Inhaled nitric oxide for avoidance of extracorporeal membrane oxygenation in the treatment of severe persistent pulmonary hypertension of the newborn.

UNLABELLED: Inhaled nitric oxide (NO) is thought to provide a noninvasive therapeutic alternative to extracorporeal membrane oxygenation (ECMO) in the treatment of persistent pulmonary hypertension of the newborn (PPHN). OBJECTIVE: Since January 1993, we have studied inhalation of NO in PPHN patients meeting the ECMO criteria of our institution. We focused on the questions of whether or not the need for ECMO could be obviated and whether differences could be found between NO responders and nonresponders. DESIGN: NO gas was delivered via conventional IPPV ventilation in incrementally increasing concentrations from 20 to 80 ppm. PATIENTS: NO therapy was attempted in ten ECMO candidates with clinical and echocardiographical evidence of PPHN (mean OI 51.9, SD 10.4). RESULTS: At various NO levels (30-60 ppm), five patients showed a significant increase in mean PaO2 (range 32.9-85.9 mmHg). Improvement was transient in three patients (6-10 h) and prolonged in two others (54-80 h); in the latter cases, ECMO was avoided. Five patients did not respond at all to treatment. Responders and nonresponders differed in their mean respiratory tidal volume (8.9 vs 4.18 ml/kg, P <0.05). CONCLUSIONS: In our study, inhalation of NO obviated the necessity of ECMO therapy in only two out of ten PPHN patients. Thus, we would discourage any overoptimistic expectations about the effectiveness of NO therapy in PPHN until larger clinical trials have been performed.

Prognosis and outcome of neonates treated either with veno-arterial (VA) or veno-venous (VV) ECMO.

A comparison was done between neonates requiring veno-arterial (VA) ECMO (too small jugular vein, inability to insert a 12 Fr double lumen catheter or cardio-circulatory instability) and neonates treated with veno-venous (VV) ECMO in the same period of time. From 1991-1995 ECMO was done in 48 neonates after failure of maximum conventional treatments, NO-inhalation and HFOV. 30/48 babies were treated with VV-ECMO, with a switch to VA-ECMO later on in 3 of them. In 18 infants VA-ECMO was installed primarily. Differences between the VA- and VV-ECMO group were: the OI was higher in the VV-treated babies (62 +/- 20 vs. 48 +/- 13, p < 0.03), as were birth weight (3385 +/- 570 vs. 2963 +/- 653 g, p < 0.04), gestational age (39.7 +/- 1.6 vs. 37.9 +/- 2.7 weeks, p < 0.01) and MAP (18.7 +/- 2.2 vs. 17.1 +/- 2.4 cm H2O, p < 0.05). Severe ICH's occurred more frequently in the VA-treated babies (29 vs. 7%, p < 0.05), the rate of other complications was equal. The mortality rates were 43% (VA) and 15% (VV), p < 0.05. About one third of neonatal ECMO candidates will be treated with VA-ECMO, even if the VV-ECMO technique is available. Need for VA-ECMO implies--due to a higher number of preterm babies and a greater severity of illness before ECMO--a higher incidence of ICH's and a higher mortality rate.

High-frequency oscillatory ventilation and nitric oxide: alternative or complementary to ECMO.

One hundred and seventy-seven term or near-term neonates were referred to an ECMO center for severe PPHN-associated diseases. In 2 time periods from 1987 to 1991 and from 1992 to April 1995 alternative treatment modes were tried in an attempt to obviate ECMO. During the first time period patients underwent trial high-frequency oscillatory ventilation before ECMO. In the second time period patients first received inhaled NO followed by HFOV in a non-responders. If this also failed HFOV was combined with INO. In both time periods about 40% of the patients were spared ECMO treatment by these alternative treatment modalities. INO only benefited 15% of the ECMO candidates who apparently had fared just as well on HFOV alone in the preceding time period. While patients who were improved by INO were spared HFOV with its potential severe complications, i.e. air leaks and cardiocirculatory instability, more extended long-term studies will have to show which of these 2 treatment modalities (INO or HFOV) should be given first priority in an attempt to avoid ECMO in neonates with severe respiratory failure.

Indication for using extracorporeal membrane oxygenation in congenital diaphragmatic hernias and pulmonary hypoplasia.

Despite the apparent surgical simplicity of the anatomic defect, congenital diaphragmatic hernia continues to be a critical problem in neonatal surgery, so that survival is still uncertain. Therefore, we must realize that the barriers to survival are pulmonary parenchymal and vascular hypoplasia as well as the complex syndrome of persisting fetal circulation. However, new treatment methods, such as extracorporeal membrane oxygenation (ECMO), although controversial, may improve survival. We believe that no infant should be excluded from diaphragmatic repair or consideration for ECMO-support before accurate predictive parameters have been developed that take both pulmonary hypoplasia and pulmonary hypertension into account. ECMO additionally enables us to postpone the operation until stabilization of the newborn (Late Operation Protocol). Apart from this, we can probably improve the long-term results after ECMO by reconstructing the common carotid artery.

A 20-year experience on neonatal extracorporeal membrane oxygenation in a referral center.

OBJECTIVE: Advances in treatment of neonatal respiratory failure are responsible for a decline in the number of newborns treated with extracorporeal membrane oxygenation (ECMO). The aim of this study are to determine demographic changes, focusing on time of referral, diagnosis, and respiratory parameters in neonates put on ECMO. DESIGN: Retrospective review. SETTING: Tertiary ECMO center. PATIENTS: A total of 321 neonates were treated with ECMO from January 1987 to December 2006. RESULTS: Overall number of patients increased with every 5-year period, whereby congenital diaphragmatic hernia (CDH) was the most common diagnosis (53%), followed by meconium aspiration syndrome (MAS) (21%), sepsis and/or pneumonia (13%), and others such as persistent pulmonary hypertension of the newborn (PPHN), respiratory distress syndrome (RDS), or hypoplasia of the lung (13%). Worsening severity of illness as measured by ECMO duration and days on ventilator has to be stated for all diagnoses. Nevertheless, survival rate remained stable; both overall and diagnosis-specific mortality rates did not change significantly. Of all children, 67% survived to discharge or transfer, while best rates were seen for MAS (94%), followed by sepsis and/or pneumonia (69%), CDH (62%), and other diagnoses (43%). Concerning survival rate, no difference between inborn and outborn children occurred. However, between early- and late-referred children, a referral to the ECMO center during the first 24 h of life was associated with a significantly higher rate of survival (77% versus 54%, p = 0.0004), predominantly seen for CDH (67% versus 35%, p = 0.02). CONCLUSION: We strongly recommend timely transfer to an ECMO center in patients with CDH who are at risk of circulatory failure.

Neonatal stroke involving the middle cerebral artery in term infants: clinical presentation, EEG and imaging studies, and outcome.

Six children with neonatal cerebral infarction of the middle cerebral artery are reported. Seizures or respiratory distress were the initial symptoms. In some cases abnormal findings appeared earlier on EEG than on ultrasound. The EEG changes were concordant with the localization of the lesion. Ultrasound examinations revealed an echodense structure within the vascular territory, after a phase of appearing to be normal, highly suggestive of cerebral infarction. The diagnosis was confirmed by CT scan. Findings on EEG, cranial ultrasound and CT suggested that the stroke represented a late intra-uterine event. At long-term follow-up, six children had failed to develop normally for age and had become obviously hemiplegic as gross motor development proceeded. Four of the patients had developed epilepsy. These data indicate that the outcome of neonatal stroke may not be as positive as previously reported.

[Unusual symptoms in brain tumors in childhood]. / Ungewöhnliche Symptome bei Hirntumoren im Kindesalter.

Headache, nausea, ataxia and diplopia are leading symptoms of brain tumors in children. We report of 3 children with unusual symptoms and findings. Patient 1 complained of occasional headaches. Clinical examination showed neurological deficits and uveitis. Lumbar puncture revealed a pleocytosis and the oligoclonal banding study was positive. Cranial MRI demonstrated an enlarged pons. Under treatment with cortisone a clinical improvement was seen, but no change of the abnormalities in MRI. Several weeks later a biopsy was performed, which verified an astrozytoma. The second child developed a torticollis, following an accident, and later a refractory constipation was noted. A clinical evaluation was within normal limits. Several weeks later the patient complained of bladder disturbances. Patient 3 had a lateralized tic disorder without any neurologic deficits. CT showed an infratentorial tumor above the 4th ventricle. The tic disorder vanished only after the tumor was completely resected in the second operation. The reported cases demonstrate the fact that in an individual patient a brain tumor can cause unusual symptoms and findings which do not make the diagnosis obvious.

Hemothorax under thrombolytic therapy with recombinant tissue: plasminogen activator (rt-PA) in a 16-year-old girl.

We present the case of a 16-year-old girl with an extended thrombosis of the femoral and iliac vein and the inferior vena cava during pleuropneumonia; predisposing risk factors for thrombophilia were: use of contraceptives, nicotine abuse and congenital deficiency of antithrombin III (not previously diagnosed). Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA; initial dose: 0.08 mg/kg/h) was started. 2 days later--after diagnosis of an extended hemothorax: 1500 ml blood were obtained after thoracocentesis, transfusion of packed red blood cells was necessary--rt-PA was stopped, with only heparin (400 U/kg/d) being administered. 36 h later--the thrombosis had not yet changed--the thrombolytic therapy with rt-PA was continued in a markedly reduced dose (0.015 mg/kg/d) with no further bleeding complications. 8 days later--after successful thrombolysis--t-PA was stopped, heparin was given for another 10 days, then cumarin was administered orally.

High frequency oscillatory ventilation and extracorporeal membrane oxygenation in severe persistent pulmonary hypertension of the newborn.

We report on 50 term and near-term neonates (birth weight greater than 1800 g, gestational age greater than 33 weeks) with severe persistent pulmonary hypertension of the newborn (PPHN), referred to us from January 1987 to July 1991 after failure of maximum conventional treatment. All infants had paO2 less than 45 mm Hg when ventilated with peak inspiratory pressure greater than 38 cm H2O and FiO2 = 1.0, hence meeting entry criteria for extracorporeal membrane oxygenation (ECMO). High frequency oscillatory ventilation (HFOV) was tried in all patients. If sufficient oxygenation could not be achieved (paO2 less than 40 mm Hg for at least 2 h), ECMO therapy was begun, which was the case in 25 children. Neonates responding to HFOV (n = 25) were of a slightly younger gestational age (37.0 weeks vs 38.8 weeks, P less than 0.05), had higher Apgar scores and were less hypoxaemic before HFOV (paO2 36.6 mm Hg vs 28.8 mm Hg, P less than 0.01); during HFOV there was a significant rise in paO2 (greater than 150 mm Hg; P less than 0.001) and a fall in pCO2 to 21.6 mm Hg (P less than 0.001). Due to air leaks, which was the main complication of HFOV (52%), ECMO therapy had to be begun in two additional infants after an initial positive effect. HFOV tended to be successful in cases of primary PPHN, meconium aspiration and sepsis, but not in infants with lung hypoplasia as a result of diaphragmatic hernia or other reasons. Success or failure of HFOV could not be reliably predicted by any parameter.(ABSTRACT TRUNCATED AT 250 WORDS)

ARDS infolge schwerer RSV-Infektion Therapeutische Optionen: Therapeutische Optionen.

We report on a strikingly frequent referral of former preterm babies with respiratory syncytial virus (RSV) infection and subsequent ARDS in our hospital during the winter 1994/95 with regard to the clinical course under application of alternative treatment modalities. Treatment modalities like inhalational ribavirin, use of bronchodilators and instillation of surfactant had been tried without success. All children (age: 1-43 months) were ventilated for 6.6 (1-17) days with FiO2 = 1.0 and a mean airway pressure of 16.4 (10-24) cm H2O. Mean arterial blood gases were 49 (paO2) and 41 (pCO2) mm Hg, the OI was 33.4. By inhalational NO in combination with IPPV or HFOV 4 patients could be stabilized, in the other 6 ECMO became necessary. Two of them died in spite of several weeks on ECMO; 8 children survived and could be discharged home after a mean hospital stay of 3 months. Even in very severe cases of RSV infection treatment modalities like NO, HFOV and ECMO can be used successfully. The use of these treatment modalities must be considered before the lung damage is irreversible; in those cases a pre-existing BPD is no contraindication even for extracorporeal lung support.

[High frequency oscillatory ventilation of infants with severe respiratory disorders: possibilities, risks and limits]. / Hochfrequenzoszillationsbeatmung bei Säuglingen mit schwersten Atemstörungen: Möglichkeiten, Risiken und Grenzen.

By pediatricians the high frequency oscillatory ventilation (HFOV) is used almost only in the neonatal period. We report on the administration of HFOV in infants with pulmonary insufficiency after failure of conventional ventilatory support. 6 infants (aged 2-7 months, all former preterm babies) were referred to our hospital due to severe pneumonia after unsuccessful conservative management. Indications for HFOV were hypoxia (mean paO2 41.8 mm Hg with FiO2 = 0.95 and mean airway pressure = 16.6 cm H2O) and/or air leak syndrome. In all cases a sufficient oxygenation could be achieved by HFOV, followed then by stepwise reduction of FiO2 and MAP. The air leaks receded. After 12-178 h on HFOV a successful switchback to conventional ventilatory support (at FiO2 = 0.48 and MAP < 12 cm H2O) was possible, all infants were extubated 6-15 days later. Possible risks of HFOV are air leaks, a necrotizing tracheobronchitis and hemodynamic changes due to compression of the heart and great vessels. With the at the moment in Germany available oscillatory ventilators HFOV as a rescue therapy must be limited for infants with a body weight below 5-6 kg.

[The role of extracorporeal membrane oxygenation (ECMO) in current neonatology]. / Die Rolle der extrakorporalen Membranoxygenierung (ECMO) in der aktuellen Neonatologie.

Two hundred term or near-term neonates were referred to an ECMO center for severe PPHN associated diseases. In 2 time periods from 1987 to 1991 and from 1992 to December 1995 alternative treatment modes were tried in an attempt to obviate ECMO. During the first time period patients underwent a trial of high-frequency oscillatory (HFOV) ventilation before ECMO. In the second time period patients first received inhaled NO followed by HFOV in non-responders. If this also failed HFOV was combined with iNO. In both time periods about 40% of the patients were spared ECMO treatment by these alternative treatment modalities. INO only benefited 15% of the ECMO candidates who apparently had fared just as well on HFOV alone in the preceding time period. While patients who were improved by iNO were spared HFOV with its potential severe complications, i.e. air leaks and cardiocirculatory instability. More extended long-term studies will have to show which of these 2 treatment modalities (iNO or HFOV) should be given-first priority in an attempt to avoid ECMO in neonates with severe respiratory failure.

Inhaled nitric oxide during extracorporeal membrane oxygenation for the treatment of severe persistent pulmonary hypertension of the newborn.

Inhaled nitric oxide (NO) as a complementary treatment was studied in 10 neonates during extracorporeal membrane oxygenation (ECMO) therapy of various persistent pulmonary hypertension of the newborn (PPHN)-associated diseases. At individually different levels of inhaled NO (20-80 ppm), the mean Pao2 increased by 59.7% in 6 responders, but it remained unchanged in 4 nonresponders. Adverse side effects of the NO inhalation were tolerable. It was associated with a reversible decrease of the mean arterial blood pressure in 1 patient. During prolonged NO inhalation, the methemoglobin (met-Hb) level increased to 0.9-4.6% in 6 patients. Based on these preliminary results, we conclude that inhaled NO during ECMO can improve oxygenation in some PPHN patients. Further studies with control groups are needed to determine whether inhaled NO can shorten ECMO treatment or improve the rate of survival among PPHN patients.

Influence of early postnatal dexamethasone therapy on ventilator dependency in surfactant-substituted preterm infants.

We examined 26 preterm infants with respiratory distress syndrome in a randomized controlled prospective study to determine whether early postnatal dexamethasone therapy (< 2 h; 0.5 mg/kg per day) over 5 days in addition to substitution of surfactant (100 mg/kg) facilitates extubation and the course of RDS. Control (n = 12) and treated (n = 14) groups were comparable in birthweight (mean +/- SD: 1219 +/- 292 versus 1446 +/- 442 g), gestational age (29.3 +/- 2.2 versus 30.6 +/- 2.7 weeks), prenatal characteristics and initial respiratory and blood gas parameters. In both groups one infant died. Infants in the dexamethasone group responded better to surfactant (12/14 versus 3/12; p < 0.01), were extubated earlier (6.6 versus 14.2 days; p < 0.02) and required less time on supplemental oxygen (4.2 versus 12.5 days; p < 0.02). Pulmonary complications tended to be lower in the dexamethasone group (1/14 versus 4/12), as was the frequency of retinopathy (2/14 versus 6/12; p < 0.05). We conclude that early postnatal dexamethasone therapy improves response to surfactant therapy resulting in better weaning and earlier extubation in premature infants.

Neurological findings in newborn infants after extracorporeal membrane oxygenation, with special reference to the EEG.

Seventeen newborn infants were treated with extracorporeal membrane oxygenation (ECMO). Two died shortly after the start of ECMO due to the underlying disease, two died later in the course due to a lack of recovery of lung function and two others died weeks after ECMO from renal damage and a cardiac defect. Of the survivors, nine are developing normally (aged between one and four years) and two are severely disabled because of infarctions of the left hemisphere, acquired before and after ECMO. Intermittent-discontinuous EEGs did not indicate a poor prognosis if normalization of the EEG occurred within seven days. However, infarcted areas on ultrasonography, persistent EEG changes or deteriorating findings indicated disability or early death.

Results of parenchymal and angiographic magnetic resonance imaging and neuropsychological testing of children after stroke as neonates.

We describe the long-term follow up of infants after neonatal stroke of the middle cerebral artery (MCA). Stroke was diagnosed by CT scan in eight full-term neonates. Three dimensional (volume) magnetic resonance angiography (MRA) is a noninvasive technique that images the arterial vessels without contrast agents. All patients, aged from 1.5 to 8.4 years, were investigated by MRI and MRA and by neuropsychological tests. Cognitive development was investigated by intelligence tests, tests of visual perception, motor and language development. Out of the eight patients, seven had a retarded mental and motor development, and 50% of the children were treated for epilepsy. Seven patients had a spastic hemiparesis. Seven out of eight children showed major cognitive deficits. In all patients, MRI revealed clear parenchymal defects with variable distribution patterns. MRA studies showed abnormalities corresponding to the expected vascular distribution. Children with complications at delivery, with seizures, and an interruption of the main stem of MCA as demonstrated on MRA had the least favourable long-term follow up prognosis with severe cognitive delays.

[Extracorporeal membrane oxygenation (ECMO) in acute cardiovascular failure caused by myocarditis]. / Extrakorporale Membranoxygenierung (ECMO) bei akutem Herz-Kreislauf-Versagen infolge Myokarditis.

Main indication for extracorporeal membrane oxygenation (ECMO) is respiratory failure in the newborn. Less frequently ECMO is used for cardiac support. We report on a 4 months old boy, who suddenly fell ill with an acute viral myocarditis and heart failure (left-ventricular shortening fraction lowered to 17%). After failure of conventional management and resuscitation (twice) due to asystolic, veno-arterial ECMO was installed for a total time of 4 days. Under ECMO there was complete recovery of left-ventricular function; the infant was discharged 1 month after admission to hospital. ECMO-therapy should not only be considered in children with respiratory failure, but also in those with potentially reversible cardiac failure.

A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant.

OBJECTIVES: To compare high-frequency oscillatory ventilation (HFOV) and intermittent positive pressure ventilation (IPPV) as a primary ventilation mode in preterm infants with respiratory distress syndrome. Primary end points were survival and maintenance of the randomized ventilation mode. STUDY DESIGN: Prospective, multicenter, randomized clinical trial. SETTING: Level III neonatal intensive care units at three university children's hospitals. PATIENTS: Ninety-six premature infants (gestational age < 32 weeks) randomly assigned to HFOV or IPPV within the first 2 hours of life. All patients received a natural surfactant. No differences were found between the study groups with respect to the demographic data or the severity of respiratory distress syndrome. Infants were stratified at randomization, by birth weight, into two groups: 750 to 1000 gm (n = 32) and 1001 to 1500 gm (n = 64). The centers involved complied with a study protocol that planned a reduction in respiratory pressures when the infant's oxygen requirement had reached a fractional concentration of inspired oxygen of 0.6. RESULTS: Five patients in the HFOV group died, and eight patients did not respond to the randomized ventilation mode; whereas four patients in the IPPV group died, and nine were switched to HFOV. No differences were found in gas exchange or ventilator support over the first 72 hours. Premature infants with a birth weight < 1000 gm had a significantly shorter course to reach fractional concentration of inspired oxygen of 0.21 while receiving IPPV than those receiving HFOV (9.3+/-4.5 days vs 27.5+/-10.2 days, p = 0.01). No differences were found between the groups in extraalveolar air (HFOV seven; IPPV, seven) and intracranial bleeding (HFOV, nine; IPPV, eight). CONCLUSION: After surfactant treatment, HFOV, as a primary ventilation mode in premature infants with respiratory distress syndrome, is as safe and efficacious as conventional ventilation.