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Anticoagulation and regional anesthesia in cardiac surgery: safety considerations
Techniques in Regional Anesthesia and Pain Management (2008) 12, 17-25
Anticoagulation and regional anesthesia in cardiac surgery: safety considerations James E. Baker, MD, FRCPC,a C. David Mazer, MD, FRCPCa,b,c a
From the Department of Anesthesia, University of Toronto, St. Michael’s Hospital, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, St. Michael’s Hospital, Toronto, Ontario, Canada; and c Interdepartmental Division of Critical Care, University of Toronto, from the Keenan Research Centre in the Li KaShing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada. b
KEYWORDS: Thoracic epidural anesthesia; Cardiac surgery; Postoperative complications; Epidural hematoma; Anticoagulation; Antiplatelet therapy
This review focuses on the impact of anticoagulation treatment on the use of neuraxial anesthetic techniques in cardiac surgery. After a short risk evaluation, the effects of different agents are discussed: heparin, low molecular weight heparin, antiplatelet and oral anticoagulation agents, thrombolytic drugs, and newer antihemostatic agents all have an impact on the use of neuraxial techniques in cardiac surgery. A detailed understanding of their mode and timing of action is important to safely practice regional techniques in cardiac surgery. Adherence to published guidelines will help to minimize the risk from the procedure and/or any coexisting antihemostatic therapies. The review gives several recommendations on if, how, and when to use neuraxial techniques when anticoagulative agents are involved. © 2008 Elsevier Inc. All rights reserved.
The notion that regional anesthetic techniques could impart positive effects on patient outcome has enjoyed tremendous allure and has engendered an industrious field of investigation.1 In the realm of noncardiac surgery, many beneficial effects of central neuraxial blockade have been postulated, and some of these appear, at least for now, to have been confirmed.2-4 What underlies the applicability of these findings is the belief that spinal and epidural anesthesia is safe, and that the risk of performing these procedures is outweighed by their capacity to improve outcome, or even simply to improve comfort. For cardiac surgery, the risk– benefit ratio has been harder to assess.5 The proposed benefits of epidural anesthesia and analgesia include not only improved postoperative analgesia (with attendant reduction of sympathetic activation and stress hormone release), but also decreased myocardial ischemia, reduced cardiac arrhythmia, improved ventricular function, increased hemodynamic stability, improved pulmonary function, extubation and ambulation, shorter ICU stay, and reducAddress reprint requests and correspondence: C. David Mazer, MD, FRCPC, Departments of Anesthesia and Critical Care, St. Michael’s Hospital, 30 Bond Street, Toronto, ON, Canada M5B 1W8. E-mail address: [email protected].
1084-208X/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2007.10.003
tion in overall cost.6-8 On the other hand, it has been difficult to assess the relevance of existing risk estimates—principally pertaining to the rare complication of epidural hematoma and permanent paralysis—since they have largely been derived from noncardiac surgical experience.9,10 Cardiac surgery differs from other settings because of the need for systemic heparin administration using doses sufficient to prevent clot formation during cardiopulmonary bypass. Further, these patients may present for surgery taking one or more of many possible types of antihemostatic medication. With ongoing publication of patient series and case reports, the global collective experience with regional anesthesia for cardiac surgery is increasing and beginning to allow meaningful assessments of risk. Further, reporting of complications, although rare, has allowed for analysis of factors that may contribute to risk and, more importantly, to safety.
Neuraxial anesthesia and anticoagulation: defining the risk Before April 2004, several authors had commented that no report yet existed of neurologic complications pertaining to
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the use of epidural catheter placement for cardiac surgery.7,11,12 However, the literature now contains its first reports of epidural hematoma, with neurologic injury, in cardiac surgery patients.13,14 For some, this has galvanized the conviction that Thoracic Epidural Anesthesia (TEA) presents unacceptable risk for any cardiac surgical patients,5 whereas for others, the potential benefits of the technique are not precluded by the magnitude of risk implied by these recent reports.8 While the benefits continue to be debated, an interesting body of work has emerged that has synthesized, from available literature, an approximation of the risk of neuraxial anesthesia and analgesia for cardiac surgery. With important and fallible assumptions borne in mind, Ho and coworkers calculated the maximum risk, with 95% confidence, of spinal hematoma based on the aggregate of published case series as of the year 1999.7 At that time, 4583 cardiac surgical patients undergoing epidural anesthesia or analgesia had been reported by various authors with a zero incidence of spinal hematoma. The mathematical technique can be used to estimate in the setting of zero complications over a given number of observations. The maximum risk for an event that has not yet occurred can be approximated by 3/n (at the upper end of the 95% confidence interval), where n is number of observations.15 Ho and coworkers thereby estimated the maximum risk of spinal hematoma, following epidural anesthesia or analgesia for cardiac surgery, to be 3:4583, ie, 1:1528. The authors suggest, plausibly, that the minimum risk should not reasonably be assumed to be any lower than what has already been described for the uncomplicated noncardiac surgical population. This risk has been estimated9,10 to be approximately 1:150,000 for epidural blockade and 1:220,000 for spinal blockade. Similarly, the maximum risk of spinal hematoma following subarachnoid anesthesia was estimated to be 1:3160, based on the finding of zero reports over 10,840 reported cardiac surgical patients. However, the precision of these estimates could be affected by the possibility that one or more spinal hematoma may have occurred without being reported, and also by the difficulty in estimating the true number of cases performed worldwide (ie, the true denominator), which was likely well in excess of the 4583 reported patients. Ruppen and coworkers performed a similar analysis with the intention of improving its validity by including only studies reporting specifically on the presence or absence of spinal hematoma, as opposed to including studies that simply failed to report its occurrence.16 This publication also benefited from the additional reports published between 1999 and 2005. In all, 4971 cardiac surgical patients were included (again with a zero incidence of spinal hematoma), suggesting a risk of 1:1700, at the maximum of the 95% confidence interval. Only patients receiving epidural catheters were studied, and not patients undergoing subarachnoid techniques. The authors also included the same patients in a broader cohort of cardiac, vascular, and thoracic surgery patients, the majority of whom received some form of heparin perioperatively. Zero complications observed over
14,105 patients suggested an estimated maximum risk of 1:4700. In a 2007 meta-analysis, Bracco and Hemmerling identified 12,000 patients from published series of cardiac surgery using combined general– epidural anesthesia.17 Unlike the analyses discussed previously, the authors assumed a numerator of one, and not zero, comprised of the sole extant case report of a spinal hematoma plausibly linked to heparin administration during cardiac surgery.14 The authors did not include a patient who developed a spinal hematoma following epidural catheter placement on the preoperative day for planned (ie, cancelled) cardiac surgery, since it was not related to intraoperative heparin administration.18 Further, they did not include a published report of a hematoma that was more plausibly linked to postoperative thrombolytic therapy.13 Based on an observed incidence of 1:12,000 patients, they estimated the risk to be between 1:2100 and 1:68,000, using a 95% confidence interval. As noted by Royse and coworkers,19 the estimation of risk will undergo refinement and improvement as new case series continue to appear, adding to the world literature. Some aspects of the case report by Rosen13 merit discussion. An 18-year-old man underwent placement of an epidural catheter immediately following induction of general anesthesia for aortic valve replacement. The patient was observed to ambulate normally on the first postoperative day without evidence of back pain or neurologic deficit. Systemic heparin therapy (4500 U bolus followed by continuous infusion) was initiated on the second postoperative day for thromboprophylaxis of the valve prosthesis. Five hours later, an occluded peripheral intravenous cannula was flushed with 2 mg alteplase (recombinant tissue plasminogen activator). Severe back pain ensued within 2 hours of this event, and blood was observed both within the epidural catheter as well as at the insertion site. The catheter was removed by critical care staff at this time, and simultaneous blood sampling demonstrated an activated partial thromboplastin time (PPT) of 87 seconds. Neurologic deficit developed shortly thereafter, and subsequent magnetic resonance imaging confirmed the presence of an epidural hematoma at the insertion site of the epidural catheter (T9 –T10). Importantly, blood work in preparation for emergency surgery demonstrated a platelet count of 76,000. Decompressive laminectomy was commenced 5 hours following the onset of neurologic symptoms, and full neurologic recovery ensued over a 6-week period. It is compelling to conjecture that the epidural hematoma might have been avoided in this instance with adherence to a small number of published precautions (see Table 1). Although specific timeframes are not given in the American Society of Regional Anesthesia and Pain Medicine (ASRA) guidelines for the avoidance of thrombolytic drugs in relation to epidural catheter placement (or removal),11 such therapy may have been premature on the second day after catheter placement and, moreover, ought certainly to have prompted a different timing of catheter removal. Although the initiation of intravenous heparin therapy in this patient
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Table 1 Summary of recommendations for patients undergoing central neuraxial blockade in the setting of recent or planned anti-coagulant therapy* Anti-hemostatic agent
Recommended precautions
Intravenous heparin
Anti-platelet agents
Subcutaneous (sc) heparin thromboprophylaxis
Low molecular weight heparin
Oral anti-coagulation (eg, coumadin)
Comments
Discontinue IV heparin infusion 2-4 hours prior to neuraxial procedure or catheter removal; confirm normal coagulation profile (PTT, PT) Delay heparin administration for ⬎60 minutes after neuraxial technique. Monitor spinal cord function for 12 hours following catheter removal. Ensure no other anti-hemostatic agents active. Aspirin and NSAIDs: Consider discontinuation when intra-operative heparin planned (aspirin 7 days; other NSAIDs, 2-3 days). Thienopyridine derivatives: discontinue clopidogrel 7 days, ticlopidine 14 days. GP IIb/IIIa inhibitors: discontinue eptifibatide or tirofiban 8 hours, abciximab 24-48 hours. Confirm platelet count. No contra-indication to neuraxial block unless other class of antihemostatic agent or coagulopathy is present Bloodwork only helpful if prolonged (⬎4 days) therapy prior to blockade or catheter removal: confirm platelet count Remove catheter 1 hour prior to next dose. Delay block or catheter placement for 1012 hours following last dose (low-dose regimens) Delay block or catheter placement for 24 hours following last dose (high dose regimens). Remove catheter 2 hours prior to post-op implementation of twice-daily dose regimen; do not initiate LMWH until 24 hours post-op. Patient may be managed with catheter during post-op once-daily regimen. May initiate LMWH 6-8 hours post-op. Remove catheter 2 hours prior to next dose.
Discontinue 4-5 days prior to neuraxial block or catheter placement. Confirm normal PT/INR. Remove catheter prior to initiation of post-op coumadin (INR ⬍ 1.3), or with confirmation of INR ⬍ 1.5.
Catheter may be placed on evening prior to surgery (no evidence in support). If neuraxial technique is bloody or traumatic, consider delay of surgery (no evidence in support). Consider avoidance of paramedian approach (no evidence in support). Avoid anti-coagulation in excess of necessary targets (no evidence in support). Asprin and NSAIDs widely held not to preclude neuraxial block per se; however, known synergy with other anti-coagulants exists. Impact of subsequent heparin for cardiopulmonary bypass is uncertain.
Small percent of patients will have systemic anticoagulation effect with thromboprophylactic dose. Bloodwork not recommended but avoid neuraxial block or catheter removal 2 hours after SC heparin (peak effect). Consider delaying initiation of therapy until after surgery (no evidence in support). Highest risk is with twice daily dose regimens. No bloodwork is recommended to enhance safety (including factor Xa levels). Example of low-dose regimens: Dalteparin 5000 U SC daily; Enoxaparin 30 mg SC twice daily or 40 mg SC daily; Tinzaparin 75 U/kg SC daily; Danaparoid 750 U SC twice daily. Example of high dose regimens: Dalteparin 120 U/kg SC twice daily or 200 U/kg daily; Enoxaparin 1.0-1.5 mg/kg twice daily; Tinzaparin 175 U/kg SC daily Maximum risk may occur 2 hours after LMWH administration. Choice of epidural infusion that allows assessment of sensorimotor function is recommended when catheter remains in situ during LMWH therapy In non-cardiac settings, low-dose or adjusted-dose thromboprophylactic regimens may be used. Such regimens may safely be implemented preop provided block or catheter placement occurs ⬍24 hours later. Catheter removal should occur while INR ⬍ 1.5.
*Emphasis is placed on the cardiac surgical patient where applicable. Derived from the American Society of Regional Anesthesia and Pain Medicine consensus guidelines.11 Abbreviations: PT, prothrombin time; PTT, partial thromboplastin time; INR, international normalized ratio; NSAID, non-steroidal anti-inflammatory drug; GP IIb/IIIa, platelet glycoprotein receptor IIb/IIIa inhibitor; LMWH, low molecular weight heparin; SC, subcutaneous.
was consistent with ASRA guidelines, it has been suggested that the infusion be discontinued for 2 to 4 hours before removal, along with confirmation of a normal coagulation profile (this patient had a prolonged PTT and thrombocy-
topenia). Some authors advise against placing the epidural catheter immediately before surgery involving heparin6 (in favor of the preoperative evening), but this recommendation is without the support of case reports or known complica-
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Table 2 Relationship between timing of decompressive laminectomy for spinal hematoma after central neuraxial blockade and quality of neurologic recovery* Timing of surgery
Good Partial Poor Intra-operative recovery recovery recovery death
ⱕ8 hours 8-24 hours ⬎24 hours No surgery Not reported
6 1 2 1 2
4 2 0 1 4
3 4 10 8 4
0 0 0 3† 0
*Note that the chance for good or partial recovery was best for those patients receiving surgery within 8 hours, whereas poor recovery was frequent in those receiving surgery after 8 hours. † Unrecognized spinal hematoma discovered at autopsy. Modified from Vandermeulen et al.9
tions that confirm its value. The ASRA guidelines advise an interval of at least 1 hour between neuraxial intervention and the subsequent administration of systemic heparin (regardless of dose). It is very noteworthy that the authors in this case reported complete neurologic recovery by their patient, having commenced the decompressive laminectomy within 5 hours following onset of symptoms. In a series of 55 patients undergoing decompressive laminectomy for spinal hematoma following central nervous blockade, the chance for neurologic recovery was significantly improved in those for whom the surgery was performed within 8 hours9 (Table 2). A second case report appears on a Web site maintained by the UK Medical Protection Society14 and describes a case that occurred 10 years before its 2005 publication. A 60-year-old male scheduled for coronary artery bypass grafting was confirmed to have normal blood cell counts and coagulation profile. On the day of surgery, an epidural catheter was placed at the T12/L1 interspace uneventfully (neither trauma nor bleeding was reported), and heparin for cardiopulmonary bypass was administered “about an hour” after induction of anesthesia. Full reversal of heparin was achieved with protamine sulfate, and coagulation was further normalized with fresh frozen plasma and platelet transfusion. Postoperative analgesia was implemented with an epidural infusion of bupivacaine and fentanyl, and the patient was observed to be stable overnight in the intensive care unit. The next morning, equivocal signs of motor deficit were observed (variously described as not moving his feet versus not moving his legs) and were attributed to drowsiness. Following extubation, and after about 3 hours, the patient was observed to have neither motor nor sensory function in the lower extremities. The epidural infusion was stopped, and the catheter was removed at this time. Mannitol was administered, and neurologic consultation resulted in diagnosis of a spinal hematoma (T5-T10) approximately 9 hours after the earliest signs of possible neurologic dysfunction were first noted. Decompressive laminectomy was commenced approximately 4 hours later, without recovery of neurologic function of the lower extremities.
This case is concerning in that, as far as can be told from the description, most standard precautions and guidelines for safe epidural catheterization were observed. Although the epidural catheter was not placed on the evening before surgery, it is noteworthy that its placement was neither bloody nor traumatic. It is difficult to conjecture what additional margin of safety might have been gained by this precaution in the setting of an uncomplicated catheter insertion. The authors do not specifically state what medications the patient had been taking preoperatively, and it should be assumed that relevant agents (such as antiplatelet or anticoagulant medications) would have been noted, if present. The decision to withdraw the catheter may be questioned, since no information is given regarding the coagulation status of the patient at that time. Still, it seems likely that the spinal hematoma had already begun to form before this event, as evidenced by the neurologic deterioration. Once again, the time elapsed between the initial presentation of clinical signs and symptoms (regardless of whether this is taken to have been before or following extubation) until the eventual decompressive laminectomy (at least 10 hours) is in keeping with the poor neurologic recovery, and the goal of rapid diagnosis and early decompressive surgery is reinforced by this report (Table 2). This case, then, is perhaps the only published instance so far of an appropriately placed catheter resulting in spinal hematoma and paralysis having no inciting factor other than standard heparinization for cardiac surgery. At this time, there are no other published case reports of epidural hematoma formation in a patient receiving neuraxial blockade followed by anticoagulation for cardiac surgery. Two case reports, however, discuss epidural hematoma formation in patients receiving epidural catheters for planned cardiac surgery, but with cancellation of the procedure as a result of the complication, ie, before heparinization.18,20 Still, it is possible that complications have occurred without being published in the literature, and allusion to three such instances appear in a recently published review.6 For some practitioners, the mere existence of such anecdotes will be of minor importance compared with the specific circumstances that surrounded them, and whether these were factors that might be controlled. These case reports demonstrate that neuraxial anesthesia and analgesia for cardiac surgery does indeed carry some risk and confirm the importance of adherence to published guidelines.11 Fortunately, published complications seem to be rare. It is likely that the paucity of such complications is largely explained by practices that promote the safety of neuraxial anesthesia, and not simply to any inherent safety of the technique itself. The following section of the review will consider the degree of risk imparted by various anticoagulant and antihemostatic medications on the performance of neuraxial blockade for cardiac surgery, as well as guidelines for minimizing this risk.
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Recommendations for patients receiving anticoagulant therapy Neuraxial blockade and intravenous heparin As discussed previously, a number of authors have published series, large and small, of cardiac surgical patients receiving neuraxial blockade, and, to date, none has reported an epidural hematoma. This is despite the routine practice of systemic heparin administration using doses required for safe cardiopulmonary bypass. It must nonetheless be borne in mind that intravenous heparin administration has indeed, in settings other than cardiac surgery, been associated with this complication following both neuraxial anesthesia and diagnostic lumbar puncture,9,21-23 and that such reports have helped to formulate the safe practices observed by the authors of the cardiac anesthesia literature. Ruff and Dougherty reported that systemic heparin administration (for acute ischemic stroke) was significantly associated with spinal hematoma when performed within 1 hour of diagnostic lumbar puncture and also in the setting of acetylsalicylic acid (ASA) therapy.22 Most cardiac and vascular surgical investigators have accordingly postponed systemic heparin administration to a minimum of 60 minutes following neuraxial instrumentation. Further, the observation that traumatic needle placement is also associated with spinal hematoma9,21,22 has led many authors to recommend either postponement of surgery (and the attendant heparin administration) for 24 hours in the case of bloody or traumatic puncture, or else that epidural catheterization be performed on the day before the scheduled procedure. Although these precautions, applied collectively, have likely contributed to the high degree of safety observed thus far in the cardiac surgical population, it is difficult to assess which of them contribute most importantly, if at all, to this result. It is known that systemic heparin administration also poses a risk at the time of epidural catheter removal, as well as at insertion.9 In the setting of intra- or postoperative intravenous heparin therapy, epidural catheter removal should be contingent on discontinuation of the heparin infusion for 2 to 4 hours and the documentation of normal indices of coagulation. Patients should be followed closely for 12 hours after catheter removal with clinical monitoring of spinal cord function.
Neuraxial blockade and antiplatelet therapy Distinct classes of antiplatelet medication should be considered differently when estimating the risk of neuraxial blockade. Pharmacologic inhibitors of cyclooxygenase (nonsteroidal antiinflammatory drugs, NSAIDS) decrease the formation of thromboxane A2, and thereby inhibit platelet aggregation, but not platelet adherence to subendothelium. None of ASA, diclofenac, ibuprofen, piroxicam, or naproxen was observed to increase the incidence of minor hemorrhagic complications during the conduct of spinal and epidural techniques in a series of 994 patients undergoing orthopedic surgery,24
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and agents of this antiplatelet class have not been observed to increase the risk of spinal hematoma formation when present as the sole defect in coagulation.25,26 In contrast, Ruff and Dougherty identified aspirin as a risk factor for spinal hematoma in patients undergoing diagnostic lumbar puncture (relative risk 7.34), but only among those who subsequently received intravenous heparin. NSAIDS appear to increase the risk of spinal hematoma formation when combined with other anticoagulants, thrombolytics, or antiplatelet agents of differing class.11,27 Importantly, this synergistic effect can be observed with agents considered to be safe (when given alone), such as subcutaneous unfractionated heparin. Except when combined with other antiplatelet or anticoagulant therapy, ASA and other NSAIDS are not considered to increase the risk of neuraxial blockade.9,25,26,28,29 The implications of this widely held belief are difficult to apply to the cardiac surgical patient, since systemic heparin administration is expected to occur, even though it is not present at the time of the neuraxial procedure. In light of the experience reported by Ruff and Dougherty,22 it would seem prudent to discontinue aspirin or other NSAID medication before planned neuraxial blockade for cardiac surgery. Platelet function normalizes 7 days after discontinuation in the case of aspirin, or 3 days after the last dose, in the case of other (ie, reversible) nonsteroidal agents. Thienopyridine derivatives (ie, clopidogrel, ticlopidine) are frequently administered to patients with cardiovascular disease. In contrast with NSAIDS, no series has specifically evaluated the thienopyridine derivatives for their potential to complicate neuraxial procedures. Notably, however, a small number of case reports have associated spinal hematoma formation with current or recent therapy using these agents, as a complication of either spinal or epidural anesthetic or therapeutic procedures.27,30,31 The ASRA guidelines have recommended discontinuation of clopidogrel for 7 days, or ticlopidine for 14 days before neuraxial intervention.11 The authors acknowledge that available literature does not permit inference of the actual risk of hematoma formation, and base their recommendation on the known intervals for normalization of platelet function, along with the increased severity of the platelet lesion induced by these agents. Whereas the anti-aggregant effect of thienopyridine derivatives and NSAIDS may be considered partial, the action of the platelet glycoprotein IIb/IIIa inhibitors is to disrupt the final common pathway of platelet aggregation, and therefore profound reduction of platelet aggregation is achieved. Currently, no case report or series directly contributes to our assessment of the risk of these agents with neuraxial anesthesia, yet there seems little doubt that such potent antiplatelet activity precludes safe spinal or epidural procedures.11,32 Knowledge of the pharmacologic profiles provides a potential basis for the interval between the use of these agents and subsequent neuraxial blockade. Platelet aggregation normalizes within 8 hours of discontinuation of eptifibatide or tirofiban, but not until 24 to 48 hours after abciximab. It is also important to consider that important degrees of antibody-mediated thrombocytopenia may occur
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in up to 2% of patients receiving these medications,33 and that confirmation of acceptable platelet count should precede neuraxial instrumentation. A variety of herbal medicines may also affect coagulation, platelet aggregation, and function. Although the mechanisms are not well understood, some of these compounds have been found to have more potent effects than aspirin. Synergism with other antiplatelet and anticoagulant agents may occur.
Neuraxial block and low-dose subcutaneous heparin The use of unfractionated subcutaneous (SC) heparin for thromboprophylaxis does not appear to increase the risk of spinal hematoma following neuraxial blockade.11,34 Although a handful of occurrences have indeed been published,9,35,36 these must be considered in light of an unquantifiable, but very large, denominator: the combination of SC heparin with central neuraxial blockade comprises standard practice for a preponderance of anesthesiologists.34 It has been recommended that, where possible, SC heparin therapy may be initiated after the neuraxial block to maximally reduce the risk. Although needles or catheters may be placed safely in the setting of established SC heparin therapy, peak systemic effect may occur at approximately 2 hours after injection,34 and the authors of at least one case report have conjectured that this may be a suboptimal time for neuraxial block and may have contributed to their complication.36 The confirmation of normal coagulation parameters is not mandated by the presence of SC heparin alone, since prolongation of partial thromboplastin time (PTT) and prothrombin time (PT) are not expected. Nonetheless, other factors that may impair coagulation or platelet count in the postoperative state may prompt verification of blood work before removal of an epidural catheter. Further, since SC heparin may result in thrombocytopenia after 4 or more days of therapy, platelets should be quantified before catheter removal in this setting. Catheter removal should occur 1 hour before the next scheduled dose of SC heparin. The combination of SC heparin with other medications that impair hemostasis may increase the risk of block-related epidural hematoma formation. This applies to agents, such as NSAID antiplatelet drugs, that may not contraindicate neuraxial blocks when taken in isolation.
Neuraxial block and low molecular weight heparin (LMWH) LMWH may be used for a variety of therapeutic and prophylactic purposes. Thromboprophylaxis in the setting of orthopedic and general surgery continues to be a major indication for these agents, but expanded indications now include established venous thromboembolism and acute coronary syndrome. Patients with elevated risk for venous or arterial thromboembolism (such as mechanical mitral
valve prosthesis) may require preoperative discontinuation of oral anticoagulant therapy, and often receive LMWH as a bridge to surgery. As such, it is possible to encounter patients presenting for cardiac surgery with recent or ongoing use of LMWH. Unfortunately, this group of drugs has been associated with approximately 60 cases of epidural hematoma following spinal and epidural anesthesia for noncardiac surgery between 1993 and 1998.11 Identification of factors that appeared to increase the risk of spinal hematoma with LMWH prompted North American guidelines that substantially reduced, to 13, the number of new case reports in the subsequent 5-year era.11 Among patients presenting for surgery with preoperative LMWH therapy, distinction must be made between regimens intended for thromboprophylaxis and regimens intended for treatment (ie, acute coronary syndrome, established DVT or bridging of patients after withdrawal of coumadin). Although it is recommended that neuraxial block be delayed for 10 to 12 hours following thromboprophylactic therapy, those receiving higher doses require at least a 24-hour delay. The authors of the ASRA consensus guidelines comment that the most dangerous period for neuraxial block may occur approximately 2 hours following LMWH heparin administration, since this corresponds with peak anticoagulant activity.11 Where implementation of neuraxial block is to be followed by postoperative initiation of LWMH therapy, optimal timing of the first dose is based on the specific thromboprophylactic regimen (not simply the distinction between thromboprophylaxis and therapeutic regimens). With oncedaily dosing, the first dose may be administered 6 to 8 hours or more following surgery. Risk is higher with twice-daily dosing regimens, and therapy should be initiated at least 24 hours postoperatively. Maintenance of an indwelling catheter is considered safer in the setting of once-daily LMWH dosing regimens, provided that the catheter is not removed until a minimum of 10 to 12 hours following the most recent dose. With twice-daily dosing regimens, an indwelling catheter should be removed at least 2 hours before the first dose (ie, not continued into the period of thromboprophylactic therapy). Regardless of dosing regimen, LMWH heparin administration should not occur sooner than 2 hours after an epidural catheter has been removed. Notwithstanding observation of a 10- to 12-hour interval before catheter placement, Sharma and coworkers reported the occurrence of a spinal hematoma in a patient receiving subcutaneous “low dose” (40 mg) daily enoxaparin.18 Although their patient was scheduled for aortic valve replacement, the surgery was delayed as a result of the neuraxial complication. Accordingly, the spinal hematoma could not be attributed to intraoperative heparin administration and might just as likely have occurred had the patient been awaiting noncardiac surgery. Still, this report confirms the importance of LMWH and its association with spinal hematoma following epidural catheter placement. Although the needle placement and catheter insertion were atraumatic, other factors that may have contributed to occurrence of this
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complication include their use of a stiff epidural catheter and recent therapy with aspirin (75 mg daily). The authors state that aspirin had been discontinued 5 days before the proposed surgery, which would indicate that it had been withheld only 4 days before the epidural procedure. As a sole defect in coagulation, aspirin therapy is not generally considered to increase the risk of spinal hematoma formation with neuraxial block or catheter placement,11,24 even without discontinuation. Nonetheless, when combined with other antihemostatic agents, including LMWH, the risk is increased.9 The platelet defect associated with aspirin therapy persists for the life of the platelet and may therefore require 7 days to be reversed by new platelet formation.9
Neuraxial block and oral anticoagulants It is intriguing that, in 1983, Odoom and Sih reported 1000 lumbar epidural blocks for 950 patients undergoing peripheral vascular surgery, despite preoperative oral anticoagulant therapy.37 Although the prothrombin time (PT) and the antiquated thrombotest were outside of normal parameters at the time of the neuraxial procedure, no patient had evidence of a spinal hematoma. Nonetheless, permanent neurologic compromise due to spinal hematoma has indeed been reported in a patient receiving oral anticoagulant therapy (phenprocoumon) at the time of epidural catheter placement,38 and it is widely held that, with limited exceptions, this family of oral anticoagulant medications that impairs vitamin K-dependent carboxylation of clotting factors poses an important contra-indication to central neuraxial blockade.9,11,38 Many patients presenting for cardiac surgery have cardiac or extra-cardiac indications for oral anticoagulation, and observation of a suitable discontinuation period is warranted before surgery in these patients, should neuraxial blockade be planned. In the case of discontinuation of coumadin (as opposed to initiation of therapy), the prothrombin time (or international normalized ratio, INR) may initially correct toward normal without restoration of global hemostatic function, as a reflection of earlier return of factor VII levels, before adequate return of factors II, IX, and X. A fully corrected INR (ie, ⬍1.3), however, may be taken as evidence of adequate (⬎40% of normal) levels of all vitamin K-dependent factors.11 This can be anticipated to occur 4 to 5 days after cessation of coumadin therapy, but should be confirmed with measurement of the INR. Although uncommon among patients undergoing cardiac surgery, the practice of initiating oral anticoagulation as a single preoperative dose is not infrequent in other surgical settings and does not preclude safe spinal or epidural anesthesia, providing that needle puncture occurs less than 24 hours after initiation of coumadin therapy. A longer interval or more than one preoperative dose of coumadin should prompt confirmation of normal hemostatic parameters (PT and INR) before neuraxial blockade. The circumstances of epidural catheter removal may hold at least as much significance as the issue of catheter placement. At least two case reports39,40 describe the sce-
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nario of catheter placement in the preoperative setting, following the initiation of postoperative thromboprophylaxis with a single preoperative dose of coumadin, and with neurologic compromise following catheter removal. If lowdose coumadin therapy (eg, 5 mg daily) has been instituted for 36 hours or longer, the ASRA guidelines recommend that the PT/INR be verified before catheter removal.11 Where coumadin therapy has been instituted with the catheter in situ, the catheter may be withdrawn with mild prolongation of the PT, provided that the INR remains ⬍1.5. This distinction pertains to the early prolongation of the PT commensurate with rapid decline in factor VII activity, but with relatively delayed impairment of factors II, IX, and X. In the setting of higher dose coumadin or the goal of establishing therapeutic levels of anticoagulant therapy (ie, INR ⬎ 2.0), the catheter should be removed as described above but with the recommendation by the ASRA guidelines of “more intensive monitoring of the coagulation status.”11 The development of INR prolongation may, for example, occur within the 36-hour interval described above. The authors recommend deferral of catheter removal in the case of marked elevation of the INR (⬎3.0), but comment that the available literature does not support definitive recommendations regarding the issue of catheter removal following establishment of therapeutic levels of anticoagulation.11 In all cases where neuraxial blockade is initiated or continued with concomitant oral anticoagulant therapy, analgesic infusions should permit regular assessment of neurologic function (ie, minimal sensorimotor blockade), both during the infusion and for a minimum of 24 hours following catheter removal.
Neuraxial blockade and thrombolytic therapy In the second ASRA consensus conference on neuraxial anesthesia and anticoagulation, it was noted that “ . . . original contraindications for thrombolytic drugs suggest avoidance of these drugs for 10 days following puncture of noncompressible vessels.” Although a definite timeframe is not given, owing to lack of data, it is stated that caution should be exercised in the use of neuraxial techniques in the setting of recent preoperative or likely intra- or postoperative thrombolytic therapy. The authors also suggest that, where this combination cannot be avoided, the use of neuraxial drugs that minimize sensorimotor disturbance may facilitate the early detection of epidural hematoma formation. Finally, the issue of catheter removal is discussed, but without defining a safe interval following thrombolytic therapy, again due to lack of published data. It is suggested that confirmation of a normal fibrinogen level may provide some reassurance.
Newer anti-hemostatic agents Direct thrombin inhibitors (DTI) are being used in some patients with cardiac disease. These medications inhibit the
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formation of fibrin clot by directly binding and inhibiting factor IIa (thrombin), which normally serves to catalyze fibrin from fibrinogen. Further, thrombin-mediated platelet activation is also reduced. Distinction is made between bivalent DTIs (recombinant hirudins or hirudin analogues) which additionally inhibit fibrinogen at its thrombin binding site, and univalent DTIs which are synthetic molecules that solely inhibit thrombin. The indications for DTIs include anticoagulation during coronary angioplasty, treatment of heparin-induced thrombocytopenia (HIT), HIT-associated thrombosis, and, importantly, anticoagulation for cardiopulmonary bypass in patients with HIT. There are currently no data to guide the clinician regarding the safety of neuraxial blockade in the patients receiving direct thrombin inhibitors, however it has been suggested that knowledge of the half-life of these drugs may assist with anticipating a safe interval for normalization of coagulation.32 This may be of importance with unplanned DTI administration in the setting of an indwelling epidural catheter. Among the univalent DTIs, argatroban has the shortest half-life (35-45 minutes) and normalization of coagulation may be confirmed using the PTT, or the ecarin clotting time (ECT). Melagatran and ximelagatran have an elimination half-life of 3 to 5 hours and may accordingly become inactive after 8 to 10 hours. Bivalent DTIs include bivalirudin, lepirudin, and desirudin. Although the elimination halflife of these molecules is relatively short (eg, 25-30 minutes for bivalirudin), it is recommended that epidural or spinal needle placement be delayed at least 8 to 10 hours after administration of these agents. Renal or hepatic dysfunction may delay clearance of some of these agents. PTT and ECT may be used to confirm normalization of coagulation function.
Conclusions Several small case series have reported on the safety of neuraxial anesthesia and analgesia for cardiac surgery. However, accurate quantitation of the risk of neuraxial blockade in these patients depends on the future publication of large case series or complication reports. For now, the minimum risk is estimated to be similar to that of the noncardiac population, with a maximum risk perhaps up to three orders of magnitude greater. Adherence to published guidelines and detailed reports of complications and their circumstances will help to minimize risk from the procedure and/or any coexisting antihemostatic therapies. Infrequent case reports and published guidelines can guide clinical practice for maximum patient safety when neuraxial anesthesia or analgesia is considered.
References 1. Gulur P, Nishimori M, Ballantyne JC: Regional anaesthesia versus general anaesthesia, morbidity and mortality. Best Pract Res Clin Anaesthesiol 20:249-263, 2006
2. Rodgers A, Walker N, Schug S, et al: Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. Br Med J 321:1493, 2000 3. Rigg JR, Jamrozik K, Myles PS, et al: Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet 359:1276-1282, 2002 4. Ballantyne JC, Carr DB, de Ferranti S, et al: The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesth Analg 86:598-612, 1998 5. Chaney MA: Cardiac surgery and intrathecal/epidural techniques: at the crossroads? Can J Anaesth 52:783-788, 2005 6. Chaney MA: Intrathecal and epidural anesthesia and analgesia for cardiac surgery. Anesth Analg 102:45-64, 2006 7. Ho AM, Chung DC, Joynt GM: Neuraxial blockade and hematoma in cardiac surgery: estimating the risk of a rare adverse event that has not (yet) occurred. Chest 117:551-555, 2000 8. Hemmerling TM, Djaiani G, Babb P, et al: The use of epidural analgesia in cardiac surgery should be encouraged. Anesth Analg 103:1592; author reply 1592-1593, 2006 9. Vandermeulen EP, Van Aken H, Vermylen J: Anticoagulants and spinal-epidural anesthesia. Anesth Analg 79:1165-1177, 1994 10. Tryba M: [Epidural regional anesthesia and low molecular heparin: Pro]. Anasthesiol Intensivmed Notfallmed Schmerzther 28:179-181, 1993 11. Horlocker TT, Wedel DJ, Benzon H, et al: Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 28:172-197, 2003 12. O’Connor CJ, Tuman KJ: Epidural anesthesia and analgesia for coronary artery bypass graft surgery: still forbidden territory? Anesth Analg 93:523-525, 2001 13. Rosen DA, Hawkinberry DW 2nd, Rosen KR, et al: An epidural hematoma in an adolescent patient after cardiac surgery. Anesth Analg 98:966-969, 2004 14. UK MPS: Epidural Emergency, in Education and Publications: UK Casebook, vol. 12(3) 2004, pp. 119-120. Available at: www. medicalprotection.org-the Medical Protection Society Ltd., London, UK 15. Hanley JA, Lippman-Hand A: If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA 249:1743-1745, 1983 16. Ruppen W, Derry S, McQuay HJ, et al: Incidence of epidural haematoma and neurological injury in cardiovascular patients with epidural analgesia/anaesthesia: systematic review and meta-analysis. BMC Anesthesiol 6:10, 2006 17. Bracco D, Hemmerling T: Epidural analgesia in cardiac surgery: an updated risk assessment. Heart Surg Forum 10:E334-E337, 2007 18. Sharma S, Kapoor MC, Sharma VK, et al: Epidural hematoma complicating high thoracic epidural catheter placement intended for cardiac surgery. J Cardiothorac Vasc Anesth 18:759-762, 2004 19. Royse CF, Soeding PF, Royse AG: High thoracic epidural analgesia for cardiac surgery: an audit of 874 cases. Anaesth Intensive Care 35:374-377, 2007 20. Yoshinaga A, Sonoda H: [Epidural hematoma caused after epidural catheterization for the coronary artery bypass graft: a case report]. Masui 53:551-554, 2004 21. Brem SS, Hafler DA, Van Uitert RL, et al: Spinal subarachnoid hematoma: a hazard of lumbar puncture resulting in reversible paraplegia. N Engl J Med 304:1020-1021, 1981 22. Ruff RL, Dougherty JH Jr: Complications of lumbar puncture followed by anticoagulation. Stroke 12:879-881, 1981 23. Martinez-Palli G, Sala-Blanch X, Salvado E, et al: Epidural hematoma after epidural anesthesia in a patient with peripheral vascular disease. Case report. Reg Anesth 21:342-346, 1996 24. Horlocker TT, Wedel DJ, Schroeder DR, et al: Preoperative antiplatelet therapy does not increase the risk of spinal hematoma associated with regional anesthesia. Anesth Analg 80:303-309, 1995
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25. Urmey WF, Rowlingson J: Do antiplatelet agents contribute to the development of perioperative spinal hematoma? Reg Anesth Pain Med 23:146-151, 1998 (suppl 2) 26. Wulf H: Epidural anaesthesia and spinal haematoma. Can J Anaesth 43:1260-1271, 1996 27. Benzon HT, Wong HY, Siddiqui T, et al: Caution in performing epidural injections in patients on several antiplatelet drugs. Anesthesiology 91:1558-1559, 1999 28. Horlocker TT: Low molecular weight heparin and neuraxial anesthesia. Thromb Res 101:V141-V154, 2001 29. Wulf HF: Spinal hematoma: a literature survey with meta-analysis of 613 patients. Neurosurg Rev 26:51, 2003 30. Kawaguchi S, Tokutomi S: [A case of epidural hematoma associated with epidural catheterization which occurred on 12th days after the last medication of ticlopidine hydrochloride]. Masui 51:526-528, 2002 31. Mayumi T, Dohi S: Spinal subarachnoid hematoma after lumbar puncture in a patient receiving antiplatelet therapy. Anesth Analg 62:777779, 1983 32. Vandermeulen E: Anaesthesia and new antithrombotic drugs. Curr Opin Anaesthesiol 18:353-359, 2005 33. Patrono C, Coller B, FitzGerald GA, et al: Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh
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ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:234S-264S, 2004 (suppl) Liu SS, Mulroy MF: Neuraxial anesthesia and analgesia in the presence of standard heparin. Reg Anesth Pain Med 23:157-163, 1998 (suppl 2) Greaves JD: Serious spinal cord injury due to haematomyelia caused by spinal anaesthesia in a patient treated with low-dose heparin. Anaesthesia 52:150-154, 1997 Sandhu H, Morley-Forster P, Spadafora S: Epidural hematoma following epidural analgesia in a patient receiving unfractionated heparin for thromboprophylaxis. Reg Anesth Pain Med 25:72-75, 2000 Odoom JA, Sih IL: Epidural analgesia and anticoagulant therapy. Experience with one thousand cases of continuous epidurals. Anaesthesia 38:254-259, 1983 Wille-Jorgensen P, Jorgensen LN, Rasmussen LS: Lumbar regional anaesthesia and prophylactic anticoagulant therapy. Is the combination safe? Anaesthesia 46:623-627, 1991 Woolson ST, Robinson RK, Khan NO, et al: Deep venous thrombosis prophylaxis for knee replacement: warfarin and pneumatic compression. Am J Orthop 27:299-304, 1998 Badenhorst CH: Epidural hematoma after epidural pain control and concomitant postoperative anticoagulation. Reg Anesth 21:272-273, 1996
Anticoagulation and regional anesthesia in cardiac surgery: safety considerations James E. Baker, MD, FRCPC,a C. David Mazer, MD, FRCPCa,b,c a
From the Department of Anesthesia, University of Toronto, St. Michael’s Hospital, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, St. Michael’s Hospital, Toronto, Ontario, Canada; and c Interdepartmental Division of Critical Care, University of Toronto, from the Keenan Research Centre in the Li KaShing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada. b
KEYWORDS: Thoracic epidural anesthesia; Cardiac surgery; Postoperative complications; Epidural hematoma; Anticoagulation; Antiplatelet therapy
This review focuses on the impact of anticoagulation treatment on the use of neuraxial anesthetic techniques in cardiac surgery. After a short risk evaluation, the effects of different agents are discussed: heparin, low molecular weight heparin, antiplatelet and oral anticoagulation agents, thrombolytic drugs, and newer antihemostatic agents all have an impact on the use of neuraxial techniques in cardiac surgery. A detailed understanding of their mode and timing of action is important to safely practice regional techniques in cardiac surgery. Adherence to published guidelines will help to minimize the risk from the procedure and/or any coexisting antihemostatic therapies. The review gives several recommendations on if, how, and when to use neuraxial techniques when anticoagulative agents are involved. © 2008 Elsevier Inc. All rights reserved.
The notion that regional anesthetic techniques could impart positive effects on patient outcome has enjoyed tremendous allure and has engendered an industrious field of investigation.1 In the realm of noncardiac surgery, many beneficial effects of central neuraxial blockade have been postulated, and some of these appear, at least for now, to have been confirmed.2-4 What underlies the applicability of these findings is the belief that spinal and epidural anesthesia is safe, and that the risk of performing these procedures is outweighed by their capacity to improve outcome, or even simply to improve comfort. For cardiac surgery, the risk– benefit ratio has been harder to assess.5 The proposed benefits of epidural anesthesia and analgesia include not only improved postoperative analgesia (with attendant reduction of sympathetic activation and stress hormone release), but also decreased myocardial ischemia, reduced cardiac arrhythmia, improved ventricular function, increased hemodynamic stability, improved pulmonary function, extubation and ambulation, shorter ICU stay, and reducAddress reprint requests and correspondence: C. David Mazer, MD, FRCPC, Departments of Anesthesia and Critical Care, St. Michael’s Hospital, 30 Bond Street, Toronto, ON, Canada M5B 1W8. E-mail address: [email protected].
1084-208X/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2007.10.003
tion in overall cost.6-8 On the other hand, it has been difficult to assess the relevance of existing risk estimates—principally pertaining to the rare complication of epidural hematoma and permanent paralysis—since they have largely been derived from noncardiac surgical experience.9,10 Cardiac surgery differs from other settings because of the need for systemic heparin administration using doses sufficient to prevent clot formation during cardiopulmonary bypass. Further, these patients may present for surgery taking one or more of many possible types of antihemostatic medication. With ongoing publication of patient series and case reports, the global collective experience with regional anesthesia for cardiac surgery is increasing and beginning to allow meaningful assessments of risk. Further, reporting of complications, although rare, has allowed for analysis of factors that may contribute to risk and, more importantly, to safety.
Neuraxial anesthesia and anticoagulation: defining the risk Before April 2004, several authors had commented that no report yet existed of neurologic complications pertaining to
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the use of epidural catheter placement for cardiac surgery.7,11,12 However, the literature now contains its first reports of epidural hematoma, with neurologic injury, in cardiac surgery patients.13,14 For some, this has galvanized the conviction that Thoracic Epidural Anesthesia (TEA) presents unacceptable risk for any cardiac surgical patients,5 whereas for others, the potential benefits of the technique are not precluded by the magnitude of risk implied by these recent reports.8 While the benefits continue to be debated, an interesting body of work has emerged that has synthesized, from available literature, an approximation of the risk of neuraxial anesthesia and analgesia for cardiac surgery. With important and fallible assumptions borne in mind, Ho and coworkers calculated the maximum risk, with 95% confidence, of spinal hematoma based on the aggregate of published case series as of the year 1999.7 At that time, 4583 cardiac surgical patients undergoing epidural anesthesia or analgesia had been reported by various authors with a zero incidence of spinal hematoma. The mathematical technique can be used to estimate in the setting of zero complications over a given number of observations. The maximum risk for an event that has not yet occurred can be approximated by 3/n (at the upper end of the 95% confidence interval), where n is number of observations.15 Ho and coworkers thereby estimated the maximum risk of spinal hematoma, following epidural anesthesia or analgesia for cardiac surgery, to be 3:4583, ie, 1:1528. The authors suggest, plausibly, that the minimum risk should not reasonably be assumed to be any lower than what has already been described for the uncomplicated noncardiac surgical population. This risk has been estimated9,10 to be approximately 1:150,000 for epidural blockade and 1:220,000 for spinal blockade. Similarly, the maximum risk of spinal hematoma following subarachnoid anesthesia was estimated to be 1:3160, based on the finding of zero reports over 10,840 reported cardiac surgical patients. However, the precision of these estimates could be affected by the possibility that one or more spinal hematoma may have occurred without being reported, and also by the difficulty in estimating the true number of cases performed worldwide (ie, the true denominator), which was likely well in excess of the 4583 reported patients. Ruppen and coworkers performed a similar analysis with the intention of improving its validity by including only studies reporting specifically on the presence or absence of spinal hematoma, as opposed to including studies that simply failed to report its occurrence.16 This publication also benefited from the additional reports published between 1999 and 2005. In all, 4971 cardiac surgical patients were included (again with a zero incidence of spinal hematoma), suggesting a risk of 1:1700, at the maximum of the 95% confidence interval. Only patients receiving epidural catheters were studied, and not patients undergoing subarachnoid techniques. The authors also included the same patients in a broader cohort of cardiac, vascular, and thoracic surgery patients, the majority of whom received some form of heparin perioperatively. Zero complications observed over
14,105 patients suggested an estimated maximum risk of 1:4700. In a 2007 meta-analysis, Bracco and Hemmerling identified 12,000 patients from published series of cardiac surgery using combined general– epidural anesthesia.17 Unlike the analyses discussed previously, the authors assumed a numerator of one, and not zero, comprised of the sole extant case report of a spinal hematoma plausibly linked to heparin administration during cardiac surgery.14 The authors did not include a patient who developed a spinal hematoma following epidural catheter placement on the preoperative day for planned (ie, cancelled) cardiac surgery, since it was not related to intraoperative heparin administration.18 Further, they did not include a published report of a hematoma that was more plausibly linked to postoperative thrombolytic therapy.13 Based on an observed incidence of 1:12,000 patients, they estimated the risk to be between 1:2100 and 1:68,000, using a 95% confidence interval. As noted by Royse and coworkers,19 the estimation of risk will undergo refinement and improvement as new case series continue to appear, adding to the world literature. Some aspects of the case report by Rosen13 merit discussion. An 18-year-old man underwent placement of an epidural catheter immediately following induction of general anesthesia for aortic valve replacement. The patient was observed to ambulate normally on the first postoperative day without evidence of back pain or neurologic deficit. Systemic heparin therapy (4500 U bolus followed by continuous infusion) was initiated on the second postoperative day for thromboprophylaxis of the valve prosthesis. Five hours later, an occluded peripheral intravenous cannula was flushed with 2 mg alteplase (recombinant tissue plasminogen activator). Severe back pain ensued within 2 hours of this event, and blood was observed both within the epidural catheter as well as at the insertion site. The catheter was removed by critical care staff at this time, and simultaneous blood sampling demonstrated an activated partial thromboplastin time (PPT) of 87 seconds. Neurologic deficit developed shortly thereafter, and subsequent magnetic resonance imaging confirmed the presence of an epidural hematoma at the insertion site of the epidural catheter (T9 –T10). Importantly, blood work in preparation for emergency surgery demonstrated a platelet count of 76,000. Decompressive laminectomy was commenced 5 hours following the onset of neurologic symptoms, and full neurologic recovery ensued over a 6-week period. It is compelling to conjecture that the epidural hematoma might have been avoided in this instance with adherence to a small number of published precautions (see Table 1). Although specific timeframes are not given in the American Society of Regional Anesthesia and Pain Medicine (ASRA) guidelines for the avoidance of thrombolytic drugs in relation to epidural catheter placement (or removal),11 such therapy may have been premature on the second day after catheter placement and, moreover, ought certainly to have prompted a different timing of catheter removal. Although the initiation of intravenous heparin therapy in this patient
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Table 1 Summary of recommendations for patients undergoing central neuraxial blockade in the setting of recent or planned anti-coagulant therapy* Anti-hemostatic agent
Recommended precautions
Intravenous heparin
Anti-platelet agents
Subcutaneous (sc) heparin thromboprophylaxis
Low molecular weight heparin
Oral anti-coagulation (eg, coumadin)
Comments
Discontinue IV heparin infusion 2-4 hours prior to neuraxial procedure or catheter removal; confirm normal coagulation profile (PTT, PT) Delay heparin administration for ⬎60 minutes after neuraxial technique. Monitor spinal cord function for 12 hours following catheter removal. Ensure no other anti-hemostatic agents active. Aspirin and NSAIDs: Consider discontinuation when intra-operative heparin planned (aspirin 7 days; other NSAIDs, 2-3 days). Thienopyridine derivatives: discontinue clopidogrel 7 days, ticlopidine 14 days. GP IIb/IIIa inhibitors: discontinue eptifibatide or tirofiban 8 hours, abciximab 24-48 hours. Confirm platelet count. No contra-indication to neuraxial block unless other class of antihemostatic agent or coagulopathy is present Bloodwork only helpful if prolonged (⬎4 days) therapy prior to blockade or catheter removal: confirm platelet count Remove catheter 1 hour prior to next dose. Delay block or catheter placement for 1012 hours following last dose (low-dose regimens) Delay block or catheter placement for 24 hours following last dose (high dose regimens). Remove catheter 2 hours prior to post-op implementation of twice-daily dose regimen; do not initiate LMWH until 24 hours post-op. Patient may be managed with catheter during post-op once-daily regimen. May initiate LMWH 6-8 hours post-op. Remove catheter 2 hours prior to next dose.
Discontinue 4-5 days prior to neuraxial block or catheter placement. Confirm normal PT/INR. Remove catheter prior to initiation of post-op coumadin (INR ⬍ 1.3), or with confirmation of INR ⬍ 1.5.
Catheter may be placed on evening prior to surgery (no evidence in support). If neuraxial technique is bloody or traumatic, consider delay of surgery (no evidence in support). Consider avoidance of paramedian approach (no evidence in support). Avoid anti-coagulation in excess of necessary targets (no evidence in support). Asprin and NSAIDs widely held not to preclude neuraxial block per se; however, known synergy with other anti-coagulants exists. Impact of subsequent heparin for cardiopulmonary bypass is uncertain.
Small percent of patients will have systemic anticoagulation effect with thromboprophylactic dose. Bloodwork not recommended but avoid neuraxial block or catheter removal 2 hours after SC heparin (peak effect). Consider delaying initiation of therapy until after surgery (no evidence in support). Highest risk is with twice daily dose regimens. No bloodwork is recommended to enhance safety (including factor Xa levels). Example of low-dose regimens: Dalteparin 5000 U SC daily; Enoxaparin 30 mg SC twice daily or 40 mg SC daily; Tinzaparin 75 U/kg SC daily; Danaparoid 750 U SC twice daily. Example of high dose regimens: Dalteparin 120 U/kg SC twice daily or 200 U/kg daily; Enoxaparin 1.0-1.5 mg/kg twice daily; Tinzaparin 175 U/kg SC daily Maximum risk may occur 2 hours after LMWH administration. Choice of epidural infusion that allows assessment of sensorimotor function is recommended when catheter remains in situ during LMWH therapy In non-cardiac settings, low-dose or adjusted-dose thromboprophylactic regimens may be used. Such regimens may safely be implemented preop provided block or catheter placement occurs ⬍24 hours later. Catheter removal should occur while INR ⬍ 1.5.
*Emphasis is placed on the cardiac surgical patient where applicable. Derived from the American Society of Regional Anesthesia and Pain Medicine consensus guidelines.11 Abbreviations: PT, prothrombin time; PTT, partial thromboplastin time; INR, international normalized ratio; NSAID, non-steroidal anti-inflammatory drug; GP IIb/IIIa, platelet glycoprotein receptor IIb/IIIa inhibitor; LMWH, low molecular weight heparin; SC, subcutaneous.
was consistent with ASRA guidelines, it has been suggested that the infusion be discontinued for 2 to 4 hours before removal, along with confirmation of a normal coagulation profile (this patient had a prolonged PTT and thrombocy-
topenia). Some authors advise against placing the epidural catheter immediately before surgery involving heparin6 (in favor of the preoperative evening), but this recommendation is without the support of case reports or known complica-
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Table 2 Relationship between timing of decompressive laminectomy for spinal hematoma after central neuraxial blockade and quality of neurologic recovery* Timing of surgery
Good Partial Poor Intra-operative recovery recovery recovery death
ⱕ8 hours 8-24 hours ⬎24 hours No surgery Not reported
6 1 2 1 2
4 2 0 1 4
3 4 10 8 4
0 0 0 3† 0
*Note that the chance for good or partial recovery was best for those patients receiving surgery within 8 hours, whereas poor recovery was frequent in those receiving surgery after 8 hours. † Unrecognized spinal hematoma discovered at autopsy. Modified from Vandermeulen et al.9
tions that confirm its value. The ASRA guidelines advise an interval of at least 1 hour between neuraxial intervention and the subsequent administration of systemic heparin (regardless of dose). It is very noteworthy that the authors in this case reported complete neurologic recovery by their patient, having commenced the decompressive laminectomy within 5 hours following onset of symptoms. In a series of 55 patients undergoing decompressive laminectomy for spinal hematoma following central nervous blockade, the chance for neurologic recovery was significantly improved in those for whom the surgery was performed within 8 hours9 (Table 2). A second case report appears on a Web site maintained by the UK Medical Protection Society14 and describes a case that occurred 10 years before its 2005 publication. A 60-year-old male scheduled for coronary artery bypass grafting was confirmed to have normal blood cell counts and coagulation profile. On the day of surgery, an epidural catheter was placed at the T12/L1 interspace uneventfully (neither trauma nor bleeding was reported), and heparin for cardiopulmonary bypass was administered “about an hour” after induction of anesthesia. Full reversal of heparin was achieved with protamine sulfate, and coagulation was further normalized with fresh frozen plasma and platelet transfusion. Postoperative analgesia was implemented with an epidural infusion of bupivacaine and fentanyl, and the patient was observed to be stable overnight in the intensive care unit. The next morning, equivocal signs of motor deficit were observed (variously described as not moving his feet versus not moving his legs) and were attributed to drowsiness. Following extubation, and after about 3 hours, the patient was observed to have neither motor nor sensory function in the lower extremities. The epidural infusion was stopped, and the catheter was removed at this time. Mannitol was administered, and neurologic consultation resulted in diagnosis of a spinal hematoma (T5-T10) approximately 9 hours after the earliest signs of possible neurologic dysfunction were first noted. Decompressive laminectomy was commenced approximately 4 hours later, without recovery of neurologic function of the lower extremities.
This case is concerning in that, as far as can be told from the description, most standard precautions and guidelines for safe epidural catheterization were observed. Although the epidural catheter was not placed on the evening before surgery, it is noteworthy that its placement was neither bloody nor traumatic. It is difficult to conjecture what additional margin of safety might have been gained by this precaution in the setting of an uncomplicated catheter insertion. The authors do not specifically state what medications the patient had been taking preoperatively, and it should be assumed that relevant agents (such as antiplatelet or anticoagulant medications) would have been noted, if present. The decision to withdraw the catheter may be questioned, since no information is given regarding the coagulation status of the patient at that time. Still, it seems likely that the spinal hematoma had already begun to form before this event, as evidenced by the neurologic deterioration. Once again, the time elapsed between the initial presentation of clinical signs and symptoms (regardless of whether this is taken to have been before or following extubation) until the eventual decompressive laminectomy (at least 10 hours) is in keeping with the poor neurologic recovery, and the goal of rapid diagnosis and early decompressive surgery is reinforced by this report (Table 2). This case, then, is perhaps the only published instance so far of an appropriately placed catheter resulting in spinal hematoma and paralysis having no inciting factor other than standard heparinization for cardiac surgery. At this time, there are no other published case reports of epidural hematoma formation in a patient receiving neuraxial blockade followed by anticoagulation for cardiac surgery. Two case reports, however, discuss epidural hematoma formation in patients receiving epidural catheters for planned cardiac surgery, but with cancellation of the procedure as a result of the complication, ie, before heparinization.18,20 Still, it is possible that complications have occurred without being published in the literature, and allusion to three such instances appear in a recently published review.6 For some practitioners, the mere existence of such anecdotes will be of minor importance compared with the specific circumstances that surrounded them, and whether these were factors that might be controlled. These case reports demonstrate that neuraxial anesthesia and analgesia for cardiac surgery does indeed carry some risk and confirm the importance of adherence to published guidelines.11 Fortunately, published complications seem to be rare. It is likely that the paucity of such complications is largely explained by practices that promote the safety of neuraxial anesthesia, and not simply to any inherent safety of the technique itself. The following section of the review will consider the degree of risk imparted by various anticoagulant and antihemostatic medications on the performance of neuraxial blockade for cardiac surgery, as well as guidelines for minimizing this risk.
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Recommendations for patients receiving anticoagulant therapy Neuraxial blockade and intravenous heparin As discussed previously, a number of authors have published series, large and small, of cardiac surgical patients receiving neuraxial blockade, and, to date, none has reported an epidural hematoma. This is despite the routine practice of systemic heparin administration using doses required for safe cardiopulmonary bypass. It must nonetheless be borne in mind that intravenous heparin administration has indeed, in settings other than cardiac surgery, been associated with this complication following both neuraxial anesthesia and diagnostic lumbar puncture,9,21-23 and that such reports have helped to formulate the safe practices observed by the authors of the cardiac anesthesia literature. Ruff and Dougherty reported that systemic heparin administration (for acute ischemic stroke) was significantly associated with spinal hematoma when performed within 1 hour of diagnostic lumbar puncture and also in the setting of acetylsalicylic acid (ASA) therapy.22 Most cardiac and vascular surgical investigators have accordingly postponed systemic heparin administration to a minimum of 60 minutes following neuraxial instrumentation. Further, the observation that traumatic needle placement is also associated with spinal hematoma9,21,22 has led many authors to recommend either postponement of surgery (and the attendant heparin administration) for 24 hours in the case of bloody or traumatic puncture, or else that epidural catheterization be performed on the day before the scheduled procedure. Although these precautions, applied collectively, have likely contributed to the high degree of safety observed thus far in the cardiac surgical population, it is difficult to assess which of them contribute most importantly, if at all, to this result. It is known that systemic heparin administration also poses a risk at the time of epidural catheter removal, as well as at insertion.9 In the setting of intra- or postoperative intravenous heparin therapy, epidural catheter removal should be contingent on discontinuation of the heparin infusion for 2 to 4 hours and the documentation of normal indices of coagulation. Patients should be followed closely for 12 hours after catheter removal with clinical monitoring of spinal cord function.
Neuraxial blockade and antiplatelet therapy Distinct classes of antiplatelet medication should be considered differently when estimating the risk of neuraxial blockade. Pharmacologic inhibitors of cyclooxygenase (nonsteroidal antiinflammatory drugs, NSAIDS) decrease the formation of thromboxane A2, and thereby inhibit platelet aggregation, but not platelet adherence to subendothelium. None of ASA, diclofenac, ibuprofen, piroxicam, or naproxen was observed to increase the incidence of minor hemorrhagic complications during the conduct of spinal and epidural techniques in a series of 994 patients undergoing orthopedic surgery,24
21
and agents of this antiplatelet class have not been observed to increase the risk of spinal hematoma formation when present as the sole defect in coagulation.25,26 In contrast, Ruff and Dougherty identified aspirin as a risk factor for spinal hematoma in patients undergoing diagnostic lumbar puncture (relative risk 7.34), but only among those who subsequently received intravenous heparin. NSAIDS appear to increase the risk of spinal hematoma formation when combined with other anticoagulants, thrombolytics, or antiplatelet agents of differing class.11,27 Importantly, this synergistic effect can be observed with agents considered to be safe (when given alone), such as subcutaneous unfractionated heparin. Except when combined with other antiplatelet or anticoagulant therapy, ASA and other NSAIDS are not considered to increase the risk of neuraxial blockade.9,25,26,28,29 The implications of this widely held belief are difficult to apply to the cardiac surgical patient, since systemic heparin administration is expected to occur, even though it is not present at the time of the neuraxial procedure. In light of the experience reported by Ruff and Dougherty,22 it would seem prudent to discontinue aspirin or other NSAID medication before planned neuraxial blockade for cardiac surgery. Platelet function normalizes 7 days after discontinuation in the case of aspirin, or 3 days after the last dose, in the case of other (ie, reversible) nonsteroidal agents. Thienopyridine derivatives (ie, clopidogrel, ticlopidine) are frequently administered to patients with cardiovascular disease. In contrast with NSAIDS, no series has specifically evaluated the thienopyridine derivatives for their potential to complicate neuraxial procedures. Notably, however, a small number of case reports have associated spinal hematoma formation with current or recent therapy using these agents, as a complication of either spinal or epidural anesthetic or therapeutic procedures.27,30,31 The ASRA guidelines have recommended discontinuation of clopidogrel for 7 days, or ticlopidine for 14 days before neuraxial intervention.11 The authors acknowledge that available literature does not permit inference of the actual risk of hematoma formation, and base their recommendation on the known intervals for normalization of platelet function, along with the increased severity of the platelet lesion induced by these agents. Whereas the anti-aggregant effect of thienopyridine derivatives and NSAIDS may be considered partial, the action of the platelet glycoprotein IIb/IIIa inhibitors is to disrupt the final common pathway of platelet aggregation, and therefore profound reduction of platelet aggregation is achieved. Currently, no case report or series directly contributes to our assessment of the risk of these agents with neuraxial anesthesia, yet there seems little doubt that such potent antiplatelet activity precludes safe spinal or epidural procedures.11,32 Knowledge of the pharmacologic profiles provides a potential basis for the interval between the use of these agents and subsequent neuraxial blockade. Platelet aggregation normalizes within 8 hours of discontinuation of eptifibatide or tirofiban, but not until 24 to 48 hours after abciximab. It is also important to consider that important degrees of antibody-mediated thrombocytopenia may occur
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in up to 2% of patients receiving these medications,33 and that confirmation of acceptable platelet count should precede neuraxial instrumentation. A variety of herbal medicines may also affect coagulation, platelet aggregation, and function. Although the mechanisms are not well understood, some of these compounds have been found to have more potent effects than aspirin. Synergism with other antiplatelet and anticoagulant agents may occur.
Neuraxial block and low-dose subcutaneous heparin The use of unfractionated subcutaneous (SC) heparin for thromboprophylaxis does not appear to increase the risk of spinal hematoma following neuraxial blockade.11,34 Although a handful of occurrences have indeed been published,9,35,36 these must be considered in light of an unquantifiable, but very large, denominator: the combination of SC heparin with central neuraxial blockade comprises standard practice for a preponderance of anesthesiologists.34 It has been recommended that, where possible, SC heparin therapy may be initiated after the neuraxial block to maximally reduce the risk. Although needles or catheters may be placed safely in the setting of established SC heparin therapy, peak systemic effect may occur at approximately 2 hours after injection,34 and the authors of at least one case report have conjectured that this may be a suboptimal time for neuraxial block and may have contributed to their complication.36 The confirmation of normal coagulation parameters is not mandated by the presence of SC heparin alone, since prolongation of partial thromboplastin time (PTT) and prothrombin time (PT) are not expected. Nonetheless, other factors that may impair coagulation or platelet count in the postoperative state may prompt verification of blood work before removal of an epidural catheter. Further, since SC heparin may result in thrombocytopenia after 4 or more days of therapy, platelets should be quantified before catheter removal in this setting. Catheter removal should occur 1 hour before the next scheduled dose of SC heparin. The combination of SC heparin with other medications that impair hemostasis may increase the risk of block-related epidural hematoma formation. This applies to agents, such as NSAID antiplatelet drugs, that may not contraindicate neuraxial blocks when taken in isolation.
Neuraxial block and low molecular weight heparin (LMWH) LMWH may be used for a variety of therapeutic and prophylactic purposes. Thromboprophylaxis in the setting of orthopedic and general surgery continues to be a major indication for these agents, but expanded indications now include established venous thromboembolism and acute coronary syndrome. Patients with elevated risk for venous or arterial thromboembolism (such as mechanical mitral
valve prosthesis) may require preoperative discontinuation of oral anticoagulant therapy, and often receive LMWH as a bridge to surgery. As such, it is possible to encounter patients presenting for cardiac surgery with recent or ongoing use of LMWH. Unfortunately, this group of drugs has been associated with approximately 60 cases of epidural hematoma following spinal and epidural anesthesia for noncardiac surgery between 1993 and 1998.11 Identification of factors that appeared to increase the risk of spinal hematoma with LMWH prompted North American guidelines that substantially reduced, to 13, the number of new case reports in the subsequent 5-year era.11 Among patients presenting for surgery with preoperative LMWH therapy, distinction must be made between regimens intended for thromboprophylaxis and regimens intended for treatment (ie, acute coronary syndrome, established DVT or bridging of patients after withdrawal of coumadin). Although it is recommended that neuraxial block be delayed for 10 to 12 hours following thromboprophylactic therapy, those receiving higher doses require at least a 24-hour delay. The authors of the ASRA consensus guidelines comment that the most dangerous period for neuraxial block may occur approximately 2 hours following LMWH heparin administration, since this corresponds with peak anticoagulant activity.11 Where implementation of neuraxial block is to be followed by postoperative initiation of LWMH therapy, optimal timing of the first dose is based on the specific thromboprophylactic regimen (not simply the distinction between thromboprophylaxis and therapeutic regimens). With oncedaily dosing, the first dose may be administered 6 to 8 hours or more following surgery. Risk is higher with twice-daily dosing regimens, and therapy should be initiated at least 24 hours postoperatively. Maintenance of an indwelling catheter is considered safer in the setting of once-daily LMWH dosing regimens, provided that the catheter is not removed until a minimum of 10 to 12 hours following the most recent dose. With twice-daily dosing regimens, an indwelling catheter should be removed at least 2 hours before the first dose (ie, not continued into the period of thromboprophylactic therapy). Regardless of dosing regimen, LMWH heparin administration should not occur sooner than 2 hours after an epidural catheter has been removed. Notwithstanding observation of a 10- to 12-hour interval before catheter placement, Sharma and coworkers reported the occurrence of a spinal hematoma in a patient receiving subcutaneous “low dose” (40 mg) daily enoxaparin.18 Although their patient was scheduled for aortic valve replacement, the surgery was delayed as a result of the neuraxial complication. Accordingly, the spinal hematoma could not be attributed to intraoperative heparin administration and might just as likely have occurred had the patient been awaiting noncardiac surgery. Still, this report confirms the importance of LMWH and its association with spinal hematoma following epidural catheter placement. Although the needle placement and catheter insertion were atraumatic, other factors that may have contributed to occurrence of this
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complication include their use of a stiff epidural catheter and recent therapy with aspirin (75 mg daily). The authors state that aspirin had been discontinued 5 days before the proposed surgery, which would indicate that it had been withheld only 4 days before the epidural procedure. As a sole defect in coagulation, aspirin therapy is not generally considered to increase the risk of spinal hematoma formation with neuraxial block or catheter placement,11,24 even without discontinuation. Nonetheless, when combined with other antihemostatic agents, including LMWH, the risk is increased.9 The platelet defect associated with aspirin therapy persists for the life of the platelet and may therefore require 7 days to be reversed by new platelet formation.9
Neuraxial block and oral anticoagulants It is intriguing that, in 1983, Odoom and Sih reported 1000 lumbar epidural blocks for 950 patients undergoing peripheral vascular surgery, despite preoperative oral anticoagulant therapy.37 Although the prothrombin time (PT) and the antiquated thrombotest were outside of normal parameters at the time of the neuraxial procedure, no patient had evidence of a spinal hematoma. Nonetheless, permanent neurologic compromise due to spinal hematoma has indeed been reported in a patient receiving oral anticoagulant therapy (phenprocoumon) at the time of epidural catheter placement,38 and it is widely held that, with limited exceptions, this family of oral anticoagulant medications that impairs vitamin K-dependent carboxylation of clotting factors poses an important contra-indication to central neuraxial blockade.9,11,38 Many patients presenting for cardiac surgery have cardiac or extra-cardiac indications for oral anticoagulation, and observation of a suitable discontinuation period is warranted before surgery in these patients, should neuraxial blockade be planned. In the case of discontinuation of coumadin (as opposed to initiation of therapy), the prothrombin time (or international normalized ratio, INR) may initially correct toward normal without restoration of global hemostatic function, as a reflection of earlier return of factor VII levels, before adequate return of factors II, IX, and X. A fully corrected INR (ie, ⬍1.3), however, may be taken as evidence of adequate (⬎40% of normal) levels of all vitamin K-dependent factors.11 This can be anticipated to occur 4 to 5 days after cessation of coumadin therapy, but should be confirmed with measurement of the INR. Although uncommon among patients undergoing cardiac surgery, the practice of initiating oral anticoagulation as a single preoperative dose is not infrequent in other surgical settings and does not preclude safe spinal or epidural anesthesia, providing that needle puncture occurs less than 24 hours after initiation of coumadin therapy. A longer interval or more than one preoperative dose of coumadin should prompt confirmation of normal hemostatic parameters (PT and INR) before neuraxial blockade. The circumstances of epidural catheter removal may hold at least as much significance as the issue of catheter placement. At least two case reports39,40 describe the sce-
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nario of catheter placement in the preoperative setting, following the initiation of postoperative thromboprophylaxis with a single preoperative dose of coumadin, and with neurologic compromise following catheter removal. If lowdose coumadin therapy (eg, 5 mg daily) has been instituted for 36 hours or longer, the ASRA guidelines recommend that the PT/INR be verified before catheter removal.11 Where coumadin therapy has been instituted with the catheter in situ, the catheter may be withdrawn with mild prolongation of the PT, provided that the INR remains ⬍1.5. This distinction pertains to the early prolongation of the PT commensurate with rapid decline in factor VII activity, but with relatively delayed impairment of factors II, IX, and X. In the setting of higher dose coumadin or the goal of establishing therapeutic levels of anticoagulant therapy (ie, INR ⬎ 2.0), the catheter should be removed as described above but with the recommendation by the ASRA guidelines of “more intensive monitoring of the coagulation status.”11 The development of INR prolongation may, for example, occur within the 36-hour interval described above. The authors recommend deferral of catheter removal in the case of marked elevation of the INR (⬎3.0), but comment that the available literature does not support definitive recommendations regarding the issue of catheter removal following establishment of therapeutic levels of anticoagulation.11 In all cases where neuraxial blockade is initiated or continued with concomitant oral anticoagulant therapy, analgesic infusions should permit regular assessment of neurologic function (ie, minimal sensorimotor blockade), both during the infusion and for a minimum of 24 hours following catheter removal.
Neuraxial blockade and thrombolytic therapy In the second ASRA consensus conference on neuraxial anesthesia and anticoagulation, it was noted that “ . . . original contraindications for thrombolytic drugs suggest avoidance of these drugs for 10 days following puncture of noncompressible vessels.” Although a definite timeframe is not given, owing to lack of data, it is stated that caution should be exercised in the use of neuraxial techniques in the setting of recent preoperative or likely intra- or postoperative thrombolytic therapy. The authors also suggest that, where this combination cannot be avoided, the use of neuraxial drugs that minimize sensorimotor disturbance may facilitate the early detection of epidural hematoma formation. Finally, the issue of catheter removal is discussed, but without defining a safe interval following thrombolytic therapy, again due to lack of published data. It is suggested that confirmation of a normal fibrinogen level may provide some reassurance.
Newer anti-hemostatic agents Direct thrombin inhibitors (DTI) are being used in some patients with cardiac disease. These medications inhibit the
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formation of fibrin clot by directly binding and inhibiting factor IIa (thrombin), which normally serves to catalyze fibrin from fibrinogen. Further, thrombin-mediated platelet activation is also reduced. Distinction is made between bivalent DTIs (recombinant hirudins or hirudin analogues) which additionally inhibit fibrinogen at its thrombin binding site, and univalent DTIs which are synthetic molecules that solely inhibit thrombin. The indications for DTIs include anticoagulation during coronary angioplasty, treatment of heparin-induced thrombocytopenia (HIT), HIT-associated thrombosis, and, importantly, anticoagulation for cardiopulmonary bypass in patients with HIT. There are currently no data to guide the clinician regarding the safety of neuraxial blockade in the patients receiving direct thrombin inhibitors, however it has been suggested that knowledge of the half-life of these drugs may assist with anticipating a safe interval for normalization of coagulation.32 This may be of importance with unplanned DTI administration in the setting of an indwelling epidural catheter. Among the univalent DTIs, argatroban has the shortest half-life (35-45 minutes) and normalization of coagulation may be confirmed using the PTT, or the ecarin clotting time (ECT). Melagatran and ximelagatran have an elimination half-life of 3 to 5 hours and may accordingly become inactive after 8 to 10 hours. Bivalent DTIs include bivalirudin, lepirudin, and desirudin. Although the elimination halflife of these molecules is relatively short (eg, 25-30 minutes for bivalirudin), it is recommended that epidural or spinal needle placement be delayed at least 8 to 10 hours after administration of these agents. Renal or hepatic dysfunction may delay clearance of some of these agents. PTT and ECT may be used to confirm normalization of coagulation function.
Conclusions Several small case series have reported on the safety of neuraxial anesthesia and analgesia for cardiac surgery. However, accurate quantitation of the risk of neuraxial blockade in these patients depends on the future publication of large case series or complication reports. For now, the minimum risk is estimated to be similar to that of the noncardiac population, with a maximum risk perhaps up to three orders of magnitude greater. Adherence to published guidelines and detailed reports of complications and their circumstances will help to minimize risk from the procedure and/or any coexisting antihemostatic therapies. Infrequent case reports and published guidelines can guide clinical practice for maximum patient safety when neuraxial anesthesia or analgesia is considered.
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