Antithrombin during veno-venous extracorporeal membrane oxygenation with heparin anticoagulation: A single-center cohort study.

INTRODUCTION: Antithrombin (AT) is a natural anticoagulant essential to enhancing the unfractionated heparin (UFH) anticoagulant effect. Its supplementation in the management of UFH-based anticoagulation during veno-venous extracorporeal membrane oxygenation (VV ECMO) has a strong pathophysiological rationale. METHODS: This is a single-center, retrospective cohort study of adult VV ECMO patients with anticoagulation maintained by UFH targeting an activated partial thromboplastin time (aPTT) of 40-50 s and AT activity >80%. We compare anticoagulation management and survival outcomes between AT subpopulations, defined by a threshold AT activity ≥80%. Linear and logistic regression analyses were used to evaluate the variation in AT activity and its association with ICU survival. RESULTS: In 244 patients enrolled from 2009 to 2022, anticoagulation was maintained by a median heparin dose of 11.4 IU/kg/h [IQR: 8.2-14.7] with a mean aPTT of 46.1 s (±7.3) and AT activity of 88.9% (±17.0). A lower mean aPTT, higher dose of UFH and shorter fraction of time without UFH were associated with higher AT activity (p < .01). Higher AT activity showed a consistent association with ICU survival (for 10% increase of AT, odds ratio for ICU mortality: 0.95; 95% CI 0.93-0.97; p value <.01). CONCLUSIONS: There is a positive association between AT activity and UFH requirements but no significant difference in the rate of bleeding events. A higher mean AT during VV ECMO was associated with ICU survival. Future studies are needed to differentiate between exogenously supplemented versus endogenous AT effect.

The role of inflammation and antithrombin supplementation on thromboelastographic parameters during veno-venous ECMO for respiratory failure.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) may act as a driver or propagator of systemic inflammation. In turn, cytokine release can modify thromboelastographic (TEG) tests which are commonly used for anticoagulation monitoring. In this context, antithrombin (AT) supplementation might further modify TEG. METHODS: This is a pre-specified sub-study of the "Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation" study (investigator-initiated, randomized, single-blind, two-arm trial) conducted in two Italian ECMO referral ICUs. Adult patients requiring vv-ECMO for respiratory failure and undergoing unfractioned heparin (UFH) administration were enrolled and randomized whether to receive AT supplementation. Plasma samples for cytokine assay (IL-8, IL-10, IL-6, IL-1ß, TNF-α and Pro-ADM) and heparinase TEG were collected from every patient before ECMO start, 24 h and 72 h after ECMO start, before ECMO removal, and 7 days after ECMO removal or upon ICU discharge whichever happened first. AT concentration, coagulation and clinical data were collected before ECMO start and at pre-fixed time points. RESULTS: Thirty-nine patients were enrolled (21 treatments, 18 controls). TEG-R had a weak-to-moderate positive correlation with IL-8, IL-6, IL-10 and TNF-α and a moderate positive correlation with Pro-ADM. TEG-ANG showed a weak negative correlation with IL-8, IL-6 and TNF-α, while TEG-MA negatively correlated with IL-8, TNF-α and Pro-ADM. AT supplementation seemed to modify the association between TEG-MA and IL-8, IL-10 and Pro-ADM; conversely, AT did not affect the relationship among TEG-R or TEG-ANG and the studied cytokines. CONCLUSIONS: High concentrations of systemic cytokines correlated with longer reaction times and decreased angle and amplitude at TEG, suggesting that an increase in inflammation is related with hypocoagulability as revealed by thromboelastography.

The relationship between antithrombin administration and inflammation during veno-venous ECMO.

Veno-venous Extracorporeal Membrane Oxygenation (ECMO) is used in the most severe cases of respiratory failure and further exacerbates the patients' inflammatory status. Antithrombin is supplemented during ECMO for its anticoagulant effects, but it also deploys anti-inflammatory properties. In this pre-specified ancillary study of the GATRA trial [NCT03208270] we aimed to evaluate the relationship between antithrombin and inflammation during ECMO. Forty-six patients were included in the study, 23 were randomized to receive antithrombin to maintain a level of 80-120% (study group) and 23 were randomized not to be supplemented (control group). Anticoagulation was provided in both groups with heparin infusion. Six cytokines were measured at 5 timepoints from prior to ECMO start to 7 days after ECMO removal. Cytokines decreased during the study but overall were not very different in the two groups. Testing the interaction between the study group and timepoints suggests that the administration of antithrombin led to a more rapid decrease over time of IL-6, IL-1ß, TNF-⍺ and Pro-ADM. Plasma levels of antithrombin (either endogenous or exogenous) were negatively associated with all cytokines. Inflammation decreases during ECMO but a causal effect of antithrombin administration on the reduction of inflammation (and its clinical relevance) must be confirmed by appropriately powered studies.

Circulating miRNAs as Promising Biomarkers to Evaluate ECMO Treatment Responses in ARDS Patients.

The use of extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) has increased in the last decade. However, mortality remains high, and the complexity of ECMO requires individualized treatment. There are some biomarkers to monitor progression and predict clinical outcomes of ARDS. This project aims to advance the management of ARDS patients treated with ECMO by exploring miRNA expression in whole blood. The analysis was conducted on two groups with different length of ECMO: Group A (longer runs) and group B (shorter runs). We analyzed miRNAs before ECMO cannulation, and at 7 and 14 days of ECMO support. Our results showed that in the group B patients, 11 deregulated miRNAs were identified, and showed an opposite trend of expression compared to the group A patients. In silico analysis revealed that these 11 miRNAs were related to processes involved in the pathogenesis and evolution of ARDS. This scenario could represent homeostatic mechanisms by which, in ECMO responsive patients, pathways activated during ARDS progression are switched-off. Circulating miRNAs could represent promising biomarkers to monitor the evolution of ARDS under ECMO support. Further studies may shed light on this topic to improve a personalized approach in such a complex setting of patients.

ECMO Retrieval over the Mediterranean Sea: Extending Hospital Arms.

The retrieval and transport of patients from peripheral hospitals to high volume extracorporeal membrane oxygenation (ECMO) centers aims to reduce complications and improve survival. In Sicily (Italy), our institute houses a mobile ECMO team that serves a population of around 10 million people for a vast area in southern Italy and Malta. This observational, descriptive study includes all patients that required veno-venous (V-V) ECMO and transport by a mobile team between October 2009 and May 2020. Linear and multiple logistic regressions were applied to explore the risk factors for mortality in the ICU. Kaplan-Meier estimates were generated to predict the survival in patients transported by helicopter or ambulance, and the two cohorts were compared according to their baseline characteristics. Of 122 patients transported, 89 (73%) survived to ICU discharge (50 (41%) patients were transported by ambulance, and 72 (59%) were transported by helicopter). Independent predictive factors associated with mortality in a stepwise multiple regression model were prone positioning, acute kidney injury, and the number of days spent on mechanical ventilation (MV). Kaplan-Meier estimates for survival favored the helicopter cohort (79%) rather than the ambulance cohort (64%). Patients transported by helicopter had better pre-ECMO profiles, with shorter hospital and ICU stays, a shorter duration of MV use, and higher RESP scores, which indicate better survival probabilities. ECMO transport can be carried out safely over long distances; in rural areas with underdeveloped roads, transportation via helicopter or ambulance can extend the arm of the hospital to remote areas. Early ECMO initiation can be crucial in improving survival outcomes, and when transportation is the limiting factor to starting ECMO support, it should be attempted at the earliest logistical stage possible.

Donor Preconditioning with Inhaled Sevoflurane Mitigates the Effects of Ischemia-Reperfusion Injury in a Swine Model of Lung Transplantation.

Primary graft dysfunction (PGD) and ischemia-reperfusion injury (IRI) occur in up to 30% of patients undergoing lung transplantation and may impact on the clinical outcome. Several strategies for the prevention and treatment of PGD have been proposed, but with limited use in clinical practice. In this study, we investigate the potential application of sevoflurane (SEV) preconditioning to mitigate IRI after lung transplantation. The study included two groups of swines (preconditioned and not preconditioned with SEV) undergoing left lung transplantation after 24-hour of cold ischemia. Recipients' data was collected for 6 hours after reperfusion. Outcome analysis included assessment of ventilatory, hemodynamic, and hemogasanalytic parameters, evaluation of cellularity and cytokines in BAL samples, and histological analysis of tissue samples. Hemogasanalytic, hemodynamic, and respiratory parameters were significantly favorable, and the histological score showed less inflammatory and fibrotic injury in animals receiving SEV treatment. BAL cellular and cytokine profiling showed an anti-inflammatory pattern in animals receiving SEV compared to controls. In a swine model of lung transplantation after prolonged cold ischemia, SEV showed to mitigate the adverse effects of ischemia/reperfusion and to improve animal survival. Given the low cost and easy applicability, the administration of SEV in lung donors may be more extensively explored in clinical practice.

Identification of a Circulating miRNA Signature to Stratify Acute Respiratory Distress Syndrome Patients.

There is a need to improve acute respiratory distress syndrome (ARDS) diagnosis and management, particularly with extracorporeal membrane oxygenation (ECMO), and different biomarkers have been tested to implement a precision-focused approach. We included ARDS patients on veno-venous (V-V) ECMO in a prospective observational pilot study. Blood samples were obtained before cannulation, and screened for the expression of 754 circulating microRNA (miRNAs) using high-throughput qPCR and hierarchical cluster analysis. The miRNet database was used to predict target genes of deregulated miRNAs, and the DIANA tool was used to identify significant enrichment pathways. A hierarchical cluster of 229 miRNAs (identified after quality control screening) produced a clear separation of 11 patients into two groups: considering the baseline SAPS II, SOFA, and RESP score cluster A (n = 6) showed higher severity compared to cluster B (n = 5); p values < 0.05. After analysis of differentially expressed miRNAs between the two clusters, 95 deregulated miRNAs were identified, and reduced to 13 by in silico analysis. These miRNAs target genes implicated in tissue remodeling, immune system, and blood coagulation pathways. The blood levels of 13 miRNAs are altered in severe ARDS. Further investigations will have to match miRNA results with inflammatory biomarkers and clinical data.

A Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation.

OBJECTIVES: Supplementation of antithrombin might decrease the amount of heparin needed to achieve a given anticoagulation target during extracorporeal membrane oxygenation. However, exogenous antithrombin itself may increase the risk of bleeding. We conceived a study to evaluate the effect of antithrombin supplementation in adult patients requiring venovenous extracorporeal membrane oxygenation for respiratory failure on heparin dose, adequacy of anticoagulation, and safety. DESIGN: Prospective randomized controlled trial. SETTING: ICUs of two Italian referral extracorporeal membrane oxygenation centers. PATIENTS: Adult patients requiring venovenous extracorporeal membrane oxygenation for severe respiratory failure and unfractionated heparin for systemic anticoagulation. INTERVENTIONS: Before extracorporeal membrane oxygenation start, patients were randomized to either receive antithrombin concentrate to maintain a plasmatic level 80-120% (treatment) or not (control) during the extracorporeal membrane oxygenation course. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the total amount of heparin required to maintain activated partial thromboplastin time ratio 1.5-2. Secondary outcomes were anti-factor Xa, the incidence of hemorrhagic and thrombotic events, and the amount of blood products transfused. Twenty-four patients in the treatment group and 24 in the control group were included in the intention-to-treat analysis. Antithrombin was 109.5% (93.0-123.0%) in the treatment group and 84.0% (68.5-98.0%) in the control group (p = 0.001). Supplementation of antithrombin did not decrease heparin dose (13.5 international units/kg/hr [9.6-17.9 international units/kg/hr] vs 15.1 international units/kg/hr [10.7-18.3 international units/kg/hr] in the treatment and control group, respectively; p = 0.33) and anti-Factor Xa levels (0.4 international units/mL [0.3-0.5 international units/mL] vs 0.3 international units/mL [0.2-0.5 international units/mL] in the treatment group and control group respectively; p = 0.65). Bleeding, blood product transfusions, and thrombosis were not different in the two groups. CONCLUSIONS: Antithrombin supplementation may not decrease heparin requirement nor diminish the incidence of bleeding and/or thrombosis in adult patients on venovenous extracorporeal membrane oxygenation.

A narrative review of antithrombin use during veno-venous extracorporeal membrane oxygenation in adults: rationale, current use, effects on anticoagulation, and outcomes.

BACKGROUND: During extracorporeal membrane oxygenation, the large contact surface between the blood and the extracorporeal circuit causes a continuous activation of coagulation and inflammation. Unfractionated heparin, a glycosaminoglycan that must bind to antithrombin as a cofactor, is currently the standard anticoagulant adopted during extracorporeal membrane oxygenation. Antithrombin, beyond being a potent natural anticoagulant, acts in the cross-talk between coagulation and inflammatory system through anticoagulation and coagulation-independent effects. OBJECTIVES: In this review, we describe, in the adult setting of veno-venous extracorporeal membrane oxygenation, the pathophysiological rationale for antithrombin use, the current practice of administration, and the effects of antithrombin on anticoagulation, bleeding, and outcomes. DATA SOURCES: Studies on adults (18 years or older) on veno-venous extracorporeal membrane oxygenation published from 1995 to 2018 in order to evaluate the use of antithrombin. RESULTS: In adults on veno-venous extracorporeal membrane oxygenation, antithrombin supplementation has a highly pathophysiological rationale since coagulation factor consumption, systemic inflammatory response syndrome, and endothelial activation are triggered by extracorporeal membrane oxygenation. Eleven articles are focused on the topic but among the authors there is no consensus on the threshold for supplementation (ranging from 70% to 80%) as well as on the dose (rarely standardized) and time of administration (bolus vs continuous infusion). Consistently, antithrombin is considered able to achieve better anticoagulation targets in or not in the presence of heparin resistance. The impact of antithrombin administration on bleeding still shows contrasting results. CONCLUSION: Antithrombin use in veno-venous extracorporeal membrane oxygenation should be investigated on the threshold for supplementation, dose, and time of administration.

Antithrombin supplementation during extracorporeal membrane oxygenation: study protocol for a pilot randomized clinical trial.

BACKGROUND: Normal levels of plasma antithrombin (AT) activity might decrease heparin requirements to achieve an adequate level of anticoagulation during treatment with extracorporeal membrane oxygenation (ECMO). Acquired AT deficiency during ECMO is common, but formal recommendations on target, timing, and rate of AT supplementation are lacking. Thus, we conceived a pilot trial to evaluate the feasibility and safety of prolonged AT supplementation in patients requiring veno-venous ECMO for respiratory failure. METHODS: Grifols Antithrombin Research Awards (GATRA) is a prospective, randomized, single blinded, multicenter, controlled two-arm trial. Patients undergoing veno-venous ECMO will be randomized to either receive AT supplementation to maintain a functional AT level between 80 and 120% (AT supplementation group) or not (control group) for the entire ECMO course. In both study groups, anticoagulation will be provided with unfractionated heparin following a standardized protocol. The primary endpoint will be the dose of heparin required to maintain the ratio of activated partial thromboplastin time between 1.5 and 2. Secondary endpoints will be the adequacy of anticoagulation and the incidence of hemorrhagic and thrombotic complications. DISCUSSION: GATRA is a pilot trial that will test the efficacy of a protocol of AT supplementation in decreasing the heparin dose and improving anticoagulation adequacy during ECMO. If positive, it might provide the basis for a future larger trial aimed at verifying the impact of AT supplementation on a composite outcome endpoint including hemorrhagic events, transfusion requirements, and mortality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03208270 . Registered on 5 July 2017.

Neurological complications after cardiac surgery: a retrospective case-control study of risk factors and outcome.

BACKGROUND: To evaluate incidence, risk factors, and outcomes of postoperative neurological complications in patients undergoing cardiac surgery. METHODS: A total of 2121 patients underwent cardiac surgery between August, 2008 and December, 2013; 91/2121 (4.3%) underwent brain computed tomography (70/91, 77%) or magnetic resonance imaging (21/91, 23%) scan because of major stroke (37/2121, 1.7%) and a spectrum of transient neurological episodes as well as transient ischemic attacks and delirium /psychosis/seizures (54/2121, 2.5%). The mean age was 65.3 ± 12.1 years and 60 (65.9%) were male. Variables were compared among study- and matched-patients (n = 113) without neurological deficits. RESULTS: A total of 37/2121 (1.7%) patients had imaging evidence of stroke. Radiological examinations were done 5.72 ± 3.6 days after surgery. Patients with and without imaging evidence of stroke had longer intensive care unit length of stay (LOS) (13.8 ± 14.7 and 12.9 ± 15 days vs. 5.7 ± 12.1 days, respectively (p < 0.001) and hospital LOS (53 ± 72.8 and 35.5 ± 29.8 days vs. 18.4 ± 29.2 days, respectively (p < 0.001) than the control group. The hospital mortality of patients with and without imaging evidence of stroke was higher than the control group (7/37 patients [19%], and 12/54 patients [22%] vs. 4/115 patients [3%], respectively (p < 0.001). Multivariate analysis showed that bilateral internal carotid artery stenosis of any grade (p < .001), and re-do operations (p = .013) increased the risk of postoperative neurological complications. CONCLUSIONS: Neurological complications after cardiac surgery increase hospitalization and mortality even in patients without radiologic evidence of stroke. Bilateral internal carotid artery stenosis of any grade, suggesting a diffuse patient propensity toward atherosclerosis, and re-do operations increase the risk of postoperative neurological complications.

Anticoagulation and Transfusions Management in Veno-Venous Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: Assessment of Factors Associated With Transfusion Requirements and Mortality.

PURPOSE: We describe an approach for anticoagulation and transfusions in veno-venous-extracorporeal membrane oxygenation (VV-ECMO), evaluating factors associated with higher transfusion requirements, and their impact on mortality. METHODS: Observational study on consecutive adults supported with VV-ECMO for acute respiratory distress syndrome (ARDS). We targeted an activated partial thromboplastin time of 40 to 50 seconds and a hematocrit of 24% to 30%. Univariate and multiple analyses were done to evaluate factors associated with transfusion requirements and the influence of increasing transfusions on mortality during ECMO. RESULTS: In a cohort of 82 VV-ECMO patients (PRedicting dEath for SEvere ARDS on VV-ECMO [PRESERVE] score: 4, Interquartile range [IQR]: 3-5, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction [RESP] score: 2, IQR: 2-4), 76 (92.7%) patients received at least 1 unit of packed red blood cells (PRBCs) during the intensive care unit stay related to ECMO (median PRBC/d 156 mL, IQR: 93-218; median ECMO duration 14 days, IQR: 8-22). A higher requirement of PRBC transfusions was associated with pre-ECMO hematocrit, and with the following conditions during ECMO: platelet nadir, antithrombin III (ATIII), and stage 3 of acute kidney injury (all P < .05). Sixty-two (75.6%) patients survived ECMO. Pre-ECMO hospital stay, PRBC transfusion, and septic shock were associated with mortality (all P < .05). The adjusted odds ratio for each 100mL/d increase in PRBC transfusion was 1.9 (95% confidence interval [CI]: 1.1-3.2, P = .01); for the development of septic shock it was 15.4 (95% CI: 1.7-136.8, P = .01), and for each day of pre-ECMO stay it was 1.1 (95% CI: 1-1.2, P = .04). CONCLUSION: Implementation of a comprehensive protocol for anticoagulation and transfusions in VV-ECMO for ARDS resulted in a low PRBC requirement, and an ECMO survival comparable to data in the literature. Lower ATIII emerged as a factor associated with increased need for transfusions. Higher PRBC transfusions were associated with ECMO mortality. Further investigations are needed to better understand the right level of anticoagulation in ECMO, and the factors to take into account in order to manage personalized transfusion practice in this select setting.

Impact of cannula design on packed red blood cell transfusions: technical advancement to improve outcomes in extracorporeal membrane oxygenation.

BACKGROUND: Technological improvement has contributed to making veno-venous extracorporeal membrane oxygenation (VV-ECMO) safer and easier, spreading its use in acute respiratory failure (ARF). METHODS: This is a retrospective observational study carried out in the ECMO center at IRCCS-ISMETT, a medical center focused on end-stage organ failure treatment in Italy. We investigated the effect of different cannula designs on the amount of blood product transfused. Eighty-nine consecutive patients affected with ARF on VV-ECMO from 2008 to 2016 were compared according to type of cannulation: older percutaneous cannula (Standard group, 52 patients) and HLS© BIOLINE-coated, but with shorter drainage cannula (BIOLINE group, 37 patients). RESULTS: The two study groups were comparable in terms of baseline characteristics [age, body mass index (BMI), Simplified Acute Physiology Score (SAPS-II), Sequential Organ Failure Assessment (SOFA), Predicting Death For Severe ARDS on VV-ECMO (PRESERVE) score] and ECMO management [median hematocrit (Htc), platelet nadir, antithrombin III (AT III), heparin, activated partial thromboplastin time (APTT)]. In the BIOLINE group, a lower amount of packed red blood cells (pRBC) was transfused considering both total number [4 units, interquartile range (IQR) 1-9 vs. 12 units, IQR 5.5-21; P<0.01] and mL of pRBC/day of ECMO support (91, IQR 21-158 vs. 193.5, IQR 140.5-254; P<0.01). In the BIOLINE group, a trend in reduction of ECMO days (P=0.05) and length of intensive care unit (ICU) stay was found (P=0.06), but no differences in rates of ECMO weaning and ICU discharge were evidenced. The BIOLINE group constituted a saving of €1,295.20 per patient/treatment, counting the costs for cannulation and pRBC administration. CONCLUSIONS: More biocompatible and shorter drainage cannula may represent one of the contributing factors to a reduction in transfusions and costs of VV-ECMO in the current ongoing technological improvement in ECMO.

Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study.

BACKGROUND: There is no consensus on the management of anticoagulation during extracorporeal membrane oxygenation (ECMO). ECMO is currently burdened by a high rate of hemostatic complications, possibly associated with inadequate monitoring of heparin anticoagulation. This study aims to assess the safety and feasibility of an anticoagulation protocol for patients undergoing ECMO based on thromboelastography (TEG) as opposed to an activated partial thromboplastin time (aPTT)-based protocol. METHODS: We performed a multicenter, randomized, controlled trial in two academic tertiary care centers. Adult patients with acute respiratory failure treated with veno-venous ECMO were randomized to manage heparin anticoagulation using a TEG-based protocol (target 16-24 min of the R parameter, TEG group) or a standard of care aPTT-based protocol (target 1.5-2 of aPTT ratio, aPTT group). Primary outcomes were safety and feasibility of the study protocol. RESULTS: Forty-two patients were enrolled: 21 were randomized to the TEG group and 21 to the aPTT group. Duration of ECMO was similar in the two groups (9 (7-16) days in the TEG group and 11 (4-17) days in the aPTT group, p = 0.74). Heparin dosing was lower in the TEG group compared to the aPTT group (11.7 (9.5-15.3) IU/kg/h vs. 15.7 (10.9-21.3) IU/kg/h, respectively, p = 0.03). Safety parameters, assessed as number of hemorrhagic or thrombotic events and transfusions given, were not different between the two study groups. As for the feasibility, the TEG-based protocol triggered heparin infusion rate adjustments more frequently (p < 0.01) and results were less frequently in the target range compared to the aPTT-based protocol (p < 0.001). Number of prescribed TEG or aPTT controls (according to study groups) and protocol violations were not different between the study groups. CONCLUSIONS: TEG seems to be safely used to guide anticoagulation management during ECMO. Its use was associated with the administration of lower heparin doses compared to a standard of care aPTT-based protocol. Trial registration ClinicalTrials.gov, October 22,2014. Identifier: NCT02271126.

Severe Acute Respiratory Failure due to Inhalation of Baby Powder and Successfully Treated with Venous-Venous Extracorporeal Membrane Oxygenation.

Accidental inhalation of powder is a potential problem for infants. The clinical effects of inhaling powder depend on the powder contents, degree of aspiration, and the child's underlying systemic response. We present a case of accidental inhalation of rice starch powder in a 17-month-old girl, which led to severe acute respiratory distress syndrome responsive to conventional treatment, ultimately requiring venous-venous extracorporeal membrane oxygenation.

Reduced red blood cell deformability over time is associated with a poor outcome in septic patients.

BACKGROUND: To investigate changes in red blood cell (RBC) rheology over time in critically ill patients with sepsis and their relationship with outcome. METHODS: In this prospective, non-interventional study, RBC rheology was assessed using the Laser-assisted Optical Rotational Cell Analyzer in a convenience sample of intensive care unit (ICU) patients with (n=64) and without (n=160) sepsis. Results were compared to measures in healthy volunteers (n=20). RBC rheology was also assessed on days 1 and 3 of the ICU stay in 32 of the non-septic and 19 of the septic patients. RBC deformability was determined by the elongation index (EI) in relation to the shear stress (0.3 to 50Pa) applied to the RBC membrane. An aggregation index (AI) was assessed simultaneously with the same device. RESULTS: The ICU mortality rate of the septic patients was 31%. RBC deformability was already reduced in septic patients at ICU admission, an effect that persisted during the study period and worsened in the non-survivors for the large majority of shear stresses studied (e.g., EI for 50Pa of shear stress was 0.527±0.064 in non-survivors vs. 0.566±0.034 in survivors, p<0.05). These changes were not observed in non-septic patients. The AI was more elevated in septic than in non-septic patients at ICU admission, but had no prognostic value. CONCLUSIONS: Alterations in RBC rheology, including reduced deformability and increased aggregation, occur early in septic patients and reductions in RBC deformability over time are associated with a poor outcome.

Effects of fluids on microvascular perfusion in patients with severe sepsis.

PURPOSE: To evaluate the effects of fluid administration on microcirculatory alterations in sepsis. METHODS: With a Sidestream Dark Field device, we evaluated the effects of fluids on the sublingual microcirculation in 60 patients with severe sepsis. These patients were investigated either within 24 h (early, n = 37) or more than 48 h (late, n = 23) after a diagnosis of severe sepsis. Hemodynamic and microcirculatory measurements were obtained before and 30 min after administration of 1,000 ml Ringer's lactate (n = 29) or 400 ml 4% albumin (n = 31) solutions. RESULTS: Fluid administration increased perfused small vessel density from 3.5 (2.9-4.3) to 4.4 (3.7-4.9) n/mm (p < 0.01), through a combined increase in the proportion of perfused small vessels from 69 (62-76) to 79 (71-83) %, p < 0.01) and in small vessel density from 5.3 (4.4-5.9) to 5.6 (4.8-6.3) n/mm (p < 0.01). Importantly, microvascular perfusion increased in the early but not in the late phase of sepsis: the proportion of perfused small vessels increased from 65 (60-72) to 80 (75-84) % (p < 0.01) in the early phase and from 75 (66-80) to 74 (67-81) (p = ns) in the late phase. These microvascular effects of fluids were not related to changes in cardiac index (R(2) = 0.05, p = ns) or mean arterial pressure (R(2) = 0.04, p = ns). CONCLUSIONS: In this non-randomized trial, fluid administration improved microvascular perfusion in the early but not late phase of sepsis. This effect is independent of global hemodynamic effects and of the type of solution.

Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock.

Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK-only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK-treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.

Early alterations of red blood cell rheology in critically ill patients.

OBJECTIVE: To investigate red blood cell rheology in a large intensive care unit population on admission, and to assess the possible influence of comorbidities on the rheology. DESIGN: : Prospective study. SETTING: Medico-surgical intensive care unit with 31 beds. SUBJECTS: All intensive care unit admissions during a 5-month period and 20 healthy volunteers. INTERVENTIONS: Blood sampling. MEASUREMENTS AND MAIN RESULTS: A total of 196 intensive care patients (160 without and 36 with sepsis) and 20 healthy volunteers were studied. Red blood cell rheology (deformability and aggregation) was assessed ex vivo using the laser-assisted optical rotational cell analyzer (LORCA; Mechatronics Instruments BV, AN Zwaag, Netherlands) within the first 24 hrs after intensive care unit admission. Red blood cell deformability was determined by the elongation index in relation to the shear stress (0.3 to 50 Pa) applied on the red blood cell membrane surface. Aggregation was assessed by the aggregation index. Septic patients were more likely to have anemia, coagulation abnormalities, and comorbidities than were nonseptic patients. Red blood cell deformability was significantly altered in septic compared to nonseptic patients and volunteers for the majority of shear stress rates studied. The aggregation index was greater in septic patients than in volunteers (67.9% [54.7-73.5] vs. 61.8% [58.2-68.4]; p < .05). Only sepsis and hematologic disease influenced the elongation index (both p < .01). Other comorbidities, like cancer, diabetes mellitus, cirrhosis, and terminal renal failure, had no effect on the elongation index. Aggregation index was related to the degree of organ failure (Sequential Organ Failure Assessment score), the red blood cell count, and fibrinogen concentrations. CONCLUSIONS: Early alterations of red blood cell rheology are common in intensive care unit patients, especially in those with sepsis. Comorbidities (other than hematologic diseases) do not significantly influence these abnormalities. These alterations could contribute to the microcirculatory alterations observed in critically ill patients.