Microcirculatory Impairment Is Associated With Multiple Organ Dysfunction Following Traumatic Hemorrhagic Shock: The MICROSHOCK Study.

OBJECTIVES: To assess the relationship between microcirculatory perfusion and multiple organ dysfunction syndrome in patients following traumatic hemorrhagic shock. DESIGN: Multicenter prospective longitudinal observational study. SETTING: Three U.K. major trauma centers. PATIENTS: Fifty-eight intubated and ventilated patients with traumatic hemorrhagic shock. INTERVENTIONS: Sublingual incident dark field microscopy was performed within 12 hours of ICU admission (D0) and repeated 24 and 48 hours later. Cardiac output was assessed using oesophageal Doppler. Multiple organ dysfunction syndrome was defined as Serial Organ Failure Assessment score greater than or equal to 6 at day 7 post injury. MEASUREMENTS AND MAIN RESULTS: Data from 58 patients were analyzed. Patients had a mean age of 43 ± 19 years, Injury Severity Score of 29 ± 14, and initial lactate of 7.3 ± 6.1 mmol/L and received 6 U (interquartile range, 4-11 U) of packed RBCs during initial resuscitation. Compared with patients without multiple organ dysfunction syndrome at day 7, patients with multiple organ dysfunction syndrome had lower D0 perfused vessel density (11.2 ± 1.8 and 8.6 ± 1.8 mm/mm; p < 0.01) and microcirculatory flow index (2.8 [2.6-2.9] and 2.6 [2.2-2.8]; p < 0.01) but similar cardiac index (2.5 [± 0.6] and 2.1 [± 0.7] L/min//m; p = 0.11). Perfused vessel density demonstrated the best discrimination for predicting subsequent multiple organ dysfunction syndrome (area under curve 0.87 [0.76-0.99]) compared with highest recorded lactate (area under curve 0.69 [0.53-0.84]), cardiac index (area under curve 0.66 [0.49-0.83]) and lowest recorded systolic blood pressure (area under curve 0.54 [0.39-0.70]). CONCLUSIONS: Microcirculatory hypoperfusion immediately following traumatic hemorrhagic shock and resuscitation is associated with increased multiple organ dysfunction syndrome. Microcirculatory variables are better prognostic indicators for the development of multiple organ dysfunction syndrome than more traditional indices. Microcirculatory perfusion is a potential endpoint of resuscitation following traumatic hemorrhagic shock.

Real-time point of care microcirculatory assessment of shock: design, rationale and application of the point of care microcirculation (POEM) tool.

BACKGROUND: Despite over a decade of research and technological advances, sublingual microcirculatory monitoring has not yet reached clinical utility. Offline analysis is time consuming and occurs away from the patient. A system to assess the microcirculation at the point of care is desirable. We present a novel 5-point grading system (the point of care microcirculation (POEM) scoring system) that can be used at the point of care during non-invasive sublingual microcirculatory monitoring. METHODS: The POEM score is an ordinal scale from 1 (worst) to 5 (best), based on a composite assessment of flow and heterogeneity of four individual sublingual video-microscopy clips. Thirty-two healthcare professionals were trained in how to assign POEM scores. Following training they assigned scores to five test sequences (each consisting of four video clips). They were blinded to clinical status. Inter-user consistency and agreement were assessed using intra-class correlation coefficient (ICC) analysis. In addition, blinded expert scores for 68 video clips were compared to offline computer analysis using traditional microcirculatory parameters including total vessel density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV), microcirculatory flow index (MFI) and microcirculatory heterogeneity index (MHI). The time taken to assign each was recorded. RESULTS: Participants showed good inter-rater consistency (ICC 0.83, 95 % CI 0.626, 0.976) and agreement (ICC 0.815, 95 % CI 0.602, 0.974) for assigned POEM scores. Expert scoring of videos correlated with offline values for PVD (R 2 = 0.39; p < 0.05), PPV (R 2 = 0.71; p < 0.001), MFI (R 2 = 0.75; p < 0.001), and MHI (R 2 = 0.68; p < 0.001). POEM scores took less time to assign than conventional offline computer analysis (2 minutes versus 44 minutes). CONCLUSION: We present for the first time a novel 5-point ordinal scale of microcirculatory flow and heterogeneity that can be used at the point of care. It has minimal inter-user variability amongst healthcare professionals after just 1 hour of training. POEM scores take a short time to assign, and correspond well to traditional offline computer-analyzed parameters.

Quantification of stroke volume in a simulated healthy volunteer model of traumatic haemorrhage; a comparison of two non-invasive monitoring devices using error grid analysis alongside traditional measures of agreement.

INTRODUCTION: Haemorrhage is a leading cause of death following traumatic injury and the early detection of hypovolaemia is critical to effective management. However, accurate assessment of circulating blood volume is challenging when using traditional vital signs such as blood pressure. We conducted a study to compare the stroke volume (SV) recorded using two devices, trans-thoracic electrical bioimpedance (TEB) and supra-sternal Doppler (SSD), against a reference standard using trans- thoracic echocardiography (TTE). METHODS: A lower body negative pressure (LBNP) model was used to simulate hypovolaemia and in half of the study sessions lower limb tourniquets were applied as these are common in military practice and can potentially affect some haemodynamic monitoring systems. In order to provide a clinically relevant comparison we constructed an error grid alongside more traditional measures of agreement. RESULTS: 21 healthy volunteers aged 18-40 were enrolled and underwent 2 sessions of LBNP, with and without lower limb tourniquets. With respect to absolute SV values Bland Altman analysis showed significant bias in both non-tourniquet and tourniquet strands for TEB (-42.5 / -49.6 ml), rendering further analysis impossible. For SSD bias was minimal but percentage error was unacceptably high (35% / 48%). Degree of agreement for dynamic change in SV, assessed using 4 quadrant plots showed a seemingly acceptable concordance rate for both TEB (86% / 93%) and SSD (90% / 91%). However, when results were plotted on an error grid, constructed based on expert clinical opinion, a significant minority of measurement errors were identified that had potential to lead to moderate or severe patient harm. CONCLUSION: Thoracic bioimpedance and suprasternal Doppler both demonstrated measurement errors that had the potential to lead to clinical harm and caution should be applied in interpreting the results in the detection of early hypovolaemia following traumatic injury.

Critically Ill COVID-19 Patients With Acute Kidney Injury Have Reduced Renal Blood Flow and Perfusion Despite Preserved Cardiac Function: A Case-Control Study Using Contrast-Enhanced Ultrasound.

BACKGROUND: Acute kidney injury (AKI) is a common complication of COVID-19 critical illness but the pathophysiology is uncertain. Some evidence has indicated that a vascular aetiology may be implicated. We used contrast-enhanced ultrasound (CEUS) and echocardiography to study renal perfusion and global blood flow and compared our findings with measurements taken in a group of septic shock patients and healthy volunteers. METHODS: Prospective case-control study. Renal perfusion variables were assessed with CEUS; macrovascular blood flow was assessed using Doppler analysis of large renal vessels; echocardiography was used to assess right and left heart function and cardiac output. RESULTS: CEUS-derived parameters were reduced in COVID-19 associated AKI compared with healthy controls (perfusion index 3,415 vs. 548 a.u., P = 0·001; renal blood volume 7,794 vs. 3,338 a.u., P = 0·04). Renal arterial flow quantified using time averaged peak velocity was also reduced compared with healthy controls (36·6 cm/s vs. 20·9 cm/s, P = 0.004) despite cardiac index being similar between groups (2.8 L/min/m2 vs. 3.7 L/min/m2, P = 0.07). There were no differences in CEUS-derived or cardiac parameters between COVID-19 and septic shock patients but patients with septic shock had more heterogeneous perfusion variables. CONCLUSION: Both large and small vessel blood flow is reduced in patients with COVID-19 associated AKI compared with healthy controls, which does not appear to be a consequence of right or left heart dysfunction. A reno-vascular pathogenesis of COVID-19 AKI seems likely.

Microcirculatory, Endothelial, and Inflammatory Responses in Critically Ill Patients With COVID-19 Are Distinct From Those Seen in Septic Shock: A Case Control Study.

ABSTRACT: Critically ill patients with COVID-19 infection frequently exhibit a hyperinflammatory response and develop organ failures; however, the underlying mechanisms are unclear. We investigated the microcirculatory, endothelial, and inflammatory responses in critically ill COVID-19 patients and compared them to a group of patients with septic shock in a prospective observational case control study. Thirty critically ill patients with COVID-19 were compared to 33 patients with septic shock.Measurements of sublingual microcirculatory flow using Incident Dark Field video-microscopy and serial measurements of IL-6 and Syndecan-1 levels were performed. COVID-19 patients had significantly less vasoactive drug requirement and lower plasma lactate than those with septic shock. Microcirculatory flow was significantly worse in septic patients than those with COVID-19 (MFI 2.6 vs 2.9 p 0.02, PPV 88 vs 97% P < 0.001). IL-6 was higher in patients with septic shock than COVID-19 (1653 vs 253 pg/mL, P 0.03). IL-6 levels in COVID 19 patients were not elevated compared to healthy controls except on the day of ICU admission. Syndecan-1 levels were not different between the two pathological groups. Compared to patients with undifferentiated septic shock an overt shock state with tissue hypoperfusion does not appear typical of COVID-19 infection. There was no evidence of significant sublingual microcirculatory impairment, widespread endothelial injury or marked inflammatory cytokine release in this group of critically ill COVID-19 patients.

The Reproducibility of the Point of Care Microcirculation (POEM) Score When Used to Assess Critically Ill Patients: A Multicenter Prospective Observational Study.

BACKGROUND: The current standard of analyzing microcirculatory video microscopy is time-consuming and occurs away from the patient, limiting its clinical utility. Point-of-care assessment with incident dark field (IDF) microscopy, however, may offer greater clinical applicability. We aimed to determine the reproducibility of the Point of Care Microcirculation (POEM) tool when used at the bedside in critically ill patients. METHODS: A multinational, multicenter, prospective observational study of adult intubated patients was undertaken during a 9-month period in Germany, the United Kingdom, and the United States. A user recorded a batch of four standardized video clips from each patient, calculated a POEM score and recorded the time for image acquisition. A second user blinded to the first repeated this process. Patients with video clips of poor quality were excluded. At a later date, the two users again blinded themselves to reassess both their own clips and those of the other user. Basic demographic information was recorded. Intrauser reliability (an individual user rescoring the same batch of videos after blinding), interuser reliability (a second user rescoring the other user's video batch after blinding), and test-retest reliability (two users individually capturing videos and recording POEM scores) were assessed using a linearly weighted kappa statistic for ordinal data. RESULTS: Sixty-five patients were included in the final analysis. Observer agreement was substantial for all tests. Intrauser agreement was 0.73 (0.95 CI 0.64-0.81), interuser agreement 0.71 (0.95 CI 0.63-0.79), and test-retest agreement 0.75 (0.95 CI 0.65-0.86). Average time to record videos and assess POEM scores 7:34 ± 3:37 minutes. CONCLUSIONS: Point-of-care assessment of the microcirculation using IDF video microscopy and POEM scoring appears to be both a feasible and reproducible approach to microcirculatory assessment. Testing of the score in critically ill patients showed substantial agreement within and between investigators, but further studies should validate its utility as a tool to guide shock resuscitation.

In vitro endothelial hyperpermeability occurs early following traumatic hemorrhagic shock.

BACKGROUND: Endothelial hyperpermeability is suggested to play a role in the development of microcirculatory perfusion disturbances and organ failure following hemorrhagic shock, but evidence is limited. OBJECTIVE: To study the effect of plasma from traumatic hemorrhagic shock patients on in vitro endothelial barrier function. METHODS: Plasma from traumatic hemorrhagic shock patients was obtained at the emergency department (ED), the intensive care unit (ICU), 24 h after ICU admission and from controls (n = 8). Sublingual microcirculatory perfusion was measured using incident dark field videomicroscopy at matching time points. Using electric cell-substrate impedance sensing, the effects of plasma exposure on in vitro endothelial barrier function of human endothelial cells were assessed. RESULTS: Plasma from traumatic hemorrhagic shock patients collected at ED admission induced a 19% loss of in vitro endothelial resistance compared to plasma from controls (p < 0.001). This loss was due to reduced cell-cell contacts (p < 0.01). Plasma withdrawn at later time points did not affect endothelial barrier function (p > 0.99). Interestingly, in vitro endothelial resistance showed a positive association with in vivo microcirculatory perfusion (r = 0.56, p < 0.01). CONCLUSIONS: Plasma from traumatic hemorrhagic shock patients obtained following ED admission, but not at later stages, induced in vitro endothelial hyperpermeability. This coincided with in vivo microcirculatory perfusion disturbances.

Impact of plasma viscosity on microcirculatory flow after traumatic haemorrhagic shock: A prospective observational study.

BACKGROUND: Preclinical studies report that higher plasma viscosity improves microcirculatory flow after haemorrhagic shock and resuscitation, but no clinical study has tested this hypothesis. OBJECTIVE: We investigated the relationship between plasma viscosity and sublingual microcirculatory flow in patients during resuscitation for traumatic haemorrhagic shock (THS). METHODS: Sublingual video-microscopy was performed for 20 trauma patients with THS as soon as feasible in hospital, and then at 24 h and 48 h. Values were obtained for total vessel density, perfused vessel density, proportion of perfused vessels, microcirculatory flow index (MFI), microcirculatory heterogeneity index (MHI), and Point of Care Microcirculation (POEM) scores. Plasma viscosity was measured using a Wells-Brookfield cone and plate micro-viscometer. Logistic regression analyses examined relationships between microcirculatory parameters and plasma viscosity, adjusting for covariates (systolic blood pressure, heart rate, haematocrit, rate and volume of fluids, and rate of noradrenaline). RESULTS: Higher plasma viscosity was not associated with improved microcirculatory parameters. Instead, there were weakly significant associations between higher plasma viscosity and lower (poorer) MFI (p = 0.040), higher (worse) MHI (p = 0.033), and lower (worse) POEM scores (p = 0.039). CONCLUSIONS: The current study did not confirm the hypothesis that higher plasma viscosity improves microcirculatory flow dynamics in patients with THS. Further clinical investigations are warranted to determine whether viscosity is a physical parameter of importance during resuscitation of these patients.

Poor microcirculatory flow dynamics are associated with endothelial cell damage and glycocalyx shedding after traumatic hemorrhagic shock.

BACKGROUND: Endothelial cell damage and glycocalyx shedding after trauma can increase the risk of inflammation, coagulopathy, vascular permeability, and death. Bedside sublingual video-microscopy may detect worse flow and perfusion associated with this endotheliopathy. We compared markers of endotheliopathy with physical flow dynamics after traumatic hemorrhagic shock. METHODS: Sublingual incident dark field video-microscopy was performed at three time points after injury (<10 hours, 10-30 hours, and 30-50 hours). Values for microcirculatory flow index (MFI), Point Of carE Microcirculation assessment (POEM) score, proportion of perfused vessels (PPV), microcirculatory heterogeneity index (MHI), perfused vessel density (PVD), and total vessel density (TVD) were obtained. ELISAs were performed to measure concentrations of thrombomodulin and syndecan-1 as biomarkers of endothelial cell damage and glycocalyx shedding respectively. Flow parameters were dichotomized to above and below average, and biomarkers compared between groups; below average MFI, POEM, PPV, PVD, and TVD, and above average MHI were considered poor microcirculatory flow dynamics. RESULTS: A total of 155 sublingual video-microscopy clips corresponding to 39 time points from 17 trauma patients were analyzed. Median age was 35 (IQR 25-52); 16/17 were men. Within 10 hours of injury, syndecan-1 concentrations were significantly higher compared to 17 age- and sex-matched healthy controls (30 [IQR 20-44] ng/mL) for worse TVD (78 [IQR 63-417] ng/mL), PVD (156 [IQR 63-590] ng/mL), PPV (249 [IQR 64-578] ng/mL), MFI (249 [IQR 64-578] ng/mL), MHI (45 [IQR] 38-68) ng/mL), and POEM scores (108 [IQR 44-462] ng/mL) (all p < 0.01). Thrombomodulin was also raised within 10 hours of injury when compared to healthy controls (2.9 [IQR 2.2-3.4] ng/mL) for worse PPV (4.1 [IQR 3.4-6.2] ng/mL) and MFI (4.1 [IQR 3.4-6.2] ng/mL) (both p < 0.05). CONCLUSIONS: Endothelial cell damage and glycocalyx shedding are associated with worse flow, density, and heterogeneity within microvessels after traumatic hemorrhagic shock. The clinical utility of these biomarkers and flow parameters at the bedside are yet to be elucidated. LEVEL OF EVIDENCE: Prognostic study, level III.

Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine.

PURPOSE: Hand-held vital microscopes (HVMs) were introduced to observe sublingual microcirculatory alterations at the bedside in different shock states in critically ill patients. This consensus aims to provide clinicians with guidelines for practical use and interpretation of the sublingual microcirculation. Furthermore, it aims to promote the integration of routine application of HVM microcirculatory monitoring in conventional hemodynamic monitoring of systemic hemodynamic variables. METHODS: In accordance with the Delphi method we organized three international expert meetings to discuss the various aspects of the technology, physiology, measurements, and clinical utility of HVM sublingual microcirculatory monitoring to formulate this consensus document. A task force from the Cardiovascular Dynamics Section of the European Society of Intensive Care Medicine (with endorsement of its Executive Committee) created this consensus as an update of a previous consensus in 2007. We classified consensus statements as definitions, requirements, and/or recommendations, with a minimum requirement of 80% agreement of all participants. RESULTS: In this consensus the nature of microcirculatory alterations is described. The nature of variables, which can be extracted from analysis of microcirculatory images, is presented and the needed dataset of variables to identify microcirculatory alterations is defined. Practical aspects of sublingual HVM measurements and the nature of artifacts are described. Eleven statements were formulated that pertained to image acquisitions and quality statements. Fourteen statements addressed the analysis of the images, and 13 statements are related to future developments. CONCLUSION: This consensus describes 25 statements regarding the acquisition and interpretation of microcirculatory images needed to guide the assessment of the microcirculation in critically ill patients.

Endotheliopathy is associated with higher levels of cell-free DNA following major trauma: A prospective observational study.

BACKGROUND: Cell free deoxyribonucleic acid (cfDNA) has been proposed as a biomarker of secondary complications following trauma. Raised thrombomodulin and syndecan-1 levels have been used to indicate endotheliopathy, and are associated with inflammation, coagulopathy, and mortality. The current study aimed to analyse the association between cfDNA and biomarkers of endotheliopathy in a cohort of trauma patients, and whether raised levels of cfDNA were associated with poorer clinical outcomes. METHODS: Serum thrombomodulin and syndecan-1 were used as biomarkers of endotheliopathy and compared to plasma cfDNA in trauma patients from two prospective longitudinal observational studies. Cohort A (n = 105) had a predicted injury severity score (ISS) >8, and had blood sampled within 1h of injury and at 4-12h. Cohort B (n = 17) had evidence of haemorrhagic shock, and had blood sampled at a median time of 3.5h after injury. Relationships between biomarkers were tested using multivariable linear regression models that included the covariates of gender, age, ISS, Glasgow Coma Scale, lactate, systolic blood pressure, and heart rate. A model was fitted to investigate whether changes in cfDNA were associated with similar changes in endothelial biomarkers. RESULTS: The mean age was 41 (SD 19), and the median ISS was 25 (IQR 12-34). There was a significant association between cfDNA levels and both syndecan-1 and thrombomodulin levels (both p<0.001). This was independent of all covariates except for ISS, which significantly correlated with cfDNA levels. 50 ng/ml change in syndecan-1 and 1 ng/ml change in thrombomodulin corresponded to 15% and 20% increases in cfDNA levels respectively (both p<0.001). Patients who died had significantly higher prehospital and in-hospital cfDNA levels (both p<0.05). CONCLUSIONS: Raised cfDNA levels are associated with markers of endotheliopathy following trauma, and are associated with mortality. This relationship is present within the first hour of injury, and a change in one biomarker level is reflected by similar changes in the others. These findings are in keeping with the hypothesis that circulating DNA and endothelial injury share a common pathway following trauma.

Microcirculatory perfusion shows wide inter-individual variation and is important in determining shock reversal during resuscitation in a porcine experimental model of complex traumatic hemorrhagic shock.

BACKGROUND: Traumatic hemorrhagic shock (THS) is a leading cause of preventable death following severe traumatic injury. Resuscitation of THS is typically targeted at blood pressure, but the effects of such a strategy on systemic and microcirculatory flow remains unclear. Failure to restore microcirculatory perfusion has been shown to lead to poor outcomes in experimental and clinical studies. Systemic and microcirculatory variables were examined in a porcine model of complex THS, in order to investigate inter-individual variations in flow and the effect of microcirculatory perfusion on reversal of the shock state. METHODS: Baseline standard microcirculatory variables were obtained for 22 large white pigs using sublingual incident dark field (IDF) video-microscopy. All animals were subjected to a standardised hind-limb injury followed by a controlled haemorrhage of approximately 35 % of blood volume (shock phase). This was followed by 60 min of fluid resuscitation with either 0.9 % saline or component blood products and a target SBP of 80 mmHg (early resuscitation phase). All animals were then given blood products to a target SBP of 110 mmHg for 120 min (mid-resuscitation phase), and a further 100 min (late resuscitation phase). IDF readings were obtained at the midpoint of each of these phases. Cardiac output was measured using a pulmonary artery catheter. Animals were divided into above average (A) and below average (B) perfused vessel density (PVD) groups based on the lowest recorded PVD measurement taken during the shock and early resuscitation phases. RESULTS: There was minimal inter-individual variation in blood pressure but wide variation of both systemic and microcirculatory flow variables during resuscitation. During shock and early resuscitation, group A (n = 10) had a mean PVD of 10.5 (SD ± 2.5) mm/mm(2) and group B (n = 12) 5.5 (SD ± 4.1) mm/mm(2). During the later resuscitation phases, group A maintained a significantly higher PVD than group B. Group A initially had a higher cardiac output, but the difference between the groups narrowed as resuscitation progressed. At the end of resuscitation, group A had significantly lower plasma lactate, higher lactate clearance, lower standard base deficit and smaller mixed venous-arterial CO2 gradient. There was no significant difference in blood pressure between the two groups at any stage. CONCLUSION: There was a wide variation in both macro- and microcirculatory flow variables in this pressure-targeted experimental model of THS resuscitation. Early changes in microvascular perfusion appear to be key determinants in the reversal of the shock state during resuscitation. Microcirculatory flow parameters may be more reliable markers of physiological insult than pressure-based parameters and are potential targets for goal-directed resuscitation.

Safety and feasibility of sublingual microcirculation assessment in the emergency department for civilian and military patients with traumatic haemorrhagic shock: a prospective cohort study.

OBJECTIVES: Sublingual microcirculatory monitoring for traumatic haemorrhagic shock (THS) may predict clinical outcomes better than traditional blood pressure and cardiac output, but is not usually performed until the patient reaches the intensive care unit (ICU), missing earlier data of potential importance. This pilot study assessed for the first time the feasibility and safety of sublingual video-microscopy for THS in the emergency department (ED), and whether it yields useable data for analysis. SETTING: A safety and feasibility assessment was undertaken as part of the prospective observational MICROSHOCK study; sublingual video-microscopy was performed at the UK-led Role 3 medical facility at Camp Bastion, Afghanistan, and in the ED in 3 UK Major Trauma Centres. PARTICIPANTS: There were 15 casualties (2 military, 13 civilian) who presented with traumatic haemorrhagic shock with a median injury severity score of 26. The median age was 41; the majority (n=12) were male. The most common injury mechanism was road traffic accident. PRIMARY AND SECONDARY OUTCOME MEASURES: Safety and feasibility were the primary outcomes, as measured by lack of adverse events or clinical interruptions, and successful acquisition and storage of data. The secondary outcome was the quality of acquired video clips according to validated criteria, in order to determine whether useful data could be obtained in this emergency context. RESULTS: Video-microscopy was successfully performed and stored for analysis for all patients, yielding 161 video clips. There were no adverse events or episodes where clinical management was affected or interrupted. There were 104 (64.6%) video clips from 14 patients of sufficient quality for analysis. CONCLUSIONS: Early sublingual microcirculatory monitoring in the ED for patients with THS is safe and feasible, even in a deployed military setting, and yields videos of satisfactory quality in a high proportion of cases. Further investigations of early microcirculatory behaviour in this context are warranted. TRIAL REGISTRATION NUMBER: NCT02111109.