Bleeding and Blocks: New Medicine, Still More Questions

By Alan Bielsky, MD; Melissa Masaracchia, MD; Beth Boulden Warren, MD, MS
Children’s Hospital Colorado Anschutz Medical Campus,
Denver, Colorado

Introduction
In many ways, the pediatric anesthesiologist lives in a world of conjecture. True to form, regional anesthesia in the pediatric population suffers from gaps in knowledge, inferences, and misconceptions. The use of neuraxial and peripheral techniques in the presence of abnormal bleeding presents a conundrum of “same old worries” in different settings with a lack of definitive data.

A scan of the literature reveals well established guidelines and a myriad of case reports that relate mainly to the risk of spinal hematoma. This data often points to the role of medical anticoagulants encountered in the adult population with vascular disease, but does less to address both the pediatric population and peripheral nerve blockade.(1-2)

Peripheral nerve blockade and risk of hematoma formation has failed to produce definitive risk establishment as this adverse event is largely absent in pediatric regional anesthesia registries.(3-5) Adult literature does contain case reports of hematoma formation, but these are mainly limited to deeper blocks such as lumbar plexus blockade.(6-9) Furthermore, a variety of techniques were used in these case reports, so it is difficult to infer the actual risk in the age of ultrasound guidance. Laboratory models do, however, show that perineural hematoma formation can result in histologic evidence of nerve damage, though clinical relevance has yet to be established. (10)  Taking this all into account, it seems prudent to use a risk benefit analysis when performing peripheral nerve blockade in the anticoagulated or coagulopathic patient; deep blocks or blocks such as lumbar plexus and paravertebral likely carry a mildly elevated risk when compared to superficial blocks like femoral nerve and interscalene blocks.

Children are exposed to anticoagulants less often than adults because they don’t bear the same burden of vascular disease and have a lower incidence of clots than adults.  Furthermore, many novel anticoagulants are not yet used in children, as there is limited authoritative pharmacokinetic data in younger age groups for many agents. (11) Nevertheless, the incidence of thromboses in children is increasing, thereby heightening the potential need for regional anesthesia in the setting of antithrombotics.(12)

Despite notable differences in the use and management of antithrombotics in adult and pediatric patients, data is still extrapolated from large adult observational and epidemiological studies and applied to children to quantify their risk of spinal hematoma. Much to the same effect, guidelines intended to minimize this risk are based on interplay between adult physiology and drug pharmacology, yet these recommendations continue to be a frame of reference for physicians making clinical decisions for pediatric patients. Given our reliance on this tool, a review of the updated guidelines for regional anesthesia in the anticoagulated patient is warranted.

The American Society of Regional Anesthesia (ASRA), European Society of Regional Anaesthesia & Pain Therapy, American Academy of Pain Medicine, International Neuromodulation Society, North American Neuromodulation Society, and World Institute of Pain have traditionally developed separate guidelines in relation to regional anesthesia and anticoagulation therapy. Recently, the American and European Societies of Regional Anesthesia have issued joint guidelines attempting to consolidate the approach to this patient population. Notably absent, however, is a thorough discussion of the pediatric population, peripheral nerve blockade, and coagulopathies.(1)(13)

Although the management of many traditionally used anticoagulants remains the same in the newest guidelines, some revisions were necessary to reflect alterations in indication for use and dosing. Additionally, supplemental recommendations were made to account for newer antiplatelet and antithrombotic medications. Major alterations noted in the 2018 guidelines are highlighted below.

Unfractionated Heparin
Unfractionated heparin plays less of a role in the pediatric world due to unreliable pharmacokinetics when given subcutaneously. (14,15) Heparin infusions still are used frequently in the pediatric realm, however. In the new ASRA guidelines, subcutaneous heparin was largely left alone, though recommendations were made for thromboprophylaxis using novel “high-dose” unfractionated (e.g. 7500–10,000 Units BID or a daily dose of ≤ 20,000 Units) for which there were no guidelines previously.(1)

[Recommendation: Neuraxial blocks should be performed 12 hours after the last subcutaneous heparin administration if dosed at 7500–10,000 Units BID or ≤ 20,000 Units daily. If doses exceed 10,000U/dose or >20,000-Units total daily dose, neuraxial should occur no earlier than 24 hours after administration of the last dose.]

Low Molecular Weight Heparin
Low molecular weight heparin (LMWH) is often used for chronic anticoagulation in children. It remains a cornerstone of pediatric anticoagulation due to dependable pharmacokinetics, lack of dietary restriction, and lack of availability of warfarin as a suspension. In children, LMWH is typically given subcutaneously twice per day, with the dose adjusted based on titration to four-hour anti –Xa levels.  Unlike in adults, LMWH is given twice per day both in treatment and prophylactic dosing. (16) Regardless, for thromboprophylaxis, a 12-hour interval between last dose and placement of neuraxial block has replaced the previously recommended 10-12-hour window. Similarly, spinal and epidural placement in patients receiving therapeutic doses of LMWH should be delayed even further to 24 hours from the last dose. The recommendations also suggest delaying subsequent dosing after catheter removal to 4-hours from a previous 2-hour interval. (1) Low molecular weight heparin can be reversed with protamine, but this should be done in cooperation with a pediatric hematologist, as the reversal is incomplete and prothrombotic risk could be elevated. (17)

[Recommendation: If any of the following medication-dosing combinations are used for anticoagulation then neuraxial anesthesia should be delayed 24 hours from the last dose: enoxaparin 1 mg/kg every 12 hours, enoxaparin 1.5 mg/kg daily, dalteparin 120 Units/kg every 12 hours, dalteparin 200 Units/kg daily, or tinzaparin 175 U/kg daily.]

Oral Anti-Factor Xa
Xa-inhibitors are new additions to the updated 2018 guidelines. These anticoagulants have gained popularity and are being used with increasing frequency in recent years, which prompted recommendations for their use to be formally added to the new guidelines. The most commonly used agents include rivaroxaban, apixaban, and edoxaban; none have been approved in children, but all are in various phases of pediatric clinical trials. (18)(11) ASRA guidelines suggest that these medications be discontinued 72 hours prior to neuraxial block, though these agents may be metabolized more quickly in children.(19-21) If the risk/benefit ratio favors epidural or spinal technique and less than 72-hours have passed since the last dose, quantifying anti–factor Xa activity level should be considered although acceptable levels have still not been determined. Neuraxial catheters should not remain in place if anticoagulation with a Xa-inhibitor is planned. For removal of neuraxial catheters, a six-hour interval should be planned before initiating therapy. If an unanticipated dose of a Xa-inhibitor is given while an indwelling catheter is in place, rivaroxaban should be held for 22-26 hours, apixaban should be held for 26-30 hours, and edoxaban should be held for 20 to 28 hours before a catheter is removed.

Betrixaban is another Xa inhibitor that has slight variations in its recommended management because of its dependence on kidney function for metabolism and excretion. In patients with creatinine clearance of less than 30 mL/min who are also on betrixaban, neuraxial anesthesia is advised against. Like the other Xa inhibitors, betrixaban should be discontinued at a minimum of 3 days prior to neuraxial block. If a catheter is to be removed, it should occur 5 hours prior to the next dose. If an unanticipated dose is given with indwelling catheter in place, it is suggested that betrixaban dosing be held for 72 hours, then the catheter removed. (1) Similarly, rivaroxaban and dabigatran are excreted primarily in urine necessitating caution in individuals with renal impairment. (22)

Andexanet is a reversal agent for anti-Xa (Xa decoy) that was just approved in May 2018, but to date there is no data on suitability of neuraxial anesthesia after administration. (23)

Oral Thrombin Inhibitors
Just as with anti-Xa medications, oral thrombin inhibitors (dabigatran) lacked any formal recommendations in previous guidelines. Because of dabigatran’s dependence on renal excretion, current recommendations for its use are based on a patient’s creatinine clearance. The antibody reversal agent idarucizumab is commercially available, but there is no experience related to neuraxial blockade.  Management of older parenteral thrombin inhibitors (i.e. desirudin, bivalirudin, and argatroban) remains the same. (1)

[Recommendation: In patients with creatinine clearance >80ml/min, discontinue 72-hours prior to neuraxial anesthesia. In patients with a creatinine clearance of 50 to 79 mL/min, discontinue 96-hours prior to neuraxial. In patients with a creatinine clearance of 30 to 49 mL/min, discontinue 120-hours prior to neuraxial. Neuraxial anesthesia is advised against in patients on dabigatran with a creatinine clearance < 30 mL/min. Neuraxial catheters should be removed 6-hours prior to the first (postoperative) dose. If an unanticipated dose of dabigatran is given with indwelling catheter, dabigatran should be held for 34 to 36 hours before the catheter is removed.]

Warfarin
New studies have suggested International Normalized Ration (INR) levels may correlate with risk for hematoma; therefore, updated guidelines emphasize using it as an additional tool to assess for appropriateness of neuraxial anesthesia in a patient who is anticoagulated with warfarin. Specifically, guidelines suggest that catheters can be maintained with caution if an INR is greater than 1.5, but must remain less than 3. Additionally, catheter removal 48-hours after initiation of warfarin presents an increased risk for hematoma when compared to catheter removal at 12-24 hours. Apart from these new recommendations, the management of warfarin has otherwise remained the same. (1)

Thienopyridines (ticlopidine, clopidogrel, prasugrel)
New recommendations for the management of patients on thienopyridines are drug-specific and are heavily dependent on whether a loading dose is administered with the initiation of therapy. The suggested time for discontinuation of ticlopidine prior to neuraxial blockade has decreased from 14 to 10 days. For clopidogrel and ticagrelor, this interval has been liberalized from 7 days to 5 to 7 days. Recommendations for prasugrel are new to the guidelines and suggest discontinuation 7 to 10 days before spinal or epidural manipulation. Thienopyridines may be restarted 24 hours postoperatively. Because of the rapid onset of prasugrel or ticagrelor, neuraxial catheters should not be maintained if resumption of this medication is planned. Because maximal antiplatelet effects are not immediately seen with ticlopidine and clopidogrel, catheters may be maintained for 1-2 days assuming no loading dose was given. If a loading dose is given, a suggested six-hour interval is needed prior to catheter removal. (1)

Platelet GP IIb/IIIa Inhibitors
Management of platelet GP IIb/IIIa inhibitors has not changed in the newest guidelines. Because these medications exert a profound effect on platelet aggregation, neuraxial techniques are contraindicated in patients who are anticoagulated with these medications. Postoperatively, the use of these medications is also advised against for the first 4 weeks after surgery. However, if one is inadvertently given following neuraxial anesthesia, epidural infusion medications should be limited to drugs that minimize sensory and motor block to facilitate assessment of neurologic function. (1)

Esoteric Anticoagulants
The newest guidelines also give recommendations on more esoteric anticoagulants including cilostazol, dipyridamole and cangrelor.

Cilostazol must be discontinued two days prior to neuraxial anesthesia. Catheters should be removed if there is a need to reinstitute cilostazol therapy postoperatively and must not be given until six hours after catheter removal.
Dipyridamole. Extended release dipyridamole should be discontinued 24 hours prior to neuraxial block. The first postoperative dose of dipyridamole should be administered six hours after neuraxial catheter removal.
Cangrelor. Based on the elimination half-life, cangrelor should be discontinued three hours prior to neuraxial manipulation. Cangrelor therapy can resume eight hours after neuraxial catheter removal. (1)

Coagulation Disorders
Coagulation disorders in children present a conundrum when considering regional anesthetic techniques. History and physical examination on a child with a primary hemostatic disorder will reveal easy bruising, petechial rashes, or mucosal bleeding. In contrast, defects of secondary hemostasis such as factor deficiency present as bleeding into joints and delayed bleeding after surgery or trauma. (24)

Hemophilia A and B are X-linked recessive disorders resulting in deficiencies of factors 8 and 9, respectively.  The severity of the disease is inversely proportional to the concentration of these factors, with the most severe symptoms existing with less than 1% of factor concentration. Mild hemophilia may only present as prolonged bleeding after trauma or surgery, but more typical symptoms of severe hemophilia include hemarthrosis and muscle bleeding. Treatment of hemophilia has traditionally centered on infusion of factor concentrates, though these therapies must be carefully monitored due to the development of antibody inhibitors in roughly a third of patients with hemophilia and 2-5% of patients with hemophilia B. (25)  Recently, emicizumab has been introduced to clinical care in the treatment of hemophilia A with inhibitors. (16) This novel drug is a recombinant human bispecific monoclonal antibody which bridges activated factors 9 and 10, normally the job of factor 8. There are no cases reports about the use of any regional anesthesia techniques in combination with emicizumab. (24)

The placement of neuraxial blocks in patients with hemophilia has been assessed in the obstetric and non-obstetric populations with 107 neuraxial techniques being performed on 85 patients with hemophilia. (26) 105 of the patients had known hemophilia, and their factor levels were replaced to normal (>0.5 IU/mL). Of note, one catastrophic spinal hematoma did occur in a patient with undiagnosed hemophilia.  To date there are no case reports or series of experiences or complications of peripheral nerve blockade in patients with hemophilia. (26)

Glanzmann’s thrombasthenia is an autosomal recessive platelet surface receptor disorder of GPIIb/IIIa complex resulting in impaired platelet aggregation and reduced clot retraction. Clinically, it presents as mucocutaneous bleeding, spontaneous bruising, bleeding during circumcision, and severe epistaxis. Laboratory evaluation will reveal normal platelet count, prothrombin time, and partial thromboplastin time. Platelet function analysis (PFA-100), platelet aggregometry and flow cytometry will reveal abnormalities. To date, there are no case reports of use of regional anesthetic techniques with this disorder, so the risk of hematoma formation is unknown but inferred to be elevated. As treatment for Glanzmann’s thrombasthenia relies on platelet transfusion and recombinant activated factor 7, it would seem that any attempt at neuraxial blockade should be accompanied by consultation with a hematologist. (27)

Von Willebrand’s disease can be a quantitative or qualitative defect in the promotion of platelet adhesion binding and aggregation by the interaction of Von Willebrand’s factor and platelets via the surface complexes GPIb-IX-V and GPIIb-IIIa. This disorder presents with varying degrees of epistaxis, gingival bleeding, heavy menstruation, and bleeding complications with minor surgeries. The laboratory evaluation of Von Willebrand’s disease is variable, largely based on the subtype of the disease. (28)

In the review of 72 neuraxial anesthetics, no complications were reported. The patients presented with varying degrees of severity and had treatment based on the severity of the disease. To date, there are no case reports or series of experiences or complications of peripheral nerve blockade in patients with Von Willebrand’s disease. If the severity of the disease and depth or location of the block were to be of a concern, one could potentially administer DDAVP or factor concentrates. (26)

Immune thrombocytopenia (ITP) is an acquired, immune related disease that presents with transient or persistent decreases in platelet counts leading to the potential for bleeding. Immune thrombocytopenia is now the standard nomenclature for what was previously known as idiopathic thrombocytopenic purpura. There are primary and secondary forms of this disorder, with secondary forms related to disease processes such as lupus, HIV, and other infections. Platelet counts must be below 100 X 10, with most platelet counts running below 30 X 10 (29) Platelet therapy is of limited use in ITP due to the rapid consumption of platelets once transfused, so this modality is largely spared for emergency bleeding.

In Choi and Brull’s review of 325 patients undergoing 326 neuraxial blocks, no adverse events were noted. There was wide variability in the platelet count, and thus the severity of the disease, but a platelet count of 50 x 10  typically resulted in treatment with platelet therapy or immune therapy before placement of the block. The lowest noted platelet count, however, was 2 X 10 . There are no case reports nor studies describing peripheral techniques in patients with ITP.(26)

Acquired coagulopathies are the result of disease processes or treatments of these diseases. Factor deficiencies either come from depletion of Vitamin K, consumptive coagulopathies as seen in disseminated intravascular coagulation, or decreased factor synthesis as seen in liver disease. Chemotherapy for cancers is another typical cause of pancytopenia leading to thrombocytopenia.

When approaching regional anesthesia in patients with coagulopathy, it is often difficult to balance information from case reports, guidelines, and clinical scenarios. The Society for Obstetric Anesthesia and Perinatology, The European Society of Regional Anaesthesia and Pain Therapy, New York School of Regional Anesthesia, and ASRA have all published guidelines with largely similar cutoffs for INR and platelet counts. (1,30,31) The Association of Anaesthetists of Great Britain and Ireland points out that this risk is largely unquantifiable due to the rarity of complications.(32) It is, therefore, difficult to establish hard laboratory parameters as contraindications to regional anesthesia. The conventional wisdom, however, points to a platelet count of above 75 and INR below 1.5 as a starting point for the establishment of risk, though critique of this hard cutoff exists (33), and INR is expected to be normal with all anticoagulants except warfarin, and in most congenital bleeding disorders.

All in all, with an ever-progressing collection of experience with altered coagulation and regional anesthesia, one can apply a rule of “being more cautious as you move towards the spine.” Altered coagulation is no longer a contraindication to peripheral blockade, but as one moves towards deep plexus blocks neuraxial blocks, increased risk must be factored into the risk benefit analysis with particular attention being paid to established guidelines.

References

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