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Prothrombin Complex Concentrate and Methylene Blue for Treatment of Coagulopathy and Vasoplegia in a Pediatric Heart Transplant Patient

Lee, Jennifer K. MD; Ing, Caleb MD, MS

doi: 10.1213/XAA.0000000000000271
Case Reports: Clinical Care

Ventricular assist devices (VADs) are associated with conditions that may complicate the perioperative course of pediatric heart transplants. A 7-year-old girl with dilated cardiomyopathy supported by a Toyobo-NCVC left VAD (Toyobo-National Cardiovascular Center, Osaka, Japan), a pulsatile extracorporeal device, and preoperatively anticoagulated with warfarin presented for orthotopic heart transplant. The course was complicated by persistent bleeding treated with prothrombin complex concentrate and refractory postbypass vasoplegia treated with methylene blue. Preoperative anticoagulation and the presence of a VAD are associated with postbypass coagulopathy and vasoplegia. We describe a case in which these conditions were successfully treated with no thrombotic complications and minimal need of vasopressors for hemodynamic stability.

From the Department of Anesthesiology, Columbia University Medical Center, New York, New York.

Accepted for publication September 3, 2015.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Jennifer K. Lee, MD, Department of Anesthesiology, Columbia University Medical Center, 622 W 168th St., New York, NY 10032. Address e-mail to

Ventricular assist devices (VADs) are associated with conditions that may complicate the perioperative course of orthotopic heart transplants (OHTs). The use of prothrombin complex concentrate (PCC) has increasingly been described in the adult population for persistent bleeding; however, reports of its use in pediatric patients have been limited.1–3 Similarly the use of methylene blue for vasoplegia has largely been described in the adult population.4,5 We present a case of a child with a left VAD (LVAD) undergoing an OHT and the use of PCC and methylene blue for coagulopathy and vasoplegia after discontinuation of cardiopulmonary bypass (CPB). Written consent has been obtained from the parents for publication of this case.

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A 7-year-old, 23.5-kg girl with a Toyobo LVAD (Toyobo-National Cardiovascular Center, Osaka, Japan) presented for OHT. She had developed dilated cardiomyopathy secondary to myocarditis and required extracorporeal membrane oxygenation and subsequent implantation of biventricular Toyobo VADs.6 The right VAD was weaned and explanted 25 days later. Subsequent attempts to wean the LVAD were unsuccessful, requiring the patient to remain on support for 9 months before the OHT. Warfarin was used for anticoagulation with a goal international normalized ratio (INR) of 4 to 4.5. On the morning of the OHT, the patient was receiving no pressors but had an INR of 4.1 despite the warfarin dose being held on the previous evening.

Given the preoperative INR, a coagulopathy after CPB was anticipated, so 0.1 mg/kg vitamin K was administered IV at the start of the case. The course before discontinuation from CPB proceeded uneventfully, and an infusion of 0.05 μg/kg/min epinephrine was started to assist in weaning from CPB. The patient was initially hypotensive with poor biventricular contractility observed on transesophageal echocardiography (TEE). The epinephrine infusion was increased to 0.07 μg/kg/min, and a bolus of 25 μg/kg of milrinone was administered followed by an infusion of 0.5 μg/kg/min. Protamine was administered for heparin reversal with a final activated clotting time of 154 seconds, and a total of 60 mL cryoprecipitate, 150 mL fresh frozen plasma (FFP), and 245 mL platelets were given to treat clinical bleeding.

After chest closure, the patient was hypotensive and required several boluses of epinephrine to maintain a mean arterial blood pressure >40 mmHg. The epinephrine infusion was increased to 0.1 μg/kg/min, and a vasopressin infusion of 0.0005 units/kg/min was started. An arterial blood gas at the time showed 1.21 mmol/L ionized calcium, 2.38 mmol/L lactic acid, 143 mg/dL glucose, and 30% hematocrit. At this time, the TEE showed normal left ventricular function with mild to moderately decreased right ventricular function without dilation. A 10-mL/kg fluid bolus was given resulting in an increase in central venous pressure from 14 to 20 mmHg without any change in arterial blood pressure. Due to persistent hypotension, the epinephrine infusion was increased to 0.15 μg/kg/min. Because there was a concern for possible compression due to a transplanted heart that was slightly large for the patient, the chest was reopened, but no improvement in hemodynamics was seen. Clinical bleeding and a lack of active clot formation were observed, and further coagulation studies were not available, so 500 units (approximately 21 units/kg) of PCC was administered. A repeat TEE with the chest open showed that right ventricular function was still moderately decreased with the left ventricular appearing underfilled despite fluid boluses and a high central venous pressure. Nitric oxide was initiated at 20 ppm to reduce pulmonary vascular resistance, but the hypotension persisted, and an increase in the vasopressin infusion to 0.001 units/kg/min was required. Because of the continued need for high doses of pressors, 1.5 mg/kg methylene blue was administered as an adjunctive vasoconstrictor. Within 15 minutes, the epinephrine infusion was titrated down to 0.05 μg/kg/min and the vasopressin to 0.0005 units/kg/min. Within 25 minutes, the patient was transferred to the pediatric intensive care unit (PICU) at which point the vasopressin infusion was discontinued and the epinephrine infusion was reduced to 0.03 μg/kg/min. Minimal chest tube output was seen at this time. There were no further complications overnight, with only an additional 10 mL/kg of platelets required. The postoperative INR was 1.3. The chest was closed on postoperative day (POD) 3, and the patient was tracheally extubated on POD 5, discharged from the PICU on POD 13, and discharged from the hospital on POD 21. There were no further complications during the PICU or hospital stay.

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The need for a VAD in patients presenting for heart transplant is associated with complications including post-CPB coagulopathy and vasoplegia. The Toyobo-NCVC is a pneumatic diaphragm-type pulsatile extracorporeal device that often requires a high level of anticoagulation, which reduces the risk of thrombotic complications but contributes to an increased post-CPB coagulopathy. The preoperative use of a VAD in adults has also been identified as an independent risk factor for post-CPB vasoplegia.7 Although the mechanism behind this is unknown, one hypothesis is that the increased propensity for bleeding and longer CPB times in patients requiring preoperative VADs may be contributory.7 Although the use of PCC for post-CPB coagulopathy has been described in the adult population for persistent bleeding because of warfarin, and in children with congenital factor deficiencies, to our knowledge, its use has not been described to treat pediatric patients receiving oral anticoagulation therapy undergoing CPB.1–3,8

PCC is a plasma-derived concentrate of vitamin K-dependent factors II, VII (in varying amounts), IX, X, and protein C and S.9 Formulations with normal amounts of factor VII are called 4-PCCs and those with low amounts are called 3-PCCs. Coumadin prevents the carboxylation of vitamin K-dependent coagulation factors in the liver, where PCCs can replenish. There are several advantages of using PCC over FFP. PCCs are easily stored at temperatures <25°C, can be administered independently of blood type, are concentrated, and can be administered quickly relative to FFP because of lower intravascular volume. The concentrates of factors II, VII, IX, and X in PCC formulations can be approximately 25 times higher than in normal plasma.9

A study by Song et al.3 reported the successful use of PCC as rescue treatment for coagulopathy after cardiac surgery in a group of 25 adult patients that included patients who were anticoagulated with warfarin. Although there was 1 patient in that study who developed an upper extremity deep vein thrombosis, our patient did not experience any thrombotic complications. It is of note that the Song et al.3 used factor VIII inhibitor bypassing activity manufactured by Baxter, which contains activated factor VII (VIIa) unlike other PCC preparations available in the United States. Recombinant factor VIIa has been associated with thrombotic complications.10 Our patient received Kcentra, a 4-PCC manufactured by CSL Behring (King of Prussia, PA) that contains factors II, VII, IX, X, and protein C and S.

The dosing of PCC in our patient was based on the doses reported in the adult literature (20–25 units/kg).2,3 On the basis of the study by Carvalho et al.,1 the PCC dose can also be determined according to the patient’s INR value, using a dose of 15 IU/kg if the INR is <5 and 30 IU/kg if the INR is >5.

In addition to coagulopathy, our patient also experienced refractory hypotension on discontinuation of CPB. The prevalence of post-CPB vasodilatory shock attributed to vasoplegia has been reported to be 8.8% to 10% in adults.11 Vasoplegic syndrome after cardiac surgery is believed to be due to dysregulation of nitric oxide synthesis and vascular smooth muscle guanylate cyclase activation. Nitric oxide activates guanylate cyclase, producing cyclic guanosine monophosphate, which leads to vascular smooth muscle vasodilation, and may also decrease myocyte contractility.12,13 CPB-triggered release of proinflammatory mediators such as interleukin-1 and oxygen-free radicals can also activate guanylate cyclase.

Methylene blue crosses cell membranes to compete with nitric oxide in binding to the iron heme moiety of soluble guanylate cyclase, thereby inhibiting its activation and preventing an increase in cyclic guanosine monophosphate.14 Methylene blue may also improve the myocardial performance by depressing the effects of molecules such as tumor necrosis factor-α and inhibiting superoxide radical formation.15

The use of methylene blue has been described for postbypass vasoplegia in doses of 1.5 to 2 mg/kg.11,16 The use of methylene blue in adult postcardiac surgery patients with vasoplegic syndrome has been found to reduce the duration of vasoplegia to <6 hours and also reduce mortality.4 Its use is rarely reported in children, with 1 case in a pediatric lung transplant patient, also resulting in the resolution of vasoplegia after administration.16 The potential risks associated with the administration of methylene blue are cardiac arrhythmias and pulmonary vasoconstriction.17 The concomitant use of inhaled nitric oxide may have had a protective effect against pulmonary vasoconstriction in our patient.

In summary, pediatric patients presenting for OHT may experience a number of complications including coagulopathy and vasodilatory shock, particularly if they require a preoperative mechanical assist device. Our experience supports the consideration of PCC for persistent bleeding resulting from oral vitamin-K antagonists and methylene blue for postbypass vasoplegia in pediatric patients.

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