In the real-world retrospective study of 945 critically ill children who were hospitalized with WHO-defined severe pneumonia, we found the mortality was as high as 9.3%, practically in line with a previous research with a larger cohort of 15709 cases7.
Several independent risk factors associated with death identified in our multivariate analyses were also observed in previous studies. Very severe pneumonia, severe underweight and lower birth weight were eminent mortality predictors of severe pneumonia3, 8, 26. Thus, we should precisely distinguish the severity of pneumonia and weight categories for children at admission. Comorbidity played an important role in the death from severe pneumonia in our study. Death was more likely to occur in the patients with more comorbidity, which was widely reported in published studies28, 29. Our findings were similar to the results of a prospective cohort study carried out by Penelope et al, who identified the mortality of severe childhood pneumonia would increase when combined with anemia and gastrointestinal hemorrhage7. It was obvious that the presence of neonatal asphyxia in infants with severe pneumonia was related to a higher mortality, similarly to what was demonstrated in foregoing investigation8, 30. Consequently, accurately diagnosing and treating actively are essential to reduce the severe pneumonia mortality. In our exploration, the strongest independent predictor for mortality was an appropriately 14 times relative raise related to mechanical ventilation. However, Children who use mechanical ventilation have higher mortality rate, which reflected acute conditions and severity of severe pneumonia rather than the influence of mechanical ventilation on mortality.
All of forementioned correlations were expected, and the extraordinary features of this research was that detailed concomitant medications during hospitalization in the real world were collected and analyzed. In the analysis for sedative-hypnotics, we excluded medications for sedation in mechanically ventilated patients. In final, there were only four sedative drugs, including phenobarbital, chloral hydrate, midazolam and diazepam used in research population. Adjusted for severity of severe pneumonia and mechanical ventilation, our multivariate results suggested that sedative-hypnotics were significantly relevant to an increased mortality, which was consistent with earlier studies. In a systematic meta-analysis of 12 controlled trials including 982 infants, phenobarbital could significantly increase the need for mechanical ventilation in children on account of inhibiting respiratory function, resulting in apnea and respiratory failure20. In their retrospective analyses, Lützen et al demonstrated that life-threatening respiratory depression would occur in patients with pneumonia who used phenobarbital, despite of the low probability of phenobarbital-induced respiratory insufficiency31. Therefore, sedative-hypnotics were generally not recommended for severe childhood pneumonia. If necessary, arterial blood gas measurement should be performed regularly to monitor End tidal CO2, and the children are at risk of apnea when the End tidal CO2 is < 30 mmHg or > 50mmHg32. What is more, probiotics were independently associated with a reduced risk of death, which was alike to the result of a prospective multicenter RCT carried out in 9 NICUs from Colombia, in which the investigator observed a lower morbidity and mortality of nosocomial infection in the probiotic group, including pneumonia19. In the other RCTs, Biswal et al described that prophylactic probiotics could apparently decrease the incidence of ventilator-associated pneumonia in children in PICU and NICU18. This might be on account of inhibiting overgrowth of pathogens through rehabilitating non-pathogenic bacteria to compete with pathogens as well as optimizing local and systemic immunity. Moreover, colonization of probiotics in the gastrointestinal tract can reduce intestinal permeability and competitively restrain attachment of pathogens, thereby depressing the possibility of colonization and translocation. In conclusion, probiotics could decrease the incidence and all-cause mortality of nosocomial infections, including severe pneumonia18, 19, 33. On the other hand, diarrhea is very common in infants and young children, accounting for almost 10% of the mortality, so did our results. A recent research showed probiotics played a protective role in preventing the diarrhea-related fatality34. Critically ill children possibly benefit from probiotics. Therefore, probiotics should be of particular concern in children with severe pneumonia in ICU. In addition, a higher mortality was observed in severe pneumonia children with corticosteroids, although there was no significant association in our multivariable analysis, Identically, Dhruti et al demonstrated that the beneficial effect of corticosteroid including inhaled corticosteroids was not confirmed in childhood pneumonia, and resulted in systemic adverse reactions22. In contrast, several researches proved corticosteroids significantly improved the severity of CAP, shortened the length of hospitalization, and decreased mortality in adults35, and similar results were observed in children with severe mycoplasma pneumoniae pneumonia21. Therefore, the validity of corticosteroid is controversial in childhood pneumonia. Only those combined with acute wheezing or with inhaled corticosteroids in the low to medium dose range might benefit from corticosteroid36–38. More and larger randomized, placebo-controlled trials are needed to establish the efficacy and safety of inhaled corticosteroids.
According to analysis for pathogens detected in 122 patients, we found Gram-negative bacteria were the most frequent in severe pediatric pneumonia in ICU, particularly Enterobacteriaceae and Klebsiella spp. being in line with the published studies39. Furthermore, severe pneumonia resulted from Gram-negative bacteria was highly associated with death, which should receive more attention. In terms of antimicrobial therapy in severe pneumonia, narrow-spectrum therapy (i.e. penicillin or ampicillin) are recommended for the children aged 2–59 months, and a combination of ampicillin/penicillin and gentamicin or the use of broader-spectrum antimicrobials alone, including the third-generation cephalosporins and chloramphenicol was recommended as the first choice for the cases with very severe pneumonia or the young infants with severe pneumonia by WHO guidelines.9–11 However, a wide range of extended spectrum antimicrobials, particularly carbapenems were widely selected as initial empiric antimicrobial regimens in critically ill children with severe pneumonia according to our analysis, which disclosed low adherence to guidelines, and that in the multivariate model, no significant difference in efficacy was observed between the guideline-recommended antimicrobials and others. Therefore, initial antimicrobial regimens for severe childhood pneumonia should be chosen on the basis of WHO classification of severity and guideline-recommended treatment consistent with the severity, which may promote rational use of antimicrobials for severe childhood pneumonia and consequently prevent antimicrobial resistance.
Despite detailed information from a real world and rigorous criteria are the strengths, our research has several limitations. First, our retrospective study might have contributed to bias to some extent. Variables that were not documented in the medical record but potentially associated with death cannot be analyzed, including vaccination status, duration of breastfeeding, adverse drug reaction, oxygen saturation as well as some inflammation markers level and so on. Second, the research was performed in a single center in China, so the external validity and generalizability are probably restricted. Third, a few comorbidities diagnosed by physicians lacked laboratory evidence such as sepsis or anemia, which significantly affected our results. Therefore, it could not be decided whether these situations were misdiagnosed. The last limitation is small sample size, especially in the group of young children aged 2–59 months, restricting the capacity to adjust for confounders.