Introduction
History of presentation
A 7-year-old previously healthy female presented to the emergency department with cough, laboured breathing, and anaemia. Mother reports she had several days of nasal congestion and cough associated with dyspnoea and non-bloody non-bilious emesis. A viral respiratory polymerase chain reaction (PCR) panel was positive for respiratory syncytial virus, and she was noted to have a grade 3/6 (3 out of 6), harsh, holosystolic blowing murmur at the apex and a 3/4 (3 out of 4), harsh, high-pitch, diastolic decrescendo murmur at the left lower sternal border. Her labs were largely normal apart from a haemoglobin of 7.7 g/dL, a blood urea nitrogen (BUN) of 38 mg/dL, serum creatinine of 0.65 mg/dL, an aspartate transaminase (AST) of 223 u/L, and alanine aminotrasferase (ALT) of 67 u/L, an erythrocyte sedimentation rate of 74 mm/hr, and a c-reactive protein 6.5 mg/dL. Chest X-ray showed cardiomegaly with pulmonary oedema. Echocardiogram was significant for severe aortic insufficiency, severe mitral regurgitation, moderate pulmonary insufficiency, moderate tricuspid regurgitation, a moderately dilated left ventricle with moderately depressed left ventricular function, and normal right ventricular size and function (Images 1–4). After consultation with cardiology, the patient was admitted to the cardiac ICU.
Transthoracic Echocardiogram (TTE) in apical 3-chamber view with color doppler showing broad regurgitant jet consistent with severe aortic insufficiency.
TTE in parasternal short axis with the aortic valve en face and color comparison again showing a broad regurgitant jet commonly seen in valvulitis.
TTE in apical 4 chamber with color doppler over the mitral valve showing an eccentric regurgitant jet with suggestion of pulmonary vein reversal consistent with severe mitral valve regurgitation.
TTE in parasternal short axis with the mitral valve en face and color doppler showing a broad regurgitant jet.
Past medical history
The patient is a previously healthy 7 year old with no known cardiac history, no known chronic medical conditions, and up-to-date immunisations.
Differential diagnosis
Viral myocarditis versus acute rheumatic fever with resulting heart disease.
Management
Given the ventricular dysfunction on the echocardiogram, acute respiratory syncytial virus infection, and evolving transaminitis, the decision was made to treat for myocarditis. Epinephrine and milrinone were started, and intravenous immunoglobulin 1 g/kg was administered. Infectious disease was consulted due to continued fevers and positive antistreptolysin-O titres. The patient met Jones criteria for acute rheumatic fever with one major (carditis) and two minor (fever, erythrocyte sedimentation rate > 60 and C-reactive protein > 3), and recommendations were made to treat with penicillin 50,000 units/kg q67h for 10 days to eradicate group-A streptococcus followed by monthly intramuscular penicillin prophylaxis.
After treatment for her acute inflammation and continued need for ionotropic support, she had persistent severely depressed left ventricular function with polyvalvar disease (severe aortic insufficiency, severe mitral regurgitation, severe tricuspid valve regurgitation, and moderate pulmonary insufficiency), leading to persistent lactic acidosis. Therefore, she was taken to the operating room and underwent aortic root enlargement with glutaraldehyde-treated autologous pericardial patch, mechanical mitral valve replacement with a 23 mm St Jude, mechanical aortic valve replacement with a 19 mm St Jude, and repair of the tricuspid valve by partial De Vega and creation of a bicuspid tricuspid valve. A postoperative transoesophageal echocardiogram showed significant improvement in valve function (no mitral or aortic regurgitation, moderate tricuspid regurgitation, and no significant pulmonary insufficiency) with severely depressed left ventricular function (ejection fraction ∼ 27%).
Initial anticoagulation management post mechanical valve implantation utilised unfractionated heparin. Our institutional protocol for mechanical mitral valve replacement was to start therapeutic unfractionated heparin once haemostasis was obtained postoperatively and titrate to a goal anti-Xa level of 0.35–0.7 units/mL. Once the patient was reliably taking enteral nutrition, warfarin was started at 0.1 mg/kg/dose (maximum initial dose of 5 mg) with an internation normalised ratio goal of 2.5–3.5. On postoperative day 7, our patient experienced a significant bleed while on therapeutic heparin with sanguinous drainage from her chest tube requiring an aminocaproic acid drip. She suffered from two more similar events both on postoperative day 13 and postoperative day 17 also requiring an aminocaproic acid drip. Anti-Xa levels remained within the upper portion of therapeutic goal during bleeding events; therefore, the unfractionated heparin goal was tightened to 0.35–0.5 units/mL. On postoperative day 16, she started to tolerate advancing nasojejunal feeds, but she developed abdominal pain and bilious emesis, prompting feeds to be held. Kidney, ureter, bladder X-ray was obtained that showed bubbly lucencies in the sigmoid colon and rectum concerning for pneumatosis. Additionally, lipase was obtained and resulted 277 u/L, meeting criteria for acute pancreatitis. Her pancreatitis progressed into complete pancreatic ductal transection resulting in a large abdominal fluid collection requiring multiple endoscopic retrograde cholangiopancreatography’s and a pancreatic stent.
On postoperative day 18, the patient developed haemoperitoneum with a Hg drop from 10.8 g/dL to 8.3 g/dL. She was taken to interventional radiology where no active bleeding was found, and heparin was cautiously resumed. On postoperative day 26, our patient developed an acute Hg drop from 11.3 g/dL to 9.6 g/dL and had CT evidence of bleeding into the lesser sac region in the setting of acute necrotising pancreatitis. The patient was emergently taken to the operating room (OR) for evacuation of ∼ 1.5 L blood with haematoma compression. After the procedure, haematology was consulted, and anticoagulation was transitioned from unfractionated heparin to bivalirudin targeting an activated partial thromboplastin time (aPTT) goal of 60–90 s. Ultimately, the patient was nothing by mouth (NPO) until postoperative day 99 resulting in the inability to reliably start warfarin, prompting a prolonged period of intravenous anticoagulation as outlined above. Serial echocardiograms were obtained weekly without any evidence of mechanical valve dysfunction or worsening regurgitation. After transition to bivalirudin and evacuation of hemoperitoneum, there were no repeat bleeding episodes.
Discussion
Patients with mechanical heart valves require indefinite anticoagulation to prevent valve-related thromboembolic events including valve thrombosis, valve leaflet dysfunction, stroke, and death. Reference Otto, Nishimura and Bonow1 Vitamin K antagonist (warfarin) therapy is the standard of care; however, critically ill patients may be unable to start warfarin immediately after valve insertion for various reasons, thus requiring systemic intravenous anticoagulation. Reference Douketis, Berger and Dunn2 Unfractionated heparin is the only IV systemic anticoagulant approved for management of mechanical heart valves during interruption of warfarin therapy. Reference Otto, Nishimura and Bonow1,Reference Douketis, Berger and Dunn2 Bivalirudin is a direct thrombin inhibitor that simultaneously binds to the active catalytic site of thrombin and the substrate recognition site on both circulating and clot-bound thrombin irrespective of antithrombin. There are emerging data for the use of bivalirudin in paediatric and adult patients requiring extracorporeal membrane oxygenation and ventricular assist devices largely due to the favourable pharmacokinetics compared to heparin. Reference Sanfilippo, Asmussen and Maybauer3–Reference Taylor, Campbell and Kelly5 Additionally, bivalirudin has a short half-life, quick peak effect, and predictable titration pharmacokinetics making it an enticing alternative when heparin is not ideal. Reference Mitchell, Sullinger and Dyer6 Given the significant bleeding events on unfractionated heparin, the decision was made to transition to bivalirudin until improvement postoperatively and warfarin could be initiated. Further complications requiring a prolonged NPO period with multiple non-cardiac procedures resulted in 76 total days of bivalirudin therapy.
Bivalirudin causes elevation of international normalised ratio, which can complicate the transition from bivalirudin to warfarin, the optimal long-term anticoagulant for mechanical mitral valve replacement. Reference Rollins, Smith and Zemrak7 There have been a few small, retrospective studies evaluating this transition, but limited data exist. Reference Rollins, Smith and Zemrak7,Reference Fetea, Gulbis and Hall8 An estimated international normalised ratio elevation of around 0.5 from baseline has been reported, but the degree of elevation likely depends on multiple factors including patient specific factors, drug dosing, and reagent. Reference Fetea, Gulbis and Hall8,Reference Gosselin, Dager and King9 When transitioning from bivalirudin to warfarin, our standard of care is an overlap of therapy for a minimum of 48 hours and to target an international normalised ratio > 2.5 to account for false elevation from bivalirudin, but an individualised approach for each patient is required. Specifically, in this case, our patient had a significantly prolonged international normalised ratio on bivalirudin monotherapy (international normalised ratio 2.1–2.3), thus we targeted and international normalised ratio > 3 prior to discontinuing bivalirudin. We started warfarin at 0.1 mg/kg/dose nightly (3 mg). After four doses of warfarin, patient’s international normalised ratio was 3.9, at which time bivalirudin was discontinued safely. Continuing the same warfarin dose, the next day the international normalised ratio was 2.5. Warfarin was slightly increased to 3.5 mg daily to target a goal of 2.5–3.5, and no further dose adjustments were necessary.
Follow-up
After a prolonged admission complicated by bleeding and further complicated by necrotising pancreatitis requiring multiple endoscopic retrograde cholangiopancreatography’s (ERCPs), the patient was discharged successfully on warfarin. On long-term follow-up, she continues to have a normally functioning mechanical aortic valve and mechanical mitral valve with recovery in her left ventricular function.
Conclusion
This case is unique in that it is, to our knowledge, the first case of a paediatric patient with multiple mechanical heart valves being managed with bivalirudin as the primary anticoagulant. This patient received bivalirudin for 76 total days of therapy without any adverse events or mechanical valve complications. In a patient who requires inpatient systemic anticoagulation and cannot tolerate enteral medication or feed administration, bivalirudin may be an additional option outside of unfractionated heparin.
Statements and declarations
The authors did not receive support or funding from any organisation for the submitted work.
Financial support
The authors have no relevant financial or non-financial interests to disclose.
Competing interests
The authors have no competing interests to disclose for the submitted work.
