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Epidurals in Patients Receiving Thromboprophylaxis with Unfractionated Heparin Three Times a Day: The Value of Activated Partial Thromboplastin Time Testing

Pace, Meredith MD; Koury, Katharine BA; Gulur, Padma MD

doi: 10.1213/ANE.0000000000000437
Regional Anesthesia: Research Report

BACKGROUND: Dosing subcutaneous (SC) unfractionated heparin (UFH) 3 times a day (TID) for deep venous thrombosis prophylaxis is used for patients in the United States undergoing nonorthopedic surgery. There is a lack of data on the risks of neuraxial techniques in patients receiving TID SC UFH; however, concerns have been raised about higher bleeding risks. In this prospective study, we evaluated the value of activated partial thromboplastin time (aPTT) testing at the time of removal of epidural catheters as a risk-reduction strategy for this population.

METHODS: We collected data from our electronic hospital databases for all patients receiving epidural analgesia in conjunction with 5000 units TID or twice daily dosing (BID) SC UFH from December 2011 to December 2013. Our cohort received aPTT testing before removal of the catheter in all patients receiving TID SC UFH. An aPTT was ordered for patients receiving BID SC UFH only if risk factors for abnormal coagulation variables were identified. Chart reviews were performed on all patients with abnormal aPTT values to evaluate contributing risk factors.

RESULTS: Over a 2-year period, 3523 epidurals were placed at our institution, including 714 (20.3%) for patients receiving TID SC UFH, and 1594 (45.2%) for patients receiving BID SC UFH. Of those patients receiving BID SC UFH, 186 (11.7%) had aPTT values drawn on the basis of risk factors. Ten (5.4 %, 95% CI: 2.6%–9.7%) of those patients had an aPTT value of greater than 35 seconds on the date of epidural removal. Of those patients receiving TID SC UFH, 20 (2.8%, 95% CI: 1.7%–4.3%) had an initial aPTT value of more than 35 seconds on the date of epidural removal. All patients who had abnormal aPTT values on TID heparin dosing were identified as having obvious concomitant risk factors for coagulation parameter abnormalities. There were no epidural hematomas in patients receiving either BID or TID dosing (95% CI: 0%–0.001%).

CONCLUSIONS: The routine use of aPTT testing on patients receiving TID SC UFH at the time of removal of epidural catheters as a risk-reduction strategy is not supported by our results, where only 2.8% (95% CI: 1.7%–4.3%) of these patients had abnormal aPTT values. Our study adds to the limited data currently available on the safety of epidural analgesia in patients receiving TID SC UFH. Given the rare incidence of neuraxial hematoma (95% CI: 0%–0.001%), definitive conclusions on the risks of TID SC UFH administration in patients receiving epidural analgesia cannot be drawn based on our sample size.

Published ahead of print September 15, 2014.

From the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Published ahead of print September 15, 2014.

Accepted for publication July 24, 2014.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence and reprint requests to Padma Gulur, MD, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 15 Parkman Street, WACC 340, Boston, MA 02114. Address e-mail to pgulur@partners.org.

Postoperative deep venous thrombosis prophylaxis with subcutaneous (SC) unfractionated heparin (UFH) dosed 3 times daily (TID) is one alternative for patients undergoing nonorthopedic surgery. Based on the low quality of data, the most recent recommendations by the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines does not differentiate between twice daily (BID) dosing and TID dosing, defining them both as “low-dose UFH.”1 Again recognizing the paucity of data regarding the risk of bleeding with TID dosing, the American Society of Regional Anesthesia (ASRA), by consensus opinion, recommends “the safety of neuraxial blockade in patients receiving doses greater than 10,000 U of UFH daily or more than twice-daily dosing of UFH has not been established. Although the use of thrice-daily UFH may lead to an increased risk of surgical-related bleeding, it is unclear whether there is an increased risk of spinal hematoma” and suggests “that the risk and benefits of thrice-daily UFH be assessed on an individual basis and that techniques to facilitate detection of new/progressive neurodeficits (e.g., enhanced neurologic monitoring occur and neuraxial solutions to minimize sensory and motor block) be applied”.2

Many institutions, including our own, have developed specific guidelines to facilitate epidural management for patients who are receiving TID SC UFH postoperatively.3,a–e The anticoagulant response to heparin can be monitored using the activated partial thromboplastin time (aPTT). As a risk-reduction strategy suggested by Davis et al.,3 practitioners confirm a normal aPTT value before removing the catheter in those patients receiving TID SC UFH.3 For patients with indwelling epidural catheters who receive BID SC UFH, routine aPTT testing is not indicated.2 Because heparin-induced thrombocytopenia may occur during heparin administration, both the European Society of Anaesthesiology and ASRA recommend that patients receiving heparin for more than 4 days have a platelet count assessed before neuraxial block and catheter removal.2,4 In addition, the ASRA guidelines suggest evaluation with full coagulation laboratory panels, including aPTT, for patients at increased risk of neuraxial hematoma secondary to traumatic epidural needle placement or the use of concomitant anticoagulants.2

There is, however, a lack of data on the actual incidence of epidural hematoma in patients receiving TID SC UFH. Conducting randomized studies to evaluate the safe management and removal of epidural catheters for patients receiving TID SC UFH is a challenge given the low incidence of epidural hematomas.3 Documentation of a normal aPTT value at the time of epidural catheter removal may seem to be a reasonable approach to decrease the risk for an unknown incidence of bleeding; however, it is not without its own implications on patient care and cost. This practice requires additional blood draws, has the potential to delay a patient’s postoperative course to discharge, and adds a laboratory fee for each aPTT test that can cost $50 to $70.5 We undertook a prospective observational study to evaluate the risk-reduction value of routine aPTT testing at epidural catheter removal for patients receiving TID SC UFH.

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METHODS

This prospective collection of data received approval from the Massachusetts General Hospital IRB. Based on an initial analysis, we determined that 18 to 24 months would be needed to collect data from at least 500 patients with epidurals receiving TID SC UFH. An electronic database containing information on patients who received epidural analgesia is actively maintained at our institution. Our group reviewed patient data over the 2-year period from December 1, 2011 to December 1, 2013. We evaluated aPTT values drawn on the day of epidural catheter removal when patients were receiving TID SC UFH, as dictated by our study protocol. For patients with other bleeding risk factors, however, such as concomitant use of other anticoagulants or antiplatelet medications, full coagulation studies (including aPTT) were evaluated independent of the thrombosis prophylaxis regimen. Removal of epidural catheters only occurred when aPTT values were ≤35, or if the benefits of removal outweighed the bleeding risks. If a patient had an abnormal aPTT value, the next dose of SC UFH was held. Repeat aPTT values were checked at least 2 hours later. If subsequent aPTT values remained high, then the Acute Pain Service assessed the overall benefits of pulling the epidural catheter. If the epidural catheter was removed in the setting of an abnormal aPTT value, then the patient was monitored for signs of neurological dysfunction for at least 24 hours. aPTT values were also collected for patients receiving BID SC UFH who exhibited risk factors for coagulation abnormalities. An aPTT test may have been drawn as part of a full coagulation laboratory analysis in these cases, depending on the specific risk factors present in each patient. Specific patient risk factors for abnormal aPTT values considered in our study protocol included preexisting liver dysfunction, administration of SC UFH for ≥5 days, and blood product transfusions.6,7

At this institution, an aPTT value of 35 is considered the upper limit of the normal range. The aPTT test is not standardized like the international normalized ratio, and so interpretation of values can be problematic. aPTT reagents differ in their sensitivities to heparin and can yield variable results among lots. For these reasons, each laboratory must establish a therapeutic range with each lot of aPTT reagent.8 Chart reviews were performed on all patients with epidurals and abnormal aPTT values to determine the exact SC UFH dose administration time before blood draw. These charts were also reviewed for risk factors that could alter coagulation variables including comorbidities and medications. The statistical results reported in this article were calculated using Exact binomial 95% confidence interval.

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RESULTS

Over the past 2 years, 3523 epidurals have been placed at our institution. Seven hundred fourteen epidurals (20.3%) were placed in and removed from patients receiving TID SC UFH, and 1594 (45.2%) epidurals were placed in and removed from patients receiving BID SC UFH. The average duration of epidural therapy for patients receiving TID SC UFH was 3.28 days in comparison with 2.94 days for patients receiving TID SC UFH. On average, blood draws were performed at 5:00 AM, approximately 9 hours after the patients’ last dose of SC UFH administration at 8:00 PM on the previous evening.

Of those patients with abnormal aPTT values receiving TID SC UFH, 60% had gastrointestinal surgical procedures, 20% had other oncologic procedures, 10% had urologic procedures, 5% had vascular procedures, and 5% had thoracic procedures. Of those patients with abnormal aPTT values receiving BID SC UFH, 70% had gastrointestinal surgical procedures, 20% had vascular procedures, and 10% had thoracic procedures (Table 1).

Table 1

Table 1

Of 714 epidurals in patients receiving TID SC UFH, 20 (2.8%, 95% CI: 1.7%–4.3%) had an initial aPTT value of higher than 35 seconds on the date of epidural removal. Four (0.56%) patients within this group had aPTT values higher than 40 seconds.

Of the 20 patients receiving TID SC UFH with abnormal aPTT values, a subsequent aPTT value of 35 seconds or less was confirmed before epidural removal in 10 patients. In 5 of the remaining 10 patients, the epidural was pulled with aPTT value between 35.1 and 35.5 seconds. The remaining 5 patients had their epidural removed with aPTT values ranging from 37 to 39 seconds.

Of those 20 patients receiving TID SC UFH with abnormal aPTT values before epidural removal, risk factors for abnormal coagulation were evident. Twelve patients in this group had undergone liver resection as a part of their surgical procedures. Two patients were having surgery for severe biliary strictures with associated liver dysfunction. Two patients received hetastarch as part of their perioperative resuscitation. One patient was noted to have an elevated preoperative aPTT value in the setting of disseminated infectious process. One patient received therapeutic IV heparin for a major vascular procedure.

Of the 1594 epidurals in patients receiving BID SC UFH, 186 (11.7%) patients had aPTT values checked because of risk factors identification. Ten (5.4%, 95% CI: 2.6%–9.7%) patients had an aPTT value higher than 35 seconds on the date of epidural removal, and 3 patients within this group (1.6%) had aPTT values higher than 40 seconds.

Of the 10 patients with abnormal aPTT values receiving BID SC UFH, a subsequent aPTT value of 35 seconds or less was confirmed before epidural removal in 4 patients. In the remaining 6 patients, the epidural was pulled with aPTT values ranging from 35.9 to 40.8 seconds.

Of those patients with abnormal aPTT values who received BID SC UFH, risk factors identified by clinicians at the time of epidural removal were collected by our group on chart review. Three patients in this group had undergone liver resection as a part of their surgical procedures. Three patients had abnormal preoperative aPTT values. Two patients received therapeutic IV heparin for major vascular procedures. One patient had preexisting liver dysfunction and received blood products intraoperatively.

Notably, there were no incidences of epidural hematoma in patients receiving TID SC UFH or BID SC UFH during the time period studied.

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DISCUSSION

As highlighted in the 2010 ASRA guidelines, the actual incidence of hemorrhagic complications associated with neuraxial blockade is unknown.2 Furthermore, the incidence of neurologic dysfunction in the setting of epidural hematoma is also unknown. Design and execution of randomized controlled trials to determine complication rates are restricted due to the rarity of these potentially devastating outcomes.2 Given the unknown incidence, but catastrophic potential of an epidural hematoma, the ASRA guidelines take a more conservative approach in their recommendation on the use of epidural analgesia in the setting of concurrent SC UFH prophylaxis.2

As a risk-reduction strategy for patients receiving TID SC UFH, Davis et al.3 have recommended routine aPTT testing to assure normal aPTT values at the time of epidural catheter removal. In this retrospective review, 928 patients received TID SC UFH therapy concurrent with postoperative epidural pain management, and 12% had an initial aPTT value of >40 seconds. For this subset of patients, subsequent heparin doses were held, and catheters were removed only when the aPTT value normalized. The authors attribute this alteration in epidural catheter management to a lower incidence of complications. They reported no incidences of epidural hematoma.

On review of the reports of neuraxial hematoma in the literature, none attribute TID SC UFH dosing as a cause of this complication.9–12 Rather, the concomitant use of antiplatelet drugs, such as nonsteroidal anti-inflammatory drugs, and difficult epidural catheter placement are implicated as possible causes for neuraxial space hemorrhage. These case studies support the idea that concurrent medications or individual patient factors may play a larger role than frequency of prophylactic SC UFH in an individual patient’s risk for epidural hematoma. Administration of prophylactic doses (5000 U) of SC heparin does not commonly prolong aPTT values.13 However, it can result in unpredictable, and possibly even therapeutic, plasma concentrations of heparin within 2 hours of administration.12 In our cohort, the majority of abnormal aPTT values were drawn more than 2 hours after administration of the last SC UFH dose. Consequently, most epidural catheters were removed several hours after this last dose of SC UFH, in an effort to avoid manipulation during peak plasma levels of heparin. Of the 30 patients with abnormal aPTT values, 6 patients had their epidural catheters removed before 2 hours had elapsed since their last SC UFH dose. In these patients, the elevated aPTT value may have been a consequence of the proximity to SC UFH dosing. None of these patients experienced bleeding complications. Of note, in the study by Davis et al.,3 37 patients had epidurals removed with aPTT values above normal, none of which experienced bleeding complications.3

Our results demonstrate that the frequency of abnormal aPTT values in patients receiving TID SC UFH is not high (2.8%, 95% CI: 1.7%–4.3%). This is lower than 12.3%, the rate reported by Davis et al.3 Importantly, the patients in our cohort who demonstrated abnormal aPTT values were also identified as having causative risk factors. Although our study protocol required documenting an aPTT value less than 35 seconds (the upper end of the normal range in our laboratory) before epidural removal in any patient receiving TID SC UFH, risk factors in these particular patients would have necessitated checking coagulation variables, regardless of the protocol. We therefore argue that the policy in place for routine checking of aPTT values in these patients did not lead to the discovery of an abnormal value that would have otherwise gone undetected. Clinical suspicion of bleeding risk was identified based on individual patient risk factors, and these patients’ coagulation status would have been monitored independent of their thromboprophylactic regimen. We propose that routine monitoring of aPTT values in all patients receiving TID SC UFH as a risk-reduction strategy is not supported.

Our data add to the growing body of literature on the safe use of epidural analgesia in patients receiving TID SC UFH because there were no epidural hematomas reported in our study cohort. Our findings do not validate routine testing of aPTT in patients receiving TID SC UFH, which has health care implications as a laboratory test that is not only invasive, but also adds cost (95% CI: 1.7%–4.3%).5 However, those patients receiving prolonged SC UFH administration or those who have comorbidities that might influence the pharmacological expression of the drug should be considered at higher bleeding risk and epidural management should include aPTT testing. For instance, patients receiving concurrent administration of UFH therapy in addition to other drugs that interfere with hemostasis are likely to be at increased risk of bleeding. These patients may require other coagulation studies, in addition to aPTT, when managing epidural catheters.2 Further research is needed to substantiate the utility of routine aPTT monitoring as a risk-reduction strategy for patients on TID SC UFH.

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ACKNOWLEDGMENTS

The authors thank Adam Carinci, MD, Brinda Kamdar, MD, JingPing Wang, MD, PhD, and Yi Zhang, MD, of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, and Hang Lee, PhD, from the Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.

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DISCLOSURES

Name: Meredith Pace, MD.

Contribution: This author collected the data, analyzed the data, and edited the manuscript to its present state.

Attestation: Meredith Pace attests to the integrity of the original data and the analysis reported in this manuscript. Meredith Pace approved the final manuscript.

Name: Katharine Koury, BA.

Contribution: This author collected the data, analyzed the data, and edited the manuscript to its present state.

Attestation: Katharine Koury attests to the integrity of the original data and the analysis reported in this manuscript. Katharine Koury approved the final manuscript.

Name: Padma Gulur, MD.

Contribution: This author designed the study, conceptualized the article, and edited the manuscript to its present state.

Attestation: Padma Gulur is the archival author, and attests to the integrity of the original data and the analysis reported in this manuscript. Padma Gulur approved the final manuscript.

This manuscript was handled by: Terese T. Horlocker, MD.

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FOOTNOTES

a Anticoagulation in the presence of neuraxial anesthesia. Available at: http://www.ucdmc.ucdavis.edu/anticoag/pdf/AnticoagulationNeuraxialAnesthesia.pdf. Accessed January 24, 2014.
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b Anticoagulation guidelines for neuraxial procedures: Guidelines to minimize risk spinal hematoma with neuraxial procedures. Available at: http://ether.stanford.edu/policies/Anticoagulation_Guidelines_Neuraxial_Procedures.html. Accessed January 24, 2014.
Cited Here...

c Anticoagulation guidelines for neuraxial or peripheral nerve procedures: Guidelines to prevent spinal hematoma following epidural/intrathecal/spinal procedures and perineural hemtatoma following peripheral nerve procedures. Available at: http://depts.washington.edu/anticoag/home/sites/default/files/Neuraxial%20Guidelines_1.pdf. Accessed January 24, 2014.
Cited Here...

d Regional anaesthesia in patients with abnormalities in coagulation. Available at: http://www.aagbi.org/sites/default/files/RAPAC%20for%20consultation.pdf. Accessed January 24, 2014.
Cited Here...

e Neuraxial anesthesia in the anticoagulated Pt. Available at: http://anesthesiology.queensu.ca/clinical_guidelines/neuraxial_anesthesia_in_the_anticoagulated_patie. Accessed January 24, 2014.
Cited Here...

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