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.

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.

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 ).

Author Correction: Optical coherence tomography angiography as a novel approach to contactless evaluation of sublingual microcirculation: A proof of principle study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Optical coherence tomography angiography as a novel approach to contactless evaluation of sublingual microcirculation: A proof of principle study.

Microcirculatory disorders are crucial in pathophysiology of organ dysfunction in critical illness. Evaluation of sublingual microcirculation is not routinely conducted in daily practice due to time-consuming analysis and susceptibility to artifacts. We investigated the suitability of optical coherence tomography angiography (OCTA) for contactless evaluation of sublingual microcirculation. Sublingual microcirculation was imaged in 10 healthy volunteers, using an OCTA device and an incident dark field (IDF) illumination microscopy (current gold standard). OCTA images were analyzed with regard to flow density and perfused vessel density (PVDbyOCTA). IDF videos were analyzed following current recommendations. Flow density was automatically extracted from OCTA images (whole en face 48.9% [43.2; 54.5]; central ring 52.6% [43.6; 60.6]). PVDbyOCTA did not differ from the PVD calculated from IDF videos (PVDbyOCTA 18.6 mm/mm² [18.0; 21.7]) vs. PVDbyIDF 21.0 mm/mm² [17.5; 22.9]; p = 0.430). Analysis according to Bland-Altman revealed a mean bias of 0.95 mm/mm² (95% Confidence interval -1.34 to 3.25) between PVDbyOCTA and PVDbyIDF with limits of agreement of -5.34 to 7.24 mm/mm². This study is the first to demonstrate the suitability of OCTA for evaluating sublingual microcirculation. Comparison of the perfused vessel density between methods showed a plausible level of agreement.

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.

Monitoring of Conjunctival Microcirculation Reflects Sublingual Microcirculation in Ovine Septic and Hemorrhagic Shock.

INTRODUCTION: The conjunctival region may serve as an alternative site for microcirculatory measurements. The present study was performed to investigate the correlation of sublingual and conjunctival microcirculation in ovine models of septic and hemorrhagic shock. METHODS: Septic shock was induced in 10 sheep by inoculation of feces into the peritoneal cavity until mean arterial pressure (MAP) was <60 mm Hg and arterial lactate level was ≥1.8 mmol· L. In another 10 sheep, hemorrhagic shock was induced by stepwise blood withdrawal of 3×10 mL·kg. Systemic hemodynamics and parameters of blood gas analysis were analyzed. Conjunctival and sublingual microcirculation were monitored and analyzed according to current recommendations. Parameters were measured at baseline and at shock time. RESULTS: Septic shock resulted in a significant drop in MAP and cardiac index (CI), and an increase in arterial lactate levels. While the total vessel density (TVD) in the sublingual microcirculation was relatively well maintained, the perfused vessel density (PVD) and the microvascular flow index (MFI) were significantly reduced in septic shock. Hemorrhagic shock reduced MAP and CI, and increased arterial lactate levels. TVD was relatively unchanged in hemorrhagic shock, while PVD and MFI were significantly decreased. The conjunctival microcirculation showed similar changes to the sublingual microcirculation in both models. CONCLUSIONS: The findings of the current study support the proposed use of the conjunctiva as an alternative site for microcirculatory monitoring in hemorrhagic and septic shock. Further studies should focus on the impact of therapy and the loss of correlation between the different microcirculatory regions in advanced shock.

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.

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.

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.

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.

Chest compression depth after change in CPR guidelines--improved but not sufficient.

AIMS: Cardiopulmonary resuscitation is one of the most vital therapeutic options for patients with cardiac arrest. Sufficient chest compression depth turned out to be of utmost importance to increase the likelihood of a return of spontaneous circulation. Furthermore, the use of real-time feedback-systems for resuscitation is associated with improvement of compression quality. The European Resuscitation Council changed their recommendation about minimal compression depth from 2005 (40 mm) to 2010 (50 mm). The aim of the present study was to determine whether this recommendation of the new guidelines was implemented successfully in an emergency medical service using a real-time feedback-system and to what extend a guideline-based CPR training leads to a "change in behaviour" of rescuers, respectively. METHODS AND RESULTS: The electronic resuscitation data of 294 patients were analyzed retrospectively within two observational periods regarding fulfilment of the corresponding chest compression guideline requirements: ERC 2005 (40 mm) 01.07.2009-30.06.2010 (n=145) and ERC 2010 (50mm) 01.07.2011-30.06.2012 (n=149). The mean compression depth during the first period was 47.1mm (SD 11.1) versus 49.6 mm (SD 12.0) within the second period (p<0.001). With respect to the corresponding ERC Guidelines 2005 and 2010, the proportion of chest compressions reaching the minimal depth decreased (73.9% vs. 49.1%) (p<0.001). There was no correlation between compression depth and patient age, sex or duration of resuscitation. CONCLUSIONS: The present study was able to show a significant increase in chest compression depth after implementation of the new ERC guidelines. Even by using a real-time feedback system we failed to sustain chest compression quality at the new level as set by ERC Guidelines 2010. In consequence, the usefulness of a fixed chest compression depth should be content of further investigations.