Venovenous extracorporeal membrane oxygenation (ECMO) is an artificial lung support that has been used for acute respiratory distress syndrome (ARDS) with promising results.1,2 ECMO requires anticoagulation with heparin. One of the well-recognized complications of heparin therapy is heparin-induced thrombocytopenia (HIT).3 Once HIT is suspected clinically, all heparin infusions should be stopped, and an alternative anticoagulant may be needed. Lepirudin is a direct thrombin inhibitor and a well-known substitute for heparin.4 Wegener’s granulomatosis (WG) is a necrotizing granulomatous vasculitis involving the upper airways, lungs, and kidneys. Up to 85% of WG patients develop lower airway involvement during the course of the disease, and in some, it can be severe enough to cause pulmonary hemorrhage and ARDS.5 These severe forms of ARDS may fail to respond to maximal conventional ventilatory support. In such cases, ECMO has been successfully used.6 We report a patient with WG in whom severe ARDS developed that warranted ECMO support. Treatment was complicated by HIT, which was successfully managed with lepirudin (recombinant hirudin, Refludan; Berlex Laboratories, Wayne, IN) anticoagulation during ECMO.
A 53-year-old previously healthy white man presented to the Accident and Emergency Department with lethargy, weight loss, loss of appetite, and diarrhea of 2 weeks duration. Chest examination revealed reduced air entry over both lung bases. Abdomen was tender over the left renal angle. Other examination findings were normal. The patient had reduced urine output (< 20 ml/h); urine analysis showed blood (+ + +), albumin (+ + +), and granular casts, but ultrasonographic examination of the kidneys produced normal findings. Chest radiograph (CXR) showed minimal bilateral effusions. Hematologic investigations showed a low hemoglobin of 7.9 g/dl (normal: 12-14 g/dl), a raised white blood cell count of 15.5 × 109/ml (normal range: 4–11 × 109/l), a platelet count of 531 × 109/l (normal range: 150–450 × 109/l), serum urea of 65 mmol/l (normal range: 3–7 mmol/l), creatinine of 1,775 μmol/l (normal range: 53-106 μmol/l), a potassium level of 7.3 mmol/l (normal range: 3.5–5 mmol/l), and C-reactive protein level of 195 mg/l (normal: < 5 mg/l). Liver function tests, stool microscopy and culture results were normal. Nephritis screen revealed a high titer of cytoplasmic pattern antineutrophil cytoplasm antibodies (c-ANCA, pr-3) of 93 au/ml (normal value: < 5 au/ml). Continuous venovenous hemofiltration (CVVH) was instituted with heparin anticoagulation. Immunosuppressive therapy with 100 mg cyclophosphamide once daily and 100 mg hydrocortisone every 6 hours was started, followed by plasmapheresis (4 l plasma exchange with 4.5% human albumin solution). On day 5, while the patient was waiting for renal biopsy, he had two episodes of severe hemoptysis of 450 ml fresh blood and required a 4-U blood transfusion. Clotting screen was normal (INR: 1.2, activated partial thromboplastin time [aPTT] 31 seconds [normal range: 35–45 seconds], prothrombin time 12 seconds [normal range: 10–14 seconds], and platelet count 238 × 109/l). The patient had acute respiratory failure requiring crash intubation and mechanical ventilation (arterial blood gases on air: pH 7.47, Pco2 33 mm Hg [4.5 Kpa], Pao2 52 mm Hg [6.9 Kpa], HCO3 25 mmol/l, base excess −0.5 mmol/l, and oxygen saturation (SaO2) 90%). A repeat CXR showed diffuse bilateral alveolar shadowing. The patient’s condition progressively deteriorated despite maximal ventilatory support. Ventilatory settings 24 hours after intubation were as follows: on pressure control and pressure support (PC/PS) mode, peak inspiratory pressure 51 cm-H2O, positive end-expiratory pressure 19 cm H2O, inspiration and expiration ratio 2.4:1, respiratory rate 25/min, tidal volume 511 ml, and lung compliance 16 ml. (arterial blood gases on FiO2100%: pH 7.20, Pco2 46 mm Hg [6.2 Kpa], Po2: 53 mm Hg [7 Kpa], HCO3 16.3 mmol/l, base excess −9.8mmol/l, and SaO2 84%). The patient also required 0.13 μg/kg/minutes noradrenaline infusion for hemodynamic stability. Hence, the decision was made to support the patient with ECMO.
Venovenous ECMO was instituted through both femoral veins (28F DLP, Medtronic, Minneapolis, MN, and 28F, Chalice Medical, Notts, UK) and right internal jugular vein (28F, Chalice Medical) cannulation by Seldinger technique. Initial ECMO flow was 5 l/min and sweep gas was 6.5 l/min. The CXR immediately after ECMO cannulation is shown in Figure 1. Once the condition of the patient was stabilized on ECMO, ventilatory support was reduced to lung rest settings. (PC/PS mode, peak inspiratory pressure 25 cm H2O, positive end-expiratory pressure 10 cm-H2O, inspiration and expiration ratio 1:1.5, respiratory rate 10 per minute, and FiO2 30%). Heparin anticoagulation was continued during ECMO, and activated clotting time (ACT) was kept between 160 and 180 seconds (Actalyke MaxACT System, Helena Laboratories, Beaumont, TX, USA). CVVH and plasmapheresis (4 l plasma exchange replacing with 50% human albumin solution and 50% fresh frozen plasma) were continued with ECMO support. The patient required a total of 10 cycles of plasmapheresis over 15 days. During ECMO, the patient also received a single intravenous dose of 900 mg cyclophosphamide and 2g/day methyl prednisolone for 3 days, which was reduced by 50% every 3 days and eventually changed to 30 mg/day oral prednisolone.
During the first 48 hours of ECMO support, the patient had a persistently low platelet count (36 × 109/l) despite adequate platelet transfusion, and a temporal relationship between heparin therapy and thrombocytopenia raised the possibility of HIT. Heparin PF4 ELISA (GCI Diagnostics, Cambridge, MA, USA) test was positive for HIT antibodies. Lepirudin was therefore substituted for heparin, and the whole ECMO circuit was changed to a new circuit primed with lepirudin. Because the patient had renal failure, lepirudin was started at lower dosage of 0.005 mg/kg per hour. The aPTT ratio (Sysmex CA1500, Kobe, JP; Sysmex America, Inc, IL, USA) was maintained between1.5 and 2.5 and ACT was monitored every 4 hours. The ACT ranged from 132 to 215 seconds with a mean of 164 seconds and a standard deviation of 21.325. The aPTT ratio ranged from 1.0 to 4.1 with a mean of 2.031 and a standard deviation of 0.6621. A clear correlation between aPTT and ACT was noted (Figure 2). The platelet count recovered after heparin therapy was discontinued.
After 157 hours of ECMO support, the patient’s respiratory function improved to a satisfactory level, and ECMO support was withdrawn. The CXR taken after withdrawal of ECMO support is shown in Figure 1. Ventilatory support was gradually weaned over 7 days. CVVH and plasmapheresis were continued for 5 more days after ECMO support. The patient’s serum creatinine and C-ANCA titer improved to 310 μmol/l and 6 au/ml, respectively. Therapy with 100 mg cyclophosphamide and 30 mg prednisolone once daily was continued, and the patient was discharged home 6 weeks later.
Wegener’s granulomatosis is a systemic vasculitis that can be associated with significant morbidity and mortality because of the nature of the disease and its treatment.5 WG can sometimes take a fulminant course with severe pulmonary hemorrhage and acute renal failure. This fulminant variant is associated with a high mortality rate (up to 66%), even with aggressive immunosuppressive therapy.7 C-ANCA, pr-3 has very high specificity and sensitivity (up to 90%) in diagnosing WG.5 Our patient initially presented with nonspecific symptoms and acute renal failure, which rapidly became a fulminant disease with acute severe respiratory failure secondary to pulmonary hemorrhage despite early immunosuppressive treatment. Despite maximal conventional ventilatory support, the patient’s respiratory function deteriorated, necessitating the use of ECMO support. During ECMO, the clinical scenario was complicated by HIT.
Heparin-induced thrombocytopenia is an iatrogenic immune-mediated disorder that occurs in approximately 1–3% of patients during heparin therapy.3 If HIT is diagnosed clinically, heparin therapy should be stopped immediately and, depending on the clinical situation, an alternative anticoagulant might be used. In this patient, the platelet count before heparin therapy was 531 × 109/l and gradually decreased to 36 × 109/l on the sixth day of heparin administration. Clinically, HIT was suspected and heparin therapy was immediately stopped. Because the patient still needed ECMO support, an alternative anticoagulant was required. Lepirudin is a selective direct antithrombin III independent thrombin inhibitor and has been used as a substitute for heparin during ECMO support.8 It exerts an anticoagulant effect by inhibiting platelet aggregation and thrombus formation and does not immunologically cross react with HIT antibodies.4 Because lepirudin has no antidote, it is difficult to reverse its anticoagulant effect and can cause major bleeding complications, especially in patients with renal failure.9 Moreover, it has prolonged half-life in patients with renal failure, and bedside anticoagulation monitoring is unreliable. Even though this patient’s condition was complicated by episodes of severe pulmonary hemorrhage and acute renal failure, lepirudin anticoagulation was successfully used for the remaining period of ECMO support.
Monitoring the level of anticoagulation is a vitally important step, especially when using lepirudin, because it is likely to have a narrow therapeutic window. The ACT is a very easily operated bedside assay system for heparin anticoagulation, but it is not an accurate monitor for lepirudin anticoagulation during cardiopulmonary bypass.10,11 In this situation, Ecarin clotting time is a more reliable monitor than aPTT and ACT.11 aPTT can also be safely used to monitor lepirudin anticoagulation for ECMO, but bedside aPTT is not efficient.8 No study has assessed the relationship between ACT and aPTT in ECMO patients during lepirudin anticoagulation. We monitored the level of anticoagulation with aPTT during ECMO and also assessed ACT. We found a statistically significant relationship (R = 0.888) between ACT measured at the bedside and aPTT ratio measured in the laboratory (Figure 2) (SPSS 11.01, Cary, NC). Unlike the cardiopulmonary bypass studies, a linear correlation was found between ACT and aPTT, which could be caused by: 1) the comparatively lower level of anticoagulation needed for ECMO support, 2) the use of low-dose lepirudin, or 3) the effect of plasmapheresis in reducing the lepirudin level.12 Even though these findings were based on a single patient, they are interesting and could be the first step toward identifying a reliable bedside monitor for lepirudin anticoagulation during ECMO.
Lepirudin anticoagulation for HIT during ECMO was successfully used to manage a fulminant variant of WG with severe pulmonary hemorrhage. The linear correlation between ACT and aPTT during lepirudin use with ECMO is encouraging and warrants further confirmation.
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