Estrategia de desarrollo clínico para la evaluación de la eficacia y seguridad de SURFACEN( / Clinical development strategy for the evaluation of the efficacy and safety of SURFACEN (

RESUMEN Fundamento: el primer reporte de la eficacia de un surfactante pulmonar exógeno en el tratamiento de la enfermedad de membrana hialina data de 1980. A partir de ese hallazgo diferentes grupos de investigadores en todo el mundo dedican sus esfuerzos al desarrollo de surfactantes pulmonares ya sean naturales o sintéticos. Objetivo: desarrollar una estrategia para la evaluación de la eficacia y seguridad de Surfacen® en el tratamiento, que permitiera su registro e introducción a la práctica habitual. Métodos: para demostrar la eficacia y seguridad de Surfacen® en el tratamiento del síndrome de dificultad respiratoria en recién nacidos pretérmino, se realizaron ensayos clínicos y la fármaco-vigilancia. En otras indicaciones como el síndrome de dificultad respiratoria aguda en niños y adultos; se ejecutaron ensayos clínicos (fase II, III y IV). En todos los ensayos se siguió la metodología establecida para cada fase. Resultados: el Surfacen® demostró su eficacia al mejorar la oxigenación, las variables ventilatorias, las radiográficas, la evolución clínica que contribuyó a reducir la mortalidad en recién nacidos pretérmino, con un perfil de seguridad similar al resto de surfactantes pulmonares comercializados a nivel internacional. La terapia con Surfacen® fue eficaz al reducir la mortalidad en niños (esta última no en adultos), demostró ser bien tolerada y segura al notificarse un número reducido de eventos adversos relacionados con su administración. Los días de estancia en las unidades de cuidados intensivos y días de ventilación mecánica no se modificaron con el esquema de tratamiento evaluado. Conclusiones: se registró Surfacen® para las indicaciones terapéuticas estudiadas y se introdujo en la práctica clínica habitual al contribuir a reducir la mortalidad en niños.

ABSTRACT Background: the first report of the efficacy of an exogenous pulmonary surfactant in the treatment of the membrane hyaline illness dates back to 1980. From this finding, different groups of investigators worldwide dedicate their efforts to the development of pulmonary surfactants either natural or synthetic. Objective: to develop a strategy for the evaluation of the efficacy and safety of Surfacen® in the treatment of respiratory distress syndrome that would allow its registration and introduction to normal practice. Methods: to demonstrate the efficacy and safety of Surfacen® in the treatment of RDS in preterm infants, clinical trials and the pharmaco-vigilance were conducted. In other indications such as acute RDS in children and adults; clinical trials (phase II, III and IV) were conducted. In all the trials, the methodology established for each phase was followed. Results: Surfacen® demonstrated its efficacy by improving oxygenation, ventilation variables, radiographic ones, clinical evolution and contributed to reduce mortality in preterm infants, with a safety profile similar to the rest of commercially available pulmonary surfactants internationally. Surfacen® therapy proved to be effective in improving oxygenation, ventilation variables, radiographic, clinical evolution, contributed to reduce mortality in children, (the latter not in adults) and proved to be well tolerated and safe to notify a reduced number of adverse events related to its administration. The days of stay in the intensive care units and days of mechanical ventilation were not modified with the treatment scheme evaluated. Conclusions: Surfacen® was registered for the therapeutic indications studied and introduced in routine clinical practice contributing to reduce mortality in children.

Administración de surfactante profiláctico por vía orofaríngea previo al pinzamiento de cordón umbilical en el recién nacido de muy bajo peso en la maternidad del Hospital Universitario / Prophylactic oropharyngeal surfactant administration before cord clamping in very low birth weight newborns at the University Children Hospital Maternity Department / Administração de surfactante profilático por via orofaríngea antes do clampeamento do cordão umbilical em recém-nascidos de baixo peso extremo na Maternidade do Hospital Pediátrico Universitário

Resumen: En la era de la búsqueda de estrategias ventilatorias mínimamente invasivas, la administración profiláctica de surfactante con técnicas sencillas, que no requieren elevada destreza y que pueden ser realizadas en ámbitos de baja complejidad, deben ser investigadas para potencialmente disminuir la morbilidad y mortalidad del pretérmino. Se reporta el uso de surfactante en la orofaringe de cuatro recién nacidos de muy bajo peso (promedio de peso de 1.236 g y 28 semanas de edad gestacional), y concomitante colocación de presión positiva continua por pieza nasal antes de la primera inspiración extrauterina manteniendo el cordón intacto. No se registraron efectos adversos y la aspiración gástrica posterior demostró que el surfactante fue inspirado a los pulmones del recién nacido. La administración de surfactante orofaríngeo es una técnica innovadora, segura, factible y reproducible. A la vez que minimizamos los riesgos de posible iatrogenia por la técnica utilizada, facilitamos una transición cardiovascular más estable, manteniendo la circulación fetoplacentaria.

Summary: In the era of minimally invasive ventilatory procedures, the prophylactic administration of surfactant using simple techniques that can be performed in low complexity settings, should be researched as a tool to potentially reduce preterm morbidity and mortality. We report the use of oropharyngeal surfactant in 4 very low birth weight newborns (average birth weight 1236g and 28 weeks of gestational age) and of continuous positive airway pressure before the first intrauterine inspiration and keeping an intact umbilical cord. No adverse effects happened, and the aspiration of gastric residual confirmed that surfactant had reached the lungs. The administration of oropharyngeal surfactant is an innovative, safe, feasible and reproducible technique. It minimizes the risks of possible iatrogenesis due to the technique used, and it also facilitates a more stable cardiovascular transition, maintaining the fetus' placental circulation.

Resumo: Na era da procura de técnicas ventilatórias minimamente invasivas, a administração profilática de surfactante utilizando técnicas simples, que não requerem muita destreza e que pode ser realizada em contextos de baixa complexidade, deve ser pesquisada para reduzir potencialmente a morbidade e mortalidade dos pré-termos. Reportamos o uso de surfactante na orofaringe em 4 recém-nascidos com baixo peso ao nascimento (peso médio de 1,236 g e 28 semanas de idade gestacional), e colocação concomitante de pressão positiva contínua por adaptador nasal, antes da primeira inspiração extrauterina e mantendo o cordão umbilical intacto. Não houve efeitos adversos e o aspirado gástrico subsequente mostrou que o surfactante foi inspirado e observado nos pulmões dos recém-nascidos. O surfactante de administração orofaríngea é uma técnica inovadora, segura, viável e reprodutível. Minimiza os riscos iatrogênicos eventuais devido à técnica utilizada, à vez que proporciona uma transição cardiovascular mais estável porque mantém a circulação da placenta fetal.

Prevalence and factors associated with surfactant use in Brazilian Neonatal Intensive Care Units: A multilevel analysis / Prevalência e fatores associados ao uso de surfactante em unidades de Terapia Intensiva Neonatais brasileiras: análise multinível

Abstract The treatment with exogenous surfactant reduces mortality and the risk of complications in preterm newborns with Respiratory Distress Syndrome. Higher usage levels have been associated with individual and institutional factors. The study aimed to identify these factors associated with use of this technology in 16 public Brazilian Neonatal Units using logistic multilevel analysis. In a sample of 630 newborns the use at some time was 82.6%. Only 24.7% made use of this technology up to two hours after birth. An intraclass correlation of 0.30 showed that 30% of the variance in the use of exogenous surfactant could be assigned to the contextual level. In the final model, a greater severity score (SNAPPE-II) was associated with increased surfactant use (OR = 2.64), whereas being small for gestational age (SGA) (OR = 0.59) was associated with lower use of this technology. At the contextual level the number of beds in the unit >15 (OR = 5.86), units with higher complexity (OR = 1.73) or units with implemented Kangaroo Mother Care (OR = 2.91), especially units in Rio de Janeiro state (OR = 16.17) were associated with greater surfactant use. Although individual clinical features explained most of the variation in the use of this technology, factors linked to the institution were also of utmost importance.

Resumo O tratamento com surfactante exógeno reduz a mortalidade e o risco de complicações em recém-nascidos com Síndrome de Angústia Respiratória. Maiores níveis de utilização dessa tecnologia têm sido associados tanto a fatores individuais como institucionais. O estudo teve como objetivo identificar esses fatores em 16 unidades neonatais públicas brasileiras usando análise multinível. De 630 recém-nascidos, 82,6% usaram a tecnologia em algum momento. Apenas 24,7% fizeram uso até duas horas após o nascimento. Uma correlação intraclasse de 0,30 mostrou que 30% da variação no uso podem ser atribuídos ao nível contextual. No modelo final, um escore de gravidade maior (SNAPPE-II) foi associado com aumento do uso de surfactante (OR = 2,64), enquanto que ser pequeno para a idade gestacional (PIG) (OR = 0,59) foi associado a um menor uso dessa tecnologia. No nível contextual o número de leitos na unidade > 15 (OR = 5,86), as unidades com mais alta complexidade (OR = 1,73) ou unidades com Método Canguru implementado (OR = 2,91), especialmente unidades no estado do Rio de Janeiro (OR = 16,17), foram associados com uma maior utilização de surfactante. Embora características individuais tenham explicado a maior parte da variação no uso desta tecnologia, fatores ligados à instituição também foram de extrema importância.

Seguridad del tratamiento con surfactante pulmonar en el síndrome de dificultad respiratoria aguda en adultos / Safety of the treatment with pulmonary surfactant in adults with acute respiratory distress syndrome

Introducción: el síndrome de dificultad respiratoria aguda (SDRA) es una enfermedad nosológica asociada con una alta morbilidad y mortalidad. Objetivo: determinar los eventos adversos (EA) asociados a la terapia con surfactante pulmonar (SURFACEN®) en adultos con SDRA. Métodos: se incluyeron 48 pacientes adultos entre 18 y 75 años con SDRA en un ensayo clínico fase II, controlado, aleatorizado y multicéntrico. El grupo A con 24 pacientes, recibió surfactante pulmonar cada ocho horas, durante tres días, en dosis de 100 mg totales, junto al tratamiento estándar (oxigenación y ventilación mecánica). El grupo B, también con 24 pacientes, recibió el tratamiento estándar. Se identificó y cuantificó la aparición de eventos adversos, así como la gravedad, seriedad y relación de causalidad con respecto al fármaco desde la inclusión del paciente en el estudio hasta el egreso de la unidad de cuidados intensivos (UCI). Resultados: el 56, 25 % de los pacientes incluidos presentó algún evento adverso: 14 (29, 17 %) en el grupo A y 13 (27, 08 %) en el B. El 42, 37 % de estos EA se manifestaron con intensidad moderada; el 39, 39 % resultó reversible y el 92, 59 % tuvo causalidad remota respecto al surfactante. La fiebre fue el EA que se reportó con mayor frecuencia. Conclusiones: el surfactante pulmonar (SURFACEN®) junto al tratamiento estándar en adultos con SDRA es seguro.

Introduction: acute respiratory distress syndrome is a nosologic disease associated to a high mortality and morbidity. Objective: to determine the adverse events associated to the therapy with pulmonary surfactant (SURFACEN®) in adults with acute respiratory distress syndrome. Methods: a randomized and multicentric clinical trial stage II was conducted in 48 adult patients between 18 and 75 years old. The group A, that included 24 patients, received doses of 100 total milligrams of pulmonary surfactant every eight hours for three days, along with the standard treatment (oxygenation and mechanical ventilation). The group B, also with 24 patients, received the standard treatment. The appearance of adverse events was identified and quantified, as well as the seriousness and the causality regarding the medicine from the inclusion of the patient in the study to the discharge from the intensive care unit. Results: the 56, 25 % of the patients included in the study presented an adverse event: 14 (29, 17 %) in the group A and 13 (27, 08 %) in the group B. The 42, 37 % of these adverse events appeared with moderate intensity; the 39, 39 % were reversible and the 92, 59 % had a remote causality regarding the surfactant. Fever was the most frequent adverse event reported. Conclusions: pulmonary surfactant (SURFACEN®), along with the standard treatment in adults with acute respiratory distress syndrome, is safe.

Uso de surfactante porcino en recién nacidos pretérminos con bronconeumonía de inicio temprano / Use of porcine surfactant in preterm newborns with early-onset bronchopneumonia

Fundamento: existen discrepancias con respecto al uso de surfactante en la bronconeumonía del recién nacido. Objetivo: evaluar el comportamiento de los recién nacidos con bronconeumonía de inicio temprano tratados con surfactante exógeno. Métodos: se realizó un estudio multicéntricos, abierto, no aleatorizado ni controlado, en 39 recién nacidos pretérminos con bronconeumonía de inicio temprano tratados con surfactante exógeno. Se estudió la edad gestacional, el peso al nacer y el tiempo de estadía en la unidad de cuidados intensivos neonatales, la relación PaO²/FiO², el tiempo en ventilación mecánica, las complicaciones del soporte ventilatorio y la mortalidad según número de dosis de surfactante exógeno y uso de esteroides prenatales para lo que se calcularon, las frecuencias absolutas y relativas, las medias y ji cuadrado. Resultados: la necesidad de administrar un mayor número de dosis se asoció a menor relación PaO²/FiO² (p=0,0103), se obtuvieron valores adecuados con la primera y segunda dosis. El uso de esteroides prenatales se asoció a un menor tiempo en ventilación mecánica (p=0,0474), a valores mayores de la relación PaO²/FiO² (p=0,0162) y a una menor mortalidad (p=0,0076). No se halló asociación estadística en las complicaciones relacionadas con la ventilación. Conclusiones: los pacientes que requirieron mayor número de dosis de surfactante tuvieron una respuesta ventilatoria desfavorable y mayor mortalidad. El uso de esteroides prenatales favoreció una mejor respuesta ventilatoria y menor mortalidad. Puede ser beneficiosa la combinación del uso prenatal de esteroides y surfactante exógeno en pretérminos con bronconeumonía de inicio temprano.

Background: there are disagreements about the use of surfactant in bronchopneumonia in newborns. Objective: to evaluate the behaviour of newborns with early bronchopneumonia treated with exogenous surfactant. Methods: an open, multicentric, non-randomized or controlled study was conducted in 39 preterm newborns with early bronchopneumonia treated with exogenous surfactant. The gestation age, the birth weight and the stay time in the neonatal intensive care unit, the relation PaO2/FiO2, the mechanical ventilation time, the complications of ventilatory support and the mortality according to the number of doses of exogenous surfactant and the use of prenatal steroids were studied. The absolute and relative frequencies, the average and the chi-squared test were calculated. Results: the need of administrating a greater number of doses was associated to a lower relation PaO²/FiO² (p=0,0103). Adequate values were obtained with the first and the second doses. The use of prenatal steroids was associated to a lesser time with mechanical ventilation (p=0,0474), to greater values of the relation PaO²/FiO² (p=0,0162) and to a lower mortality (p=0,0076). No statistical association was found in the complications related to ventilation. Conclusions: those patients who required a greater number of doses of surfactant had an unfavorable ventilatory response and a greater mortality. The use of prenatal steroids favoured a better ventilatory response and a lower mortality. The combination of prenatal steroids and exogenous surfactant can be beneficial in preterm newborns with early bronchopneumonia.

Surfactante exógeno como tratamiento de la atelectasia pulmonar masiva / Exogenous surfactant as treatment for lung massive atelectasis

Fundamento: las atelectasias son un estado de colapso y falta de aire en todo el pulmón o en una zona del mismo. Una vez establecido el diagnóstico de colapso bronquial, el tratamiento debe orientarse directamente a la causa de la obstrucción y a la infección que habitualmente concomita. Objetivo: utilizar como estrategia de tratamiento el lavado broncoalveolar con surfactante exógeno (Surfacen®) unido a la fisioterapia respiratoria. Caso clínico: se presenta un caso de una paciente de 16 años de edad con el antecedente patológico personal de Epilepsia desde los dos años de vida bajo tratamiento con valproato de sodio, que ingresa en la unidad de cuidados intensivos del hospital pediátrico Dr. Eduardo Agramonte Piña, a la que se diagnostica por clínica, radiología y gasometría el síndrome de dificultad respiratoria aguda resultante de una causa pulmonar directa, al quinto día de tratamiento presenta compromiso respiratorio agudo con caída brusca de la oxigenación y se diagnostica radiológicamente una atelectasia masiva del pulmón izquierdo, se le realizó lavado broncoalveolar amplio con solución salina al 0,9 % y luego se instiló surfactante exógeno en dosis de 100 mg diluidos en 10 mL de agua para inyección, dos veces al día, administrado por vía intrabronquial. Luego del segundo lavado broncoalveolar y la kinesioterapia respiratoria, se logra la expansión total de la zona colapsada y recuperación notable de los parámetros de oxigenación. La radiografía reveló una mejoría evidente luego del tratamiento. Se retira la ventilación mecánica cinco días después de esta complicación, mantuvo buena evolución posterior. Conclusiones: la aplicación del lavado broncoalveolar con surfactante exógeno mejoró el compromiso de oxigenación que ocasiona la atelectasia masiva y permitió una rápida evolución radiográfica en la paciente, así como la disminución de los parámetros ventilatorios.

Background: atelectasis is a collapse state and shortness of breath in part or all of one lung. Once the diagnosis of bronchial collapse is established, the treatment must be directed towards the find of the cause of obstruction and the infection that is usually concomitant. Objective: to use bronchoalveolar lavage with exogenous surfactant (Surfacen®), along with respiratory physiotherapy as treatment. Clinical case: the case of a sixteen-year-old female patient with a personal-pathological history of epilepsy since she was two years old is presented. The patient was under treatment with valproate sodium. She is admitted in the intensive care unit of Dr. Eduardo Agramonte Piña Pediatric Hospital. The patient is diagnosed clinically, radiologically and gasometrically as having respiratory distress syndrome of a direct pulmonary cause. On the fifth day of treatment the patient presented acute respiratory problems with sudden oxygenation fall and is diagnosed radiologically as having massive atelectasis of the left lung. She underwent a wide bronchoalveolar lavage with 9 % saline solution and then the instillation of exogenous surfactant in 100 mg doses diluted in 10 ml of water per injection administered intrabronchially twice a day. After the second bronchoalveolar lavage and the respiratory kinesiotherapy, the total expansion of the collapsed area and a notable improvement of the oxygenation parameters were achieved. The mechanical ventilation was moved five days after the complication. The patient kept a good subsequent progress. Conclusions: the application of bronchoalveolar lavage with exogenous surfactant improved the oxygenation problem that causes massive atelectasis and allowed a rapid radiographic progress in the patient, as well as the decrease of the ventilatory parameters.

A multicenter, randomized, double-blind trial of a new porcine surfactant in premature infants with respiratory distress syndrome / Ensaio clínico multicêntrico duplo-cego randomizado com um novo surfactante de origem porcina em prematuros com síndrome do desconforto respiratório

Objective To compare the efficacy and safety of a new porcine-derived pulmonary surfactant developed by Instituto Butantan with those of animal-derived surfactants commercially available in Brazil, regarding neonatal mortality and the major complications of prematurity in preterm newborns with birth weight up to 1500g and diagnosed with respiratory distress syndrome. Methods Neonates diagnosed with respiratory distress syndrome were randomized to receive either Butantan surfactant (Butantan group) or one of the following surfactants: Survanta® or Curosurf®. Newborns receiving Survanta® or Curosurf® comprised the control group. The main outcome measures were mortality rates at 72 hours and at 28 days of life; the typical complications of prematurity as evaluated on the 28th day of life were defined as secundary outcomes. Results No differences were observed between the Butantan (n=154) and control (n=173) groups in relation to birth weight, gestational age, sex, and prenatal use of corticosteroids, or in mortality rates both at 72 hours (14.19% versus 14.12%; p=0.98) and at 28 days (39.86% versus 33.33%; p=0.24) of life. Higher 1- and 5-minute Apgar scores were observed among control group newborns. No differences were observed as regards the secondary outcomes, except for greater need for supplemental oxygen and a higher incidence of interstitial pulmonary emphysema in the Butantan group. Conclusion The mortality rates at 72 hours and 28 days of life and the incidence of major complications of prematurity were comparable to those found with the animal-derived surfactants commercially available in Brazil, showing the efficacy and safety of the new surfactant in the treatment of respiratory distress syndrome ...

Objetivo Comparar a eficácia e a segurança de um novo surfactante pulmonar de origem porcina, desenvolvido pelo Instituto Butantan, com os surfactantes de origem animal disponíveis no país, em relação à mortalidade neonatal e às principais complicações da prematuridade, em prematuros com peso de nascimento até 1500g e diagnóstico de síndrome do desconforto respiratório. Métodos Recém-nascidos com diagnóstico de síndrome do desconforto respiratório foram randomizados para receber surfactante Butantan (Grupo Butantan) ou um dos seguintes surfactantes: Survanta® ou Curosurf®. Os recém-nascidos que receberam Survanta® ou Curosurf® formaram o Grupo Controle. Foram definidas, como variáveis primárias, as mortalidades com 72 horas e 28 dias de vida e, como variáveis secundárias, as principais complicações típicas da prematuridade, avaliadas no 28O dia de vida. Resultados Não foram observadas diferenças em relação ao peso de nascimento, idade gestacional, sexo e corticoide pré-natal, assim como em relação à mortalidade dos recém-nascidos dos Grupos Butantan (n=154) e Controle (n=173), tanto com 72 horas (14,19% versus 14,12%; p=0,98) como em 28 dias de vida (39,86% versus 33,33%; p=0,24). Foram observados maiores valores do boletim de Apgar de 1 e de 5 minutos entre os recém-nascidos do Grupo Controle. Os grupos não diferiram em relação às variáveis secundárias, exceto por uma maior necessidade de uso de oxigênio e de enfisema pulmonar intersticial no Grupo Butantan. Conclusão As taxas de mortalidade com 72 horas ...

Presión positiva continua en la vía aérea comparada con la respiración mecánica asistida en prematuros de 28 a 32 semanas de gestación con administración precoz de surfactante pulmonar / Nasal CPAP versus mechanical ventilation in 28 to 32-week preterm infants with early surfactant administration

Introducción. La presión positiva continua en la vía aérea ( Continuous Positive Airway Pressure , CPAP) es útil en prematuros de 28 a 32 semanas de gestación con síndrome de dificultad respiratoria, pero no se ha precisado si es mejor que la respiración mecánica asistida después de la administración precoz de surfactante pulmonar. Objetivo. Comparar la incidencia de eventos adversos en prematuros de 28 a 32 semanas de gestación con síndrome de dificultad respiratoria atendidos con surfactante y respiración mecánica asistida o CPAP de burbuja. Materiales y métodos. Se atendieron 147 neonatos con respiración mecánica asistida y 176 con CPAP, ninguno de los cuales presentaba asfixia perinatal o apnea. Resultados. La incidencia de fracaso de la CPAP fue de 6,5 % (IC 95% 11,3-22,8 %). Fallecieron 29 pacientes, 7 de los cuales habían recibido CPAP (4,0 %) y, 22, respiración mecánica asistida (15,0 %; p<0,001). El riesgo relativo (RR) de morir de quienes recibieron CPAP, comparado con el de quienes recibieron respiración mecánica asistida, fue de 0,27 (IC 95% 0,12-0,61), pero, al ajustar por los factores de confusión, el uso de CPAP no implicó mayor riesgo de morir (RR=0,60; IC 95% 0,29-1,24). La letalidad con respiración mecánica asistida fue de 5,70 (IC 95% 3,75-8,66) muertes por 1.000 días-paciente, mientras que con CPAP fue de 1,37 (IC 95% 0,65-2,88; p<0,001). La incidencia de neumopatía crónica fue menor con CPAP (RR=0,71, IC 95% 0,54-0,96), al igual que la de hemorragia cerebral (RR=0,28; IC 95% 0,09-0,84) y la de sepsis (RR=0,67; IC 95% 0,52-0,86), pero fue similar en cuanto a escapes de aire (RR=2,51; IC 95% 0,83-7,61) y enterocolitis necrosante (RR=1,68; IC 95% 0,59-4,81). Conclusión. La incidencia de neumopatía crónica, hemorragia ventricular y sepsis es menor con el uso de CPAP.

Introduction: Continuous positive airway pressure (CPAP) is useful in low birth weight infants with respiratory distress, but it is not known if it is a better alternative to mechanical ventilation after early pulmonary surfactant administration. Objective: To compare the incidence of adverse events in 28 to 32-week newborns with respiratory distress managed with mechanical ventilation or CPAP after early surfactant administration. Materials and methods: In total, 176 newborns were treated with CPAP and 147 with mechanical ventilation, all with Apgar scores >3 at five minutes and without apnea. Results: The incidence of CPAP failure was 6.5% (95% CI: 11.3-22.8%); 29 patients died: 7 with CPAP (4.0%) and 22 with mechanical ventilation (15.0%, p<0.001). The relative risk of dying with CPAP versus mechanical ventilation was 0.27 (95% CI: 0.12-0.61), but after adjusting for confounding factors, CPAP use did not imply a higher risk of dying (RR=0.60; 95% CI: 0.29-1.24). Mechanical ventilation fatality rate was 5.70 (95% CI: 3.75-8.66) deaths/1,000 days-patient, while with CPAP it was 1.37 (95% CI: 0.65-2.88, p<0.001). Chronic lung disease incidence was lower with CPAP than with mechanical ventilation (RR=0.71; 95% CI: 0.54-0.96), as were intracranial hemorrhage (RR=0.28, 95% CI: 0.09-0.84) and sepsis (RR=0.67; 95%CI: 0.52-0.86), and it was similar for air leaks (RR=2.51; 95% CI: 0.83-7.61) and necrotizing enterocolitis (RR=1.68, 95% CI: 0.59-4.81). Conclusion: CPAP exposure of premature infants with respiratory distress syndrome is protective against chronic lung disease, intraventricular hemorrhage and sepsis compared to mechanical ventilation. No differences were observed regarding air leak syndrome or death.

Administración de surfactante sin intubación endotraqueal: Reporte de primeros pacientes en Uruguay / Surfactant administration without endotracheal intubation

Resumen Introducción: desde 1990 en que se introdujo en Uruguay la administración del surfactante exógeno para el tratamiento del Síndrome Dificultad Respiratoria (SDR) del recién nacido, el procedimiento se realiza a través de un tubo endotraqueal mientras son ventilados con presión positiva intermitente. Algunos efectos adversos y morbilidad asociada a esta práctica se han adjudicado al uso de la prótesis endotraqueal y sus efectos como cuerpo extraño. A principios de este siglo se propuso usar el tubo endotraqueal exclusivamente para la administración del surfactante, retirándolo inmediatamente después y se le denominó InSurE (Intubation Surfactant Extubation). Recientemente se ha demostrado que la seguridad es mayor si el surfactante se administra en el recién nacido con respiración espontánea, sin asistencia ventilatoria mecánica y a través de un catéter fino guiado por laringoscopia. El catéter se retira al finalizar la administración y se reintroduce para la segunda dosis si es necesario. Por su similitud con otras modalidades de administración de fluidos por catéter (clisis) en nuestro medio se le denomina traqueoclisis (TQ). Objetivo: comunicar la realización de esta técnica en un grupo de recién nacidos en nuestro medio. Reporte de casos: de los registros clínicos se recogieron las características de peso al nacer, perímetro craneano, edad gestacional, administración antenatal de corticoides para inducir maduración pulmonar, vía de nacimiento, puntaje de Apgar, edad a la primera instilación de surfactante, necesidad posterior de intubación orotraqueal y asistencia ventilatoria por tubo endotraqueal, la evolución clínica y radiológica y eventos adversos. Resultados: desde junio 2012 hasta abril 2013 se realizó el procedimiento en 8 recién nacidos con SDR que requirieron soporte respiratorio con presión positiva continua vía nasal (nCPAP). Los pacientes se asistieron en la Unidad de Perinatología Especializada Maternidad del Servicio Médico Integral (UPE-SMI) de Uruguay. Se observó mejoría clínica y radiológica en todos los casos, sin eventos adversos durante el procedimiento, ni fue necesaria su intubación en las primeras 72 horas de vida. Conclusiones: comprobamos la similitud empírica de nuestros resultados con los reportados en otros estudios y series internacionales recientes. La instilación de surfactante por TQ en recién nacidos con SDR apoyados con nCPAP es una nueva modalidad de manejo sencilla y segura.

Summary Introduction: since the introduction of the administration of exogenous surfactant for the treatment of Respiratory Distress Syndrome (RDS) of the newborn infant in Uruguay in1990, the procedure is done through an endotracheal tube while being ventilated with intermittent positive pressure. Some of the adverse effects and morbidity of this procedure may be caused by the tube itself acting as a foreign body. After a decade of use it was proposed to reduce to a minimum the duration of endotracheal tube and this practice is known as InSurE (Intubation Surfactant Extubation). More recently it has been reported that it is safer if the exogenous surfactant is administered through a thin catheter introduced in the trachea guided by laryngoscopy during spontaneous breathing and removed at the end of the administration. For its similarity to other modes of administration of fluids through catheters (clysis) we call it tracheoclysis (TQ). Objective: to report the usage of this technique in a group of preterm infants. Case report: we report the characteristics of these patients as registered in their clinical records: birth weight, head circumference, gestational age, antenatal administration of corticosteroids to induce lung maturation, birth route, Apgar score, age at first instillation of surfactant, subsequent need for endotracheal intubation and ventilatory assistance by endotracheal tube clinical and radiological immediate outcomes and adverse events. Results: from june 2012 to april 2013 the procedure was performed in 8 patients with RDS who required respiratory support via nasal continuous positive airway pressure (nCPAP). Patients were cared at the Unidad de Perinatología Especializada Maternidad of the Servicio Medico Integral (UPE-SMI) of Montevideo, Uruguay. There was clinical and radiological improvement in all cases, no adverse events were observed during the procedure, during the following first 72 hours of life. Conclusions: we empirically corroborated the similarity of our results with those reported in the recent international literature. Administration of surfactant by tracheoclysis in newborns with RDS supported with nCPAP is a new way of simple and safe care, reducing the need endotracheal intubation in the first 72 hours of life.

Timing of initial surfactant treatment in very low birth weight newborns / Momento do tratamento com surfactante em recém-nascidos de muito baixo peso

Objective: To correlate the timing of treatment using exogenous surfactant with the main variables related to respiratory distress syndrome or prematurity. Methods: A historic cohort study between January 1, 2004 and June 30, 2007, including very low birth weight newborns (birth weight <1,500 g) admitted to the hospital and who required surfactant therapy. Newborns were divided into three study groups: early (treatment during the first two hours); intermediate (treatment between two and six hours) and late (treatment after six hours). Variables analyzed were: air leak syndrome, mortality, bronchopulmonary dysplasia, intracranial hemorrhage, patent ductus arteriosus, retinopathy of prematurity, duration of oxygen therapy, duration of mechanical ventilation, length of hospital stay and number of surfactant doses. Results: A total of 63 newborns were included (Early Group, n = 21; Intermediate Group, n = 26 and Late Group, n = 16), there was a statistical significance between birth weight and gestational age. Multivariate logistic regression analysis was used to compensate the effects of gestational age, birth weight and other possible interferences over the variables. This analysis revealed a greater incidence of air leak syndrome among newborns of the Early Group compared to the Intermediate Group (OR = 6.98; 95%CI = 1.24-39.37; p = 0.028), with no difference compared to the Late Group (OR = 3.72; 95% CI = 0.28-49.76; p = 0.321). There were no differences regarding the other variables analyzed. Conclusions: In this retrospective, non-randomized study, surfactant administration during the first two hours of life enhanced the risk of air leak syndrome, compared to the treatment between two and six hours after birth, with no reduction of early or late neonatal mortality or bronchopulmonary dysplasia, compared to later treatment after birth.

Objetivo: Relacionar o momento do tratamento com surfactante com as principais variáveis relacionadas à síndrome do desconforto respiratório do recém-nascido ou à prematuridade. Métodos: Coorte histórica, sendo analisados os dados de recém-nascidos de muito baixo peso (peso de nascimento < 1.500 g) admitidos no período entre 1º de janeiro de 2004 e 30 de junho de 2007, que necessitaram de tratamento com surfactante. Os recém-nascidos foram divididos em três grupos: precoce (tratamento até a segunda hora); intermediário (tratamento entre duas e seis horas); e tardio (tratamento a partir da sexta hora). Foram analisadas: ocorrência de síndrome de escape de ar, mortalidade, displasia broncopulmonar, hemorragia intracraniana, persistência do canal arterial, retinopatia da prematuridade, tempo de oxigênio, de ventilação mecânica, tempo de internação e o número de doses de surfactante. Resultados: Foram analisados 63 recém-nascidos (Grupo Precoce, n = 21; Grupo Intermediário, n = 26 e Grupo Tardio, n = 16); os grupos diferiram em relação ao peso de nascimento e à idade gestacional. Na análise multivariada por regressão logística, realizada para compensar os efeitos da idade gestacional, do peso de nascimento e de outras possíveis interferências sobre as variáveis analisadas, foi observada uma maior incidência de síndrome de escape de ar entre os recém-nascidos do Grupo Precoce em relação aos do Grupo Intermediário (OR = 6,98; IC95% = 1,24-39,37; p 0,028), porém sem diferença em relação ao Grupo Tardio (OR = 3,72; IC95 = 0,28-49,76; p = 0,321). Não foram observadas diferenças em relação às outras variáveis analisadas. Conclusões: Neste estudo retrospectivo e não-randomizado, a administração de surfactante nas primeiras duas horas de vida aumentou o risco da ocorrência de síndrome de escape de ar em relação ao tratamento realizado entre duas e seis horas de vida, sem redução na mortalidade neonatal precoce ou tardia e sem modificação na evolução para displasia broncopulmonar, em comparação com o tratamento realizado em períodos mais tardios em relação ao nascimento.

Avaliação da maturidade pulmonar fetal pela contagem dos corpos lamelares no líquido amniótico / Evaluation of fetal lung maturity by lamellar bodies counting in amniotic fluid

Objetivo: comparar o teste de contagem de corpos lamelares (CCL) no líquido amniótico com o teste da polarização fluorescente (PF) como parâmetro diagnóstico para avaliação da maturidade pulmonar fetal. Método: estudo transversal, analítico e controlado realizado com 60 gestantes atendidas no período de março de 2002 a dezembro de 2007. Foram colhidas amostras de líquido amniótico e realizados os testes de CCL e PF (TDxFLM II), considerados de referência, e comparados à presença ou ausência da Síndrome do Desconforto Respiratório (SDR). Foram estabelecidos valores de corte para maturidade de 30 mil corpos lamelares/µL para o teste da CCL e 55 mg/g de albumina para o PF. Foram avaliadas as características maternas e perinatais, a evolução neonatal e o desempenho dos testes diagnósticos para predição da maturidade pulmonar fetal. Na análise estatística, foram utilizadas medidas descritivas e calculados os valores referentes à sensibilidade, especificidade, valor preditivo positivo e negativo dos testes, considerando-se significativos valores de p<0,05. Resultados: a idade materna variou entre 15 e 43 anos, com média de 26,6 anos. A idade gestacional variou entre 24,3 e 41,6 semanas, com média de 35,1 semanas. A Síndrome do Desconforto Respiratório foi diagnosticada em 13,3 por cento dos neonatos. As características perinatais, como peso, índice de Apgar, incidência de SDR, foram comparadas aos resultados dos testes de CCL e PF, sendo observada uma correspondência, estatisticamente significativa (p<0,05), entre os grupos de neonatos clinicamente classificados como imaturos e maduros em ambos os testes. Os testes foram concordantes em 68,3 por cento dos casos. Quando se comparou o teste da PF com o teste da CCL, a sensibilidade foi de 100 por cento para ambos, e a especificidade do teste da CCL foi superior (73,1 por cento), quando comparado com o teste de PF (51,9 por cento). O padrão-ouro para determinação da maturidade fetal é a ocorrência da SDR. O valor...

Purpose: to compare the lamellar body number density (LBND) count in amniotic fluid using the fluorescent polarization (FP) test as a diagnostic parameter for the assessment of fetal pulmonary maturity. Method: this was an analytical, controlled cross-sectional study conducted on 60 pregnant women from March 2002 to December 2007. Amniotic fluid specimens were obtained by amniocentesis or at the time of caesarean section, and submitted to the LBND and FP tests (TDxFLM®, Abbott Laboratories), the latter considered to be a reference test, and compared in terms of the presence or absence of respiratory distress syndrome (RDS). Cut-off values for maturity were established at 30,000 lamellar bodies/µL for the LBND test and 55 mg/g albumin for the FP test. Maternal and perinatal characteristics and neonatal evolution were evaluated, and the performance of the diagnostic tests regarding fetal pulmonary maturity was determined. In the statistical analysis, descriptive measures were used and the sensitivity, specificity and positive and predictive values of the tests were determined with the level of significance set at p<0.05. Results: maternal age ranged from 15 to 34 years (mean: 26.6 years) and gestational age ranged from 24.3 to 41.6 weeks (mean: 35.1 weeks). RDS was diagnosed in 35.1 percent of neonates. Perinatal characteristics such as weight, Apgar score, and RDS incidence were compared to the results of the LBND and FP tests and a significant correspondence (p<0.05) was observed between the groups of neonates clinically classified as mature and immature in both tests. The tests were concordant in 68.3 percent of the cases. Comparison of the PF and LBND tests revealed 100 percent specificity for both and a higher specificity for the LBND test (73.1 percent as opposed to 51.9 percent for the PF test). The gold standard for the determination of fetal maturity is the occurrence of RDS. The positive predictive value of the LBND test was higher (36.4%) than that...

Retinopatia da prematuridade limiar em crianças submetidas à terapia com surfactante exógeno endotraqueal / Threshold retinopathy of prematurity in children undergoing exogenous endotracheal surfactant therapy

OBJETIVO: Estudar a freqüência da retinopatia da prematuridade (ROP) em qualquer estadiamento e da retinopatia da prematuridade limiar em prematuros que usaram ou não surfactante endotraqueal, para tratamento da síndrome da membrana hialina e avaliar a resposta dos olhos que necessitaram tratamento de ablação da retina periférica. MÉTODOS: Cento e sessenta e oito prematuros, nascidos com 1.500 gramas ou menos e/ou idade gestacional de 32 semanas ou menos, foram triados para a ROP por avaliação oftalmoscópica. Foram comparados os achados de 40 crianças tratadas pelo surfactante endotraqueal com os de 128 que não precisaram desta terapia. A ablação da retina periférica, com laser ou crioterapia, foi realizada nos pacientes com ROP limiar. Para análise estatística foram usados os testes t de Student, qui-quadrado e Kruskal-Wallis, além do teste exato de Fisher com significância para p<0,05. RESULTADOS: A ROP, em qualquer estadiamento, ocorreu em 51,2 por cento dos casos. ROP limiar ocorreu em 12 pacientes (7,4 por cento). Não houve diferença, estatisticamente significativa, entre os pacientes que usaram e os que não usaram o surfactante, em relação à presença de ROP e de ROP limiar. Com o tratamento de ablação da retina periférica, 9 (75 por cento) dos 12 bebês com ROP limiar tiveram regressão da doença. CONCLUSÃO: A freqüência da ROP nesta casuística pode ser considerada elevada quando comparada com outros estudos. Crianças com síndrome da membrana hialina, tratadas com o surfactante, não apresentaram maior risco de ROP limiar. O tratamento foi eficaz para promover regressão da ROP limiar.

OBJECTIVE: To study the frequency of retinopathy of prematurity (ROP) in any stage and its threshold form in premature infants, either treated or non-treated with exogenous surfactant to neonatal respiratory distress syndrome, and evaluate the response of eyes with threshold retinopathy to ablation treatment. METHODS: One hundred and sixty eight premature infants who weighed 1500 grams or less and/or who had a gestational age of 32 weeks or less, were screened for ROP by ophthalmoscopy. We compared findings in 40 patients treated with exogenous endotracheal surfactant, with those of 128 patients who did not require such therapy. Ablation of ischaemic peripheral retina, either with laser or cryotherapy, was applied in cases of threshold ROP. For statistical analysis Student's t, qui-square, Kruskal-Wallins and Fisher's exact tests were used, with p value of < 0.05 considered as significant. RESULTS: ROP, in any stage, occurred in 51,2 percent of children. Threshold ROP, requiring treatment, was found in 12 (7,4 percent) of them and regressed in 9. There was no significant difference between surfactant treated and non-treated patients, regarding the occurrence of ROP and threshold ROP. CONCLUSION: In this study frequency of ROP can be considered high, when compared with other series. Children with distress respiratory syndrome, treated with surfactant, did not show a higher risk of threshold ROP. Treatment was successfull in promoting disease regression.