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    Thayyil S, Shankaran S, 2018,

    Current status of therapeutic hypothermia in India: few concerns

    , Indian Pediatrics, Vol: 55, Pages: 347-348, ISSN: 0019-6061
    Oliveira V, Kumutha JR E N, Somanna J, Benkappa N, Bandya P, Chandrasekeran M, Swamy R, Mondkar J, Dewang K, Manerkar S, Sundaram M, Chinathambi K, Bharadwaj S, Bhat V, Madhava V, Nair M, Lally PJ, Montaldo P, Atreja G, Mendoza J, Bassett P, Ramji S, Shankaran S, Thayyil Set al., 2018,

    Hypothermia for encephalopathy in low-income and middle-income countries: feasibility of whole-body cooling using a low-cost servo-controlled device

    , BMJ Paediatrics Open, Vol: 2, ISSN: 2399-9772

    Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC. Design: We recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge. Results: Eighty-two babies were included-61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality. Conclusions: The low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs. Clinical trial registration number: NCT01760629.

    Thayyil S, 2018,

    Cooling Therapy for Neonatal Encephalopathy in Low- and Middle-income Countries.

    , Indian Pediatrics, Vol: 55, Pages: 197-198, ISSN: 0019-6061
    Munroe PB, Addison S, Abrams DJ, Sebire NJ, Cartwright J, Donaldson I, Cohen MM, Mein C, Tinker A, Harmer SC, Aziz Q, Terry A, Struebig M, Warren HR, Vadgama B, Fowler DJ, Peebles D, Taylor AM, Lally PJ, Thayyil Set al., 2018,

    Postmortem genetic testing for cardiac ion channelopathies in stillbirths

    , Circulation: Cardiovascular Genetics, Vol: 11, ISSN: 1942-325X

    BackgroundAlthough stillbirth is a significant health problem worldwide, the definitive cause of death remains elusive in many cases, despite detailed autopsy. In this study of partly explained and unexplained stillbirths, we used next-generation sequencing to examine an extended panel of 35 candidate genes known to be associated with ion channel disorders and sudden cardiac death.Methods and ResultsWe examined tissue from 242 stillbirths (≥22 weeks), including those where no definite cause of death could be confirmed after a full autopsy. We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes, 12 for inherited long- and short-QT syndrome genes (LQT1-LQT12 and SQT1-3), and 23 additional candidate genes derived from genome-wide association studies. We examined the functional significance of a selected variant by patch-clamp electrophysiological recording. No predicted damaging variants were identified in KCNQ1 (LQT1) or KCNH2 (LQT2). A rare putative pathogenic variant was found in KCNJ2(LQT7) in 1 case, and several novel variants of uncertain significance were observed. The KCNJ2 variant (p. R40Q), when assessed by whole-cell patch clamp, affected the function of the channel. There was no significant evidence of enrichment of rare predicted damaging variants within any of the candidate genes.ConclusionsAlthough a causative link is unclear, 1 putative pathogenic and variants of uncertain significance variant resulting in cardiac channelopathies was identified in some cases of otherwise unexplained stillbirth, and these variants may have a role in fetal demise.

    Chandrasekaran M, Swamy R, Ramji S, Shankaran S, Thayyil Set al., 2017,

    Therapeutic hypothermia for neonatal encephalopathy in Indian neonatal units: A survey of national practices

    , Indian Pediatrics, Vol: 54, Pages: 969-970, ISSN: 0019-6061

    This cross-sectional web-based survey suggests that cooling therapy is offered as standard of care for babies with neonatal encephalopathy in 10/25 (40%) of public and 37/68 (51%) of private level 2 or 3 neonatal units in India. 25 (53%) used locally improvised cooling methods, and the cooling practices differed from established protocols in high-income countries.

    Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, Boyle R, Nguyen K-A, Mir I, Pappas A, Montaldo P, Thayyil S, Sánchez PJ, Shankaran S, Laptook AR, Sant'Anna Get al., 2017,

    Prospective research on infants with mild encephalopathy: the PRIME study.

    , Journal of Perinatology, Vol: 38, Pages: 80-85, ISSN: 0743-8346

    OBJECTIVE: To determine short-term outcomes of infants with evidence of hypoxia-ischemia at birth and classified as mild neonatal encephalopathy (NE) at <6 h of age. STUDY DESIGN: Prospective multicenter study. Mild NE was defined as ⩾1 abnormal category in modified Sarnat score. Primary outcome was any abnormality on early amplitude integrated electroencephalogram (aEEG) or seizures, abnormal brain magnetic resonance imaging (MRI) or neurological exam at discharge. RESULTS: A total of 54/63 (86%) of enrolled infants had data on components of the primary outcome, which was abnormal in 28/54 (52%): discontinuous aEEG (n=4), MRI (n=9) and discharge exam (n=22). Abnormal tone and/or incomplete Moro were the most common findings. MRI abnormalities were confined to cerebral cortex but two infants had basal ganglia and/or thalamus involvement. The 18 to 24 months follow-up is ongoing. CONCLUSIONS: A larger than expected proportion of mild NE infants with abnormal outcomes was observed. Future research should evaluate safety and efficacy of neuroprotection for mild NE.Journal of Perinatology advance online publication, 2 November 2017; doi:10.1038/jp.2017.164.

    Lally PJ, Montaldo P, Oliveira V, Swamy RS, Soe A, Shankaran S, Thayyil Set al., 2017,

    Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy

    , Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F383-F387, ISSN: 1359-2998

    We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5-13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage).

    Sánchez-Illana Á, Thayyil S, Montaldo P, Jenkins D, Quintás G, Oger C, Galano J-M, Vigor C, Durand T, Vento M, Kuligowski Jet al., 2017,

    Novel free-radical mediated lipid peroxidation biomarkers in newborn plasma.

    , Analytica Chimica Acta, Vol: 996, Pages: 88-97, ISSN: 0003-2670

    Oxidative stress derived from perinatal asphyxia appears to be closely linked to neonatal brain damage and lipid peroxidation biomarkers have shown to provide predictive power of oxidative stress related pathologies in situations of hypoxia and reoxygenation in the newborn. The objective of this work was to develop and validate of a comprehensive liquid chromatography tandem mass spectrometry approach for the quantitative profiling of 28 isoprostanoids in newborn plasma samples covering a broad range of lipid peroxidation product classes. The method was developed taking into account the specific requirements for its use in neonatology (i.e. limited sample volumes, straightforward sample processing and high analytical throughput). The method was validated following stringent FDA guidelines and was then applied to the analysis of 150 plasma samples collected from newborns. Information obtained from the quantitative analysis of isoprostanoids was critically compared to that provided by a previously developed approach aiming at the semi-quantitative detection of total parameters of fatty acid derived lipid peroxidation biomarkers.

    Oliveira V, Singhvi DP, Montaldo P, Lally PJ, Mendoza J, Manerkar S, Shankaran S, Thayyil Set al., 2017,

    Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK

    , Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F388-F390, ISSN: 1359-2998

    Although major cooling trials (and subsequent guidelines) excluded babies with mild encephalopathy, anecdotal evidence suggests that cooling is often offered to these infants. We report a national survey on current cooling practices for babies with mild encephalopathy in the UK. From 74 neonatal units contacted, 68 were cooling centres. We received 54 responses (79%) and included 48 (five excluded due to incomplete data and one found later not to offer cooling). Of these, 36 centres (75%) offered cooling to infants with mild encephalopathy. Although most of the participating units reported targeting 33-34°C core temperature, seven (19%) considered initiating cooling beyond 6 hours of age and 13 (36%) discontinued cooling prior to 72 hours. Babies were ventilated for cooling in two (6%) units and 13 (36%) sedated all cooled babies. Enteral feeding was withheld in 15 (42%) units and reduced below 25% of requirements in eight (22%) units. MRI and neurodevelopmental outcome evaluation were offered to all cooled babies in 29 (80%) and 27 (75%) units, respectively. Further research is necessary to ensure optimal neuroprotection in mild encephalopathy.

    Thayyil S, Oliveira V, Lally PJ, Swamy R, Bassett P, Chandrasekaran M, Mondkar J, Mangalabharathi S, Benkappa N, Seeralar A, Shahidullah M, Montaldo P, Herberg J, Manerkar S, Kumaraswami K, Kamalaratnam C, Prakash V, Chandramohan R, Bandya P, Mannan MA, Rodrigo R, Nair M, Ramji S, Shankaran S, HELIX Trial groupet al., 2017,

    Hypothermia for encephalopathy in low and middle-income countries (HELIX): study protocol for a randomised controlled trial.

    , Trials, Vol: 18, ISSN: 1745-6215

    BACKGROUND: Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18-22 months after neonatal encephalopathy, in LMICs. METHODS: We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1-2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. DISCUSSION: Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. TRIAL REGISTRATION:, NCT02387385 . Registered on 27 February 2015.

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