Anticoagulants and neuro-axis blockades

MISCELLANEOUS

Anticoagulants and neuro-axis blockades^*

Anticoagulantes e bloqueios espinhais

Anticoagulantes y bloqueos espinales

Itagyba Martins Miranda Chaves, TSA, M.D.^I; Leandro Fellet Miranda Chaves, M.D.^II

^IProfessor Adjunto IV da Disciplina de Anestesiologia da FM da UFJF; Responsável pelo CET/SBA do Hospital Universitário de Juiz de Fora (HUJF); Supervisor da Residência e Serviço de Anestesiologia do HUJF (C.N.R.M.MEC)

^IIPreceptor Voluntário do Serviço de Anestesiologia do HUJF; Chefe do Serviço de Anestesiologia do Hospital ASCOMCER (Associação de Combate ao Câncer), Juiz de Fora; Anestesiologista do Hospital João Penido da FHEMIG (Fundação Hospitalar do Estado de Minas Gerais), Juiz de Fora

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: The use of anticoagulants for thromboprophylaxis has increased the incidence of spinal blockades hematomas. This review aimed at checking the incidence of spinal hematomas and its correlation with anticoagulant drugs.

CONTENTS: Some clinical and pharmacological considerations are made about thromboprophylactic drugs (cumarinics, aspirin and heparin). Risk factors are highlighted, especially those related to patients developing epidural hematomas due to the simultaneous use of low molecular weight heparin and epidural anesthesia.

CONCLUSIONS: There is an important correlation between epidural hematomas and hemorrhagic disorders, especially in patients under anticoagulant therapy. The awareness of the increased risk associated to epidural and spinal anesthesia, as well as the continuous surveillance and education are fundamental to prevent future cases.

Key Words: ANESTHETIC TECHNIQUES, Regional: epidural, spinal block; ANTICOAGULANTS; COMPLICATIONS: epidural hematoma

RESUMO

JUSTIFICATIVA E OBJETIVOS: Com o uso de anticoagulantes para tromboprofilaxia, a incidência de hematomas em anestesias espinhais aumentou. O objetivo desta revisão é verificar a ocorrência de casos de hematomas espinhais e sua correlação com o uso de drogas utilizadas na tromboprofilaxia.

CONTEÚDO: São feitas algumas considerações clínicas e farmacológicas sobre as drogas utilizadas em tromboprofilaxia (cumarínicos, aspirina e heparina). São ressaltados os fatores de risco, particularmente aos relatos de casos de pacientes que desenvolveram hematoma peridural decorrente do uso simultâneo de heparina de baixo peso molecular e anestesia peridural.

CONCLUSÕES: Existe importante associação entre hematoma peridural e distúrbios hemorrágicos, principalmente em pacientes em tratamento com anticoagulantes. O reconhecimento do aumento do risco da associação da anestesia peridural, da anestesia subaracnóidea, a continuada vigilância e a educação são fundamentais para evitar futuros casos.

Unitermos: ANTICOAGULANTES; COMPLICAÇÕES: hematoma peridural; TÉCNICAS ANESTÉSICAS, Regional: peridural, subaracnóidea

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Con el uso de anticoagulantes para tromboprofilaxia, la incidencia de hematomas en anestesias espinales aumentó. El objetivo de esta revisión es verificar la ocurrencia de casos de hematomas espinales y su correlación con el uso de drogas utilizadas en la tromboprofilaxia.

CONTENIDO: Son hechas algunas consideraciones clínicas y farmacológicas sobre las drogas utilizadas en tromboprofilaxia (cumarínicos, aspirina y heparina). Se destacan los factores de riesgo, particularmente a los relatos de casos de pacientes que desenvolvieron hematoma peridural decurrente del uso simultáneo de heparina de bajo peso molecular y anestesia peridural.

CONCLUSIONES: Existe importante asociación entre hematoma peridural y disturbios hemorrágicos, principalmente de pacientes en tratamiento con anticoagulantes. El reconocimiento del aumento del riesgo de la asociación de la anestesia peridural, de la anestesia subaracnóidea, la continuada vigilancia y la educación son fundamentales para evitar futuros casos.

INTRODUCTION

The incidence of spinal hematomas after spinal or epidural (simple or continuous) anesthesias in patients under anti-platelet agents, oral anticoagulants or heparin, although unknown, has been considered minor by several authors and is estimated to be 1 in every 150,000 epidural anesthesias and 1 in every 220,000 spinal anesthesias ^1.2. The Brazilian Journal of Anesthesiology has published two reports of clinical spinal hematomas, being one unrelated to previous use of anticoagulants ³ and the other, although published by a Brazilian author, has occurred abroad ⁴.

Although the complication may be caused by needle or catheter trauma in epidural or subarachnoid spaces, until 1964 more than 100 cases of spontaneous hematomas (neoplasic disease, vascular abnormalities) had been reported, 25 of which related to the use of anticoagulants ⁵. This article aimed at reviewing this potentially catastrophic complication, especially because in the last five years, several classic statements have been reviewed due to the increasing number of spinal anesthesia hematomas.

ANTICOAGULANT DRUGS

Oral anticoagulants, including cumarinic drugs, have an indirect action by interfering with vitamin K synthesis (factors VII, IX, X and thrombin). Due to the short biological half-life of factor VII (6 to 8 hrs), prothrombin time can be prolonged in 24 to 36 hrs. However, according to some authors, adequate anticoagulation is obtained in 2 to 3 days, while others state the need for 4 to 6 days of treatment. Factors II and X, for having a longer half-life, need more time to be totally depressed, unless a higher initial dose of cumarinics (15 to 30 mg) is used, what would increase the chance of hemorrhagic events. Its anticoagulant effect persists for 4 to 6 days after withdrawal and is rapidly reverted with frozen fresh plasma transfusion, vitamin K or prothrombin concentrate ^1,2-6.

PLATELET ANTI-AGGREGANTS

Aspirin (AAS) inhibits cycloxygenase, the key enzyme of the arachdonic acid cascade, in a dose-dependent way (30 to 300 mg/day) preventing the production of thromboxane A2 which, in addition to being a potent vasoconstrictor, facilitates secondary platelet aggregation. However, prostacyclin production (potent vasodilator and inhibitor of platelet aggregation) in the vascular endothelium requires higher aspirin doses to be inhibited (1.5 to 2 g/day). In general, low AAS doses inhibit platelet aggregation ⁷.

The effects of aspirin may last for 7 to 10 days ⁷. It acts on hemostasis first two stages and in clot formation⁹. It has been suggested that Ivy's bleeding time is the most reliable predictor of abnormal bleeding in patients receiving antiplatelet drugs ¹⁰. However, bleeding time determination after the use of aspirin is not reliable since, even with the exam normalizing in 3 days, platelet function evaluated by response to adenosine diphosphate or epinephrine may take 7 days to get normal ¹¹. In a paper published in 1997, Chestnut stated that "there was only one published case of hematoma after epidural anesthesia in a pre-eclampsia patient ... and what was interesting, with a 3 minutes bleeding time of unknown etiology". The author concluded that "the bleeding time analysis of 640 publications has shown that its diagnostic value is still obscure" ¹².

Some studies suggest that low aspirin doses (60 to 75 mg) do not significantly increase BT in pregnant women. The author stated that he does not ask BT for patients who present as sole risk factor the use of low aspirin doses ¹².

Non steroid anti-inflammatory drugs (NSAIDs) have also platelet anti-aggregant properties. The major NSAIDs mechanism is, as with aspirin, the inhibition of cycloxygenase activity, decreasing prostaglandin synthesis and interfering with the arachdonic acid cascade. Their platelet anti-aggregant properties, however, have short duration: 1 to 3 days after withdrawal ¹³, what led the authors to consider it insignificant as a risk factor ¹⁷. In a comprehensive review of cases reported between 1906 and 1994 where 61 spinal hematomas were found, there was only one case with the concomitant use of NSAIDs (indometacine) ⁷.

Ticlopidin is a platelet anti-aggregant of irreversible action, pharmacologically different from aspirin. Its risk of producing hematomas is still unknown. However, it cannot be ignored, since this drug has been increasingly used, especially in patients where aspirin is counterindicated ¹.

Thrombolytic agents (streptokinase and urokinase) dissolve already formed clots and decrease the levels of plasminogen and fibrin. Clot lysis leads to increase in fibrin breakdown products, which in turn have an anticoagulant effect for inhibiting platelet aggregation ¹.

HEPARINS

Non-fractionated or standard heparin has a mean molecular weight of 12,000 to 15,000 daltons and acts as anticoagulant by binding to and catalyzing antithrombin III.

The heparin-antithrombin III complex inhibits several procoagulant proteases, including factors IIa (thrombin), IXa, Xa, XIa and XIIa¹⁴. Its bioavailability reaches 30% at most ⁷. Intravenous 10,000 units heparin prolongs coagulation time 2 - 4 times in five minutes. Its plasma half-life is approximately 1,5 - 2 hours and the therapeutic effect disappears 4 to 6 hours after withdrawal. It can also be rapidly neutralized by protamine¹. Muscularly or subcutaneously, 5,000 units reach their anticoagulant peak in 40 to 50 minutes, which lasts for 4 to 6 hours ¹.

Low molecular weight heparins have a mean weight of 4,000 to 5,000 daltons, complete anti-Xa and relatively lower anti-IIa (thrombin) activities. After subcutaneous administration, they present 90% of bioavailability and anti-Xa activity peak in 3 to 4 hours. After 12 hours, plasma level is still approximately 50% of the initial peak. Their plasma half-life is 2 to 4 times that of standard heparin and is increased in renal failure.

With protamine it is possible to revert 90% of anti-IIa and 60% of anti-Xa activities. Being low molecular weight heparins administered by subcutaneous and deposit route, it must be highlighted that anti-IIa and anti-Xa activities may resume up to 3 hours after reversion with protamine due to absorption ¹⁴.

The types of heparin available in the market and their doses (prophylactic and therapeutic) are:

Non fractionated heparin: prophylaxis for low to moderate risk patients, subcutaneous 5,000 Ul.h^-1 every 12 hours; high risk patients, subcutaneous dose sufficient to maintain TTPa 1.5 times the testimonial. Treatment: intravenous 5,000 to 10,000 Ul priming dose and intravenous 1,300 Ul.h^-1 maintenance dose.

Low molecular weight heparin: enoxiparin (Clexane^®), nadroparin (Fraxiparin^®) and dalteparin (Fragmin^®). Prophylaxis for low and moderate risk patients; enoxiparin 0.2 ml (20 mg) once a day, nadroparin 0.3 ml (3,075 Ul) once a day and dalteparin 2.5 ml (2,500 Ul) once a day. For high risk patients the same doses are recommended, but at every 12 hours. Low molecular weight heparins are administered subcutaneously, as it is well known.

RISK FACTORS

A literature review shows that there is an important correlation between epidural hematomas and hemorrhagic disorders, especially in patients under anticoagulant therapy.

Two important studies point out the risk factors for hematomas formation. The first one is a classic work made by Vandermeulen ⁷. In a comprehensive review (1906-1994) of the most popular anticoagulants drugs, case reports of spinal hematomas after epidural and/or spinal anesthesias and the variables involved, in addition to a review of clinical trials of neuroaxial blocks in patients under anticoagulant therapy, he states that risk factors are: none (33%), patient's (21%) and drugs' (54%), distributed as follows: intravenous heparin (26%), subcutaneous heparin (13%), antiplatelets (7%), thrombolitics (3%) and others (5%). Another study carried out by a German University ¹⁵, also reviewing case reports from 1966 to 1995 (MEDLINE), shows some risk factors differences as compared to the first study: 51 cases of epidural anesthesia-related hematomas were confirmed, most of them related to difficult or traumatic catheter insertion (21 cases). Other risk factors were: antifibrinolitics (2 cases), previous unknown spinal disease (2 cases), low molecular weight heparin (2 cases), intravenous heparin (18 cases), aspirin or other non steroid anti-inflammatory drug (3 cases), catheter insertion during general anesthesia (3 cases), previous coagulopathies (14 cases), thrombocytopenia (5 cases) and ankilosing spondilytis (5 cases). In summary, 30 out of 61 cases between 1906-1994 and 25 out of 51 cases between 1966-1995 involved anticoagulants, especially heparin IV^7-15. For the association between epidural/spinal anesthesia and hematomas there have been 6 cases with epidural needles, 32 cases with catheters, 15 cases with spinal anesthesia without catheter and 8 unknown cases ⁷.

STUDIES AND CURRENT STATUS

Epidural hematoma is the most common cause of spinal injury with legal consequences ¹⁶. A study ¹⁷ has evaluated the risk of hematomas in 188 patients submitted to total knee replacement. Patients mean age was 68.5 + 9 years, being 105 females and 83 males. One week before, 23 were using 933 + 850 mg aspirin. All patients received postoperative continuous epidural analgesia. Their platelet counts were above 100,000, except for one with 96,000. Epidural catheters were introduced through an 18G needle and maintained for 1 to 4 days. Bleeding was seen in 13 cases during needle or catheter insertion. For postoperative thromboembolism prophylaxis, all patients received low warfarin doses (2.6 to 4.6 mg) to maintain prothrombin time between 15 and 17.3 s (normal of 10.9 to 12.8 s). In addition to warfarin, 36 patients with indwelling epidural catheters received NSAIDs. No spinal hematoma was detected. The authors concluded for the relative safety of low warfarin doses, stressing, however, that if the study had zero hematoma incidence, one should not expect the risk to be also zero. They draw attention to the great variability in patients' response to warfarin, demanding frequent coagulation analysis to avoid excessively prolonged prothrombin time. Patients with epidural catheters should be observed for signs and symptoms suggesting medullar compression, which demand immediate CT or MRI scanning. If the presence of hematoma is confirmed, the treatment is an early decompressive laminectomy, since recovery is unlikely after 12 hours delay.

Another prospective study ¹⁸ performed in 924 patients submitted to epidural or spinal anesthesia with or without catheter for 1,000 orthopedic surgeries, aimed at establishing the risk of regional anesthesia-related hemorrhagic complications. One hundred and fifteen patients had previous history of coagulation problems. Anti-platelet therapy was defined as aspirin ingestion up to one week before surgery (193 patients), NSAID up to 3 days before or heparin (25 patients). No patient submitted to preoperative anti-platelet therapy presented any minor hemorrhagic complications, especially signs and symptoms of spinal hematoma. However, the authors draw attention to risk factors such as: female gender, older age, history of important bleeding, hip surgery, continuous anesthetic techniques, large diameter needles, several puncture attempts and difficult catheter insertion.

Another important study to evaluate intravenous heparin safety involved 3,164 patients submitted to continuous epidural anesthesia and 847 to continuous spinal anesthesia. Exclusion criteria were coagulation disorders, plaquetopenia, anticoagulant therapy and those with bloody puncture. Heparin was administered one hour after catheter insertion to maintain activated coagulation time twice the baseline, and was repeated every 6 hours. No patient had signs or symptoms of spinal hematoma, including those with bloody puncture (n = 4), who were submitted to general anesthesia ¹⁹. These data, although tranquilizing and widely accepted, should not be overestimated, since the risk for spinal hematoma, even for this study, is high: 0.35%. However, in a prospective study ²⁰, 7 cases were found of spinal hematoma in 342 patients (2%) receiving intravenous heparin for diagnostic lumbar puncture. More recently, analyzing concluded sues, 13 out of 21 cases of medullar lesions occurred in patients submitted to anticoagulant therapy with heparin ¹⁶.

Regarding subcutaneous heparin, a review of more than 5,000 patients submitted to epidural or spinal anesthesia receiving different subcutaneous heparin doses found no spinal hematoma. According to this author, there are only three spinal hematoma reports in the literature in patients submitted to epidural or spinal anesthesia who received low subcutaneous heparin doses, two of them under continuous epidural anesthesia ¹⁴.

Low molecular weight heparin was first used in Europe in 1987. A study ²¹ reviewing 19 articles involving 9,013 patients in use of low molecular weight heparin submitted to epidural or spinal anesthesia has not found a single spinal hematoma, thus considering the association safe. Moreover, according to an estimate, more than one million patients had already been submitted to the above-mentioned procedure and only one case of hematoma was reported. In spite of this, a lot of care is recommended ²². A review of the European experience shows that the safety initially found may be false; the literature itself, between 1993 and 1995, brings practical and consistent guidelines among European Societies. Those guides recommend to avoid punctures and catheters removal in the 8 to 12 hours period following low molecular weight heparin administration, as well as delaying its administration to 1 to 2 hours after catheters removal and delaying even further after traumatic punctures, in addition to guides for patients neurological monitoring. Such recommendations have shown good results since only 11 cases of low molecular weight heparin-related spinal hematomas were reported in Europe since 1987²³. In The United States, noxiparin was approved by the Food and Drug Administration (FDA) in May 1993, with 30 mg every 12 hours regimen, first dose administered "as soon as possible after surgery". In one year, two spinal hematomas were reported, leading to a review of the drug's packet insert in 1995 to alert physicians about the risk of spinal hematomas in patients with indwelling catheters or being simultaneously treated with anti-platelet drugs. The new recommendation was that the first dose should be given 12 to 24 hours after surgery. Even then, spinal hematoma reports continued to increase and, in December 1997, after more than 30 cases, the FDA published a message to the Public Health Council which is summarized below ²⁴:

• The FDA would like to draw attention to recent reports of patients developing spinal hematomas with the simultaneous use of low molecular weight heparin and epidural/spinal anesthesia or lumbar puncture. Many of those hematomas have caused neurological injuries, including prolonged or permanent paralysis... It is still impossible to evaluate its incidence because reports were volunteer, but due to the severity of complications, patients and health professionals should be notified ... Although those cases involved patients treated with sodium enoxiparin, the same could be expected if drugs with similar pharmacological actions would also be used. Hence, the FDA asked low molecular weight heparin and heparinoid producers to adopt measures and provide information for the safe and effective use of such drugs, specifically precautions and care included in the packet insert...

• Until November 1997, more than 30 spinal hematoma cases were reported, 75% of them in elderly female patients submitted to orthopedic surgery...

• To date, the FDA believes that physicians should be alert for the following points when using such products:

1. Epidural and spinal anesthesia or lumbar puncture may cause prolonged neurological injuries or even permanent motor paralysis ...

2. This risk may be increased with the use of epidural catheters or drugs such as NSAIDs, platelet anti-aggregants or other anticoagulants, as well as traumatic or repeated spinal punctures ...

3. Patients should be monitored for neurological signs and symptoms which, if present, shall require urgent treatment...

4. Physicians should consider the risk/benefit ratio before performing epidural/spinal anesthesia and lumbar puncture in patients under anticoagulants therapy for thromboembolism prophylaxis ...

5. The FDA will continue to carefully monitor new cases ..."

In 1997, Tryba and Wedel compared the European experience (20 to 40 mg twice a day and practical guidelines) with that of the United States (30 mg twice a day) and estimated the hematoma's incidences of 1 case out of 2,250,000 and 1 out of 40,000, respectively ²⁵. Until April 1998, there were 40 cases in the USA, 11 in Europe and 5 in Australia until August 1999, with dalteparin or enoxiparin. It seems that the differences in doses between the USA and other countries is the major factor explaining the incidence discrepancies, so that from 1998 on, the USA adopted the regimen of 40 mg once a day for pulmonary embolism high risk patients ²⁶. In Brazil, the drug is administered once a day, and most pneumologists recommend a single daily enoxiparin dose of 20 mg for medium risk patients and 40 mg when the embolism risk is high. To date, there are no reports in the Brazilian Journal of Anesthesiology of spinal hematomas related to low molecular weight heparin and epidural or spinal anesthesia, despite the large number of anesthesias performed in patients at high and medium risk for pulmonary embolism, especially spinal anesthesia in elderly female patients submitted to orthopedic surgery (where there have been a 75% incidence in the USA). This reinforces the thesis that the single daily dose regimen is critical.

It is important to stress that, although the above mentioned incidence of spontaneous spinal hematomas⁷ and vascular puncture remaining between 1.6% and 10.6% in pediatric caudal anesthesia, there is no report in the literature of epidural hematoma after pediatric caudal anesthesia. A case report analysis between 1966 and 1995 after epidural anesthesia led to an estimate of one case of hematoma out of 190,000 anesthesias, where risk factors were coagulopathies and total anticoagulation. Thromboprophylaxis with low doses of heparin and treatment with NSAIDs have not increased the risk for subdural hematomas ²⁷.

CONCLUSIONS

For what has been said, it is difficult to elaborate guidelines that would totally eliminate such catastrophic complication, but it is possible to follow minimum standards for better safety, like those recommended by Wedel and Horlocker ²³, which should be divulged, even if summarized:

1. The lowest effective low molecular weight heparin dose should be administered in the preoperative period. The FDA has recently approved 40 mg enoxiparin once a day for thromboembolism prophylaxis after total hip replacement. A single daily dose is effective and allows catheter removal;

2. Low molecular weight heparin therapy should be delayed at least for 12 hours, and ideally, 24 hours after surgery;

3. Platelet anti-aggregants or anticoagulants, administered together with heparin, may increase spinal hematoma risk;

4. Spinal hematoma risk is higher in patients with indwelling catheters receiving low molecular weight heparin. Catheter removal before beginning heparin therapy eliminates this risk;

5. Catheter should only be removed when anticoagulation is low; if low molecular weight heparin is being used twice a day, it is recommended to skip one dose 12 hours before catheter removal, what will probably not increase the risk of thromboembolism;

6. All patients should be repeatedly neurologically evaluated. Diluted local anesthetics or opioids solutions do no impair evaluation. Progressive symptoms such as motor weakness, numbness, back pain, urinary dysfunctions or feces incontinence are very relevant when investigating the disease. In these cases, neurosurgical intervention is not only necessary but urgent (do not wait more than 8 hours) to avoid irreversible sequelae.

The recognition of the increased risk of the association of epidural/spinal anesthesia with low molecular weight heparin, the continuous surveillance, the frequent evaluation of information and education are critical to avoid future spinal hematomas.

REFERENCES

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Submitted for publication August 23, 2000

Accepted for publication October 25, 2000

*

Received from Universidade Federal de Juiz de Fora, MG (UFJF)

Publication Dates

• Publication in this collection
  10 Feb 2011
• Date of issue
  June 2001

History

• Received
  23 Aug 2000
• Accepted
  25 Oct 2000