Early risk factors for death in neonates with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide / 中国当代儿科杂志

OBJECTIVES@#To evaluate the early risk factors for death in neonates with persistent pulmonary hypertension of the newborn (PPHN) treated with inhaled nitric oxide (iNO).@*METHODS@#A retrospective analysis was performed on 105 infants with PPHN (gestational age ≥34 weeks and age <7 days on admission) who received iNO treatment in the Department of Neonatology, Children's Hospital of Nanjing Medical University, from July 2017 to March 2021. Related general information and clinical data were collected. According to the clinical outcome at discharge, the infants were divided into a survival group with 79 infants and a death group with 26 infants. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for death in infants with PPHN treated with iNO. The receiver operating characteristic (ROC) curve was used to calculate the cut-off values of the factors in predicting the death risk.@*RESULTS@#A total of 105 infants with PPHN treated with iNO were included, among whom 26 died (26/105, 24.8%). The multivariate Cox regression analysis showed that no early response to iNO (HR=8.500, 95%CI: 3.024-23.887, P<0.001), 1-minute Apgar score ≤3 points (HR=10.094, 95%CI: 2.577-39.534, P=0.001), a low value of minimum PaO2/FiO2 within 12 hours after admission (HR=0.067, 95%CI: 0.009-0.481, P=0.007), and a low value of minimum pH within 12 hours after admission (HR=0.049, 95%CI: 0.004-0.545, P=0.014) were independent risk factors for death. The ROC curve analysis showed that the lowest PaO2/FiO2 value within 12 hours after admission had an area under the ROC curve of 0.783 in predicting death risk, with a sensitivity of 84.6% and a specificity of 73.4% at the cut-off value of 50, and the lowest pH value within 12 hours after admission had an area under the ROC curve of 0.746, with a sensitivity of 76.9% and a specificity of 65.8% at the cut-off value of 7.2.@*CONCLUSIONS@#Infants with PPHN requiring iNO treatment tend to have a high mortality rate. No early response to iNO, 1-minute Apgar score ≤3 points, the lowest PaO2/FiO2 value <50 within 12 hours after admission, and the lowest pH value <7.2 within 12 hours after admission are the early risk factors for death in such infants. Monitoring and evaluation of the above indicators will help to identify high-risk infants in the early stage.

Óxido nítrico inalatório no tratamento da hipertensão pulmonar persistente do recém-nascido / Inhaled nitric oxide to treat persistent pulmonary hypertension of the newborn

Objetivos: conhecer as indicações do uso de NOi, dose média utilizada e resposta ao tratamento em recém-nascidos internados em Unidade de Terapia Intensiva Neonatal. Métodos: foram analisados 62 prontuários e considerados dois grupos de recém-nascidos (RN) de acordo com o desfecho para sobrevida (n=39) ou óbito (n=23). Testes t-Student e binomial, p<0,05. Resultados: do total, 47 eram masculinos, 18 nasceram de parto normal e 44 de cesariana. Os RNs que sobreviveram tinham maior idade gestacional clínica e mais peso ao nascimento (p<0,05). Cardiopatia congênita, hipoplasia pulmonar, sepse e síndrome da membrana hialina (SMH) foram mais frequentes nos RNs que evoluíram para óbito, enquanto que a síndrome de aspiração de mecônio (SAM)estava mais presente nos RNs que sobreviveram (p<0,05). Não houve diferença significativa quanto a: asfixia perinatal, hérnia diafragmática, hipertensão pulmonar persistente neonatal (HPPN) e taquipneia transitória do recém-nascido (p>0,05). A dose inicial de NOi e a duração do tratamento foram maiores nos RNs que sobreviveram (p<0,05). A idade de início do tratamento, a dose máxima de NOi e o tempo de ventilação mecânica não apresentaram diferenças entre os grupos (p>0,05). O índice de oxigenação foi significativamente mais alto nos óbitos (p<0,05). Não foram observados efeitos colaterais. Conclusões: a terapia com NOi foi indicada principalmente na asfixia perinatal, SAM, SMH e sepse. As doses de NOi entre 15 e 30 ppm mostraram-se seguras e a diminuiçãodo índice de oxigenação sugere resposta positiva ao tratamento.

Objectives: To know the inhaled nitric oxide (iNO) use indications, the average used dose, and the reaction to treatment in newborns hospitalized at the Neonatal Intensive Care Unit. Methods: 62 medical records were analyzed and two newborn groups were considered according to the survival (n=39) or death (n=23) outcome. t-Student and binomial tests, p<0.05. Results: From the total, 47 subjects were male, 18 were born from natural childbirth, and 44 from cesarean section. The newborns that survived had a higher clinical gestational age and more weight at birth (p>0.05). Congenital heart defect, pulmonary hipoplasia, sepsis, and hyaline membrane syndrome (HMS) were more frequent in newborns that evolved to death, while the meconium aspiration syndrome (MAS) was more present in the ones that survived (p<0.05). There was no significant difference concerning: perinatal asphyxia, diaphragmatichernia, neonatal persistent pulmonary hypertension (NPPH), and newborn transient taquipneia (p>0.05). The iNO initial dose and treatment time were superior in newborns that survived (p<0.05). Age in the beginning of the treatment, maximum doses of iNO, and time of mechanical ventilation did not present significant differences between the groups (p>0.05).The oxygenation index was significantly higher in the deceased ones (p<0.05). No adverse effects were seen. Conclusions: Therapy with iNO was mainly indicated for perinatal asphyxia, MAS, HMS, and sepsis. iNO doses between 15 and 30 ppm proved to be safe, and the decrease of the oxygenation index suggests a positive reaction to the treatment.

Uso de milrinona no tratamento da hipertensão pulmonar persistente do recém-nascido / Milrinone for persistent pulmonary hypertension of the newborn treatment

OBJETIVO: Descrever uma série de casos de recém-nascidos com hipertensão pulmonar persistente grave, que receberam milrinona para promover a vasodilatação pulmonar. MÉTODOS: Análise retrospectiva de prontuários de 28 pacientes com diagnóstico de hipertensão pulmonar persistente do recém-nascido (HPPRN). Após o diagnóstico, todos os pacientes receberam uma dose de ataque de 50mcg/kg de milrinona, seguida por 0,75mcg/kg/min. O índice de oxigenação (IO) foi calculado no início da infusão e 72 horas após o início da medicação. RESULTADOS: Todos os neonatos receberam milrinona e o sildenafil foi associado em 54 por cento. O uso de dopamina assegurou a manutenção da pressão arterial em nível adequado em todos os casos. Sedação contínua, alcalinização e surfactante foram medidas coadjuvantes no tratamento. Durante a internação, sete pacientes (25 por cento) evoluíram a óbito e todos eles apresentaram aumento do IO, com elevação da média de 25 para 38 com a milrinona. Os sobreviventes, com exceção de um neonato, apresentaram redução do IO em uso de milrinona, com queda da média de 19 para 7. CONCLUSÕES: O uso da milrinona parece ser uma alternativa para o tratamento da HPPRN, na ausência do óxido nítrico. A redução do IO com a medicação foi fator determinante da boa evolução dos pacientes. O índice de falha no tratamento com a milrinona nesta casuística foi semelhante ao encontrado na literatura para o uso de óxido nítrico.

OBJECTIVE: To describe a series of neonates with severe persistent pulmonary hypertension, who received milrinone as the main treatment for pulmonary vasodilatation. METHODS: Retrospective analysis by chart review of 28 neonates with persistent pulmonary hypertension. A dose of 0.75µg/kg/min of milrinone was given, after a loading dose of 50µg/kg. The oxygenation index (OI) was calculated before and 72 hours after the medication. RESULTS: All infants received milrinone and sildenafil was associated to milrinone in 54 percent. The use of dopamine assured normal blood pressure during milrinone treatment in all patients. Continuous sedation, alcalinization and surfactant were additional measures in the treatment. During the hospitalization period, seven (25 percent) patients died and all of them presented an OI increase after milrinone (the average OI rose from 25 to 38). All but one of the 21 surviving patients presented improvement of the OI with milrinone, with a reduction of the mean index from 19 to 7. CONCLUSIONS: Milrinone can be used to treat persistent pulmonary hypertension of the newborn, in the absence of nitric oxide. The reduction of the OI during treatment was associated with clinical improvement. The failure rate for milrinone treatment in this series of cases was similar to that found in the literature regarding nitric oxide.

Inhaled iloprost for severe persistent pulmonary hypertension of the newborn.

The authors report one case of persistent pulmonary hypertension that had hypoxia although receiving treatment with high frequency oscillation, inotropic drugs, blood transfusion, and oral sildenafil for pulmonary vasodilatation. The patient developed hypotension after two doses of oral sildenafil and no response to high dose of inotropic drugs. So aerosolized iloprost was given via endotracheal tube and oxygen saturation improved within 10 minutes. Oxygen was weaned at 36 hours after treatment with this drug and no any side effect was found.

Factors Affecting the Response to Inhaled Nitric Oxide Therapy in Persistent Pulmonary Hypertension of the Newborn Infants

Persistent pulmonary hypertension of the newborn infant (PPHN), is a clinical syndrome characterized by elevated pulmonary vascular resistance, resulting from reactive vasoconstriction or structural remodeling of the pulmonary vasculature. Although inhaled nitric oxide (iNO) has emerged as a novel selective treatment of PPHN, responses to iNO are variable according to the etiologies or the clinical situation. A retrospective chart review of 51 newborn infants with PPHN and treated with iNO, was undertaken to evaluate the factors affecting response to iNO. Response to iNO was defined as a reduction in the oxygenation index (OI) of more than 20%, or disappearance of the difference in oxygen saturation between preductal and postductal circulation after iNO therapy. The patients were divided into two groups; the responder group and the non- responder group. Respiratory distress syndrome (RDS) was more commonly associated with PPHN in the responder group than in the non-responder group (p < 0.05), while there were many more patients with congenital diaphragmatic hernia (CDH) in the non-responder group than in the responder group (p < 0.05). Infants with meconium aspiration syndrome (MAS) were similar in both of the two groups. Initial OI, initial mean airway pressure (MAP), and initial and peak NO concentration were significantly lower in the responder group compared to the non-responder group (p < 0.05). Rapid response (response to iNO within the first hour) was shown in 74% of the responder group and 33% of the nonresponder group (p < 0.05). There was no significant differences in the initial chest radiographic findings, such as normal, focal or bilateral diffuse infiltration, with the exception of CDH, between each group. Lower initial OI, lower initial MAP and significant response within the first hour were shown to be favourable factors in response to iNO therapy. Patients with RDS associated with PPHN responded much better to iNO than those with other diseases.

The use of L-arginine [correction of F-arginine] and phosphodiesterase inhibitor (dipyridamole) to wean from inhaled nitric oxide.

A full-term, female neonate developed acute hypoxemic respiratory failure complicated by persistent pulmonary hypertension of the newborn (PPHN), and responded to high-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO). Discontinuation of iNO was attempted three times and was followed by severe desaturation due to right-to-left shunt through the patent ductus arteriosus and patent foramen ovale. As a result of iNO dependency state and rebound pulmonary hypertension, the neonate was maintained on iNO therapy for dipyridamole alone was unsuccessful. However, successful discontinuation of iNO therapy was achieved by combination of L-Arginine and dipyridamole. Exogeous NO may lead to down regulation of endogenous NO production, and further lead to rapid hydrolization of cyclic guanosine 3', 5' monophosphate (cGMP), the smooth muscle relaxant, by the enzyme phosphodiesterase. Moreover L-Arginine, the precursor for the formation of endogenous NO, has been found to be deficient in neonates with PPHN, so we speculated that by inhibiting phosphodiesterase and administrating L-Arginine smooth muscle relaxation occurred, and consequent weaning from iNO was achieved.

Uso combinado de alcalinização e tolazolina em recém-nascidos com hipertensão pulmonar persistente / Using alkalinization and tolazoline combination in pulmonary hypertension of the newborn

A hipertensão pulmonar (HP) do recém-nascido (RN) apresenta alta morbimortalidade. O objetivo deste estudo é relatar o uso de tolazolina combinada à alcalinização no tratamento da HP grave do RN. Este trabalho retrospectivo com RN com HP [pressão sistólica em artéria pulmonar (PAP) >=35 mmHg por ecocardiografia] abrangeu 4 anos. Os RN foram divididos em 2 grupos: GI - suporte ventilatório(O2 e/ou ventilação mecânica); GII - suporte ventilatório + drogas (tolazolina - ataque: 1/2 mg/kg, manutenção: 0,5 a 1 mg/kg/h e NaHCO3: 0,5-1 mEq/kg/h). A alcalinização e a tolazolina foram indicadas na ausência de resposta à hiperventilação (Pinsp >= 28 mmHg, FR >= 60/min), MAP (pressão média de vias aéreas) >= 14 mmHg e IO (índice de oxigenação) >= 20 por cento. A eficácia da terapêutica foi avaliada por diminuição dos parâmetros ventilatórios, MAP e IO (pré e pós o uso das drogas). Foram estudados 24 RN (GI:n=12, GII n=12). Os grupos não diferiram quanto à idade gestacional (médias: 354/7 e 36 3/7 sem) e peso de nascimento (médias: 2.560g e 2.799g). Em relação à citologia da HP obteve-se: asfixia - GI 3 (25 por cento), GII 2 (16,6 por cento); doença das membranas hialinas: GI 2 (16,6 por cento), GII (16,6 por cento); taquipnéia transitória: GI 1 (8,4 por cento); pneumotórax: GII 3 (25 por cento); síndrome de aspiração meconial: GII 2 (16,6 por cento); persistência de padrão fatal: GI 6 (50 por cento); hérnia diafragmática: GII 1 (8,4 por cento). A média das PAP foi de 52 mmHg (35-75) - GI e 66 mmHg (45-75) - GII.

Inhaled nitric oxide in the management of persistent pulmonary hypertension of the newborn: a meta-analysis

OBJECTIVES: To evaluate the use of inhaled nitric oxide (NO) in the management of persistent pulmonary hypertension of the newborn. METHODS: Computerized bibliographic search on MEDLINE, CURRENT CONTENTS and LILACS covering the period from January 1990 to March 1998; review of references of all papers found on the subject. Only randomized clinical trials evaluating nitric oxide and conventional treatment were included. OUTCOMES STUDIED: death, requirement for extracorporeal membrane oxygenation (ECMO), systemic oxygenation, complications at the central nervous system and development of chronic pulmonary disease. The methodologic quality of the studies was evaluated by a quality score system, on a scale of 13 points. RESULTS: For infants without congenital diaphragmatic hernia, inhaled NO did not change mortality (typical odds ratio: 1.04; 95 percent CI: 0.6 to 1.8); the need for ECMO was reduced (relative risk: 0.73; 95 percent CI: 0.60 to 0.90), and the oxygenation was improved (PaO2 by a mean of 53.3 mm Hg; 95 percent CI: 44.8 to 61.4; oxygenation index by a mean of -12.2; 95 percent CI: -14.1 to -9.9). For infants with congenital diaphragmatic hernia, mortality, requirement for ECMO, and oxygenation were not changed. For all infants, central nervous system complications and incidence of chronic pulmonary disease did not change. CONCLUSIONS: Inhaled NO improves oxygenation and reduces requirement for ECMO only in newborns with persistent pulmonary hypertension who do not have diaphragmatic hernia. The risk of complications of the central nervous system and chronic pulmonary disease were not affected by inhaled NO

Nitric oxide: biological role and clinical uses.

Nitric oxide is a product of the conversion of L-arginine by the enzyme nitric oxide synthase. Nitric oxide is involved in a variety of physiological situations and is produced by many different cell types. It is involved in neurotransmission, maintenance of vascular smooth muscle tone, and cytotoxicity. Nitric oxide has been suggested to play an anti-inflammatory role by inhibiting the expression of the genes for inflammatory cytokines. The pathophysiological role of nitric oxide is also evident in a variety of diseases, including septic shock, asthma, reperfusion injury, etc. Nitric oxide, by stimulating the production of cyclic GMP, relaxes smooth muscles of the cardiovascular, respiratory, gastrointestinal, and genito-urinary systems. Recent studies have provided important information on the use of inhaled nitric oxide for the management of several diseases characterized by the presence of abnormal pulmonary vascular tone, such as persistent pulmonary hypertension of the newborn. This review addresses the biology and clinical uses of inhaled nitric oxide.

Echocardiographic assessment of inhaled nitric oxide in newborn infants with severe hypoxemia

Nitric oxide inhalation can benefit newborn babies with persistent pulmonary hypertension with right to left extrapulmonary shunt [EPS]. We compared the effects of inhaled nitric oxide [NO] on systemic oxygenation and mean pulmonary blood flow velocity [MPBFV] using doppler ultrasound in severely hypoxic newborn infants with or without extrapulmonary shunt. With a median dose of 20 parts per million [ppm], oxygenation index decreased significantly in both groups [EPS, [p < 0.001] and non-EPS [p <0.05]]. The percentage decrease was significantly greater in the EPS group [p<0.001]. MPBFV increased significantly in the EPS group [p<0.001] only. There was significant correlation between the percentage decrease in oxygenation index and the percentage increase in MPBFV after 1 h of inhaled NO in the EPS group only. We conclude that inhaled NO may improve some newborn infants with severe hypoxemia without significant EPS by improving ventilation perfusion matching. Careful Doppler ultrasound could help to predict the likelihood of beneficial effects of inhaled NO. Nitric oxide being more effective in newborn infants with extrapulmonary shunting than those without by increasing pulmonary blood flow

Hipertención pulmonar persistente en un neonato con hernia diafragmática: tratamiento con sulfato de magnesio / Persistent pulmonary hipertension and congenital diaphragmatic hernia in a newborn. Treatment with magnesium sulphate

La hipertensión pulmonar persistente neonatal (HPPN) es factor determinante en el pronóstico de neonatos con hernia diafragmática congénita (HDC). Se han reportado efectos benéficos del sulfato de magnesio (MgSO4) sistémico en neonatos con HPPN. Se presenta el caso de un neonato a término, con HDC e insuficiencia respiratoria severa desde el nacimiento. Se administró una dosis de impregnación de MgSO4 (200 mg/kg) seguida por dosis de mantenimiento de 30 mg/kg/h. Durante la infusión se observó un incremento de la PaO2 postductal así como disminución de la diferencia de oxígeno alveolo arterial y del índice de oxigenación. Al segundo día se llevó a cabo la cirugía con evolución satisfactoria. Se concluye que el uso del MgSO4 es una alternativa fácilmente disponible y de bajo costo en el tratamiento de la HPPN en pacientes con HDC, que pudiera mejorar la morbimortalidad de este padecimiento en países que no poseen alta tecnología