María Carmen Bravo

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.

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.

Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

Background:Inodilators are routinely used in cardiovascular surgery with cardiopulmonary bypass (CPB). Information regarding safety and tolerability of the novel molecule, levosimendan (LEVO), in newborns is anecdotal; no pharmacokinetic data in this population are available.Methods:This was a phase I, randomized, and blinded study. Neonates undergoing surgical repair for congenital heart defects received stepwise dose increases of milrinone (MR; 0.5–1 μg/kg/min, n = 9) or LEVO (0.1–0.2 μg/kg/min, n = 11) as an i.v. continuous infusion, starting before CPB. Infants had continuous, time-locked, physiological, and near-infrared spectroscopy (NIRS) (cerebral and peripheral) recordings during the first 24 h, and at 48 and 96 h postsurgery. Serial biochemistry and pharmacokinetic studies were performed.Results:During the first 24 h postsurgery, patients showed time-related, group-independent increased cerebral tissue oxygenation and decreased diastolic blood pressure; in addition, group-dependent differences in heart rate and peripheral perfusion were found. Early postsurgery, MR-treated infants showed lower pH, higher glycemia, and higher inotrope score. The groups differed in cerebral NIRS-derived variables from 24 to 96 h. Study drug withdrawal at 96 h was more frequent with LEVO. LEVO intermediate metabolites were detected in plasma at day 14 after surgery.Conclusion:LEVO is well tolerated in critically ill neonates. LEVO may have advantages over MR in terms of the dosing regimen.

Acute Effects of Levosimendan on Cerebral and Systemic Perfusion and Oxygenation in Newborns: An Observational Study

Background: Cardiovascular drugs play a major role in the pre- and postoperative care in neonates with congenital heart disease. Management strategies aim to optimise contractility, improve diastolic function, maintain adequate preload, and reduce afterload. Levosimendan, a novel inodilator agent, enhances myocardial contractility and causes peripheral and coronary vasodilation. Objectives: A systematic approach was used to evaluate the acute haemodynamic effects of levosimendan in critically ill infants with low cardiac output syndrome (LCOS). Methods: Infants received a continuous infusion of levosimendan, at a dose increased stepwise (range 0.1–0.2 µg/kg/min), during 48 h. Two near-infrared units were used to assess cerebral (frontal-parietal, c) and peripheral (thigh, p) perfusion and oxygenation. The changes in cerebral blood volume (ΔCBV), cerebral (cΔHbD) and peripheral (pΔHbD) intravascular oxygenation and the cerebral (cTOI) and peripheral (pTOI) tissue oxygenation index that followed levosimendan administration were continuously monitored. Blood pressure, heart rate, and temperature were continuously recorded. In addition, baseline and end-of-study pH, blood gases, lactate and haematocrit were determined. Results: Seven doses of levosimendan were investigated. The mean study time was 13.3 (7–19) h. Levosimendan produced an increase in cΔHbD (p < 0.05) and pΔHbD (NS) and a decrease in heart rate (p < 0.001) and lactate (p < 0.05). Trends showed an increase in mean blood pressure (NS). These results were independent of the effect of time. Mixed linear model analysis identified blood pressure changes and levosimendan as factors independently associated with cΔHbD. Conclusions: Levosimendan improves cerebral and systemic perfusion and oxygenation in critically ill infants suffering from LCOS.

Randomized, Placebo-Controlled Trial of Dobutamine for Low Superior Vena Cava Flow in Infants

OBJECTIVE To gather information for a future confirmatory trial of dobutamine (DB) for circulatory impairment (ie, low superior vena cava [SVC] flow). STUDY DESIGN A total of 127 infants born at < 31 weeks gestational age were serially scanned from birth to 96 hours after birth. The infants were randomly assigned to 2 groups and were treated with DB (stepwise dose increase, 5-10-15-20 μg/kg/min) or placebo if they had an SVC flow < 41 mL/kg/min within the first 24 hours after birth. The primary outcome measures were the achievement and maintenance of an SVC flow ≥ 41 mL/kg/min. Secondary outcome measures were the short-term evolution of clinical and biochemical variables, near-infrared spectroscopy, cranial Doppler ultrasound, and clinical outcomes. RESULTS SVC flow increased throughout the first 96 hours for the entire cohort. All of the randomized infants (n = 28) except 2 achieved and maintained an SVC flow ≥ 41 mL/kg/min after intervention; however, the infants treated with DB (n = 16) showed a higher heart rate and improved base excess compared with those treated with placebo (n = 12). Low SVC flow was associated with low gestational age (P = .02) and poor condition at birth (P = .02). Low SVC flow significantly increased the risk of severe ischemic events (OR, 13; 95% CI, 2.4-69.2; P < .01). CONCLUSION This exploratory trial demonstrates a tendency toward improved short-term clinical and biochemical perfusion variable outcomes in infants with low SVC flow treated with DB. TRIAL REGISTRATION ClinicalTrials.gov (NCT01605279) and the European Clinical Trials Database (EurodraCT 2009-010901-35).

Randomised controlled clinical trial of standard versus echocardiographically guided ibuprofen treatment for patent ductus arteriosus in preterm infants: a pilot study

Abstract Objective: The aim of this study was to explore the efficacy of echocardiographically guided (EchoG) pharmacological closure of the ductus arteriosus in reducing the number of required ibuprofen doses without increasing the reopening rate. Methods: We performed a randomised controlled trial that included 49 infants with a duct ≥1.5 mm who were randomised to either EchoG or standard ibuprofen treatment. Echocardiography was serially performed on days 1, 2, 3, 4, 7, 10 and 17 after inclusion. The primary outcome was the ductus reopening rate, and an intention-to-treat analysis was performed. Results: Twenty-eight (EchoG treatment) and 21(standard treatment) infants were enrolled (27.2 versus 27.3 weeks, p = 0.3). The patients received 2 (1–5.7) and 3 (3–4) doses of ibuprofen in the EchoG and standard treatment groups, respectively (p = 0.04) and experienced a similar ductus reopening rate (11% versus 5%, p = 0.6). Conclusion: Echocardiographically guided ibuprofen treatment of patent ductus arteriosus is feasible and reduces unnecessary doses of medication.

The SafeBoosC phase II clinical trial: an analysis of the interventions related with the oximeter readings

Background The SafeBoosC phase II randomised clinical trial recently demonstrated the benefits of a combination of cerebral regional tissue oxygen saturation (rStO2) by near-infrared spectroscopy (NIRS) and a treatment guideline to reduce the oxygen imbalance in extremely preterm infants. Aims To analyse rStO2-alarm-related clinical decisions and their heterogeneity in the NIRS experimental group (NIRS monitoring visible) and their impact on rStO2 and SpO2. Methods Continuous data from NIRS devices and the alarms (area under the curve of the rStO2 out of range had accumulated 0.2%h during 10 min), clinical data at discrete time points and interventions prompted by the alarms were recorded. Results Sixty-seven infants had data that fulfilled the requirements for this analysis. 1107 alarm episodes were analysed. The alarm triggered a treatment guideline intervention in 25% of the cases; the type of intervention chosen varied among clinical sites. More than 55% of alarms were not followed by an intervention (‘No action’); additionally, in 5% of alarms the rStO2 value apparently was considered non-reliable and the sensor was repositioned. The percentage of unresolved alarms at 30 min after ‘No action’ almost doubled the treatment guideline intervention (p<0.001). Changes in peripheral oxygen saturation (SpO2), were observed only after treatment guideline interventions. Conclusions This study shows that 25% of rStO2 alarms were followed by a clinical intervention determined by the treatment guideline. However, the rStO2 and SpO2 returned to normal ranges after the intervention, supporting the notion that decisions taken by the clinicians were appropriate. Trial registration number ClinicalTrial.gov NCT01590316.

Lethal pulmonary hypertension associated with ibuprofen treatment in a very low birth weight infant.

We read with interest the article by Keir and Wilkinson and support their call for formal training in communication skills. Their article did not mention post-graduate university studies as a pathway for developing skills in communication. We would like to bring to their attention that from 2014 The University of Western Australia is offering a post-graduate masters degree in neonatology. Within this degree students can choose two practicum units. Each of these practicum units include a significant component of formal communication teaching.

Prevention of Low Cardiac Output Syndrome (LCOS) in Neonates Undergoing Open Heart Surgery: a Pilot-Phase Ii Study About the Equivalence of Two Inodilators (INDS)

Background: Neonates are at particular risk of suffering surgery-related LCOS, characterized by impaired myocardial contractility and the peripheral effects of ischemia/reperfusion on endothelium. INDs are strongly recommended although based on suboptimal studies.Aims: Systematic approach to dose-dependent haemodynamic effects of continuous i.v. infusion of Milrinone (MR) and Levosimendan (LEVO), starting before cardiopulmonary bypass.Methods: Intervention (first 48h, blinded): step- increase in INDs dose (D1: intraoperatively; D2: on NICU admission; D3: 2h - 48 h from admission). INDs withdrawal: LEVO at 48 h ; MR beyond 48h as per attending physician criteria. Continuous, time-locked physiological and near-infrared spectroscopy (cerebral-NIRSc/thigh-NIRSp) data recording during the first 24h (T-1), at 48h (T-2) and 96h (T-3) post-surgery. Blood samples for biochemistry and pharmacokinetics (PKs). Serial echocardiography and cranial-Doppler ultrasound studies.Results: 20 infants [postnatal age: MR, 13 (10) days; LEVO, 15 (9) days] were randomized [(MR=9; D1 0.5- D2 0.75- D3 1mg/k/min ); (LEVO=11; D1 0.1- D2 0.15- D3 0.2mg/k/min)]. MR showed lower pH and higher glycemia and more need for other inotropes during the first hours post-surgery. MR and LEVO showed no differences in time-related changes on NIRSc (increased tissue oxygenation) or blood pressure (decreased diastolic pressure) in T-1. However, groups differed in NIRSc-derived variables from T-1 to T-3. INDs withdrawal at T-3 was 37% in MR vs 91% in LEVO. PKs (LEVO and metabolites) were successfully analyzed.Conclusions: LEVO is well tolerated in critically ill neonates. Potential advantages of LEVO related to dose regimen.

Lethal pulmonary hypertension associated with ibuprofen treatment in a very low birth weight infant: Letters to the Editor

We read with interest the article by Keir and Wilkinson and support their call for formal training in communication skills. Their article did not mention post-graduate university studies as a pathway for developing skills in communication. We would like to bring to their attention that from 2014 The University of Western Australia is offering a post-graduate masters degree in neonatology. Within this degree students can choose two practicum units. Each of these practicum units include a significant component of formal communication teaching.