Background
Methods
Study population
Inclusion and exclusion criteria
Therapeutic plasma exchange (TPE)
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NE dose to maintain MAP ≥ 65 mmHg
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MAP
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6-h fluid balances
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C-reactive protein (CRP), procalcitonin (PCT), white blood cell (WBC) counts
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International normalized ratio (INR), platelets
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cytokines (interleukin (IL)-6, IL-1b, IL-8, and IL-10)
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permeability-regulating factors (angiopoietin-1, -2, and soluble receptor of tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (sTie2))
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preload (stroke volume variance (SVV) and global end-diastolic volume index (GEDI))
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afterload (systemic vascular resistance index (SVRI))
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cardiac index
Endothelial ex-vivo stimulation with plasma from septic shock patients
Fluorescent immunocytochemistry
Transendothelial electrical resistance (TER)
Measurement of circulating cytokines and permeability factors
Statistical analysis
Results
Cohort characterization
Characteristic | Value |
---|---|
Age (years) | 52 (30–58) |
Sex (male/female), n (%) | 13/7 (65/35) |
Weight (kg) | 85 (71–103) |
Height (m) | 1.79 (1.7–1.85) |
BMI (kg/m2) | 26.9 (22.2–31.9) |
Sepsis onset, n (%) | |
Community-acquired | 10 (50) |
Hospital-acquired | 10 (50) |
Site of infection, n (%) | |
Lung | 11 (55) |
Abdomen | 3 (15) |
Urogenital | 1 (5) |
Soft tissue | 3 (15) |
Endocarditis | 1 (5) |
Mixed | 1 (5) |
Pathogen, n (%) | |
Gram-positive | 3 (15) |
Gram-negative | 5 (25) |
Fungi | 1 (5) |
Mixed | 5 (25) |
Not identified | 6 (30) |
APACHE II | 40.5 (35–46) |
SOFA | 18 (16–20) |
ADAMTS13 (%) | 44 (29–56.5) |
Norepinephrine dose (μg/kg/min) | 0.82 (0.61–1.17) |
Mechanical ventilation, n (%) | 19 (95) |
Oxygenation index (PaO2/FiO2) | 132 (96–229) |
Renal replacement therapy, n (%) | 13 (65) |
Organ failure, n (%) | |
Respiratory | 19 (95) |
Coagulation | 14 (70) |
Liver | 10 (50) |
Cardiovascular | 20 (100) |
Neurological | 19 (95) |
Renal | 16 (80) |
Multi organ failure, n (%) | |
Two | 0 (0) |
Three | 1 (5) |
Four | 6 (30) |
Five | 7 (35) |
Six | 6 (30) |
Immunosuppression, n (%) | 13 (65) |
Feasibility and safety
Immediate effects of TPE on clinical parameters
Variable | Therapeutic plasma exchange (TPE) | p value | |
---|---|---|---|
Before | After | ||
Clinical parameters | |||
MAP (mmHg) | 65.5 (54.5–75.3) | 69 (64–79.3) | 0.07 |
NE dose (μg/kg/min) | 0.82 (0.61–1.17) | 0.56 (0.41–0.78) | 0.0002* |
MAP/NE (mmHg/μg/kg/min) | 74.9 (48.5–116.8) | 114.3 (75.3–166.7) | < 0.0001* |
HR (bpm) | 110.5 (91.3–125.5) | 103.5 (86.8–119) | 0.11 |
SVV (%) | 20 (12.5–29) | 11 (6–14.5) | 0.008* |
SVRI (dyne/s/cm5/m2) | 1450 (980–1873) | 1520 (1060-2126) | 0.67 |
SVRI/NE (dyne/s/cm5/m2)/(μg/kg/min) | 1743 (1008-2921) | 2547 (1213-3923) | 0.06 |
EVLWI (mL/kg) | 14 (8–17) | 11.5 (8–16.5) | 0.93 |
GEDI (mL/m2) | 670 (483–909) | 755 (622–998) | 0.12 |
Cardiac index (L/min/m2) | 2.85 (2.39–4.32) | 3.42 (2.71–5.19) | 0.39 |
Fluid balance/6 h (mL) | 3411 (2295-4933) | 2190 (1431-4060) | 0.007* |
Gas exchange | |||
Oxygenation index (PaO2/FiO2) | 132 (96–229) | 115 (102–212) | 0.94 |
AaDO2 (mmHg) | 360 (251–541) | 329 (247–489) | 0.28 |
Inflammatory biomarkers | |||
CRP (mg/L) | 236 (147–302) | 174 (86–288) | 0.07 |
PCT (ng/mL) | 24.1 (16.9–83.7) | 31 (14.8–87.3) | 0.86 |
WBC (1/nL) | 11.2 (0.93–34.8) | 8.4 (1.2–25.6) | 0.73 |
PLT (1/nL) | 43.0 (16.8–112) | 34.0 (20–66) | 0.11 |
INR | 1.76 (1.44–2.1) | 1.43 (1.26–2.1) | 0.16 |
Acid base balance | |||
pH | 7.28 (7.19–7.34) | 7.33 (7.23–7.38) | 0.01* |
pCO2 (mmol/L) | 44.5 (35.3–56.3) | 46 (37–55) | 0.99 |
HCO3− (mmol/L) | 20.0 (17–23.8) | 22.0 (20–24.7) | 0.001* |
Lactate (mmol/L) | 6.5 (2.8–11.3) | 6.5 (3.2–10.8) | 0.84 |
Cytokines | |||
IL-8 (ng/mL) | 1.35 (0.6–10.81) | 1.09 (0.4–7.1) | 0.009* |
IL-1b (pg/mL) | 147.1 (57.1–241.6) | 92.2 (42.9–184.8) | 0.01* |
IL-6 (ng/mL) | 10.8 (2.54–27.6) | 4.6 (0.9–13.7) | 0.005* |
IL-10 (pg/mL) | 143.3 (65.5–259.2) | 98.1 (59.6–180.4) | 0.05 |
Vasoactive substances | |||
Angiopoietin-1 (ng/mL) | 3.27 (2.01–5.36) | 2.97 (1.42–5.15) | 0.1 |
Angiopoietin-2 (ng/mL) | 9.51 (5.06–13.2) | 5.14 (3.04–11.18) | < 0.0001* |
sTie2 (ng/mL) | 16.03 (10.91–19.51) | 8.36 (6.67–12.85) | < 0.0001* |
Effects of TPE on biochemical parameters, circulating cytokines, and vasoactive substances
Predictors of responsiveness to TPE
Effect on 28-day mortality
Effect on vascular barrier function: ex-vivo analysis
Discussion
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feasibility and safety of the procedure
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hemodynamic improvement indicated by a NE reduction often achieved within minutes after TPE start
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improved preload and fluid balance possibly due to a protective effect on vascular permeability
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decline in plasma concentrations of proinflammatory mediators
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reversibility of the septic endothelial phenotype ex vivo from 60% of patients plasma after TPE