Nikolaus Neu

Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration

ObjectiveMeconium aspiration induces acute lung injury (ALI) and subsequent pulmonary arterial hypertension (PAH) which may lead to right ventricular failure. Increase of endothelin-1, thromboxane-A, and phosphodiesterases are discussed molecular mechanisms.We investigated the intrapulmonary and hemodynamic effects of the intravenous dual endothelin Axa0and B receptor blocker tezosentan and inhalational iloprost in axa0model of ALI due to meconium aspiration.DesignAnimal study.SettingUniversity-affiliated research laboratory.SubjectsWhite farm pigs.InterventionsAcute lung injury was induced in 24 pigs by instillation of meconium. Animals were randomly assigned to four groups to receive either intravenous tezosentan, inhalational iloprost, or combined tezosentan and iloprost, or to serve as controls.Measurements and resultsAfter meconium aspiration-induced lung injury each treatment increased oxyhemoglobin saturations (TEZO: 88u202f±u202f6% (pu202f=u202f0.02), ILO: 85u202f±u202f13% (pu202f=u202f0.05), TEZO-ILO: 89u202f±u202f6% (pu202f=u202f0.02), control: 70u202f±u202f18%). TEZO but not ILO significantly decreased pulmonary arterial pressure and pulmonary vascular resistance (both pu202f<u202f0.01). ILO alone decreased intrapulmonary shunt blood flow (pu202f<u202f0.01). Compared with control, TEZO-ILO yielded the highest arterial partial pressure of oxygen (70u202f±u202f6 torr vs.49u202f±u202f9 torr, pu202f=u202f0.04), although it decreased arterial blood pressure (change from 71u202f±u202f13u202fmmHg to 62u202f±u202f12u202fmmHg vs.85u202f±u202f14u202fmmHg to 80 u202f±u202f11u202fmmHg (pu202f=u202f0.01).ConclusionsIntravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration. Inhaled ILO improves gas exchange only, thereby reducing intrapulmonary shunt blood flow. Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity.

Tezosentan Decreases Pulmonary Artery Pressure and Improves Survival Rate in an Animal Model of Meconium Aspiration

Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 ± 4.0 mm Hg to 24.7 ± 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 ± 1.4 mm Hg · L–1 · min · m2 to 5.2 ± 0.7 mm Hg · L–1 · min · m2. All animals treated with tezosentan survived, whereas in the control group four out of six animals died. Tezosentan improved survival and decreased pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration. Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.

Extracorporeal membrane oxygenation as a rescue therapy for leukaemic children with pulmonary failure

In patients with leukaemia, acute respiratory distress syndrome (ARDS) secondary to intensified chemotherapy‐induced immunosuppression is a devastating disorder resulting in high morbidity and mortality. Compared to standard indications for extracorporeal membrane oxygenation (ECMO), cytopenia further increases the risks of infection and bleeding. We describe the use of ECMO in four children with ARDS and leukaemia. Two patients (50%) survived, pulmonary function recovered and they are in prolonged first remission. The two other patients died from ARDS and pulmonary leukaemic infiltration. Although ECMO support is a high‐risk setup for nosocomial infection we observed no additional septic episodes. All patients had a highly increased demand for packed platelet and red blood cell transfusions. This increased demand and unmanageable chronic bleeding into both lungs in one patient were probably caused by a combination of coagulopathy from the primary illness, the use of anticoagulants, chemotherapy‐induced cytopenia, and a reduced survival rate of platelets and red cells due to permanent contact to foreign surface. We concluded that ECMO is a supportive tool to reduce the incidence of early death, treatment‐related mortality and, ultimately, to improve overall survival in childhood leukaemia.

Intravenous tezosentan and vardenafil attenuate acute hypoxic pulmonary hypertension.

Excessive hypoxic pulmonary hypertension imposes right ventricular strain by increasing afterload that may lead to right heart failure and death. Increased phosphodiesterase activity, as well as increased levels of endothelin-1, has been discussed as molecular mechanisms. We investigated the hemodynamic and intrapulmonary effects of the intravenous dual endothelin A and B receptor blocker tezosentan, and of the phosphodiesterase-5 (PDE-5) antagonist vardenafil in a pig model of acute normobaric hypoxic pulmonary hypertension. Eighteen 4-week-old ventilated white farm pigs were exposed to normobaric hypoxia (FiO2 12%) and randomly assigned to three groups (n = 6) in order to receive either intravenous tezosentan or vardenafil or to serve as control. Arterial alveolar oxygen differences were the same with both drugs. After 90 min of treatment, pulmonary artery pressure and vascular resistance were significantly lower in both treatment groups when compared to controls (p < 0.001). Cardiac index increased significantly with vardenafil alone (2.8 l x min(-1) x m2 +/- 0.7 to 4.2 l x min x m2 +/- 0.7, p = 0.0003). Intravenous tezosentan, as well as vardenafil equipotently attenuate acute hypoxic pulmonary hypertension without afflicting pulmonary gas exchange. However, cardiac index increases with vardenafil only.

Acute Lung Failure During Mechanical Circulatory Support

The use of venoarterial extracorporal membrane oxygenation and ventricular assist-devices in children with end stage heart failure is well established. The use of a bridge-to-bridge strategy leads to excellent survival rates in pediatric patients. We present an adolescent, who acquired acute respiratory failure, due to possible transfusion related lung injury, and who was successfully treated with venovenous extracorporal membrane oxygenation while on ventricular assist-device support.

Fulminant Clostridium perfringens sepsis during induction chemotherapy in childhood leukemia

Thromboembolic events are well-known complications in solid tumors and malignant hematological diseases. Risk of thromboembolism is aggravated by therapeutic agents like Lasparaginase, particularly in combination with corticosteroids. Here we describe a patient with newly diagnosed acute lymphoblastic T-cell leukemia (T-ALL), receiving L-asparaginase and prednisone, who manifested symptoms mimicking lower limb deep venous thrombosis, that proved instead to reflect fulminant Clostridium perfringens sepsis with rapidly progressive necrotizing myofasciitis.

Prolonged But Successful Weaning from Left Ventricular Assist Device After Cardiac Decompensation due to Late-Recognized Coarctation of the Aorta in a Toddler

A 2-year-old boy was presented with late-recognized coarctation of the aorta and pulmonary hypertension due to left ventricular failure. The coarctation was corrected at the day of admission with a good postoperative result. However, weaning from the respirator failed despite multiple drug support due to left ventricular failure. Consequently, a left ventricular assist device (LVAD) was implanted 22 days later. The further course was complicated by systemic hypertension and ongoing pulmonary hypertension requiring extensive antihypertensive therapy. The first attempt to wean from LVAD failed and the left ventricle was left completely unloaded for additional 4 weeks. The second weaning attempt, using a very smooth weaning protocol, led to a recovered left ventricle and facilitated the removal of the assist device after a total of 120 days. The patient was discharged with normal cardiac function, but he still requires antihypertensive therapy. We believe that the slow reduction of the LVAD support was the key measure that leads to the successful weaning of the patient, thereby avoiding heart transplantation.

Ethylene glycol intoxication presenting with high anion gap metabolic acidosis, acute kidney injury and elevated lactate

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Prolonged extracorporeal membrane oxygenation for pediatric necrotizing pneumonia due to Streptococcus pneumonia and influenza H1N1 co-infection: how long should we wait for native lung recovery?

Most children with severe respiratory failure require extracorporeal membrane oxygenation (ECMO) for 7–10xa0days. However, some may need prolonged duration ECMO (>u200914xa0days). To date, no consensus exists on how long to wait for native lung recovery. Here we report the case of a 3-year-old boy who developed severe necrotizing pneumonia requiring venovenous (VV) ECMO after 19xa0days of mechanical ventilation. In the first 4xa0weeks of his ECMO run, he showed no lung aeration, requiring total extracorporeal support. However, after we started strategies for promoting lung recovery such as daily prone positioning and regular use of toilet bronchoscopy and inhalative DNAse to clear secretions, by week five his tidal volumes gradually increased and he was successfully decannulated after 43xa0days. Moreover, we decided not to proceed to a surgical removal of the necrotic lung area. At present, he is 1-year post discharge and has fully recovered. This report shows that unexpected native lung recovery is possible even after prolonged loss of lung function and that a previous healthy lung can recover from apparent irreversible lung injury.

Extracorporeal membrane oxygenation offers long-term survival in childhood leukemia and acute respiratory failure

Dear Editor: Survival for childhood cancer has dramatically improved, particularly for acute lymphoblastic leukemia, reaching over 90% overall survival in industrialized countries [1]. However, some patients may encounter severe adverse events, limiting this high success rate. ARF is one of the most serious complications and is associated with high mortality if conventional therapy fails [2]. Escalation to ECMO has rarely been used in patients with malignancy due to its limited success rates and higher risk for infectious and bleeding complications [3–5]. We report on a single centre experience of ECMO on patients with childhood leukemia and ARF. This retrospective study was approved by the local research ethics committee. Nine patients with childhood leukemia received ECMO in induction treatment (8/9 at first remission, 1/9 at second remission) between January 2004 and June 2017. Details on these patients are provided in Table 1. ARF resulted from pulmonary infections (two patients with Candida albicans, one patient with Aspergillus terreus, four patients with no organisms identified) and pulmonary non-infectious complications (one patient with transfusion-related acute lung injury and one patient with leukemic infiltration). Median duration of mechanical ventilation before ECMO was 3 days (range 0.4–14). The median duration of ECMO support was 14 days (range 2–24). Five (56%) patients survived ECMO und four (44%) survived to hospital discharge. When compared to survivors, non-survivors had a significantly higher vasoactive inotrope score (VIS) at ECMO initiation (85 vs. 11; p = 0.032), including two patients requiring veno-arterial cannulation. Time on ECMO support was shorter (5 vs. 15 days; p = 0.032) in non-survivors and was stopped because of multiorgan failure (22%), intracranial bleeding (11%) and progressive leukemia (11%). One patient (11%) recovered from hematopoietic stem cell transplantation performed on ECMO, but died two months later of septic shock. Moreover, non-survivors had significantly lower platelet count on ECMO (30 × 10/μL vs 98 × 10/μL; p = 0.041). Eight (89%) patients received chemotherapy in the four weeks prior to and five (56%) were neutropenic at ECMO cannulation. Neutropenic patients did not have higher mortality compared to those without neutropenia (3/5 vs 2/4). All four survivors are in complete oncologic remission at a median follow-up of 8.4 years (range 1.8–13.1), are restored to full health, and are all engaged to full-time study or work. Our data is limited by a small sample size and by its retrospective analysis. Nevertheless, it indicates that ECMO provides an effective rescue therapy in childhood leukemic patients with ARF.