Measuring cerebrovascular autoregulation in preterm infants using near-infrared spectroscopy:An overview of the literature

Introduction: The preterm born infant's ability to regulate its cerebral blood flow (CBF) is crucial in preventing secondary ischemic and hemorrhagic damage in the developing brain. The relationship between arterial blood pressure (ABP) and CBF estimates, such as regional cerebral oxygenation as measured by near-infrared spectroscopy (NIRS), is an attractive option for continuous non-invasive assessment of cerebrovascular autoregulation.Areas covered: The authors performed a literature search to provide an overview of the current literature on various current clinical practices and methods to measure cerebrovascular autoregulation in the preterm infant by NIRS. The authors focused on various aspects: Characteristics of patient cohorts, surrogate measures for cerebral perfusion pressure, NIRS devices and their accompanying parameters, definitions for impaired cerebrovascular autoregulation, methods of measurements and clinical implications.Expert commentary: Autoregulation research in preterm infants has reported many methods for measuring autoregulation using different mathematical models, signal processing and data requirements. At present, it remains unclear which NIRS signals and algorithms should be used that result in the most accurate and clinically relevant assessment of cerebrovascular autoregulation. Future studies should focus on optimizing strategies for cerebrovascular autoregulation assessment in preterm infants in order to develop autoregulation-based cerebral perfusion treatment strategies

Biomarkers of intrauterine hypoxia and perinatal asphyxia, and gestational age as predictors of neonatal outcome

Fetal life occurs in a relatively hypoxic environment. During normal pregnancy, several compensatory mechanisms secure fetal oxygenation and wellbeing. In complicated pregnancies, however, intrauterine hypoxia predisposes the fetus to growth restriction, stillbirth, neurodevelopmental sequelae such as cognitive dysfunction and cerebral palsy (CP), and adverse long-term health impacts. Impairment of respiratory gas exchange—during either pregnancy or delivery—leads to tissue hypoxia, and, if prolonged, to metabolic acidosis and asphyxia. Worldwide, such asphyxia, diagnosed at birth, annually accounts for a million neonatal deaths. Furthermore, neonatal hypoxic ischemic encephalopathy (HIE) originating from perinatal asphyxia may lead to a variety of neurodevelopmental impairments. Therapeutic neuroprotective interventions such as hypothermia have significantly improved the prognosis of severe neonatal encephalopathy. Increased risk for intrauterine fetal hypoxia and perinatal asphyxia occur in various circumstances and pregnancy complications—such as intrauterine growth restriction (IUGR), which affects up to 10% of pregnancies. Timing the delivery in preterm pregnancy with severe IUGR is challenging, owing to balancing between risks related to prematurity and to fetal hypoxia. Another obstetric challenge concerns timing of delivery as well: Neonatal outcomes vary by gestational age also among term pregnancies. In pregnancies beyond 41 gestational weeks, the risk for perinatal morbidity and mortality increases, probably due to the relative insufficiency of the aging placenta. Numerous methods such as fetal Doppler assessments and computerized cardiotocography help in monitoring placental function and fetal wellbeing. These methods, however, are not unequivocally efficient in predicting adverse neonatal outcomes in IUGR or in prolonged pregnancies. Furthermore, the time window for neuroprotective treatment in birth asphyxia is narrow, and additional methods for identifying those neonates who would benefit from neuroprotective actions are essential. We thus searched for biomarkers identifying those fetuses at risk for hypoxia-caused complications, and for predicting outcome after birth asphyxia. Erythropoietin (EPO) is a biomarker of chronic hypoxia, with high levels of EPO associating with increased risk for adverse outcome. S100B is a biomarker of brain- cell damage, and its levels rise in early phases of acute asphyxia. Copeptin, a by-product of arginine vasopressin (AVP) production, is a potential biomarker of birth asphyxia and HIE. Additionally, we aimed to evaluate the association of gestational age with perinatal asphyctic complications and long-term neurologic morbidity. The biomarker studies (I-III) were conducted in the University Hospital of Helsinki, Finland. Data on maternal pregnancy and delivery characteristics, and short-term neonatal outcomes such as Apgar score, originated from hospital charts. The study populations comprised 66 pregnancies complicated by preterm IUGR, 93 low-risk term and prolonged pregnancies, and 140 term neonates with birth asphyxia. Amniotic fluid samples for EPO evaluations we obtained by amniocentesis, at cesarean section, or vaginally at amniotomy. Umbilical serum plasma samples for EPO, copeptin, and S100B assessments we collected at birth. Biomarker levels in amniotic fluid and umbilical plasma samples we measured by immunoassays. Normal amniotic fluid EPO levels we defined as < 3 IU/L, with abnormal levels exceeding 27 IU/L. We considered as normal umbilical plasma EPO levels below 40 IU/L. The register-based cohort study on asphyxia and neurologic morbidity (IV) comprised 1 138 109 women with singleton pregnancies and their newborns between 1989 and 2008 in Finland. The Finnish Medical Birth Register (MBR), maintained by the National Institute for Health and Welfare (THL), provided data for this study. Statistical analyses we performed with the Statistical Package for Social Sciences (SPSS, Chicago, IL, USA), GraphPad Prism 6 and SAS version 9.3 (SAS Institute, Inc, Cary, NC, USA). All tests were two-sided, with probability (p) values of < 0.05 as statistically significant. In IUGR pregnancies, abnormal amniotic fluid EPO levels were associated with decreased umbilical artery pH and base excess (BE) values, abnormal biophysical profile, and reversed end-diastolic flow in the umbilical artery. Most importantly, such abnormal EPO levels were associated with composite adverse neonatal outcomes defined as intraventricular hemorrhage, periventricular leukomalacia, cerebral infarction, or necrotizing enterocolitis (p < 0.001). In low-risk term and postterm pregnancies, EPO levels in amniotic fluid and in umbilical serum correlated with gestational age. Furthermore, EPO levels in amniotic fluid correlated with the levels in umbilical serum, even after vaginal delivery. Among low-risk pregnancies, however, EPO levels correlated with neither umbilical artery pH or BE, nor with other adverse pregnancy outcomes. In our study on biomarkers in birth asphyxia, only copeptin correlated with arterial pH. Its correlation with umbilical artery BE was significantly stronger than were the correlations of S100B or of EPO. Copeptin levels, significantly higher among neonates with birth asphyxia, we demonstrated to increase as a function of labor duration. In the cohort study, multivariate analysis demonstrated an increased risk for low (< 4) one- and five-minute Apgar score, CP, intellectual disability, sensorineural defects, and perinatal mortality among early-term births. Postterm birth resulted in increased risk for low one- and five-minute Apgar scores (< 4), low umbilical artery pH ≤ 7.10, and intellectual disability, whereas risks for CP, epilepsy, sensorineural defects, and perinatal mortality showed no increase. In conclusion, among preterm IUGR pregnancies, high amniotic fluid EPO levels were associated with decreased umbilical artery pH and BE, and with adverse neonatal outcomes. In selected risk-pregnancies, determining amniotic fluid EPO may thus be a useful additional tool in fetal surveillance and in optimizing delivery timing. In term pregnancies, EPO levels correlated with gestational age, probably explained by advancing gestation resulting in weakening placental function and relative hypoxemia. Among low-risk populations, however, EPO was not related to adverse delivery outcomes, and thus may not prove clinically useful in such populations. Furthermore, in cases of acute birth asphyxia, S100B and EPO as biomarkers may not prove valid. In contrast, copeptin has potential for routine use as a biomarker for acute birth asphyxia and neonatal distress. Future studies should determine the correlation of biomarker levels at birth with severity of HIE and with long-term neurological outcome following birth asphyxia. Concerning gestational age at birth, we found an increased risk for low Apgar score, increased neurologic morbidity, and perinatal mortality among early-term neonates. Among postterm births, the risk for birth asphyxia was increased. The long-term neurologic health impacts of postterm birth, however, were less important than previously expected, meaning that further studies on the optimal management of pregnancies beyond 41 gestational weeks are essential.Raskauden aikana sikiö elää verrattain vähähappisessa ympäristössä. Normaalin raskauden aikana lukuisat kompensaatiomekanismit varmistavat sikiön riittävän hapensaannin ja hyvinvoinnin. Sen sijaan komplisoituneissa raskauksissa sikiön kroonisen hapenpuutteen riski on suurentunut lisäten sikiökuoleman, kasvuhidastuman, neurologisten kehityshäiriöiden ja pitkäaikaisten terveysongelmien todennäköisyyttä. Näissä raskauksissa optimaalisen synnytysajankohdan määrittely on usein haastavaa, koska tällöin on huomioitava kohdunsisäisen hapenpuutteen, ennenaikaisen synnytyksen, sekä obstetristen toimenpiteiden aiheuttamat mahdolliset haitat. Sikiön hengityskaasujen vaihdon ongelmat raskauden tai synnytyksen aikana johtavat kudosten hapenpuutteeseen ja hiilidioksidin kertymiseen eli asfyksiaan, mikä pitkittyessään väistämättä johtaa aineenvaihdunnalliseen happamuuteen. Maailmanlaajuisesti perinataalinen asfyksia aiheuttaa vuosittain jopa miljoonan vastasyntyneen kuoleman. Asfyksian aiheuttama hypoksis-iskeeminen enkefalopatia voi myös johtaa pysyvään vammautumiseen ja vakaviin neurologisiin kehityshäiriöihin. Keskushermoston suojaamiseen tähtäävät hoitotoimenpiteet - kuten vastasyntyneen viilennyshoito - ovat olennaisesti parantaneet vastasyntyneen vaikean enkefalopatian ennustetta. Sikiön hyvinvoinnin ja istukan toiminnan seurannassa käytetään lukuisia menetelmiä, kuten sikiön sydänäänten monitorointia ja Doppler-ultraäänitutkimuksia. Käytössä olevilla menetelmillä ei kuitenkaan aina pystytä yksiselitteisesti ennustamaan vastasyntyneen epäsuotuisaa lopputulemaa riskiraskauksissa. Vastasyntyneen asfyksiadiagnoosin asetuksen ja keskushermostoa suojaavien hoitojen käynnistämisen aikaikkuna on kapea, eikä kaikkia intensiivistä tehohoitoa tarvitsevia vastasyntyneitä löydetä nykymenetelmien avulla ajoissa. Uusia menetelmiä kaivataan sekä hapenpuutteen riskissä olevien sikiöiden, että intensiivisestä tehohoidosta hyötyvien vastasyntyneiden tunnistamiseen ja ennusteen arviointiin. Erytropoietiini (EPO) on punasolujen muodostumista lisäävä hormoni, jota käytetään myös hapenpuutteen merkkiaineena. Napaplasman ja lapsiveden kohonneet EPO-pitoisuudet liittyvät vastasyntyneen huonoon lopputulemaan. S100B-proteiini on aivokudoksen soluvaurion merkkiaine, jonka pitoisuudet nousevat myös asfyksiaan liittyvien vaurioiden ilmaantuessa. Vasopressiini on elimistön nestetasapainoa ylläpitävä hormoni, jonka eritys lisääntyy monentyyppisissä stressitilanteissa. Kopeptiini on vasopressiini-erityksen sivutuote, jota pidetään potentiaalisena perinataalisen asfyksian ja hypoksis-iskeemisen aivovaurion merkkiaineena. Tutkimuksessamme selvitimme näiden valikoitujen biomerkkiaineiden käyttöä hapenpuutteen riskissä olevien sikiöiden tunnistamisessa, sekä näiden merkkiaineiden käytettävyyttä perinataalisen asfyksian diagnostiikassa ja vastasyntyneen ennusteen arvioinnissa. Lisäksi selvitimme raskauden keston vaikutuksia perinataalisen asfyksian ja pitkäaikaisen neurologisen sairastavuuden esiintyvyyteen täysiaikaisissa ja yliaikaisissa raskauksissa. Sikiön kasvuhidastumaa ennenaikaisissa raskauksissa käsittelevässä tutkimuksessamme (n=66) totesimme kohonneiden lapsiveden EPO-pitoisuuksien liittyvän napavaltimon vakava-asteisiin virtausmuutoksiin, sekä vastasyntyneen alentuneisiin napavaltimon pH- ja BE-arvoihin. Lisäksi kohonneet EPO-pitoisuudet liittyivät vastasyntyneen vakavaan sairastavuuteen, mukaan lukien vaikea-asteiset aivokammioverenvuodot, aivoinfarktit, periventrikulaarinen leukomalasia, sekä nekrotisoiva enterokoliitti (p < 0.001). Matalan riskin täysiaikaisissa ja lasketun ajan ohittaneissa raskauksissa (≥41 raskausviikkoa) (n=93) EPO-pitoisuudet korreloivat raskauden keston kanssa. Näissä raskauksissa emme todenneet yhteyttä lapsiveden EPO-pitoisuuden ja vastasyntyneen huonon lopputuleman välillä. Asfyktisilla vastasyntyneillä (n=140) totesimme selvästi korkeammat kopeptiinipitoisuudet kuin hyväkuntoisilla vastasyntyneillä. Kopeptiinipitoisuudet myös nousivat synnytyksen keston myötä. Rekisteritutkimuksemme asfyksiasta ja neurologisesta sairastavuudesta kattoi 1 138 109 raskautta vuosina 1989 – 2008. Totesimme varhaiseen täysiaikaiseen syntymään (raskausviikoilla 37+0-38+6) liittyvän matalien Apgarin pisteiden, CP-vamman, älyllisen kehitysvammaisuuden, aistitoimintojen vammojen, sekä perinataalikuolleisuuden suurentuneen riskin. Yliaikainen raskaus (≥42 raskausviikkoa) lisäsi matalan syntymä-pH:n, matalien Apgarin pisteiden, sekä älyllisen kehitysvammaisuuden riskiä, mutta ei liittynyt yleiseen neurologiseen sairastavuuteen eikä lisännyt perinataalikuolleisuutta. Johtopäätöksenä totesimme, että tietyissä riskiraskauksissa lapsiveden EPO-pitoisuuden määrittäminen saattaa olla hyödyllinen lisämenetelmä sikiön voinnin ja synnytyksen ajankohdan arvioinnissa. Toisaalta matalan riskin raskauksissa EPO-pitoisuuden määrityksestä ei vaikuttaisi olevan hyötyä edes lasketun ajan ylittämisen jälkeen. Kopeptiini vaikuttaa erittäin lupaavalta vastasyntyneen asfyksian ja hypoksis-iskeemisen enkefalopatian biomerkkiaineelta, joskin kopeptiinin käytettävyys pitkäaikaisennusteen arvioinnissa edellyttää jatkotutkimuksia. Kohorttitutkimuksessamme totesimme varhaiseen täysiaikaisuuteen liittyvän suurentuneen riskin vastasyntyneen sairastavuuteen ja kuolleisuuteen, sekä pitkäaikaiseen neurologiseen sairastavuuteen. Löydös tukee nykyistä hoitosuositusta synnytyksen ajoittamisesta mahdollisuuksien mukaan lasketun ajan tuntumaan. Toisaalta laajassa kotimaisessa kohortissamme yliaikaisuuden vaikutukset lapsen pitkäaikaiseen neurologiseen terveyteen olivat oletettua vähäisemmät

ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease)

"The ACC and the AHA have long been involved in the joint development of practice guidelines designed to assist healthcare providers in the management of selected cardiovascular disorders or the selection of certain cardiovascular procedures. The determination of the disorders or procedures to develop guidelines for is based on several factors, including importance to healthcare providers and whether there are sufficient data from which to derive accepted guidelines. One important category of cardiac disorders that affect a large number of patients who require diagnostic procedures and decisions regarding long-term management is valvular heart disease. During the past 2 decades, major advances have occurred in diagnostic techniques, the understanding of natural history, and interventional cardiology and surgical procedures for patients with valvular heart disease. These advances have resulted in enhanced diagnosis, more scientific selection of patients for surgery or catheter-based intervention versus medical management, and increased survival of patients with these disorders. The information base from which to make clinical management decisions has greatly expanded in recent years, yet in many situations, management issues remain controversial or uncertain. Unlike many other forms of cardiovascular disease, there is a scarcity of large-scale multicenter trials addressing the diagnosis and treatment of patients with valvular disease from which to derive definitive conclusions, and the information available in the literature represents primarily the experiences reported by single institutions in relatively small numbers of patients.

Towards respiratory muscle-protective mechanical ventilation in the critically ill: technology to monitor and assist physiology

Inadequate delivery of ventilatory assist and unphysiological respiratory drive may severely worsen respiratory muscle function in mechanically ventilated critically ill patients. Diaphragm weakness in these patients is exceedingly common (>60% of patients) and associated with poor clinical outcomes, including difficult ventilator liberation, increased risks of intensive care unit (ICU) and hospital readmission, and mortality. The underlying mechanisms of diaphragm dysfunction were extensively discussed in this thesis. Pathways primarily include the development of diaphragm disuse atrophy due to muscle inactivity or low respiratory drive (strong clinical evidence), and diaphragm injury as a result of excessive breathing effort due to insufficient ventilator assist or excessive respiratory drive (moderate evidence, mostly from experimental work). Excessive breathing effort may also worsen lung injury through pathways that include high lung stress and strain, pendelluft, increased lung perfusion, and patient-ventilator dyssynchrony. Relatively little attention has been paid to the effects of critical illness and mechanical ventilation on the expiratory muscles; however, dysfunction of these muscles has been linked to inadequate central airway clearance and extubation failure. The motivation for performing the work presented in this thesis was the hypothesis that maintaining physiological levels of respiratory muscle activity under mechanical ventilation could prevent or attenuate the development respiratory muscle weakness, and hence, improve patient outcomes. This strategy, integrated with lung-protective ventilation, was recently proposed by international experts from different professional societies (this thesis), and is referred to as a combined lung and diaphragm-protective ventilation approach. Today, an important barrier for implementing and evaluating such an approach is the lack of feasible, reliable and well-understood modalities to assess breathing effort at the bedside, as well as strategies for assisting and restoring respiratory muscle function during mechanical ventilation. Furthermore, monitoring breathing effort is crucial to identify potential relationships between patient management and detrimental respiratory (muscle) function that can be targeted to improve clinical outcomes. In this thesis we identified and improved monitoring modalities for the diaphragm (Part I), we investigated the impact of mechanical ventilation on the respiratory pump, especially the diaphragm (Part II), and we evaluated a novel strategy for maintaining expiratory muscle activity under mechanical ventilation (Part III)