Flora Yuen-Wait Wong

Impaired Autoregulation in Preterm Infants Identified by Using Spatially Resolved Spectroscopy

OBJECTIVE. The absence of cerebral autoregulation in preterm infants has been associated with adverse outcome, but its bedside assessment in the immature brain is problematic. We used spatially resolved spectroscopy to continuously measure cerebral oxygen saturation (expressed as a tissue-oxygenation index) and used the correlation of tissue-oxygenation index with spontaneous fluctuations in mean arterial blood pressure to assess cerebral autoregulation. PATIENTS AND METHODS. The tissue-oxygenation index and mean arterial blood pressure were continuously measured in very premature infants (n = 24) of mean (±SD) gestational age of 26 (±2.3) weeks at a mean postnatal age of 28 (±22) hours. The correlation between mean arterial blood pressure and tissue-oxygenation index in the frequency domain was assessed by using cross-spectral analysis techniques (coherence and transfer-function gain). Values of coherence reflect the strength of linear correlation, whereas transfer-function gain reflects the amplitude of tissue-oxygenation index changes relative to mean arterial blood pressure changes. RESULTS. High coherence (coherence ≥ 0.5) values were found in 9 infants who were of lower gestational age, lower birth weight, and lower mean arterial blood pressure than infants with coherence of <0.5; high-coherence infants also had higher median Clinical Risk Index for Babies scores and a higher rate of neonatal deaths. Coherence of ≥0.5 predicted mortality with a positive predictive value of 67% and negative predictive value of 100%. In multifactorial analysis, coherence alone was the best predictor of mortality and Clinical Risk Index for Babies score alone was the best predictor of coherence. CONCLUSIONS. High coherence between mean arterial blood pressure and tissue-oxygenation index indicates impaired cerebral autoregulation in clinically sick preterm infants and is strongly associated with subsequent mortality. Cross-spectral analysis of mean arterial blood pressure and tissue-oxygenation index has the potential to provide continuous bedside assessment of cerebral autoregulation and to guide therapeutic interventions.

Successful treatment of molybdenum cofactor deficiency type A with cPMP

Molybdenum cofactor deficiency (MoCD) is a rare metabolic disorder characterized by severe and rapidly progressive neurologic damage caused by the functional loss of sulfite oxidase, 1 of 4 molybdenum-dependent enzymes. To date, no effective therapy is available for MoCD, and death in early infancy has been the usual outcome. We report here the case of a patient who was diagnosed with MoCD at the age of 6 days. Substitution therapy with purified cyclic pyranopterin monophosphate (cPMP) was started on day 36 by daily intravenous administration of 80 to 160 μg of cPMP/kg of body weight. Within 1 to 2 weeks, all urinary markers of sulfite oxidase (sulfite, S-sulfocysteine, thiosulfate) and xanthine oxidase deficiency (xanthine, uric acid) returned to almost normal readings and stayed constant (>450 days of treatment). Clinically, the infant became more alert, convulsions and twitching disappeared within the first 2 weeks, and an electroencephalogram showed the return of rhythmic elements and markedly reduced epileptiform discharges. Substitution of cPMP represents the first causative therapy available for patients with MoCD. We demonstrate efficient uptake of cPMP and restoration of molybdenum cofactor–dependent enzyme activities. Further neurodegeneration by toxic metabolites was stopped in the reported patient. We also demonstrated the feasibility to detect MoCD in newborn-screening cards to enable early diagnosis.

Initiation of Resuscitation with High Tidal Volumes Causes Cerebral Hemodynamic Disturbance, Brain Inflammation and Injury in Preterm Lambs

Aims Preterm infants can be inadvertently exposed to high tidal volumes (VT) in the delivery room, causing lung inflammation and injury, but little is known about their effects on the brain. The aim of this study was to compare an initial 15 min of high VT resuscitation strategy to a less injurious resuscitation strategy on cerebral haemodynamics, inflammation and injury. Methods Preterm lambs at 126 d gestation were surgically instrumented prior to receiving resuscitation with either: 1) High VT targeting 10–12 mL/kg for the first 15 min (n = 6) or 2) a protective resuscitation strategy (Prot VT), consisting of prophylactic surfactant, a 20 s sustained inflation and a lower initial VT (7 mL/kg; n = 6). Both groups were subsequently ventilated with a VT 7 mL/kg. Blood gases, arterial pressures and carotid blood flows were recorded. Cerebral blood volume and oxygenation were assessed using near infrared spectroscopy. The brain was collected for biochemical and histologic assessment of inflammation, injury, vascular extravasation, hemorrhage and oxidative injury. Unventilated controls (UVC; n = 6) were used for comparison. Results High VT lambs had worse oxygenation and required greater ventilatory support than Prot VT lambs. High VT resulted in cerebral haemodynamic instability during the initial 15 min, adverse cerebral tissue oxygenation index and cerebral vasoparalysis. While both resuscitation strategies increased lung and brain inflammation and oxidative stress, High VT resuscitation significantly amplified the effect (p = 0.014 and p<0.001). Vascular extravasation was evident in the brains of 60% of High VT lambs, but not in UVC or Prot VT lambs. Conclusion High VT resulted in greater cerebral haemodynamic instability, increased brain inflammation, oxidative stress and vascular extravasation than a Prot VT strategy. The initiation of resuscitation targeting Prot VT may reduce the severity of brain injury in preterm neonates.

Cerebral Oxygenation Is Highly Sensitive to Blood Pressure Variability in Sick Preterm Infants

Objectives The significance of blood pressure variability (BPV) for cerebral oxygenation in extremely preterm infants has not been explored, though BPV may well be associated with end organ injury. We hypothesized that increased BPV in sick preterm infants, by exceeding the cerebral autoregulatory capacity, is associated with cerebral oxygenation changes which closely follow the blood pressure fluctuations. We assessed the autoregulatory capacity in the early postnatal period, by determining the correlation between BPV (mmHg2) and coherence of mean arterial blood pressure (MABP mmHg) and cerebral oxygenation (tissue oxygenation index, TOI %). Study Design Thirty-two preterm infants of mean gestational age of 26.3 (±1.5) weeks were studied on the first 3 postnatal days. Spectral analysis (Coherence and transfer-function gain analysis) was used to calculate coherence of MABP and TOI; BPV was quantified using power spectral density of MABP. Results Overall, maximum Coherence showed a trend for positive correlation with BPV (n = 32, p = 0.06). Infants identified as clinically unstable with documented brain injury (n = 7) had high Coherence values at low BPV. Separate analysis of stable infants (excluding the 7 critically ill infants) revealed a significant association between maximum Coherence and BPV (n = 25, p = 0.006). Conclusions Fluctuation in cerebral oxygenation is closely associated with increased BPV in preterm infants undergoing intensive care. Moreover, in the critically sick preterm infant, blood pressure-dependent variations in cerebral oxygenation occur even with relatively lower BPV, suggesting they have severely impaired autoregulation, and placing them at greater vulnerability to cerebral injury arising from blood pressure fluctuations.

Cerebral Oxygenation Is Depressed During Sleep in Healthy Term Infants When They Sleep Prone

OBJECTIVE: Prone sleeping is a major risk factor for the sudden infant death syndrome and is associated with lower blood pressure and impaired arousability from sleep, both of which may be signs of cerebral hypoxia. However, the impact of sleep position on cerebral oxygenation during infancy remains unknown. We assessed the effects of sleeping position, sleep state, and postnatal age on cerebral oxygenation by measuring tissue oxygenation index (TOI) during the first 6 months of infancy. SUBJECTS AND METHODS: Seventeen healthy term infants (8 girls and 9 boys) were recruited as study participants. Infants were studied at ages 2 to 4 weeks, 2 to 3 months, and 5 to 6 months by use of daytime polysomnography, with additional measurements of blood pressure (Finometer, FMS Finometer Medical Systems, Amsterdam, Netherlands) and tissue oxygenation index (TOI) (NIRO 200 spectrophotometer, Hamamatsu Photonics KK, Tokyo, Japan). RESULTS: In infants who slept in the prone position, TOI was lower in both quiet sleep (QS) and active sleep (AS) at age 2 to 4 weeks and in QS at age 2 to 3 months (P < .05). TOI was lower in AS compared with QS in infants aged 2 to 4 weeks (P < .05). When the infants reached 5 to 6 months of age, TOI was greater in AS (P < .05), as there was a profound decrease in TOI during QS (P < .05) over this period. No relationship was identified between blood pressure and TOI at any age. CONCLUSIONS: In healthy infants cerebral oxygenation is reduced during sleep in the prone position. This reduction may underpin the reduced arousability from sleep exhibited by healthy infants who sleep prone, a finding that provides new insight into potential risks of prone sleeping and mechanisms of sudden infant death syndrome.

Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study

BACKGROUND Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. METHODS In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. FINDINGS Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. INTERPRETATION cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. FUNDING German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

Cerebral vascular regulation and brain injury in preterm infants

Cerebrovascular lesions, mainly germinal matrix hemorrhage and ischemic injury to the periventricular white matter, are major causes of adverse neurodevelopmental outcome in preterm infants. Cerebrovascular lesions and neuromorbidity increase with decreasing gestational age, with the white matter predominantly affected. Developmental immaturity in the cerebral circulation, including ongoing angiogenesis and vasoregulatory immaturity, plays a major role in the severity and pattern of preterm brain injury. Prevention of this injury requires insight into pathogenesis. Cerebral blood flow (CBF) is low in the preterm white matter, which also has blunted vasoreactivity compared with other brain regions. Vasoreactivity in the preterm brain to cerebral perfusion pressure, oxygen, carbon dioxide, and neuronal metabolism is also immature. This could be related to immaturity of both the vasculature and vasoactive signaling. Other pathologies arising from preterm birth and the neonatal intensive care environment itself may contribute to impaired vasoreactivity and ineffective CBF regulation, resulting in the marked variations in cerebral hemodynamics reported both within and between infants depending on their clinical condition. Many gaps exist in our understanding of how neonatal treatment procedures and medications have an impact on cerebral hemodynamics and preterm brain injury. Future research directions for neuroprotective strategies include establishing cotside, real-time clinical reference values for cerebral hemodynamics and vasoregulatory capacity and to demonstrate that these thresholds improve long-term outcomes for the preterm infant. In addition, stimulation of vascular development and repair with growth factor and cell-based therapies also hold promise.

The development of cardiovascular and cerebral vascular control in preterm infants.

Over the past three decades there has been a steady increase in the incidence of preterm birth. The worldwide rate of preterm birth is estimated to be 9.6% of all births, a total of almost 13 million births annually. Preterm birth is associated with a range of adverse cardiovascular and central nervous system outcomes, which may be attributed to altered development of these systems following preterm birth. Preterm birth has a considerable impact on cardiovascular parameters with preterm infants displaying higher heart rates and reduced blood pressure when compared to term born infants at matched ages. Furthermore, premature infants have altered autonomic control of cardiovascular parameters which manifests as abnormalities in heart rate variability and baroreflex mediated control of heart rate and blood pressure. As a result, systemic cardiovascular parameters can be unstable following preterm birth which may place stress on the neonatal brain. The brain of a preterm infant is particularly vulnerable to these fluctuations due to immature cerebral haemodynamics. Preterm infants, particularly those who are very preterm or unwell, display fluctuating pressure-passivity between systemic blood pressure and cerebral blood flow representing a considerably increased risk of cerebral haemorrhage or hypoxia. This is further compounded by immaturity of cerebral blood flow-metabolism coupling, which means increased metabolic demand cannot adequately be met by increased cerebral blood flow. It has been suggested that adverse long-term outcomes following preterm birth may occur as a result of exposure to physiological stress either in-utero or early in infancy.

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients

IntroductionPurpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels.MethodsIn Germany, patients receiving protein C concentrate (Ceprotin®, Baxter AG, Vienna, Austria) are registered. The database was used to locate all pediatric patients with PF treated with PC from 2002 to 2005 for this national, retrospective, multi-centered study.ResultsComplete datasets were acquired in 94 patients, treated in 46 centers with human, non-activated protein C concentrate for purpura fulminans. PC was given for 2 days (median, range 1-24 days) with a median daily dose of 100 IU/kg. Plasma protein C levels increased from a median of 27% to a median of 71% under treatment. 22.3% of patients died, 77.7% survived to discharge. Skin grafts were required in 9.6%, amputations in 5.3%. PF recovered or improved in 79.8%, remained unchanged in 13.8% and deteriorated in 6.4%. Four adverse events occurred in 3 patients, none classified as severe. Non-survivors had lower protein C plasma levels (P < 0.05) and higher prevalence of coagulopathy at admission (P < 0.01). Time between admission and start of PC substitution was longer in patients who died compared to survivors (P = 0.03).ConclusionsThis retrospective dataset shows that, compared to historic controls, only few pediatric patients with PF under PC substitution needed dermatoplasty and/or amputations. Apart from epistaxis, no bleeding was observed. Although the data comes from a retrospective study, the evidence we present suggests that PC had a beneficial impact on the need for dermatoplasty and amputations, pointing to the potential value of carrying out a prospective randomised controlled trial.

Cerebral arterial and venous contributions to tissue oxygenation index measured using spatially resolved spectroscopy in newborn lambs.

Background:Bedside assessments of cerebral oxygenation are sought to monitor cerebral injury in patients undergoing intensive care. Spatially resolved spectroscopy measures tissue oxygenation index (TOI, %) which reflects mixed cerebral arterial and venous oxygenations. We aimed to evaluate arterial and venous components of TOI (cerebral arterial to venous volume ratio [A:V ratio]) in the newborn lamb brain using cerebral arterial and venous blood samples, and to investigate the impact of acute hypoxemia on the A:V ratio and TOI. Method:Nine lambs were ventilated with varied inspired oxygen to generate arterial oxygen saturations between 25% and 100%. Cerebral arterial and venous oxygen saturations analyzed using cooximeter of arterial and superior sagittal sinus blood were used to estimate TOI (TOIcox), assuming cerebral A:V ratio of 25:75. TOIcox was compared with the TOI measured by spatially resolved spectroscopy (TOIsrs). Actual cerebral arterial and venous volume fractions were reestimated using TOIsrs = cerebral arterial volume fraction* cerebral arterial oxygen saturation + cerebral venous volume fraction*cerebral venous oxygen saturation. Results:Median (range) TOIsrs was 48.5% (32.0–64.1%), and TOIcox was 48.4% (13.7–74.4%), and the two were significantly correlated (R2 = 0.77). The mean difference between TOIsrs and TOIcox was 2.4% (limits of agreement ± 18.1%). The TOIsrs − TOIcox difference varied with oxygen saturations, with TOIsrs higher than TOIcox at low saturations, and lower at high saturations. Cerebral arterial volume fraction was 22.9–27.5% in normoxia and markedly increased in hypoxemia. Conclusion:TOI corresponds with cerebral oxygenation. The variable agreement of TOIsrs with TOIcox may reflect changes in cerebral A:V ratio due to arterial oxygenation-related vasoreactivity.