Examination of severe, hospital acquired infections affecting extremely low birthweight (ELBW) infants

PURPOSE: A nationwide questionnaire survey was carried out in 77 major neonatal intensive care unit (NICU) facilities in Japan. The survey investigated severe, hospital acquired infections occurring in extremely low birthweight (ELBW) infants at each institution. METHODS: The nationwide questionnaire survey involved 77 major NICU facilities and ELBW infants born in 1996. The actual status of severe infection in these infants was investigated. RESULTS: Replies were obtained from 57 of the 77 facilities that were sent a questionnaire (74% recovery). During the survey period, the total number of patients hospitalized in 57 facilities was 13697, of which there were 836 ELBW infants. During this period, severe infection occurred in 126 of the ELBW infants. Of those, 98 who developed delayed infection (72 h or more after birth) on the basis of the date of onset were investigated. Methicillin-resistant staphylococcus aureus (MRSA) was the most common organism found, (38 infants, 38.8%), followed by Pseudomonas (10 infants, 10.2%) and Candida (8 infants, 8.2%). Septicemia was present in 67 patients (68.4%), while pneumonia and gastrointestinal complications were found in 15 patients (15.3%). With respect to therapy, the selection of antibiotics varied between facilities. Vancomycin (VCM) was used in 31 cases (31.6%) because MRSA was the most common organism. VCM was used from the early stage of treatment in as many as 20 infants (20.4%). Fifty-eight infants survived (59.2%), 28 infants died (28.6%), and 12 subsequentially had obvious complications (12.2%). CONCLUSION: It was confirmed that severe, hospital acquired infections caused by MRSA are still a significant problem in many institutions. Despite active prevention and treatment, the incidence of severe, hospital acquired infection has not decreased and the prognosis has not improved. Considering the inadequacy of the medical care environment in Japan, it seems impossible to solve these problems at present.     

Chorioamnionitis with or without funisitis increases the risk of hypotension in very low birthweight infants on the first postnatal day but not later

OBJECTIVE: To evaluate the relation between chorioamnionitis and hypotension in very low birthweight infants. METHODS: Retrospective cohort study in infants with a birth weight of <1500 g born between January 2002 and September 2004. The placentas were examined for evidence of chorioamnionitis and funisitis. Hypotension was defined by the use of vasopressors. RESULTS: Of 105 infants, 37 (35%) were chorioamnionitis positive. The onset of hypotension had a skewed distribution: day 1 for 30 episodes and scattered from day 2 to day 19 for the remaining 22. Of the 30 infants who developed hypotension on day 1, 17 (57%) were chorioamnionitis positive. The mean maturity of the chorioamnionitis positive group was 27.91 weeks, marginally less than the mean maturity of 29.05 weeks of the chorioamnionitis negative group (p = 0.05). After adjustment of the effects for confounding variables (birth weight, gestation, surfactant therapy, mechanical ventilation on day 1, high frequency oscillatory ventilation, patent ductus arteriosus), chorioamnionitis was the significant factor in line with hypotension developing on day 1 (adjusted odds ratio 5.14, 95% confidence interval 1.51 to 17.50). There was no evidence that hypotension developing after day 1 was associated with chorioamnionitis. CONCLUSIONS: There is a strong association between chorioamnionitis and hypotension developing on day 1 in very low birthweight infants.     

Time‐course effect of a single dose of hydrocortisone for refractory hypotension in preterm infants

Background: The aim of this study was to determine the time‐course effect of a single dose of hydrocortisone (HC) on arterial blood pressure in extremely low gestational age newborns (ELGAN) with refractory hypotension during the first 3 days of life. Methods: We carried out a matched case–control study of a cohort of 116 infants born between 23 and 27 weeks' gestation at a tertiary center. Twelve infants (10%) were treated with HC for refractory hypotension (HC group). HC was administered at a dose of 2 mg/kg when mean arterial pressure (MAP) was below 30 mmHg (25 mmHg for infants <25 weeks of gestational age) despite the use of inotropes and volume expanders. Changes in the MAP after the HC administration were compared with those in the infants who were not treated with HC and matched for gestational age (Control group). Results: The mean MAP before administration of HC was significantly lower in the HC group than that in the control group (24.0 ± 3.2 vs 33.3 ± 4.8 mmHg; P < 0.01). The mean MAP in the HC group increased significantly at 2 h after HC treatment, and then reached levels comparable to those in the Control group at 5 h (31.3 ± 4.0 vs 33.9 ± 4.7 mmHg; P= 0.18), and remained at normal levels until 12 h after HC treatment. Conclusion: A single dose of HC treatment induces a rapid and sustained improvement in blood pressure in ELGAN with refractory hypotension.     

Late‐onset circulatory collapse of prematurity

Late‐onset circulatory collapse (LCC) is a refractory hypotension occurring after the early neonatal period (>day 7), in very low‐birthweight infants. Typically, infants stabilized within the early neonatal period develop sudden onset of circulatory collapse after the early neonatal period. The underlying pathophysiology of LCC is considered to be relative adrenal insufficiency, which is well known in Japan, but is not widely accepted in North America or Europe. The current increase in LCC in Japan suggests that the principal trigger is related to recent trends in neonatal medicine and/or newly introduced treatments for preterm infants, but the pathophysiology has not been fully elucidated. In this review, based on current knowledge regarding LCC, the pathophysiology is discussed.     

Nationwide surveillance of circulatory collapse associated with levothyroxine administration in very‐low‐birthweight infants in Japan

Background: Although the administration of levothyroxine sodium (LT4) to premature infants had been considered safe, several cases of late‐onset circulatory collapse (LCC) following the administration of LT4 in very‐low‐birth‐weight (VLBW) infants have been reported in Japan since 2008. This study was performed to investigate the incidence of LCC associated with the administration of LT4 to VLBW infants. Methods: A questionnaire regarding LCC with or without an association with LT4 administration in VLBW infants from 2006 to 2008, was sent to 212 hospitals belonging to the Japan Neonatologist Association. Results: Data of 8727 VLBW infants were analyzed, and 46 cases of LCC associated with the administration of LT4 were reported in this surveillance. Especially, an analysis for infants weighing between 1000 and 1499 g at birth revealed that the incidence of LCC with the administration of LT4 was higher than that of those without LT4. Conclusions: LT4 is widely used for infants, including VLBW infants, and no major complications have been reported. However, our study revealed that more than a few cases of LCC were associated with the administration of LT4 in VLBW infants. In conclusion, careful attention is necessary when initiating the administration of LT4 to VLBW infants.     

Ampicillin versus penicillin in the empiric therapy of extremely low‐birthweight neonates at risk of early onset sepsis

Background: There are no comparative data on the impact of different empiric antibiotic regimens on early bowel colonization as well as on clinical efficacy in extremely low‐birthweight (ELBW) neonates at risk of early onset sepsis (EOS). Methods: A subgroup analysis was carried out of ELBW neonates recruited into a two‐center, prospective, cluster randomized study comparing ampicillin and penicillin both combined with gentamicin, within the first 72 h of life. A composite primary end‐point (need for change of antibiotics within 72 h and/or 7 day all‐cause mortality) and the rate and duration of colonization by opportunistic aerobic microorganisms were assessed using hierarchical models corrected for study center and period. Results: In the ampicillin (n= 36) and penicillin (n= 39) groups change of antibiotics, 7 day mortality and the composite end‐point occurred at similar rates. Neonatal intensive care unit mortality for infants with gestational age <26 weeks was lower in the ampicillin group. Ampicillin treatment was associated with a higher colonization rate by Klebsiella pneumoniae, including ampicillin‐resistant strains. Conclusion: Preliminary data indicate an urgent need for adequately powered studies of early antibiotic therapy in the subpopulation of ELBW neonates at risk of EOS.     

Interleukin‐6 polymorphism and bronchopulmonary dysplasia risk in very low‐birthweight infants

Background: The aim of the present study was to evaluate the role of interleukin (IL)‐6‐634 polymorphism in neonatal disorders such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL) in very low‐birthweight (VLBW) infants. Methods: This prospective cohort study included 202 infants (gestational age at birth, 23–34 weeks; birthweight, 500–1499 g). Genotypic analysis (polymerase chain reaction–restriction fragment length polymorphism) was performed with DNA extracted from whole‐blood samples. Results: Genotype distribution (66.8% CC, 28.2% CG, 5.0% GG) was similar to that in the adult Japanese population. BPD occurred in 85 infants (42.1%) among 202 VLBW infants. The duration of O₂ therapy in infants with CG/GG genotypes was significantly longer than that in infants with the CC genotype (CG/GG vs CC: 40.3 ± 52.2 days vs 28.4 ± 32.6 days, P < 0.05), but the prevalence of BPD was not associated with the CG/GG genotype (CG/GG, 40.0%; CC, 46.3%, P= 0.24). Infants with CG/GG genotypes were more likely to have received postnatal corticosteroid therapy for BPD than those with the CC genotype (CG/GG vs CC: 20.9% vs 11.1%, P= 0.05). PVL occurred in six infants (3.0%). There was no significant difference in the prevalence of PVL among IL‐6‐634 polymorphisms (CG/GG, 3.0%; CC, 3.0%, P= 0.65). Conclusions: IL‐6‐634 polymorphism is associated with duration of oxygen therapy in VLBW infants. This suggests that the IL‐6‐634 polymorphism G allele is an aggravating factor of BPD. IL‐6‐634 polymorphism is not associated with PVL.     

Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birthweight infants

AIM—To compare the efficacy of hydrocortisone with dopamine for the treatment of hypotensive, very low birthweight (VLBW) infants.METHODS—Forty infants were randomly allocated to receive either hydrocortisone (n=21) or dopamine (n=19).RESULTS—All 19 infants randomised to dopamine responded; 17 of 21 (81%) did so in the hydrocortisone group. Three of the four non-responders in the hydrocortisone group had clinically significant left to right ductal shunting. The incidence of bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular haemorrhage, necrotising enterocolitis, symptomatic patent ductus arteriosus, hyperglycaemia, sepsis (bacterial or fungal) or survival did not differ between groups. The adrenocorticotrophic hormone (ACTH) stimulated plasma cortisol activity, either before or after treatment, did not differ between the two groups of infants. Although a significant difference in efficacy between dopamine and hydrocortisone was not noted (P = 0.108), there were four treatment failures in the hydrocortisone group, compared with none in the dopamine group.CONCLUSION—Both hydrocortisone and dopamine are effective treatments for hypotension in very low birthweight infants.     

Outcomes of very‐low‐birthweight infants at 3 years of age born in 2003–2004 in Japan

Background: The aim of this study was to describe and compare neurodevelopmental outcomes with birthweight (BW) groups at 250‐g intervals of very‐low‐birthweight (VLBW) infants at 3 years of age in a multicenter cohort in Japan. Methods: A total of 3104 VLBW infants born in 2003 and 2004 registered in a NICU‐network database were followed in the study. Neurodevelopmental impairment (NDI) was defined as any of the following impairments: cerebral palsy, unilateral or bilateral blindness, severe hearing impairment, or developmental delay; a developmental quotient (DQ) <70 measured using the Kyoto Scale of Psychological Development test or judged by physicians in infants without the test. Results: A total of 257 infants died and follow‐up data were obtained from 1826 infants. Of the 1826 infants, 155 (8.5%) had cerebral palsy, 25 (1.4%) had visual impairment, and 12 (0.7%) had hearing impairment. Of the 1197 infants in whom DQ was measured, 184 (15.4%) had DQ < 70. The proportion of NDI in the evaluated infants was 19.2% (n= 350), ranging from 11.9% (BW 1251–1500 g) to 42.0% (BW ≤ 500 g). Odds ratios (95%CI) of NDI or death against the group BW 1251–1500 g were 20.62 (13.29–31.97) in BW ≤ 500 g, 7.25 (5.45–9.64) in BW 501–750 g, 2.85 (2.12–3.82) in BW 751–1000 g and 1.18 (0.85–1.64) in BW 1001–1250 g. Conclusion: The increasing proportion of NDI or death, an indicator of adverse outcome, was associated with decrement in the BW of the groups. Although we have to consider a bias due to loss of follow‐up data, the incidence of NDI was similar to previous overseas cohort studies despite the higher survival proportion in our study.     

Preterm infants fed nutrient‐enriched formula until 6 months show improved growth and development

Background: The purpose of the present study was to determine the effect of feeding nutrient‐enriched preterm formula to preterm infants until 6 months' corrected age (CA) on growth and development in the first 18 months of life. Methods: Very low‐birthweight preterm infants were fed preterm formula until term (40 weeks CA). Infants were then assigned to one of three groups and were fed term formula until 6 months' CA (group 1, n= 29); preterm formula to 3 months' CA and then term formula to 6 months' CA (group 2, n= 30); or preterm formula until 6 months' CA (group 3, n= 31). Anthropometry was performed at term, 3, 6, 9, 12, 15, and at s18 months' CA. Mental and psychomotor development were assessed using the Bayley Scales of Infant Development II at 18 months' CA. Results: Although body weight, length, head circumference and z score for CA at term in group 3 were significantly lower than those of groups 1 and 2, growth rates of these parameters were significantly higher in group 3 up to 18 months CA', as compared to groups 1 and 2. The mental developmental index and psychomotor developmental index of the Bayley test were not significantly different between the three groups. Conclusions: Very low‐birthweight preterm infants fed nutrient‐enriched preterm formula until 6 months' CA demonstrated significantly improved growth rates for bodyweight, length and head circumference, and comparable mental and psychomotor development throughout the first 18 months of life.