State Secretary, ISA, TamilNadu Anesthesia and newer anticoagulants Dr.AL.Meenakshi sundaram MD DA Prof of Anesthesiology, Thanjavur Medical College GC Member, ISA National State Secretary, ISA, TamilNadu

Why special? Increased awareness of DVT Increased prophylaxis Increased use of anticoagulants Increased surgical patients with anticoagulants

Types of Anticoagulants UNFRACTIONATED HEPARIN LMWH WARFARIN ANTIPLATELET AGENTS THROMBOLYTICS FIBRINOLYTICS

On /for Thrombolytic therapy At risk of serious hemorrhagic events, particularly those who have undergone an invasive procedure. Second Consensus Conference on Neuraxial Anesthesia and Anticoagulation (April 25-28, 2002) Queries prior to the thrombolytic therapy Recent history of lumbar puncture Spinal or epidural anesthesia Epidural steroid injection Allow appropriate monitoring

On /for Thrombolytic therapy Evaluate whether fibrinolytic or thrombolytic drugs have been used preoperatively Any likelihood of being used intraoperatively or postoperatively Spinal or epidural anesthetic only in highly unusual circumstances Data are not available to clearly outline the length of time neuraxial puncture should be avoided after discontinuation of these drugs

On /for Thrombolytic therapy If neuraxial blocks at or near the time of fibrinolytic and thrombolytic therapy, neurological monitoring should be continued for an appropriate interval Interval of monitoring should not be more than two hours between neurologic checks Epidural catheter infusion should be limited to drugs minimizing sensory and motor block There is no definitive recommendation for removal of neuraxial catheters in patients who unexpectedly receive fibrinolytic and thrombolytic therapy during a neuraxial catheter infusion The measurement of fibrinogen level (one of the last clotting factors to recover) may be helpful

Anesthetic Management --Unfractionated Heparin Established over two decades ago Supported by in-depth reviews of case series & spinal hematoma and the ASA Closed Claims Project Subcutaneous (mini-dose) prophylaxis – no contraindication The risk of neuraxial bleeding reduced by delay of the heparin inj increased in debilitated patients after prolonged therapy. platelet count assessed prior to neuraxial block and catheter removal (More than 4 days of Heparin Therapy– HITS)

Combining neuraxial techniques with intraoperative heparin 1.Avoid the technique in patients with other coagulopathies 2.Heparin to be delayed for 1 hour after needle placement 3.Indwelling neuraxial catheters should be removed 2-4 hours after the last heparin dose and the patient's coagulation status is evaluated 4.Re-heparinization should occur one hour after catheter removal

Combining neuraxial techniques with intraoperative heparin 5.Monitor the patient postoperatively to provide early detection of motor blockade 6.use of minimal concentration of local anesthetics -- early detection of a spinal hematoma 7.There are no data to support mandatory cancellation of a case in a bloody tap

Preoperative LMWH Can be assumed to have altered coagulation Needle placement should occur at least 10-12 hours after the LMWH Patients receiving higher (treatment) doses of LMWH, such as enoxaparin 1 mg/kg every 12 hours, enoxaparin 1.5 mg/kg daily, dalteparin 120 U/kg every 12 hours, dalteparin 200 U/kg daily, or tinzaparin 175 U/kg daily will require delays of at least 24 hours to assure normal hemostasis at the time of needle insertion Neuraxial techniques should be avoided in patients with LMWH two hours preoperatively ( peak anticoagulant activity) Preoperative LMWH

Postoperative LMWH Twice daily dosing Increased risk of spinal hematoma The first dose of LMWH should be administered no earlier than 24 hours postoperatively (surgical) hemostasis Indwelling catheters should be removed prior to initiation of LMWH thromboprophylaxis If a continuous technique is selected, the epidural catheter may be left indwelling overnight and removed the following day, with the first dose of LMWH administered at least two hours after catheter removal Postoperative LMWH

Postoperative LMWH Single daily dosing This dosing regimen approximates the European application The first postoperative LMWH dose should be administered 6-8 hours postoperatively The second postoperative dose should occur no sooner than 24 hours after the first dose Indwelling neuraxial catheters may be safely maintained The catheter should be removed a minimum of 10-12 hours after the last dose of LMWH Subsequent LMWH dosing should occur a minimum of 2 hours after catheter removal

Regional Anesthetic Management of the Patient on Oral Anticoagulants Perioperative warfarin--- controversial The anticoagulant must be stopped, (ideally 4-5 days prior to the planned procedure) and the PT/INR measured prior to initiation of neuraxial block. Early after discontinuation of warfarin therapy, the PT/INR reflect predominantly factor VII levels, and in spite of acceptable factor VII levels, factors II and X levels may not be adequate for normal hemostasis. Adequate levels of II, VII, IX, and X may not be present until the PT/INR is within normal limits The concurrent use of medications that affect other components of the clotting mechanisms may increase the risk of bleeding complications without influencing the PT/INR(Aspirin, NSAIDs, ticlopidine and clopidogrel, unfractionated heparin and LMWH

Management of the Patient on Oral Anticoagulants Warfarin prior to surgery, (first dose was given more than 24 hours earlier) the PT/INR should be checked prior to neuraxial block Low dose warfarin therapy during epidural analgesia -- PT/INR monitored on a daily basis, and checked before catheter removal, if initial doses of warfarin are administered more than 36 hours preoperatively 5 mg of warfarin –safe epidural analgesia . Higher dose warfarin may require more intensive monitoring of the coagulation status Neuraxial catheters should be removed when the INR is <1.5. This value was derived from studies correlating hemostasis with clotting factor activity levels greater than 40%.

Warfarin Neurologic testing of sensory and motor function should be performed routinely during epidural analgesia for patients on warfarin therapy An INR > 3 should prompt the physician to withhold or reduce the warfarin dose in patients with indwelling neuraxial catheters

Anesthetic Management of the Patient Receiving Antiplatelet Medications Antiplatelet medications, including NSAIDs, thienopyridine derivatives (ticlopidine and clopidogrel) and platelet GP IIb/IIIa antagonists (abciximab, eptifibatide, tirofiban) exert diverse effects on platelet function There is no wholly accepted test, including the bleeding time, which will guide antiplatelet therapy History of easy bruisability/excessive bleeding, female gender, and increased age The actual risk of spinal hematoma with ticlopidine and clopidogrel and the GP IIb/IIIa antagonists is unknown Discontinuation of thienopyridine therapy and neuraxial blockade is 14 days for ticlopidine and 7 days for clopidogrel

Platelet GP IIb/IIIa inhibitors exert a profound effect on platelet aggregation Following administration, the time to normal platelet aggregation is 24-48 hours for abciximab and 4-8 hours for eptifibatide and tirofiban Neuraxial techniques should be avoided until platelet function has recovered. GP IIb/IIIa antagonists are contraindicated within four weeks of surgery Cyclooxygenase-2 inhibitors have minimal effect on platelet function and should be considered in patients who require anti-inflammatory therapy in the presence of anticoagulation

inhibiting platelet aggregation blocking coagulation factors New Anticoagulants (Direct Thrombin Inhibitors and Fondaparinux) New antithrombotic drugs which target various steps in the hemostatic system inhibiting platelet aggregation blocking coagulation factors enhancing fibrinolysis are continually under development. The most extensively studied are antagonists of specific platelet receptors and direct thrombin inhibitors Many agents have prolonged half-lives and are difficult to reverse without administration of blood components

Thrombin Inhibitors Recombinant hirudin derivatives, including desirudin, lepirudin, and bivalirudin inhibit both free and clot-bound thrombin. Argatroban, an L-arginine derivative, has a similar mechanism of action Due to the lack of information available, no statement regarding risk assessment and patient management can be made

Fondaparinux Antithrombotic effect through factor Xa inhibition. The FDA released it with a black box warning similar to that of the LMWHs The actual risk of spinal hematoma with fondaparinux is unknown Close monitoring of the surgical literature Until further clinical experience is available, performance of neuraxial techniques should occur under conditions utilized in clinical trials (single needle pass, atraumatic needle placement, avoidance of indwelling neuraxial catheters) If this is not feasible, an alternate method of prophylaxis should be considered

NSAID NSAIDs appear to represent no added significant risk At this time, there do not seem to be specific concerns as to the timing of single-shot or catheter techniques in relationship to the dosing of NSAIDs, postoperative monitoring, or the timing of neuraxial catheter removal.

WHY THE CONCERNS……. TRYBA ETAL, INCIDENCE OF OF SPINAL HEMATOMA IS LESS THAN 1 IN 1,50000 FOR EPIDURALS; 1 IN 220000 FOR SPINAL ANESTHETICS VANDER MUELLEN ETAL,ANESTH ANALG 1994;79;1165-77 REVIEW OF LITERATURE BETWEEN 1906 AND 1994 REVEALED 42 SPINAL HEMATOMAS ASSOCIATED WITH NEURAXIAL BLOCKADE AMERICAN HEART ASSOCIATION TASK FORCE ON MANAGEMENT OF PATIENTS WITH MI RECOMMENDS ASPIRIN/CLOPIDOGREL UNFRACTIONATED HEPARIN/LMWH GP IIb-IIIa ANTAGONIST

SIXTH AMERICAN COLLEGE OF CHEST PHYSICIANS CONSENSUS CONFERENCE

CASE 1 80 YR OLD FEMALE POSTED FOR ELECTIVE TOTAL KNEE ARTHROPLASTY.PAST H/O AF, CCF AND HEMORRHAGIC GASTRITIS FOLLOWING ASPIRIN INGESTION. CURRENTLY ON CLOPIDOGREL,FRUSEMIDE, VERAPAMIL, AND LANZOPERAZOLE COAGULATION SCREEN NORMAL. DALTEPARIN SC GIVEN 10 HRS BEFORE THE ELECTIVE SURGERY TO PREVENT DVT. CONCERNS???????

LACK OF MONITORING DEVICE FOR ANTI X a ACTIVITY PROLONGED HALF LIFE IRREVERSIBILITY WITH PROTAMINE PROLONGED IN RENAL FAILURE REVIEW OF LITERATURE 40 CASES OF SPINAL HEMATOMA REPORTED IN U.S.A AFTER 5YRS OF USE OF LMWH 13 CASES OF SPINAL HEMATOMA REPORTED IN EUROPE AFTER 10 YRS OF USE OF LMWH

WHY THIS DIFFERENCE???? IT WAS A OD DOSING IN EUROPE WITH FIRST DOSE BEING ADMINISTERED 12H PREOPERATIVELY. IN U.S IT WAS A BD DOSING REGIME WITH FIRST DOSE ADMINISTERED IN IMMEDIATE POST OPERATIVE PERIOD. FDA ISSUED WARNINGS………. FIRST CONSENSUS CONFERENCE IN 1998 RADICULAR PAIN WAS NOT THE PRESENTING SYMPTOM MORE THAN HALF OF PATIENTS DEVELOPED NEURO DEFICIT 12H AFTER CATHETER REMOVAL MEDIAN TIME BETWEEN LMWH THERAPY AND NEURO DYSFUNCTION WAS 3 DAYS TIME FROM ONSET OF SYMPTOMS TO LAMINECTOMY WAS >24HRS LESS THAN 1/3 PATIENTS REPORTED FAIR RECOVERY

DOSING VARIABLES ASSOCIATED WITH SPINAL HEMATOMA PATIENT FACTORS FEMALE GENDER INCREASED AGE ANESTHETIC FACTORS TRAUMATIC NEEDLE/CATHETER PLACEMENT EPIDURALTECHNIQUE INDWELLING CATHETER DURING LMWH ADMINISTRATION LMWH DOSING FACTORS IMMEDIATE PREOPERTIVE LMWH ADMINISTRATION EARLY POSTOPERATIVE LMWH ADMINISRATION CONCOMITANT ANTIPLATELET ADMINISTRATION BD LMWH ADMINISTRATION

CURRENT GUIDELINES TIME INTERVALS BETWEEN NEURAXIAL NEEDLE PLACEMENT AND LMWH ADMINISTRATION SHOULD BE MAINTAINED. ASK NURSING STAFF TO ADMINISTER LMWH AT A SPECIFIC TIME. OD DOSING PREFERRED TO BD REGIME. ANTI Xa MONITORING NOT MANDATORY; IT DOES NOT PREDICT THE RISK OF BLEEDING. PRESENCE OF BLOOD DURING NEEDLE AND CATHETER PLACEMENT DOES NOT NECISSATE POSTPONEMENT. BUT INITIATION OF LMWH SHOULD BE DELAYED FOR 24 HRS POSTOPERATIVE.

10 HRS LATER THE PATIENT WAS GIVEN A CSE. EPIDURAL CATHETER CONTINUED FOR POSTOPERATIVE ANALGESIA PATIENT C/O PAIN OVER THE OPERATIVE SITE AND HER BACK FOLLOWING WHICH THE INFUSION RATE WAS INCREASED. THROMBOPROPHYLAXIS RESUMED- OD REGIME PHYSIOTHERAPIST NOTED NUMBNESS IN THE NON OPERATED LEG THE NEXT DAY WHICH SHE ATTRIBUTED TO THE EPIDURAL. 3RD POD THE EPIDURAL CATHETER WAS REMOVED, 12 HRS AFTER DALTEPARIN 5 HRS AFTER REMOVAL, THE NUMBNESS WAS PRESENT WITH MILD MOTOR WEAKNESS, ATTRIBUTED TO RESIDUAL EPIDURAL BLOCK. NEURO OPINION SOUGHT 48 HRS LATER AND A MRI OF SPINE WAS DONE.

CASE 2 55 yr old gentleman, h/o unstable angina, currently admitted to the coronary care unit. he is started on aspirin, atenelol,ntg and heparin iv. bypass grafting is planned and patient is interested in postoperative epidural pain relief Concerns?????? Preoperative heparin Intraoperative heparin Postoperative heparin

PREOPERATIVE HEPARIN SC low dose heparin 5000 u sc q 12 h for prevention of DVT No detectable changes in a pTT 9 published series over 9000 patients have had no complications Three surveys of opinions of anesthesiologists in UK, Denmark and Newzealand appear to feel that SC heparin should not be a contraindication for neuraxial blockade Heparin to be delayed till 2 hrs after blockade Heparin > 4 days platelet count to be assessed prior to neuraxial block or catheter removal

PREOPERATIVE IV HEPARIN Ideally neuraxial block 1-2 hrs before iv heparin. In the presence of traumatic attempt- incidence of spinal hematoma is 50 %. Cancellation of the surgery????? Risk of spinal hematoma Ho etal, chest;2000,117, 551-55 Complex mathematical analysis for the probability of spinal hematoma– 1:1528 for epidural;1:3610 for spinal The authors hypothesised that this is an acceptable risk compared mortality of post op myocardial infarction

INTRAOPERATIVE AND POSTOPERATIVE HEPARIN HEPARIN TO BE AVOIDED FOR 1 HR AFTER NEEDLE PLACEMENT CATHETERS REMOVED 2-4 HRS AFTER LAST HEPARIN; PATIENTS COAGULATION STATUS EVALUATED,RE HEPARINISATION STARTED 1 HR LATER MONITOR PATIENT POSTOPERATIVELY FOR MOTOR BLOCK BLOODY TAP- DISCUSS WITH SURGEON THE RISK BENEFIT ANALYSIS.

CASE 3 60 yr old lady with parkinsonism, dementia and AF, posted for THR. She is currently on warfarin, anti parkinsonian drugs. INR was 2.1. Given vit K injection. INR dropped to 1.7. Concerns???? Warfarin inhibits vit K dependent factors. But the effects of warfarin not apparent until a significant amount of biologically inactive factors are present. Dependent on factor half life…….

WHAT IT MEANS…………….. 40% activity of Factor II, VII, IX, X is adequate for normal hemostasis INR AND PTT are most sensitive to changes in FAC X AND VII , its relative insensitive to FAC II activity. INR = 1.2 When FAC VII ACTIVITY IS 55%; INR =1.5 When FAC VII ACTIVITY IS 40%. Other problems with warfarin Narrow therapeutic range Enhanced response in old age, females, pre existing medical conditions[low wt, renal, cardiac, liver disease]

GUIDELINES On discontinuation of warfarin, Factor VII activity will rapidly rise, so inr will decrease. Factor II AND X activities recover much more slowly; so hemostasis may not be adequate till then In emergency- inject VIT K, USE FFP Warfarin ideally stopped 4-5 days prior PTT/INR Done Prior To Block For those where warfarin is started for DVT,[low dose 5 mg] DO INR / PT IF a] DOSE GIVEN 24 HRS PRIOR B] MORE THAN 1 DOSE GIVEN C] EPIDURAL CATHETER IN SITU

CONTD….. REMOVE CATHETER ONCE INR <1.5 NEURO TESING FOR SENSORY AND MOTOR FUNCTION AFTER REMOVAL OF CATHETER. INR>3 , WITHHOLD WARFARIN IF THERE IS AN INDWELLING CATHETER.

CASE 4 58 YR OLD MAN WITH H/O MULTIPLE TIAs, HYPERTENSION, POSTED FOR LAPAROTOMY. HE IS ON ATENELOL, ASPIRIN AND CLOPIDOGREL CONCERNS??????

ANTIPLATELET MEDICATIONS Aspirin in low doses [60-325 mg/day] inhibits platelet COX In higher doses 1.5 to2 g/day inhibits prostacyclin production[platelet aggregation inhibitor] Other NSAIDs- (Naproxen, Piroxicam, Ibuprofen) have antiplatelet activity , which normalises in 3 days. Thienopyridine derivatives- clopidogrel and ticlopidine which inhibit ADP induced platelet aggregation. Platelet GPIIB-IIIA receptor antagonists- Abciximab, Eptifibatide,tirofiban.

HOW TO MANAGE…….. No wholly accepted test which will guide antiplatelet therapy. Thromboelastogram has been proposed to monitor clopidogrel therapy NSAIDS add no significant risk for spinal hematoma. So use of NSAIDs alone is not a risk for contraindication for neuraxial block. For thienopyridines Stop clopidogrel 7 days prior; ticlopidine 14 days prior GPIIB-IIIA RECEPTOR BLOCKERS Time for normal platelet aggregation after a single dose- 24 –48 hrs after abciximab; 4-8 hrs after eptifibatide and tirofiban

PLEXUS AND PERIPHERAL BLOCKS All cases of major bleeding after non neuraxial techniques occurred after psoas compartment or lumbar sympathetic block Case reports in literature with heparin, LMWH, thienopyridine derivatives Most have them had huge retroperitoneal hematomas , with blood loss as great as 3 litre So significant blood loss rather than neural deficits are the major complications with drop in Hb, and hypotension. Treated with blood transfusion and conservative mangaement

I THOT A THOT, BUT THE THOT I THOT WAS NEVER THE THOT I EVER THOT I THOT A THOT, BUT THE THOT I THOT WAS NEVER THE THOT I EVER THOT. SO I NEVER THOT THE THOT I THOT!!!!!

SUMMARY

Summary Consensus statements represent the collective experience of recognized experts in the field of neuraxial anesthesia and anticoagulation They are based on case reports, clinical series, pharmacology, hematology, and risk factors for surgical bleeding An understanding of the complexity of this issue is essential to patient management; a "cookbook" approach is not appropriate. Timing of catheter removal in a patient receiving antithrombotic therapy should be made on an individual basis Weighing the small, though definite risk of spinal hematoma with the benefits of regional anesthesia for a specific patient

Coagulation status should be optimized at the time of spinal or epidural needle/catheter placement, and the level of anticoagulation must be carefully monitored during the period of epidural catheterization Indwelling catheters should not be removed in the presence of therapeutic anticoagulation, as this appears to significantly increase the risk of spinal hematoma. Identification of risk factors and establishment of guidelines will not completely eliminate the complication of spinal hematoma. Vigilance in monitoring is critical

There are two ways of meeting the difficulties You alter the difficulties You alter yourself to meet the difficulty

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