Thromboprophilaxis and neuraxial blockade

REVIEW ARTICLE

Thromboprophilaxis and neuraxial blockade^*

Tromboprofilaxia e bloqueio regional

Tromboprofilaxia y bloqueo regional

Américo Massafuni Yamashita, TSA, M.D.^I; Heitor Yassuda, M.D.^II

^IProfessor Assistente de Anestesiologia da Universidade Federal do Estado de São Paulo (UNIFESP)

^IIAnestesiologista do Hospital Nipo-Brasileiro, Especialista em Dor pela UNIFESP

Correspondence

SUMMARY

BACKGROUND AND OBJECTIVES: Among peripheral vascular diseases, thromboembolytic venous disease has gained significant importance due to its high frequency, morbidity and mortality, and, moreover, due to the possibility of interrupting its evolution when there is an adequate diagnosis and treatment. The increasing use of thromboprophylaxis has become a problem for anesthesiologists since those agents have increased the incidence of spinal hematoma when associated to regional anesthesia. After a broad literature review, this study aimed at presenting to anesthesiologists the biochemistry and pharmacology of most commonly used anticoagulants as well as recommendations for regional blockade in patients under anticoagulants.

CONTENTS: Characteristics of different anticoagulants and regional anesthesia implications are presented. After each drug description there are considerations about the most important recommendations.

CONCLUSIONS: Regional anesthesia under thromboprophylaxis demands lots of caution, especially as to the use of epidural catheters and repeated and traumatic punctures because, in those cases, there is an increased risk for spinal hematomas. In addition, communication between the clinical and nursing staff involved in the management of patients receiving anticoagulants is essential in order to decrease the risk for severe hemorrhagic complications. Patients should be closely monitored for early signs of cord compression. If spinal hematoma is suspected, radiographic confirmation must be immediately sought due to the risk for irreversible cord ischemia.

Key words: ANESTHETIC TECHNIQUES, Regional: epidural, spinal block; ANTICOAGULANTS

RESUMO

JUSTIFICATIVA E OBJETIVOS: No contexto das doenças vasculares periféricas, a doença venosa tromboembólica tem assumido maior importância, à medida em que se apresenta com freqüência e morbi-mortalidade elevadas e, sobretudo, pela possibilidade de alteração de sua evolução quando há reconhecimento e tratamento adequados. O uso cada vez mais freqüente de tromboprofiláticos tornou-se um problema para os anestesiologistas, uma vez que esses agentes têm aumentado a incidência de hematoma espinhal, quando associados a bloqueios regionais. Este trabalho tem o propósito de apresentar aos anestesiologistas, a partir de ampla revisão de literatura, aspectos farmacológicos e bioquímicos dos anticoagulantes mais comumente utilizados e orientações quando houver necessidade de bloqueio regional nos pacientes em esquema de anticoagulação.

CONTEÚDO: São apresentadas as características dos diferentes anticoagulantes e implicações no bloqueio regional. No final da descrição de cada fármaco, seguem-se considerações a respeito das recomendações mais importantes.

CONCLUSÕES: A realização de bloqueio regional, na vigência de tromboprofilaxia, exige redimensionamento das cautelas, principalmente nos aspectos concernentes à utilização de cateter peridural, punções repetidas e traumáticas; pois, nestes casos, o risco da ocorrência de hematoma espinhal estará aumentado. Adicionalmente, fazem-se necessárias ampla comunicação e preparo das equipes médica e de enfermagem quanto aos pacientes recebendo anticoagulantes, a fim de diminuir os riscos das complicações hemorrágicas. Esses pacientes devem ser monitorizados minuciosamente, a fim de que sejam detectados precocemente sinais incipientes de compressão medular. Se houver suspeita de hematoma espinhal, a confirmação radiográfica deverá ser providenciada imediatamente, devido ao risco de isquemia medular irreversível.

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

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: En el contexto de las enfermedades vasculares periféricas, la enfermedad venosa tromboembólica ha asumido mayor importancia, a medida en que se presenta con frecuencia, y morbi-mortalidad elevadas y, sobretodo, por la posibilidad de alteración de su evolución cuando hay reconocimiento y tratamiento adecuados. El uso cada vez más frecuente de tromboprofilácticos se tornó un problema para los anestesiologistas, una vez que esos agentes han aumentado la incidencia de hematoma espinal, cuando asociados a bloqueos regionales. Este trabajo tiene el propósito de presentar a los anestesiologistas, a partir de una amplia revisión de literatura, aspectos farmacológicos y bioquímicos de los anticoagulantes más comunes utilizados y orientaciones cuando haya necesidad de bloqueo regional en los pacientes en esquema de anticoagulación.

CONTENIDO: Son presentadas las características de los diferentes anticoagulantes e implicaciones en el bloqueo regional. Al final de la descripción de cada fármaco, se siguen consideraciones a respecto de las recomendaciones más importantes.

CONCLUSIONES: La realización de bloqueo regional, en vigencia de tromboprofilaxia, exige redimensionamento de las cautelas, principalmente en los aspectos concernientes a la utilización de catéter peridural, punciones repetidas y traumáticas; pues, en estos casos, el riesgo de la ocurrencia de hematoma espinal estará aumentado. Adicionalmente, se hacen necesarias amplia comunicación y preparo de los equipos médicos y de enfermaría cuanto a los pacientes recibiendo anticoagulantes, a fin de diminuir los riesgos de las complicaciones hemorrágicas. Esos pacientes deben ser monitorizados minuciosamente, con la finalidad de que sean detectados de forma precoz, señales incipientes de compresión medular. En caso de que haya sospecha de hematoma espinal, la confirmación radiográfica deberá ser providenciada inmediatamente, debido al riesgo de isquemia medular irreversible.

INTRODUCTION

Postoperative deep vein thrombosis (DVT) depends on patient and surgery-related factors. The incidence ranges from 10% to 80% such as in orthopedic trauma, and may evolve to fatal embolism in 2.5% of times ^1-6. These figures may however be underestimated if postmortem studies about thromboembolytic phenomena are taken into consideration ⁷.

Even under adequate anticoagulation therapy, approximately 50% of proximal DVT cases, such as those affecting the ileum-femoral segment, will cause pulmonary embolism and only 20% of patients will have total thrombi lysis after six months of treatment ⁸.

Pulmonary embolism (PE) is the most severe acute DVT complication being the third major cause of death in the USA with a mortality of 15% to 20% (approximately 200.000 American citizens a year) ⁹.

Some studies involving risk patients ^1,3,4,10 have shown that the use of prophylactic subcutaneous heparin or of low molecular weight heparin (LMWH) may reduce DVT risk.

Thromboprophylaxis, on the other hand, when associated to regional anesthesia, has increased spinal hematoma incidence in the USA, especially after a wide use of low molecular weight heparin. From 1993 to 1998, 40 spinal hematoma cases were reported in the USA ¹¹. In Europe, spinal hematomas incidence has been lower, in spite of the use of LMWH since the 80’s. This is probably due to management standardization after the first incidents. There were 11 hematomas after 1987 ¹². In spite of such risk, regional anesthesia is encouraged in patients under anticoagulation therapy due to postoperative benefits such as: decrease in abdominal ileum, pulmonary complications, adverse cardiac effects, thrombi incidence in patients submitted to vascular surgeries ¹³ and improved motility in orthopedic patients ¹⁴.

This study aimed at discussing the characteristics of different anticoagulant and antiplatelet drugs and their implications in regional anesthesia. After each drug description there are considerations about the most important recommendations.

DEEP VEIN THROMBOSIS ETIOLOGY

Approximately 80% to 90% of times, thrombosis may be identified by laboratory evaluation ¹⁵. DVT-related factors may be divided into clinical factors and hereditary or acquired plasma defects ^16-18.

Clinical DVT-related conditions are: venous stasis, sepsis, postoperative period, neoplasias, trauma, congestive heart failure, nephrotic syndrome, venous failure, obesity, burns, elder age, estrogen-containing drugs and anatomic vascular problems ¹⁹.

Hematological changes predisposing to thrombotic phenomena are: deficiency of antithrombin III, protein C, protein S, plasminogen, heparin co-factor II, plasminogen tissue activator (t-PA), cystionin B synthetase, defibrinogenemia, the recently described factor V molecular defect, which makes it resistant to activated protein C, polycythemia, the presence of antilupus anticoagulant or antiphospholipid antibodies, benign and malignant thrombocytosis and increase in t-PA type 1 inhibitor. Factor XII deficiency, factor VII increase, fibrinogen and lipoprotein A deficiency may also be associated to hypercoagulation. Literature has shown that from all juvenile or recurrent thrombosis, approximately 40% are associated to resistance to activated protein C and 10% are related to protein S, C and antithrombin III deficiency in addition to less frequent conditions ^20,21. Considering venous thrombosis as a whole, only 20% are related to those causes ²².

DEEP VEIN THROMBOSIS

Venous thrombosis varies depending on risk factors and the severity of some diseases. There are no accurate data on the actual incidence of such disease, especially in Brazil. American literature refers that orthopedic patients represent a group of special risk for thromboembolytic complications, especially total hip or knee arthroplasty. Other patients are routinely submitted to thromboprophylaxis, especially when there is the possibility of prolonged imobilization²³.

HEMATOMA AND CENTRAL NERVOUS BLOCKADE

Data on hematomas and central nervous block are not precise. Wulf, in a retrospective study in 1996 ²⁴, reported a post epidural anesthesia incidence of 1:190.000 to 1:200.000.

Vandermuelen et al. ²⁵ have identified 61 hematomas associated to spinal or epidural anesthesia in the period 1906-1994.

In the last 30 years, 199 spontaneous epidural hematomas were identified, 20% of which associated to anticoagulation therapy ²⁶.

THROMBOPROPHYLAXIS INDICATIONS, COUNTERINDICATIONS AND COMPLICATIONS

Thromboprophylaxis is indicated in the following conditions ^19,27,28:

· Venous thromboembolism;

· Acute arterial occlusion;

· Cardiac prosthesis;

· Atrial fibrillation;

· Cardioversion;

· Myocardial infarction;

· Disseminated intravascular coagulation;

· Others: arterial shunt occlusion prevention (venous or synthetic) and bypass device occlusion prevention (intravascular catheters, hemodialysis machines, cardiopulmonary bypass machines).

Thromboprophylaxis is counterindicated in the following conditions ^19,27,28:

· Hemorrhage risk or presence of hemorrhagic problems;

· Hypertension (systolic or diastolic);

· Stroke or recent CNS surgery;

· Recent eye surgery;

· Traumas or major surgeries with extensive detachments (for less than 10 days);

· Severe liver or renal failure;

· Pregnancy (oral anticoagulants): 1^st and 3^rd trimesters.

Thromboprophylaxis is not free from complications and the most common are²⁹:

· Hemorrhages;

· Thrombocytopenia (heparin);

· Osteoporosis;

· Urticaria;

· Hyperaldosteronism;

· Skin necrosis;

· Embryopathies.

RISK FOR DEEP VEIN THROMBOSIS

Risk Groups for deep vein thrombosis are ²⁹:

· DVT or pulmonary embolism (PE) history;

· Varicose veins;

· More than 40 years of age;

· Paraplegia or quadriplegia;

· Anesthetic duration for more than 30 minutes;

· Surgical trauma, especially orthopedic;

· Trauma, especially fractures;

· Malignancy;

· Obesity;

· Chemotherapy;

· Prolonged immobilization;

· Estrogen;

· Pregnancy;

· Burns;

· Congestive heart failure;

· Inflammatory bowel disease;

· Hematological diseases (erythrocytosis, thrombocytosis);

· Hypercoagulation.

SURGERY AND VENOUS THROMBOEMBOLISM

There are several proposals to correlate type of surgery to DVT ²⁹. Chart I was prepared according to the European consensus ³⁰. DVT prophylaxis is recommended for high and moderate risk patients.

Brazilian Journal of Anesthesiology, 2001; 51: 4: 350 - 366

Thromboprophilaxis and neuraxial blockade

Américo Massafuni Yamashita; Heitor Yassuda

RISK FACTORS FOR SPINAL HEMATOMA

A literature review on spinal hematoma and regional blocks allowed for the identification of some risk factors which should be taken into consideration before anesthesia induction:

· Elder age. According to Rudorfer and List, 75% were female patients with more than 75 years of age ³¹;

· Continuous epidural anesthesia ³²;

· Other drugs affecting hemostasia ²⁴;

· Repeated and/or traumatic punctures ^24,33;

· Previous/family dyscrasia history;

· Liver disease, alcoholism;

· Renal disease and low molecular weight heparin ³⁴.

PHARMACOLOGICAL CHARACTERISTICS OF THROMBOPROPHYLACTIC AGENTS AND RECOMMENDATIONS FOR REGIONAL ANESTHESIA

Oral Anticoagulants

Oral anticoagulants or anti-vitamin K drugs (AVK) have structures similar to vitamin K and act by simple competition with the natural molecule. The hemostatic defect after AVK administration is the deficiency of factors II, VII, IX and X and of proteins C and S.

Oral anticoagulants are administered in patients needing chronic anticoagulation and perioperative thromboprophylaxis.

Oral anticoagulants do not have an immediate effect and depend on several factors such as the type of drug, individual response and variations in dietary vitamin K ³⁵.

Lab monitoring of anti-vitamin K (AVK) drugs is performed by measuring prothrombin time (PT) or by the Quick method, which is a more sensitive test for vitamin K-dependent factors deficiency ³⁶. Results may be expressed in seconds as compared to normal individuals plasma (in general, the day control) and as a percentage of normal control (prothrombin activity). Prothrombin activity should be maintained between 20% and 30%, or 1.5 to 2 times the control ¹⁵. Comparison of different laboratory results is difficult due to the non-standardization of thromboplastin, substrate of different origins used for such determination.

The International Society for Hemostasia and Thrombosis ³⁷ has established, in 1980, a standardization system which allows for a parallelism among different thromboplastins with a standard thromboplastin³⁸. Such standardization may be achieved by determining the “International Sensitivity Index” (ISI) for each prothrombin, calculated for each batch and expressed in the reagent’s packet insert. Once the ISI is determined, it is possible to calculate INR (International Normalized Ratio). So, it is possible to define a desirable anticoagulation level for each clinical situation, ruling out possible sensitive differences of all reagents available in the market. Oral anticoagulant dose adjustment must be based on such criteria. The adequate anticoagulation level for each situation has been determined by clinical trials based on thrombosis frequency and bleeding risk ³⁶. Anticoagulation levels are summarized in table I ¹⁹.

Brazilian Journal of Anesthesiology, 2001; 51: 4: 350 - 366

Thromboprophilaxis and neuraxial blockade

Américo Massafuni Yamashita; Heitor Yassuda

It is known that INR is more variable in the beginning of the treatment and that regimens are proposed to predict the initial dose for the therapeutic dose to be reached as early as possible ³⁹.

Coagulation factors involved have different half-lives (Factor VII from 6 to 8 hours; Factor II from 36 to 48 hours; Factor X from 72 to 96 hours) ⁴⁰. As a consequence, INR values (1.4 or normal) not always provide a normal coagulation status in patients acutely interrupting oral anticoagulation therapy.

In early anticoagulation therapy, PT value reflects primarily the fast Factor VII depletion. Factor VII may be within acceptable values (PT is prolonged when Factor VII activity is reduced in approximately 55%), however factors II and X may be in inadequate levels for a normal hemostasia ⁴¹.

Preliminary studies indicate a safe epidural block for patients under low warfarin doses (mean of 5 mg/day) ⁴². Higher doses need more intensive monitoring of the coagulation system.

Antiplatelet therapy associated to oral anticoagulants may be used to prevent arterial processes. In those cases, recommended anticoagulant control indices should be decreased.

There are two regional anesthesia-related spinal hematomas reported in patients receiving preoperative warfarin for thromboembolism prophylaxis. Both cases had an inadequate catheter removal time. In the first report ⁴³, the epidural catheter was removed in the second postoperative day with an INR of 6.3. In a different report ⁴⁴, the catheter was removed 30 days after surgery with a PT of 17.3 seconds.

Recommendations ⁴¹:

1. Oral anticoagulants are to be withdrawn from chronic patients and prothrombin time and INR should be evaluated before spinal anesthesia.

2. The concurrent administration of drugs affecting other coagulation cascade components may increase the risk for bleeding complications in patients under oral anticoagulants, without changes in PT and INR. Such drugs include aspirin, NSAIDs and heparin.

3. PT and INR should be evaluated before neuraxial blockade in patients receiving an initial preoperative warfarin dose (if the first dose was administered more than 24 hours ago or if a second oral anticoagulant dose is administered).

4. PT and INR should be daily evaluated in patients receiving low warfarin doses during epidural anesthesia. Such evaluation should also be performed before epidural catheter removal.

5. Sensory and motor function exams should be routinely performed in patients with epidural analgesia and under warfarin. Low concentrations of local anesthetics associated to opioids should be preferably used to decrease sensory and motor block intensity. Such exams should be performed even after epidural catheter removal at least for 24 hours after such maneuver, and for a longer period if INR is above 1.5 at catheter removal.

6. If INR value is above 3, the anesthesiologist should withdraw or decrease warfarin dose in catheterized patients. When continuous infusion is being used, risk/benefit ratio should be evaluated as to catheter removal or maintenance.

7. Warfarin dose should be decreased in patients with possible exacerbated drug response.

Antiplatelet Drugs - Acetylsalicylic Acid, Ticlopidine, Dipiramidol, Dextrane, Chlofibrate

Acetylsalicylic acid causes an irreversible acetylation of cycloxygenase, which is the central enzyme of the arachidonic acid cascade activation, and deactivates it. Depending on the dose, acetylsalicylic acid may induce differential inhibition of prostaglandin synthesis in platelets and endothelial cells. Platelet cycloxygenase is inhibited by low acetylsalicylic acid doses (30 to 300 mg/day) especially by blocking thromboxane A production (potent vasoconstrictor and platelet aggregator). The production of prostacyclin (potent vasodilator and platelet aggregation inhibitor) in the vascular endothelium is less influenced by acetylsalicylic acid, which will only cause inhibition at higher doses (1.5 to 2 g/day) ^45-47.

NSAIDs promote reversible competitive platelet inhibition. Platelet function returns to normal within 1 to 3 days after drug withdrawal ⁴⁶. They are used in arterial thrombosis prophylaxis and are useless in deep vein thrombosis patients ³⁶.

Antiplatelet drugs alone do not pose a significant risk for spinal hematomas in patients to be submitted to epidural or spinal anesthesia ⁴⁶.

Some studies^48-50 have shown the absence of spinal hematomas associated to antiplatelet drugs, but this cannot be definitively accepted because such drugs increase this risk, although there is only one hematoma case reported by the literature. The association of antiplatelet drugs to other anticoagulants increases the risk for hemorrhagic complications ^50,51.

There is no lab test generally accepted as a reference for antiplatelet therapy ⁴⁶. Patient’s careful preoperative evaluation to identify organic changes contributing to bleeding is critical ⁴⁶.

To date, there are no specifications for the association of catheter to NSAIDs, postoperative monitoring time or adequate catheter removal time ⁴⁶.

Fibrinolytic and Thrombolytic Drugs

These drugs may be classified in two groups: a) normal fibrinolysis-stimulating agents, such as pyrogens, epinephrine, insulin, nicotinic acid; b) thrombolytic agents, which are direct fibrinolysis activators: streptokinase, urokinase and recombinant tissue plasminogen activator factor (rt-PA) ⁵².

Streptokinase is a simple polypeptide chain protein derived from the betahemolytic streptococcus. Its biochemical structure is similar to human tripsin and forms a 1:1 stechiometric complex with plasminogen activating both circulating and fibrin-bound forms.

Excessive circulating plasmin breaks down fibrinogen and factors V and VII causing systemic hypocoagulation for 24 to 36 hours, until they undergo a new liver synthesis. Streptokinase is antigenic and the levels of anti-streptokinase antibodies increase as from the 5^th to the 7^th day with a peak around the 3^rd month and returning to baseline levels after 6 to 9 months ⁵³.

Natural t-PA synthesization by endothelial cells into simple chain molecules, is rapidly cleaved in double chain, both with similar fibrinolytic activity. As opposed to streptokinase, it is inactive in the absence of fibrin, but when present, there is a 1000-fold increase in its plasminogen activating ability. Since plasmin production is limited to the clot surface, there is a minor systemic hypocoagulation. It is produced by recombinant DNA technique under the form of simple (alteplase) or double (duteplase) chain ⁵³.

Urokinase, a fibrinolytic enzyme isolated from human urine, is rapidly inactivated by urinary uropeptidase. It is not antigenic and directly activates plasminogen. Obtained from the culture of renal parenchyma embryonary cells and of E. Coli bacteria, it is currently produced by genetic engineering techniques (recombinant DNA) ^53,54.

Thrombolytic agents dissolve already formed thrombi, differently from anticoagulants which prevent the growth, embolization and development of new thrombi ⁵².

Such agents are used to treat vascular disease, myocardial infarction and may represent a risk for regional anesthesia.

They promote plasminogen cleavage into plasmin, promoting pathological and hemostatic thrombolysis.

Some authors have observed hematomas after the use of thrombolytic agents and regional anesthesia ^24,55-58.

With the advance of fibrinolytic-thrombolytic therapy, such drugs are being increasingly used in the perioperative period, demanding a better control of such patients ⁵⁹.

Recommendations:

1. Invasive procedures (e.g. central venous puncture) in general should be avoided during thrombolytic therapy ^49,50.

2. The association of regional blockade in patients under fibrinolytics and/or thrombolytics is counterindicated. When perioperatively needed, general anesthesia is recommended.

STANDARD/NON FRACTIONATED HEPARIN

Heparin is a heterogeneous mixture of natural polysaccharide polymers extracted from animal organs, with a molecular weight between 3000 to 30000 Dalton (mean of 12000 to 15000) and may be associated to sodium or calcium salts ^19,28.

Action mechanisms may be primary or secondary ^19,28:

Primary:

· Prothrombin into thrombin translation inhibition (anti-IIa action);

· Factor X (anti-Xa) inhibition, especially LMWH;

· Fibrinogen into fibrin translation inhibition;

· Platelet aggregation inhibition.

Secondary:

1. Interferes with other coagulation proteases (such as factors IX, XI and XII);

2. Prevents fibrin stabilization by factor XIII;

3. Acts as a plasma lipemic clarifying factor.

Its biological action, expressed in IU (international units) does not meet current evaluation criteria for biological drugs. New products have used anti-Xa activity expression ⁶⁰.

Heparin is metabolized by the liver and excreted by the kidney.

Heparin, for not crossing placental barrier, does not produce noxious fetal effects.

Heparin is not orally absorbed. Heparin’s bioavailability is limited (30% intravenous and 15% subcutaneous) due to its binding to plasma proteins, plasma, endothelial cells and vessel wall proteins.

Low doses are indicated to prevent DVT in patients with a certain thrombotic risk (postoperative period of abdominal and orthopedic surgeries, presence of neoplasias or sepsis, prolonged rest ⁶¹). The benefits of heparin prophilactic use is attributed to its high biding affinity to antithrombin III. Such affinity results in elective inhibition of thrombin (factor IIa), factor Xa, factor XIa, factor IXa, XIa and XIIa. Thrombin (factor IIa) is more responsive to this binding affinity resulting in more sensitivity to inhibion when antithrombin III and heparin are associated ¹⁹.

Subcutaneous Non Fractionated Heparin (NFH)

The recommended dose is 5000 IU every 12 hours ⁵². Peri or postoperative hemorrhagic complications are seldom significant; however, NFH administration is restricted to 60 minutes after regional blockade.

Subcutaneous NFH onset time is 90 minutes and its half-life is more than 4 hours. Subcutaneous heparin peaks at 2 to 4 hours.

In general, lab tests are normal for patients under subcutaneous NFH; however, TTPa must be controlled in hyper-reactive patients or those in simultaneous use of other drugs affecting coagulation, prolonged heparinization and weak patients ⁶².

Intravenous Non-Fractionated Heparin (NFH)

Intravenous NFH is administered as an anticoagulant in cardiovascular surgery patients and to prevent arterial thrombosis. Intravenous bolus administration results in an immediate anticoagulant effect and has a 1 to 2-hour half-life. Half-life is dose-dependent and its action may be substantially different in high doses. In general, 2500 to 5000 IU are used as the priming dose ⁵².

NFH’s anticoagulant effect is neutralized by an equimolar protamine dose (neutralizes factor anti IIa).

In some clinical situations, such as vascular surgeries, there is the need to maintain NFH in the peri and postoperative period, thus counterindicating regional block.

Studies have shown that systemic heparinization one to two hours after spinal block is relatively safe and frequently used in vascular surgery ^44,63,64. Regional blocks increase blood flow in the limbs of occlusive arteriosclerosis patients reducing postoperative prosthesis thrombosis ¹³.

In cardiac surgeries, spinal blocks have benefits including: postoperative analgesia, stress response attenuation and cardiac sympathectomy. Some care must be taken with patients to be submitted to systemic heparin for cardiocirculatory bypass because there is an increased risk for hematomas.

There are few studies on the risk-benefit ratio of inducing a spinal block in patients submitted to cardiac surgeries with cardiocirculatory bypass (CCB) ⁶⁵.

In general, surgery should be delayed for 24 hours after traumatic puncture with bleeding, but there is no consensus as to such approach. In this case, communication with the surgeon is critical ⁶⁵.

Coagulation tests based on total blood or plasma coagulation time are, in theory, sensitive to heparin. However, plasma tests such as TTPa, thrombin time (TT) and residual factor Xa activity determination with chromogenic substrate are more sensitive and accurate.

Chronic Use of Non Fractionated Heparin

NFH is administered to maintain TTP values 1.5 to 2 times baseline. Bleeding risk attributed to heparin in anticoagulated patients is high ⁶⁶. There are 18 cases described of epidural hematoma after neuraxial blockade in the presence of prolonged anticoagulant therapy ⁶⁴. Plaquetopenia occurs after 5 days of continuous NFH and may trigger bleeding. There is only one prospective study with 337 patients receiving caudal injection to treat chronic pain in the presence of systemic anticoagulation with no reference to spinal hematomas ⁵¹. In general, the risk for spinal hematoma overrides any potential benefit of neuraxial block techniques in the presence of prolonged therapeutic anticoagulation ⁶⁴.

If a patient with an epidural catheter starts receiving heparin, there will be the potential risk for hematoma at catheter removal. In a study of Vandermeulen et al. ²⁵ on epidural hematomas, 50% of the cases were associated to systemic heparin at catheter removal. Heparin should be withdrawn at least 2 to 4 hours before catheter removal. The coagulation system should be evaluated even before catheter manipulation, as well as sensitivity and motor functions no later than 12 hours after catheter removal ⁶⁴.

Possible interactions should be considered before combining NFH and regional block both for anticoagulation and venous thromboembolism prophylaxis.

Recommendations

1. Mini subcutaneous prophylactic heparin doses are not a counterindication for regional block ^24,64,67,68. Neuraxial bleeding risk may be decreased if heparin is administered 60 minutes after blockade. Such risk may be higher in weak patients or after prolonged therapy;

2. The combination of neuraxial block and perioperative anticoagulation with heparin in cardiovascular surgeries may be accepted, provided the following precautions are taken ⁶⁴:

· Blockade in patients with additional coagulopathies should be avoided;

· Heparin administration should begin one hour after blockade;

· Catheter should be removed one hour before a subsequent heparin dose or from 2 to 4 hours after the last heparin dose;

· The use of minimum local anesthetic concentrations to diagnose spinal hematoma should be considered;

· Spinal hematoma risk is increased in the presence of technical difficulties or blood during regional blockade induction.

3. Currently there are not enough data or experience to determine whether the risk for spinal hematoma increases when combining regional blockade and total anticoagulation in cardiac surgery patients ⁶⁴.

4. Prolonged NFH anticoagulation increases the risk for spinal hematoma, especially when heparin is combined to other anticoagulant or thrombolytic drug (neuraxial blockade should be avoided in those cases). If total anticoagulation therapy is started after neuraxial catheter insertion, it is recommended to remove it 2 to 4 hours after heparin withdrawal and with a previous evaluation of the coagulation system ⁶⁴.

5. The simultaneous use of drugs affecting other coagulation system components in patients receiving NFH increases the risk for bleeding complications. Such drugs include: aspirin, NSAIDs, low molecular weight heparin and oral anticoagulants ⁶⁴.

LOW MOLECULAR WEIGHT HEPARIN

Low molecular weight heparin is obtained from heparin depolymerization with the production of fragments with molecular weight between 4000 and 6000 Dalton. Such fragments are less able to catalyze thrombin inhibition but maintain the ability of catalyzing factor Xa inhibition. LMWH has less affinity with plasma and vascular proteins, endothelial cells, macrophages and platelets. As a consequence, they are more bioavailable with plasma half-life, less plaquetopenia-related side-effects and bleeding ⁶⁹. Due to the low incidence of thrombocytopenia, associated to safety and easy administration, especially in outpatients, it is increasingly taking the role of non fractionated heparin (NFH).

Although with a similar anticoagulant action (antithrombin activation), LMWH has total anti factor Xa activity and less anti IIa (thrombin) activity. NFH has equivalent anti factor Xa and anti-thrombin activity. LMWH anticoagulant activity is partially reverted by protamine while maintaining anti-Xa residual activity. LMWH has high subcutaneous bioavailability. After 12 hours, the level of factor anti-Xa will be approximately at 50% of peak value. Half-life is 2 to 4 times higher than NFH and is increased in the presence or renal failure.

Anticoagulation level evaluation is made difficult because LMWH does not change TTP, which is traditionally used to monitor NFH ⁵⁸.

There are prescription differences between the USA and Europe ^11,70. In the USA, the preconized dose is 30 mg (3000 U) every 12 hours, with the first dose administered 12 to 24 hours after surgery ^70,71. In Europe the dose is 40 mg (4000 U) every 24 hours and the anticoagulation regimen is started 12 hours before surgery ^11,70.

The concomitant administration of LMWH and drugs affecting hemostasis mechanisms, such as antiplatelet drugs, non fractionated heparin or dextran, poses an additional risk for hemorrhagic complications, including spinal hematoma ⁷¹.

Recommendations:

1. Neuraxial block and LMWH may represent a significant risk, as observed by the FDA. If the blockade is to be used, single puncture without catheter should be preferred. When using a catheter, it should be inserted 2 to 4 hours before any LMWH dose and removed between 10 and 12 hours after any dose and 2 hours before the subsequent dose ^11,58,70.

2. Puncture or catheter insertion should be performed 10 to 12 hours after subcutaneous LMWH when plasma concentration is low. Patients receiving high doses (1.0 mg.kg^-1 every 2 hours) must have the blockade delayed for 24 hours ⁷¹.

3. Blood in the needle or catheter during blockade does not necessarily mean that surgery should be delayed. In this case, LMWH should only be started 24 hours after surgery. Traumatic needle or catheter insertion significantly increases the risk for spinal hematoma ⁷¹.

4. When the epidural catheter is associated to LMWH care must be taken as to the decision of removing the catheter. Strict surveillance of patients’ neurological status is critical. Opioids associated to low local anesthetic concentrations are recommended for allowing frequent neurological function monitoring (1 hour). If analgesia is scheduled to last more than 24 hours, LMWH administration should be delayed (in some cases) or an alternative method should be adopted (intermittent pneumatic compression) ⁷¹.

5. After catheter removal, surveillance should continue for 12 to 24 hours ⁷².

Anticoagulants and Drug Interactions

Some drugs may change anticoagulants action. On the other hand, anticoagulants may interfere with the action of other drugs ²⁹.

Anticoagulants action is exacerbated by: chloramphenicol, tetracyclin, cholestiramine, mineral oils, phenylbutazone, oxyphenylbutazone, clofibrate, ethacrynic acid, nalidixic acid, flulenamic acid, methotrexate, mefenamic acid, salicylates, sulfonamides, sulfinpyrazone, allopurinol, metanidazole, cimetidine, disufisan, trimetoprim, sextrotirosine, steroids, probenicid, sulfinpyrazone, thienylic acid, aspirin, paracetamol, quinine, quinidine, azathioprine, mercaptopurine and others.

Anticoagulation is inhibited by: colchicine, barbiturates, meprobramates, carbamazepine, griseofulvin, rifampicin, diuretics, estrogens, contraceptives and others.

Sulfas, hypoglycemic drugs, fenantine and carbamazepine effects are exacerbated by anticoagulants.

CONCLUSIONS

The association of regional blockade with thromboprophylaxis poses a risk for spinal hematomas and may result in prolonged or permanent paralysis. Specialists should consider potential risks and benefits before inducing regional blocks in patients under thromboprophylaxis ¹¹.

The risk for hematoma increases when epidural catheters are associated to agents affecting coagulation. The risk will be even higher with traumatic or repeated puncture and coagulopathies.

Patients should be frequently monitored as to signs of motor and sensory involvement. Most patients present with: loss of sensitivity and lower limb weakness, decreased perineal sensitivity and urinary/intestinal dysfunction. Acute dorsal pain and sensory deficits are frequent ²⁵.

If there is neurological involvement, intervention must be urgent. All hospitals adopting such approach should be prepared for urgent diagnosis by MRI or mielography and subsequent surgical decompression in confirmed cases. Early compression diagnosis was fundamental in a study by Wulf ²⁴ because 90% had total function remission when decompression was performed 8 hours after beginning of symptoms ²⁴.

Recovery prognosis is less than 10% when the treatment is started after 24 hours ²⁴.

Centers using the association of regional block and thromboprophylaxis should develop guidelines for nursing and medical staffs about early detection of spinal compression symptoms. Those guidelines should include care with catheter manipulation because there is the possibility of epidural hematoma after undue catheter removal (heparin action during anticoagulation) ⁷².

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*

Recebido da Universidade Federal do Estado de São Paulo (UNIFESP)

Publication Dates

• Publication in this collection
  21 Mar 2011
• Date of issue
  2001

History

• Accepted
  06 Mar 2001
• Received
  14 Dec 2000