Marcella C. A. Müller

Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review

IntroductionCoagulation abnormalities are frequent in sepsis. Conventional coagulation assays, however, have several limitations. A surge of interest exists in the use of point-of-care tests to diagnose hypo- and hypercoagulability in sepsis.We performed a systematic review of available literature to establish the value of rotational thromboelastography (TEG) and thromboelastometry (ROTEM) compared with standard coagulation tests to detect hyper- or hypocoagulability in sepsis patients. Furthermore, we assessed the value of TEG/ROTEM to identify sepsis patients likely to benefit from therapies that interfere with the coagulation system.MethodsMEDLINE, EMBASE, and the Cochrane Library were searched from 1 January 1980 to 31 December 2012. The search was limited to adults, and language was limited to English. Reference lists of retrieved articles were hand-searched for additional studies. Ongoing trials were searched on http://www.controlled-trials.com and http://www.clinicaltrials.gov. Studies addressing TEG/ROTEM measurements in adult patients with sepsis admitted to the ICU were considered eligible.ResultsOf 680 screened articles, 18 studies were included, of which two were randomized controlled trials, and 16 were observational cohort studies. In patients with sepsis, results show both hyper- and hypocoagulability, as well as TEG/ROTEM values that fell within reference values. Both hyper- and hypocoagulability were to some extent associated with diffuse intravascular coagulation. Compared with conventional coagulation tests, TEG/ROTEM can detect impaired fibrinolysis, which can possibly help to discriminate between sepsis and systemic inflammatory response syndrome (SIRS). A hypocoagulable profile is associated with increased mortality. The value of TEG/ROTEM to identify patients with sepsis who could possibly benefit from therapies interfering with the coagulation system could not be assessed, because studies addressing this topic were limited.ConclusionTEG/ROTEM could be a promising tool in diagnosing alterations in coagulation in sepsis. Further research on the value of TEG/ROTEM in these patients is warranted. Given that coagulopathy is a dynamic process, sequential measurements are needed to understand the coagulation patterns in sepsis, as can be detected by TEG/ROTEM.

Transfusion of fresh-frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial (CME).

Prophylactic use of fresh‐frozen plasma (FFP) is common practice in patients with a coagulopathy undergoing an invasive procedure. Evidence that FFP prevents bleeding is lacking, while risks of transfusion‐related morbidity after FFP have been well demonstrated. We aimed to assess whether omitting prophylactic FFP transfusion in nonbleeding critically ill patients with a coagulopathy who undergo an intervention is noninferior to a prophylactic transfusion of FFP.

Low-risk transfusion-related acute lung injury donor strategies and the impact on the onset of transfusion-related acute lung injury: a meta-analysis

Transfusion‐related acute lung injury (TRALI) is the leading cause of transfusion‐related mortality. In the past decade blood banks have implemented low‐risk TRALI donor strategies, including a male‐only donor policy for plasma‐containing blood products to prevent onset of TRALI. We performed a meta‐analysis to determine whether use of low‐risk TRALI donor strategies for plasma indeed reduces onset of TRALI.

Transfusion of fresh frozen plasma in non-bleeding ICU patients -TOPIC TRIAL: study protocol for a randomized controlled trial

BackgroundFresh frozen plasma (FFP) is an effective therapy to correct for a deficiency of multiple coagulation factors during bleeding. In past years, use of FFP has increased, in particular in patients on the Intensive Care Unit (ICU), and has expanded to include prophylactic use in patients with a coagulopathy prior to undergoing an invasive procedure. Retrospective studies suggest that prophylactic use of FFP does not prevent bleeding, but carries the risk of transfusion-related morbidity. However, up to 50% of FFP is administered to non-bleeding ICU patients. With the aim to investigate whether prophylactic FFP transfusions to critically ill patients can be safely omitted, a multi-center randomized clinical trial is conducted in ICU patients with a coagulopathy undergoing an invasive procedure.MethodsA non-inferiority, prospective, multicenter randomized open-label, blinded end point evaluation (PROBE) trial. In the intervention group, a prophylactic transfusion of FFP prior to an invasive procedure is omitted compared to transfusion of a fixed dose of 12 ml/kg in the control group. Primary outcome measure is relevant bleeding. Secondary outcome measures are minor bleeding, correction of International Normalized Ratio, onset of acute lung injury, length of ventilation days and length of Intensive Care Unit stay.DiscussionThe Transfusion of Fresh Frozen Plasma in non-bleeding ICU patients (TOPIC) trial is the first multi-center randomized controlled trial powered to investigate whether it is safe to withhold FFP transfusion to coagulopathic critically ill patients undergoing an invasive procedure.Trial RegistrationTrial registration: Dutch Trial Register NTR2262 and ClinicalTrials.gov: NCT01143909

Potential diagnostic markers for disseminated intravascular coagulation of sepsis

Disseminated intravascular coagulation (DIC) is an acquired thrombo-haemorrhagic disorder which arises in clinical scenarios like sepsis, trauma and malignancies. The clinic-laboratory diagnosis of DIC is made in a patient who develops the combination of laboratory abnormalities in the appropriate clinical scenario. The most common laboratory parameters in this setting have been the clotting profile, platelet count, serum fibrinogen and fibrin degradation markers. These tests had the advantage that they could be performed easily and in most laboratories. However, with the better understanding of the pathophysiology of DIC, in recent years, more specific tests have been suggested to be useful in this setting. The newer tests can also prove to be useful in prognostication in DIC. In addition, they may provide assistance in the selection and monitoring of patients diagnosed with DIC.

Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy: Comment

See also M€ uller MCA, Straat M, Meijers JCM, Klinkspoor JH, de Jonge E, Arbous MS, Schultz MJ, Vroom MB, Juffermans NP. Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy. J Thromb Haemost 2015; 13: 989–97 and M€ uller MCA, Juffermans NP. Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy: reply. This issue, pp 1943–4.

High-dose acetylsalicylic acid is superior to low-dose as well as to clopidogrel in preventing lipopolysaccharide-induced lung injury in mice.

Background Use of aspirin (acetylsalicylic acid [ASA]) was found to improve outcome in animal models of acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome. In patients with acute respiratory distress syndrome, data indicating a protective effect of ASA are less convincing. We hypothesize that ASA in a high dose is superior to low-dose ASA in preventing lung injury. Also, the effect on lung injury of inhibiting platelet activation by clopidogrel was investigated. Methods Acute lung injury was induced by intranasal instillation of 10 &mgr;g lipopolysaccharide (LPS). Before LPS, BALB/c mice were pretreated with either high dose of ASA (100 &mgr;g/g intraperitoneally, low-dose ASA (12.5 &mgr;g/g i.p), clopidogrel (50 &mgr;g/g i.p), or clopidogrel in combination with low dose of ASA. Controls received vehicle or LPS without intervention. Five hours after LPS, bronchoalveolar lavage fluid (BALF) and plasma were obtained. Measurements and Main Results All treatment regimens reduced neutrophil influx in the BALF compared with LPS controls (high-dose ASA 75% ± 2% [mean ± SD], low-dose ASA 86% ± 3%, clopidogrel 82% ± 1%, and low-dose ASA–clopidogrel 82% ± 3% vs. LPS control 88% ± 2%; P ⩽ 0.05). High-dose ASA reduced BALF levels of protein compared with LPS controls (median [interquartile range], 0.2 [15] vs. 75 [20] pg/mL; P < 0.01), to a greater extent than after low-dose ASA (48 [32] pg/mL), clopidogrel (37 [23] pg/mL), or low-dose ASA–clopidogrel (57 [8] pg/mL). Conclusions High-dose ASA is superior to low-dose ASA, clopidogrel, and to a combination of clopidogrel and low-dose ASA in attenuating LPS-induced lung injury in mice, suggesting high-dose ASA to be the antiplatelet therapy of choice in further research on preventing ALI.

Medical-grade honey does not reduce skin colonization at central venous catheter-insertion sites of critically ill patients: a randomized controlled trial

IntroductionCatheter-related bloodstream infections (CRBSIs) associated with short-term central venous catheters (CVCs) in intensive care unit (ICU) patients are a major clinical problem. Bacterial colonization of the skin at the CVC insertion site is an important etiologic factor for CRBSI. The aim of this study was to assess the efficacy of medical-grade honey in reducing bacterial skin colonization at insertion sites.MethodsA prospective, single-center, open-label randomized controlled trial was performed at the ICU of a university hospital in The Netherlands to assess the efficacy of medical-grade honey to reduce skin colonization of insertion sites. Medical-grade honey was applied in addition to standard CVC-site dressing and disinfection with 0.5% chlorhexidine in 70% alcohol. Skin colonization was assessed on a daily basis before CVC-site disinfection. The primary end point was colonization of insertion sites with >100 colony-forming units at the last sampling before removal of the CVC or transfer of the patient from the ICU. Secondary end points were quantitative levels of colonization of the insertion sites and colonization of insertion sites stratified for CVC location.ResultsColonization of insertion sites was not affected by the use of medical-grade honey, as 44 (34%) of 129 and 36 (34%) of 106 patients in the honey and standard care groups, respectively, had a positive skin culture (P = 0.98). Median levels of skin colonization at the last sampling were 1 (0 to 2.84) and 1 (0 to 2.70) log colony-forming units (CFUs)/swab for the honey and control groups, respectively (P = 0.94). Gender, days of CVC placement, CVC location, and CVC type were predictive for a positive skin culture. Correction for these variables did not change the effect of honey on skin-culture positivity.ConclusionsMedical-grade honey does not affect colonization of the skin at CVC insertion sites in ICU patients when applied in addition to standard disinfection with 0.5% chlorhexidine in 70% alcohol.Trial registrationNetherlands Trial Registry, NTR1652.

Transfusion-related acute lung injury: a preventable syndrome?

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Recent insights into the pathophysiology of TRALI have led to various preventive strategies. Strategies in donor management range from antibody testing of sensitized donors to the deferral of female plasma donors altogether. However, knowledge on the efficacy of measures to reduce TRALI is limited. In addition, the various measures may lead to a substantial loss of donors, hampering steady blood supply. Thereby, consensus among countries and blood-collecting facilities regarding the optimal strategy to prevent TRALI is lacking. In this review, the advantages and disadvantages of various preventive measures to prevent TRALI are discussed, related to both patient factors as well as blood component-processing strategies, including transfusion policy, donor management and practices of preparation and storage conditions of blood components.

Anemia and blood transfusion and outcome on the intensive care unit

The observation of Sakr and colleagues that transfusion may be beneficial in certain subgroups of intensive care unit (ICU) patients [1] is interesting, since large observational studies demonstrate that transfusion is independently associated with an increased risk of death [2]. Also, a systematic review showed that the benefits of transfusion in the ICU do not outweigh the risks [3]. Sakr and colleagues ascribe their discrepant results to the fact that transfused blood was leukoreduced. Of the 17 randomized controlled trials on the association of nonleukoreduced blood with mortality, however, a benefit of leukoreduction was found only in cardiac surgery patients [4]. A meta-analysis confirmed that available evidence does not justify universal leukoreduction [5].Given the increased risk of nosocomial infection, multiple organ failure and acute respiratory distress syndrome, an explanation of a beneficial effect from transfusion in anemic critically ill patients is tempting. We propose that the results of this study may be related to the indication of transfusion, this being active bleeding and not correction of anemia associated with critical illness. Hereby, transfusion may have prevented adverse events due to postoperative bleeding, explaining the survival benefit. The fact that 76% of patients were referred from the operating/recovery room and that the median length of ICU stay was only 1 day may support this hypothesis. Based on numerous reports on the association of transfusion with adverse outcome, a liberal transfusion strategy in critically ill anemic patients in the absence of acute bleeding should not be advocated.