Regional anaesthesia in patients at risk of bleeding

Abstract

Learning objectivesBy reading this article, you should be able to:•Outline the risk of neuraxial and peripheral nerve blocks in a patient who is anticoagulated.•Specify the classes of anticoagulant drugs, their key mechanisms of action and the available reversal agents.•Explain which patient groups are at especially high risk of vertebral canal haematoma.•Discuss principles guiding risk/benefit decisions before performing peripheral nerve blocks in patients who are anticoagulated.Key points•Vertebral canal haematoma is a rare, potentially devastating complication of neuraxial anaesthesia. The risk is higher in patients who are anticoagulated.•Major bleeding in peripheral nerve blocks can also have serious sequelae.•Guidelines set out recommended time intervals between stopping anticoagulants and performing neuraxial anaesthesia.•These guidelines and a recent expert consensus opinion describe the principles underlying risk/benefit decisions in peripheral nerve blocks in anticoagulated patients.•Separate guidance exists for patients with acute hip fractures, patients who are pregnant, and patients with chronic pain. By reading this article, you should be able to:•Outline the risk of neuraxial and peripheral nerve blocks in a patient who is anticoagulated.•Specify the classes of anticoagulant drugs, their key mechanisms of action and the available reversal agents.•Explain which patient groups are at especially high risk of vertebral canal haematoma.•Discuss principles guiding risk/benefit decisions before performing peripheral nerve blocks in patients who are anticoagulated. •Vertebral canal haematoma is a rare, potentially devastating complication of neuraxial anaesthesia. The risk is higher in patients who are anticoagulated.•Major bleeding in peripheral nerve blocks can also have serious sequelae.•Guidelines set out recommended time intervals between stopping anticoagulants and performing neuraxial anaesthesia.•These guidelines and a recent expert consensus opinion describe the principles underlying risk/benefit decisions in peripheral nerve blocks in anticoagulated patients.•Separate guidance exists for patients with acute hip fractures, patients who are pregnant, and patients with chronic pain. Regional anaesthesia is associated with a decreased rate of complications, reduced length of stay and decreased odds of ICU admission compared with GA alone in patients undergoing major truncal and lower limb surgery.1Smith L.M. Cozowicz C. Uda Y. Memtsoudis S.G. Barrington M.J. Neuraxial and combined neuraxial/general anesthesia compared to general anesthesia for major truncal and lower limb surgery.Anesth Analg. 2017; 125: 1931-1945Crossref PubMed Scopus (40) Google Scholar Central neuraxial block (CNB) may also improve perioperative outcomes after total hip and total knee arthroplasty.2Johnson R.L. Kopp S.L. Burkle C.M. et al.Neuraxial vs general anaesthesia for total hip and total knee arthroplasty: a systematic review of comparative-effectiveness research.Br J Anaesth. 2016; 116: 163-176Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Patients most likely to benefit from regional anaesthesia are often taking medications that increase the propensity for bleeding. Vertebral canal haematoma (VCH) is a potentially catastrophic complication of neuraxial anaesthesia. If not diagnosed and treated within 8–12 h, paraplegia is likely.3Neal J.M. Barrington M.J. Brull R. et al.The second ASRA practice advisory on neurologic complications associated with regional anesthesia and pain medicine.Reg Anesth Pain Med. 2015; 40: 401-430Crossref PubMed Scopus (162) Google Scholar Whilst permanent neurological complications following peripheral nerve blocks (PNBs) are rare, seriously disabling consequences for a patient are still possible.4Maier C. Gleim M. Weiss T. Stachetzki U. Nicolas V. Zenz M. Severe bleeding following lumbar sympathetic blockade in two patients under medication with irreversible platelet aggregation inhibitors.Anesthesiology. 2002; 97: 740-743Crossref PubMed Scopus (72) Google Scholar Estimates of the incidence of VCH vary substantially in the literature. Nevertheless, three large retrospective studies in Sweden (1.7 million CNB), the UK (700,000 CNB) and Finland (1.4 million CNB) indicate that this is a rare complication.5Moen V. Dahlgren N. Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990–1999.Anesthesiology. 2004; 101: 950-959Crossref PubMed Scopus (675) Google Scholar, 6Royal College of AnaesthetistsNAP 3 complications of neuraxial blockade.2009https://www.nationalauditprojects.org.uk/NAP3_homeDate accessed: January 7, 2021Google Scholar, 7Pitkänen M.T. Aromaa U. Cozanitis D.A. Förster J.G. Serious complications associated with spinal and epidural anaesthesia in Finland from 2000 to 2009.Acta Anaesthesiol Scand. 2013; 57: 553-564Crossref PubMed Scopus (57) Google Scholar The Swedish study found that the incidence of VCH varied substantially by patient population: one in 200,000 in women undergoing obstetric epidural or combined spinal–epidural (CSE), but one in 3,600 females (and one in 9,000 males) undergoing knee arthroplasty under epidural or CSE.5Moen V. Dahlgren N. Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990–1999.Anesthesiology. 2004; 101: 950-959Crossref PubMed Scopus (675) Google Scholar The UK 3rd National Audit Project of the Royal College of Anaesthetists found an overall incidence of VCH of one in 117,000 for all CNBs (perioperative, obstetric, chronic pain and paediatric perioperative), but the incidence of VCH following perioperative epidural (excluding spinal anaesthesia and obstetric, paediatric and pain epidurals) was one in 16,321.6Royal College of AnaesthetistsNAP 3 complications of neuraxial blockade.2009https://www.nationalauditprojects.org.uk/NAP3_homeDate accessed: January 7, 2021Google Scholar Similarly, the Finnish study found incidences of VCH haematoma of one in 775,000 following spinal anaesthesia, one in 26,400 for epidural anaesthesia and one in 17,800 for CSE.7Pitkänen M.T. Aromaa U. Cozanitis D.A. Förster J.G. Serious complications associated with spinal and epidural anaesthesia in Finland from 2000 to 2009.Acta Anaesthesiol Scand. 2013; 57: 553-564Crossref PubMed Scopus (57) Google Scholar A meta-analysis of the results of four large studies with an aggregated denominator of just over 1 million epidurals in obstetric patients found an incidence of one in 168,000.8Ruppen W. Derry S. McQuay H. Moore R.A. Incidence of epidural hematoma, infection, and neurologic injury in obstetric patients with epidural analgesia/anesthesia.Anesthesiology. 2006; 105: 394-399Crossref PubMed Scopus (234) Google Scholar Overall, it is clear that VCH is a rare complication of CNB. Incidence is higher in the perioperative setting than obstetrics, especially in the setting of underlying spinal pathology (spinal stenosis, scoliosis, etc.). Spinal block is considerably lower risk than epidural or CSE. Increased age, female sex and use of anticoagulants are also risk factors.3Neal J.M. Barrington M.J. Brull R. et al.The second ASRA practice advisory on neurologic complications associated with regional anesthesia and pain medicine.Reg Anesth Pain Med. 2015; 40: 401-430Crossref PubMed Scopus (162) Google Scholar In this review, we discuss the management of a patient who is anticoagulated when considering central or peripheral regional anaesthetic technique. Recent reviews have covered the pharmacology of antiplatelet and oral anticoagulants and their management in the perioperative period.9Filipovic M. New antiplatelet drugs and new oral anticoagulants.Br J Anaesth. 2016; 117: 74-84Abstract Full Text Full Text PDF Scopus (21) Google Scholar,10Mcilmoyle K. Tran H. Perioperative management of oral anticoagulation.BJA Educ. 2018; 18: 259-264Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Over the past decade a number of new agents have been licensed. Both the Association of Anaesthetists (AoA) in the UK and the American Society of Regional Anesthesia (ASRA) have published guidelines to inform decisions on central neuraxial anaesthesia in a patient taking antiplatelet or anticoagulant medications.11Harrop-Griffiths W. Cook T. Gill H. et al.Regional anaesthesia and patients with abnormalities of coagulation.Anaesthesia. 2013; 68: 966-972Crossref PubMed Scopus (107) Google Scholar,12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar Older guidelines from other societies are not considered further here.13Gogarten W. Vandermeulen E. Van Aken H. Kozek S. Llau J.V. Samama C.M. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology.Eur J Anaesthesiol. 2010; 27: 999-1015Crossref PubMed Scopus (367) Google Scholar,14Breivik H. Bang U. Jalonen J. Vigfússon G. Alahuhta S. Lagerkranser M. Nordic guidelines for neuraxial blocks in disturbed haemostasis from the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.Acta Anaesthesiol Scand. 2010; 54: 16-41Crossref PubMed Scopus (120) Google Scholar Both the ASRA and AoA guidelines set out recommended minimum time intervals after stopping anticoagulant medications at which it is appropriate to perform CNB, and time intervals at which the drugs can be restarted after the procedure or removal of an epidural catheter.11Harrop-Griffiths W. Cook T. Gill H. et al.Regional anaesthesia and patients with abnormalities of coagulation.Anaesthesia. 2013; 68: 966-972Crossref PubMed Scopus (107) Google Scholar,12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar When interpreting these timings, practitioners should consider factors that may increase risk of a haemorrhagic complication after neuraxial or regional approaches. For example, risk factors for VCH amongst patients receiving thromboprophylaxis with enoxaparin include female sex, old age (>65 yrs), a history of easy bruising or excessive (surgical) bleeding, spinal column abnormalities and renal insufficiency.12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar Furthermore, in complicated or emergent cases, the risk of VCH in a patient who is anticoagulated needs to be weighed against the risks of GA. The AoA's guidelines state that any abnormality of coagulation is only a relative contraindication to a regional technique and that the anaesthetist must consider that the risks of a GA may be greater. Decision-making in such cases should involve senior anaesthetists and surgeons, and, if appropriate, advice from a haematologist. In addition, a thorough risk/benefit discussion with the patient should be undertaken and documented appropriately. Where there is concern about difficult neuraxial anatomy (e.g. kyphoscoliosis), appropriate imaging (e.g. ultrasound) should be considered.3Neal J.M. Barrington M.J. Brull R. et al.The second ASRA practice advisory on neurologic complications associated with regional anesthesia and pain medicine.Reg Anesth Pain Med. 2015; 40: 401-430Crossref PubMed Scopus (162) Google Scholar Several classes of antiplatelet agents are in clinical use, and their implications for performance of neuraxial puncture vary substantially (Table 1). Platelet pharmacology has been covered in a recent article in this journal.15Ramalingam G. Jones N. Besser M. Platelets for anaesthetists—part 2: pharmacology.BJA Educ. 2016; 16: 140-145Abstract Full Text Full Text PDF Scopus (1) Google ScholarTable 1Time intervals before and after neuraxial blocks for antiplatelet agents: American Society of Regional Anesthesia (ASRA) and Association of Anaesthetists (AoA) guidelines compared.Antiplatelet agentAcceptable time to neuraxial block after drug stoppedGuidance on giving drug with neuraxial catheter in situAcceptable time after neuraxial block/catheter removal for next drug doseASRAAoAASRAAoAASRAAoAAspirinNo additional precautionsNo additional precautionsNo additional precautionsNo additional precautionsNo additional precautionsNo additional precautionsNSAIDSNo additional precautionsNo additional precautionsNo additional precautionsNo additional precautionsNo additional precautionsNo additional precautionsClopidogrel5–7 days7 daysAcceptable to maintain for 1–2 days providing no loading dose (start 24 h postoperative)Not recommendedImmediately (loading dose: 6 h)6 hPrasugrel7–10 days7 daysNot recommendedNot recommendedImmediately (loading dose: 6 h)6 hTiclopidine10 daysNot coveredAcceptable to maintain for 1–2 days providing no loading dose (start 24 h after surgery)Not coveredImmediately (loading dose: 6 h)Not coveredTicagrelor5–7 days5 daysNot recommendedNot recommendedImmediately (loading dose: 6 h)6 hCangrelor3 hNot coveredNot recommendedNot covered8 hNot coveredAbciximab24–48 h48 hContraindicated within 4 weeks of surgeryNot recommendedNo specific guidance6 hTirofiban4–8 h8 hContraindicated within 4 weeks of surgeryNot recommendedNo specific guidance6 hEptifibatide4–8 h8 hContraindicated within 4 weeks of surgeryNot recommendedNo specific guidance6 hDipyridamole24 h for extended release formulationNo additional precautionsNot recommendedNo additional precautions6 h6 hCilostazol2 daysNot coveredNot recommendedNot covered6 hNot covered Open table in a new tab These drugs act via inhibition of cyclooxygenase (COX). At the low doses used for primary and secondary prevention of stroke and myocardial infarction, platelet COX is inhibited, thereby preventing formation of the potent platelet aggregator thromboxane-A2. Aspirin affects platelet function for the duration of platelet life; other NSAIDs affect function only transiently. Both guidelines recommend that no extra additional precautions need to be taken in performing CNB in patients taking these agents. Blocking of the P2Y12 receptor leads to inhibition of adenosine-diphosphate-mediated platelet aggregation. Agents licensed in the UK in this class include the thienopyridines (clopidogrel, prasugrel and ticlopidine) and the non-thienopyridines (ticagrelor and cangrelor). Both guidelines recommend that all of these agents (excluding cangrelor) should be stopped 5–7 days before CNB (10 days for ticlopidine). The AoA guidelines recommend no use of these agents with a neuraxial catheter and a 6 h delay after CNB performance or catheter removal before restarting these agents. The recent ASRA guidelines are more nuanced: a non-loading dose of clopidogrel, prasugrel, ticlopidine or ticagrelor can be given immediately after catheter removal or CNB performance. With an indwelling neuraxial catheter, clopidogrel or ticlopidine can be given from 24 h postoperatively and the catheter only used for 1–2 days, provided a loading dose is not given. This is because the antiplatelet effect takes time to take effect. Cangrelor is an i.v. agent that can be used as perioperative antiplatelet bridging therapy. It received US Food and Drug Administration approval in 2015 and is not mentioned in the AoA guidelines. As the risk of bleeding following CNB is unknown for this agent, the tentative recommendations of ASRA are based on the elimination half-life of the drug. Notably, neuraxial block is acceptable 3 h after drug administration. Glycoprotein IIb/IIIa receptor antagonists inhibit platelet aggregation via interference with platelet fibrinogen and platelet von Willebrand factor binding, both of which are dependent on this receptor. Agents include abciximab, eptifibatide and tirofiban. All can be used during primary percutaneous coronary intervention, whilst the latter two are also licensed (in the UK) during non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina.16National Institute for Health and Care Excellence. BNF: British National Formulary–NICE. Available from: https://bnf.nice.org.uk/treatment-summary/antiplatelet-drugs.html. [Accessed 7 January 2021].Google Scholar Time intervals recommended by both guidelines before CNB are based on time to return of normal platelet aggregation and are longer (24–48 h) for abciximab than for eptifibatide and tirofiban (4–8 h). The AoA guidelines recommend that these agents should be avoided whilst a neuraxial catheter is in place and for 6 h after removal. Dipyridamole is used principally in the prevention of ischaemic stroke. Its mechanism of action is controversial.12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar ASRA states that there is no evidence to support stopping the drug before neuraxial block, but the drug is often used in combination with aspirin, and together they are associated with a higher risk of bleeding than clopidogrel. Notably, there is a case report of a patient taking dipyridamole suffering serious haemorrhagic complications after ilioinguinal nerve block.17Parvaiz M.A. Korwar V. McArthur D. Claxton A. Dyer J. Isgar B. Large retroperitoneal haematoma: an unexpected complication of ilioinguinal nerve block for inguinal hernia repair.Anaesthesia. 2012; 67: 78-80Crossref Scopus (15) Google Scholar The AoA recommends no special precautions for this agent. The ASRA guidelines are more cautious and recommend discontinuing the extended release formulation 24 h before CNB, and state that the drug should not be given with a neuraxial catheter in situ. Cilostazol inhibits phosphodiesterase IIIa and thereby platelet aggregation.12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar It is used for vascular patients with intermittent claudication, as it also has vasodilatory properties. ASRA recommends discontinuation for 48 h before neuraxial block. Unfractionated heparin (UFH) binds to antithrombin, thereby potentiating inactivation of thrombin (factor IIa), factor Xa and factor IXa. Unfractionated heparin given i.v. acts immediately, whilst 5,000 I.U. given subcutaneously has an anticoagulant effect at approximately 1 h.12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar The AoA states that neuraxial blocks should not be performed for 4 h or until normal activated partial thromboplastin time ratio (APTTR) for both s.c. and i.v. UFH. They advise caution regarding giving the agent with a neuraxial catheter in place. Recommendations on time intervals from ASRA are more complex and depend on the route of administration and, for s.c. UFH, on the dose. Time intervals before CNB for s.c. UFH can be up to 24 h after the last dose. They additionally recommend that any patient receiving UFH for more than 4 days should have a platelet count before CNB (or catheter removal) to exclude heparin-induced thrombocytopenia. Low-molecular-weight heparins (LMWHs) act predominantly to inhibit factor Xa. In addition to venous thromboembolism (VTE) prophylaxis and treatment, they are sometimes used to ‘bridge’ patients undergoing surgery with mechanical heart valves or at high risk of arterial or VTE. A recent review covered perioperative anaesthetic management of bridging.10Mcilmoyle K. Tran H. Perioperative management of oral anticoagulation.BJA Educ. 2018; 18: 259-264Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Whilst anti-factor Xa can be used to monitor drug concentrations, there is no known safe level at which neuraxial puncture can be performed, and so ASRA recommends against routine testing. The AoA's timings recommend no CNB for 12 h after prophylactic dose or 24 h after treatment dose, and no LMWH until 4 h after block/catheter removal. If the neuraxial block is traumatic, the AoA's advice is to consider increasing this to 24 h. The AoA recommends caution with neuraxial catheters in patients having prophylactic dose LMWH and no catheters in patients having treatment dose. The time intervals recommended by ASRA are the same before a block, but they advise a 12 h interval after neuraxial puncture until the first prophylactic dose and a 24 h interval for therapeutic LMWH. The recommendations state that catheters can be maintained only if the patient is receiving once daily prophylactic dosing and should be removed 12 h after the last once-daily prophylactic dose. Parenteral heparin alternatives can be grouped into agents that inhibit factor Xa (fondaparinux and danaparoid) and the thrombin inhibitors (argatroban and bivalirudin). For danaparoid, the AoA recommends complete avoidance of neuraxial block. Danaparoid was withdrawn from the US market and is not covered by ASRA's guidance. The AoA's guidance also recommends avoidance of CNB in patients receiving fondaparinux at treatment dose. At prophylactic dose, the AoA recommends waiting 36–42 h after the last dose and considering anti-factor Xa levels. ASRA's guidance suggests that if a patient has received fondaparinux, then CNB is only appropriate in the following circumstances: single-needle pass, atraumatic procedure and no neuraxial catheter. The direct thrombin inhibitors argatroban and bivalirudin have produced no case reports of VCH.12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar Their effect is monitored by activated partial thromboplastin time (APTT) and is present for up to approximately 3 h after i.v. administration. ASRA's guidance recommends against all neuraxial techniques in patients taking argatroban and bivalirudin, but the AoA suggests CNB is acceptable with normal APTTR or at 4 and 10 h, respectively, after the last dose. The direct oral anticoagulants (DOACs) similarly consist of those drugs that inhibit factor Xa and those that inhibit thrombin. Drugs that inhibit factor Xa have the suffix ‘-xaban’; they ‘banish’ factor Xa. Examples include rivaroxaban, edoxaban and apixaban. For rivaroxaban, both guidelines acknowledge that recommended time intervals depend on the dose and the patient's renal function. ASRA suggests longer time intervals than the AoA. ASRA also states that testing for anti-Xa is not definitive, as there is no determined safe level of residual anti-Xa. Time intervals are laid out in Table 2. Apixaban and edoxaban (not covered by the AoA) have similar time intervals to those of rivaroxaban. In May 2019, the European Medicines Agency recommended a conditional marketing authorisation for the first reversal agent for apixaban and rivaroxaban. Andexanet alfa (Ondexxya) reverses the effect of both agents in minutes by acting as a decoy factor Xa for these drugs, thereby preventing binding to endogenous factor Xa. A recent National Institute for Health and Care Excellence (NICE) consultation concluded that Ondexxya could not be recommended in view of limited evidence and concerns regarding cost-effectiveness (approximately £15,000 per patient treated).18European Medicines AgencyFirst antidote for reversal of anticoagulation with factor Xa inhibitors apixaban and rivaroxaban.2019https://www.ema.europa.eu/en/news/first-antidote-reversal-anticoagulation-factor-xa-inhibitors-apixaban-rivaroxabanDate accessed: January 7, 2021Google Scholar,19National Institute for Health and Care ExcellenceRecommendations. Andexanet alfa for reversing anticoagulation.2020https://www.nice.org.uk/consultations/891/1/recommendationsDate accessed: November 5, 2020Google Scholar Dabigatran is the only agent in this class. It is primarily used in the prevention and treatment of VTE and in reducing the risk of stroke. It is more than 80% renally excreted, and safe interval times depend largely on renal function.12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar In the absence of recent measurement of renal function, ASRA recommends a minimum interval of 120 h after the last dose before neuraxial puncture. Where measurement has occurred and there are no additional risk factors (age >65 yrs, antiplatelet medication and hypertension), ASRA recommends a graduated approach based on creatine clearance. The AoA takes a similar approach. ASRA recommends somewhat longer time intervals before CNB than the AoA; even a patient with a creatinine clearance (CrCl) >80 ml min−1 should have dabigatran discontinued for 72 h. Both bodies recommend no administration of the agent whilst neuraxial catheters are in situ, and their removal 6 h before administration of the agent. Dabigatran can be reversed by idarucizumab (Praxbind), a monoclonal antibody that binds to the agent itself and reverses the anticoagulant effect within minutes. It was licensed by NICE in the UK in 2016 and costs £2,400 per dose—in some circumstances, patients may require two doses.20National Institute for Health and Care ExcellenceReversal of the anticoagulant effect of dabigatran: idarucizumab.2016https://www.nice.org.uk/advice/esnm73/resources/reversal-of-the-anticoagulant-effect-of-dabigatran-idarucizumab-pdf-1502681164008901Date accessed: January 5, 2021Google Scholar Warfarin inhibits the synthesis of vitamin-K-dependent clotting factors II, VII, IX and X. ASRA's guidance outlines patient characteristics with associated increased sensitivity to warfarin: age >65 yrs; female; weight <100 lb (45 kg); liver, cardiac or renal disease; Asian ancestry; and past excessive surgical blood loss. The AoA recommendations are that CNB is acceptable with an international normalised ratio (INR) of ≤1.4, avoidance of the drug whilst a neuraxial catheter is in situ and that warfarin can be recommenced as soon as the catheter is removed. ASRA's guidelines recommend a normal INR (i.e. ≤1.1), but state that administration of the drug with a neuraxial catheter in place is acceptable with caution (e.g. neurological observations of sensory and motor function), where the INR is 1.5–3.0. Removal of catheters is recommended with an INR below 1.5 and with continuance of neurological observations for 24 h. Warfarin can be reversed in the absence of major bleeding with vitamin K (i.v. infusion acts in 6–8 h) or with prothrombin complex concentrate (Octaplex and Beriplex), which contains significant quantities of clotting factors, including factor VII. Fresh frozen plasma is not recommended.21Keeling D. Baglin T. Tait C. et al.Guidelines on oral anticoagulation with warfarin—fourth edition.Br J Haematol. 2011; 154: 311-324Crossref PubMed Scopus (426) Google Scholar Thrombolytic/fibrinolytic agents interact with plasminogen to produce plasmin that lyses links between fibrin molecules, thereby dissolving clots. Agents include alteplase and streptokinase, and are indicated in acute myocardial infarction, pulmonary embolism and cerebrovascular accident. ASRA cites six cases of VCH following administration of these agents. They recommend that neuraxial puncture should generally be avoided, and only considered at least 48 h after administration of these agents in a patient, where clotting studies (including fibrinogen count) are normal. The AoA guidelines suggest CNB should not be performed until 10 days after discontinuation of the agent. ASRA also recommends that in patients who have received a thrombolytic agent close to neuraxial puncture, neurological observations should be detailed regularly, ideally every 2 h. ASRA states that the three herbal medications that impair haemostasis most are garlic, ginkgo and ginseng, but the effect is inconsequential to CNB. The AoA has recently produced new guidance on the anaesthetic management of patients with hip fractures.22Griffiths R. Babu S. Dixon P. et al.Management of Hip Fractures 2020. Association of Anaesthetists, London2020Google Scholar It is recognised that 30–40% of patients with hip fractures take anticoagulant medications, VCH is an extremely rare complication and that the elevated risk in a patient who is anticoagulated is unquantifiable but likely small. Therefore, this new AoA guidance argues that in some patients taking anticoagulant medications, the risk of VCH may be assessed as being considerably lower than the risks of GA or delaying surgery beyond 24–48 h. The AoA hip fracture guidelines state that where an experienced anaesthetist considers a spinal anaesthetic the optimum treatment for a patient with an acute hip fracture, then any single antiplatelet medication (e.g. aspirin, clopidogrel, ticagrelor) is not a contraindication to spinal anaesthesia. The guidelines also suggest that dual antiplatelet medication is not an absolute contraindication to spinal anaesthetic in this context, but there must be a compelling reason to not proceed with a general anaesthetic. For patients with an acute hip fracture taking warfarin, the guideline recommends proceeding to surgery with an INR of ≤1.8, and that a spinal anaesthetic is acceptable with an INR of ≤1.5. Warfarin can be restarted 12–24 h after surgery in the absence of active bleeding. For those taking DOACs, it suggests waiting for at least two drug half-lives before proceeding with surgery. Accordingly, spinal anaesthesia is acceptable 24 h after the last ingested dose of a Xa inhibitor (e.g. apixaban and rivaroxaban), provided that the measured creatinine clearance is >30 ml min−1. For dabigatran, the guidance recommends that the patient should be listed for surgery on the afternoon of the day after the last ingested dose. Thrombin time should be measured at 0800 on the day of surgery, and, if normal, it is acceptable to proceed to surgery under spinal anaesthesia or GA. If thrombin time is prolonged, the guideline recommends contacting haematology and considering reversal with idarucizumab. These recommendations are summarised in Figure 1. The Society for Obstetric Anesthesia and Perinatology has recently published a consensus statement on the Anesthetic Management of Pregnant and Postpartum Women Receiving Thromboprophylaxis or Higher Dose Anticoagulants.24Leffert L. Butwick A. Carvalho B. et al.The Society for Obstetric Anesthesia and Perinatology Consensus Statement on the anesthetic management of pregnant and postpartum women receiving thromboprophylaxis or higher dose anticoagulants.Anesth Analg. 2018; 126: 928-944Crossref PubMed Scopus (71) Google Scholar This will be covered in a forthcoming article in BJA Education. ASRA has also published a guideline on Interventional Spine and Pain Procedures in Patients on Antiplatelet and Anticoagulant Medications with input from a number of American and European societies.25Narouze S. Benzon H.T. Provenzano D. et al.Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications (Second Edition): guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain.Reg Anesth Pain Med. 2018; 43: 225-262PubMed Google Scholar The guideline sets out recommended time intervals for a wide range of antiplatelet and anticoagulant medications, including the DOACs. These intervals depend on whether the procedure is deemed high, intermediate or low risk. High-risk procedures include insertion of spinal cord stimulators; intermediate-risk procedures include sympathetic blocks, such as those of the stellate ganglion and coeliac plexus; and low-risk procedures include PNBs and thoracic/lumbar facet joint injections. The guidance recommends stopping some agents before high-risk procedures that are not routinely stopped before central neuraxial block, notably aspirin and NSAIDs. There are a number of groups of patients and circumstances, in which extra care is warranted in considering CNB or PNB. The AoA's guidance for these groups is briefly summarised as follows. The guidelines state that the majority of such patients are aware of their disease and have a deficiency of a known factor or group of factors. Haematology advice should be sought to normalise coagulation in advance of planned or emergency surgery, and risks and benefits of both CNB and PNB should be carefully considered. Trauma leads to a coagulopathic state from shock, haemodilution, hypothermia, acidaemia and inflammation. Massive transfusion may also cause further dilution and consumption of clotting factors. In general, it is recommended that coagulation status and, if platelet transfusion has occurred, platelet function are assessed (e.g. point-of-care platelet function analysis) before any regional technique is performed. Severe sepsis is associated with a procoagulant state, and chemical thromboprophylaxis is usually indicated. However, septic shock may lead to a consumptive coagulopathy. In any case, CNB is relatively contraindicated in sepsis because of concerns regarding meningitis and epidural abscess. ASRA has also published helpful advice on the prevention and management of infectious complications after neuraxial techniques.26Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: an updated report by the American Society of Anesthesiologists Task Force on Infectious Complications Associated with Neuraxial Techniques and the American Society of Regional Anesthesia and Pain Medicine.Anesthesiology. 2017; 126: 585-601Crossref PubMed Scopus (28) Google Scholar All clotting factors, except factor VIII, are synthesised in the liver. These patients are a high-risk group for any regional technique, and coagulation should be formally assessed before proceeding. Patients with uraemia may display thrombocytopenia, and platelet function should be assessed before any regional technique. Desmopressin (DDAVP) may improve platelet function. Patients on haemodialysis may remain anticoagulated because of residual heparin (unfractionated or LMWH), and if a regional catheter technique is used, consideration must be given to the timing for safe removal, given that the patient is likely to receive heparin during further haemodialysis. In a patient with known disseminated intravascular coagulopathy, neuraxial puncture is unsafe. Peripheral nerve blocks should only ever be considered on a risk/benefit basis and only at compressible sites. Both ASRA and the AoA give guidance on the applicability of their recommendations for CNB to plexus and PNB. There are relatively few data available regarding the frequency and consequences of haemorrhagic complications after plexus or PNB. A 2018 review article examined the available studies on PNBs (excluding eye blocks) in patients receiving antiplatelets or anticoagulants. Between 1978 and 2018, they found six observational studies, of which only one used ultrasound guidance in performing the blocks. There were 65 bleeding complications in 9,688 regional blocks. More than 90% of these related to one study, in which patients with an indwelling femoral catheter after total knee arthroplasty were given prophylactic dose rivaroxaban. No bleeding complication was associated with a neuropathy in these studies.27Joubert F. Gillois P. Bouaziz H. Marret E. Iohom G. Albaladejo P. Bleeding complications following peripheral regional anaesthesia in patients treated with anticoagulants or antiplatelet agents: a systematic review.Anaesth Crit Care Pain Med. 2019; 38: 507-516Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar ASRA's guidelines include a summary of the 32 published case reports of patients who have had serious haemorrhagic complications after plexus or PNB. Of these 32 patients, 14 were not anticoagulated, whilst 18 were receiving antithrombotic therapy. One patient, receiving clopidogrel until 3 days prior, died as a result of a massive retroperitoneal haemorrhage 12 h after a lumbar sympathetic block.4Maier C. Gleim M. Weiss T. Stachetzki U. Nicolas V. Zenz M. Severe bleeding following lumbar sympathetic blockade in two patients under medication with irreversible platelet aggregation inhibitors.Anesthesiology. 2002; 97: 740-743Crossref PubMed Scopus (72) Google Scholar A number of trends are noteworthy from these case reports. First, in those patients who suffered neurological deficits, all had complete recovery by 12 months. Second, patients receiving antithrombotic therapy who developed complications were more likely to require hospitalisation, and in all but one case, their stay was complicated and prolonged. Third, complications in the anticoagulated patient appear to be more a result of significant blood loss than neurological damage. Fourth, deep plexus (e.g. lumbar plexus block) and deep peripheral blocks (e.g. proximal sciatic approaches) appear to carry the most risk. Fifth, there is often no evidence of vessel trauma.12Horlocker T.T. Vandermeuelen E. Kopp S.L. Gogarten W. Leffert L.R. Benzon H.T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy.Reg Anesth Pain Med. 2018; 43: 263-309Crossref PubMed Scopus (242) Google Scholar The ASRA guidelines recommend that patients undergoing perineuraxial, deep plexus or deep peripheral block who are taking anticoagulant medication should be managed as if they are undergoing CNB. For all other regional anaesthesia techniques (i.e. non-deep plexus and peripheral nerves), they recommend that performing a block should be considered in light of the vascularity and compressibility of the anatomical site and the potential consequences of bleeding at that site. The AoA guidelines are based on similar concepts and are helpfully specific regarding the relative risk of the various blocks ranging from a high-risk group titled ‘paravertebral’ blocks (including paravertebral block itself, but also deep cervical plexus and lumbar plexus blocks), through deep blocks (e.g. supraclavicular brachial plexus block), superficial perivascular blocks (e.g. popliteal sciatic block), fascial blocks (e.g. transverse abdominis plane block) and finally superficial blocks (e.g. forearm nerve blocks and ankle blocks). The AoA guidelines also state that catheter techniques are likely to be higher risk, that there is likely to be risk with catheter removal and that ultrasound-guided regional anaesthesia used appropriately may make blocks safer in the presence of abnormal coagulation. A recent response to the ASRA guidelines has been published by the Regional Anesthesia and Acute Pain Section of the Canadian Anesthesiologists’ Society.28Tsui B.C.H. Kirkham K. Kwofie M.K. et al.Practice advisory on the bleeding risks for peripheral nerve and interfascial plane blockade: evidence review and expert consensus.Can J Anaesth. 2019; 66: 1356-1384Crossref PubMed Scopus (11) Google Scholar This response attempts to provide guidance on risk levels for bleeding with PNB, largely in response to a perceived lack of risk stratification of blocks within the ASRA guidance. It provides expert-level opinion at best, as the evidence base is weak. As the use of newer techniques increases, advice may evolve regarding their safety. The AoA's recent hip fracture guidelines do not specifically discuss fascia iliaca block in the anticoagulated patient with acute hip fracture, but both the AoA's 2013 guidelines and the recent consensus opinion from the Canadian Anesthesiologists’ Society suggest that the infrainguinal fascia iliaca block can be considered a relatively low-risk block for bleeding complications.11Harrop-Griffiths W. Cook T. Gill H. et al.Regional anaesthesia and patients with abnormalities of coagulation.Anaesthesia. 2013; 68: 966-972Crossref PubMed Scopus (107) Google Scholar,28Tsui B.C.H. Kirkham K. Kwofie M.K. et al.Practice advisory on the bleeding risks for peripheral nerve and interfascial plane blockade: evidence review and expert consensus.Can J Anaesth. 2019; 66: 1356-1384Crossref PubMed Scopus (11) Google Scholar Overall, practitioners considering PNB techniques in patients who are anticoagulated will need to consider the likelihood and consequences of haemorrhagic complications and the compressibility of the site. These risks will also need to be weighed against the risks of stopping the patient's anticoagulation medication in elective cases and the risks of GA in the particular patient in both elective and emergency cases. Vertebral canal haematoma is a rare but potentially catastrophic complication of CNB. Both the AoA and the more recent ASRA guidelines provide excellent advice on safe intervals for the performance of CNB. Differences in some time intervals between these guidelines are relatively minor. There are a number of groups of patients in whom extra care is warranted. There remains no definitive guidance on safe intervals for the performance of PNBs, although the existing guidelines set out a number of useful principles to help direct practice.