Lung ultrasound and procalcitonin, improving antibiotic management and avoiding radiation exposure in pediatric critical patients with bacterial pneumonia: a randomized clinical trial.

BACKGROUND: Pneumonia is a major public health problem with an impact on morbidity and mortality. Its management still represents a challenge. The aim was to determine whether a new diagnostic algorithm combining lung ultrasound (LUS) and procalcitonin (PCT) improved pneumonia management regarding antibiotic use, radiation exposure, and associated costs, in critically ill pediatric patients with suspected bacterial pneumonia (BP). METHODS: Randomized, blinded, comparative effectiveness clinical trial. Children < 18y with suspected BP admitted to the PICU from September 2017 to December 2019, were included. PCT was determined at admission. Patients were randomized into the experimental group (EG) and control group (CG) if LUS or chest X-ray (CXR) were done as the first image test, respectively. Patients were classified: 1.LUS/CXR not suggestive of BP and PCT < 1 ng/mL, no antibiotics were recommended; 2.LUS/CXR suggestive of BP, regardless of the PCT value, antibiotics were recommended; 3.LUS/CXR not suggestive of BP and PCT > 1 ng/mL, antibiotics were recommended. RESULTS: 194 children were enrolled, 113 (58.2%) females, median age of 134 (IQR 39-554) days. 96 randomized into EG and 98 into CG. 1. In 75/194 patients the image test was not suggestive of BP with PCT < 1 ng/ml; 29/52 in the EG and 11/23 in the CG did not receive antibiotics. 2. In 101 patients, the image was suggestive of BP; 34/34 in the EG and 57/67 in the CG received antibiotics. Statistically significant differences between groups were observed when PCT resulted < 1 ng/ml (p = 0.01). 3. In 18 patients the image test was not suggestive of BP but PCT resulted > 1 ng/ml, all of them received antibiotics. A total of 0.035 mSv radiation/patient was eluded. A reduction of 77% CXR/patient was observed. LUS did not significantly increase costs. CONCLUSIONS: Combination of LUS and PCT showed no risk of mistreating BP, avoided radiation and did not increase costs. The algorithm could be a reliable tool for improving pneumonia management. CLINICAL TRIAL REGISTRATION: NCT04217980.

Lung UltrasouNd Guided surfactant therapy in preterm infants: an international multicenter randomized control trial (LUNG study).

BACKGROUND: The management of respiratory distress syndrome (RDS) in premature newborns is based on different types of non-invasive respiratory support and on surfactant replacement therapy (SRT) to avoid mechanical ventilation as it may eventually result in lung damage. European guidelines currently recommend SRT only when the fraction of inspired oxygen (FiO2) exceeds 0.30. The literature describes that early SRT decreases the risk of bronchopulmonary dysplasia (BPD) and mortality. Lung ultrasound score (LUS) in preterm infants affected by RDS has proven to be able to predict the need for SRT and different single-center studies have shown that LUS may increase the proportion of infants that received early SRT. Therefore, the aim of this study is to determine if the use of LUS as a decision tool for SRT in preterm infants affected by RDS allows for the reduction of the incidence of BPD or death in the study group. METHODS/DESIGN: In this study, 668 spontaneously-breathing preterm infants, born at 25+0 to 29+6 weeks' gestation, in nasal continuous positive airway pressure (nCPAP) will be randomized to receive SRT only when the FiO2 cut-off exceeds 0.3 (control group) or if the LUS score is higher than 8 or the FiO2 requirements exceed 0.3 (study group) (334 infants per arm). The primary outcome will be the difference in proportion of infants with BPD or death in the study group managed compared to the control group. DISCUSSION: Based on previous published studies, it seems that LUS may decrease the time to administer surfactant therapy. It is known that early surfactant administration decreases BPD and mortality. Therefore, there is rationale for hypothesizing a reduction in BPD or death in the group of patients in which the decision to administer exogenous surfactant is based on lung ultrasound scores. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05198375 . Registered on 20 January 2022.

Lung Ultrasound Scores Progress Differently in Extreme and Very Preterm Infants after Birth: A Multicentre Prospective Study.

INTRODUCTION: The lung ultrasound score (LUS) has been suggested to predict moderate-severe bronchopulmonary dysplasia (msBPD) in preterm infants. We aimed to assess LUS evolution after birth in preterm infants and the effect of gestational age. METHODS: This multicentre prospective observational study was performed with newborns born before 33 weeks of gestation. We created two groups: group 1 (23-27 weeks) and group 2 (28-32 weeks). We compared LUSs between the groups from birth until 36 weeks of postmenstrual age, and we estimated the LUS evolution in each group with a linear multilevel mixed-effects regression model. The effects of the need for surfactant or an msBPD diagnosis were also studied. RESULTS: We included 339 patients: 122 (36%) in group 1 and 217 (64%) in group 2. The infants in group 1 showed a steady progression in the LUS from birth until 4 weeks of age and a subsequent decrease; the infants in group 2 showed a progressive decrease in the LUS throughout the study. This progression varied significantly in the first weeks of life in infants who required surfactant at birth and after the first week of life in the patients diagnosed with msBPD. DISCUSSION/CONCLUSIONS: Extremely preterm infants showed persistently high LUSs during the first weeks of life, regardless of the progression to msBPD. In this group, the infants who did not require surfactant at birth exhibited an increase in their LUSs after the first week until their values were equal to the remaining infants in their group.

Lung ultrasound scores in neonatal clinical practice: A narrative review of the literature.

Lung ultrasound (LU) has in recent years increasingly been used as a point-of-care method. Initially, LU was used as a so-called descriptive diagnostic method for neonatal respiratory diseases. Instead, this review article focuses on the use of LU as a "functional" tool using classification of findings in patterns or using semiquantitative scores. We review and describe the evidence that led to the implementation of LU in predicting the need for surfactant replacement therapy in preterm infants and in the identification of newborns at risk of developing bronchopulmonary dysplasia. LU appears to be a very promising method for the future of clinical management of newborns in both acute and chronic phases of pulmonary pathologies related to prematurity. However, further studies are needed to define its role before full implementation.

Mid-regional pro-adrenomedullin for diagnosing evolution after cardiac surgery in newborns: the PRONEW study.

Newborns are the most vulnerable patients after cardiac surgery. Although mortality risk scores before surgery may help predict the risk of poor outcome, new tools are required, and biomarkers could add objective data to these tools. The aim of this study was to assess the ability of mid-regional pro-adrenomedullin (pro-ADM) and pro-atrial natriuretic peptide (pro-ANP) to predict poor outcome after cardiac surgery. This is a pilot diagnostic accuracy study that includes newborns and infants under 2 months admitted to an intensive care unit after cardiac surgery. Pro-ADM and pro-ANP were determined immediately upon admission. Poor outcome was defined as mortality, cardiac arrest, requiring extracorporeal support, requiring renal replacement therapy, or neurological injury. Forty-four patients were included. Twenty-six (59%) had a STAT category of ≥ 4. Ten patients (22.7%) presented a poor outcome, four of whom (9.1%) died. Pro-ADM was higher in patients with poor outcome (p = 0.024) and death (p = 0.012). Pro-ADM showed the best area under curve (AUC) for predicting poor outcome (0.735) and mortality alone (0.869). A pro-ADM of 2 nmol/L had a Sn of 75% and a Sp of 85% for predicting mortality. Pro-ADM > 2 nmol/L was independently associated with poor outcome (OR 5.8) and mortality (OR 14.1). Although higher pro-ANP values were associated with poor outcomes, no cut-off point were found. The combination of STAT ≥ 4 and the biomarkers did not enhance predictive power for poor outcome or mortality.Conclusion: Pro-ADM and pro-ANP determined immediately after surgery could be helpful for stratifying risk of poor outcome and mortality in newborns. What is Known: • Some congenital heart diseases must be corrected/palliated during the first days of life. A useful tool to predict the risk of severe complications has not been proposed. • Most unstable newborns would have higher values of biomarkers such as pro-ADM and pro-ANP related to shock and compensatory actions. What is New: • Pro-ADM and pro-ANP seem to be good biomarkers to predict poor outcome after cardiac surgery. A pro-ADM < 2 nmol/L would imply a low likelihood of a poor outcome. • Deepening the analysis of biomarkers can help in making decisions to prevent/treat complications.

An algorithm combining procalcitonin and lung ultrasound improves the diagnosis of bacterial pneumonia in critically ill children: The PROLUSP study, a randomized clinical trial.

BACKGROUND: Lung ultrasound (LUS) and procalcitonin (PCT) are independently used to improve accuracy when diagnosing lung infections. The aim of the study was to evaluate the accuracy of a new algorithm combining LUS and PCT for the diagnosis of bacterial pneumonia. METHODS: Randomized, blinded, comparative effectiveness clinical trial. Children <18 years old with suspected pneumonia admitted to pediatric intensive care unit were included, and randomized into experimental group (EG) or control group (CG) if LUS or chest X-Ray (CXR) were done as the first pulmonary image, respectively. PCT was determined. In patients with bacterial pneumonia, sensitivity, specificity, and predictive values of LUS, CXR, and of both combined with PCT were analyzed and compared. Concordance between the final diagnosis and the diagnosis concluded through the imaging test was assessed. RESULTS: A total of 194 children, with a median age of 134 (interquartile range [IQR]: 39-554) days, were enrolled, 96 randomized into the EG and 98 into the CG. Bacterial pneumonia was diagnosed in 97 patients. Sensitivity and specificity for bacterial pneumonia diagnosis were 78% (95% confidence interval [CI]: 70-85) and 98% (95% CI: 93-99) for LUS, 85% (95% CI: 78-90) and 53% (95% CI: 43-62) for CXR, 90% (95% CI: 83-94) and 85% (95% CI: 76-91) when combining LUS and PCT, and 95% (95% CI: 90-98) and 41% (95% CI: 31-52) when combining CXR and PCT. The positive predictive value for LUS and PCT was 88% (95% C:I 79%-93%) versus 68% (95% CI: 60-75) for CXR and PCT. The concordance between the final diagnosis and LUS had a kappa value of 0.69 (95% CI: 0.62-0.75) versus 0.34 (95% CI: 0.21-0.45) for CXR, (p < 0.001). CONCLUSIONS: The combination of LUS and PCT presented a better accuracy for bacterial pneumonia diagnosis than combining CXR and PCT. Therefore, its implementation could be a reliable tool for pneumonia diagnosis in critically ill children.

Procalcitonin and lung ultrasound algorithm to diagnose severe pneumonia in critical paediatric patients (PROLUSP study). A randomised clinical trial.

BACKGROUND: Lung ultrasound (LUS) in combination with a biomarker has not yet been studied. We propose a clinical trial where the primary aims are: 1. To assess whether an algorithm with LUS and procalcitonin (PCT) may be useful for diagnosing bacterial pneumonia; 2. To analyse the sensitivity and specificity of LUS vs chest X-ray (CXR). METHODS/DESIGN: A 3-year clinical trial. INCLUSION CRITERIA: children younger than 18 years old with suspected pneumonia in a Paediatric Intensive Care Unit. Patients will be randomised into two groups: Experimental Group: LUS will be performed as first lung image. CONTROL GROUP: CXR will be performed as first pulmonary image. Patients will be classified according to the image and the PCT: a) PCT < 1 ng/mL and LUS/CXR are not suggestive of bacterial pneumonia (BN), no antibiotic will be prescribed; b) LUS/CXR are suggestive of BN, regardless of the PCT, antibiotic therapy is recommended; c) LUS/CXR is not suggestive of BN and PCT > 1 ng/mL, antibiotic therapy is recommended. CONCLUSION: This algorithm will help us to diagnose bacterial pneumonia and to prescribe the correct antibiotic treatment. A reduction of antibiotics per patient, of the treatment length, and of the exposure to ionizing radiation and in costs is expected. TRIAL REGISTRATION: NCT04217980 .

Lung ultrasound in children: What does it give us?

Lung ultrasound (LUS), a non-invasive non-ionizing radiation tool, has become essential at the bedside in both adults and children, particularly in the critically ill. This manuscript reviews normal LUS patterns and the most important pathologies that LUS allows to diagnose. Normal LUS is represented by the pleural line, the lung-sliding and the A-lines and B-lines. These two last findings are artifacts derived from the pleural line. Pleural effusion appears as an anechoic collection. Pneumothorax is suspected when only A-lines are present, without lung-sliding and B-lines. Alveolo-interstitial syndrome is characterized by different degrees of confluent B-lines and can be present in different pathologies such as pulmonary edema and acute respiratory distress syndrome. The distribution of B-lines helps to differentiate between them. LUS is useful to evaluate the response to lung recruitment in pathologies such as acute respiratory distress syndrome or acute chest syndrome. The distribution of B-lines also appears to be useful to monitor the response to antibiotics in pneumonia. However, further studies are needed to further ascertain this evidence. LUS is also useful to guide thoracocentesis.

Neonatal Non-compacted Cardiomyopathy: Predictors of Poor Outcome.

Non-compacted cardiomyopathy (NCM) is a heterogenous myocardial disorder. Although much has been published in recent years, little is known about NCM in the neonatal period. The objective of this study is to characterize the involvement of newborns affected with NCM and to identify risk factors associated with increased mortality. This is a retrospective study including all neonates diagnosed with NCM between 2006 and 2018. Diagnosis was based on echocardiographic findings. Data were collected regarding prenatal history, gestational age and weight at birth, gender, age at diagnosis, left or biventricular involvement and associated malformations, medical and surgical treatments, and evolution. Fourteen patients were included. The median follow-up duration was 34 months (range 1-87 months). The left ventricular apex and lateral wall were involved in all cases (100%). Thirteen patients (92.8%) had other associated heart malformations. Six patients (42.8%) died during the follow-up period. Patients who had biventricular involvement and poor ventricular function presented a higher risk of death. The main cause of death was ventricular dysfunction (5/6 [83.3%]). During follow-up, eight patients (57.1%) underwent surgery for their cardiac malformations, without higher mortality. NCM must be included in the differential diagnosis of neonatal cardiomyopathy. The higher mortality observed in our series is related not only to the high association with congenital heart disease, but also to a greater presence of early and severe left ventricular dysfunction. We did not find that patients who underwent surgery with cardiopulmonary bypass had worse outcomes.

Lung Ultrasound to Assess the Etiology of Persistent Pulmonary Hypertension of the Newborn (LUPPHYN Study): A Pilot Study.

INTRODUCTION: Persistent pulmonary hypertension of the newborn (PPHN) is a neonatal syndrome associated with significant morbidity and mortality that is caused by the failure of postnatal drop in pulmonary vascular resistance. In extreme cases, patients may require extracorporeal membrane oxygenation therapy (ECMO). The aim of this study was to explore lung ultrasound (LUS) patterns in newborns with PPHN requiring ECMO. PATIENTS AND METHODS: From January 2014 to January 2018, LUS was performed on patients with PPHN admitted for ECMO treatment. PPHN diagnosis was based on clinical and echocardiographic findings. LUS was performed before patients underwent ECMO cannulation. An underlying diagnosis was made taking into account the patient's complete medical history, excluding LUS information. A blinded physician, unaware of the patient's clinical condition, analyzed the stored ultrasound images. Results were then compared with chest x-ray (CXR) diagnoses. RESULTS: Seventeen patients were recruited; 12 were male (70.6%). The median gestational age was 38.7 weeks, with 13 term newborns (76.5%). Twelve were cannulated for VA ECMO, with a median ECMO run of 111.2 h. Six patients (35%) survived. Patients with alveolar capillary dysplasia with misaligned pulmonary veins, fetal ductus arteriosus constriction, or sepsis had normal LUS patterns (A-lines with lung sliding). LUS showed a better sensitivity (88.9%) and specificity (85%) than CXR (55.6 and 77.5%, respectively) in identifying patients with nonparenchymal lung disease. CONCLUSIONS: LUS can provide essential information to help diagnose the underlying cause of PPHN in an earlier and more effective way than CXR. LUS is suitable for routine utilization in the intensive care unit.

Neuroprotection with hypothermia and allopurinol in an animal model of hypoxic-ischemic injury: Is it a gender question?

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term newborns after perinatal hypoxic ischemic injury (HI). Despite this, TH does not provide complete neuroprotection. Allopurinol seems to be a good neuroprotector in several animal studies, but it has never been tested in combination with hypothermia. Clinical findings show that male infants with (HI) fare more poorly than matched females in cognitive outcomes. However, there are few studies about neuroprotection taking gender into account in the results. The aim of the present study was to evaluate the potential additive neuroprotective effect of allopurinol when administrated in association with TH in a rodent model of moderate HI. Gender differences in neuroprotection were also evaluated. METHODS: P10 male and female rat pups were subjected to HI (Vannucci model) and randomized into five groups: sham intervention (Control), no treatment (HI), hypothermia (HIH), allopurinol (HIA), and dual therapy (hypothermia and allopurinol) (HIHA). To evaluate a treatment's neuroprotective efficiency, 24 hours after the HI event caspase3 activation was measured. Damaged area and hippocampal volume were also measured 72 hours after the HI event. Negative geotaxis test was performed to evaluate early neurobehavioral reflexes. Learning and spatial memory were assessed via Morris Water Maze (MWM) test at 25 days of life. RESULTS: Damaged area and hippocampal volume were different among treatment groups (p = 0.001). The largest tissue lesion was observed in the HI group, followed by HIA. There were no differences between control, HIH, and HIHA. When learning process was analyzed, no differences were found. Females from the HIA group had similar results to the HIH and HIHA groups. Cleaved caspase 3 expression was increased in both HI and HIA. Despite this, in females cleaved caspase-3 was only differently increased in the HI group. All treated animals present an improvement in short-term (Negative geotaxis) and long-term (WMT) functional tests. Despite this, treated females present better long-term outcome. In short-term outcome no sex differences were observed. CONCLUSIONS: Our results suggest that dual therapy confers great neuroprotection after an HI event. There were functional, histological, and molecular improvements in all treated groups. These differences were more important in females than in males. No statistically significant differences were found between HIHA and HIH; both of them present a great improvement. Our results support the idea of different regulation mechanisms and pathways of cell death, depending on gender.

Patent Ductus Arteriosus Banding for Circular Shunting After Pulmonary Valvuloplasty.

We report two cases of newborns with critical pulmonary stenosis having intact ventricular septum, who underwent pulmonary valve balloon valvuloplasty followed by banding of a patent ductus arteriosus. Transcatheter pulmonary valvuloplasty was performed one week after delivery. Following the procedure, both developed "circular shunting" as a consequence of left-to-right ductal flow and pulmonary regurgitation. This in turn caused increased blood flow into a dysfunctional right ventricle and low systemic cardiac output syndrome. The PDA banding was performed urgently as a rescue measure in order to restore systemic flow while still maintaining some duct-dependent pulmonary blood flow. This approach resolved the circular shunting. Outcome was favorable in both the patients.

Procalcitonin Is a Better Biomarker than C-Reactive Protein in Newborns Undergoing Cardiac Surgery: The PROKINECA Study.

OBJECTIVES: To assess the kinetics of procalcitonin (PCT) and C-reactive protein (CRP) in newborns after cardiothoracic surgery (CS), with and without cardiopulmonary bypass, and to assess whether PCT was better than CRP in identifying sepsis in the first 72 hours after CS. PATIENTS AND METHODS: This is a prospective study of newborns admitted to the neonatal intensive care unit after CS. INTERVENTIONS: PCT and CRP were sequentially drawn 2 hours before surgery and at 0, 12, 24, 48, and 72 hours after surgery. RESULTS: A total of 65 patients were recruited, of which 14 were excluded because of complications. We compared the kinetics of PCT and CRP after CS in bypass and non-bypass groups without sepsis; there were no differences in the PCT values at any time (24 hours, P = 0.564; 48 hours, P = 0.117; 72 hours, P = 0.076). Thirty-five patients needed bypass, of whom four were septic (11.4%). Significant differences were detected in the PCT values on comparing the septic group to the nonseptic group at 48 hours after cardiopulmonary bypass (P = 0.018). No differences were detected in the CRP values in these groups. A suitable cutoff for sepsis diagnosis at 48 hours following bypass would be 5 ng/mL, with optimal area under the curve of 0.867 (confidence interval 0.709-0.958), P < 0.0001, and sensitivity and specificity of 87.5% (29.6-99.7) and 72.6% (53.5-86.4), respectively. CONCLUSION: This is a preliminary study but PCT seems to be a good biomarker in newborns after CS. Values over 5 ng/mL at 48 hours after CS should alert physicians to the high risk of sepsis in these patients.