penatalaksaaan asfixia terbaru

7/24/2019 penatalaksaaan asfixia terbaru

1/6

J Pediatr (Rio J). 2015;91(6 Suppl 1):S78---S83

www.jped.com.br

REVIEW ARTICLE

Hypothermia therapy for newborns with hypoxic

ischemic encephalopathy

Rita C. Silveiraa,b, Renato S. Procianoya,b,

a Department ofPediatrics, Universidade Federal do Rio Grande do Sul (UFRGS), PortoAlegre, RS, Brazilb NeonatologyService, Hospital de Clnicas de PortoAlegre, PortoAlegre, RS, Brazil

Received 31 July 2015; accepted 3 August 2015

Available online 4 September 2015

KEYWORDSHypothermia;Neonates;Perinatal asphyxia;Hypoxic-ischemicencephalopathy;Outcomes

Abstract

Objective: Therapeutic hypothermia reduces cerebral injury and improves the neurological

outcome secondary to hypoxic ischemic encephalopathy in newborns. It has been indicated

for asphyxiated full-term or near-term newborn infants with clinical signs ofhypoxic-ischemic

encephalopathy (HIE).

Sources: A search was performed for articles on therapeutic hypothermia in newborns with

perinatal asphyxia in PubMed; the authors chose those considered most significant.

Summaryofthefindings: There are two therapeutic hypothermia methods: selective head

cooling and total body cooling. The target body temperature is 34.5 C for selective head cool-ing and 33.5 C for total body cooling. Temperatures lower than 32 C are less neuroprotective,

and temperatures below 30 C are very dangerous, with severe complications. Therapeutic

hypothermia must start within the first 6 h after birth, as studies have shown that this rep-

resents the therapeutic window for the hypoxic-ischemic event. Therapy must be maintained

for 72 h, with very strict control of the newborns body temperature. It has been shown that

therapeutic hypothermia is effective in reducing neurologic impairment, especially in full-term

or near-term newborns with moderate hypoxic-ischemic encephalopathy.

Conclusion: Therapeutic hypothermia is a neuroprotective technique indicated for newborn

infants with perinatal asphyxia and hypoxic-ischemic encephalopathy.

2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Please cite this article as: Silveira RC, Procianoy RS. Hypothermia therapy for newborns with hypoxic ischemic encephalopathy. J Pediatr(Rio J). 2015;S91:78---83. Corresponding author.E-mail: [email protected] (R.S. Procianoy).

http://dx.doi.org/10.1016/j.jped.2015.07.0040021-7557/ 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.
http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.jped.2015.07.004http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.jped.2015.07.004http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.jped.2015.07.004http://www.jped.com.br/mailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.jped.2015.07.004http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.jped.2015.07.004mailto:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.jped.2015.07.004&domain=pdfhttp://www.jped.com.br/http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.jped.2015.07.004


2/6

Hypothermia for neonates S79

PALAVRAS-CHAVEHipotermiateraputica;Recm-nascidos;Asfixia perinatal;Encefalopatiahipxico isqumica;

Desfechos

Hipotermia teraputica para recm-nascidos com encefalopatia hipxico isqumica

Resumo

Objetivo: A hipotermia teraputica reduz a leso cerebral e melhora o desfecho neurolgico

de recm-nascidos aps insulto hipxico isquemico. Indicada para recm-nascidos a termo ou

prximo do termo com evidncia de asfixia perinatal e Encefalopatia Hipxico Isquemica (EHI).

Fontes dos dados: Foi feita uma procura no PubMed por publicaces sobre hipotermia terapu-

tica em recm-nascidos com asfixia perinatal e selecionadas aquelas julgadas mais relevantes

pelos autores.Sntese dos dados: H duas tcnicas de resfriamento corprea: hipotermia seletiva da cabeca

e hipotermia corprea total. A temperatura de resfriamento deve ser 34,5 C para seletiva de

cabeca e 33,5 C para corprea total; temperaturas inferiores a 32 C so menos neuroprote-

toras e abaixo de 30 C h efeitos adversos sistmicos graves. Indica-se o incio da hipotermia

teraputica at 6 horas aps o nascimento, pois estudos evidenciaram que esta a janela ter-

aputica da agresso hipxico e isqumica. A hipotermia deve ser mantida por 72 horas com

rigorosa monitorizaco da temperatura corporal do recm-nascido. A hipotermia tem sido efe-

tiva em reduzir seqelas neurolgicas, principalmente em recm-nascidos de termo ou prximo

do termo com encefalopatia hipxico isqumica moderada e em melhorar o prognstico em

longo prazo dos recm-nascidos com EHI.

Concluso: A hipotermia teraputica uma tcnica neuroprotetora indicada para recm-

nascidos com asfixia perinatal.

2015 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Todos os direitos

reservados.

Introduction

More than a decade ago, experimental evidence, and sub-sequently, good-quality clinical trials initially appeared,suggesting that therapeutic hypothermia reduces brain dam-age and improves neurological outcome after neonatalhypoxic-ischemic injury.1---4 The best result in terms oftherapeutic hypothermia prognosis seems to be in mildto moderate injuries, while the real benefit has beenquestioned for infants with severe encephalopathy. A mul-ticenter study by the NICHD (National Institute of ChildHealth and Human Development) showed that cases persist-ing with severe hypoxic-ischemic encephalopathy (HIE) signsand altered neurological assessment at the discharge fromthe neonatology service after 72 h oftherapeutic hypother-mia had higher mortality or morbidity in the follow-up at 18months of life.5

The extent of cerebral injury following a hypoxic-ischemic insult basically depends on the balance betweenthe causative mechanisms of irreversible injury, such neu-

ronal necrosis or persistent inflammation, and endogenousprotection (acute phase response, recovery, and neu-ronal repair). The neuroprotective strategy of therapeutichypothermia involves the modulation of some irreversibleinjury mechanisms, such as inflammatory cascade inhibition,reduced production ofreactive oxygen species, reduction inthe metabolic rate with reduced oxygen consumption andcarbon dioxide production, and an endogenous neuropro-tective effect.6---9

The objective of this review is to understand the mech-anism of action of therapeutic hypothermia, searching forevidence in the literature to establish the type ofnewbornthat is a good candidate for this type oftherapy, describing

the protocol, possible complications, and supportive carefor the management ofnewborns submitted to therapeutichypothermia.

Mechanism ofaction oftherapeutichypothermia

Hypothermia results in a reduction of cerebral metabolismby approximately 5% for each 1 C decrease in body temper-ature, which delays the onset ofanoxic cell depolarization.The reduction in excitatory amino acids such as aspartateand glutamate, during the ischemic phase of therapeutichypothermia, is due to the fact that they promote depo-larization delay and intracellular calcium influx reduction.These effects have been demonstrated in different man-ners in experimental models of ischemia and reperfusion inrodents after cardiac arrest in young adult dogs, or duringand immediately after hypoxic-ischemic injury in newbornpigs.8

Hypoxia-ischemia-reperfusion injury in the central ner-

vous system activates a pro-inflammatory cascade ofeventscharacterized by leukocyte influx, including polymorphonu-clear cells and monocytes, and microglial activation. Manyofthese inflammatory reactions are mediated by cytokines,especially neuronal apoptosis modulation. The cytokineswith best-known actions in the CNS are: TNF-, IL-1, andIL-6. Part of the neuroprotective effect of hypothermia isdue to proinflammatory pathway blockade.6,8

Cytokines are mediators of the systemic inflammatoryresponse activation mechanism. In a situation of ischemia,enhanced endothelial activation occurs by monocyte acti-vation, stimulating production of TNF-, which promotesgreater endothelial activation. The production of IL-6,


3/6

S80 Silveira RC, Procianoy RS

IL-1, IL-8, and PAF (platelet activating factor) occursthrough several interactions.10 Furthermore, through theactions ofsoluble receptors, IL-6, IL-1, and TNF- increasethe expression ofadhesion molecules, especially intercellu-lar adhesion molecule-1 (ICAM-1) in endothelial cells and inastrocytes, facilitating leukocyte infiltration and increasingleukocyte activation, with consequent promotion of sys-temic inflammatory response as the final result. Cytokines

induce nitric oxide synthetase enzyme, which, together withTNF- and IL-1, promotes neurotoxic effects.8,9 Caspaseactivation may induce local inflammatory response involvingenergy consumption and increase in the number of apop-totic neurons, with the possibility of injury reversal, whichis neuroprotective.6

In experimental models, prolonged hypothermia mecha-nism (72 h) induced the reduction of necrosis and neuronalapoptosis.7,11 Cytochrome C suppression by mitochondriawas demonstrated, as well as activation ofcaspase 3 in thecortex, thalamus, and hippocampus of rats with HIE thatreceived hypothermia therapy for 72 h.11

Therapeutic window

Hypoxic-ischemic insult involves an ongoing injury process,where the severity of HIE depends on the duration andextent of this process. The central role of therapeutichypothermia in neuroprotection involves the interruption orreduction of this process; essentially divided into acute orprimary phase, in which some neural cells die and othersrecover, at least partially; the latent phase, with partiallyrecovered oxidative metabolism, even with suppressed elec-troencephalographic activity9; and the secondary phase,which occurs after moderate to severe injury, initiating

hours later, on average within 6 up to 15 h, clinicallymanifested by the presence of seizures, cytotoxic edema,accumulation of excitatory amino acids, and failure ofmitochondrial oxidative activity, which is the main factorassociated with neuronal death.

It is important to act before the secondary phase, dur-ing the therapeutic window ofopportunity when apoptoticneurons are able to recover. The degree of energy failuredetermines the type ofneuronal damage (death) during theearly and late stages, and the degree of trophic supportinfluences angiogenesis and neurogenesis during the recov-ery phase ofHIE.

Although exactly when the brain injury becomesirreversible has yet to be precisely established, there are

consistent data indicating that the latency phase, alsoknown as the early phase ofrecovery from transient restora-tion of cerebral oxidative metabolism, before the start ofthe secondary phase ofenergy failure, represents the bestwindow for therapeutic intervention.8 Because this is anongoing process, these phases are close, and therefore thetransition to the moment ofirreversible cell death is almostimperceptible.11,12

Since the first series of clinical cases of perinatalasphyxia, therapeutic hypothermia initiation has been indi-cated within 6 h after birth, due to all the experimentalevidence demonstrating that this represents the therapeuticwindow to inhibit or reduce the hypoxic-ischemic injury.11

Meet both criteria:

1. Evidence of perinatal asphyxiaumbilical cord blood

Umbilical cord blood gas analysis or in the first hour of

life with pH < 7.0 or EB < -16Or history of perinatal acute event (placental abruption,

cord prolapse)

Or Apgar score 5 in the 10th minute of lifeOr need for ventilation beyond the tenth minute of life

and

2. Evidence of moderate to severe encephalopathy before 6 hours of life:

Seizures, level of consciousness, spontaneous activity, posture, tone,reflexes, and autonomic system.

Figure 1 Therapeutic hypothermia indication.

Selection ofnewborn candidates fortherapeutic hypothermia

In the 2010 Consensus, the International Consensus on Car-diopulmonary Resuscitation (ILCOR) included the indicationof therapeutic hypothermia for every newborn at term ornear term who had developed moderate to severe HIE, usinga specific protocol and follow-up coordinated by the regionalreference care system.13

Overall, the indication of therapeutic hypothermia fornewborns follows the recommendations found on the site ofthe Brazilian Society ofPediatrics and ILCOR13,14: newbornswith gestational age > 35 weeks, birth weight > 1800 g, whohave fewer than 6 h oflife, and meet the following criteria.14

Evidence ofperinatal asphyxia: umbilical cord blood gasanalysis or in the first hour of life with pH


4/6


approximately half of the newborns with HIE submitted totherapeutic hypothermia.17---19

Amplitude-integrated electroencephalogram (aEEG) hasbeen used in a few studies to decide whether a new-born with encephalopathy is a candidate for therapeutichypothermia.20,21 In neonates with mild HIE, a study witha small sample size showed to be more effective in iden-tifying which patients with encephalopathy would develop

severe neurological diseases.22The use of aEEG is relevant considering that the time

to decide whether a newborn is a candidate for therapeutichypothermia is limited, and any mistakes regarding the startofsuch a promising treatment should be avoided; neverthe-less, the aEEG is not routinely used to select candidates forthis type oftherapy.13---15,23

Results and prognosis after therapeutichypothermia

Hypothermia has been effective in reducing neurologicalsequelae, particularly in newborns with moderate HIE, andin improving the long-term prognosis ofnewborns with HIE.Meta-analysis studies have shown that the use oftherapeu-tic hypothermia decreases mortality and improves prognosisregarding the neurodevelopment of infants with HIE.1,4,5

There is evidence from three large randomized trialsand two small clinical trials demonstrating that inducedhypothermia (33.5---34.5 C), when started within the 6-hwindow after the birth of full-term asphyxiated newborns,is beneficial in reducing mortality and neurodevelopmentaldelay assessed by the Bayley scale in the follow-up at 18months of life.20,21,24---26 The results are better if there arewell-organized protocols for hypothermia indication and

induction, as well as adequate rewarming.1,24

In the context of the newborn candidate for thera-peutic hypothermia, it has been observed that maternalhyperthermia is associated with high incidence of perina-tal respiratory depression, neonatal seizures, cerebral palsy,and higher neonatal mortality, confirming the deleteriouseffect of hyperthermia. It is possible that in situations ofmaternal chorioamnionitis and fetal inflammatory responsesyndrome in utero, the result of therapeutic hypother-mia is limited. In the presence of infection/inflammationin a randomized clinical trial of therapeutic hypothermiaafter encephalopathy secondary to bacterial meningitis, thechoice of therapeutic hypothermia was ineffective.27 MRIdata obtained after therapeutic hypothermia in a small

prospective study ofnewborns whose mothers had histolog-ical chorioamnionitis demonstrated that hypothermia wasless effective in this infectious condition.28

Hyperthermia after neonatal HIE is associated withhigher mortality and adverse neurological outcome at 18---22months of age and at 6---7 years of age, with lower intel-ligence scores and an up to 3.5-fold higher incidence ofmoderate to severe cerebral palsy in newborn infants withhigher temperatures in the first days after birth.29,30 There-fore, high temperature after the hypoxic ischemic insultrepresents an additional risk factor for adverse outcomesand, avoiding hyperthermia is as important as therapeutichypothermia in these cases.

The results oftherapeutic hypothermia are strongly influ-enced by the severity of HIE. Several experimental andclinical studies have concluded that the neuroprotectiveaction oftherapeutic hypothermia is less effective in severeHIE, partly because the latency period is even shorter, withhigher energy failure and accelerated neuronal necrosis ofcortical gray matter, basal ganglia, thalamus, and seriousdamage to the white matter, associated with cerebral palsy

at varying levels.1 A meta-analysis showed that therapeutichypothermia was significantly protective for the outcomedeath and disability in cases of HIE, with better results inmoderate than in severe cases. The challenge is to able toindividualize the decision to initiate therapeutic hypother-mia in severe cases, especially since the establishment ofencephalopathy severity is difficult, imprecise, and subjec-tive when based only on clinical evaluation.4

All patients undergoing hypothermia therapy shouldbe followed longitudinally to establish the long-termoutcome.5,13 Moreover, for the hypothermia to be effec-tive, a high level of neonatal intensive care support isrequired; not all centers are capable of performing ther-apeutic hypothermia.

Protocol: establishing safety and efficacy

Randomized clinical trials have employed two body cool-ing techniques in order to inhibit, reduce, and improvebrain lesion evolution and neurological sequelae resultingfrom HIE: selective head hypothermia20 with temperaturesreduced to 34.5 C, and total body hypothermia with tem-perature reduced to 33.5 C4,24; both techniques recommendthe maintenance of hypothermia for 72 h. According toILCOR, both techniques are appropriate, and the rewarming

phase must be slow and gradual, conducted over a 4-h periodwith an increase of 0.5 C per hour until the temperaturereaches 36.5 C; this process aims to prevent complicationscaused by rapid rewarming.1,13,15

Selective head cooling is performed with a helmet, andtotal body cooling with a thermal mattress in which theinfant is placed, with a servo control apparatus to regu-late the mattress temperature higher or lower according tothe patients temperature.21,24 The use of ice packs is notthe best method because the monitoring ofthermal controlis precarious, although a randomized study employed thistechnique in moderate HIE, recommending it as an alter-native if started within 6 h after the event and until thenewborn is able to be transferred to a referral center to

undergo therapeutic hypothermia.31

The temperature must remain above 33 C during theentire hypothermia period; temperatures below 32 C areless neuroprotective, and very severe systemic adverseeffects and increased mortality have been observed withtemperatures below 30 C.1,13,15 To ensure the effective-ness and safety of total body cooling, the esophageal orrectal temperature should be maintained at 33.5 C, andfor selective head cooling, at 34.5 C; the temperaturemust be continuously monitored in both situations.13 Arecent multicenter study demonstrated no benefit and sug-gested deleterious effects with a total body cooling protocolover a longer period of time (120 h) or lower esophageal


5/6

S82 Silveira RC, Procianoy RS

temperature (32 C) or both; the study was interruptedbefore the estimated sample size was achieved.32

All protocols ofstudies on neuroprotection after HIE withtherapeutic hypothermia had similar inclusion criteria (ges-tational age > 35---36 weeks, significant acidosis or severedepression at birth, moderate to severe encephalopathywith or without aEEG). In the majority, the exclusion criteriawere age older than 6 h oflife, chromosomal abnormalities,

and major congenital malformations or severe intrauterinegrowth restriction.3,20,21,24---26

Although a recent study consecutively compared 83 casesof therapeutic hypothermia, including 34 newborns sub-mitted to selective head cooling and 49 to total bodycooling, the findings ofbrain damage based upon MRI weremore severe and frequent in the selective head coolinggroup, suggesting greater neuroprotection in newborns whowere submitted to the total body cooling technique33; how-ever, other studies suggest the same benefit with bothtechniques.1

In the absence of adequate conditions, ventilation, andhemodynamic support, as well as constant temperaturemonitoring at every stage, cooling, and rewarming, thera-peutic hypothermia for neonatal HIE has shown unfavorableresults and is not recommended, as it increases mortalityin these conditions.34 Procedural safety requires months ofmultidisciplinary team training, with emphasis on under-standing the multisystemic involvement related to perinatalasphyxia, associated with potential systemic complicationsofthis treatment modality.35

The possible adverse effects of hypothermia therapyshould be carefully monitored, such as hypotension andprolonged QT interval, thrombocytopenia, and clotting dis-orders in general (altered prothrombin time --- PT andactivated partial thromboplastin time --- aPTT), skin burnsand scleredema, and metabolic and electrolytic disorders.35

It is important to recognize that some events are notdirectly related to therapeutic hypothermia but ratherto multiorgan dysfunction, which characterizes hypoxicischemic syndrome and overlaps with the adverse effectsof neonatal therapeutic hypothermia. One example is per-sistent pulmonary hypertension (PPH), directly associatedwith perinatal asphyxia and, conversely, hyperthermia cancause hemoconcentration, hyperviscosity, and pulmonaryvasoconstriction.10,35 A meta-analysis of four randomizedclinical trials showed no hypoglycemia in the group submit-ted to therapeutic hypothermia.1

These adverse events are more associated with lowertemperatures than those recommended in the protocols,thus the importance ofcareful monitoring. Adequate knowl-

edge of how hypothermia affects all organ systems ofasphyxiated newborns that are already severely ill is crit-ical to prevent and avoid the complications ofexaggeratedcooling.35

The pharmacokinetics ofsome drugs is altered by cooling.In an observational study, newborns with HIE treated withhypothermia and receiving normal morphine infusions hadsignificantly higher serum concentrations ofthe latter whencompared to the group with normal temperature. There-fore, the rate ofmorphine infusion must be lower than thatusually recommended during therapeutic hypothermia.36

All the evidence suggests that the neuroprotectiveresponse is time-dependent (therapeutic window) and that

effectiveness depends on initiating the protocol in up to 6 h.In practice, it is necessary to consider at this time, that thecrib should be already off and the thermometer should beinserted (if it is transesophageal, a chest X-ray is obtainedto assess whether it is well placed; i.e., middle-third ofthe esophagus). By continually assessing body temperature,even before using the total body hypothermia mattress, thephysicians ensure the safety and care quality ofthe protocol.

After 72 h, the rewarming phase should be carefully moni-tored, as fluctuations in cerebral blood flow are associatedwith brain hemorrhage after fast rewarming. Near-infraredspectroscopy (NIRS) is an effective tool to monitor brainperfusion changes in newborns with HIE submitted to ther-apeutic hypothermia.37

Conclusion

Therapeutic hypothermia significantly reduces morbidityand mortality for many asphyxiated newborns. However,some still die or survive with sequelae at varying levels inoutpatient follow-up, demonstrating the need for associa-

tion with other neuroprotective strategies. The safety andeffectiveness of protocols performed in reference centersmust be continuously assessed. In this review, evidence isprovided that supports the benefit oftherapeutic hypother-mia in infants with moderate encephalopathy. A future goalwill be finding ways to improve therapy effectiveness.

Conflicts ofinterest

The authors declare no conflicts of interest.

References

1. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA.Hypothermia for neonatal hypoxic ischemic encephalopathy:an updated systematic review and meta-analysis. Arch PediatrAdolesc Med. 2012;166:558---66.

2. Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, DonovanEF, Fanaroff AA, et al. Whole-body hypothermia for neonatalencephalopathy: animal observations as a basis for a ran-domized, controlled pilot study in term infants. Pediatrics.2002;110:377---85.

3. Thoresen M, Whitelaw A. Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant. Curr OpinNeurol. 2005;18:111---6.

4. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E,Levene M, et al. Neurological outcomes at 18 months of ageafter moderate hypothermia for perinatal hypoxic ischaemicencephalopathy: synthesis and meta-analysis of trial data. BrMed J. 2010;340:c363.

5. Shankaran S, Laptook AR, Tyson JE, Ehrenkranz RA, Bann CM,Higgins RD, et al. Evolution of encephalopathy during wholebody hypothermia for neonatal hypoxic-ischemic encephalo-pathy. J Pediatr. 2012;160:567---72.

6. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature.2000;407:802---9.

7. Northington FJ, Graham EM, Martin LJ. Apoptosis in perinatalhypoxic-ischemic brain injury: how important is it and should itbe inhibited? Brain Res. 2005;50:244---57.

8. Wassink G, Gunn ER, Drury PP, Bennet L, Gunn AJ. Themechanisms and treatment of asphyxial encephalopathy. FrontNeurosci. 2014;8:40.
http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0225http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0220http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0215http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0210http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0205http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0200http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0195http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0190


6/6


9. Drury PP, Bennet L, Gunn AJ. Mechanisms of hypothermic neu-roprotection. Semin Fetal Neonatal Med. 2010;15:287---92.

10. Silveira RC, Procianoy RS. Interleukin-6 and tumor necrosisfactor-a levels in plasma and cerebrospinal fluid of term new-borns infants with hypoxic-ischemic encephalopathy. J Pediatr.2003;143:625---9.

11. Ohmura A, Nakajima W, Ishida A, Yasuoka N, Kawamura M,Miura S, et al. Prolonged hypothermia protects neonatal ratbrain against hypoxic-ischemia by reducing both apoptosis and

necrosis. Brain Dev. 2005;27:517---26.12. Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell

death in neonatal hypoxia-ischemia. Ann Neurol. 2011;69:743---58.

13. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, ChameidesL, Goldsmith JP, et al. Part 11: neonatal resuscitation: 2010international consensus on cardiopulmonary resuscitation andemergency cardiovascular care science with treatment recom-mendations. Circulation. 2010;122:S516---38.

14. Procianoy RS. Hipotermia teraputica. SBP. Departamentode Neonatologia. Documento cientfico [cited 2015 Jul25]. Available from: http://www.sbp.com.br/pdfs/hipotermia-terapeutica.pdf.

15. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, DavisPG. Cooling for newborns with hypoxic ischaemic encephalo-

pathy. Cochrane Database Syst Rev. 2013;1:CD003311.16. Miller SP, Ramaswamy V, Michelson D, Barkovich AJ, Holshouser

B, Wycliffe N, et al. Patterns of brain injury in term neonatalencephalopathy. J Pediatr. 2005;146:453---60.

17. Gunn AJ, Wyatt JS, Whitelaw A, Barks J, Azzopardi D, BallardR, et al. Therapeutic hypothermia changes the prognostic valueof clinical evaluation of neonatal encephalopathy. J Pediatr.2008;152:55---8.

18. MurrayDM, BoylanGB, Ryan CA,ConnollyS. Early EEG findings inhypoxic-ischemic encephalopathy predict outcomes at 2 years.Pediatrics. 2009;124:e459---67.

19. Nash KB, Bonifacio SL, Glass HC, Sullivan JE, Barkovich AJ,Ferriero DM, et al. Video-EEG monitoring in newborns withhypoxic-ischemic encephalopathy treated with hypothermia.Neurology. 2011;76:556---62.

20. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD,Ferriero DM, et al. Selective head cooling with mild systemichypothermia after neonatal encephalopathy: multicentre ran-domised trial. Lancet. 2005;365:663---70.

21. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL,Juszczak E, et al. Moderate hypothermia to treat perinatalasphyxial encephalopathy. N Engl J Med. 2009;361:1349---58.

22. Toso PA, Gonzlez AJ, Prez ME, Kattan J, Fabres JG, Tapia JL,et al. Clinical utility of early amplitude integrated EEG in mon-itoring term newborns at risk of neurological injury. J Pediatr(Rio J). 2014;90:143---8.

23. Shankaran S, Pappas A, McDonald SA, Laptook AR, Bara R,Ehrenkranz RA, et al. Predictive value of an early amplitudeintegrated electroencephalogram and neurologic examination.Pediatrics. 2011;128:e112---20.

24. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE,McDonald SA, Donovan EF, et al. Whole-body hypother-mia for neonates with hypoxic-ischemic encephalopathy. NEngl J Med. 2005;353:1574---84.

25. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT,Kaufman DA, et al. Moderate hypothermia in neonatal ence-phalopathy: efficacy outcomes. Pediatr Neurol. 2005;32:11---7.

26. Lin ZL, Yu HM, Lin J,ChenSQ, Liang ZQ, Zhang ZY. Mildhypother-mia via selective head cooling as neuroprotective therapy in

term neonates with perinatal asphyxia: an experience from asingle neonatal intensive care unit. J Perinatol. 2006;26:180---4.

27. Mourvillier B, Tubach F, van de Beek D, Garot D, PichonN, Georges H, et al. Induced hypothermia in severebacterial meningitis: a randomized clinical trial. JAMA.2013;310:2174---83.

28. Wintermark P, Boyd T, Gregas MC, Labrecque M, Hansen A.Placental pathology in asphyxiated newborns meeting thecriteria for therapeutic hypothermia. Am J Obstet Gynecol.2010;203:579e1---9.

29. Laptook A, Tyson J, Shankaran S, McDonald S, Ehrenkranz R,Fanaroff A, et al. Elevated temperature after hypoxic-ischemicencephalopathy: risk factor for adverse outcomes. Pediatrics.2008;122:491---9.

30. Laptook AR, McDonald SA, Shankaran S, Stephens BE, Vohr BR,

Guillet R, et al. Elevated temperature and 6- to 7-year outcomeof neonatal encephalopathy. Ann Neurol. 2013;73:520---8.

31. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR,McNamara PJ, et al. Whole-body hypothermia for term andnear-term newborns with hypoxic-ischemic encephalopathy:a randomized controlled trial. Arch Pediatr Adolesc Med.2011;165:692---700.

32. Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, TysonJE, et al. Effect ofdepth and durationof cooling on deathsin theNICU among neonates with hypoxic ischemic encephalopathy: arandomized clinical trial. JAMA. 2014;312:2629---39.

33. Sarkar S, Donn SM, Bapuraj JR, Bhagat I, Barks JD. Distributionand severity of hypoxic-ischaemic lesions on brain MRI followingtherapeutic cooling: selective head versus whole body cooling.Arch Dis Child Fetal Neonatal Ed. 2012;97:F335---9.

34. Pauliah SS, Shankaran S, Wade A, Cady EB, Thayyil S. Ther-apeutic hypothermia for neonatal encephalopathy in low-and middle-income countries: a systematic review and meta-analysis. PLOS ONE. 2013;8:e58834.

35. Sarkar S, Barks JD. Systemic complications and hypothermia.Semin Fetal Neonatal Med. 2010;15:270---5.

36. Rka A, Melinda KT, Vsrhelyi B, Machay T, Azzopardi D,Szab M. Elevated morphine concentrations in neonates treatedwith morphine and prolonged hypothermia for hypoxic ischemicencephalopathy. Pediatrics. 2008;121:e844---9.

37. Wintermark P, Hansen A, Warfield SK, Dukhovny D, SoulJS. Near-infrared spectroscopy versus magnetic resonanceimaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia. Neuroim-age. 2014;85:287---93.
http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0230http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0230http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0230http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0235http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0235http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0235http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0235http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0235http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0240http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0240http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0240http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0240http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0240http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0245http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0245http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0245http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0245http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0250http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0250http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0250http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0250http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0250http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0250http://www.sbp.com.br/pdfs/hipotermia-terapeutica.pdfhttp://www.sbp.com.br/pdfs/hipotermia-terapeutica.pdfhttp://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0260http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0260http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0260http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0265http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0265http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0265http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0265http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0270http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0270http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0270http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0270http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0270http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0275http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0275http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0275http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0275http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0280http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0280http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0280http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0280http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0280http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0285http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0285http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0285http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0285http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0285http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0290http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0290http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0290http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0290http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0370http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0365http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0360http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0355http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0350http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0345http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0340http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0335http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0330http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0325http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0320http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0315http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0310http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0305http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0300http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbref0295http://refhub.elsevier.com/S0021-7557(15)00123-0/sbr

penatalaksaaan asfixia terbaru

Documents