Persistent pulmonary hypertension of the newborn (PPHN) is a common and critical disease in the neonatus characterized by persistent pulmonary hypertension and hypoxemia, with a high mortality.Except for intubation and ventilator support, recognized treatments often require the application of pulmonary vasodilators drugs, such as inhaled nitric oxide, Sildenafil, etc, each with its own advantages.In recent years, L-citrulline, as a potential therapeutic option, has shown huge potential in PPHN treatment.The purpose of this review is to explore the possible potential of L-citrulline in the treatment of PPHN in terms of therapeutic mechanism, pharmacokinetics, current status of research and future perspectives.

Objective:To study the early predictors of refractory septic shock (RSS) in neonates.Methods:From July 2020 to December 2021, clinical data of neonates with septic shock admitted to the Neonatal Department of our hospital were retrospectively reviewed. According to the maximum septic shock score (SSS) during clinical course, the neonates were assigned into RSS group and non-RSS group. Perinatal data, laboratory results and hemodynamic parameters at diagnosis were compared between the two groups. Multiple logistic regression analysis was used to identify independent risk factors of RSS and septic shock-related death. Receiver operating characteristic (ROC) curve was constructed to evaluate the early predictors of poor prognosis.Results:A total of 130 neonates were enrolled, including 54 in RSS group and 76 in non-RSS group. Compared with the non-RSS group, the RSS group had significantly lower pH, base excess (BE), stroke volume index (SVI), cardiac output (CO) and cardiac index (CI).Meanwhile, the RSS group had significantly higher mean arterial pressure (MAP) to CI ratio (MAP/CI) and SSS [including bedside SSS (bSSS), computed SSS (cSSS) and modified version of cSSS (mcSSS)] (all P<0.05). Multiple logistic regression analysis showed that increased MAP/CI was an independent predictor of RSS. The cut-off value of MAP/CI was 11.6 [sensitivity 62%, specificity 87%, positive predictive value (PPV) 79% and negative predictive value (NPV) 77%], with an area under the curve (AUC) of 0.734. Increased mcSSS was an independent predictor of septic shock-related death. The cut-off value of mcSSS was 5.8 (sensitivity 83%, specificity 72%, PPV 21% and NPV 97%), with an AUC of 0.845. Conclusions:Increased MAP/CI (≥11.6) and mcSSS (≥5.8) may be early predictors of RSS and septic shock-related death in neonates.

Objective:To study the predictive value of vasoactive-inotropic score (VIS), fluid overload (FO) and lactate level for the outcome of preterm infants with refractory septic shock.Methods:Preterm infants diagnosed with refractory septic shock and required hydrocortisone treatment in our Department from January 2016 to December 2021 were analyzed retrospectively. Preterm infants were assigned into three gestational age groups (<28 weeks, 28-31 weeks, 32-36 weeks). According to the outcome of the disease, the children were further divided into good prognosis group and poor prognosis group. The relationship between the maximum VIS, FO and the mean lactic acid before hydrocortisone and the outcome of refractory septic shock was analyzed by receiver operating characteristic (ROC) curve, the cut-off point of ROC curve was calculated to obtain the predictive efficacy of the three indicators for the outcome of refractory septic shock in preterm infants.Results:A total of 50 preterm infants with refractory septic shock and received hydrocortisone treatment were enrolled, including 20 in the good prognosis group and 30 in the poor prognosis group. There were no significant differences in the maximum VIS, FO and mean lactic acid before hydrocortisone treatment between the two groups of gestational age of <32 weeks ( P> 0.05). The maximum VIS, FO and mean lactic acid of gestational age of 32-36 weeks in the poor prognosis group were higher than those in the good prognosis group, VIS: 56.1±15.7 vs. 37.1±12.9, FO (%): 108.2 (78.6,137.7) vs. 55.5 (10.3, 100.7), and mean lactic acid (mmol/L): 8.3 (4.6, 12.0) vs. 4.8 (-0.8, 10.5), all P<0.05. The area under the ROC curve of the mean lactic acid was the largest, the cut-off value was 4.1 mmol/L, and the Youden index was 1.732. Conclusions:VIS, FO and lactate level are difficult to be used for determining the outcome of refractory septic shock in preterm infants of <32 weeks. While the mean lactic acid has the best predictive performance in preterm infants of 32-36 weeks.

Objective:To explore the effect of quality improvement of hemodynamic monitoring on fluid overload (FO) and outcome in newborns with septic shock.Methods:Non-invasive cardiac output monitoring and functional cardiac ultrasound quality improvement program was started during January 2020 in our hospital. Neonates with septic shock admitted before and after the program were retrospectively analyzed. From January 2018 to December 2019 was pre-improvement period when fluid resuscitation was routinely performed and vasoactive drugs was selected empirically. From January 2020 to December 2021 was post-improvement period when fluid resuscitation and/or use and adjustment of vasoactive drugs were guided by hemodynamic parameters. The 24 h, 48 h, 72 h FO, duration of invasive respiratory support, vasoactive-inotropic score, septic shock score, incidences of complications and all-cause mortality were compared between the two groups.Results:A total of 284 eligible cases were enrolled, including 136 cases in pre-improvement group and 148 cases in post-improvement group. Post-improvement group had significantly lower gestational age (GA), birth weight (BW) and body weight at disease onset than pre-improvement group ( P<0.05). Incidences of 48 h and 72 h FO, fluid resuscitation volume within 72 h, pulmonary hemorrhage and periventricular leukomalacia (PVL) were significantly lower in the post-improvement group ( P<0.05). No significant differences existed in 24 h FO, other complications and all-cause mortality between the two groups ( P>0.05). No significant differences existed in GA and BW for neonates with pulmonary hemorrhage and PVL between the two groups ( P>0.05). Conclusions:Quality improvement of hemodynamic monitoring can effectively improve FO and reduce the incidences of pulmonary hemorrhage and PVL.

Objective:To analyze the time of recovery to the respiratory baseline after treatment of retinopathy of prematurity (ROP) and the possible influencing factors.Methods:The preterm infants with ROP who received ophthalmic treatment from January 2016 to December 2020 in the Department of Neonatology, Guangdong Women and Children′s Hospital were enrolled retrospectively.The baby who received vitreous injection were included in the injection group, and who received laser photocoagulation were included in the photocoagulation group.The patients were divided into two groups according to whether they returned to the respiratory baseline within 48 hours after ROP surgery.Relevant data were collected, including respiratory baseline, the respiratory status 24 hours, 48 hours, 72 hours, 96 hours, 5 days and 7 days after treatment, gestational age, birth weight, gender, corrected gestational age at surgery, weight at surgery, laser points, and treatment location.Wilcoxon signed-rank test was used for continuous variables. Data were expressed as the number and percentage of patients for categorical variables, using Chi-square test or Fisher′ s exact test. Binary Logistic regression analysis was used to analyze the influencing factors.The time taken by preterm infants to return to the preoperative respiratory baseline after treatment and its influencing factors were analyzed. Results:A total of 386 ROP infants were included in this study.There were 157 infants who did not return to the respiratory baseline within 48 hours after treatment.No significant difference in the source, gender, gestational age, birth weight, corrected gestational age at surgery, weight at surgery, and respiratory pressure support required before surgery were found between the group who returned to the respiratory baseline within 48 hours and the group who did not (all P>0.05). However, there were significant differences in treatment methods and location between two groups (all P<0.01). The ratio of returning to the respiratory baseline in the group receiving intravitreal injection was significantly different from that in the group treated with laser therapy at 24 h, 48 h, 72 h, and 96 h after treatment (77% vs.14%, 82% vs.33%, 86% vs.58%, 89% vs.76%; all P<0.01). There was no difference in that ratio between two groups at 5 d and 7 d after treatment (91% vs.86%, 95% vs.92%; P>0.05). Of the 157 infants who did not return to the respiratory baseline within 48 hours after treatment, 108 cases (68.8%) required additional supplemental oxygen, whereas 153 cases (98.5%) required more intensive respiratory support ( P<0.001). According to the multivariate Logistic regression analysis results, the preterm infants who received laser therapy were less likely to return to the respiratory baseline within 48 hours than those who received intravitreal injection ( OR=0.099, 95% CI: 0.060-0.164). A small corrected gestational age at surgery was an independent risk factor for infants not returning to the respiratory baseline within 48 hours ( OR=1.147, 95% CI: 1.009-1.302). Conclusions:Infants with ROP who receive intravitreal injection can return to the respiratory baseline more quickly than those who underwent laser photo-coagulation under. The difference persisted up to 4 days. The smaller the corrected gestational age at treatment, the less likely return to the respiratory baseline within 48 hours in photocoagulation group..

Objective:To study the predictive value of vasoactive-inotropic score (VIS), shock score and lactate level for the outcome of term infants with septic shock.Methods:From January 2019 to October 2020, clinical data of term infants with septic shock admitted to our department were reviewed. According to their clinical outcome, the infants were assigned into the survival group and the deceased group and the differences of the two groups were compared. Logistic regression was used to determine the risk factors of mortality in term infants with septic shock. Receiver operating characteristic curve was used to compare the predictive efficacy of VIS, shock score and lactate level for the outcome of septic shock.Results:Significant differences existed between the survival group and the deceased group in the following: maximum VIS, maximum shock score, maximum lactate level, the mean value of VIS during the second 24 h, the mean value of lactate during the first and second 24 h ( P < 0.05). Meanwhile, maximum VIS ( OR = 1.038, 95% CI 1.014~1.063), maximum shock score ( OR = 2.372, 95% CI 1.126~4.999) and the mean value of lactate during the first 24h ( OR = 2.983, 95% CI 1.132~7.862) were correlated with mortality in the infants ( P < 0.05). The area under the curve of maximum VIS was the most prominent, with 58.5 as cut-off. Conclusions:Among the three indicators, VIS has the best predictive value for mortality outcome in term infants with septic shock, followed by shock score and lactate level.

Objective:To study the threshold of fluid overload (FO) and its risk factors in neonatal septic shock.Methods:From January 2019 to November 2020, clinical data of infants with septic shock hospitalized in the neonatal department of our hospital were reviewed. With poor prognosis as the outcome, ROC curve was drawn based on 24 h (from the beginning of septic shock), 48 h and 72 h FO value. FO cutoff value was determined as area under curve (AUC) reached maximum. Risk factors of FO were analyzed between FO

Objective:To study the efficacy of norepinephrine in the treatment of neonates with septic shock.Methods:A prospective observation study of neonates with septic shock, who received norepinephrine in the neonatal intensive care unit of Guangdong Women and Children's Hospital from January 2019 to November 2020. All infants had functional echocardiography for hemodynamic monitoring before norepinephrine treatment and 1 hour thereafter blood pressure, heart rate, arterial blood gas analyses were recorded at the same time. The intravenous fluid volume and urine volume from the diagnosis of shock to the commencement of norepinephrine therapy (T0) and 24 hours thereafter (T1) were recorded, and the hemodynamic parameters, vasoactive drugs and clinical outcomes were analyzed.Results:A total of 66 newborns were enrolled, including 27 cases of mild shock, 33 cases of moderate shock and 6 cases of severe shock. 48 were male infants, 38 cases were premature infants. The gestational age was (35.2±4.1) weeks and the birth weight was (2 476±909) g. The median time of shock diagnosis was 2 days after birth, and the median shock score was 4 points. The median time from the diagnosis of shock to the start of norepinephrine treatment was 7.5 hours. Compared with that before norepinephrine treatment, stroke volume, stroke volume index, cardiac output, cardiac index, left ventricular ejection fraction, shortening fraction, systolic blood pressure, diastolic blood pressure, mean arterial pressure, blood pH and BE at 1 hour after treatment were increased, heart rate and blood lactic acid were decreased, the differences were statistically significant ( P<0.05). Urine volume was increased 24 hours after treatment ( P<0.05), and fluid overload decreased ( P<0.05). The maximum dopamine dose, the down-regulation time and duration of vasoactive drugs were positively correlated with the time to start norepinephrine therapy ( r=0.325、 r=0.383、 r=0.319, P<0.05). Among the 66 infants, 58 infants with shock had been corrected and 14 infants died within 28 days. Conclusions:Norepinephrine is effective and feasible in the treatment of neonatal septic shock and can significantly improve hemodynamic parameters.

Objective:To study the clinical value of neonatal shock score (NSS) and septic shock score (SSS) in the evaluation of mortality and serious complications of neonatal refractory septic shock.Method:From January 2019 to November 2020, clinical data of neonates with septic shock admitted to Neonatal Department of our hospital were retrospectively reviewed. According to the final outcomes, neonates were assigned into good prognosis group (neonates survived without serious complications) and poor prognosis group (neonates were dead within 28 days after birth and/or had serious complications). The NSS and SSS were calculated according to the worst value of each index during the septic shock course. SSS included computed septic shock score (cSSS) and bedside septic shock score (bSSS). The receiver operating characteristic (ROC) curve was used to analyze the efficacy of each scoring system evaluating the risk of poor prognosis due to septic shock. The correlation of each scoring system with the duration of vasoactive drugs was analyzed using Spearman rank correlation analysis.Result:A total of 72 neonates were enrolled, including 45 in good prognosis group and 27 in poor prognosis group. The vasoactive drug score, serum lactate level, NSS and cSSS in poor prognosis group were significantly higher than good prognosis group ( P<0.05).And bSSS score showed no significant differences between the two groups ( P>0.05). The area under the ROC curve (AUC) of NSS and cSSS predicting the adverse prognosis of neonates with septic shock were 0.644 (95% CI 0.510~0.777, P<0.05) and 0.765 (95% CI 0.654~0.877, P<0.05). The best cut-off values for NSS and cSSS predicting poor prognosis were 4.0 and 80.5, respectively. The positive predictive value (PPV) (81.3% vs. 47.5%) and negative predictive value (NPV) (75.0% vs. 70.6%) of cSSS were higher than NSS. Spearman rank correlation analysis showed that cSSS was positively correlated with the duration of vasoactive drugs( r=0.487, P<0.01). Conclusion:Both shock scoring systems have an evaluation value for the prognosis of neonatal septic shock. The evaluation value of cSSS is better than NSS, and can be used as a main tool for the evaluation of neonatal refractory septic shock.

Objective: To analyze the predictive value of lactate/albumin(L/A) ratio in neonatal infants with septic shock. Methods: The data of 185 neonatal infants with sepsis from January to December 2017 were retrospective analyzed in Guangdong Women and Children Hospital.The data were divided into low level of L/A group(L/A<0.1), medium level of L/A group(0.1≤L/A<0.2) and high level of L/A group(L/A≥0.2)according to L/A ratio level within 24 hours of sepsis.The clinical features, related laboratory indications and prognosis among the 3 groups were compared.Multivariate Logistic regression was used to analyze the effects of various factors on the occurrence of neonatal septic shock.Receiver operating characteristic (ROC) curve analysis was performed to evaluate the early predictive va-lue of related indicators for neonatal septic shock. Results: A total of 185 neonatal infants with sepsis were collected.There were 88 cases in low level of L/A group, 64 cases in medium level of L/A group and 33 cases in high level of L/A group.There were no significant difference in gender, gestational age, birth weight, 1 and 5-minute Apgar scores, small for gestational age, use of pulmonary surfactant, maternal preeclampsia, gestational diabetes mellitus, maternal fever and severe meconium stained (all P>0.05). There were no statistical differences among three groups in C-reactive protein, white blood cell count, neutrophil count and proportion, leucine count and proportion and platelet count(all P>0.05). Compared with low and medium level of L/A groups, the high level of L/A group had higher proportion of cesarean section, higher procalcitonin and lactate, severe intracranial hemorrhage, periventricular leucomalacia, multiple organ dysfunction syndrome, disseminated intravascular coagulation, septic shock and the dead; low level of L/A group had higher proportion of maternal premature rupture of membranes>24 hours, albumin, pH or base excess(BE), and there were statistically significant differences in all of those(all P<0.05). Multivariate Logistic regression analysis showed that hypoalbuminemia, hyperlacticemia, decreased pH and L/A≥0.1 were independent predictors for neonatal septic shock.L/A more than 0.114 within 24 hours was associated with neonatal septic shock, with a sensitivity of 76.90% and specificity of 81.30%. Conclusions The increased of L/A within 24 hours of sepsis can be used as an independent risk factor for predicting septic shock in neonatal infants.