Randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS): protocol for a randomized controlled trial.

BACKGROUND: Albumin is a key regulator of fluid distribution within the extracellular space and has several properties beyond its oncotic activity. The accumulating evidence suggests that supplementation of albumin may provide survival advantages only when the insult is severe as in patients with septic shock. METHODS/DESIGN: The randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS) investigates whether the replacement with albumin and the maintenance of its serum levels of at least 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. Adult patients (≥ 18 years) with septic shock are randomly assigned within a maximum of 24 h after the onset of septic shock after obtaining informed consents to treatment or control groups. Patients assigned to the treatment group receive a 60-g loading dose of human albumin 20% over 2-3 h. Serum albumin levels are maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. The control group is treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock. The primary endpoint is 90 days mortality and secondary endpoints include 28-day, 60-day, ICU, and in-hospital mortality, organ dysfunction/failure, total amount of fluid administration and total fluid balance in the ICU, and lengths of ICU and hospital stay. In total, 1412 patients need to be analysed, 706 per group. For the sample size estimation, a 15% reduction in 90-day mortality is assumed, i.e. an absolute reduction of 7.5% points to 42.5% (relative risk 1.18). Assuming a dropout rate of 15%, a total of 1662 patients need to be allocated. DISCUSSION: The results of the clinical trial may influence the treatment of patients with septic shock. The expected improvement in patient survival may result in a reduction in the resources currently used in the treatment of these patients and in the socioeconomic burden of this disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03869385 . Registration on 18 July 2019. Protocol version: Final 3.0.

Transcutaneous PTCCO2 measurement in combination with arterial blood gas analysis provides superior accuracy and reliability in ICU patients.

Hyper or hypoventilation may have serious clinical consequences in critically ill patients and should be generally avoided, especially in neurosurgical patients. Therefore, monitoring of carbon dioxide partial pressure by intermittent arterial blood gas analysis (PaCO2) has become standard in intensive care units (ICUs). However, several additional methods are available to determine PCO2 including end-tidal (PETCO2) and transcutaneous (PTCCO2) measurements. The aim of this study was to compare the accuracy and reliability of different methods to determine PCO2 in mechanically ventilated patients on ICU. After approval of the local ethics committee PCO2 was determined in n = 32 ICU consecutive patients requiring mechanical ventilation: (1) arterial PaCO2 blood gas analysis with Radiometer ABL 625 (ABL; gold standard), (2) arterial PaCO2 analysis with Immediate Response Mobile Analyzer (IRMA), (3) end-tidal PETCO2 by a Propaq 106 EL monitor and (4) transcutaneous PTCCO2 determination by a Tina TCM4. Bland-Altman method was used for statistical analysis; p < 0.05 was considered statistically significant. Statistical analysis revealed good correlation between PaCO2 by IRMA and ABL (R2 = 0.766; p < 0.01) as well as between PTCCO2 and ABL (R2 = 0.619; p < 0.01), whereas correlation between PETCO2 and ABL was weaker (R2 = 0.405; p < 0.01). Bland-Altman analysis revealed a bias and precision of 2.0 ± 3.7 mmHg for the IRMA, 2.2 ± 5.7 mmHg for transcutaneous, and -5.5 ± 5.6 mmHg for end-tidal measurement. Arterial CO2 partial pressure by IRMA (PaCO2) and PTCCO2 provided greater accuracy compared to the reference measurement (ABL) than the end-tidal CO2 measurements in critically ill in mechanically ventilated patients patients.

Multicenter comparison of cortisol as measured by different methods in samples of patients with septic shock.

PURPOSE: To compare inter-laboratory and inter-assay measurements of total cortisol in patients with septic shock and to evaluate current recommendations for diagnosis of corticosteroid insufficiency in septic shock. METHODS: In the multinational CORTICUS study duplicate serum samples were taken before and after corticotropin stimulation tests in patients with septic shock. Serum cortisol was measured in paired samples, one being measured by the chemical laboratory of each participating site and the other by a central laboratory using an electrochemiluminescence immunoassay. Cortisol levels measured by tandem mass spectrometry were used as a 'gold standard' reference method in a subset of samples. RESULTS: A total of 425 corticotropin tests (850 cortisol samples) were available for comparison of local and central laboratory measurements. The concordance correlation coefficient between central laboratory immunoassay and local hospital assays was 0.98 (CI 0.97-0.99) when the immunoassay of one manufacturer was used and 0.60 (CI 0.54-0.65) when immunoassays of different manufacturers were used. The comparison with the reference method of mass spectrometry showed concordance correlation coefficients ranging from 0.43 to 0.97 depending on the assay under study. Diagnosis of corticosteroid insufficiency was diverging due to inter-assay variations in up to 27% of cases. CONCLUSION: In samples taken from patients in septic shock, there was a high inter-assay variation of total serum cortisol. Comparisons with a reference method revealed both over- and underestimations of true cortisol levels. These inter-assay variations in samples of patients with septic shock complicate the diagnosis of corticosteroid insufficiency.

Is hyperlipasemia in critically ill patients of clinical importance? An observational CT study.

OBJECTIVE: To assess morphological alterations of the pancreas by contrast-enhanced computed tomography (cCT) and subclinical cellular damage of the pancreas by measuring pancreatitis-associated protein (PAP) in critically ill patients without prior pancreatic disorder who presented with raised serum lipase levels. DESIGN: Prospective, observational study SETTING: Mixed surgical/neurosurgical intensive care unit of a German university hospital. PATIENTS: One hundred and thirty consecutive critically ill patients without prior damage or disease of the pancreas and an expected length of stay of more than 5 days. INTERVENTIONS: Daily serum lipase measurements and daily serum PAP measurements. Contrast-enhanced upper abdominal cCT study in patients with triple increase of serum lipase. MEASUREMENTS AND RESULTS: Thirty-eight patients showed raised serum lipase levels and qualified for the cCT scan study. In 20 patients cCT scans were performed. Morphological alterations of the pancreas were found in 7 out these 20 patients while serum PAP levels were raised in all patients. CONCLUSION: Hyperlipasemia is a common finding in critically ill patients without prior pancreatic disorder. While elevated serum PAP levels indicate pancreatic cellular stress morphological alterations of the pancreas are rare and of little clinical importance.

Artificial acrylic finger nails may alter pulse oximetry measurement.

INTRODUCTION: Pulse oximetry is the most common technique to monitor oxygen saturation (SpO(2)) during intensive care therapy. However, intermittent co-oximetry is still the "gold standard" (SaO(2)). Besides acrylic nails, numerous other factors have been reported to interfere with pulse oximetry. Data of measurements with artificial finger nails are not sufficiently published. MATERIALS AND METHODS: A prospective clinical-experimental trial in mechanically ventilated and critically ill patients of an ICU was performed. Patients were randomly assigned to either group S (S: Siemens pulse oximeter) or group P (P: Philips pulse oximeter) prior to the measurements. SpO(2) was determined in each patient three times alternately in standard ((N)SpO(2)) and sideways position at the natural nail ((N90)SpO(2)). For the reference measurements oxygen saturation was measured by means of a haemoximeter (co-oximetry). Thereafter, SpO(2) was obtained at the acrylic finger nail in the same way ((A)SpO(2) and (A90)SpO(2)). Bias was calculated as DeltaS=(N)SpO(2)-SaO(2) and DeltaS=(A)SpO(2)-SaO(2). Accuracy (mean difference) and precision (standard deviation) were used to determine the measurement discrepancy. P<0.05 was considered significant. RESULTS: Accuracy and precision without acrylic nails applied were comparable to SaO(2) in both groups (n.s.). With acrylic nails applied a bias of DeltaS=-1.1+/-3.14% for group S (P=0.00522) and a bias of DeltaS=+0.8+/-3.04% for group P was calculated (n.s.). CONCLUSION: Acrylic finger nails may impair the measurement of oxygen saturation depending on the pulse oximeter used and may cause significant inaccuracy. Hence, removal of artificial acrylic finger nails may be helpful to assure an accurate and precise measurement with pulse oximetry.

Effect of nail polish on oxygen saturation determined by pulse oximetry in critically ill patients.

INTRODUCTION: Nail polish of different colours may alter accuracy and precision of pulse oximetry as previous data in healthy volunteers suggest. This trial evaluates the oxygen saturation determined by pulse oximetry and haematoximetry with nail polish of nine different colours applied. MATERIAL AND METHODS: Fifty critically ill and mechanically ventilated patients in an ICU were investigated in a prospective clinical-experimental trial. On nine finger nails polish of different colours was applied in a predetermined consecutive order. Functional oxygen saturation was determined by pulse oximetry (SpO2) on each finger for each colour with the finger sensor probe both in the normal position and at a 90 degrees rotation. Simultaneously oxygen saturation was determined by haematoximetry (SaO2). Accuracy (bias, DeltaS = SaO2-SpO2) and precision (standard deviation, S.D.) of pulse oximetry were analyzed with the t-test. A value of P < 0.05 was considered significant. RESULTS: While black (DeltaS = +1.6+/-3.0%), purple (DeltaS = +1.2+/-2.6%) and dark blue nail polish (DeltaS = +1.1+/-3.5%, each N = 50) had the greatest effect (P < 0.05), all other colours, including colourless nail polish, had a smaller effect (mean bias +0.2 to +0.9%). A rotation of 90 degrees reduced the bias from +2.8 to +1.3% (N = 10, n.s.). CONCLUSION: Nail polish does not alter pulse oximetry readings in mechanically ventilated patients to a clinically relevant extent. The mean error of measurement for all colours was within the manufacturers' specified range of +/-2%. A 90 degrees rotation of the sensor probe does not eliminate errors in measurement. To remove nail polish might be helpful to decrease the error of measurement in some cases.

Changes in the serum proteome of patients with sepsis and septic shock.

BACKGROUND: Sepsis is still the leading cause of death in the intensive care unit. Our goal was to elucidate potential early differences in serum between survivors (SURV) and non-survivors (NON-SURV) on day 28. METHODS: We applied proteomic technology to serum samples of patients with sepsis and septic shock. Serum samples from 18 patients with sepsis and septic shock were obtained during the first 12 h after diagnosis of septic shock. Patients were grouped into SURV and NON-SURV on day 28. RESULTS: Seven patients survived and 11 patients died. Using proteome analysis, two-dimensional gel electrophoresis detected more than 200 spots per gel. A differential protein expression was discovered between SURV and NON-SURV, whereby protein alterations not yet described in sepsis were revealed. CONCLUSIONS: Our results show that proteomic profiling is a useful approach for detecting protein expression dynamics in septic patients, and may bring us closer to achieving a comprehensive molecular profiling compared with genetic studies alone.

Pharmacological profile and toxicity of fluorescein-labelled sinistrin, a novel marker for GFR measurements.

There is an evident and growing medical need for an accurate determination of kidney function for a broad spectrum of indications. The glomerular filtration rate (GFR) is the most accepted indicator of renal function. Due to difficulties in performing the test, GFR is currently determined rarely in clinical practice. A procedure for such GFR determination has to be safe, accurate and easy to handle. By using the new compound fluorescein isothiocyanate-sinistrin (FS) these requirements are met. The pharmacological profile and tolerability of FS, selected from among various newly synthesized, labelled compounds intended for use as GFR markers, was characterized in male Sprague-Dawley rats following i.v. application. Using the newly described fluorometric method, FS can be determined much more easily in serum and urine than with the established enzymatic method. After i.v. dosing, FS concentrations in serum declined rapidly in various experimental groups to a comparable extent (t (1/2), mean+/-SD: 22.4+/-8.3 to 26.2+/-5.4 min). Its increase after unilateral nephrectomy reflects the loss of filtration capacity. Comparable concentration-time curves of FS in serum measured fluorometrically and enzymatically suggest no relevant alteration of pharmacokinetic behaviour by the labelling. This notion is supported by the high urinary excretion rate and absence of biliary excretion. The higher sensitivity of the fluorometric method suggests a dose of FS of 100 mg in humans compared with 5 g of sinistrin or inulin. FS was well tolerated after single and multiple applications. On the basis of these results, the kinetics of FS are comparable with the gold standard inulin or sinistrin, but FS is superior in handling. Providing the data can be transferred from rat to human, determination of GFR using the new method should result in an improvement of acceptance by both physicians and patients.

Increasing hydraulic residence time in constructed stormwater treatment wetlands with designed bottom topography.

The treatment efficiency of wetlands depends primarily on the residence time of the polluted storm water (Walker, 1998). Because of this, increasing hydraulic residence times (HRTs) at various flow levels will increase the treatment efficiency of constructed wetlands. In this research, the effects of characteristic bottom topographic features that increase HRT were explored through the use of a two-dimensional hydrodynamic model. Based on numerical simulations of rectangular test wetlands, relationships were made between topographic features and their effects on HRT. Results from the simulations showed that creating baffled wetlands with multiple vertical-scale topography can markedly increase HRT, as is illustrated in a design example. When compared (using the hydrodynamic model) with a wetland having no bottom topography, the design example wetland increased HRT by 113% for the low-flow (142 L/sec) peak flood, and 39% for the 2-year flood event (1700 L/sec).

Direct fluorometric analysis of a newly synthesised fluorescein-labelled marker for glomerular filtration rate.

There is an obvious and growing medical need for an accurate determination of kidney function in the diagnosis and management of renal diseases. The glomerular filtration rate (GFR) is the accepted gold standard measurement of kidney function. Several approaches to estimate the GFR are available, but most of them are inconvenient and, therefore, of limited acceptance. A new method of quantification with fluorescein-isothiocyanate (FITC) sinistrin (FS), a novel GFR marker, has been evaluated. The method is based on the fluorescence label of FS and can be performed with a standard fluorometer. To control the interference of protein with the fluorescence signal, a calibration function was developed. The accuracy of the fluorometric method established is comparable to the so-called "gold standard" of enzymatic determination of polyfructosan. Moreover, FS is easy to handle and requires low-cost instruments. Our results demonstrate the potential of the direct fluorometric analysis of the new FITC-labelled marker of being a precise, simple, rapid and cost-effective method for diagnosing disturbed kidney function and monitoring its treatment efficacy. The dramatic decrease in analytical effort will result in a significantly higher acceptability of GFR determination.

Detection of a systolic pressure threshold for reliable readings in pulse oximetry.

OBJECTIVE: To determine the error of measurement in pulse oximetry with a decreased arterial perfusion and to identify a systolic pressure threshold for (1) initial detection and (2) a reliable reading of oxygen saturation. DESIGN: An experimental clinical prospective study. The study was approved by the local ethics committee. SETTING: Eighteen bed intensive care unit at a University hospital. PATIENTS AND PARTICIPANTS: Twenty-five adult mechanically ventilated and critically ill patients in the ICU during a 3-month period. INTERVENTIONS: A blood pressure cuff at the upper arm (same side as an arterial catheter already in place) was inflated to decrease the arterial pulsatile flow. The cuff was deflated stepwise and the resulting oxygen saturation was measured simultaneously. The error of measurement [delta S = SpO2 (baseline)-SpO2 (indicated)] was calculated for each 5 mmHg of blood pressure (BP). MEASUREMENTS AND RESULTS: Twenty-five patients (9 female, 16 male, 48 +/- 15.9 years old) with a mean SpO2 of 98.3 +/- 1.5% and a BP of 129 +/- 18.4 mmHg participated. The mean systolic BP to obtain initial readings with pulse oximetry was 45.8 +/- 17.7 (range, 25-101) mmHg (35% of the baseline pressure) resulting in lower readings of pulse oximetry (mean -11.5 +/- 13.6%, range -45 to +4%). With a systolic BP > 80 mmHg the mean bias was within the manufacturers limits of +/-2%. CONCLUSIONS: Pulse oximetry is reliable with a systolic blood pressure > 80 mmHg. The lower the BP, the lower the pulse oximetry readings leading to a bias of up to -45%.

Use of soluble fibrin antigen instead of D-dimer as fibrin-related marker may enhance the prognostic power of the ISTH overt DIC score.

The overt DIC score of the DIC subcommittee of the ISTH includes a fibrin-related marker (FRM) as indicator of intravascular fibrin formation. The type of marker to be used has not been specified, but D-dimer antigen, or fibrin degradation products are used by most investigators. Soluble fibrin complexes have been suggested as more specific indicators of acute intravascular fibrin formation. The aim of the present study was to compare the predictive value of the overt DIC score concerning clinical outcome in a surgical intensive care cohort, using either D-dimer antigen, or soluble fibrin antigen as FRM. The cutoff values for 2 and 3 score points for the FRM were assigned on the basis of the 25% and 75% quartiles of 1870 plasma samples obtained from 359 ICU patients during a period of 6 months. For 331 patients with complete diagnostic workup and day 1 blood samples, the Iatro SF as FRM component of the overt DIC score displayed the highest prognostic power concerning clinical outcome. The 28-day mortality of patients with overt DIC at day 1, using Iatro SF as FRM assay was 50.0%, whereas 28-day mortality of patients without overt DIC was 14.0% (p <0.0001). Using MDA D-dimer, and TINAquant D-dimer, 28-day mortality was between 35.5% and 39.3% in patients with overt DIC, and 15.5% to 15.6% in patients without overt DIC. Selection of the FRM as component of the DIC score has a small, but relevant impact on the prognostic performance of the overt DIC score. The present data on the distribution of values may provide a basis for the selection of appropriate cutoff points for assigning 2, and 3 points in the score.

p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the anti-inflammatory protein pancreatitis-associated protein I.

p8 is a transcription cofactor whose expression is strongly and rapidly activated in pancreatic acinar cells during the acute phase of pancreatitis. A p8-deficient mouse strain was generated as a tool to investigate its function. Upon induction of acute pancreatitis, myeloperoxidase activity in pancreas and serum concentrations of amylase and lipase were much higher and pancreatic lesions more severe in p8-deficient mice than in wild-type, indicating that p8 expression decreased pancreatic sensitivity to pancreatitis induction. The protective mechanism might involve the pancreatitis-associated protein (PAP I), whose strong induction during pancreatitis is p8-dependent, because administration of anti-PAP I antibodies to rats increased pancreatic inflammation during pancreatitis. In addition, 100 ng/ml PAP I in the culture medium of macrophages prevented their activation by tumor necrosis factor alpha, strongly suggesting that PAP I was an anti-inflammatory factor. Finally, PAP I was able to inhibit NFkappaB activation by tumor necrosis factor alpha, in macrophages and in the AR42J pancreatic acinar cell line. In conclusion, p8 improves pancreatic resistance to inducers of acute pancreatitis by a mechanism implicating the expression of the anti-inflammatory protein PAP I.

Mice with targeted disruption of p8 gene show increased sensitivity to lipopolysaccharide and DNA microarray analysis of livers reveals an aberrant gene expression response.

BACKGROUND: p8 is a DNA-binding protein induced in many tissues in response to LPS treatment. Hence, p8 could be a mediator of LPS-associated effects or, on the contrary, p8 expression may be part of the protective mechanism of the tissues in response to LPS. Finally, p8 expression in response to LPS could also be a simple epiphenomenon. METHODS: To investigate the role of p8 in vivo, we generated p8-deficient mice by gene targeting. Because p8 is a stress protein, we analyzed the response of p8-/- mice to a systemic stress induced by LPS injection. Liver was chosen as model organ to monitor alterations in gene expression. RESULTS: LPS resulted in higher serum TNF-alpha concentration and higher mortality rate in p8-deficient mice than in wild-type. Also, liver and pancreas, but not lung, from p8-/- mice showed increased amounts of MPO and HPO. To gain insight into the molecular bases of such susceptibility, we used high density DNA microarrays consisting of ~6000 genes and ESTs to compare gene regulation in response to LPS in p8+/+ and p8-/- livers. In wild-type, 105 genes and 73 ESTs were up-regulated and 232 genes and 138 ESTs down-regulated. By contrast, 212 genes and 125 ESTs were found up-regulated and 90 genes and 85 ESTs down regulated in p8-/- mice. Among them, only 93 (51 induced and 42 repressed) corresponded to the wild-type pattern, demonstrating that p8 deficiency hinders the normal response to LPS, which may account for the increased sensitivity of p8-/-mice to the endotoxin. CONCLUSIONS: The large number of genes showing abnormal regulation after LPS suggests that p8 is an important regulatory factor involved in many cellular defence pathways.

Clusterin protects the lung from leukocyte-induced injury.

Clusterin (CLU) is a multifunctional 75- to 80-kDa glycoprotein that is upregulated during cellular stress and might represent a defense mechanism during local cellular damage. Mechanisms discussed are antiapoptotic, antioxidative, and anticomplement properties as well as chaperone-like features protecting stressed proteins. The aim of this study was to investigate potential protective effects of CLU on pulmonary vasculature after in situ PMN activation in isolated rabbit lungs. The experiments were performed on 24 isolated and ventilated rabbit lungs that were perfused with 200 mL of Krebs-Henseleit-10% blood buffer with a constant flow of 150 mL/min in a recirculating system. It was tested whether pretreatment with CLU (2.5 microg/ml; n = 8) or catalase (CAT, 5000 U/ml; n = 8) before N-formyl-Met-Leu-Phe (fMLP; 10(-8) M) injection influenced pulmonary artery pressure (PAP) peak airway pressures (PAW) and edema formation as compared with controls (n = 8). Baseline values of PAP were 9-11 mmHg and PAW 11-13 cm H2O. Application of fMLP resulted in an acute significant (P < 0.01) increase of PAP (48 +/- 29 mmHg) within 2 min in the control group and PAW increased to 35 +/- 7 cm H2O within 30 min. Pretreatment with CLU completely suppressed the PAP and PAW response as a result of the fMLP challenge (P < 0.001), whereas a transient PAW increase up to 27 +/- 15 mmHg was observed after CAT. Complement factor C3a release was suppressed by CAT, whereas CLU blocked the complement cascade at the level of C5b-9 formation. Moreover, generation of thromboxane A(2) was reduced after CLU and CAT. Lung edema occurred in the fMLP group but was absent (P < 0.001) after CLU and CAT treatment. Both CLU and CAT prevented fMLP-induced lung injury. Stabilizing effects of CLU, point towards complement regulating features at the level of the terminal complement sequence. Elevated levels of CLU during inflammation could reflect a compensatory organ protective mechanism. Further studies are required to elucidate the clinical impact of the observed organ-protective properties of CLU.