Intensive Core Med psd org/10.1007/500134-022-06650-7 ASTING LEGACY IN INTENSIVE CARE MEDICINE Thromboprophylaxis in critical care & Julie Heims'"®, Saskia Middeldorp* and Alex C. Spyropoulos*” ea mb Gea, prof Spinger Rane Venous thromboembolism (VTE) in critically il patients may be a life-threatening complication increasing dura- tion of mechanical ventilation and stay in the intensive care unit (ICU). Both early diagnosis and effective and safe thromboprophylaxis are, therefore, daily challenges. Despite its major clinical impact, the risk of VTE in ICU has long been pooriy characterized (Suppl. Figure 1), and high-quality evidence comparing pharmacologic and ‘mechanical VTE prophylaxis strategies is stil limited. Although the anticoagulant effect of heparin was elu- cidated in 1939, it only became used from the 1950s to prevent VTE in post-surgical patients. In 1960, a land- ‘mark trial established heparin to be effective in reducing, mortality from pulmonary embolism (PE), as only surgi- cal options were considered previously [1]. Low-molec- tular-weight heparin (LMWH) was discovered in the 1980s and improved thromboprophylaxis through more consistent pharmacokinetics/pharmacodynamic, simpli fied dosing, reduced bleeding, and less frequent heparin- induced thrombocytopenia than with unfractionated heparin (UFH) [2]. Which pharmacological thromboprophylaxis for critically il patients? ‘With regard to type of prophylaxis, LMWH might have superior efficacy compared to UFH in medical and surg cal critically ill patients. PROTECT (3] is the largest RCT to date to compare LMWH (dalteparin, 5000 1U/day) and UFH (5000 IU/12 h) in 3764 critically ill patients, of whom 90% were mechanically ventilated. Patients at *Coneipandence ulehmaschnatatbouai " Univers de Srosboug[UNSTRA) acute de Meine: Hite unnerstaves de Statboura, Servce de Medecine tev Reonmation, Newel pal Gul Sratourg France Fultautharinferaton easbie st the end ofthe rile a Springer very high risk of bleeding were excluded, Dalteparin did not decrease the rate of proximal deep vein thrombosis (DVT) compared to UFH, but the rate of PE was sig cantly lower with dalteparin (1.3% vs. 2.3%) (HR 0.51; 95% CI 0.30-0.88; p=0.01), without difference in major bleeding or in-hospital death, Also, LMWH was more effective than low-dose heparin in preventing VTE after major trauma [4], Ina recent systematic review including 13 randomized controlled trials (RCTS) (9619 critically ill patients) and. comparing the efficacy and safety of thromboprophylaxis| in ICU, the authors showed with a moderate certainty that LMWH reduced the rate of DVT compared to UFH (OR 0.72 [95% C1 0.46-0.98}) and with a high certainty that it reduced the rate of DVT compared to control (OR 0.59 [95% Crk: 0.33-0.90]; high certainty), while UFH ‘may reduce DVT compared to control (OR 0.82 [95% Crl: 0.47-1,37)) with a low certainty of evidence [5]. In this meta-analysis, the effect of LMWH compared to UFH on Eis uncertain, because of very low-quality of evidence. Consistent with clinical studies which seem to provide a superior efficacy of LMWH compared to UFH, with- ‘out an inerease in bleeding complications, the European, and American guidelines [2, 6] recommend pharmaco- logical prophylaxis with LMWH over UFH in critically ill patients (Grade 1B) (Fig. 1). For patients with severe renal insufficiency, the guidelines suggest the use of UFH_ (Grade 2C), dalteparin (Grade 2B) or reduced doses of enoxaparin (Grade 2C) and monitoring of anti-Xa act ity (Grade 2C). The guidelines also suggest no prophy- laxis or the use of intermittent pneumatic compression in patients with a platelet count less than 50,000/mm? or a high risk of bleeding (Grade 2C) and the careful use of pharmacological prophylaxis in patients with severe iver failureMechanical thromboprophylaxis in critically ill patients ‘The place of mechanical thromboprophylaxis is still debated [5] In the PREVENT tral [7 the use of adjunc- tive compression devices in addition to pharmacologic prophylaxis did not result in @ reduction in DVT com- pared to pharmacologic prophylaxis alone. Consistently, the aforementioned meta-analysis [5] showed that com- pressive devices might reduce the risk of DVT compared toa control group made of a composite of no prophy- laxis, placebo, or compression stockings only (OR 0:85 [95% Crl: 0.50-1.50), although certainty evidence was low. ‘The European guidelines recommend against the use of graduated compression stockings alone without phar- macological thromboprophylaxs for prevention of VTE in patients at intermediate and high risk (Grade 1B) (6, 8]. They recommend the use of mechanical prophylaxis for patients with contraindications for anticoagulation (Grade 1B) or in selected patients at very high risk of VTE prophylaxis in addition to pharmacological proph- ylaxis (Grade 2B), and suggest the use of intermittent pneumatic compression over graduated compression stockings (GCS, Grade 2B). The American guidelines do rot support the use of combination therapy over either pharmacologic therapy or compression therapy alone (2) Important considerations and pending questions Even if these recommendations are clear, there are still several considerations that need to be taken into account for critically ill patients. Although the availability of high-resolution reliable imaging allowed a more acute awareness for VTE over the past decades, compliance with VTE prophylaxis should still be improved. In a recent retrospective analy- is of more than 1.4 million critically ill patients, 4% of nts did not receive any form of thromboprophy- Taxis within the fst 24 afer ICU admission without obvious reason [9]. This, together with pharmacologic thromboprophylaxis being often withheld in ICU due to complications or surgical/invasive procedures, leading, to less efficent thromboprophylaxis. Also, as tisk factors for thromboprophyiaxis failure include an elevated BMI, a personal/family history of VTE, or vasopressor use, it is likely that more aggressive and multimodal strate- gies should be used in some at-risk patients [10], maybe Including mechanical thromboprophylaxis. Then, anti-factor Xa thresholds protective of VTE are still a matter of debate in critically il patients receiving, [Thromboprophylaxis in critically il patients No contraindication 7 ee oe wm & © somicere sms aRe y “No anticoagulation (ede 22) + Low-dose heparine (rade 2c) Careful anticoagulation (arate 20) “ICP>GCS (rae 18) + Datopar (rae 25) "Reduced dose ‘snoxaparin ede 2) ‘Assessment ata (ane 20) Fig. 1 Thrombeproptyans in thecal il,Gading ofthe recommendations are based ont ‘homboemboltm pps in intensive Care] and'on mechanieathiemboprophyians [2 and on the most ecet quienes en the use cof antccagulation fr hromboprophyiaes in patents with COMD-19 fm the ternational Socety of rromboss and Haemostass (STH [5 (Onl coronas disease 2018, 6S gradated compresion stacking, HIT hepaininduced thrombocytopenia AC Intermittent Preumat Compression, UMWHow-molecuar weight hepa RCTs randomiaed conrlle tral UFH unfractionated heparin European guidelines on perioperative venousprophylactic LMWH, and personalizing thromboprophy- laxis to decrease adverse events in this specific popula- tion not only at high risk of VTE, but also at high risk of bleeding complications, would need an alternative anti- ‘coagulation monitoring technique [11, 12]. In this line, ‘when a targeted level of anticoagulation is not achieved in response to heparin dose increase, heparin resistance 3 be invoked. The hypercoagulabilty of critica ill- ness, as described for example in SARS-CoV-2 or other acute infections, might be responsible for elevated factor Vill and fibrinogen levels leading to shortened aPTT, and, binding of heparin to acute-phase inflammatory proteins that decreases its effects [13]. This leads us to consider the question of a possible spe- ifc thromboprophylaxis regimen in critically ill patients with coronavirus disease 2019 (COVID-19), who have early been identified at increased risk of thrombotic events {14}. Consistent with several negative RCTs, the ‘most recent guidelines from the International Society of Thrombosis and Haemostasis (ISTH) recommend using. prophylactic- over therapeutic- oF intermediate-intensity| anticoagulation to reduce risk of adverse events, includ- ing mortality and thromboembolism (moderate strength of recommendation, level of evidence B-Randomized, RCTS) (15). Take-home message Considering the high risk of thrombosis in critically il patients, general consensus currently establishes use of some form of heparin in pharmacological prophylaxis at the time of ICU admission, or mechanical thrombo- prophylaxis in those with contraindications to pharma- ‘cological thromboprophylaxis. LMWH is preferred over UEH for VTE prophylaxis in the ICU, unless in patients ‘with severe renal insufficiency, where the use of low-dose heparin, dalteparin or reduced doses of enoxaparin might be preferred. Supplementary information ‘Thponine sen contine suplemetaymateralvalsbe stip cong Oona E8507, ‘nuthor deta " verse de Svasbous[UNSTR) Faculté de Médecine: Héptaue univer staves destasbourg ence de meine tensive Réanimation Nove Fpl Ci Stastoug. Fence“ INSERM French Nationalist Heh na Meshal Rezer) UNE 260, Regenerstvehanomcne FI, RTS, Stasnoug rane Department itemal Wedene and Radbous ete af eat scenes HS, Nimegen The Netherlands “Radboud Unies Mesial Cnt Njmegen The Nthelands*he Donald apd Baibwa Zak Scheal ef eine at HofsrNortel, Hempstead, USA "Insitute Heath System cence, The esate tts edi eseeteh Manhasset USA *heicongulatn ad Cll Tomb Services North Heath at Lene iosptal 13 770 St New York NY 1075, USA Declarations confit of interest {has ecelved honeara fr lectures fern DagnosticaStaga Per PFE France apd ara vents France Sit os eceived peso es rom Dah Saye Saye Paes Soerergerngahewn Postl/Aenan, AB, MS- Pet Son and sal pit erst, nd ants om Bosch Sankyo Byer Per, ond Boevinger ngs AS receives conta es rom lassen, er rite Myer SQuBE, Sno Alon, ALAS Group and research Funds em nse Publisher's Note Springer Note reins nesta wth og otscioa caimsin p> Ished mapsane rsttutoral afistors Received 13 une 2022 Accepted: 2 July 2022 Published online: 29 August 2022 References TT Bart Jordan C960) Anticoagulant hugs inthe wean of pulmonaryemscier kcontolesrs ance 1303-'312, 2 Sehunemann Hi Cushran Burt AE. 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