The effectiveness of a brief intervention for intensive care unit patients with hazardous alcohol use: a randomized controlled trial.

BACKGROUND: Screening for hazardous alcohol use and performing brief interventions (BIs) are recommended to reduce alcohol-related negative health consequences. We aimed to compare the effectiveness (defined as an at least 10% absolute difference) of BI with usual care in reducing alcohol intake in intensive care unit survivors with history of hazardous alcohol use. METHODS: We used Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score to assess history of alcohol use. PATIENTS: Emergency admitted adult ICU patients in three Finnish university hospitals, with an AUDIT-C score > 5 (women), or > 6 (men). We randomized consenting eligible patients to receive a BI or treatment as usual (TAU). INTERVENTION: BI was delivered by the time of ICU discharge or shortly thereafter in the hospital ward. CONTROLS: Control patients received TAU. OUTCOME: The primary outcome was self-reported alcohol consumption during the preceding week 6 and 12 months after randomization. Secondary outcomes were the change in AUDIT-C scores from baseline to 6 and 12 months, health-related quality of life, and mortality. The trial was terminated early due to slow recruitment during the pandemic. RESULTS: We randomized 234 patients to receive BI (N = 117) or TAU (N = 117). At 6 months, the median alcohol intake in the BI and TAU groups were 6.5 g (interquartile range [IQR] 0-141) and 0 g (0-72), respectively (p = 0.544). At 12 months, it was 24 g (0-146) and 0 g (0-96) in the BI and TAU groups, respectively (p = 0.157). Median change in AUDIT-C from baseline to 6 months was - 1 (- 4 to 0) and 2 (- 6 to 0), (p = 0.144) in the BI and TAU groups, and to 12 months - 3 (- 5 to - 1) and - 4 (- 7 to - 1), respectively (p = 0.187). In total, 4% (n = 5) of patients in the BI group and 11% (n = 13) of patients in the TAU group were abstinent at 6 months, and 10% (n = 12) and 15% (n = 17), respectively, at 12 months. No between-groups difference in mortality emerged. CONCLUSION: As underpowered, our study cannot reject or confirm the hypothesis that a single BI early after critical illness is effective in reducing the amount of alcohol consumed compared to TAU. However, a considerable number in both groups reduced their alcohol consumption. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03047577).

Risk stratification-based thromboprophylaxis does not affect mortality after fast-track hip and knee arthroplasty.

BACKGROUND AND PURPOSE: Use of thromboprophylaxis effectively prevents pulmonary embolism (PE) and deaths after total hip and knee arthroplasty (THA and TKA). The optimum length of thromboprophylaxis is not known and has traditionally been based on the type of operation. Nowadays, a more individualized approach is preferred. This study analyzed if risk stratification-based planning of thromboprophylaxis has an association with the all-cause mortality after fast-track THA and TKA. PATIENTS AND METHODS: We compared fast-track THAs and TKAs operated between 2015-2016 and 2020-2021. Between 2015 and 2016, all patients received a routine length of thromboprophylaxis. From 2020 onwards, thromboprophylaxis was planned by risk stratification, and patients at low risk for venous thromboembolism received thromboprophylaxis only during hospitalization. All causes of death within 90 days of surgery were identified and the incidence of mortality was calculated. Mortality rates between the two periods were then compared. RESULTS: Between 2015 and 2016, 3192 arthroplasties were performed. A total of eight deaths occurred within 90 days of surgery, yielding an incidence of all-cause mortality of 0.3% (95% CI 0.1-0.5). Between 2020 and 2021, a total of 3713 arthroplasties were performed to patients who received risk stratification-based thromboprophylaxis. Thirteen of these patients died within 90 days of surgery, yielding an all-cause mortality incidence of 0.4% (95% CI 0.2-0.6). Cardiovascular diseases were the main cause of death during both study periods. None of the deaths were caused by PEs. INTERPRETATION: Risk stratification-based thromboprophylaxis was not associated with increased all-cause mortality within 90 days of fast-track THA and TKA.

Increased blood coagulation is associated with poor neurological outcome in aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Patients with aneurysmal subarachnoid hemorrhage (aSAH) have demonstrated increased blood coagulation which is thought to contribute to delayed cerebral ischemia (DCI) and to a worse outcome. Therefore, we sought to determine whether this increased blood coagulation, detectable with rotational thromboelastometry (ROTEM), was associated with DCI and neurological outcome. METHODS: We conducted a prospective observational study of 60 consecutive adult aSAH patients. ROTEM's EXTEM and FIBTEM assays and D-dimer were analyzed at admission and post-bleed days (PBDs) 2-3, 4-5, 7-8, and 11-12. ROTEM's clot formation time (CFT) represents the stabilization of the clot, and the maximum clot firmness (MCF) the maximum clot strength. Glasgow Outcome Scale extended (GOSe) at three months determined the neurological outcome. RESULTS: DCI incidence was 41.7%. EXTEM-CFT was significantly shorter in patients with unfavorable neurological outcome (GOSe 1-4) on PBDs 4-5 and 7-8, p < 0.05, respectively. FIBTEM-MCF was significantly higher in patients with unfavorable neurological outcomes on PBD 4-5 (p < 0.05), PBD 7-8 (p < 0.05), and PBD 11-12 (p < 0.05). EXTEM-CFT decreased, and FIBTEM-MCF rose during the study period in all patients. Patients with unfavorable neurological outcome had a higher D-dimer at all studied time points, p < 0.05. No difference was found in the ROTEM parameters or D-dimer when assessing patients with and without DCI. CONCLUSIONS: Patients were in a state of increased blood coagulation after aSAH, with those with unfavorable neurological outcome being more coagulable than those with favorable outcome. However, increased blood coagulation was not associated with DCI. CLINICALTRIALS: gov, NCT03985176.

Venous thromboembolism is rare after total hip and knee joint arthroplasty with long thromboprophylaxis in Finnish fast-track hospitals.

INTRODUCTION: Pharmacological thromboprophylaxis effectively prevents venous thromboembolism (VTE) after total knee (TKA) and total hip arthroplasty (THA). Less is known about the influence of fast-track arthroplasty on VTE risk. We conducted a register-based study to determine the incidence of VTE after fast-track TKA and THA in Finland using long thromboprophylaxis. MATERIALS AND METHODS: All primary TKAs and THAs operated during 2015-2016 in 3 fast-track hospitals were identified from the Finnish Arthroplasty Register. Pulmonary embolism (PE) and deep vein thrombosis (DVT) diagnosed in this patient cohort within 90 days of surgery were identified from the Finnish Hospital Discharge Register. The recommended length of thromboprophylaxis was 10 to 14 days for TKA and 28 days for THA during study period. RESULTS: During the study period, 3 831 THAs, 4 394 TKAs and 286 bilateral TKAs (BTKAs) were performed. Of all these patients, 60% were females. Venous thromboembolism (VTE) incidence within 90 days of surgery was 0.3% (95% CI 0.2-0.4). These VTEs comprised 10 PEs and 15 DVTs. None of the VTE patients´ died within the 90-day period. CONCLUSION: VTE incidence is low in Finnish fast-track TKA and THA patients with long thromboprophylaxis.

Thromboelastometry-guided treatment algorithm in postpartum haemorrhage: a randomised, controlled pilot trial.

BACKGROUND: Postpartum haemorrhage causes significant mortality among parturients. Early transfusion of blood products based on clinical judgement and conventional coagulation testing has been adapted to the treatment of postpartum haemorrhage, but rotational thromboelastometry (ROTEM) may provide clinicians means for a goal-directed therapy to control coagulation. We conducted a parallel design, randomised, controlled trial comparing these two approaches. We hypothesised that a ROTEM-guided protocol would decrease the need for red blood cell transfusion. METHODS: We randomised 60 parturients with postpartum haemorrhage of more than 1500 ml to receive either ROTEM-guided or conventional treatment, with 54 patients included in the final analysis. The primary outcome was consumption of blood products, and secondarily we assessed for possible side-effects of managing blood loss such as thromboembolic complications, infections, and transfusion reactions. RESULTS: The median (25th-75th percentile) number of RBC units transfused was 2 (1-4) in the ROTEM group and 3 (2-4) in the control group (P=0.399). The median number of OctaplasLG® units given was 0 in both groups (0-0 and 0-2) (P=0.030). The median total estimated blood loss was 2500 ml (2100-3000) in the ROTEM group and 3000 ml (2200-3100) in the control group (P=0.033). No differences were observed in secondary outcomes. CONCLUSIONS: ROTEM-guided treatment of postpartum haemorrhage could have a plasma-sparing effect but possibly only a small reduction in total blood loss. CLINICAL TRIAL REGISTRATION: NCT02461251.

Anti-factor X activity levels with continuous intravenous infusion and subcutaneous administration of enoxaparin after coronary artery bypass grafting: A randomized clinical trial.

BACKGROUND: Low-molecular-weight heparin enoxaparin is widely used in pharmacological thromboprophylaxis after coronary artery bypass grafting (CABG). The aim of this study was to compare anti-factor X activity (anti-Xa) levels when the thromboprophylactic dose of enoxaparin was provided after CABG, with two different administration routes: continuous intravenous infusion (CIV) and subcutaneous bolus (SCB) injection. We hypothesized that the current standard method of SCB administration might lead to lower anti-Xa levels than recommended in other patient groups, due to reduced bioavailability. METHODS: In this prospective, randomized, controlled clinical trial, 40 patients scheduled for elective CABG were randomized to receive 40 mg of enoxaparin per day either as CIV or SCB for 72 h. Enoxaparin was initiated 6-10 h after CABG. Anti-Xa levels were measured 12-14 times during the study period. The primary outcome, that is, the maximum anti-Xa concentration over 0-24 h (Cmax0-24h ), was calculated from these measured values. Secondary outcomes were Cmax25-72h and the trough concentration of anti-Xa after 72 h of enoxaparin initiation (C72h ). RESULTS: Twenty patients were randomized to the CIV-group and 19 to the SCB-group. The median anti-Xa Cmax0-24h was significantly lower in the CIV-group than in the SCB-group: 0.15 [interquartile range (IQR) 0.13-0.19] IU/ml versus 0.25 (IQR 0.18-0.32) IU/ml, p < .005. The median anti-Xa Cmax25-72h was 0.12 (IQR, 0.1-0.17) IU/ml versus 0.23 (IQR 0.19-0.31) IU/ml, respectively, p < .005. At 72 h, there was no difference between the groups in their anti-Xa levels. CONCLUSIONS: In this low-risk CABG patient population, SCB administration of a thromboprophylactic dose of enoxaparin provided anti-Xa levels that are considered sufficient for thromboprophylaxis in other patient groups. CIV administration resulted in lower anti-Xa levels compared to the SCB route.

Platelet count is not associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as defined by the 2010 consensus definition.

BACKGROUND: Although delayed cerebral ischemia (DCI) commonly complicates recovery in survivors of aneurysmal subarachnoid hemorrhage (aSAH), its pathophysiology is incompletely understood. Previous studies examining the association of DCI and platelet count have demonstrated contradictory results. This study aimed to investigate this association in a cohort of aSAH patients using the 2010 consensus definition of DCI. METHODS: We conducted a retrospective single-center observational study of consecutive adult aSAH patients admitted to the intensive care unit from January 2010 to December 2014. Platelet count and DCI evaluations were performed daily in the first 14 days after admission. DCI was defined according to the 2010 consensus criteria. RESULTS: A total of 340 patients were included for analysis. DCI incidence was 37.1%. Platelet count was not significantly associated with occurrence of DCI on any day. Mean platelet count was lowest on day 3 after aSAH and then increased to exceed the count at admission on day 6. Treatment modality and use of dual antiplatelet therapy were not associated with DCI. CONCLUSIONS: Platelet count was not associated with DCI as defined by the 2010 consensus criteria. Future studies adhering to the 2010 consensus definition of DCI are needed to clarify the role of platelets and platelet function in DCI pathophysiology.

Low incidence of clinically relevant bleeding complications after fast-track arthroplasty: a register study of 8,511 arthroplasties.

BACKGROUND AND PURPOSE: Fast-track total joint replacement (TJR) has become increasingly common. Routine thromboprophylaxis for pulmonary embolism and deep venous thrombosis prevention lasts from 2 to 5 weeks. This retrospective registry study focused on clinically relevant bleeding complications 90 days after fast-track primary TJR. PATIENTS AND METHODS: All primary fast-track total hip (THA) and knee arthroplasties (TKA) performed between 2015 and 2016 were extracted from the Finnish Arthroplasty Register and Finnish Hospital Discharge Register. Type of arthroplasty and indication for the operation were combined with diagnoses of clinically relevant bleeding complications within 90 days of surgery. The incidence of these bleedings was the primary outcome measure. RESULTS: Of the total of 8,511 patients (mean age 67 years (SD 10); 60% female), 45% underwent unilateral THA, 52% unilateral TKA, and 3% bilateral TKA. The incidence of clinically relevant bleeding complications within 90 days was 1% (95% CI 0.8-1.3). No difference was observed in bleeding incidence between the groups. The 87 bleedings comprised 57 operative site bleedings, 17 gastrointestinal bleedings, 6 intracranial non-traumatic bleedings, 5 bleedings from the nose or another undetermined site, and 2 intraocular bleedings. 1 death due to intracranial bleeding was recorded, and hence clinically relevant bleeding-specific 90-day mortality was 0.01%. INTERPRETATION: The incidence of clinically relevant bleeding complications was low. However, they cause patient discomfort, increase the use of healthcare services, and can be life-threatening and even fatal.

Prognostic value of the 2010 consensus definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) complicates the recovery of approximately 30% of patients with aneurysmal subarachnoid hemorrhage (aSAH). The definition of DCI widely varies, even though a consensus definition has been recommended since 2010. This study aimed to evaluate the prognostic value of the 2010 consensus definition of DCI in a cohort of patients with aSAH. METHODS: We conducted a single-center, retrospective, observational study that included consecutive adult patients with aSAH who were admitted to the intensive care unit from January 2010 to December 2014. DCI was evaluated 48 h to 14 days after onset of aSAH symptoms using the 2010 consensus criteria and outcome was assessed by the Glasgow Outcome Scale (GOS) at discharge from hospital. RESULTS: A total of 340 patients were analyzed and the incidence of DCI was 37.1%. The median time from primary hemorrhage to the occurrence of DCI was 97 h. Neurological deterioration was observed in most (89.7%) of the patients who fulfilled the DCI criteria. The occurrence of DCI was strongly associated with an unfavorable outcome (GOS 1-3) at hospital discharge (OR 2.65, 95% CI 1.69-4.22, p < 0.001). CONCLUSIONS: The incidence of DCI after aSAH is high and its occurrence is strongly associated with an unfavorable neurological outcome. This finding adds to the previous literature, which has shown that DCI appears to be a major contributor affecting the functional ability of survivors of aSAH. To further advance reliable knowledge of DCI, future studies should adhere to the consensus definition of DCI.

Continuous intravenous infusion of enoxaparin controls thrombin formation more than standard subcutaneous administration in critically ill patients. A sub-study of the ENOKSI thromboprophylaxis RCT.

INTRODUCTION: Standard subcutaneous low-molecular-weight heparin (LMWH) thromboprophylaxis yields low anti-factor Xa activity in patients in the intensive care unit (ICU). The aim of the study was to assess coagulation status in ICU patients randomized to receive enoxaparin thromboprophylaxis either as a standard subcutaneous bolus (SCB) or continuous intravenous infusion (CII) for 3 consecutive days after the initiation of LMWH thromboprophylaxis. MATERIALS AND METHODS: Thirty-eight patients were studied by conventional coagulation variables: prothrombin fragment F 1+2 (F 1+2) representing FXa inhibition and antithrombin (AT). Additionally, 18 patients were analyzed by the thrombin generation assay-calibrated automated thrombogram (TGA-CAT). Blood samples were collected before the initiation of the LMWH thromboprophylaxis (ie, baseline), at 51 h, and at 72 h. RESULTS: At beginning, no differences in coagulation biomarkers were observed. The levels of F 1+2 were significantly lower at 51 and 72 h in the CII group than in the SCB group. AT levels increased during the follow-up in the CII group, unlike in the SCB group. TGA-CAT was poor in some patients overall. In a subset of patients at 51 h lag time (4.3 vs 7.5 min, respectively, P < 0.05) and time to peak (7.7 vs 14.3 min, respectively, P < 0.05) were prolonged in the SCB group. At 72 h, however, peak thrombin was lower in the CII than in the SCB group: 271 vs 356 nM, respectively (P < 0.05). CONCLUSIONS: Enoxaparin thromboprophylaxis administered by CII inhibited more prominently FXa and preserved better the AT level, compared with standard subcutaneous care.

Prevalence of risk-drinking in critically ill patients, screened with carbohydrate-deficient transferrin and AUDIT-C score: A retrospective study.

Background Studies demonstrate that up to one-third of intensive care unit (ICU) admissions are directly or indirectly related to alcohol. Screening for alcohol use is not routine. This study examined the prevalence of elevated %CDT (carbohydrate-deficient transferrin) and above risk-level AUDIT-C (Alcohol Use Disorders Identification Test, Consumption) in patients admitted to ICU. Methods We conducted a retrospective analysis of clinical and laboratory data from a single ICU where %CDT and AUDIT-C were included in routine assessment. After excluding readmissions, 2532 adult patients from a 21-month period were included. Admission values of %CDT were available for 2049 patients, and AUDIT-C was available for 1617 patients. The association of %CDT and AUDIT-C with short- and long-term outcome was studied by using univariate and multivariate logistic regression analysis. Results %CDT was above the reference value in 23.7% (486/2048) of patients with available %CDT. Of patients with available AUDIT-C, 33% (544/1617) had a risk-level AUDIT-C score. Patients with a risk-level AUDIT-C score were significantly younger than those with a lower score (51 vs 64 years, P < .0001). Increased %CDT was associated with higher severity of illness. AUDIT-C was associated independently with increased risk of long-term mortality in multivariate analysis (P = .007). Conclusion One in three of ICU patients are risk-level alcohol users as measured with AUDIT-C score, and one in four are analysed with %CDT. The prevalence varies according to the method used and any method alone may be insufficient to detect risk-level consumption reliably. Editorial Comment Alcohol overconsumption is associated with need for ICU admission and with less favorable outcomes. Diagnosis of alcohol overconsumption though is problematic due to low sensitivity in screening. In a pilot study, a biomarker and a screening tool are compared. The finding is that multiple tools are needed to achieve an adequate sensitivity for detection.

Endotoxin Removal in Septic Shock with the Alteco LPS Adsorber Was Safe But Showed no Benefit Compared to Placebo in the Double-Blind Randomized Controlled Trial-the Asset Study.

PURPOSE: Lipopolysaccharides (LPS) are presumed to contribute to the inflammatory response in sepsis. We investigated if extracorporeal Alteco LPS Adsorber for LPS removal in early gram-negative septic shock was feasible and safe. Also, effects on endotoxin level, inflammatory response, and organ function were assessed. METHODS: A pilot, double-blinded, randomized, Phase IIa, feasibility clinical investigation was undertaken in six Scandinavian intensive care units aiming to allocate 32 septic shock patients with abdominal or urogenital focus on LPS Adsorber therapy or a Sham Adsorber, therapy without active LPS binding. The study treatment was initiated within 12 h of inclusion and given for 6 h daily on first 2 days. LPS was measured in all patients. RESULTS: The investigation was terminated after 527 days with eight patients included in the LPS Adsorber group and seven in the Sham group. Twenty-one adverse effects, judged not to be related to the device, were reported in three patients in the LPS Adsorber group and two in the Sham group. Two patients in the Sham group and no patients in the LPS Adsorber group died within 28 days. Plasma LPS levels were low without groups differences during or after adsorber therapy. The changes in inflammatory markers and organ function were similar in the groups. CONCLUSIONS: In a small cohort of patients with presumed gram-negative septic shock, levels of circulating endotoxin were low and no adverse effects within 28 days after LPS adsorber-treatment were observed. No benefit compared with a sham device was seen when using a LPS adsorber in addition to standard care. TRIAL REGISTRATION: Clinicaltrials.gov NCT02335723. Registered: November 28, 2014.

Association of endothelial and glycocalyx injury biomarkers with fluid administration, development of acute kidney injury, and 90-day mortality: data from the FINNAKI observational study.

BACKGROUND: Injury to endothelium and glycocalyx predisposes to vascular leak, which may subsequently lead to increased fluid requirements and worse outcomes. In this post hoc study of the prospective multicenter observational Finnish Acute Kidney Injury (FINNAKI) cohort study conducted in 17 Finnish intensive care units, we studied the association of Syndecan-1 (SDC-1), Angiopoetin-2 (Ang-2), soluble thrombomodulin (sTM), vascular adhesion protein-1 (VAP-1) and interleukin-6 (IL-6) with fluid administration and balance among septic critical care patients and their association with development of acute kidney injury (AKI) and 90-day mortality. RESULTS: SDC-1, Ang-2, sTM, VAP-1 and IL-6 levels were measured at ICU admission from 619 patients with sepsis. VAP-1 decreased (p < 0.001) and IL-6 increased (p < 0.001) with increasing amounts of administered fluid, but other biomarkers did not show differences according to fluid administration. In linear regression models adjusted for IL-6, only VAP-1 was significantly associated with fluid administration on day 1 (p < 0.001) and the cumulative fluid balance on day 5/ICU discharge (p = 0.001). Of 415 patients admitted without AKI, altogether 112 patients (27.0%) developed AKI > 12 h from ICU admission (AKI>12 h). They had higher sTM levels than patients without AKI, and after multivariable adjustment log, sTM level was associated with AKI>12 h with OR (95% CI) of 12.71 (2.96-54.67), p = 0.001). Ninety-day non-survivors (n = 180; 29.1%) had higher SDC-1 and sTM levels compared to survivors. After adjustment for known confounders, log SDC-1 (OR [95% CI] 2.13 [1.31-3.49], p = 0.002), log sTM (OR [95% CI] 7.35 [2.29-23.57], p < 0.001), and log Ang-2 (OR [95% CI] 2.47 [1.44-4.14], p = 0.001) associated with an increased risk for 90-day mortality. Finally, patients who had high levels of all three markers, namely, SDC-1, Ang-2 and sTM, had an adjusted OR of 5.61 (95% CI 2.67-11.79; p < 0.001) for 90-day mortality. CONCLUSIONS: VAP-1 and IL-6 associated with fluid administration on the first ICU day. After adjusting for confounders, sTM was associated with development of AKI after 12 h from ICU admission. SDC-1, Ang-2 and sTM were independently associated with an increased risk for 90-day mortality.

Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy.

OBJECTIVE: We wished to explore the use, diagnostic capability and outcomes of bronchoscopy added to noninvasive testing in immunocompromised patients. In this setting, an inability to identify the cause of acute hypoxaemic respiratory failure is associated with worse outcome. Every effort should be made to obtain a diagnosis, either with noninvasive testing alone or combined with bronchoscopy. However, our understanding of the risks and benefits of bronchoscopy remains uncertain. PATIENTS AND METHODS: This was a pre-planned secondary analysis of Efraim, a prospective, multinational, observational study of 1611 immunocompromised patients with acute respiratory failure admitted to the intensive care unit (ICU). We compared patients with noninvasive testing only to those who had also received bronchoscopy by bivariate analysis and after propensity score matching. RESULTS: Bronchoscopy was performed in 618 (39%) patients who were more likely to have haematological malignancy and a higher severity of illness score. Bronchoscopy alone achieved a diagnosis in 165 patients (27% adjusted diagnostic yield). Bronchoscopy resulted in a management change in 236 patients (38% therapeutic yield). Bronchoscopy was associated with worsening of respiratory status in 69 (11%) patients. Bronchoscopy was associated with higher ICU (40% versus 28%; p<0.0001) and hospital mortality (49% versus 41%; p=0.003). The overall rate of undiagnosed causes was 13%. After propensity score matching, bronchoscopy remained associated with increased risk of hospital mortality (OR 1.41, 95% CI 1.08-1.81). CONCLUSIONS: Bronchoscopy was associated with improved diagnosis and changes in management, but also increased hospital mortality. Balancing risk and benefit in individualised cases should be investigated further.

Activation of Blood Coagulation After Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Trial of Rotational Thromboelastometry.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) has been reported to actuate blood coagulation. Rotational thromboelastometry (ROTEM) is a dynamic hemostatic test that can differentiate various coagulation abnormalities. For example, increased coagulation activity can be detected as a wider amplitude of tracing (maximal clot firmness [MCF]). ROTEM had not been used to evaluate coagulation changes after aSAH. We evaluated the on-going coagulation process in patients with aSAH in a prospective, observational study to compare their ROTEM assay results with the control values obtained from patients undergoing clipping of nonruptured aneurysms. METHODS: ROTEM analyses were performed at 12, 24, 48, and 72 hours after the onset of aSAH and compared with the preoperative analyses from the control group. A total of 17 patients with aSAH treated in the intensive care unit and 16 control patients were enrolled. RESULTS: At 72 hours, EXTEM-MCF was significantly greater in patients with aSAH compared with the baseline values of the control group (68.0 mm [interquartile range (IQR), 66.0-71.0] versus 64.5 mm [IQR, 59.5-66.8]; P = 0.024). This was mainly due to increased fibrin formation and fibrin polymerization. The same comparison in the FIBTEM-MCF analysis yielded similar results (aSAH group, 23.0 mm [IQR, 19.0-25.0] vs. control group, 15.4 mm [IQR, 12.5-17.8], respectively; P = 0.001). CONCLUSIONS: Blood coagulation is activated at 72 hours after aSAH onset, which can be detected by ROTEM EXTEM-MCF analysis. Also, the FIBTEM-MCF was elevated, implying that the relative contribution of fibrin formation and fibrin polymerization is essential.

Autoimmune heparin-induced thrombocytopenia of delayed onset: a clinical challenge.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) usually appears at 5 to 10 days after initiation of heparin. Autoimmune HIT can arise after discontinuation of heparin treatment (delayed-onset HIT) or without any preceding heparin exposure (spontaneous HIT syndrome). CASE REPORT: This case presents a course of autoimmune HIT with delayed onset. The patient was hospitalized due to influenza pneumonia and received low-molecular-weight heparin thromboprophylaxis for 9 days. Seven days after discharge, she was readmitted because of a cerebral sinus vein thrombosis and severe thrombocytopenia. Intracranial bleeding and brain infarction caused her death. DISCUSSION: Autoimmune HIT was confirmed by functional heparin-induced platelet (PLT) activation test. Intracranial bleeding prevented continuous and effective anticoagulation. PLT transfusions were given, although they are generally advised against in HIT patients due to potential risk of thromboembolic events. CONCLUSION: This case presents that testing PLT-activating antibodies both in the presence and in the absence of current heparin treatment helps to diagnose patients with autoimmune HIT. There is conflicting evidence to refuse PLT transfusion when HIT is complicated with life-threatening bleeding.

Plasma anti-FXa concentration after continuous intravenous infusion and subcutaneous dosing of enoxaparin for thromboprophylaxis in critically ill patients. A randomized clinical trial.

INTRODUCTION: In intensive care unit (ICU) patients, subcutaneous low-molecular weight heparin thromboprophylaxis results in lower plasma anti-factor Xa (anti-FXa) levels compared to general ward patients. The aim of this study was to examine whether enoxaparin thromboprophylaxis given as a continuous intravenous infusion (CII) results in more constant and predictable anti-FXa concentration than standard subcutaneous bolus (SCB) administration. MATERIALS AND METHODS: This was a prospective, single-blind, multicenter, randomized controlled trial where ICU patients requiring thromboprophylaxis received enoxaparin either 40mg as a SCB once daily or 40mg as a CII over 24h for three consecutive days. The primary outcome was maximum serum anti-FXa concentration (Cmax24h) within the first 24h; the secondary outcome was anti-FXa area under the curve (AUC)(0-24h). Trough level was measured at 72h. RESULTS: Thirty-nine patients were included in the intention to treat analysis. The median anti-FXa Cmax24h was 0.05 (interquartile range, IQR, 0.05-0.18) IU/ml in the CII group and 0.18 (IQR, 0.12-0.33) IU/ml in the SCB group (p=0.05). Median anti-FXa AUC(0-24h) was 1.20 (IQR, 0.98-2.88) in the CII and 1.54 (IQR, 1.22-4.12) in the SCB group (p=0.095). After 72h, 66.7% of patients in the CII group had a detectable anti-FXa concentration of >0.1IU/ml, compared with 16.7% in the SCB group (p=0.019). CONCLUSIONS: Continuous infusion of enoxaparin led to lower anti-FXa Cmax24h than standard SCB administration. No difference in anti-FXa AUC0-24h was detected.

Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) - endotoxin removal in abdominal and urogenital septic shock with the Alteco® LPS Adsorber: study protocol for a double-blinded, randomized placebo-controlled trial.

BACKGROUND: Severe sepsis and septic shock are common in intensive care and carry high mortality rates. In patients with Gram-negative infections, early and extensive removal of endotoxin may limit the inflammatory response that characterizes septic shock. The Alteco® LPS Adsorber (hereafter referred to cited as the lipopolysaccharide (LPS) Adsorber) can be used for endotoxin removal and attenuate the deleterious inflammatory and clinical responses seen in septic shock. METHODS/DESIGN: The Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) trial is a pilot study investigating the feasibility and safety of LPS Adsorber therapy. This pilot, multicenter, stratified, parallel, double-blinded, randomized, phase IIa, feasibility clinical investigation will be performed in five Scandinavian intensive care units. Thirty-two subjects with early septic shock and organ failure, following adequate resuscitation, will be randomized to receive either: extracorporeal veno-venous hemoperfusion therapy with the LPS Adsorber or veno-venous hemoperfusion therapy with a placebo adsorber (without active LPS-binding peptide). Patients will be stratified by infection focus such that 20 subjects with an abdominal focus (stratum A) and 12 subjects with a urogenital focus (stratum B) will be included in a parallel design. Thereafter, an interim analysis will be performed and an additional 12 patients may be included in the study. The study is designed as adaptive a priori: the patients from this study can be included in a later phase IIb study. The aim of the study is to investigate the feasibility of LPS Adsorber therapy commenced early in the time-course of septic shock. The primary endpoint will be a characterization of all reported unanticipated serious adverse device effects and anticipated serious adverse device effects. Secondary outcomes are decrease in endotoxin plasma concentration, impact on clinical outcome measures and impact on inflammatory response by LPS Adsorber therapy, as well as detailed description of the relevant mediators bound to the LPS Adsorber. Recruitment of patients will start in September 2015. DISCUSSION: The ASSET trial will give insight into the feasibility and safety of this LPS Adsorber therapy and preliminary data on its potential clinical effects in septic shock. Moreover, this pilot trial will provide with necessary data for designing future studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02335723 . Registered on 28 November 2014.

Targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S): study protocol and statistical analysis plan for a randomized controlled trial.

BACKGROUND: Septic shock has a 90-day mortality risk of up to 50 %. The hemodynamic targets, including mean arterial pressure (MAP) are not based on robust clinical data. Both severe hypotension and high doses of vasopressors may be harmful. Hence, re-evaluation of hemodynamic targets in septic shock is relevant. METHODS/DESIGN: The targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S) trial is a prospective, two-parallel-group, randomized, open-label, multicenter trial with assessor-blinded outcome evaluation. We will randomize at least 200 patients with septic shock in four European intensive care units (ICUs) to test whether a tissue perfusion-guided treatment strategy based on capillary refill time, peripheral temperature, arterial lactate concentrations, and accepting lower MAP levels, leads to a faster resolution of shock than macrocirculation target-guided standard care. The primary outcome measure is days alive in 30 days with normal arterial blood lactate (first value of <2 mmol/L) and without any inotropic or vasopressor agent. Secondary outcomes include individual components of the primary outcome, days alive without renal replacement, days alive without mechanical ventilation in 30 days, and new acute kidney injury. The sample size enables detection of a 13.5-h difference in the primary outcome with a type 1 error of 5 % and power of 80 %, assuming 25 % mortality and a mean of 650 h (SD 30) among the 30-day survivors. After 150 included patients the statistician masked for allocation group will recalculate the sample size potentially increasing the sample up to 300. The Data Safety and Monitoring Board (DSMB) will review the safety data after 100 patients. DISCUSSION: The TARTARE-2S trial will provide important clinical data on treatment targets in septic shock, evaluating the impact of clinical tissue perfusion-guided hemodynamic treatment on a surrogate outcome combining resolution of shock (hyperlactatemia and vasopressors/inotropes), and 30-day mortality. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02579525 . Registered on 19 October 2015.

Plasma anti-FXa level as a surrogate marker of the adequacy of thromboprophylaxis in critically ill patients: A systematic review.

BACKGROUND: Critical care patients are prone to venous thromboembolism (VTE) and, thus, pharmacological thromboprophylaxis is generally advised. Low-molecular weight heparins (LMWHs) have become the drug of choice in ICU patients, since their predictable and reproducible dose response. Monitoring their pharmacological effect is not usually necessary except in special occasions (i.e. with obese or renal failure patients), where anti-FXa level measuring is recommended. However, there is neither recommendation of adequate anti-FXa levels in critically ill patients nor is it known whether peak or trough level should be measured. The aim of this systematic review was to evaluate the recommended LMWH doses, and the reasons to monitor anti-FXa levels. METHODS: We searched MEDLINE, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.com to identify all potentially relevant studies. Prospective studies done in critically ill patients were included if at least one anti-FXa level (i.e. peak or trough) after any specified LMWH thromboprophylaxis dose was measured. RESULTS: Total 18 eligible studies including 1644 patients were included. There was a wide variation in the median peak anti-FXa levels (<0.1-0.35IU/ml). Trough levels were generally low. Of note, none of the studies detected any correlation with bleeding events and anti-FXa levels. Low trough level increased incidence of DVT in one study only. CONCLUSION: Based on the current literature, no definite conclusions can be drawn on targeted anti-FXa level in critically ill patients when using LMWH thromboprophylaxis.