Discussion

Recombinant activated factor VII (rFVIIa) has been primarily used in patients with haemophilia. The off-label use of rFVIIa has been increasing in non-haemophiliac patients to treat uncontrolled bleeding in adults, children, neonates, and even preterm neonates. ^{Reference Park2} Case reports and clinical studies have reported as well the effectiveness of rFVIIa in diffuse pulmonary haemorrhage mainly in haematology and oncology adult patients such as metastatic choriocarcinoma, haematopoietic stem cell transplantation, graft-versus-host disease, pneumonia, and sepsis; ^{Reference Lauque, Cadranel and Lazor1–Reference Mandal, Sagar and Sahoo4} However, many questions still remain pending regarding the formulations, doses, dosing regimens, and routes of administration either systemically or locally through endotracheal tube. ^{Reference Lauque, Cadranel and Lazor1–Reference Mandal, Sagar and Sahoo4} There are limited data on its intrapulmonary application in paediatric patients, and its benefit for neonates and infants less than 1 year of age remains unclear. ^{Reference Lauque, Cadranel and Lazor1–Reference Park3}

rFVIIa promotes hemostasis by activating the extrinsic coagulation pathway by enhancing thrombin generation on the surface of activated platelets. ^{Reference Monroe, Hoffman and Oliver5} rFVIIa is a biological drug with a difficulty to pass the alveolo-capillary membrane if applied intravenously which necessitates a high systemic concentration with a higher risk of adverse systemic effects in compared to local application at the targeted site. ^{Reference Heslet, Nielsen and Nepper-Christensen6}

Diffuse pulmonary haemorrhage in infants carries poor prognosis and may lead to death. The current treatment depends on treating possible aetiology and may include spectrum of interventions and medications such as avoiding local irritation, corticosteroids, antimicrobial agents, transfusions of different blood products to correct coagulopathy or anaemia, applying local vasoconstrictive agents, applying positive end-expiratory pressure and mechanical ventilation, extracorporeal membrane oxygenation, immunosuppressant, and exogenous surfactant. Surgical and bronchoscopy interventions can be considered in specific condition. ^{Reference Lauque, Cadranel and Lazor1,Reference Park2,Reference Heslet, Nielsen and Nepper-Christensen6} In our paediatric cardiac patient, we followed initially the traditional strategies to control pulmonary haemorrhage locally and systematically with no improvement. However, the bleeding persisted leading to cardio-respiratory embarrassment and life-threatening instability that justified in our judgment the off-label use of novel treatment with locally injected rFVIIa in endotracheal tube to control bleeding and to continue thereafter high frequency oscillator ventilation.

The exact duration needed for local rFVIIa injection to control pulmonary haemorrhage is difficult to define in the literature. However, we found immediate decline of pulmonary haemorrhage after local rFVIIa injection and total bleeding control within 15 minutes of local injection.

Multiple resuscitation doses of epinephrine through intravenous and endotracheal access were needed to manage symptomatic sinus bradycardia episodes in our patient. The bradycardia episodes were mainly due to severe hypoxia and poor gas exchange from pulmonary haemorrhage. With massive pulmonary haemorrhage intravenous epinephrine was more efficient to reverse frequent bradycardia than endotracheal epinephrine but both failed to control bleeding until endotracheal rFVIIa was administered.

Several risk factors have been associated with the development of pulmonary haemorrhage in infants, but the exact pathogenesis remains obscure. The association of massive alveolar haemorrhage with aspiration pneumonitis is unusual. ^{Reference Zahr, Ashfaq and Marron-Corwin7} Pulmonary haemorrhage can be induced by local trauma such as tracheal suctioning or airway instrumentation or even feeding tube insertion. However, in our case, there was neither local trauma nor attempt for device insertion in upper airway prior to pulmonary haemorrhage. The bleeding that was noted only after the first cycle of resuscitation appeared as frothy oral bloody secretions and continued thereafter from endotracheal tube that was inserted by atraumatic intubation. Following insertion of advanced airway, no bleeding was noted from nasopharynx or oropharyngeal cavities by direct exam. Furthermore, the possibility of infectious causes of bleeding was excluded as tracheal aspirates cultures and nasopharyngeal swabs remained negative for bacterial and viral causes. Our patient was started 4 weeks before the event on enoxaparin for multiple thrombosis at sites of central venous accesses. The use of anti-coagulation can contribute to bleeding particularly with out of range values. The low molecular weight heparin assay of 0.35 IU/mL in our patient was in the lower limit of therapeutic range (0.4–1 IU/mL) and it is unlikely to be the cause of massive pulmonary haemorrhage. Other possible qualitative or quantitative hematological aetiologies for pulmonary haemorrhage were also excluded by extensive investigations.

Although it is understandable that the poor left ventricle function or mitral regurgitation can lead to dilated left chambers and offer a risk factor for pulmonary haemorrhage. However, the retrospective analysis of cardiac images in our case before the arrest showed mild mitral regurgitation and mild depressed cardiac function with mild dilatation of left chambers which could be seen in such surgeries. In our case, we attributed the pulmonary haemorrhage post cardiac surgery to multiple factors including aspiration, cardiopulmonary resuscitation, anti-coagulation, endo-vasculitis, and mild mitral regurgitation.

Pulmonary haemorrhage is known to be associated with comorbidity and mortality. In one published studies, the authors reported that death or survival with neurosensory impairment were at least doubled after serious pulmonary haemorrhage in infants. ^{Reference Zahr, Ashfaq and Marron-Corwin7} We observed no major consequences after pulmonary haemorrhage in our patient and was discharged home in satisfactory condition.