Deep Vein Thrombosis Prophylaxis With Heparin and Heparin-Like Drugs Used in Combination With Neuraxial Anesthesia and Deep Plexus Blocks


INTRODUCTION

Early recovery after surgery (ERAS) and the current opioid pandemic have made health care providers and patients consider regional anesthesia (RA) options, including neuraxial anesthesia and nerve/nerve plexus blocks, as alternatives to traditional opioids. RA has been shown to be associated with additional benefits of lower volume of blood loss and transfusion rate, decreased perioperative infections such as pneumonia, and decreased length of stay. In the meantime, continuously evolving standards for the prevention of perioperative venous thromboembolism (VTE) in conjunction with the introduction of new antithrombotic medications (e.g., fondaparinux, rivaroxaban) and an increase in the dosage or frequency of existing medications (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH]) have resulted in concerns regarding the potentially heightened risk for neuraxial bleeding.

Neuraxial hematoma is a rare and catastrophic complication associated with both epidural and spinal anesthesia. The incidence of symptomatic hematoma has been estimated to be less than 1 per 220,000 for spinal anesthesia and less than 1 per 150,000 for epidural anesthesia in the population, with a much lower rate in labor epidural (1: 200,000) and a much higher rate in elderly females undergoing total knee arthroplasty (TKA; 1: 3600). Risk factors for bleeding associated with spinal epidural anesthesia have been identified in retrospective studies and include thrombocytopenia, hepatic dysfunction, renal insufficiency, the use of anticoagulants or antiplatelet agents, difficult needle placement, multiple punctures, anatomic abnormalities such as spina bifida occulta and vascularized tumor, the use of epidural anesthesia rather than spinal anesthesia, and catheter removal.

Spontaneous spinal epidural hematoma is a rare condition with an estimated incidence of 0.1 per 100,000 patients per year. A meta-analysis of 613 cases of all neuraxial hematomas indicated that about one-third of the cases belonged to this idiopathic spontaneous hemorrhage group, forming the largest group of patients who developed spinal/epidural hematomas. The second-largest group included patients on anticoagulation therapy (17%) without neuraxial blocks. Neuraxial anesthesia placed in patients with anticoagulation therapy was actually the fifth most common cause, and spinal and epidural procedures alone without anticoagulation were the tenth most common etiologic factor. This result is confirmed by a recent study of 83,71l lumbar puncture patients; the rate of 30-day spinal hematoma was 0.2% in patients without coagulopathy and 0.23% with coagulopathy. When making clinical decisions, bear in mind that the published estimations are from retrospective studies and/or self-reported with inherent limitations.

Symptoms of spinal hematoma are often occult, making diagnosis challenging; presenting symptoms could include lower extremity weakness (46%), radicular back pain (38%), paresthesia (14%), and occasionally stroke-like hemiparesis, myocardial infarction, and atypical abdominal pain. The diagnosis may be complicated or even delayed because of residual paresthesia or anesthesia produced by the neuraxial anesthesia or deep plexus block. There is likely a temporal relationship between the onset of paraplegia, surgical evacuation of hematoma, and recovery, even though the exact treatment for a neuraxial hematoma remains controversial. Short-acting and motor block–sparing local anesthetic agents are therefore recommended to be used in neuraxial and deep plexus blocks, especially in high-risk patients, to facilitate frequent neurologic monitoring and early detection of bleeding should it occur.

Increased emphasis has been placed on perioperative VTE prophylaxis because of the catastrophic outcome of VTE in moderate- to high-risk surgeries. Although for certain procedures, such as major neurosurgery, transurethral resection of the prostate, or radical prostatectomy, it is recommended against pharmacologic prophylaxis, for major trauma surgery or major gynecologic surgery, the American Society of Hematology (ASH) 2019 guideline suggests pharmacologic prophylaxis over no prophylaxis. For major general surgery, ASH suggests pharmacologic prophylaxis over no prophylaxis, using LMWH or UFH. For patients undergoing major orthopedic procedures such as total hip arthroplasty (THA) or TKA, even though there are variations on preferred pharmacologic agents, it is universally accepted that mechanical prophylaxis alone is not sufficient unless chemoprophylaxis is contraindicated according to the American Academy of Orthopedic Surgeons (AAOS) guideline ( www.aaos.org/research/guidelines/VTE/VTE_full_guideline.pdf ).

ASH has conditionally recommended using either aspirin or anticoagulants for VTE perioperative prophylaxis, and it recommends a direct oral anticoagulant over LMWH, whereas the American College of Chest Physicians (ACCP) has chosen LMWH over other oral agents such as fondaparinux, dabigatran, apixaban, or rivaroxaban. For nonorthopedic and noncancer procedures with moderate to high VTE risk, the ACCP recommends UFH or LMWH, whereas for patients undergoing abdominal or pelvic surgery because of cancer with a high risk for VTE, the ACCP recommends LMWH for the extended duration of 4 weeks.

Societies and organizations historically have issued conflicting recommendations regarding RA bleeding in the context of perioperative VTE prophylaxis or treatment, but the fourth edition of American Society of Regional Anesthesia and Pain Medicine (ASRA) anticoagulation guideline changed that by working in conjunction with the European Society of Anaesthesiology (ESA), incorporating information from the National Partnership for Maternal Safety (NPMS) and Society for Obstetric Anesthesia and Perinatology (SOAP), and using US Food and Drug Administration (FDA)-approved labeling. This offered practitioners a more unified set of recommendations across governing agencies and across broader geographic locations. As the ASRA 2018 guideline states well, these guidelines have the intention to foster safety and quality care but cannot guarantee outcomes because spinal epidural hematoma can still occur even if the guidelines are followed and there are no additional identifiable risk factors. The ASRA guideline further highlights the importance of daily chart review of medications changes and routine and repeated monitoring of anticoagulation status because concurrent use of other hemostasis-altering medications such as antiplatelets have been associated with a higher risk for bleeding. In addition, in the cases of new anticoagulants where insufficient clinical data are available, some recommendations are often pharmacologically based. Recommended time intervals between discontinuation of an anticoagulant at therapeutic dosage and subsequent neuraxial block are often 5 half-lives (adjust with renal function), with about 3% residual anticoagulation effect. With lower levels of anticoagulation effects associated with prophylactic dosage, only a 2-half-life interval may be sufficient. The time to start or restart the next dose of VTE is calculated as 8 hours, which is the time that it takes for a stable platelet plug to form, minus the time it takes for the anticoagulant to reach peak effect.

In this chapter we present a synopsis of the use of neuraxial anesthesia and deep plexus block techniques in patients receiving heparin and heparin-like drugs (UFH, LMWH, fondaparinux, and rivaroxaban) in the perioperative setting under VTE prophylaxis or treatment. The use of direct thrombin inhibitors, vitamin K antagonists, platelet inhibitors, and other hemostasis-altering medications is discussed elsewhere either in this or earlier editions of this text.

Unfractionated Heparin

Options/Therapies

As an integral part of hemostasis, the intrinsic and extrinsic coagulation systems converge at Factor X to form the final common pathway, which is ultimately responsible for the production of thrombin (Factor IIa), which converts fibrinogen to fibrin. It is at the level of the conversion of Factor X to Xa that heparin and heparin-related drugs (LMWH, fondaparinux, and rivaroxaban) interrupt the coagulation cascade. The mechanism of action of both UFH and LMWH works through enhancement of antithrombin III (ATIII) activity, an important endogenous inhibitor of coagulation that acts primarily by inactivating Factor IIa and Factor Xa.

UFH is a negatively charged, water-soluble glycosamine with a variable molecular weight of about 15,000 daltons (range of 5000–30,000 daltons). The anticoagulant effect of UFH is typically monitored with the aPTT. Anti–factor Xa testing offers improvements over aPTT testing for a smoother dose-response curve and accurate measurement of heparin levels compared with aPTT. The activated clotting time (ACT) is typically used to monitor higher doses of UFH given during cardiopulmonary bypass. Adequate therapeutic effect is typically achieved with a prolongation of the aPTT to between 1.5 and 2.5 times the baseline value, heparin level of 0.2 to 0.4 U/mL, or anti–factor Xa level of 0.3 to 0.7 U/mL. ,

One of the advantages of UFH anticoagulation is that its effect may be rapidly reversed and serious bleeding controlled with equimolar doses of protamine, a positively charged protein derived from salmon sperm. Each milligram of protamine can neutralize 100 U of UFH. Both UFH and LMWH are derived from animal sources. This explains the uncommon but serious occurrence of heparin-induced thrombocytopenia and thrombosis (HITT). The HITT syndrome is an IgG-mediated significant decrease in platelet counts that usually occurs 4 to 5 days after initiating heparin therapy, which may be complicated by pathologic thrombosis and bleeding. Therefore it is routinely recommended to monitor platelet counts after UFH use for 4 days.

Evidence

Low-dose subcutaneous UFH.

Low-dose subcutaneous UFH (<15,000 U/day) is commonly used for prophylaxis against development of VTE; a large amount of data suggest it is both safe and efficacious. Administration of 5000 U of UFH subcutaneously twice daily (BID) has been used extensively and effectively for VTE prophylaxis in patients undergoing lower extremity orthopedic procedures and general, urologic, and gynecologic operations with a neuraxial block with very little risk for hematoma. Recently there is a shift toward 5000 U thrice daily (TID). Instead of suggesting avoiding epidural anesthesia in patients with a subcutaneous dose of more than 10,000 U daily, as in the ASRA 2010 guideline, the 2018 guideline allows for UFH 5000 U TID during neuraxial and deep plexus single injection and continuous catheter placement because for both dosing regimens, there is little risk for spinal epidural hematoma. On the other hand, the ASRA 2018 guideline did suggest that the timing of needle placement and catheter removal occur at the lowest level of anticoagulant activity, 4 to 6 hours after the last dose. These recommendations are based on the intention to minimize residual anticoagulation effects at the time of procedure and not because of an increase in neuraxial hematomas. The pharmacology of subcutaneous 5000-U dose of UFH results in an anticoagulant effect 1 hour after administration that persists for 4 to 6 hours. , In addition, there is no need for testing before procedures in the majority of the patients because this low dose of UFH does not induce any measurable changes in the value of aPTT, anti–factor Xa level, or serum UFH level. With a minority of patients (up to 15%) that may exhibit aPTT elevations, the values are rarely more than 1.5 times the normal level and normalize within 4 to 6 hours after administration, the time interval recommended for neuraxial and deep plexus procedures.

High-dose subcutaneous UFH.

Higher-dose subcutaneous UFH (single dose >5000 U or total daily dose >15,000 U) are typically used on obstetric patients. Based on pharmacokinetic and pharmacodynamic variations among patients, subcutaneously administered heparin at a single dose greater than 5000 U or daily dose greater than 15,000 U will increase the intensity and duration of the anticoagulant effect disproportionally in a nonlinear pattern. Because at this dose the anticoagulation effects behave in a less predictable pattern than lower-dose heparin, it is recommended to assess coagulation status after an interval of 12 hours (single dose 7500–10,000 or daily dose 15,000–20,000 U) or 24 hours (single dose >10,000 U or daily dose >20,000 U).

Intravenous UFH.

Intraoperative heparinization typically involves the injection of 5000 to 10,000 U of UFH intravenously every several hours during the operative period, particularly in the setting of vascular surgery to minimize thrombosis during cross-clamping of the artery or instrumentation within the artery. Neuraxial anesthetic techniques are often desirable for these patients because of severe and multiple comorbidities but may also be associated with an increased risk for spinal epidural hematoma. , , Maintaining a minimum 1-hour interval between needle placement and subsequent heparinization, and avoiding other hemostasis-altering medications such as antiplatelet agents, decreases the risk for significant bleeding. Management of a traumatic neuraxial procedure or bloody tap are still controversial in terms of whether or not the case should be canceled, even though the presence of a bloody tap or a traumatic neuraxial block is associated with nearly 50% of all spinal epidural hematoma events. Direct communication and discussion with the surgical team on the risks and benefits of proceeding versus canceling each case are therefore of utmost important. Some centers chose to place the epidural catheter the day before the surgery to avoid this dilemma. The removal of a neuraxial catheter in the presence of heparin therapy is another important risk factor for hematoma to the point that heparin should be discontinued for 2 to 4 hours, and the coagulation status should be assessed before any neuraxial catheter manipulation including removal.

Controversies/Areas of Uncertainty

It is still controversial if indwelling neuraxial catheters can be safely maintained in patients receiving postoperative higher-dose subcutaneous UFH (single dose >5000 U or daily total dose >15,000 U). The ASRA 2018 guideline suggested that the risk and benefits be assessed on an individual basis. In addition, it recommended techniques to facilitate neurologic exams and early detection of new/progressive neurologic changes, including increasing frequency of neurologic monitoring and using lower concentration and short-acting local anesthetics to minimize sensory and motor blockade.

Regarding neuraxial anesthesia under cardiopulmonary bypass, it remains controversial whether or not the perceived benefits, including better analgesia, improved pulmonary function, and less cardiac arrhythmia (but no reduction in hospital stay, myocardial infarction, or mortality), outweigh the risk. , The estimated risk for neuraxial hematoma is approximately 1:1528 for epidural anesthesia and 1:3610 for spinal anesthesia during cardiopulmonary bypass. If, after a thorough discussion with the surgical team on the risks and benefits, everyone agrees to proceed, the following have been recommended to minimize neuraxial hematoma 30 :

  • Neuraxial blocks should be avoided in a patient with known coagulopathy from any cause.

  • Surgery should be delayed 24 hours in the event of a traumatic tap.

  • Time from instrumentation to systemic heparinization should exceed 60 minutes.

  • Heparin effect and reversal should be tightly controlled (smallest amount of heparin for the shortest duration compatible with therapeutic objectives).

  • Epidural catheters should be removed when normal coagulation is restored, and patients should be closely monitored postoperatively for signs and symptoms of hematoma formation.

Guidelines

See Table 38.1 . The following are the ASRA 2018 guidelines on subcutaneous UFH:

  • Preoperatively in patients receiving subcutaneous thromboprophylactic low-dose UFH at regimens of 5000 U BID or TID, neuraxial block may occur 4 to 6 hours after.

  • Preoperatively in patients receiving subcutaneous thromboprophylactic higher-dose UFH at regimens of 7500 to 10,000 U BID or a daily dose of up to 20,000 U, neuraxial block may occur 12 hours after and with assessment of coagulation status.

  • Preoperatively in patients receiving a subcutaneous therapeutic dose of UFH at regimens of individual dose greater than 10,000 U or daily dose greater than 20,000 U, neuraxial block may occur 24 hours after and with assessment of coagulation status.

  • Postoperatively for low-dose subcutaneous thromboprophylactic UFH, there is no contraindication to maintaining indwelling neuraxial catheters. Catheter removal should occur 4 to 6 hours after heparin administration. Subsequent heparin administration may occur 1 hour after catheter removal.

TABLE 38.1
Use of Heparin and Heparin-Like Drugs With Neuraxial Anesthesia and Deep Plexus Blocks
Drug 2018 Regional ASRA Guidelines
When to discontinue When to restart
Intravenous heparin 4–6 hours before to needle placement and catheter removal (normal aPTT documented) 1 hour after nontraumatic needle placement and catheter removal
Subcutaneous heparin 5,000 U
twice a day
4–6 hours Immediately
Subcutaneous heparin 5,000 U three times a day
Subcutaneous heparin 7500–10,000 U twice a day
(< 20,000 U/day)
12 hours NA
Subcutaneous heparin >10,000 U/ dose or >20,000 U/day 24 hours NA
LMWH Prophylactic dosing

  • Enoxaparin 30 mg twice a day

  • Enoxaparin 40 mg daily

  • Deltaparin 5000 units daily

12 hours before needle placement or catheter removal Single daily dosing
First dose 12 hours after needle placement
Second dose 24 hours after the first dose
At least 4 hours after catheter removal
Twice daily dosing
Not recommended with catheter in place
At least 12 hours after needle/catheter placement
4 hours after catheter removal
LMWH Therapeutic dosing

  • Enoxaparin 1.5 mg/kg daily or 1 mg/kg twice a day

  • Dalteparin 120 units twice a day or 200 units daily

  • Tinzaparin 175 U/kg daily

24 hours Epidural catheter contraindicated
4 hours after catheter removal and at least 24 hours after needle placement
24 hours after a low-risk bleeding procedure
48–72 hours after a high-risk bleeding procedure
Rivaroxaban 3 days before puncture, catheter manipulation, or removal 6 hours after puncture, catheter manipulation, or removal
If given with catheter in place, wait 22–26 hours until catheter removal
Apixaban 3 days before puncture, catheter manipulation, or removal 6 hours after puncture, catheter manipulation, or removal
If given with catheter in place, wait 26–30 hours until catheter removal
Edoxaban 3 days before puncture, catheter manipulation, or removal 6 hours after puncture, catheter manipulation, or removal
If given with catheter in place, wait 22–28 hours until catheter removal
Betrixaban 3 days before puncture, catheter manipulation, or removal 5 hours after puncture, catheter manipulation, or removal
Contraindicated if Cr Cl< 30 mL/min If given with catheter in place, wait 72 hours until catheter removal
aPTT , Activated partial thromboplastin time; ASRA , American Society of Regional Anesthesia and Pain Medicine; CrCl , creatine clearance; INR , international normalized ratio; LMWH , low-molecular-weight heparin; NA , not available.

The following are the 2018 guidelines on intravenous UFH:

  • Discontinue heparin infusion 4 to 6 hours and verify normal coagulation status before neuraxial blockade or manipulation of neuraxial catheter.

  • Avoid neuraxial techniques in patients with other coagulopathies.

  • Delay heparin administration for 1 hour after needle placement or catheter manipulation, including removal.

  • Monitor the patient at regular intervals postoperatively and consider using the minimal concentration of local anesthetics to enhance the early detection of a spinal hematoma.

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