Utilization and Efficacy of Resuscitation Endpoints in Trauma and Burn Patients: A Review Article.

Shock is a sequelae in trauma and burn patients that substantially increases the risk for morbidity and mortality. The use of resuscitation endpoints allows for improved management of these patients, with the potential to prevent further morbidity/mortality. We conducted a review of the current literature on the efficacy of hemodynamic, metabolic, and regional resuscitation endpoints for use in trauma and burn patients. Hemodynamic endpoints included mean arterial pressure (MAP), heart rate (HR), urinary output (UO), compensatory reserve index (CRI), intrathoracic blood volume, and stroke volume variation (SVV). Metabolic endpoints measure cellular responses to decreased oxygen delivery and include serum lactic acid (LA), base deficit (BD), bicarbonate, anion gap, apparent strong ion difference, and serum pH. Mean arterial pressure, HR, UO, and LA are the most established markers of trauma and burn resuscitation. The evidence suggests LA is a superior metabolic endpoint marker. Newer resuscitation endpoint technologies such as point-of-care ultrasound (PoCUS), thromboelastography (TEG), and rotational thromboelastometry (ROTEM) may improve patient outcomes; however, additional research is needed to establish the efficacy in trauma and burn patients. The endpoints discussed have situational strengths and weaknesses and no single universal resuscitation endpoint has yet emerged. This review may increase knowledge and aid in guideline development. We recommend clinicians continue to integrate multiple endpoints with emphasis on MAP, HR, UO, LA, and BD. Future investigation should aim to standardize endpoints for each clinical presentation. The search for universal and novel resuscitation parameters in trauma and burns should also continue.

Shock-Induced Endothelial Dysfunction is Present in Patients With Occult Hypoperfusion After Trauma.

BACKGROUND: Shock-induced endothelial dysfunction, evidenced by elevated soluble thrombomodulin (sTM) and syndecan-1 (Syn-1), is associated with poor outcomes after trauma. The association of endothelial dysfunction and overt shock has been demonstrated; it is unknown if hypoperfusion in the setting of normal vital signs (occult hypoperfusion [OH]) is associated with endothelial dysfunction. We hypothesized that sTM and Syn-1 would be elevated in patients with OH when compared to patients with normal perfusion. METHODS: A single-center study of patients requiring highest-level trauma activation (2012-2016) was performed. Trauma bay arrival plasma Syn-1 and sTM were measured by enzyme-linked immunosorbent assay. Shock was defined as systolic blood pressure (SBP) <90 mm Hg or heart rate (HR) ≥120 bpm. OH was defined as SBP ≥ 90, HR < 120, and base excess (BE) ≤-3. Normal perfusion was assigned to all others. Univariate and multivariable analyses were performed. RESULTS: Of 520 patients, 35% presented with OH and 26% with shock. Demographics were similar between groups. Patients with normal perfusion had the lowest Syn-1 and sTM, while patients with OH and shock had elevated levels. OH was associated with increased sTM by 0.97 ng/mL (95% CI 0.39-1.57, p = 0.001) and Syn-1 by 14.3 ng/mL (95% CI -1.5 to 30.2, p = 0.08). Furthermore, shock was associated with increased sTM by 0.64 (95% CI 0.02-1.30, p = 0.04) and with increased Syn-1 by 23.6 ng/mL (95% CI 6.2-41.1, p = 0.008). CONCLUSIONS: Arrival OH was associated with elevated sTM and Syn-1, indicating endothelial dysfunction. Treatments aiming to stabilize the endothelium may be beneficial for injured patients with evidence of hypoperfusion, regardless of vital signs.

Refractory Shock from Amlodipine Overdose Overcomed with Hyperinsulinemia.

Intoxication from calcium channel blockers exhibits almost 50% mortality rates. Amlodipine is a long-acting dihydropyridine and inappropriate dosage poses a great threat for profound vasodilation, hypotension, and refractory vasopressor-resistant shock. A 72-year-old woman with unremarkable medical history presented to the emergency department due to amlodipine overdose after a suicide attempt attributed to COVID-19 pandemic severe anxiety disorder. Vital signs at presentation: heart rate 82 beats/ min, arterial pressure 72/55 mmHg, and oxygen saturation 98%. Resuscitation was initiated with intravenous infusion of normal saline 0,9%, noradrenaline, and calcium chloride, while activated charcoal was orally administrated; however, blood pressure remained at 70/45 mmHg. Abruptly, she experienced acute pulmonary edema and was finally intubated. We commenced high-dose insulin infusion with Dextrose 10% infusion to maintain euglycemic hyperinsulinemia. Hemodynamic improvement occurred after 30 min, systolic blood pressure raised to 95 mmHg, and decongestion was achieved with intravenous furosemide. Insulin effect was dose-dependent and patient's hemodynamic status improved after insulin uptitration. Eight days later, the patient was weaned from the mechanical ventilation and she was successfully discharged after 14 days. High-dose intravenous infusion of insulin up to 10 units/kg per hour appears as an inotropic agent possibly through alterations in myocardial metabolism of fatty acids and augmentation of insulin secretion and uptake. This regimen possibly exhibits additional vasotropic properties. We conclude that euglycemic hyperinsulinemia is a potentially advantageous treatment in CCB toxicity.

Arterial or cuff pressure: Clinical predictors among patients in shock in a critical care resuscitation unit.

OBJECTIVES: Blood pressure (BP) measurement is essential for managing patients with hypotension. There are differences between invasive arterial blood pressure (IABP) and noninvasive blood pressure (NIBP) measurements. However, the clinical applicability of these differences in patients with shock [need for vasopressor or serum lactate ≥ 4 millimole per liter (mmol/L)] has not been reported. This study investigated differences in IABP and NIBP as well as changes in clinical management in critically ill patients with shock. METHODS: This was a retrospective study involving adult patients admitted to the Critical Care Resuscitation Unit (CCRU). Adult patients who received IABP upon admission between 01/01/2017-12/31/2017 with non-hypertensive diseases were eligible. The primary outcome, clinically relevant difference (CRD), was defined as difference of 10 mm of mercury (mmHg) between IABP and NIBP and change of blood pressure management according to goal mean arterial pressure (MAP) ≥ 65 mmHg. We performed forward stepwise multivariable logistic regression to measure associations. RESULTS: Sample size calculation recommended 200 patients, and we analyzed 263. 121 (46%) patients had shock, 23 (9%) patients had CRD. Each mmol/L increase in serum lactate was associated with 11% higher likelihood of having CRD (OR 1.11, 95%CI 1.002-1.2). Peripheral artery disease and any kidney disease was significantly associated with higher likelihood of MAP difference ≥ 10 mmHg. CONCLUSION: Approximately 9% of patients with shock had clinically-relevant MAP difference. Higher serum lactate was associated with higher likelihood of CRD. Until further studies are available, clinicians should consider using IABP in patients with shock.

Altered Expression of microRNAs in Serum Extracellular Vesicles in Rats with Severe Burns during Shock Stage.

BACKGROUND: The shock stage of severe burns is a critical determinant of prognosis and the induction of systemic inflammatory response syndrome and multiple organ failure. Extracellular vesicles (EVs) containing abundant miRNAs are known to participate in various biological processes. Due to the lack of research on alternations of miRNAs in severe burns, our study analyzed the miRNA profiles of EVs in severe burns during the shock stage. METHODS: EVs were extracted from the serum of rats with severe burns (30% of total body surface area, III°), and the expression of miRNAs in serum EVs was determined by next-generation sequencing. Functional analysis of target genes of miRNAs that were significantly differentially expressed (DE) was performed using GO Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: Thirty-four DE miRNAs were identified at the early stage of severe burn shock and 63 at the late stage of severe burn shock. In addition, miRNA-339-5p, miRNA-1, miRNA-382-5p, miRNA134-5p, miRNA-133a-5p, and miRNA-365a-5p were DE throughout the entire shock stage, based on P < 0.01 and |log2 (foldchange)| ≥ 1 criteria. GO and KEGG analysis revealed that the target genes of DE miRNAs mainly enriched the metabolic process, immune system processes, and signal pathways. CONCLUSION: To our best knowledge, this is the first study demonstrating the miRNA expression profiles of EVs isolated from serum with severe burns during the shock stage. There are significant differences between downregulation and upregulation. Thus, miRNAs have the potential for novel biomarkers for the complication of severe burns.

Good Platelets Gone Bad: The Effects of Trauma Patient Plasma on Healthy Platelet Aggregation.

BACKGROUND: Altered postinjury platelet behavior is recognized in the pathophysiology of trauma-induced coagulopathy (TIC), but the mechanisms remain largely undefined. Studies suggest that soluble factors released by injury may inhibit signaling pathways and induce structural changes in circulating platelets. Given this, we sought to examine the impact of treating healthy platelets with plasma from injured patients. We hypothesized that healthy platelets treated ex-vivo with plasma from injured patients with shock would impair platelet aggregation, while treatment with plasma from injured patients with significant injury burden, but without shock, would enhance platelet aggregation. METHODS: Plasma samples were isolated from injured patients (pretransfusion) and healthy donors at a Level I trauma center and stored at -80°C. Plasma samples from four separate patients in each of the following stratified clinical groups were used: mild injury/no shock (injury severity score [ISS] 2-15, base excess [BE]>-6), mild injury/with shock (ISS 2-15, BE≤-6), severe injury/no shock (ISS>25, BE>-6), severe injury/with shock (ISS>25, BE≤-6), minimal injury (ISS 0/1, BE>-6), and healthy. Platelets were isolated from three healthy adult males and were treated with plasma for 30 min. Aggregation was stimulated with a thrombin receptor agonist and measured via multiple-electrode platelet aggregometry. Data were normalized to HEPES Tyrode's (HT) buffer-only treated platelets. Associations of plasma treatment groups with platelet aggregation measures were tested with Mann-Whitney U tests. RESULTS: Platelets treated with plasma from patients with shock (regardless of degree of injury) had significantly impaired thrombin-stimulated aggregation compared with platelets treated with plasma from patients without shock (P = 0.002). Conversely, platelets treated with plasma from patients with severe injury, but without shock, had amplified thrombin-stimulated aggregation (P = 0.030). CONCLUSION: Shock-mediated soluble factors impair platelet aggregation, and tissue injury-mediated soluble factors amplify platelet aggregation. Future characterization of these soluble factors will support development of novel treatments of TIC.

Plasma procalcitonin levels remain low at the onset of gram-positive bacteremia regardless of severity or the presence of shock: A retrospective analysis of patients with detailed clinical characteristics.

OBJECTIVES: Procalcitonin (PCT) is an early diagnosis marker of sepsis/bacteremia. However, some reports refer to its lower responsiveness to gram-positive bacteremia. We retrospectively evaluated the PCT values at the onset of bacteremia in relation to severity index. METHODS: Patients with bacteremia caused by two gram-negative bacteria (46 E. coli and 50 Klebsiella pneumoniae) and three gram-positive bacteria (45 S. aureus, 56 S. epidermidis, and 10 S. mitis) were studied. The plasma PCT and C-reactive protein (CRP) levels were compared between species and different Sequential Organ Failure Assessment (SOFA) score groups. RESULTS: The median PCT level was higher in gram-negative than in gram-positive bacteremia in overall (13.09 vs. 0.50 ng/mL, p < 0.0001), in SOFA score≥4 group (28.85 vs.1.72 ng/mL, p < 0.0001) and in SOFA<4 group (2.64 vs. 0.42 ng/mL, p < 0.0001). Only 46%, and 11% of patients showed PCT ≥0.5 ng/mL in S. epidermidis, and S. mitis bacteremia, respectively. PCT was significantly better than CRP in discriminating gram-negative from gram-positive bacteremia (AUCROC; 0.828 and 0.634, p < 0.001), but it was low in Staphylococcus epidermidis bacteremia regardless of SOFA scores. CONCLUSIONS: PCT levels are lower in gram-positive bacteremia regardless of SOFA scores or the presence of shock. The conventional sepsis cutoff of 0.5 ng/mL may overlook certain proportions of gram-positive bacteremia.

The Prognostic Value of Lactate in Cardiac Intensive Care Unit Patients With Cardiac Arrest and Shock.

BACKGROUND: Lactate is a prognostic marker in critically ill patients, although currently available illness severity scores do not include lactate as a predictive parameter. We sought to describe the association between lactate and hospital mortality in patients admitted to the cardiac intensive care unit (CICU) with cardiac arrest (CA) and shock. METHODS: Retrospective observational analysis of Mayo Clinic CICU patients admitted from 2007 to 2018 with measured lactate on admission, including patients with and without CA or shock. We examined hospital mortality as a function of admission lactate in patients. Multivariable logistic regression was used to determine predictors of hospital mortality. RESULTS: We included 3,042 patients with a median age of 70 years (IQR 60-80), including 41% females, 26% with CA, and 39% with shock. The median APACHE-IV predicted mortality was 24% (IQR 11-51%), and the median admission lactate was 1.8 mmol/L (IQR 1.1-3.0). Hospital mortality occurred in 23% of patients and rose progressively with higher admission lactate, including in patients with and without CA or shock. After multivariable adjustment for clinical characteristics, therapies, and illness severity, a higher lactate remained associated with increased hospital mortality (adjusted OR 1.13 per mmol/L, 95% CI 1.06-1.20, P < 0.001). CONCLUSIONS: Admission lactate levels are strongly associated with increased hospital mortality among CICU patients, including those with and without CA or shock. The prognostic value of lactate levels is independent of established ICU prognostic scores and dependent on admission diagnosis, which may help inform clinicians caring for CICU patients.

Serum citrullinated histone H3 concentrations differentiate patients with septic verses non-septic shock and correlate with disease severity.

PURPOSE: Microbial infection stimulates neutrophil/macrophage/monocyte extracellular trap formation, which leads to the release of citrullinated histone H3 (CitH3) catalyzed by peptidylarginine deiminase (PAD) 2 and 4. Understanding these molecular mechanisms in the pathogenesis of septic shock will be an important next step for developing novel diagnostic and treatment modalities. We sought to determine the expression of CitH3 in patients with septic shock, and to correlate CitH3 levels with PAD2/PAD4 and clinically relevant outcomes. METHODS: Levels of CitH3 were measured in serum samples of 160 critically ill patients with septic and non-septic shock, and healthy volunteers. Analyses of clinical and laboratory characteristics of patients were conducted. RESULTS: Levels of circulating CitH3 at enrollment were significantly increased in septic shock patients (n = 102) compared to patients hospitalized with non-infectious shock (NIC) (n = 32, p < 0.0001). The area under the curve (95% CI) for distinguishing septic shock from NIC using CitH3 was 0.76 (0.65-0.86). CitH3 was positively correlated with PAD2 and PAD4 concentrations and Sequential Organ Failure Assessment Scores [total score (r = 0.36, p < 0.0001)]. The serum levels of CitH3 at 24 h (p < 0.01) and 48 h (p < 0.05) were significantly higher in the septic patients that did not survive. CONCLUSION: CitH3 is increased in patients with septic shock. Its serum concentrations correlate with disease severity and prognosis, which may yield vital insights into the pathophysiology of sepsis.

Acute Cardiovascular Manifestations in 286 Children With Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe.

BACKGROUND: The aim of the study was to document cardiovascular clinical findings, cardiac imaging, and laboratory markers in children presenting with the novel multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) infection. METHODS: This real-time internet-based survey has been endorsed by the Association for European Paediatric and Congenital Cardiologists Working Groups for Cardiac Imaging and Cardiovascular Intensive Care. Children 0 to 18 years of age admitted to a hospital between February 1 and June 6, 2020, with a diagnosis of an inflammatory syndrome and acute cardiovascular complications were included. RESULTS: A total of 286 children from 55 centers in 17 European countries were included. The median age was 8.4 years (interquartile range, 3.8-12.4 years) and 67% were boys. The most common cardiovascular complications were shock, cardiac arrhythmias, pericardial effusion, and coronary artery dilatation. Reduced left ventricular ejection fraction was present in over half of the patients, and a vast majority of children had raised cardiac troponin when checked. The biochemical markers of inflammation were raised in most patients on admission: elevated C-reactive protein, serum ferritin, procalcitonin, N-terminal pro B-type natriuretic peptide, interleukin-6 level, and D-dimers. There was a statistically significant correlation between degree of elevation in cardiac and biochemical parameters and the need for intensive care support (P<0.05). Polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was positive in 33.6%, whereas immunoglobulin M and immunoglobulin G antibodies were positive in 15.7% cases and immunoglobulin G in 43.6% cases, respectively, when checked. One child in the study cohort died. CONCLUSIONS: Cardiac involvement is common in children with multisystem inflammatory syndrome associated with the Covid-19 pandemic. The majority of children have significantly raised levels of N-terminal pro B-type natriuretic peptide, ferritin, D-dimers, and cardiac troponin in addition to high C-reactive protein and procalcitonin levels. In comparison with adults with COVID-19, mortality in children with multisystem inflammatory syndrome associated with COVID-19 is uncommon despite multisystem involvement, very elevated inflammatory markers, and the need for intensive care support.

The Use of Central Venous to Arterial Carbon Dioxide Tension Gap for Outcome Prediction in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: In this systematic review and meta-analysis, we assessed whether a high CO2 gap predicts mortality in adult critically ill patients with circulatory shock. DATA SOURCES: A systematic search of MEDLINE and EMBASE electronic databases from inception to October 2019. STUDY SELECTION: Studies from adult (age ≥ 18 yr) ICU patients with shock reporting CO2 gap and outcomes of interest. Case reports and conference abstracts were excluded. DATA EXTRACTION: Data extraction and study quality assessment were performed independently in duplicate. DATA SYNTHESIS: We used the Newcastle-Ottawa Scale to assess methodological study quality. Effect sizes were pooled using a random-effects model. The primary outcome was mortality (28 d and hospital). Secondary outcomes were ICU length of stay, hospital length of stay, duration of mechanical ventilation, use of renal replacement therapy, use of vasopressors and inotropes, and association with cardiac index, lactate, and central venous oxygen saturation. CONCLUSIONS: We included 21 studies (n = 2,155 patients) from medical (n = 925), cardiovascular (n = 685), surgical (n = 483), and mixed (n = 62) ICUs. A high CO2 gap was associated with increased mortality (odds ratio, 2.22; 95% CI, 1.30-3.82; p = 0.004) in patients with shock, but only those from medical and surgical ICUs. A high CO2 gap was associated with higher lactate levels (mean difference 0.44 mmol/L; 95% CI, 0.20-0.68 mmol/L; p = 0.0004), lower cardiac index (mean difference, -0.76 L/min/m; 95% CI, -1.04 to -0.49 L/min/m; p = 0.00001), and central venous oxygen saturation (mean difference, -5.07; 95% CI, -7.78 to -2.37; p = 0.0002). A high CO2 gap was not associated with longer ICU or hospital length of stays, requirement for renal replacement therapy, longer duration of mechanical ventilation, or higher vasopressors and inotropes use. Future studies should evaluate whether resuscitation aimed at closing the CO2 gap improves mortality in shock.

Admission base deficit is superior to lactate in identifying shock and resuscitative needs in trauma patients.

BACKGROUND: Base Deficit (BD) and lactate have been used as indicators of shock and resuscitation. This study was done to evaluate the utility of BD and lactate in identifying shock and resuscitative needs in trauma patients. METHODS: A prospective observational study was performed from 3/2014-12/2018. Data included demographics, admission systolic BP, ISS, BD, lactate, blood transfusion, and outcomes. BD and lactate were modeled continuously and categorically and compared. RESULTS: 2271 patients were included. BD and lactate were moderately correlated (r2 = 0.63 p < 0.001). On univariate regression, BD and lactate were associated with transfusion requirement and mortality (p < 0.001), but on multivariate regression, only BD was associated with transfusion requirement and mortality (OR = 1.2, p < 0.001; OR = 1.1, p < 0.001, respectively). BD discriminated better than lactate for hypotension, higher ISS, increased transfusion requirements and mortality. CONCLUSIONS: Admission BD and lactate levels are correlated following injury, but BD is superior to lactate in identifying shock, resuscitative needs and mortality in severely injured trauma patients.

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial.

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Circulating dipeptidyl peptidase-3 at admission is associated with circulatory failure, acute kidney injury and death in severely ill burn patients.

BACKGROUND: Dipeptidyl peptidase-3 (DPP3) is a metallopeptidase which cleaves bioactive peptides, notably angiotensin II, and is involved in inflammation regulation. DPP3 has been proposed to be a myocardial depressant factor and to be involved in circulatory failure in acute illnesses, possibly due to angiotensin II cleavage. In this study, we evaluated the association between plasmatic DPP3 level and outcome (mortality and hemodynamic failure) in severely ill burn patients. METHODS: In this biomarker analysis of a prospective cohort study, we included severely ill adult burn patients in two tertiary burn intensive care units. DPP3 was measured at admission (DPP3admin) and 3 days after. The primary endpoint was 90-day mortality. Secondary endpoints were hemodynamic failure and acute kidney injury (AKI). RESULTS: One hundred and eleven consecutive patients were enrolled. The median age was 48 (32.5-63) years, with a median total body surface area burned of 35% (25-53.5) and Abbreviated Burn Severity Index (ABSI) of 8 (7-11). Ninety-day mortality was 32%. The median DPP3admin was significantly higher in non-survivors versus survivors (53.3 ng/mL [IQR 28.8-103.5] versus 27.1 ng/mL [IQR 19.4-38.9]; p < 0.0001). Patients with a sustained elevated DPP3 had an increased risk of death compared to patients with high DPP3admin but decreased levels on day 3. Patients with circulatory failure had higher DPP3admin (39.2 ng/mL [IQR 25.9-76.1] versus 28.4 ng/mL [IQR 19.8-39.6]; p = 0.001) as well as patients with AKI (49.7 ng/mL [IQR 30.3-87.3] versus 27.6 ng/mL [IQR 19.4-41.4]; p = 0.001). DPP3admin added prognostic value on top of ABSI (added chi2 12.2, p = 0.0005), Sequential Organ Failure Assessment (SOFA) score at admission (added chi2 4.9, p = 0.0268), and plasma lactate at admission (added chi2 6.9, p = 0.0086) to predict circulatory failure within the first 48 h. CONCLUSIONS: Plasma DPP3 concentration at admission was associated with an increased risk of death, circulatory failure, and AKI in severely burned patients. Whether DPP3 plasma levels could identify patients who would respond to alternative hemodynamic support strategies, such as intravenous angiotensin II, should be explored.

Identification of injury and shock driven effects on ex vivo platelet aggregometry: A cautionary tale of phenotyping.

BACKGROUND: Platelet behavior in trauma-induced coagulopathy is poorly understood. Injured patients have impaired platelet aggregation (dysfunction) in ex vivo agonist-stimulated platelet aggregometry (PA). However, PA assumes that platelets are inactivated before ex vivo stimulated aggregation, which may be altered by injury. We hypothesized that following trauma, platelet aggregation (area under the curve) is decreased regardless of injury burden, but that (1) minor injury is associated with an increased baseline electrical impedance, characteristic of a functional platelet phenotype (platelets that activate in response to injury), and that (2) severe injury is not associated with an increased baseline electrical impedance, characteristic of a dysfunctional phenotype (platelets that do not activate well in response to injury) compared with healthy controls. METHODS: Blood from 458 trauma patients and 30 healthy donors was collected for PA. Baseline electrical impedance (Ω); platelet aggregation stimulated by adenosine diphosphate, collagen, thrombin, and arachidonic acid; and rotational thromboelastometry were measured. Multivariate regression was performed to identify associations of PA measures with blood transfusion. RESULTS: Compared with healthy controls, injured patients had impaired platelet aggregation in response to ex vivo stimulation, regardless of injury burden. However, minorly injured patients had increased endogenous platelet activation (baseline electrical impedance, Ω: with shock, p = 0.012; without shock, p = 0.084), but severely injured patients did not have significant increases in endogenous platelet activation (baseline electrical impedance, Ω: with shock, p = 0.86; without shock, p = 0.37). For every 10 Ω increase in baseline electrical impedance, there was an 8% decrease in units of blood transfused in the first 24 h (-0.08; confidence interval, -0.14 to -0.02; p = 0.015). CONCLUSION: Injury and shock confer differential patterns of platelet aggregation in PA. Minor injury overestimates the presence of platelet dysfunction, while severe injury induces a truly dysfunctional phenotype-platelets that do not activate nor aggregate appropriately after injury. This is consequential in improving accurate phenotyping of postinjury platelet behavior for platelet-based therapeutics. LEVEL OF EVIDENCE: Prognostic, level IV.

Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock.

BACKGROUND: In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. METHODS: We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes. RESULTS: Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P <  0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P <  0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P <  0.0001), lower ANG II levels (P <  0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P <  0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses. CONCLUSIONS: Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Blood lactate and lactate kinetics as treatment and prognosis markers for tissue hypoperfusion.

Objective: Blood lactate concentration (L) and lactate kinetic (LK) over time might be a helpful marker of the shock severity. The purpose of this study is to analyze whether the L and LK could correlate with the outcome and the therapy of patients with different types of shock.Methods: Design: A 3.5-year retrospective observational study. Patients: Eighteen years of age or older, diagnosed with shock were included. Arterial L measurements were performed upon admission and approximatively 3 and 6 h later. The evolution of lactate over this period of time was correlated with the outcome and therapy. Interventions: Univariate and multivariable statistical tests were performed to examine the relation between the initial L/LK and the in-hospital mortality, total mortality, length of stay (LOS), the LOS at the intensive care unit and the administered therapy. The optimal cut-off point of the LK over time to predict the mortality was calculated.Results: The initial L and the 6 h LK were significantly associated with the outcome. The higher the initial L and lower the LK, the higher the risk of mortality in the hospital or within 6 months. Moreover, the higher the initial L and lower the 6 h LK, the longer was the LOS. A relation between the initial L/LK and the required therapy was found. The optimal cut-off for the 6-h LK is 38.1%. Patients with a 6 h LK >38.1% had a significantly higher chance of survival.Conclusions: A significant relationship between the L/6-h LK and the outcome and treatment was found. The optimal survival cut-off point of 6 h LK in our study was 38.1%.

Metabolic Systems Analysis of Shock-Induced Endotheliopathy (SHINE) in Trauma: A New Research Paradigm.

OBJECTIVE: Investigate the endothelial cell phenotype (s) that causes Shock-Induced Endotheliopathy in trauma. BACKGROUND: We have studied more than 2750 trauma patients and identified that patients with high circulating syndecan-1 (endothelial glycocalyx damage marker) in plasma have an increased mortality rate compared with patients with lower levels. Notably, we found that patients suffering from the same trauma severity could develop significantly different degrees of endothelial dysfunction as measured by syndecan-1. METHODS: Prospective observational study of 20 trauma patients admitted to a Level 1 Trauma Centre and 20 healthy controls. Admission plasma syndecan-1 level and mass spectrometry were measured and analyzed by computational network analysis of our genome-scale metabolic model of the microvascular endothelial cell function. RESULTS: Trauma patients had a significantly different endothelial metabolic profile compared with controls. Among the patients, 4 phenotypes were identified. Three phenotypes were independent of syndecan-1 levels. We developed genome-scale metabolic models representative of the observed phenotypes. Within these phenotypes, we observed differences in the cell fluxes from glucose and palmitate to produce Acetyl-CoA, and secretion of heparan sulfate proteoglycan (component of syndecan-1). CONCLUSIONS: We confirm that trauma patients have a significantly different metabolic profile compared with controls. A minimum of 4 shock-induced endotheliopathy phenotypes were identified, which were independent of syndecan-1level (except 1 phenotype) verifying that the endothelial response to trauma is heterogeneous and most likely driven by a genetic component. Moreover, we introduced a new research tool in trauma by using metabolic systems biology, laying the foundation for personalized medicine.