Reversible skin microvascular hyporeactivity in patients with immune-mediated thrombocytopenic thrombotic purpura.

BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by arteriolar and capillary microthrombosis precipitating organ failure. However, the contribution of endothelial dysfunction on impaired microvascular blood flow in iTTP patients has been poorly explored. This pilot observational study aimed to explore endothelial-mediated vasoreactivity in iTTP patients at admission and its changes after plasma exchange therapy (PE). METHODS: We conducted a prospective observational study in patients (> 18-year old) admitted in ICU for iTTP. Using laser Doppler flowmetry and acetylcholine (Ach) iontophoresis in the forearm, we recorded the skin microvascular blood flow and the endothelium-mediated vasoreactivity at admission and after PE. Demographics, biological, clinical courses, and outcomes were also collected. As a control group, we used a previously published cohort of young diabetic patients after correction of ketoacidosis. RESULTS: Eighteen confirmed iTTP patients and 34 controls were included in the study, mainly female (72%) aged 43 ± 16-year-old. At admission, 55% had neurological abnormalities, 50% cardiac issues and 27.8% an acute kidney injury. Median platelet count was 19 G/mL [10-37]. Baseline microvascular blood flow was decreased in iTTP patients when compared to controls (5.97 ± 4.5 vs. 10.1 ± 6.3 PU, P = 0.03), associated with markedly impaired endothelial-mediated skin microvascular reactivity (AUC: 9627 ± 8122 vs. 16,475 ± 11,738, P = 0.03). Microvascular reactivity improved after the first PE session (AUC: 9627 ± 8122 vs 16,558 ± 10,699, P = 0.007, respectively, baseline and post-PE1) and much more after the second session (26,431 ± 23,181, P = 0.04 post-PE1 vs post-PE2). Hemolysis biomarkers (LDH and bilirubin) negatively correlated with skin microvascular flow and vasoreactivity. CONCLUSION: We highlighted a marked yet reversible skin endothelium-mediated microvascular hyporeactivity in iTTP patients that could participate in organ injury pathophysiology.

Impact of corticosteroids on the procoagulant profile of critically ill COVID-19 patients: a before-after study.

BACKGROUND: Several studies have reported an increased risk of thrombotic events in COVID-19 patients, but the pathophysiology of this procoagulant phenotype remains poorly understood. We hypothesized that corticosteroids may attenuate this procoagulant state through their anti-inflammatory effects. The aim of this study was to evaluate the impact of dexamethasone (DXM) on the coagulation profile of severely ill COVID-19 patients. METHODS: We conducted a retrospective, observational before/after bi-centric cohort study among ICU patients hospitalized for severe COVID-19 and receiving therapeutic anticoagulation by unfractionated heparin (UFH). Before and after the standardized use of DXM, we compared inflammatory and coagulation profiles, as well as the kinetics of heparin requirement, adjusted for weight and anti-Xa activity. RESULTS: Eighty-six patients were included, 35 in the no-DXM group, and 51 in the DXM group. At admission, CRP and fibrinogen levels were not different between groups, neither were UFH infusion rates. At day 3 after ICU admission, CRP (178±94 mg/L vs. 99±68 mg/L, P<0.001) and fibrinogen (7.2±1.4 g/L vs. 6.1±1.4 g/L, P=0.001) significantly decreased in the DXM group, but not in the no-DXM group. Over time, UFH infusion rates were lower in the DXM group (P<0.001) without any significant difference in plasma anti-Xa activity. CRP variations correlated with heparin dose variations between Day 0 and Day 3 (r=0.39, P=0.009). Finally, the incidence of venous thromboembolic events during in-ICU stay was significantly reduced in the DXM group (4 vs. 43%, P<0.0001). CONCLUSIONS: In critically ill COVID-19 patients, dexamethasone use was associated with a decrease in both pro-inflammatory and procoagulant profile.

Kinetics of capillary refill time after fluid challenge.

BACKGROUND: Capillary refill time (CRT) is a valuable tool for triage and to guide resuscitation. However, little is known about CRT kinetics after fluid infusion. METHODS: We conducted a prospective observational study in a tertiary teaching hospital. First, we analyzed the intra-observer variability of CRT. Next, we monitored fingertip CRT in sepsis patients during volume expansion within the first 24 h of ICU admission. Fingertip CRT was measured every 2 min during 30 min following crystalloid infusion (500 mL over 15 min). RESULTS: First, the accuracy of repetitive fingertip CRT measurements was evaluated on 40 critically ill patients. Reproducibility was excellent, with an intra-class correlation coefficient of 99.5% (CI 95% [99.3, 99.8]). A CRT variation larger than 0.2 s was considered as significant. Next, variations of CRT during volume expansion were evaluated on 29 septic patients; median SOFA score was 7 [5-9], median SAPS II was 57 [45-72], and ICU mortality rate was 24%. Twenty-three patients were responders as defined by a CRT decrease > 0.2 s at 30 min after volume expansion, and 6 were non-responders. Among responders, we observed that fingertip CRT quickly improved with a significant decrease at 6-8 min after start of crystalloid infusion, the maximal improvement being observed after 10-12 min (-0.7 [-0.3;-0.9] s) and maintained at 30 min. CRT variations significantly correlated with baseline CRT measurements (R = 0.39, P = 0.05). CONCLUSIONS: CRT quickly improved during volume expansion with a significant decrease 6-8 min after start of fluid infusion and a maximal drop at 10-12 min.

Peripheral tissue hypoperfusion predicts post intubation hemodynamic instability.

BACKGROUND: Tracheal intubation and invasive mechanical ventilation initiation is a procedure at high risk for arterial hypotension in intensive care unit. However, little is known about the relationship between pre-existing peripheral microvascular alteration and post-intubation hemodynamic instability (PIHI). METHODS: Prospective observational monocenter study conducted in an 18-bed medical ICU. Consecutive patients requiring tracheal intubation were eligible for the study. Global hemodynamic parameters (blood pressure, heart rate, cardiac function) and tissue perfusion parameters (arterial lactate, mottling score, capillary refill time [CRT], toe-to-room gradient temperature) were recorded before, 5 min and 2 h after tracheal intubation (TI). Post intubation hemodynamic instability (PIHI) was defined as any hemodynamic event requiring therapeutic intervention. RESULTS: During 1 year, 120 patients were included, mainly male (59%) with a median age of 68 [57-77]. The median SOFA score and SAPS II were 6 [4-9] and 47 [37-63], respectively. The main indications for tracheal intubation were hypoxemia (51%), hypercapnia (13%), and coma (29%). In addition, 48% of patients had sepsis and 16% septic shock. Fifty-one (42%) patients develop PIHI. Univariate analysis identified several baseline factors associated with PIHI, including norepinephrine prior to TI, sepsis, tachycardia, fever, higher SOFA and high SAPSII score, mottling score ≥ 3, high lactate level and prolonged knee CRT. By contrast, mean arterial pressure, baseline cardiac index, and ejection fraction were not different between PIHI and No-PIHI groups. After adjustment on potential confounders, the mottling score was associated with a higher risk for PIHI (adjusted OR: 1.84 [1.21-2.82] per 1 point increased; p = 0.005). Among both global haemodynamics and tissue perfusion parameters, baseline mottling score was the best predictor of PIHI (AUC: 0.72 (CI 95% [0.62-0.81]). CONCLUSIONS: In non-selected critically ill patients requiring invasive mechanical ventilation, tissue hypoperfusion parameters, especially the mottling score, could be helpful to predict PIHI.

Impaired skin microvascular endothelial reactivity in critically ill COVID-19 patients.

BACKGROUND: Some clinical and histological studies have reported that SARS-CoV-2 infection may damage the endothelium. However, the impact of this virus on endothelial function in vivo remains poorly characterized. In this single-center pilot observational study, we performed iontophoresis of acetylcholine coupled with Laser doppler to investigate microvascular endothelial reactivity in COVID-19 patients compared to patients with non-COVID-19 bacterial pneumonia (NCBP) patients. RESULTS: During three consecutive months, 32 COVID-19 patients and 11 control NCBP patients with acute respiratory failure were included. The median age was 59 [50-68] and 69 [57-75] years in COVID-19 and NCBP groups, respectively (P = 0.11). There was no significant difference in comorbidities or medications between the two groups, except for body mass index, which was higher in COVID-19 patients. NCBP patients had a higher SAPS II score compared to COVID-19 patients (P < 0.0001), but SOFA score was not different between groups (P = 0.51). Global hemodynamic and peripheral tissue perfusion parameters were not different between groups. COVID-19 patients had significantly lower skin microvascular basal blood flow than NCBP patients (P = 0.02). In addition, endothelium-dependent microvascular reactivity was threefold lower in COVID-19 patients than NCBP patients (P = 0.008). CONCLUSIONS: Both baseline skin microvascular blood flow and skin endothelial-dependent microvascular reactivity were impaired in critically ill COVID-19 patients compared to NCBP patients, despite a lower disease severity score supporting a specific pathogenic role of SARS-CoV-2 on the endothelium.

Endothelial Activation and Microcirculatory Disorders in Sepsis.

The vascular endothelium is crucial for the maintenance of vascular homeostasis. Moreover, in sepsis, endothelial cells can acquire new properties and actively participate in the host's response. If endothelial activation is mostly necessary and efficient in eliminating a pathogen, an exaggerated and maladaptive reaction leads to severe microcirculatory damage. The microcirculatory disorders in sepsis are well known to be associated with poor outcome. Better recognition of microcirculatory alteration is therefore essential to identify patients with the worse outcomes and to guide therapeutic interventions. In this review, we will discuss the main features of endothelial activation and dysfunction in sepsis, its assessment at the bedside, and the main advances in microcirculatory resuscitation.

Vitamin C improves microvascular reactivity and peripheral tissue perfusion in septic shock patients.

BACKGROUND: Vitamin C has potential protective effects through antioxidant and anti-inflammatory properties. However, the effect of vitamin C supplementation on microvascular function and peripheral tissue perfusion in human sepsis remains unknown. We aimed to determine vitamin C effect on microvascular endothelial dysfunction and peripheral tissue perfusion in septic shock patients. METHODS: Patients with septic shock were prospectively included after initial resuscitation. Bedside peripheral tissue perfusion and skin microvascular reactivity in response to acetylcholine iontophoresis in the forearm area were measured before and 1 h after intravenous vitamin C supplementation (40 mg/kg). Norepinephrine dose was not modified during the studied period. RESULTS: We included 30 patients with septic shock. SOFA score was 11 [8-14], SAPS II was 66 [54-79], and in-hospital mortality was 33%. Half of these patients had vitamin C deficiency at inclusion. Vitamin C supplementation strongly improved microvascular reactivity (AUC 2263 [430-4246] vs 5362 [1744-10585] UI, p = 0.0004). In addition, vitamin C supplementation improved mottling score (p = 0.06), finger-tip (p = 0.0003) and knee capillary refill time (3.7 [2.6-5.5] vs 2.9 [1.9-4.7] s, p < 0.0001), as well as and central-to-periphery temperature gradient (6.1 [4.9-7.4] vs 4.6 [3.4-7.0] °C, p < 0.0001). The beneficial effects of vitamin C were observed both in patients with or without vitamin C deficiency. CONCLUSION: In septic shock patients being resuscitated, vitamin C supplementation improved peripheral tissue perfusion and microvascular reactivity whatever plasma levels of vitamin C. ClinicalTrials.gov Identifier: NCT04778605 registered 26 January 2021.

Impact of COVID-19 on the association between pulse oximetry and arterial oxygenation in patients with acute respiratory distress syndrome.

Managing patients with acute respiratory distress syndrome (ARDS) requires frequent changes in mechanical ventilator respiratory settings to optimize arterial oxygenation assessed by arterial oxygen partial pressure (PaO2) and saturation (SaO2). Pulse oxymetry (SpO2) has been suggested as a non-invasive surrogate for arterial oxygenation however its accuracy in COVID-19 patients is unknown. In this study, we aimed to investigate the influence of COVID-19 status on the association between SpO2 and arterial oxygenation. We prospectively included patients with ARDS and compared COVID-19 to non-COVID-19 patients, regarding SpO2 and concomitant arterial oxygenation (SaO2 and PaO2) measurements, and their association. Bias was defined as mean difference between SpO2 and SaO2 measurements. Occult hypoxemia was defined as a SpO2 ≥ 92% while concomitant SaO2 < 88%. Multiple linear regression models were built to account for confounders. We also assessed concordance between positive end-expiratory pressure (PEEP) trial-induced changes in SpO2 and in arterial oxygenation. We included 55 patients, among them 26 (47%) with COVID-19. Overall, SpO2 and SaO2 measurements were correlated (r = 0.70; p < 0.0001), however less so in COVID-19 than in non-COVID-19 patients (r = 0.55, p < 0.0001 vs. r = 0.84, p < 0.0001, p = 0.002 for intergroup comparison). Bias was + 1.1%, greater in COVID-19 than in non-COVID-19 patients (2.0 vs. 0.3%; p = 0.02). In multivariate analysis, bias was associated with COVID-19 status (unstandardized ß = 1.77, 95%CI = 0.38-3.15, p = 0.01), ethnic group and ARDS severity. Occult hypoxemia occurred in 5.5% of measurements (7.7% in COVID-19 patients vs. 3.4% in non-COVID-19 patients, p = 0.42). Concordance rate between PEEP trial-induced changes in SpO2 and SaO2 was 84%, however less so in COVID-19 than in non-COVID-19 patients (69% vs. 97%, respectively). Similar results were observed for PaO2 regarding correlations, bias, and concordance with SpO2 changes. In patients with ARDS, SpO2 was associated with arterial oxygenation, but COVID-19 status significantly altered this association.

Graft Versus Host Disease Associated with Immune Checkpoint Inhibitors: A Pharmacovigilance Study and Systematic Literature Review.

Background: In patients with allogenic hematopoietic stem cell transplantation (allo-HSCT), immune-checkpoint inhibitors (ICI) are used to treat malignancy recurrence. However, ICI are also associated with graft vs. host disease (GVHD). In this pharmacovigilance analysis, we aimed to characterize cases of GVHD associated with ICI, drawn from the World Health Organization pharmacovigilance database, VigiBase®, and from literature. Methods: We performed VigiBase® query of cases of GVHD associated with ICI. These cases were combined with those of literature, not reported in VigiBase®. The Bayesian estimate of disproportionality analysis, the information component, was considered significant if its 95% credibility interval lower bound was positive; denoting a significant association between GVHD and the suspected ICI. Time to onset between ICI and GVHD onset and subsequent mortality were assessed. Results: Disproportionality analysis yielded 93 cases of GVHD associated with ICI (61.8% men, median age 38 [interquartile range = 27; 50] years). Cases were mostly associated with nivolumab (53/93, 57.0%), pembrolizumab (23/93, 24.7%) and ipilimumab (12/93, 12.9%) monotherapies. GVHD events occurred after 1 [1; 5.5] injection of ICI, with a time to onset of 35 [IQR = 14; 176] days. Immediate subsequent mortality after GVHD was 24/93, 25.8%. There was no significant difference in mortality depending on the molecule (p = 0.41) or the combination regimen (combined vs. monotherapy, p = 0.60). Previous history of GVHD was present in 11/18, 61.1% in cases reported in literature. Conclusion: In this worldwide pharmacovigilance study, disproportionality yielded significant association between GVHD and ICI, with subsequent mortality of 25.8%. Previous history of GVHD was reported in more than half of cases. Clinicaltrials.gov identifier: NCT03492242.