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.

Differences in capillary recruitment between cardiac surgery and septic patients after fluid resuscitation.

BACKGROUND: Clinical evaluation of the effects of fluid therapy remains cumbersome and strategies are based on the assumption that normalization of macrohemodynamic variables will result in parallel improvement in organ perfusion. Recently, we and others suggested the use of direct in-vivo observation of the microcirculation to evaluate the effects of fluid therapy. METHODS: A single-centre observational study, using in-vivo microscopy to assess total vessel density (TVD) in two subsets of ICU patients. RESULTS: After fluid resuscitation TVD showed no difference between sepsis patients (N = 47) and cardiac surgery patients (N = 52): 18.4[16.8-20.8] vs 18.7[16.8-20.9] mm/mm2, p = 0.59. In cardiac surgery patients there was a significant correlation between the amount of fluids administered and TVD, with an optimum in the third quartile. However, such correlation was absent in septic patients. CONCLUSIONS: TVD after fluid administration is not different between 2 subtypes of intensive care patients. However, only in septic patients we observed a lack of coherence between the amount of fluids administered and TVD. Further research is needed to determine if TVD may serve as potential endpoint for fluid administration.

Ultrafiltration rate is an important determinant of microcirculatory alterations during chronic renal replacement therapy.

BACKGROUND: Hemodialysis (HD) with ultrafiltration (UF) in chronic renal replacement therapy is associated with hemodynamic instability, morbidity and mortality. Sublingual Sidestream Dark Field (SDF) imaging during HD revealed reductions in microcirculatory blood flow (MFI). This study aims to determine underlying mechanisms. METHODS: The study was performed in the Medical Centre Leeuwarden and the Lithuanian University of Health Sciences. Patients underwent 4-h HD session with linear UF. Nine patients were subject to combinations of HD and UF: 4 h of HD followed by 1 h isolated UF and 4 h HD with blood-volume-monitoring based UF. Primary endpoint: difference in MFI before and after intervention. During all sessions monitoring included blood pressure, heartrate and SDF-imaging. TRIAL REGISTRATION NUMBER: NCT01396980. RESULTS: Baseline characteristics were not different between the two centres as within the HD/UF modalities. MFI was not different before and after HD with UF. Total UF did not differ between modalities. Median MFI decreased significantly during isolated UF [2.8 (2.5-2.9) to 2.5 (2.2-2.8), p = 0.03]. Baseline MFI of each UF session was correlated with MFI after the intervention (r s = 0.52, p = 0.006). CONCLUSION: During HD with UF or isolated HD we observed no changes in MFI. This indicates that non-flow mediated mechanisms are of unimportance. During isolated UF we observed a reduction in MFI in conjunction with a negative intravascular fluid balance. The correlation between MFI before and after intervention suggests that volume status at baseline is a factor in microvascular alterations. In conclusion we observed a significant decrease of sublingual MFI, related to UF rate during chronic renal replacement therapy.

Effects of ketanserin on microcirculatory alterations in septic shock: An open-label pilot study.

INTRODUCTION: Microcirculatory alterations in sepsis are associated with increased morbidity and mortality. These alterations occur despite macrohemodynamic resuscitation. Alternative pro-microcirculatory strategies, including vasodilatory drugs, have been suggested to improve capillary blood flow. Ketanserin, a serotonin receptor antagonist, is an attractive candidate because of its vasodilatory, antithrombotic, and anti-inflammatory effects. METHODS: This is an open-label pilot study on the effect of ketanserin administration on microcirculatory alterations in septic shock, defined as microvascular flow index (MFI)≤2.5 after a strict macrohemodynamic resuscitation protocol. Sidestream dark-field imaging was applied to assess the microcirculation. A stepwise incremental dose regiment was applied until an MFI>2.9, the primary end point, was reached. RESULTS: Ten patients (Acute Physiology and Chronic Health Evaluation IV scores of 115 [100-136]) were included. Baseline MFI was 1.71 (1.31-2.32) and was significantly increasing to 2.96 (2.54-3.00; P=.021) during the ketanserin infusion. The total ketanserin dose was 0.09 (0.08-0.13) mg/kg per patient in 60 (30-60) minutes. In 3 patients (30%), the ketanserin infusion was discontinued due to refractory hypotension. CONCLUSION: An improvement in microcirculatory perfusion was observed during ketanserin administration in patients with septic shock after macrohemodynamic resuscitation. This finding needs further exploration in a placebo-controlled setting.

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.

Microcirculatory perfusion and vascular reactivity are altered in post cardiac arrest patients, irrespective of target temperature management to 33 °C vs 36 °C.

AIM: In previous reports both microcirculatory alterations and impaired vascular reactivity have been described in post cardiac arrest patients treated with mild therapeutic hypothermia. As of now it is unknown whether these alterations are related to the temperature management or to the cardiac arrest itself. Aim of the present study was to investigate the potential difference in microcirculatory alterations and vascular reactivity in comatose patients after out of hospital cardiac arrest treated with target temperature management of 33 °C (TTM33) in comparison to patients treated with 36 °C (TTM36). METHODS: Our study was designed as a predefined substudy of the open label randomized controlled TTM trial in 2 Dutch mixed ICU's. Sublingual microvascular flow index (MFI) was assessed by Side Stream Darkfield imaging and vascular reactivity at the thenar region of the hand by near infrared spectroscopy. Variables, including systemic hemodynamics were recorded at start study (T1), after 12h (T2) and after 24h (T3). RESULTS: 22 patients were included, 13 in TTM33 and 9 in TTM36. At T1 MFI between groups did not differ significantly (1.08 [0.4-1.9] versus 1.67 [0.7-2.4] respectively, p = 0.59). The difference between groups remained insignificant over time. At T1 tissue oxygenation (StO2) was significantly lower in TTM36 in comparison to TTM33: (44.6 ± 15.8 versus 58.9 ± 13.5, p = 0.03). Over time this difference between groups disappeared. However, vascular reactivity, expressed as the descending and ascending slope of StO2 after a standardized ischemic occlusion test was similar between groups. CONCLUSIONS: In this relatively small sample size study microcirculatory blood flow and vascular reactivity did not differ nor change between TTM33 and TTM36.