The effect of treatment and clinical course during Emergency Department stay on severity scoring and predicted mortality risk in Intensive Care patients.

BACKGROUND: Treatment and the clinical course during Emergency Department (ED) stay before Intensive Care Unit (ICU) admission may affect predicted mortality risk calculated by the Acute Physiology and Chronic Health Evaluation (APACHE)-IV, causing lead-time bias. As a result, comparing standardized mortality ratios (SMRs) among hospitals may be difficult if they differ in the location where initial stabilization takes place. The aim of this study was to assess to what extent predicted mortality risk would be affected if the APACHE-IV score was recalculated with the initial physiological variables from the ED. Secondly, to evaluate whether ED Length of Stay (LOS) was associated with a change (delta) in these APACHE-IV scores. METHODS: An observational multicenter cohort study including ICU patients admitted from the ED. Data from two Dutch quality registries were linked: the Netherlands Emergency department Evaluation Database (NEED) and the National Intensive Care Evaluation (NICE) registry. The ICU APACHE-IV, predicted mortality, and SMR based on data of the first 24 h of ICU admission were compared with an ED APACHE-IV model, using the most deviating physiological variables from the ED or ICU. RESULTS: A total of 1398 patients were included. The predicted mortality from the ICU APACHE-IV (median 0.10; IQR 0.03-0.30) was significantly lower compared to the ED APACHE-IV model (median 0.13; 0.04-0.36; p < 0.01). The SMR changed from 0.63 (95%CI 0.54-0.72) to 0.55 (95%CI 0.47-0.63) based on ED APACHE-IV. Predicted mortality risk changed more than 5% in 321 (23.2%) patients by using the ED APACHE-IV. ED LOS > 3.9 h was associated with a slight increase in delta APACHE-IV of 1.6 (95% CI 0.4-2.8) compared to ED LOS < 1.7 h. CONCLUSION: Predicted mortality risks and SMRs calculated by the APACHE IV scores are not directly comparable in patients admitted from the ED if hospitals differ in their policy to stabilize patients in the ED before ICU admission. Future research should focus on developing models to adjust for these differences.

Non-invasive assessment of fluid responsiveness to guide fluid therapy in patients with sepsis in the emergency department: a prospective cohort study.

BACKGROUND: Little is known about optimal fluid therapy for patients with sepsis without shock who present to the ED. In this study, we aimed to quantify the effect of a fluid challenge on non-invasively measured Cardiac Index (CI) in patients presenting with sepsis without shock. METHODS: In a prospective cohort study, CI, stroke volume (SV) and systemic vascular resistance (SVR) were measured non-invasively in 30 patients presenting with sepsis without shock to the ED of a large teaching hospital in the Netherlands between May 2018 and March 2019 using the ClearSight system. After baseline measurements were performed, a passive leg raise (PLR) was done to simulate a fluid bolus. Measurements were then repeated 30, 60, 90 and 120 s after PLR. Finally, a standardised 500 mL NaCl 0.9% intravenous bolus was administered after which final measurements were done. Fluid responsiveness was defined as >15% increase in CI after a standardised fluid challenge. MEASUREMENTS AND MAIN RESULTS: Seven out of 30 (23%) patients demonstrated a >15% increase in CI after PLR and after a 500 mL fluid bolus. Fluid responders had a higher estimated glomerular filtration rate (eGFR) (64 (44-78) vs 37 (23-47), p=0.009) but otherwise similar patient and treatment characteristics as non-responders. Baseline measurements of cardiac output (CO), CI, SV and SVR were unrelated to PLR fluid responsiveness. The change in CI after PLR was strongly positive correlated to the change in CI after a 500 mL NaCl 0.9% fluid bolus (r=0.88, p<0.001). CONCLUSION: The results of the present study demonstrate that in patients with sepsis in the absence of shock, three out of four patients do not demonstrate a clinically relevant increase in CI after a standardised fluid challenge. Non-invasive CO monitoring in combination with a PLR test has the potential to identify patients who might benefit from fluid resuscitation and may contribute to a better tailored treatment of these patients.

Renal Function is a Major Determinant of ICU-acquired Hypernatremia: A Balance Study on Sodium Handling.

BACKGROUND AND OBJECTIVES: The development of ICU-acquired hypernatremia (IAH) is almost exclusively attributed to 'too much salt and too little water'. However, intrinsic mechanisms also have been suggested to play a role. To identify the determinants of IAH, we designed a prospective controlled study. METHODS: Patients with an anticipated length of stay ICU > 48 hours were included. Patients with hypernatremia on admission and/or on renal replacement therapy were excluded. Patients without IAH were compared with patients with borderline hypernatremia (≥ 143 mmol/L, IAH 143) and more severe hypernatremia (≥ 145 mmol/L, IAH 145). RESULTS: We included 89 patients, of which 51% developed IAH 143 and 29% IAH 145. Sodium intake was high in all patients. Fluid balances were slightly positive and comparable between the groups. Patients with IAH 145 were more severely ill on admission, and during admission, their sodium intake, cumulative sodium balances, serum creatinine and copeptin levels were higher. According to the free water clearance, all the patients conserved water. On multivariate analysis, the baseline serum creatinine was an independent risk factor for the development of IAH 143 and IAH 145. Also, the copeptin levels remained significant for IAH 143 and IAH 145. Sodium intake remained only significant for patients with IAH 145. CONCLUSIONS: Our data support the hypothesis that IAH is due to the combination of higher sodium intake and a urinary concentration deficit, as a manifestation of the renal impairment elicited by severe illness.

Determinants of non-recovery in physical health-related quality of life one year after cardiac surgery: a prospective single Centre observational study.

BACKGROUND: Recent studies show that substantial percentage of patients experienced worsening of health related quality of life (HRQoL) 1 year after cardiac surgery. The aim of this study is to identify risk factors that interfere with improvement of HRQoL. METHODS: From December 2015 till July 2017 a prospective single centre observational study was carried out in 1920 patients participated who underwent non-salvage cardiac surgery. All patients were requested to complete a Short Form 36 (SF-36) questionnaire before and 1 year after surgery. Primary aim of the study was to identify risk factors for non-recovery in the physical domain of the SF-36 in all cardiac surgery patients. Secondary aim was to identify identical risk factors in patients with isolated coronary artery bypass grafting. RESULTS: After cardiac surgery, the questionnaires for physical and mental health were completed by respectively 803 and 807 patients. Median age was 69[62-75] years, and 77% was male. In comparison to the preoperative status, 176 patients (21.9%) did not display an improvement in the SF-36 physical domain score 1 year after cardiac surgery. In a multivariate analysis independent risk factors for non-recovery in the SF-36 physical domain were baseline SF36 physical domain score (OR 0.954[0.942-0.965], P < 0.001), diabetes (OR 0.437 [0.265-0.720], P 0.001), female sex (OR 0.492 [0.307-0.789], P 0.003), post-operative infection (OR 0.240 [0.109-0.525], P < 0.001) and PCI within 1 year (OR 0.113 [0.036-0.349], P < 0.001) For isolated CABG, 23.2% of patients did not display an improvement in the physical domain score and risk factors appeared to be identical. CONCLUSIONS: Twenty two percent of all cardiac surgery patients did not show an improvement in the physical domain score of the HRQoL between the preoperative period and 1 year after surgery. Independent risk factors for non-recovery after cardiac surgery were baseline SF-36 physical domain score, diabetes, female sex, any postoperative infection and the need for PCI in the first year. Further research is needed to tailor the patient selection procedure prior to surgery and potentially modify risk factors in the perioperative process. TRIAL REGISTRATION: Due to type of study not applicable. https://www.ccmo.nl/metcs/erkende-metcs/regionale-toetsingscommissie-patientgebonden-onderzoek .

Automated Algorithm Analysis of Sublingual Microcirculation in an International Multicentral Database Identifies Alterations Associated With Disease and Mechanism of Resuscitation.

OBJECTIVES: Reliable automated handheld vital microscopy image sequence analysis and the identification of disease states and effects of therapy are prerequisites for the routine use of quantitative sublingual microcirculation measurements at the point-of-care. The present study aimed to clinically validate the recently introduced MicroTools software in a large multicentral database of perioperative and critically ill patients and to use this automatic algorithm to data-mine and identify the sublingual microcirculatory variable changes in response to disease and therapy. DESIGN: Retrospective algorithm-based image analysis and data-mining within a large international database of sublingual capillary microscopy. Algorithm-based analysis was compared with manual analysis for validation. Thereafter, MicroTools was used to identify the functional microcirculatory alterations associated with disease conditions and identify therapeutic options for recruiting functional microcirculatory variables. SETTING: Ten perioperative/ICU/volunteer studies in six international teaching hospitals. PATIENTS: The database encompass 267 adult and pediatric patients undergoing surgery, treatment for sepsis, and heart failure in the ICU and healthy volunteers. INTERVENTIONS: Perioperative and ICU standard of care. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred twenty-five handheld vital microscopy image sequences containing 149,257 microscopy images were analyzed. 3.89 × 10 RBC positions were tracked by the algorithm in real time, and offline manual analysis was performed. Good correlation and trending ability were found between manual and automatic total and functional capillary density (r = 0.6-0.8; p < 0.0001). RBC tracking within the database demonstrated changes in functional capillary density and/or RBC velocity in septic shock, heart failure, hypovolemia, obstructive shock, and hemodilution and thus detected the presence of a disease condition. Therapies recruiting the microcirculatory diffusion and convection capacity associated with systemic vasodilation and an increase in cardiac output were separately identified. CONCLUSIONS: Algorithm-based analysis of the sublingual microcirculation closely matched manual analysis across a broad spectrum of populations. It successfully identified a methodology to quantify microcirculatory alterations associated with disease and the success of capillary recruitment, improving point-of-care application of microcirculatory-targeted resuscitation procedures.

Relationship between norepinephrine dose, tachycardia and outcome in septic shock: A multicentre evaluation.

PURPOSE: Septic shock is associated with massive release of endogenous catecholamines. Adrenergic agents may exacerbate catecholamine toxicity and contribute to poor outcomes. We sought to determine whether an association existed between tachycardia and mortality in septic shock patients requiring norepinephrine for more than 6 h despite adequate volume resuscitation. MATERIALS AND METHODS: Multicentre retrospective observational study on 730 adult patients in septic shock consecutively admitted to eight European ICUs between 2011 and 2013. Three timepoints were selected: T1 (first hour of infusion of norepinephrine), Tpeak (time of highest dose during the first 24 h of treatment), and T24 (24-h post-T1). Binary logistic regression models were constructed for the three time-points. RESULTS: Overall ICU mortality was 38.4%. Mortality was higher in those requiring high-dose (≥0.3 mcg/kg/min) versus low-dose (<0.3 mcg/kg/min) norepinephrine at T1 (53.4% vs 30.6%; p < 0.001) and T24 (61.4% vs 20.4%; p < 0.0001). Patients requiring high-dose with concurrent tachycardia had higher mortality at T1; in the low-dose group tachycardia was not associated with mortality. Resolving tachycardia (from T1 to T24) was associated with lower mortality compared to patients where tachycardia persisted (27.8% vs 46.4%; p = 0.001). CONCLUSIONS: Use of high-dose norepinephrine and concurrent tachycardia are associated with poor outcomes in septic shock.

An observational study on intracutaneous sodium storage in intensive care patients and controls.

The development of ICU-acquired sodium disturbances is not fully understood. Alterations in non-osmotic skin sodium storage, hypothetically inflammation-driven, could play a role. To investigate this in critically ill patients we conducted a patient-control study with skin punch biopsies in patients with sepsis (n = 15), after coronary artery bypass grafting (CABG, n = 15) and undergoing total hip arthroplasty (THA-controls, n = 15) respectively, together representing a range in severity of systemic inflammation. Biopsies were taken within 24 hours (sepsis) and within 2 hours (CABG) after ICU-admission, and prior to arthroplasty. Biopsies were analysed for sodium content. In addition immunostainings and quantitative real time PCR were performed. The primary aim of this study was to detect possible differences in amounts of cutaneous sodium. The secondary aims were to quantify inflammation and lymphangiogenesis with concomitant markers. The highest amounts of both water and sodium were found in patients with sepsis, with slightly lower values after CABG and the lowest amounts in THA-controls. Correlation between water and sodium was 0.5 (p<0.01). In skin biopsies in all groups comparable amounts of macrophages, T-cells and lymph vessels were found. In all groups comparable expression of inflammation markers were found. However, higher mRNA transcript expression levels of markers of lymphangiogenesis were found in patients with sepsis and after CABG. The conjoint accumulation of water and sodium points towards oedema formation. However, the correlation coefficient of 0.5 leaves room for alternative explanations, including non-osmotic sodium storage. No signs of dermal inflammation were found, but upregulation of markers of lymphangiogenesis could indicate future lymphangiogenesis.

Model for End-Stage Liver Disease Excluding INR (MELD-XI) score is associated with hemodynamic impairment and predicts mortality in critically ill patients.

PURPOSE: We aimed (i) to evaluate Model for End-stage Liver Disease excluding INR (MELD-XI) score for prediction of mortality in a cohort of critically ill patients and (ii) to investigate associations of MELD-XI with microcirculation and (iii) to evaluate microcirculation for prediction of mortality in high-risk patients, e.g., with high MELD-XI scores. METHODS: 308 patients were included in our retrospective analysis, a subgroup of the multicenter micro-SOAP-study. Microcirculation was evaluated by Sidestream Dark Field (SDF) imaging. Evaluation of associations with mortality was done by logistic regression analysis, an optimal cut-off was calculated by means of the Youden Index. We divided the cohort in two sub-groups based on their MELD-XI score at the optimal cut-off (12 score points). RESULTS: Patients with a MELD-XI > 12 points were of similar age (60 ±â€¯1 years vs 62 ±â€¯2 years; p = 0.32), but clinically sicker as mirrored by higher APACHE II scores (20 ±â€¯1 vs 16 ±â€¯1; p < 0.001). In the MELD-XI > 12 cohort in-hospital mortality was significantly higher compared to the MELD ≤ 12 group (48% vs 24%%; HR 2.98 95%CI 1.76-5.04; p = 0.003) and MELD-XI score was associated with mortality even after correction for relevant clinical confounders (HR 1.04 95%CI 1.01-1.07; p = 0.004) There were no associations between MELD-XI and parameters of microvascular perfusion. CONCLUSIONS: MELD-XI is associated with in-hospital mortality and constitutes a useful tool for risk stratification in intensive care medicine. Interestingly, there were no associations between MELD-XI and microcirculation. Possibly parameters of the microcirculation present an online tool of hemodynamic assessment while MELD-XI presents an assessment of already established organ failure.

Phase angle is related to outcome after ICU admission; an observational study.

INTRODUCTION: Malnutrition at the time of ICU admission is associated with an increased morbidity and mortality. Malnutrition is most often assessed by a questionnaire but can also be determined with bio-impedance and measurement of phase angle. In a single-centre observational study we compared the percentage of malnutrition in patients admitted to our ICU, according to the Short Nutritional Assessment Questionnaire (SNAQ) with the phase angle measured with bio-impedance. Furthermore, we questioned whether malnutrition is related to outcome parameters. METHODS: In a 15 week period consecutive patients admitted to the ICU were included. Exclusion criteria included age <18 years, anatomical and/or neurological abnormalities of the limbs and an ICU stay less than 6 h. Bio-impedance measurements were performed shortly after admission, the SNAQ was obtained from the patient or legal representative. Malnutrition is considered with a SNAQ ≥2 or a phase angle of <5° for men and <4.6° for women. The study was approved by our local ethical committee (MCL, nWMO 77, April 18, 2015). RESULTS: 299 Patients were included (66% male, age 66 ± 12 year, BMI 27 ± 4 kg/m2 and APACHE II score 14 [11-17]), of which 64% elective and 36% acute admissions. Hospital mortality was 7.4%. Malnutrition was present in 16% according to the SNAQ and in 36% according to phase angle. There was a fair accordance between the SNAQ and phase angle. Phase angle was significantly higher in patients with a SNAQ score of 0-1 (5.5°±1.3) in comparison with patients with a SNAQ score ≥2 (4.4°± 1.1) (p < 0.001). Logistic regression analysis showed a significant relation between SNAQ and BMI, malignant disease and hospital length of stay and between phase angle and age, sex, BMI, malignant disease, hospital length of stay and hospital mortality. CONCLUSION: Malnutrition was present in 16% according to the SNAQ and in 36% according to phase angle in our IC population. Malnutrition was associated with prolonged hospital length of stay. In this small population of mixed ICU patients, a low phase angle was found to independently predict hospital mortality. CLINICAL TRIALS. GOV NUMBER: NCT02911181.

Plasma glutamine levels before cardiac surgery are related to post-surgery infections; an observational study.

BACKGROUND: A low plasma glutamine level was found in 34% of patients after elective cardiothoracic surgery. This could be a result of the inflammation caused by surgical stress or the use of extracorporeal circulation (ECC). But it is also possible that plasma glutamine levels were already lowered before surgery and reflect an impaired metabolic state and a higher likelihood to develop complications. In the present study plasma glutamine levels were measured before and after cardiac surgery and we questioned whether there is a relation between plasma glutamine levels and duration of ECC and the occurrence of postoperative infections. METHODS: We performed a single-centre prospective, observational study in a closed-format, 20-bed, mixed ICU in a tertiary teaching hospital. We included consecutive patients after elective cardiac surgery with use of extracorporeal circulation. Blood samples were collected on the day prior to surgery and at admission on the ICU. The study was approved by the local Medical Ethics Committee (Regional Review Committee Patient-related Research, Medical Centre Leeuwarden, nWMO 115, April 28th 2015). RESULTS: Ninety patients were included. Pre-operative plasma glutamine level was 0.42 ± 0.10 mmol/l and post-operative 0.38 ± 0.09 mmol/l (p < 0.001). There was no relation between duration of extracorporeal circulation or aortic occlusion time and changes in plasma glutamine levels. A logistic regression analysis showed a significant correlation between the presence of a positive culture during the post-operative course and pre-operative plasma glutamine levels (p = 0.04). CONCLUSION: Plasma glutamine levels are significantly lower just after cardiac surgery compared to pre-operative levels. We did not find a relation between the decrease in plasma glutamine levels and the duration of extracorporeal circulation or aortic clamp time. There was a correlation between pre-operative plasma glutamine levels and the presence of a positive culture after cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02444780 .

Use of an Image Acquisition Stabilizer Improves Sidestream Dark Field Imaging of the Serosa during Open Gastrointestinal Surgery.

AIM: To investigate whether an image acquisition stabilizer (IAS) mounted on the sidestream dark field camera (SDF) during gastrointestinal surgery improves image stability and acquisition. METHODS: Serosal SDF imaging was compared with SDF imaging combined with an IAS (SDF + IAS) during gastrointestinal surgery. Stability was assessed as the image drift in pixels and the time to obtain stable images. The success rate was determined as the percentage of analyzable images after recording. The effect of negative pressure from the IAS was determined during single-spot measurements and by comparing microvascular parameters between groups. Data are presented as mean ± SD. RESULTS: Sixty serosal measurements were performed per group; 87% were successful in the SDF group and 100% in the SDF + IAS group (p = 0.003). Image drift in the SDF group was 148 ± 36 versus 55 ± 15 pixels in the SDF + IAS group; p < 0.001. Time to stable image was 96 ± 60 s in the SDF group versus 57 ± 31 s in the SDF + IAS group; p = 0.03. No effect of negative pressure was seen. CONCLUSION: The use of an IAS mounted on an SDF camera during serosal microvascular assessment improves the success rate of image acquisition and stability and reduces the time to stable image with no effect on the microcirculation.

Cytocam-IDF (incident dark field illumination) imaging for bedside monitoring of the microcirculation.

BACKGROUND: Orthogonal polarized spectral (OPS) and sidestream dark field (SDF) imaging video microscope devices were introduced for observation of the microcirculation but, due to technical limitations, have remained as research tools. Recently, a novel handheld microscope based on incident dark field illumination (IDF) has been introduced for clinical use. The Cytocam-IDF imaging device consists of a pen-like probe incorporating IDF illumination with a set of high-resolution lenses projecting images on to a computer controlled image sensor synchronized with very short pulsed illumination light. This study was performed to validate Cytocam-IDF imaging by comparison to SDF imaging in volunteers. METHODS: This study is a prospective, observational study. The subjects consist of 25 volunteers. RESULTS: Sublingual microcirculation was evaluated using both techniques. The main result was that Cytocam-IDF imaging provided better quality images and was able to detect 30% more capillaries than SDF imaging (total vessels density Cytocam-IDF: 21.60 ± 4.30 mm/mm(2) vs SDF: 16.35 ± 2.78 mm/mm(2), p < 0.0001). Comparison of the images showed increased contrast, sharpness, and image quality of both venules and capillaries. CONCLUSIONS: Cytocam-IDF imaging detected more capillaries and provided better image quality than SDF imaging. It is concluded that Cytocam-IDF imaging may provide a new improved imaging modality for clinical assessment of microcirculatory alterations.

How to evaluate the microcirculation: report of a round table conference.

INTRODUCTION: Microvascular alterations may play an important role in the development of organ failure in critically ill patients and especially in sepsis. Recent advances in technology have allowed visualization of the microcirculation, but several scoring systems have been used so it is sometimes difficult to compare studies. This paper reports the results of a round table conference that was organized in Amsterdam in November 2006 in order to achieve consensus on image acquisition and analysis. METHODS: The participants convened to discuss the various aspects of image acquisition and the different scores, and a consensus statement was drafted using the Delphi methodology. RESULTS: The participants identified the following five key points for optimal image acquisition: five sites per organ, avoidance of pressure artifacts, elimination of secretions, adequate focus and contrast adjustment, and recording quality. The scores that can be used to describe numerically the microcirculatory images consist of the following: a measure of vessel density (total and perfused vessel density; two indices of perfusion of the vessels (proportion of perfused vessels and microcirculatory flow index); and a heterogeneity index. In addition, this information should be provided for all vessels and for small vessels (mostly capillaries) identified as smaller than 20 microm. Venular perfusion should be reported as a quality control index, because venules should always be perfused in the absence of pressure artifact. It is anticipated that although this information is currently obtained manually, it is likely that image analysis software will ease analysis in the future. CONCLUSION: We proposed that scoring of the microcirculation should include an index of vascular density, assessment of capillary perfusion and a heterogeneity index.