Adelina Pellicer

Near-infrared spectroscopy: a methodology-focused review.

Near infrared spectroscopy (NIRS) is a light-based technology used to monitor tissue oxygen status. Refinements to the method since it was first described have extended its applicability to different research and clinical settings due to its non-invasiveness, instrument portability and ease of use. Classic NIRS recordings, based in the Beer-Lambert law, can be used for the trend monitoring of changes in tissue perfusion-oxygenation parting from an arbitrary zero point. However, in order to derive intermittently quantitative values in absolute terms, certain manoeuvres must be performed. More recently, the evolution of the technique has led to the development of instruments that provide an absolute value of regional hemoglobin saturation in a continuous manner. This review will focus on the physical principles of tissue spectroscopy including a brief description of the different operating principles that are currently in use or under development. The theoretical details, experimental procedures and data analysis involved in the measurements of physiological variables using NIRS will be described. The future beyond the scope of NIRS and potential lines of research will also be discussed.

Cerebral near infrared spectroscopy oximetry in extremely preterm infants : Phase II randomised clinical trial

Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. Design Phase II randomised, single blinded, parallel clinical trial. Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). Main outcome measures The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥26 weeks). Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. Results The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device. Conclusions Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring. Trial registration ClinicalTrial.gov NCT01590316.

Dopamine Versus Epinephrine for Cardiovascular Support in Low Birth Weight Infants: Analysis of Systemic Effects and Neonatal Clinical Outcomes

BACKGROUND. Early postnatal adaptation to transitional circulation in low birth weight infants frequently is associated with low blood pressure and decreased blood flow to organs. Catecholamines have been used widely as treatment, despite remarkably little empirical evidence on the effects of vasopressor/inotropic support on circulation and on clinically important outcomes in sick newborn infants. AIMS. To explore the effectiveness of low/moderate-dose dopamine and epinephrine in the treatment of early systemic hypotension in low birth weight infants, evaluate the frequency of adverse drug effects, and examine neonatal clinical outcomes of patients in relation to treatment. DESIGN/METHODS. Newborns of <1501-g birth weight or <32 weeks of gestational age, with a mean blood pressure lower than gestational age in the first 24 hours of life, were assigned randomly to receive dopamine (2.5, 5, 7.5, and 10 μg/kg per minute; n = 28) or epinephrine (0.125, 0.250, 0.375, and 0.5 μg/kg per minute; n = 32) at doses that were increased stepwise every 20 minutes until optimal mean blood pressure was attained and maintained (responders). If this treatment was unsuccessful (nonresponders), sequential rescue therapy was started, consisting first of the addition of the second study drug and then hydrocortisone. OUTCOME MEASURES. These included: (1) short-term changes (first 96 hours, only responders) in heart rate, mean blood pressure, acid-base status, lactate, glycemia, urine output, and fluid-carbohydrate debit; and (2) medium-term morbidity, enteral nutrition tolerance, gastrointestinal complications, severity of lung disease, patent ductus arteriosus, cerebral ultrasound diagnoses, retinopathy of prematurity, and mortality. RESULTS. Patients enrolled in this trial did not differ in birth weight or gestational age (1008 ± 286 g and 28.3 ± 2.3 weeks in the dopamine group; 944 ± 281 g and 27.7 ± 2.4 weeks in the epinephrine group). Other main antenatal variables were also comparable. However, responders and nonresponders differed significantly with respect to the need for cardiorespiratory resuscitation at birth (3% vs 23%), Critical Risk Index for Babies score (3.8 ± 3 vs 7 ± 5), and premature rupture of membranes >24 hours (39.5% vs 13.6%), respectively. No differences were found in the rate of treatment failure (dopamine: 36%; epinephrine: 37%) or need for rescue therapy according to treatment allocation. Groups did not differ in age at initiation of therapy (dopamine: 5.3 ± 3.9 hours; epinephrine: 5.2 ± 3.3 hours), but withdrawal was significantly later in the dopamine group. For short-term changes, mean blood pressure showed a significant increase from baseline throughout the first 96 hours with no differences between groups. However, epinephrine produced a greater increase in heart rate than dopamine. After treatment began, epinephrine patients showed higher plasma lactate (first 36 hours) and lower bicarbonate and base excess (first 6 hours) and received more bicarbonate. Patients in the epinephrine group also had higher glycemia (first 24 hours) and needed insulin therapy more often. Groups did not differ in urine output or fluid-carbohydrate supply during the first 96 hours. For medium-term morbidity, there were no differences in neonatal clinical outcomes in responders. However, significant differences were found in the incidence of patent ductus arteriosus, bronchopulmonary dysplasia, need for high-frequency ventilation, occurrence of necrotizing enterocolitis, and death between responders and nonresponders. CONCLUSIONS. Low/moderate-dose epinephrine is as effective as low/moderate-dose dopamine for the treatment of hypotension in low birth weight infants, although it is associated with more transitory adverse effects.

Early Systemic Hypotension and Vasopressor Support in Low Birth Weight Infants: Impact on Neurodevelopment

BACKGROUND. The duration and severity of systemic hypotension have been related with altered neurodevelopment. Cerebral circulation is pressure-passive in low birth weight infants with early systemic hypotension who receive cardiovascular support. The treatment of early systemic hypotension is controversial, because it has been associated with short-term and long-term morbidity in retrospective studies. However, there has been no prospective information on cardiovascular support for hypotension and morbidity. OBJECTIVE. Our goal for this prospective study was to evaluate the effect on neurodevelopment resulting from the use of vasopressors/inotropes for early systemic hypotension. METHODS. Low birth weight infants with early systemic hypotension (<24 hours of life; study group) were assigned randomly to receive dopamine (2.5–10 μg/kg per minute) or epinephrine (0.125–0.5 μg/kg per minute) in progressively larger doses until target blood pressure was attained (treatment-success subgroup). Hemodynamically stable patients who did not receive cardiovascular support were the control group. Outcome measures were serial cranial ultrasound up to 40 weeks, structured neurologic evaluation (every 3 months), and neurodevelopmental test at 2 to 3 years of age. RESULTS. One hundred thirty patients were included (study = 60; treatment success = 38; controls = 70). Study-group patients had lower birth weight, gestational age, and 5-minute Apgar score, higher rates of premature rupture of membranes, need for cardiorespiratory resuscitation at birth, and sickness shortly after birth than the control group. The patients in the study group also had significantly higher serum troponin I levels at birth. Initial cranial ultrasound findings did not differ between groups, but the final cranial ultrasounds revealed higher rates of severe periventricular hemorrhage in the study group and higher rates of normal cranial ultrasounds in the control group. Only the latter remained when the treatment-success subgroup and control group were compared. Multivariate analysis did not detect any association between final cranial ultrasounds and the use of vasopressors/inotropes. Sixteen infants died and 103 were followed up (90% survival rate). No differences between groups were found in the rates of abnormal neurologic status, developmental delay, or combined adverse outcome (death or cerebral palsy or severe neurodevelopmental delay). CONCLUSIONS. Cautious use of cardiovascular support to treat early systemic hypotension in low birth weight infants seems to be safe. The question of whether raising systemic blood pressure to within a normal range will improve outcome should be examined by using appropriate study designs.

The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

Postnatal adaptation of brain circulation in preterm infants.

Global and regional postnatal cerebral circulatory changes in stable preterm infants were studied, and their relation to brain injury was assessed. Thirty-five preterm infants were studied on the first and second days of age. Cerebral blood flow (CBF) (mL/hg per min) and cerebral blood volume (CBV) (mL/hg) were measured using near-infrared spectroscopy. The cerebral blood flow velocity (cm/second) (peak systolic, diastolic flow, mean flow) and resistance index (RI) were determined in the internal carotid, anterior cerebral, and striate arteries by color Doppler flow imaging. Serial cerebral ultrasound studies were performed to detect changes in brain parenchymal echogenicity or intraventricular hemorrhage (IVH); the maximum severity of these findings was considered. CBF and cerebral blood flow velocity increased significantly with time, and such changes were independent of mean blood pressure, PO(2), PCO(2), hematocrit, or glycemia. In contrast, CBV and RI remained unchanged. According to the results of sonograms, no differences were found in postnatal CBF and cerebral blood flow velocity changes, regardless of whether patients had or did not have parenchymal lesions or IVH. However, higher CBV values were found on the second day in infants with IVH compared with infants without IVH. Early coupling of CBF and metabolic demands is independent of blood pressure. Improved venous return, instead of vasodilation, could be important in this adaptation.

Effect of the cyclo-oxygenase blocker ibuprofen on cerebral blood volume and cerebral blood flow during normocarbia and hypercarbia in newborn piglets.

Indomethacin modifies baseline cerebral haemodynamics and metabolism, as well as vasomotor adaptive responses. However, the significance of arachidonic acid metabolites in the regulation of cerebral circulation remains unclear. A study was made of the effect of inhibition of the cyclo‐oxygenase pathway on baseline cerebral haemodynamics and CO2‐induced vasodilation using the more specific cyclo‐oxygenase blocker ibuprofen in a neonatal pig model. Two methods were used: radiolabelled microspheres to measure cerebral blood flow and near infrared spectroscopy to calculate absolute changes in cerebral blood volume. The relationship between CO2‐induced changes in these two haemodynamic parameters was evaluated. Fifteen newborn piglets <7 d old received an i.v. infusion of either ibuprofen (30 mg/kg) (IB group, n= 8) or saline (control group, n= 7). Cerebral blood flow and absolute changes in cerebral blood volume were measured while the piglets were breathing room air at baseline and 30 min after infusion of ibuprofen or saline, and 15 min and 30 min after inducing hypercarbia. Global and regional cerebral blood flow (ml/hg/min) and absolute changes in cerebral blood volume (ml/hg) did not vary between baseline and 30 min after infusion of ibuprofen or saline. During hypercarbia, global and regional cerebral blood flow and absolute changes in cerebral blood volume increased significantly in both the ibuprofen and control groups (p < 0.01). The mean percentage increases in blood flow and blood volume at each measurement were almost identical, with approximately 90% of the increase in both parameters occurring after 15 min of hypercarbia, then reaching a plateau. However, we found no agreement between cerebral blood flow changes and absolute changes in cerebral blood volume. We conclude that ibuprofen did not alter either baseline cerebral circulation or physiological CO2‐induced vasodilation in newborn pigs. We speculate that hypercarbic cerebral vasodilation could be caused either by mediators other than the cyclo‐oxygenase metabolites of arachidonic acid or by a direct effect on vessel walls.

Ultrasonographic findings in thalamus and basal ganglia in term asphyxiated infants

Three severely asphyxiated term neonates demonstrated bilateral hyperechogenicity in the thalamus and basal ganglia. During evolution, areas of attenuated echogenicity appeared in these structures at the same time as periventricular cysts were evident in 2 patients with coexistent periventricular leukomalacia. All 3 patients developed ventricular dilatation; in the 2 patients with periventricular leukomalacia, the ventricular border was irregular in the outer (dorsal) margin, and interhemispheric fissures were widened as a manifestation of cerebral atrophy. Furthermore, the thalamic inner (ventral) margins of the lateral ventricles were irregular in all 3 patients. This previously unrecognized finding points to a particular form of cerebral atrophy localized in the gangliothalamic region that contributes to the development of ventriculomegaly. The reported sonographic sequence implies profound damage in the thalamus and basal ganglia in asphyxiated infants which undoubtedly has contributed to the poor outcomes of our patients.

The SafeBoosC II randomized trial : Treatment guided by near-infrared spectroscopy reduces cerebral hypoxia without changing early biomarkers of brain injury

Background:The SafeBoosC phase II multicentre randomized clinical trial investigated the benefits and harms of monitoring cerebral oxygenation by near-infrared spectroscopy (NIRS) combined with an evidence-based treatment guideline vs. no NIRS data and treatment as usual in the control group during the first 72 h of life. The trial demonstrated a significant reduction in the burden of cerebral hypoxia in the experimental group. We now report the blindly assessed and analyzed treatment effects on electroencephalographic (EEG) outcomes (burst rate and spectral edge frequency 95% (SEF95)) and blood biomarkers of brain injury (S100β, brain fatty acid-binding protein, and neuroketal).Methods:One hundred and sixty-six extremely preterm infants were randomized to either experimental or control group. EEG was recorded at 64 h of age and blood samples were collected at 6 and 64 h of age.Results:One hundred and thirty-three EEGs were evaluated. The two groups did not differ regarding burst rates (experimental 7.2 vs. control 7.7 burst/min) or SEF95 (experimental 18.1 vs. control 18.0 Hz). The two groups did not differ regarding blood S100β, brain fatty acid-binding protein, and neuroketal concentrations at 6 and 64 h (n = 123 participants).Conclusion:Treatment guided by NIRS reduced the cerebral burden of hypoxia without affecting EEG or the selected blood biomarkers.

A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial

BackgroundEvery year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2.Methods/DesignSafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the ‘burden of hypoxia and hyperoxia’ expressed in ‘%hours’. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events.DiscussionCerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia.Trial registrationClinicalTrial.gov, NCT01590316