Therapeutic Hypothermia for Neonatal Encephalopathy: Global Perspective
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Rapid response to:
Research
Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data
Therapeutic Hypothermia for Neonatal Encephalopathy: Global Perspective
The recent meta-analysis of the cooling trials by David Edwards and
colleagues, provide conclusive evidence for safety and efficacy of
therapeutic
hypothermia in neonatal encephalopathy[1]. The number needed to treat of 8
(95% CI 5 to 17) for intact survival and 14 (95% CI 8 to 47) for mortality
[1] is
indeed remarkable for any medical therapy, particularly for such an
unpredictable and devastating condition. Therapeutic hypothermia is now
widely offered to moderately or severely asphyxiated infants in countries
and
centres which participated in the trials [2]. Anecdotally, other countries
are
also adopting cooling therapy.
Neonatal encephalopathy is a rare event in the high income
countries[3]; in
contrast, at least one million deaths occur every year from this
condition, in
low and middle income countries, and a significant proportion survive with
variable handicap [4]. Unfortunately all the major cooling trials so far
have
been conducted in high income countries[1].
Many tertiary and secondary perinatal centres in low and mid-income
countries have facilities for good neonatal intensive care, both medical
and
surgical. Doctors in these settings may be understandably reluctant to
withhold a treatment simply on the basis that it has not been proven
effective
in these settings. In the recent international symposia on therapeutic
hypothermia conducted in India (www.isnnth.com) and South Africa[5], it
was
apparent that some neonatal units in these settings have already
introduced
cooling into clinical practice.
However, there are several compelling reasons why the safety data on
therapeutic hypothermia from high-income countries cannot be readily
extrapolated to the neonatal units in the low and mid-income countries.
The
association between increased mortality, sepsis, birth asphyxia and
hypothermia is very well established [6]. The incidence (8 to 30 per 1000
live
births) and profile of perinatal and blood stream infections in developing
countries is significantly different to that of developed countries[7].
Clinical
features of sepsis are non-specific in neonates and sepsis can be
associated
with an encephalopathy[8, 9]. Cooling in the presence of infection might
be
deleterious as hypothermia may impair innate immune function and
neutrophil migration and function [10]. In addition there is a higher
incidence
of meconium aspiration syndrome and intrauterine growth restriction in mid
and low resourced settings, which may make hypothermia unsafe and less
effective. A feasibility trial conducted in a large neonatal unit in the
low
resource settings of sub Saharan Africa showed a higher mortality in the
babies who were cooled[11].
Moreover, the initiation of cooling within the therapeutic window is
challenging due to the lack of effective referral and neonatal transport
systems[12]; delayed introduction of cooling may render it ineffective.
Benefits of cooling may be apparent only when the neurological monitoring
and management is optimal, which may not be the case in many neonatal
units in the low and mid-income countries. The lack of an infrastructure
for
careful long-term follow up, makes evaluation of efficacy of any
neuroprotective therapy, challenging.
Furthermore, the brain injury in the population recruited to
published cooling
trials differs from those likely to receive cooling in the low and mid-
income
countries. In the TOBY trial, > 90% of infants required continued
resuscitation
at 10 minutes and were ventilated; more than 60% had severe encephalopathy
[13]. Such babies are likely to be stillborn or die soon after birth in
many
neonatal units in the low and mid-income countries [14]. The pilot cooling
studies performed in the low and mid-income countries, have therefore used
less severe criteria for recruitment [15-18](e.g 5 minute Apgar scores
instead
of 10 minutes) and the majority of recruited babies were not ventilated
and
had less severe encephalopathy [15-17]. This may alter risk benefits of
cooling due to lower control event rates [12].
There is also evidence that the long term neurodevelopmental outcome
for a
given degree of hypoxic ischemic brain injury in the low and mid-income
countries [19, 20] is worse than developed countries. Experimental studies
have shown that the combination of hypoxia ischaemia and infection may be
particularly damaging in the neonatal brain [21]. A mild hypoxic insult
which
would not usually be of sufficient severity to cause damage can do so when
it
occurs in combination with infection/inflammation. In clinical
epidemiological
studies, cerebral palsy is related histological chorioamnionitis and
funisitis
[22]. This “double-hit” by combined infection/inflammation and hypoxia may
be a frequent concomitant in neonatal brain damage in these settings and
may reduce efficacy of cooling. Similarly widespread micronutrient
deficiencies and intra uterine growth retardation (IUGR) may also be
associated with adverse neurodevelopmental outcomes.
Finally, even though several pilot studies have shown that
therapeutic
hypothermia can be provided through a variety of low tech methods like
ice[15], gel packs[17, 23], phase changing material[16], water bottles[11]
or
fans[18], none of these studies have reported improvement in long term
clinical outcomes as yet [24]. Manual cooling methods have a higher
temperature variability[25, 26] and a lower effective cooling time[26],
when
compared to modern servo controlled equipments, even though the exact
relation of cooling efficacy and clinical efficacy is unclear. Many low
tech
cooling methods are more labour intensive[11, 26], cooling efficacy may be
dependent on the environmental temperature (or babies need to be kept
naked in air conditioned rooms)[18] or may cause shivering [17, 18],[26].
There is experimental and clinical data[27],[28] suggesting that shivering
is
associated with worse outcomes.
We acknowledge that there is a variation in populations and
availability of
medical facilities in the low and mid-income countries, but we suggest
that
the conclusions of Edwards et al can only be applied where babies and
facilities are comparable to those centres that took part in the studies
informing the meta-analysis. In settings where this is not the case, we
propose that carefully conducted trials of the safety and efficacy of
cooling
are urgently needed. Until more safety data is available from such trials,
we
urge the clinicians in such settings not offer therapeutic hypothermia in
clinical practice and to adhere to the principle of ‘primum non nocere’.
Therapeutic hypothermia is not intervention that can be used in
community
neonatal care, where most funding and international attention are
currently
focused[29]. Further more, cooling trials in low and mid-income countries
are challenging due to the lack of research infrastructure and ethical
issues
related to the availability of the intervention outside the setting of a
clinical
trial. A joint approach between clinicians in low and mid-income
countries,
experienced trialists and funding bodies are required to ensure that a
safe
and effective therapy in wealthy countries does not become an unsafe and
harmful practice in the mid and low resource settings.
Dr Sudhin Thayyil,
Academic Neonatology,
University College London-Institute for Women’s Health,
London, United Kingdom
Dr Sandeep Kadam,
King Edward Medical College,
Pune, India,
Prof Anand Pandit,
King Edward Medical College,
Pune, India,
Prof Zulfiqar A Bhutta,
Aga Khan University & Hospital,
Karachi, Pakistan
Dr Alan Horn,
Department of Paediatrics, University of Cape Town,
Cape Town, South Africa
Dr Michael C Harrison,
Department of Paediatrics, University of Cape Town,
Cape Town, South Africa
Dr Niranjan Thomas,
Christian Medical College,
Vellore, India
Prof Neil Marlow,
Academic Neonatology,
University College London-Institute for Women’s Health,
London, United Kingdom
Prof Siddarth Ramji,
Maulana Azad Medical College,
New Delhi, India
Dr Nicola J Robertson,
Academic Neonatology,
University College London-Institute for Women’s Health,
London, United Kingdom
REFERENCES
1. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E,
Levene M, et
al. Neurological outcomes at 18 months of age after moderate hypothermia
for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-
analysis
of trial data. Bmj 2010;340:c363.
2. Kapetanakis A, Azzopardi D, Wyatt J, Robertson N. Therapeutic
hypothermia for neonatal encephalopathy: a UK survey of opinion, practice
and neuro-investigation at the end of 2007. Acta Paediatr 2009;98(4):631-
5.
3. Confidential Enquiry into Maternal and Child Health (CEMACH)
Perinatal
Mortality 2007: United Kingdom. CEMACH: London, 2009.
4. Lawn JE, Lee AC, Kinney M, Sibley L, Carlo WA, Paul VK, et al. Two
million
intrapartum-related stillbirths and neonatal deaths: Where, why, and what
can be done? Int J Gynaecol Obstet 2009;107:S5-S19.
6. Kumar V, Shearer JC, Kumar A, Darmstadt GL. Neonatal hypothermia
in low
resource settings: a review. J Perinatol 2009;29(6):401-12.
7. Sundaram V, Kumar P, Dutta S, Mukhopadhyay K, Ray P, Gautam V, et
al.
Blood culture confirmed bacterial sepsis in neonates in a North Indian
tertiary
care center: changes over the last decade. Jpn J Infect Dis 2009;62(1):46-
50.
8. Rennie JM, Hagmann C, Robertson NJ. The baby who was depressed at
birth. Neonatal Cerebral Investigation. Cambridge: Cambridge University
Press, 2008:130-172.
9. Shalak LF, Perlman JM. Infection markers and early signs of
neonatal
encephalopathy in the term infant. Ment Retard Dev Disabil Res Rev
2002;8(1):14-9.
10. Biggar W, Barker C, Bohn D, Kent G. Partial recovery of
neutrophil
functions during prolonged hypothermia in pigs. J Appl Physiol.
1986;60(4):1186-9.
11. Robertson NJ, Nakakeeto M, Hagmann C, Cowan FM, Acolet D, Iwata
O, et
al. Therapeutic hypothermia for birth asphyxia in low-resource settings: a
pilot randomized controlled trial. Lancet 2008;372(9641):801-3.
12. Thayyil S, Bhutta ZA, Ramji S, Costello A, Robertson NJ. Global
Applications Of Therapeutic Hypothermia To Treat Perinatal Asphyxial
Encephalopathy. International Health (Lancet-Global Health) 2010;(in
press).
13. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak
E, et
al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N
Engl
J Med 2009;361(14):1349-58.
14. Carlo WA, M DS, Jehan I, Chomba E, Tshefu A, Garces A, et al.
Newborn-
Care Training and Perinatal Mortality in Developing Countries. N Engl J
Med
2010;362(7):614-623.
15. Thomas N, Kuruvilla, Jana A. Whole Body Cooling in Newborn
Infants with
Perinatal Asphyxia in a Low Resource Setting: A Feasibility Trial.
International
Symposium of Neonatal Neurology and Therapeutic Hypothermia. Cochin,
India, 2009.
16. Thayyil S, Ayer M, Guhan B, Marlow N, Jacobs I, Costello AM, et
al. Whole
Body Cooling Using Phase Changing Material In Neonatal Encephalopathy: A
Pilot Randomised Control Trial. Procedings of the Neonatal Society, London
2009.
17. Bhatt V, Bharadwaraj S. Therapeutic Hypothermia for Term Neonates
with
Perinatal Asphyxia using Cooling Gel Packs. International Symposium of
Neonatal Neurology and Therapeutic Hypothermia. Cochin, India, 2009.
18. Horn A, Thompson C, Woods D, Nel A, Bekker A, Rhoda N, et al.
Induced
hypothermia for infants with hypoxic- ischemic encephalopathy using a
servo-controlled fan: an exploratory pilot study. Pediatrics
2009;123(6):e1090-8.
19. Ellis M, Manandhar N, Shrestha PS, Shrestha L, Manandhar DS,
Costello
AM. Outcome at 1 year of neonatal encephalopathy in Kathmandu, Nepal. Dev
Med Child Neurol 1999;41(10):689-95.
20. Pandit A, Kadam S. One year neurodevelopmental outcome following
neonatal encephalopathy. International Symposium of Neonatal Neurology
and Therapeutic Hypothermia. Cochin, India, 2009.
21. Eklind S, Mallard C, Leverin A, Gilland E, Blomgren K, Mattsby-
Baltzer I, et
al. Bacterial endotoxin sensitizes the immature brain to hypoxic--
ischaemic
injury. Eur J Neurosci 2001;13(6):1101-6.
22. Longo M, Hankins GD. Defining cerebral palsy: pathogenesis,
pathophysiology and new intervention. Minerva Ginecol 2009;61(5):421-9.
23. Horn AR, Harrison MC, Linley LL. Evaluating a Simple Method of
Neuroprotective Hypothermia for Newborn Infants. J Trop Pediatr 2009.
24. Jacobs SE, Stewart M, Inder T, Doyle LW, Morley CJ. ICE: the
Australian
cooling trial for hypoxic-ischemic encephalopathy—in hospital
outcomes. Proceedings of the Hot Topics in Neonatology Conference.
Washington, DC, 2008.
25. Azzopardi D, Strohm B. Temperature control during therapeutic
moderate
whole body hypothermia for neonatal encephalopathy. Arch Dis Child Fetal
Neonatal Ed 2009.
26. Robertson NJ, Kendall G, Thayyil S. Techniques used for
Therapeutic
Hypothermia during Transport and in Hospital for Perinatal Asphyxial
Encephalopathy. Semin Fetal Neonatal Med 2010:(in press).
27. Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C,
et al.
Twenty-four hours of mild hypothermia in unsedated newborn pigs starting
after a severe global hypoxic-ischemic insult is not neuroprotective.
Pediatr
Res 2001;50(3):405-11.
28. Polderman KH. Mechanisms of action, physiological effects, and
complications of hypothermia. Crit Care Med 2009;37(7 Suppl):S186-202.
29. Anderson T. How can child and maternal mortality be cut? Bmj
2010;340:c431.
Competing interests:
Alan Horn is an inventor of a
cooling fan, which is patented by
the University of Cape Town.
Competing interests:
No competing interests
27 February 2010
Sudhin Thayyil
Academic Neonatology
Sandeep Kadam, Anand Pandit, Zulfiqar A. Bhutta. Alan Horn, Michael Harrison, Niranjan Thomas, Neil Marlow, Siddarth Ramji and Nicola J Robertson
UCL Institute for Women's Health, 86-96 Chenies Mews, London WC1E 6HX
Rapid Response:
Therapeutic Hypothermia for Neonatal Encephalopathy: Global Perspective
The recent meta-analysis of the cooling trials by David Edwards and
colleagues, provide conclusive evidence for safety and efficacy of
therapeutic
hypothermia in neonatal encephalopathy[1]. The number needed to treat of 8
(95% CI 5 to 17) for intact survival and 14 (95% CI 8 to 47) for mortality
[1] is
indeed remarkable for any medical therapy, particularly for such an
unpredictable and devastating condition. Therapeutic hypothermia is now
widely offered to moderately or severely asphyxiated infants in countries
and
centres which participated in the trials [2]. Anecdotally, other countries
are
also adopting cooling therapy.
Neonatal encephalopathy is a rare event in the high income
countries[3]; in
contrast, at least one million deaths occur every year from this
condition, in
low and middle income countries, and a significant proportion survive with
variable handicap [4]. Unfortunately all the major cooling trials so far
have
been conducted in high income countries[1].
Many tertiary and secondary perinatal centres in low and mid-income
countries have facilities for good neonatal intensive care, both medical
and
surgical. Doctors in these settings may be understandably reluctant to
withhold a treatment simply on the basis that it has not been proven
effective
in these settings. In the recent international symposia on therapeutic
hypothermia conducted in India (www.isnnth.com) and South Africa[5], it
was
apparent that some neonatal units in these settings have already
introduced
cooling into clinical practice.
However, there are several compelling reasons why the safety data on
therapeutic hypothermia from high-income countries cannot be readily
extrapolated to the neonatal units in the low and mid-income countries.
The
association between increased mortality, sepsis, birth asphyxia and
hypothermia is very well established [6]. The incidence (8 to 30 per 1000
live
births) and profile of perinatal and blood stream infections in developing
countries is significantly different to that of developed countries[7].
Clinical
features of sepsis are non-specific in neonates and sepsis can be
associated
with an encephalopathy[8, 9]. Cooling in the presence of infection might
be
deleterious as hypothermia may impair innate immune function and
neutrophil migration and function [10]. In addition there is a higher
incidence
of meconium aspiration syndrome and intrauterine growth restriction in mid
and low resourced settings, which may make hypothermia unsafe and less
effective. A feasibility trial conducted in a large neonatal unit in the
low
resource settings of sub Saharan Africa showed a higher mortality in the
babies who were cooled[11].
Moreover, the initiation of cooling within the therapeutic window is
challenging due to the lack of effective referral and neonatal transport
systems[12]; delayed introduction of cooling may render it ineffective.
Benefits of cooling may be apparent only when the neurological monitoring
and management is optimal, which may not be the case in many neonatal
units in the low and mid-income countries. The lack of an infrastructure
for
careful long-term follow up, makes evaluation of efficacy of any
neuroprotective therapy, challenging.
Furthermore, the brain injury in the population recruited to
published cooling
trials differs from those likely to receive cooling in the low and mid-
income
countries. In the TOBY trial, > 90% of infants required continued
resuscitation
at 10 minutes and were ventilated; more than 60% had severe encephalopathy
[13]. Such babies are likely to be stillborn or die soon after birth in
many
neonatal units in the low and mid-income countries [14]. The pilot cooling
studies performed in the low and mid-income countries, have therefore used
less severe criteria for recruitment [15-18](e.g 5 minute Apgar scores
instead
of 10 minutes) and the majority of recruited babies were not ventilated
and
had less severe encephalopathy [15-17]. This may alter risk benefits of
cooling due to lower control event rates [12].
There is also evidence that the long term neurodevelopmental outcome
for a
given degree of hypoxic ischemic brain injury in the low and mid-income
countries [19, 20] is worse than developed countries. Experimental studies
have shown that the combination of hypoxia ischaemia and infection may be
particularly damaging in the neonatal brain [21]. A mild hypoxic insult
which
would not usually be of sufficient severity to cause damage can do so when
it
occurs in combination with infection/inflammation. In clinical
epidemiological
studies, cerebral palsy is related histological chorioamnionitis and
funisitis
[22]. This “double-hit” by combined infection/inflammation and hypoxia may
be a frequent concomitant in neonatal brain damage in these settings and
may reduce efficacy of cooling. Similarly widespread micronutrient
deficiencies and intra uterine growth retardation (IUGR) may also be
associated with adverse neurodevelopmental outcomes.
Finally, even though several pilot studies have shown that
therapeutic
hypothermia can be provided through a variety of low tech methods like
ice[15], gel packs[17, 23], phase changing material[16], water bottles[11]
or
fans[18], none of these studies have reported improvement in long term
clinical outcomes as yet [24]. Manual cooling methods have a higher
temperature variability[25, 26] and a lower effective cooling time[26],
when
compared to modern servo controlled equipments, even though the exact
relation of cooling efficacy and clinical efficacy is unclear. Many low
tech
cooling methods are more labour intensive[11, 26], cooling efficacy may be
dependent on the environmental temperature (or babies need to be kept
naked in air conditioned rooms)[18] or may cause shivering [17, 18],[26].
There is experimental and clinical data[27],[28] suggesting that shivering
is
associated with worse outcomes.
We acknowledge that there is a variation in populations and
availability of
medical facilities in the low and mid-income countries, but we suggest
that
the conclusions of Edwards et al can only be applied where babies and
facilities are comparable to those centres that took part in the studies
informing the meta-analysis. In settings where this is not the case, we
propose that carefully conducted trials of the safety and efficacy of
cooling
are urgently needed. Until more safety data is available from such trials,
we
urge the clinicians in such settings not offer therapeutic hypothermia in
clinical practice and to adhere to the principle of ‘primum non nocere’.
Therapeutic hypothermia is not intervention that can be used in
community
neonatal care, where most funding and international attention are
currently
focused[29]. Further more, cooling trials in low and mid-income countries
are challenging due to the lack of research infrastructure and ethical
issues
related to the availability of the intervention outside the setting of a
clinical
trial. A joint approach between clinicians in low and mid-income
countries,
experienced trialists and funding bodies are required to ensure that a
safe
and effective therapy in wealthy countries does not become an unsafe and
harmful practice in the mid and low resource settings.
Dr Sudhin Thayyil,
Academic Neonatology,
University College London-Institute for Women’s Health,
London, United Kingdom
Dr Sandeep Kadam,
King Edward Medical College,
Pune, India,
Prof Anand Pandit,
King Edward Medical College,
Pune, India,
Prof Zulfiqar A Bhutta,
Aga Khan University & Hospital,
Karachi, Pakistan
Dr Alan Horn,
Department of Paediatrics, University of Cape Town,
Cape Town, South Africa
Dr Michael C Harrison,
Department of Paediatrics, University of Cape Town,
Cape Town, South Africa
Dr Niranjan Thomas,
Christian Medical College,
Vellore, India
Prof Neil Marlow,
Academic Neonatology,
University College London-Institute for Women’s Health,
London, United Kingdom
Prof Siddarth Ramji,
Maulana Azad Medical College,
New Delhi, India
Dr Nicola J Robertson,
Academic Neonatology,
University College London-Institute for Women’s Health,
London, United Kingdom
REFERENCES
1. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E,
Levene M, et
al. Neurological outcomes at 18 months of age after moderate hypothermia
for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-
analysis
of trial data. Bmj 2010;340:c363.
2. Kapetanakis A, Azzopardi D, Wyatt J, Robertson N. Therapeutic
hypothermia for neonatal encephalopathy: a UK survey of opinion, practice
and neuro-investigation at the end of 2007. Acta Paediatr 2009;98(4):631-
5.
3. Confidential Enquiry into Maternal and Child Health (CEMACH)
Perinatal
Mortality 2007: United Kingdom. CEMACH: London, 2009.
4. Lawn JE, Lee AC, Kinney M, Sibley L, Carlo WA, Paul VK, et al. Two
million
intrapartum-related stillbirths and neonatal deaths: Where, why, and what
can be done? Int J Gynaecol Obstet 2009;107:S5-S19.
5. Neonatal Brain Cooling Workshop. (http://www.uct-
cmc.co.za/Conferences/conf-main.asp?Conf_ID=108&Page=Home) 2009;
Cape Town, South Africa.
6. Kumar V, Shearer JC, Kumar A, Darmstadt GL. Neonatal hypothermia
in low
resource settings: a review. J Perinatol 2009;29(6):401-12.
7. Sundaram V, Kumar P, Dutta S, Mukhopadhyay K, Ray P, Gautam V, et
al.
Blood culture confirmed bacterial sepsis in neonates in a North Indian
tertiary
care center: changes over the last decade. Jpn J Infect Dis 2009;62(1):46-
50.
8. Rennie JM, Hagmann C, Robertson NJ. The baby who was depressed at
birth. Neonatal Cerebral Investigation. Cambridge: Cambridge University
Press, 2008:130-172.
9. Shalak LF, Perlman JM. Infection markers and early signs of
neonatal
encephalopathy in the term infant. Ment Retard Dev Disabil Res Rev
2002;8(1):14-9.
10. Biggar W, Barker C, Bohn D, Kent G. Partial recovery of
neutrophil
functions during prolonged hypothermia in pigs. J Appl Physiol.
1986;60(4):1186-9.
11. Robertson NJ, Nakakeeto M, Hagmann C, Cowan FM, Acolet D, Iwata
O, et
al. Therapeutic hypothermia for birth asphyxia in low-resource settings: a
pilot randomized controlled trial. Lancet 2008;372(9641):801-3.
12. Thayyil S, Bhutta ZA, Ramji S, Costello A, Robertson NJ. Global
Applications Of Therapeutic Hypothermia To Treat Perinatal Asphyxial
Encephalopathy. International Health (Lancet-Global Health) 2010;(in
press).
13. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak
E, et
al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N
Engl
J Med 2009;361(14):1349-58.
14. Carlo WA, M DS, Jehan I, Chomba E, Tshefu A, Garces A, et al.
Newborn-
Care Training and Perinatal Mortality in Developing Countries. N Engl J
Med
2010;362(7):614-623.
15. Thomas N, Kuruvilla, Jana A. Whole Body Cooling in Newborn
Infants with
Perinatal Asphyxia in a Low Resource Setting: A Feasibility Trial.
International
Symposium of Neonatal Neurology and Therapeutic Hypothermia. Cochin,
India, 2009.
16. Thayyil S, Ayer M, Guhan B, Marlow N, Jacobs I, Costello AM, et
al. Whole
Body Cooling Using Phase Changing Material In Neonatal Encephalopathy: A
Pilot Randomised Control Trial. Procedings of the Neonatal Society, London
2009.
17. Bhatt V, Bharadwaraj S. Therapeutic Hypothermia for Term Neonates
with
Perinatal Asphyxia using Cooling Gel Packs. International Symposium of
Neonatal Neurology and Therapeutic Hypothermia. Cochin, India, 2009.
18. Horn A, Thompson C, Woods D, Nel A, Bekker A, Rhoda N, et al.
Induced
hypothermia for infants with hypoxic- ischemic encephalopathy using a
servo-controlled fan: an exploratory pilot study. Pediatrics
2009;123(6):e1090-8.
19. Ellis M, Manandhar N, Shrestha PS, Shrestha L, Manandhar DS,
Costello
AM. Outcome at 1 year of neonatal encephalopathy in Kathmandu, Nepal. Dev
Med Child Neurol 1999;41(10):689-95.
20. Pandit A, Kadam S. One year neurodevelopmental outcome following
neonatal encephalopathy. International Symposium of Neonatal Neurology
and Therapeutic Hypothermia. Cochin, India, 2009.
21. Eklind S, Mallard C, Leverin A, Gilland E, Blomgren K, Mattsby-
Baltzer I, et
al. Bacterial endotoxin sensitizes the immature brain to hypoxic--
ischaemic
injury. Eur J Neurosci 2001;13(6):1101-6.
22. Longo M, Hankins GD. Defining cerebral palsy: pathogenesis,
pathophysiology and new intervention. Minerva Ginecol 2009;61(5):421-9.
23. Horn AR, Harrison MC, Linley LL. Evaluating a Simple Method of
Neuroprotective Hypothermia for Newborn Infants. J Trop Pediatr 2009.
24. Jacobs SE, Stewart M, Inder T, Doyle LW, Morley CJ. ICE: the
Australian
cooling trial for hypoxic-ischemic encephalopathy—in hospital
outcomes. Proceedings of the Hot Topics in Neonatology Conference.
Washington, DC, 2008.
25. Azzopardi D, Strohm B. Temperature control during therapeutic
moderate
whole body hypothermia for neonatal encephalopathy. Arch Dis Child Fetal
Neonatal Ed 2009.
26. Robertson NJ, Kendall G, Thayyil S. Techniques used for
Therapeutic
Hypothermia during Transport and in Hospital for Perinatal Asphyxial
Encephalopathy. Semin Fetal Neonatal Med 2010:(in press).
27. Thoresen M, Satas S, Loberg EM, Whitelaw A, Acolet D, Lindgren C,
et al.
Twenty-four hours of mild hypothermia in unsedated newborn pigs starting
after a severe global hypoxic-ischemic insult is not neuroprotective.
Pediatr
Res 2001;50(3):405-11.
28. Polderman KH. Mechanisms of action, physiological effects, and
complications of hypothermia. Crit Care Med 2009;37(7 Suppl):S186-202.
29. Anderson T. How can child and maternal mortality be cut? Bmj
2010;340:c431.
Competing interests:
Alan Horn is an inventor of a
cooling fan, which is patented by
the University of Cape Town.
Competing interests: No competing interests