Salmonella typhosa) at incremental doses until the mean arterial pressure was <65 mm Hg and arterial lactate was ≥ 2 mmol·L⁻¹ or (if arterial hypotension was absent) arterial lactate was ≥ 4 mmol·L⁻¹. The subjects were then randomized to receive no fluid resuscitation (control group, n = 5) or blinded infusion of a balanced crystalloid (n = 9), 0.9% saline-based (n = 8), or balanced 6% hydroxyethyl starch 130/0.4 (n = 9) up to a maximum dose of 50 mL·kg⁻¹, followed by open-label infusion of balanced crystalloid. Animals surviving the 12-hr intervention period were deeply anesthetized and killed. Kidney samples were taken immediately for transmission electron microscopic analyses. Additional specific experiments were performed to take kidney samples ex vivo. MEASUREMENTS AND MAIN RESULTS: Endotoxemia was associated with arterial hypotension and capillary leakage. Fluid resuscitation established a hypotensive-hyperdynamic circulation in all resuscitated animals without significant hemodynamic differences among groups. Plasma creatinine and urea concentrations were higher in both hydroxyethyl starch groups as compared to the crystalloid group (creatinine, 1.2 ± 0.1 and 1.4 ± 0.3 vs. 0.8 ± 0.1 mg·dL⁻¹; urea, 21 ± 1 and 21 ± 2 vs. 17 ± 2 mg·dL⁻¹; p < .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids at 8 hrs). In contrast, kidney function, as measured by creatinine clearance and cumulative creatinine excretion, was similar between the colloid and crystalloid treatment groups (creatinine clearance at 8 hrs, 122 ± 18 and 108 ± 31 vs. 107 ± 13 mL·min⁻¹·m⁻²; creatinine excretion per hour alive, 283 ± 29 and 264 ± 19 vs. 291 ± 24 mg·hr⁻¹; p > .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids), whereas kidney function deteriorated markedly in control animals. The electron microscopic tubular injury score was lower in hydroxyethyl starch-treated animals as compared to the crystalloid group. Vacuolar tubular cell alterations were present in all groups. The percentage of intact microvilli brush borders was significantly higher in sheep treated with either hydroxyethyl starch solution as compared to the other groups. CONCLUSIONS: The present study provides evidence that renal function, as measured by creatinine clearance and cumulative creatinine excretion as well as ultrastructural tubular integrity, is preserved with the use of 6% tetrastarch solutions despite increases in plasma levels of renal retention variables in ovine endotoxemic shock.

Effects of two different dosing regimens of terlipressin on organ functions in ovine endotoxemia.

OBJECTIVE AND DESIGN: To test the hypothesis that a continuous infusion of the vasopressin analog terlipressin is associated with less organ dysfunction as compared to intermittent bolus infusion in an ovine sepsis model. SUBJECTS: Twenty-seven adult female sheep. TREATMENT: All sheep were subjected to a Salmonella typhosa endotoxin infusion (10 ng/kg/min). After 16 h of endotoxemia, the surviving animals (n = 24) were randomized to (1) an untreated control group, (2) a continuous terlipressin group (2 mg/24 h), or (3) a terlipressin bolus group (1 mg/6 h). METHODS: Hemodynamic variables were measured and blood was withdrawn at specific time points for the assessment of organ functions. RESULTS: Continuous terlipressin infusion was associated with improved surrogate parameters of myocardial, renal, and hepatic function as compared with terlipressin bolus infusion. Reduced vascular hyperpermeability was evidenced by an attenuated decrease in plasma protein concentrations in sheep treated with continuous terlipressin infusion as compared to bolus injection or no treatment. CONCLUSIONS: Continuous infusion of low-dose terlipressin preserved several surrogate parameters of organ function better than intermittent bolus injections in sheep with systemic inflammation.

Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock.

INTRODUCTION: The present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20% in the microvascular flow index of small vessels among groups. METHODS: The design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 µg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization. RESULTS: TP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 µg/kg/minute (0.29 to 1.04) vs. 0.16 µg/kg/minute (0.03 to 0.37) for TP and 0.40 µg/kg/minute (0.20 to 1.05) vs. 0.23 µg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7% (2.6 to 19.8) for TP, 8.9% (0.0 to 17.8) for AVP, and 6.9% (3.5 to 10.1) for placebo (P < 0.05 vs. baseline for each comparison), as well as perfused vessel density 18.6% (8.6 to 36.9) for TP, 20.2% (-3.0 to 37.2) for AVP, and 11.4% (-3.0 to 19.4) for placebo (P < 0.05 vs. baseline for each comparison). CONCLUSIONS: The present study suggests that to achieve a MAP of 65 to 75 mmHg in septic patients treated with NE, the addition of continuously infused low-dose TP or AVP does not affect sublingual microcirculatory blood flow. In addition, our results suggest that microcirculatory flow abnormalities are mainly related to other factors (for example, volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se. TRIAL REGISTRATION: ClinicalTrial.gov NCT00995839.

Fluid resuscitation in multiple trauma patients.

PURPOSE OF REVIEW: Fluid resuscitation in trauma patients with hemorrhagic shock is controversially discussed in the literature. The coincidence of brain injury complicates management of these patients. This article summarizes the current knowledge on nonblood component fluid resuscitation and choice of fluids in patients with multiple trauma. RECENT FINDINGS: Whereas current evidence suggests the efficacy of fluid therapy in hemorrhagic shock without active bleeding, experimental and clinical data demonstrate that aggressive volume challenge may be futile or even deleterious in the setting of uncontrolled hemorrhage. Large amounts of isotonic crystalloids may be associated with hypothermia, acidosis and inflammation. In patients with traumatic brain injury hypertonic solutions may positively influence inflammation and intracranial pressure without affecting neurologic outcome or mortality. SUMMARY: To date no large-scale clinical studies exist to either support or refute the use of nonblood component fluid resuscitation of hemorrhagic shock in trauma patients. The optimal choice of fluid remains to be determined, but existing evidence suggests avoiding crystalloids in favor of hypertonic solutions. The role of modern, iso-oncotic colloids in the treatment of hemorrhagic shock has not yet been sufficiently defined. In patients with concomitant brain injury, arterial hypotension must be avoided and infusion of hypotonic solutions is obsolete, whereas administration of hypertonic solutions may exert beneficial effects beyond hemodynamic stabilization.