Periventricular hemorrhagic infarction in preterm neonates: Etiology and time of development.

BACKGROUND: To find the obstetrical and delivery associated risk factors of antenatal and postnatal grade III intraventricular hemorrhage (IVH) or periventricular hemorrhagic infarction (PVHI) in preterm neonates. METHODS: A retrospective study of obstetric and delivery associated risk factors included neonates (<35 gestational weeks) with severe IVH/PVHI (n = 120) and a prospectively collected control group (n = 50). The children were divided into: (1) antenatal onset group (n = 27) with insult visible on cerebral ultrasonography within the first 12 hours of birth or periventricular cystic changes visible in PVHI within the first 3 days; (2) neonatal onset group (n = 70) with insult diagnosed after initial normal findings or I-II grade IVH, and (3) unknown time-onset group (n = 23) with insult visible at > 12 h of age. RESULTS: The mothers of the antenatal onset group had significantly more bacterial infections before delivery compared to the neonatal onset group: 20/27 (74.1%) versus 23/69 (33.3%), (odds ratio (OR) 5.7 [95% confidence interval 2.1-16]; p = 0.0008) or compared to the control group (11/50 (22%); OR 11 [2.8-42]; p = 0.0005). Placental histology revealed chorioamnionitis more often in the antenatal compared to the neonatal onset group (14/21 (66.7%) versus 16/42 (38.1%), respectively; OR 3.7 [1.18-11]; p = 0.025). Neonates with neonatal development of severe IVH/PVHI had significantly more complications during delivery or intensive care. CONCLUSIONS: Bacterial infection during pregnancy is an important risk factor for development of antenatal onset severe IVH or PVHI. In neonates born to mothers with severe bacterial infection during pregnancy, cerebral ultrasonography is indicated for early detection of severe IVH or PVHI.

Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam during high volume haemodiafiltration in patients with septic shock.

BACKGROUND: The purpose of the study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of piperacillin and tazobactam during high-volume haemodiafiltration (HVHDF). METHODS: A single dose of piperacillin/tazobactam (4/0.5 g) was administered as 30 minute infusion during HVHDF to 10 patients with acute kidney injury due to septic shock. Arterial blood samples were collected before and at 30 or 60 min intervals over 8 h (12 samples) after study drug administration. Concentrations of piperacillin and tazobactam were determined by HPLC-MS/MS. R software was used for population PK analysis and Monte Carlo Simulation of probability of PK/PD target attainment (PTA) in 1000 subjects. RESULTS: A total of 101 samples were collected during HVHDF. The median (IQR) estimated glomerular filtration rate of the patients was 16 (11.25-27.5) ml/min/1.73 m(2) and HVHDF effluent rate was 208 (146.3-298.3) ml/kg/h. A final two-compartment population PK model predicted mean (%SE) total piperacillin clearance on HVHDF was 6.9 (6.4) l/h, volume of distribution of central compartment 9.0 (10.1) l and of peripheral compartment 11.2 (12.2) l. The PTA of 50% fT>MIC for piperacillin 4 g/tazobactam 0.5 g dosed every 8 h as 0.5-h and 4-h infusion was 84.3% and 100% for MIC of 16 mg/l respectively. Aiming 100% fT>MIC of 16 mg/l, the PTA values were 88.6% and 61.0%, for piperacillin 4 g/tazobactam 0.5 g 4-h infusion every 6 and 8 h respectively. CONCLUSIONS: For bactericidal PK/PD target attainment piperacillin/tazobactam doses of 4/0.5 g every 8 h appear appropriate in septic shock patients with minimal residual renal function during HVHDF.

Severe Trauma in Estonia: 256 consecutive cases analysed and the impact on outcomes comparing two regions.

PURPOSE: The purpose of this study was to investigate epidemiology of severe injuries in Estonia while comparing outcomes at regional trauma facilities. METHODS: After the ethics review board approval, all consecutive trauma admissions with Injury Severity Score (ISS) > 15 to North Estonia Medical Center/Tallinn Children's Hospital (NEMC + TCH) and Tartu University Hospital (TUH) were identified between 1/1/2013 and 31/12/2013. Data collection included demographics, admission data, injury severity variables, interventions, and in-hospital outcomes. Primary outcome was in-hospital mortality. Secondary outcomes were complications per Clavien-Dindo and hospital length of stay (HLOS). Logistic regression analysis was used to compare adjusted mortality between the two regional hospitals. RESULTS: A total of 256 patients met inclusion criteria. The mean ISS for the cohort was 23.6 ± 7.8, 13.3 % were hypotensive on admission, and 44.1 % had a Glasgow Coma Scale < 9. Overall rate of complications was 40.2 % that did not differ between the facilities. The mean HLOS at the NEMC + TCH and the TUH were 20.1 ± 25.1 and 10.5 ± 11.2 days (p < 0.001), respectively. Overall mortality was 20.7 % (n = 53). Mortality was 25.4 and 14.9 % for the NEMC + TCH and the TUH, respectively (p = 0.04). Logistic regression analysis resulted in comparable mortality at the regional trauma facilities (adj. OR 1.38; 95 % CI 0.66-2.92; p value 0.39). CONCLUSIONS: The annual incidence of injuries with ISS > 15 was 256 cases with overall mortality at 20.7 % in Estonia. We observed comparable adjusted outcomes at the major regional trauma facilities. This study contains benchmarking data on severely injured patients in Estonia providing potential for future trauma care evaluation and regional outcome comparisons.

An observational study of blood concentrations and kinetics of methyl- and propyl-parabens in neonates.

PURPOSE: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients. METHODS: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. 'Dried Blood Spot' samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach. RESULTS: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21 days 0.88 L/h. CONCLUSIONS: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Risk assessment of neonatal excipient exposure: lessons from food safety and other areas.

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Five-year prospective surveillance of nosocomial bloodstream infections in an Estonian paediatric intensive care unit.

BACKGROUND: Few studies provide rates of nosocomial bloodstream infections (BSIs) in mixed neonatal and paediatric intensive care units (PICUs). AIM: To determine the rate, pathogens and outcome of BSIs in an Estonian PICU. METHODS: Data were collected prospectively from 1st January 2004 to 31st December 2008 in the PICU of Tartu University Hospital. The definition criteria of the US Centers for Disease Control and Prevention were applied for the diagnosis of laboratory-confirmed BSI. FINDINGS: A total of 126 episodes of BSI were identified in 89 patients (74 neonates, eight infants, seven patients aged >1 year). Among neonates 42 (57%) had birth weight <1000 g. The overall incidence of BSI was 9.2 per 100 admissions, incidence density 12.8 per 1000 patient-days. Primary BSI was diagnosed in 92 episodes. Central line (CL)-associated BSI incidence density for neonates was 8.6 per 1000 CL-days with the highest incidence (27.4) among neonates with extremely low birth weight. The most common pathogens were coagulase-negative staphylococci (43%) and Serratia marcescens (14%). Resistance to meticillin was detected in four out of seven S. aureus isolates (all were part of an outbreak) and 23% of Enterobacteriaceae were extended spectrum beta-lactamase (ESBL)-producing strains. Overall case-fatality rate was 10%. CONCLUSION: We observed higher rates of BSIs in our mixed PICU than reported previously. High levels of antimicrobial resistance were detected. Future research should focus on the effects of infection control measures to prevent outbreaks and to decrease incidence of CL-associated BSI.

Mucosal surveillance cultures in predicting Gram-negative late-onset sepsis in neonatal intensive care units.

This study aimed to examine the spectrum and time course of gut and nasopharyngeal colonization with Gram-negative micro-organisms, and to define the value of surveillance cultures in predicting late-onset sepsis in neonates admitted to neonatal intensive care units. Nasopharyngeal and rectal swabs were collected on admission and twice weekly thereafter in 278 neonates admitted within the first 72 h of life with risk factors of early-onset sepsis. Sterile body fluid cultures were obtained on admission and subsequently as clinically indicated. Approximately half of the rectal (693/1250, 55%) and nasopharyngeal (558/1153, 48%) samples but only 6% (32/555) of the sterile fluid samples in 26 patients were culture positive for Gram-negative organisms. In total, 2108 invasive and mucosal culture pairs were analysed. The overall sensitivity, specificity, and positive and negative predictive values of a mucosal sample to predict late-onset sepsis were 27%, 66%, 4% and 94%, respectively. Patients with pre-existing colonization with Klebsiella pneumoniae (P = 0.011), Klebsiella oxytoca (P = 0.002), Escherichia coli (P = 0.003), Stenotrophomonas spp. (P = 0.003) and Pseudomonas spp. (P ≤ 0.001) were more likely to develop late-onset sepsis. No such association was found for Acinetobacter baumannii, Serratia spp. or Enterobacter cloacae. In conclusion, routine mucosal cultures are inefficient for the prediction of Gram-negative late-onset sepsis in neonatal intensive care units. However, targeted screening for specific organisms in an outbreak (e.g. Klebsiella spp., E. coli, Stenotrophomonas spp. and Pseudomonas spp.) may offer an opportunity to improve infection control measures and enable timely initiation of appropriate antibiotic therapy.

Impact of empiric antibiotic regimen on bowel colonization in neonates with suspected early onset sepsis.

The purpose of this study was to compare the impact of ampicillin and penicillin used for empiric treatment of early onset sepsis (EOS) on initial gut colonization by aerobic and facultative anaerobic microorganisms. A cluster-randomized, two-center, switch-over study was conducted in two paediatric intensive care units in Estonia and included 276 neonates. Rectal swabs were collected twice a week until discharge or day 60. Colonizing microbes were identified on species level and tested for ampicillin resistance (AR). The number of patients colonized with Gram negative microorganisms and Candida spp was similar in both treatment arms but ampicillin resulted in longer colonization duration (CD) of K. pneumonia (p = 0.012), AR Serratia spp (p = 0.012) and Candida spp (p = 0.02) and penicillin in that of AR Acinetobacter spp (p = 0.001). As for Gram positive microorganisms penicillin treatment was associated with a greater number of colonized patients and higher CD of Enterococcus spp and S. aureus but lower ones of S. haemolyticus and S. hominis. Influence of ampicillin and penicillin on initial gut colonization is somewhat different but these differences are of low clinical relevance and should not be a limiting step when choosing between these two antibiotics for the empiric treatment of EOS.

Comparison of ampicillin plus gentamicin vs. penicillin plus gentamicin in empiric treatment of neonates at risk of early onset sepsis.

AIM: We aimed to compare the clinical efficacy of ampicillin (AMP) vs. penicillin (PEN) both combined with gentamicin in the empirical treatment of neonates at risk of early onset neonatal sepsis (EOS). METHODS: We performed an open label cluster randomized equivalence study in both Estonian neonatal intensive care units, including neonates with suspected EOS, aged less than 72 h. Primary end-point was clinical failure rate, expressed by need for change of antibiotic regimen within 72 h and/or 7-day all cause mortality. Bowel colonization was followed with biweekly perineal swab cultures. RESULTS: Incidence of proven EOS was 4.9%. Among neonates receiving AMP (n = 142) or PEN (n = 141) change of antibiotic regimen within 72 h (10/142 vs. 10/141; OR 1.02; 95% CI 0.40-2.59), 7-day mortality (11/142 vs. 14/141; OR 0.76; 95% CI 0.33-1.75) and over-all treatment failure (20/142 vs. 20/141; OR 1.01; 95% CI 0.52-1.97) occurred at similar rates. The only differences in gut colonization were lower number of patients colonised with enterococci, S. aureus and AMP resistant Acinetobacter spp. in AMP and lower number of those with S. haemolyticus and S. hominis in PEN arm. CONCLUSIONS: AMP and PEN combined with gentamicin have similar effectiveness in the empiric treatment of suspected neonatal EOS.

Prenatal Cushing's syndrome secondary to nodular adrenocortical hyperplasia with unsuppressed plasma ACTH levels.

We report a newborn girl (36th week of gestation, birth weight 1,054 g) with Cushing's syndrome secondary to nodular adrenocortical hyperplasia with normal plasma ACTH levels. From birth she was hypertensive, hyperglycaemic and slightly hirsuit. Hypercortisolaemia (>1,380 nmol/l) was accompanied by normal plasma ACTH levels (8.64-23.9 pg/ml). A 48-h dexamethasone suppression test decreased plasma cortisol by 35%, indicating some degree of ACTH dependency. However, there was no ACTH rise on CRF test. MRI showed enlarged adrenal glands with a possible cyst on the right; the pituitary gland was normal. At the age of 6 weeks she underwent bilateral adrenalectomy. Histology showed enlarged adrenals with multiple non-pigmented nodules (up to 5 mm) in both glands. However, over the next few weeks she developed liver failure and sepsis. She died at the age of 3 months. Post mortem examination confirmed the diagnosis. Nodular adrenocortical hyperplasia may present at birth with severe Cushing's syndrome and unsuppressed ACTH levels, indicating some degree of ACTH dependency in this condition.

Cerebral blood-flow velocities in predicting outcome of asphyxiated newborn infants.

AIM: To evaluate the role of early (up to 12 h) changes in cerebral blood-flow (CBF) velocity in predicting the severity of hypoxic-ischaemic encephalopathy (HIE) and long-term outcome in asphyxiated term infants. METHODS: CBF velocities were investigated by colour Doppler ultrasonography in 81 healthy and 60 asphyxiated term infants at least three times during the first 5 d of life. The psychomotor development of infants was followed up to 18 mo. RESULTS: No differences in CBF velocities were found at the age of 2-6 h between infants with severe and mild-moderate HIE, mean CBF velocity [mean (95% CI of mean CBF velocity)] in anterior cerebral artery [14.9 (1.4-28.4)cm/s] and [13.9 (11.1-16.7) cm/s], respectively, and between infants with poor outcome (death or severe disability) and with normal development/mild impairments. By the age of 12 h infants with mild-moderate HIE and infants with normal development/mild impairments had decreased CBF velocity in the anterior cerebral artery, and infants with severe HIE or poor outcome had increased mean CBF velocity in anterior, medial cerebral and basilar artery compared to the control group. CONCLUSION: The value of CBF velocity changes to predict poor outcome in asphyxiated infants is low 2-6 h after asphyxia, but increases by the age of 12 ho.

Septic shock with disseminated microfoci in multiple organs in humans.

OBJECTIVE: Histological assessment of tissue damage and localisation of bacteria in autopsy materials of patients who died of septic shock. DESIGN: Prospective observational study. SETTING: General and paediatric intensive care units, Tartu University Hospitals and Institute of Anatomy, Tartu University. PATIENTS: 2 patients, who died of septic shock; 1 patient, who died of trauma. MEASUREMENTS AND RESULTS: Tissue samples of different organs (lungs, heart, spleen, pancreas, liver, adrenals, kidneys and brain) were studied for the presence of bacteria and for the local inflammatory reaction with light microscopy. Bacteria (cocci) were found in the capillaries and tissues of both septic shock patients, but not in the control patient. Capillary dilation, oedema, stasis and cell death, but no polymorphonuclear infiltration, were seen around the foci of bacterial invasion. CONCLUSIONS: Massive penetration of bacteria into all tissues without significant polymorphonuclear infiltration may take place in severe septic shock.