Time between drug administration and neuraxial puncture, catheter manipulation or withdrawal
Time between neuraxial puncture, catheter manipulation or withdrawal and drug administration
Laboratory tests
ESA
ASRA
ESA
ASRA
Unfractionated heparin (prophylaxis)
4–6 h
No time interval
1 h
1 h
Check platelets if treatment >5 daysa/>4 daysb
Unfractionated heparin (treatment)
IV 4–6 h
2–4 h
1 h
1 h
Check APTT, ACT, platelets
SC 8–12 h
–
1 h
–
LMWH (prophylaxis)
12 h
10–12 h
4 h
6–8 h (NP)/>2 h (CW)
Check platelets if treatment >5 daysa
LMWH (treatment)
24 h
24 h
4 h
24 h (NP)/>2 h (CW)
Check platelets if treatment >5 daysa
Fondaparinux (prophylaxis, 2.5 mg per day)
36–42 h
36 hc
6–12 h
12 hc
(anti-Xa standardised for specific agenta)
Rivaroxaban (prophylaxis, 10 mg o.d.)
22–26 h (CW)
–
4–6 h
–
(PT standardised for specific agent)
Aspirin/acetylsalicylic acid
None
None
None
None
NSAIDs
None
None
None
None
Clopidogrel
7 days
7 days
After CW
–
Ticlopidine
10 days
14 days
After CW
–
Abciximab
48 h (CW)
24–48 h
–
–
Check platelets
Eptifibatide
8–10 h (CW)
4–8 h
–
–
Check platelets
Tirofiban
8–10 h (CW)
4–8 h
–
–
Check platelets
Warfarin/Coumarins
INR ≤1.4
4–5 days + normal INR (NP)/INR <1.5 (CW)
After CW
After CW
INR
Hirudins (desirudin, lepirudin)
8–10 h
C/I
2–4 h
C/I
APTT/ECTa
Argatroband
4 h
C/I
2 h
C/I
APTT, /ECT, ACTa
Dabigatran (prophylaxis, 75 mg b.d., 110 mg b.d.)
C/I by manufacturer
–
6 h
–
21.7.1 Parenteral Anticoagulants
21.7.1.1 Unfractionated Heparin
Unfractionated Heparin (UFH) has a half-life of 1–2 h when administered intravenously. The anticoagulant effect is monitored using the activated partial thromboplastin time (APTT). Key recommendations for the anesthetic management of patients treated with UFH are as follows:
ASRA advocates no contraindication to the use of neuraxial techniques for patients on prophylactic subcutaneous UFH (5,000 IU twice a day). However, the ESA recommends a delay of 4–6 h between drug administration and neuraxial puncture or catheter manipulation/withdrawal.
Patients treated for more than 4 days (according to ASRA) or more than 5 days (according to ESA) should have a platelet count prior to central neuraxial block due to the risk of heparin induced thrombocytopenia (HIT).
Confirmation that the APTT is within normal range prior to removal of the catheter may be warranted.
When the patient is treated with IV heparin, neuraxial placement or epidural catheter removal should occur 1 h before any subsequent heparin administration; or 4–6 h (ESA) or 2–4 h (ASRA) after the last heparin dose. The APTT should be checked prior to performing the neuraxial block
21.7.1.2 Low Molecular Weight Heparins
Low Molecular Weight Heparins (LMWHs) differ from UFH in that the molecular chain length is shorter resulting in greater anti-Factor Xa (FXa) activity than anti-thrombin activity. They also have greater bioavailability and a longer half-life. The time to peak anti-coagulant activity for subcutaneous LMWHs is 3–6 h and it is during this period after dosing that neuraxial procedures should be avoided. Activity falls to around 50 % after 10–12 h. Although anti-FXa levels measure its anticoagulant effect, monitoring the level in patients undergoing neuraxial block is not recommended as it does not predict the risk of bleeding [101].
Key recommendations with regard to patients receiving LMWH therapy according to the ESA and ASRA are as follows:
For patients receiving LMWH thromboprophylaxis (e.g. dalteparin 5,000 IU or enoxaparin 40 mg once a day), neuraxial placement should be delayed for at least 10–12 h after the last LMWH dose.
For patients receiving higher (treatment) doses of LMWH (i.e. enoxaparin 1 mg/kg every 12 h, enoxaparin 1.5 mg/kg daily, dalteparin 120 IU/kg every 12 h, dalteparin 200 IU/kg daily or tinzaparin 175 IU/kg daily), needle placement should be avoided for at least 24 h after the last dose of LMWH, in order to ensure normal haemostasis at the time of needle insertion.
For patients on a once a day dosing regimen with an indwelling epidural catheter, the catheter can be removed after a minimum of 10–12 h after the last dose.
Post-operative LMWH dosing should occur a minimum of 4 h according to the ESA (or a minimum of 24 h according to the ASRA) after epidural catheter insertion or removal
21.7.1.3 Fondaparinux
Fondaparinux produces its antithrombotic effect by inhibition of FXa activity without inhibition of Factor IIa [102, 103]. It has a long half-life (17–21 h) and is renally excreted [102]. There is limited data in pregnancy (see Chap. 2) and the risk of spinal haematoma associated with this drug is unknown. There also appears to be limited data and no consensus as to the ideal time interval between last administration of fondaparinux and neuraxial placement. Due to the lack of clinical experience at the time, the ASRA Consensus advised limiting the performance of central neuraxial block to clinical trial conditions. In Europe, however, the ESA has recommended a time interval of 22–42 h between the last administration of the drug and neuraxial placement. There are case reports of parturients managed successfully using neuraxial techniques [104, 105].
21.7.1.4 Parenteral Direct Thrombin Inhibitors
Thrombin inhibitors inhibit any further growth of a thrombus by inactivating fibrin already bound to thrombin. The thrombin inhibitors available include the recombinant hirudins (desirudin and lepirudin) and argatroban. They are commonly used for prophylaxis against thrombosis (desirudin) and to treat patients with type-II heparin-induced thrombocytopenia (HIT II) (lepirudin, argatroban). Their action on hemostasis can be monitored using the APTT. These drugs are, however, associated with an increased bleeding tendency, particularly at higher doses, and their actions cannot be reversed (dialysis aids elimination). Although recombinant hirudins are not recommended for use in pregnancy due to evidenced transplacental transfer of the drug [106], there have been case reports of its successful use in pregnant women for the management of HIT II and recurrent VTEs [107–109]. None of these cases reported any adverse effects on the neonate, however, its use in pregnancy remains rare.
While the ASRA has stated that the use of direct thrombin inhibitors is a contraindication to neuraxial blockade, the ESA has not and provides some guidance for the use of these drugs. They advise:
Recombinant Hirudins
A time interval of 8–10 h between administration of the prophylactic dose hirudin and central neuraxial blockade or epidural catheter removal in patients with normal renal function
Administration of these drugs following neuraxial procedure should be delayed for 2–4 h
Avoid combining hirudins with other antithrombotic agents
Like most antithrombotic agents, the hirudins are renally excreted, hence they can accumulate in patients with renal impairment, causing prolonged drug activity; in this situation, monitoring of the APTT is advisable.
Argabatroban
Argatroban is administered as an IV infusion and the APTT returns to normal 2–4 h after the infusion is stopped. It is eliminated exclusively through the liver and dose reduction is necessary in the presence of impaired liver function. The guidelines reviewed do not suggest a time interval between cessation of the infusion and performing a neuraxial block. However, in a recent case report, a woman treated with an argatroban infusion was successfully managed with neuraxial analgesia during labor without any complications [105].
However, there is very limited experience of its use in conjunction with central neuraxial blockade. Even though there have been no reports of spinal haematoma to date, both the ESA and ASRA advise extreme caution when using central neuraxial blockade in patients taking this drug. At present, the ASRA does not provide any guidelines for Rivaroxaban; however, the ESA suggests a 22–26 h interval between the last drug dose and epidural catheter withdrawal, and a delay of 4–6 h between catheter withdrawal and the next dose.
21.7.2 Oral Anticoagulants
21.7.2.1 Warfarin and Other Vitamin K Antagonists
Despite the concerns about fetal safety (see Chap. 2), warfarin therapy may be encountered in the parturient, for example with a mechanical heart valve where it may be deemed a more effective treatment than heparin to prevent valve thrombosis and systemic emboli.
The use of warfarin or other oral VKA is an absolute contraindication to central neuraxial blockade. Key principles in the management of patients on these drugs include:
Cessation of warfarin 4–5 days prior to initiation of neuraxial block if on therapeutic dose (INR (International Normalised Ratio) >1.4 (ASRA), INR >1.5 (ESA)). The INR should also be checked prior to needle placement to ensure that it is within normal reference limits, indicating the return of adequate levels of factor II, VII, IX and X for safe neuraxial blockade.
When the woman has received an initial dose of warfarin more than 24 h prior to surgery, or if a second dose has been administered (ASRA), the INR should be checked prior to central neuraxial blockade
The neuraxial catheter should be removed only when the INR is ≤1.4 Neurological testing of motor and sensory function should be continued for 24 h after catheter removal and longer if the INR was >1.4 at the time of catheter removal.
21.7.2.2 New Oral Anticoagulants/Oral Direct Inhibitors of Coagulation
The non-vitamin K antagonist oral anticoagulants (NOAC) include dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban (Pradaxa®, Xarelto®, Eliquis®)[110–112], direct factor Xa inhibitors. Dabigatran, rivaroxaban and apixaban are approved by the National Institute for Health and Care Excellence in England (NICE) and the US Food and Drug Administration (FDA) for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement, and the prevention of stroke or systemic embolization in patients with atrial fibrillation. These agents have also undergone phase III trials for the treatment of acute deep venous thrombosis (DVT) and pulmonary embolism (PE) and secondary prevention of VTE, and have been licensed for these indications. All three agents have been approved for VTE treatment by the FDA and rivaroxaban and dabigatran are approved by NICE, with NICE review of apixaban underway. The manufacturers recommend that all are contraindicated during pregnancy and breastfeeding.
Rivaroxaban
There is very limited experience of rivaroxaban use in conjunction with central neuraxial blockade. Even though there have been no reports of spinal haematoma to date, both the ESA and ASRA advise extreme caution when using central neuraxial blockade in patients taking this drug. At present, the ASRA does not provide any guidelines for Rivaroxaban; however, the ESA suggests a 22–26 h interval between the last drug dose and epidural catheter withdrawal, and a delay of 4–6 h between catheter withdrawal and the next dose. The ESA guidance applies to prophylactic dose rivaroxaban (10 mg daily), where rivaroxaban has been has been shown to provide superior prevention of VTE when compared with enoxaparin (40 mg once daily) in patients undergoing hip or knee replacement [113].
Dabigatran Etexilate
The ESA has suggested a time interval of at least 34 h between the last dose of dabigatran and epidural catheter manipulation or withdrawal. This guidance applies to prophylactic dose dabigatran (75 and 110 mg BD respectively), where dabigatran has been found at a dose of 110 mg BD to be comparable in efficacy to enoxaparin (40 mg once daily) in patients undergoing hip or knee replacement [114]. Although there have been no reported spinal haematomas in the initial studies where thromboprophylaxis with dabigatran was initiated 4–6 h after epidural catheter removal, the manufacturer advises against its use in conjunction with central neuraxial blockade. For this reason, the medicolegal consequences should a spinal haematoma develop, must be considered where central neuraxial blockade is to be employed in a woman taking this drug.
21.7.2.3 Antiplatelet Drugs
Evidence from the Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP) [115] and from studies by Horlocker et al. [116, 117] has concluded that low-dose aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) do not represent a contraindication to central neuraxial blockade, provided they are not combined with other anti-thrombotic agents.
Thienopyridines, which include clopidogrel and ticlopidine, inhibit platelet aggregation. This group of drugs irreversibly inhibit platelet function. Platelet levels are restored 6–14 days after withdrawal of the drug. The guidelines recommend that a minimum interval of 7 days for clopidogrel and 10 (ESA) to 14 (ASRA) days for ticlopidine between the last drug dose and neuraxial puncture.
Glycoprotein IIb/IIIa antagonists reversibly inhibit the binding of Von Willebrand Factor and fibrinogen to receptor sites. Abciximab should be stopped for 48 h while eptifibatide and tirofiban for 8–10 h prior to neuraxial placement according to ESA. The ASRA advocates a similar approach, recommending intervals of 24–48 h for Abciximab and 4–8 h for eptifibatide and tirofiban. Neuraxial block should be avoided until platelet function has recovered, and is contraindicated when glycoprotein IIb/IIIa inhibitors are used in conjunction with other anticoagulants or aspirin.
21.8 Ehlers-Danlos Syndrome and Other Blood Vessel Wall Disorders
21.8.1 Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders with differing clinical, biochemical and genetic findings. The prevalence in the population is around 1:5,000 [118, 119]. The mutated genes coding for structural collagens and for enzymes associated with normal collagen synthesis are either deficient or defective, resulting predominantly in weakness in the supporting structure of skin, the musculoskeletal system, vascular wall, and visceral organs. Although 11 different subgroups have been identified, the syndrome has been described within six subtypes [118]. The classical, benign hypermobility, and vascular are the most common subtypes, making up 96 % of the affected population (60, 30 and 6 %, respectively). The other groups include the kyphoscoliosis, arthrochalasia and dermatosparaxia subtypes. All have autosomal dominant inheritance, with the exception of the vascular and dermatosparaxis subtypes, which are autosomal recessive. EDS is associated with an increased risk of miscarriage and antepartum hemorrhage.
21.8.1.1 Clinical Features and Complications in the Puerperium
The main features of EDS are connective tissue fragility, hypermobility and hyperextensibility affecting the skin and musculoskeletal systems. Complications include poor wound healing, scarring, skin friability (skin breakdown, pressure sores), joint hypermobility (subluxation, dislocation, hemarthrosis) and spinal abnormalities (kyphoscoliosis, spondylolisthesis). Pregnant women with the classical and hypermobility subtypes of EDS have an increased risk of separation of the symphysis pubis, fetal malpresentation, intrauterine growth restriction, premature rupture of membranes, preterm birth, and uterine prolapse. Severe, potentially life-threatening hemorrhage due to vessel wall fragility may be encountered and is usually associated with the vascular and hypermobility subtypes. This may present as post-operative hemorrhage, PPH, spontaneous rupture of blood vessels and excessive bleeding from obstetric trauma. Laboratory analysis of hemostasis including clotting screen, platelet count and aggregation are often normal. However, some patients may present with accompanying coagulation factor and platelet disorders [120]. Other serious complications include rupture of viscera such as the uterus or gastrointestinal tract, and spontaneous pneumothorax due to ruptured bullae. For patients with the vascular subtype of EDS, pregnancy can be life-threatening, with a 12 % risk of death from peripartum arterial or uterine rupture [118, 121].
Cardiovascular complications associated particularly with the vascular subtype of EDS include congenital and valvular heart disease (typically mitral valve prolapse and regurgitation), conduction defects, coronary artery disease and aortic dissection or rupture. Dysautonomia is a recognised complication of the hypermobility subtype [122]. If required, a stress echocardiogram or thalium scan may be preferred to cardiac catheterisation because of the risk of possible vessel rupture and hemorrhage with the latter.
21.8.1.2 Anesthetic Management of EDS
Anesthesia during labor and delivery presents unique risks for the woman with EDS. Key points for the anesthetic management of these patients have been highlighted by some authors based on reported cases [123–127]:
Genetic consultation to assess the type and severity of disease. Knowing this, likely complications can be anticipated and appropriate multidisciplinary antenatal care can be organised. Due to the potentially life-threatening complications in women with the vascular subtype, they should be considered high risk and managed at a tertiary delivery unit
Careful pre-assessment should include detailed assessment of bleeding history, cardiac function and any spinal abnormalities
Evaluation of the airway. Patients with the hypermobility subtype may potentially present difficulties with airway management due to an unstable cervical spine and temporomandibular joint dysfunction. The cervical spine and corresponding nerve roots should be thoroughly examined, along with appropriate imaging where necessary
Specialised tests of hemostasis to exclude a concomitant hemostatic defect
Ensure adequate cross-matched red cells are available
Ensure that adequate IV access is carefully established prior to operation. Vascular access may be hindered by scarring and by the inability to feel the needle passing through the vessel wall. Arterial and central venous lines should be avoided unless absolutely essential, in order to avoid the possibility of post-puncture aneurysm and hematoma formation. All cannulation sites should be reviewed regularly for signs of extravasation.
Careful insertion of neuraxial block where there are no contraindications
Careful, atraumatic tracheal intubation in the case of general anesthesia
Maintenance of low airway pressures to reduce the risk of pneumothorax
Avoid hypertension, particularly during intubation and extubation, in order to prevent exacerbation of blood loss and the rupture of occult aneurysms.
The decision as to whether to perform neuraxial blockade on the parturient with EDS should be made on a case-by-case basis after full evaluation of the potential risks of bleeding and neurological injury. Vascular fragility per se is unlikely to increase the risk of epidural hematoma; however, uncertainty remains regarding the effect of abnormal vascular collagen on primary hemostasis. There are no reports in the literature of spinal hematoma associated with EDS. Different neuraxial techniques have been described in case reports involving the classic, hypermobility and vascular subtypes of EDS [29, 124–126, 128]. Case reports have indicated that patients with hypermobility type EDS may have resistance to local anesthetics [127, 129, 130] although in a series from our unit, central neuraxial blocks worked well, even in those who gave a history of local anesthetic resistance [131].
When deciding on management for Cesarean section, the risks of neuraxial blockade should also be weighed against the risks associated with general anesthesia. During general anesthesia, attention should be paid to careful patient positioning and padding of areas susceptible to the effects of pressure, in order to prevent tissue damage. Sood and colleagues [127] reported a case of difficult intubation during rapid sequence induction in a patient with the hypermobility subtype of EDS. They suggested that when difficult intubation is encountered using this technique, releasing the cricoid pressure may help to alleviate the obstruction that can result from a collapsed trachea. They also suggest minimal cervical spine movement during positioning and intubation and the use of fibreoptic techniques where there is significant cervical spine instability.
Related posts:
Systemic Thromboembolism in Pregnancy: Heritable and Acquired Thrombophilias
Inherited Bleeding Disorders in Pregnancy: Rare Coagulation Factor Defects
Inherited Bleeding Disorders in Pregnancy: Platelet Defects
The Neonate
Inherited Bleeding Disorders in Pregnancy: von Willebrand Disease, Factor XI Deficiency, and Hemophilia A and B Carriers
Antithrombotic Therapy for Cardiac Disorders in Pregnancy
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