Systemic Inflammation in Preterm Infants

Even though mortality among preterm infants has decreased, their risk for chronic complications such as bronchopulmonary dysplasia (BPD) and neurological disability remains significant. One common risk factor for these is exposure to inflammation. The fetus may be exposed prenatally during maternal chorioamnionitis. Pre-eclampsia is also associated with low-grade maternal inflammation. Postnatally, local and systemic inflammation is present during respiratory distress syndrome (RDS). Furthermore, septic infections in the preterm infant are an important source of inflammatory stimuli and can lead to death in only a few hours. The diagnosis of septic infection is difficult, since reliable diagnostic markers are unavailable. This thesis evaluates peri- and postnatal systemic inflammation in preterm infants in septic infections, in RDS treated with mechanical ventilation and surfactant treatment, and in preterm infants prenatally exposed to chorioamnionitis and pre-eclampsia. Surface expressions of the activation markers CD11b, CD54, and CD62L, determined by flow cytometry on circulating phagocytes and T lymphocytes, serve as indicators of systemic inflammation. The main findings: I) In preterm infants with developing late-onset sepsis and fulminant necrotizing enterocolitis, a significant increase in CD11b expression on circulating phagocytes is already present on the day of onset of clinical symptoms. II) In preterm infants with RDS, circulating phagocytes become activated within hours after start of mechanical ventilation. In preterm infants treated for RDS with nasal continuous positive airway pressure, no such activation occurs. III) In preterm infants, RDS is associated during the first days of life with fewer circulating helper and cytotoxic T lymphocytes, of which the greater proportions are activated. Even greater proportions of circulating T cells are activated in infants subsequently developing BPD. IV) In preterm infants born after maternal pre-eclampsia, RDS-associated phagocyte CD11b up-regulation is greater than in preterm infants not exposed to pre-eclampsia during the first week of life. These findings suggest that I) an increase in CD11b expression on circulating phagocytes can identify preterm infants with late-onset sepsis as early as at sampling for blood culture and may thus aid in the diagnosis. II) In preterm infants with RDS, initiation of mechanical ventilation, but not the use of nasal continuous positive airway pressure, promotes a systemic inflammatory reaction; exogenous surfactant does not seem to promote inflammation. III) In addition to activation of circulating cells of the innate immunity in preterm infants with RDS, the circulating cells of the adaptive immunity are activated. The activation of adaptive immunity may link acute inflammation and development of chronic inflammation-associated problems such as BPD. IV) Maternal pre-eclampsia may prime neonatal immunity to react more strongly to postnatal stimuli. In conclusion, the preterm infant is exposed to numerous potentially injurious events such as intrauterine inflammation, respiratory distress syndrome (RDS), and systemic infections, all evoking systemic inflammation. Due to ongoing development of the lung and the brain, this may, in addition to acute injury, lead to aberrant lung and brain development and to clinical syndromes of BPD and neurologic sequelae.

The incidence and outcome of severe sepsis in Finland : The Finnsepsis Study

Severe sepsis is associated with common occurrence, high costs of care and significant mortality. The incidence of severe sepsis has been reported to vary between 0.5/1000 and 3/1000 in different studies. The worldwide Severe Sepsis Campaign, guidelines and treatment protocols aim at decreasing severe sepsis associated high morbidity and mortality. Various mediators of inflammation, such as high mobility group box-1 protein (HMGB1) and vascular endothelial growth factor (VEGF), have been tested for severity of illness and outcome in severe sepsis. Long-term survival with quality of life (QOL) assessment is important outcome after severe sepsis. The objective of this study was to evaluate the incidence, severity of organ dysfunction and outcome of severe sepsis in intensive care treated patients in Finland (study I)). HMGB1 and VEGF were studied in predicting severity of illness, development and type of organ dysfunction and hospital mortality (studies II and III). The long-term outcome and quality of life were assessed and quality-adjusted life years and cost per one QALY were estimated (study IV). A total of 470 patients with severe sepsis were included in the Finnsepsis Study. Patients were treated in 24 Finnish intensive care units in a 4-month period from 1 November 2004 to 28 February 2005. The incidence of severe sepsis was 0.38 /1,000 in the adult population (95% confidence interval 0.34-0.41). Septic shock (77%), severe oxygenation impairment (71.4%) and acute renal failure (23.2%) were the most common organ failures. The ICU, hospital, one-year and two-year mortalities were 15.5%, 28.3%, 40.9% and 44.9% respectively. HMGB1 and VEGF were elevated in patients with severe sepsis. VEGF concentrations were lower in non-survivors than in survivors, but HMGB1 levels did not differ between patients. Neither HMGB1 nor VEGF were predictive of hospital mortality. The QOL was measured median 17 months after severe sepsis and QOL was lower than in reference population. The mean QALY was 15.2 years for a surviving patient and the cost for one QALY was 2,139 . The study showed that the incidence of severe sepsis is lower in Finland than in other countries. The short-term outcome is comparable with that in other countries, but long-term outcome is poor. HMGB1 and VEGF are not useful in predicting mortality in severe sepsis. The mean QALY for a surviving patient is 15.2 and as the cost for one QALY is reasonably low, the intensive care is cost-effective in patients with severe sepsis.

Vastasyntyneen varsan sepsis osa II - Infektion diagnosoiminen, aiheuttajamikrobit ja mikrobilääkeresistenssi

Sepsis eli infektion aiheuttama yleistynyt tulehdusreaktio on merkittävä kuolleisuuden aiheuttaja vastasyntyneillä varsoilla. Kirjallisuuskatsauksessa on käsitelty sepsiksen patofysiologiaa ja kliinisiä oireita vastasyntyneillä varsoilla sekä sepsikselle altistavia tekijöitä. Vastasyntyneen varsan sepsiksen diagnosoimisessa kliinisten oireiden arvioinnilla on keskeinen merkitys sairauden varhaisessa tunnistamisessa ja hoidon aloittamisessa. Sairauden nopean etenemisen ja veriviljelytulosten hitaan valmistumisen vuoksi antibioottihoito joudutaan aloittamaan jo ennen viljelytulosten valmistumista. Veriviljelyllä on kuitenkin tärkeä merkitys sepsisdiagnoosin ja valitun antibioottihoidon varmistamisessa. Sairaalakohtaisten veriviljelynäytetulosten seuranta mahdollistaa ensisijaisen mikrobilääkkeen valinnan aiemmin eristettyjen aiheuttajamikrobien esiintyvyyden ja mikrobilääkeherkkyyksien perusteella. Yleisimpiä vastasyntyneen varsan sepsiksen aiheuttajia ovat kirjallisuuden mukaan suolistoperäiset gram-negatiiviset bakteerit. Escherichia colin osuus vastasyntyneiltä varsoilta otetuista veriviljelynäytteistä eristetyistä bakteerikannoista on vaihdellut eri tutkimuksissa 18,7 - 50,0 %. Pohjois-Amerikassa tehdyissä tutkimuksissa varsojen veriviljelynäytteistä eristettyjen E.coli -kantojen herkkyys yleisesti käytetylle trimetopriimi-sulfadiatsiinille on ollut huono (57–71 %). Penisilliinin ja gentamisiinin yhdistelmälle enterobakteerien herkkyyden on raportoitu olevan hyvä. Suomessa tilanteen on arvioitu olevan parempi. Tutkimuksessa kartoitettiin retrospektiivisesti veriviljelyn käyttöä varsojen sepsiksen diagnostiikassa, sepsiksen aiheuttajamikrobien esiintymistä ja mikrobilääkkeiden käyttöä Yliopistollisessa eläinsairaalassa (YES) vuosina 2004–2006. Tutkimusaineisto koostuu yhteensä 90 korkeintaan 10 päivän ikäisenä YES:aan tuodun varsan potilastiedoista. Sairaalaan saapuneista varsoista 30 % oli otettu veriviljelynäyte. Veriviljelynäytteistä positiivisia oli 62,5 %. 60 % positiivisista näytteistä kasvoi vähintään kahta bakteerilajia. Yleisin aiheuttajabakteeri oli Escherichia coli (23,1 %). Yksi eristetyistä E.coli -kannoista oli resistentti ampisilliinille, gentamisiinille ja trimetopriimi-sulfadiatsiinille. Aineiston pienen koon vuoksi tutkimus ei kuitenkaan anna luotettavaa kuvaa eristettyjen aiheuttajamikrobien mikrobilääkeherkkyydestä laajemmin. Sekakasvujen osuus oli suuri ja tyypillisten veriviljelynäytteitä kontaminoivien bakteerilajien (Streptococcus viridans sp., Micrococcus sp., koagulaasinegatiiviset stafylokokit) osuus oli yli 30 % eristetyistä bakteerikannoista. Tämä viittaa ongelmiin veriviljelynäytteenottotekniikassa riittävän aseptiikan saavuttamien osalta. Koagulaasinegatiiviset stafylokokit voivat myös aiheuttaa sepsiksen, mutta niiden merkitys vastasyntyneiden varsojen sepsiksen aiheuttajina on epäselvä.