Cerebral oxygenation during subclinical seizures in neonatal hypoxic-ischaemic encephalopathy – docslide.com.br nanoxia ncore retro



Entre, 246 clayton road, clayton, melbourne, VIC 3168, australia


Metabolism and worse neurodevelopmental outcome, a causa-

Tive relationship has not been established between seizure and

Dictory findings onwhetherneonatal seizures exacerbate injury

Tion of subclinical seizures in HIE on cerebral oxygenation and

The potential for exacerbation of brain injury.

5 the work was performed at monash newborn, monash medical centre, melbourne, australia.

* corresponding author. The ritchie centre, monash university, level 5, monash medical centre, 246 clayton road, clayton, melbourne,

VIC 3168, australia.

Tel.: þ613 95945700; fax: þ613 95946811.

Official journal of the european paediatric neurology society

nanoxia ncore retro

E u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 4e3 0 7

E-mail address: flora.Wong@med.Monash.Edu.Au (F.Y. Wong).

Seizure incidence during the neonatal period is estimated to be

The highest throughout childhood.1 hypoxic-ischaemic

Encephalopathy (HIE) is an important cause of neonatal

Seizures and is associated with significant morbidity and

Mortality. Seizure management in HIE is controversial, as

Despite the association of seizure with impaired cerebral

In HIE.2,3 further unresolved issues are whether subclinical/

Electrographic seizures are injurious and should be treatedwith

Anticonvulsants in the same way as clinical seizures.

Measurement of cerebral oxygenation by near infrared

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Spectroscopy (NIRS) provides insight into the pathophysiology

Of newborn brain injury.4 this report illustrates the associa-

Near infrared spectroscopy

Cerebral oxygenation


1. Introduction further brain injury.1 animal studies have also yielded contra-

A r t i c l e i n f o

Article history:

Received 9 march 2011

Received in revised form

23 july 2011

Accepted 18 september 2011




Hypoxic-ischaemic encephalopathy


1090-3798/$ e see front matter ª 2011 europ


A b s t r a c t

Treatment of subclinical seizures in newborn HIE remains a contentious issue, especially

In light of potential adverse effects of aggressive use of anticonvulsants. We report on the

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Association of subclinical seizures with changes in cerebral oxygenation in an infant with

HIE. Our results show that subclinical seizures of longer durations and with associated

Autonomic disturbance (increased blood pressure) are more likely to be associated with

Fluctuation in cerebral oxygenation, with some seizures resulting in cerebral hypoxia.

Future studies should aim to delineate the effects of subclinical seizure and anticonvulsant

Treatment on cerebral oxygenation, and their relationships to developmental outcome.

Level of cerebral oxygenation may play a role in refining anti-convulsant treatment and

Management of subclinical seizures in newborns.

ª 2011 european paediatric neurology society.Nanoxia ncore retro published by elsevier ltd. All rights

BMonash newborn, monash medical C

CDepartment of pediatrics, monash un

Melbourne, VIC 3168, australia

, melbourne, VIC 3168, australia

AThe ritchie centre, monash university, level 5, monash medical C


Reshma silas a,b, arvind sehgal b, adrian M. Walker a, flora Y. Wong a,b,c,*

Case study

Cerebral oxygenation during s

Hypoxic-ischaemic encephalop

Ean paediatric neurology

Bclinical seizures in neonatal


Society. Published by elsevier ltd. All rights reserved.

2. Case report

A male infant of 39 weeks gestation (birthweight 3.9 kg) was

Outborn and transferred to NICU at 7 h of life with HIE. He was

Delivered by emergency caesarean section for reduced fetal

Movements and poor CTG variability, and thick meconium

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Was noted at delivery. He received 3 min of cardiopulmonary

Resuscitation before the first gasp. APGAR scores were 01, 45

And 610. Venous cord lactate was 16 mmol/L, and base excess

At 50 min was �24.7 mmol/L. Therapeutic hypothermia was

Administered from 3 h of life age for 72 h. He was intubated at

Birth till 7 d of life for respiratory distress with pulmonary

Hypertension secondary to meconium aspiration. Daily

Echocardiography showed good cardiac function.

2.1. Seizure management

Two-channel amplitude-integrated electroencephalograph

(aeeg) was recorded (BRM3, natus, california, USA), with

Electrodes at F3-P3, F4-P4 positions (international 10/20

System). Clinical seizures with lip smacking and startling

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Movements were noted between 10 and 14 h of age, and

Treated with phenobarbitone (20 mg/kg). Only subclinical

Seizures were recorded from 14 to 53 h of age. All seizure

Activities were present in bilateral hemispheres. He received

Further doses of phenobarbitone (20 mg/kg) and phenytoin

(20mg/kg) at 16e20 h of age for continued subclinical seizures.

The background activity on the aeeg was discontinuous

Between 10 and 16 h of age, changed to burst-suppression

After 16 h of age and became continuous low voltage after

Midazolam was commenced at 22 h, returned to burst

Suppression at 31 h and discontinuous pattern at 44 hrs. Upper

And lower cerebral activities were above 10 and 5 mv respec-

Tively by 72 h of age.Nanoxia ncore retro

2.2. Cerebral and cardiorespiratory monitoring

Cerebral tissueoxygenation index (TOI,%)wasmeasuredusing

Spatially resolved spectroscopy (SRS) (NIRO 200, hamamatsu

Photonics K.K, japan). The study had hospital ethics approval

And informed parental consent. Optodes were attached to the

Right frontal parietal region and coveredwith light-proof cloth.

Analogue signals of intra-arterial blood pressure, ECG,

Transcutaneous partial pressure of carbon dioxide (paco2),

And beat-to-beat arterial oxygen saturation (sao2) recorded

From right upper limb, were collected continuously and

Simultaneously with TOI measurements. Data were digital-

Ised at 400 hz (powerlab 16SP, adinstruments, NSW,

Australia) and averaged at 1 hz.Nanoxia ncore retro

3. Results

Continuous TOI recording was performed for 5e6 h daily, at





(%) ΔTOI ΔTOI received





19.2 15 44.0 þ34.2 20





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19.5 15 39.0 þ43.8 20

35.3 3 52.4 �5.0 3

Seizure episodes not associated with TOI changes

14.1 5 42.6 no change no chan

14.7 5 47.1 no change no chan

16.7 10 46.8 þ32 14

36.5 1 56.9 no change no chan

36.6 1 56.9 no change no chan

PHB phenobarbitone dose in mg/kg.

PHY phenytoin dose in mg/kg.

Midazolam infusion up to 60mcg/kg/hr was started at 22 h of

Age, after which the aeeg showed occasional brief subclinical


Table 1 e timing, duration and physiological changes durin

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Age (hours)




Baseline MABP




(% of baseline





Seizure episodes associated with TOI changes

14.5 8 47.1 þ35.7 10.

15.0 7 46.8 þ17.0 8.

17.5 10 45.0 þ31.6 14.

18.1 15 44.7 þ17.3 15

18.5 10 49.2 þ35.6 8.

MID midazolam infusion in mg/kg/hr.

) (% of baseline



76.4 �7.8 10.2 PHB 20

76.2 þ2.3 2 PHB 20

74.9 þ6.9 4 PHB 30

60.3 þ6.8 15 PHB 30

59.4 �28.0 9.6 PHB 30

59.2 þ3.5 12.1 PHB 30

63.0 þ6.5 4 PHB 40

75.6 �2.9 3 PHB 40

PHY 20

MID 40

77.5 no change no change PHB 20

76.4 no change no change PHB 20

76.3 no change no change PHB 30

74.4 no change no change PHB 40

PHY 20

MID 40

74.4 no change no change PHB 40

PHY 20

MID 40

Postnatal ages of 14e19 h, 35e41 hrs, 61e66 h and 85e91 h.Nanoxia ncore retro

Overall, TOI andmean arterial blood pressure (MABP) for the 4

Recording periods averaged 70.0% and 44.9 mmhg, 75.1% and

The subclinical seizures.

Of baseline TOI maximum duration of anticonvulsant

53.4 mmhg, 83.7% and 60.6 mmhg, and 80.2% and 58.5 mmhg

Respectively. TOI was recorded during 13 episodes of

Subclinical seizures detected by aeeg (table 1). Of these, eight

Persisted for 7 min or longer, and each was associated with an

Increase in MABP, while TOI changes occurred in 7 of the 8

Episodes. The lowest TOI value during a subclinical seizure

Was 42e45% for 1 min 20 s (fig. 1A). For the other 5 subclinical

Seizures of less than 7 min duration, 4 seizures were not

Associated with any change in MABP and none were associ-

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Ated with any TOI changes (fig. 1B). SaO2 and paco2 were

Unchanged during all 13 subclinical seizures.

Magnetic resonance imaging (MRI) on day 5 showed

Profound acute hypoxic-ischaemic changes, with preferential

Involvement in the bilateral cortex with relatively lesser

Involvement of the deep grey matter, but with restricted

Diffusion seen in cortex, putamenandboth thalami. The infant

Was discharged home on day 21. MRI at 6 wk showed ence-

Phalomalacia in the frontal, parietal and occipital lobes bilat-

Erally. When last reviewed at 8 months of age, the infant was

Interactive with smiles and vocalisations, but had an increase

In tone and extensor posturing consistent with cerebral palsy.

4. Discussion

To our knowledge, this is the first description of the associa-

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Tion of subclinical seizures on cerebral oxygenation in HIE. In

Older infants, heterogenous findings in cerebral oxygenation

Were reported relating to different seizure types and cerebral

Pathologies.5 we have identified that in an HIE infant with

Stable arterial oxygen saturation, subclinical seizures of

Longer durations and with associated autonomic disturbance

(increased blood pressure) are more likely to be associated

With fluctuation in cerebral oxygenation, with some seizures

Resulting in cerebral hypoxia. The finding is consistent with

The cerebral effect of prolonged seizures in asphyxiated near-

Term lambs.6 the seizures observed on aeeg during our study

Were all present bilaterally (fig. 1), in conjunction with bilat-

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Eral brain injury on MRI, therefore unlikely to cause unilateral

Changes in TOI.

Seizures typically increase both cerebral blood flow (CBF)

And cerebral metabolic rate.7 our findings suggest that in the

Human infant any increase in CBF may not always be suffi-

Cient to match the cerebral metabolic demand during pro-

Longed seizures, indicating cerebral blood flow-metabolism

Uncoupling6 which led to the reduced TOI. Accordingly,

Seizure-related cerebral hypoxia may amplify hypoxic-

Ischaemic cerebral injury. Notably, the TOI reduction may be

Further exacerbated with hypotension or ventilation-related

Hypoxia which frequently occur in HIE and may impact

Adversely on cerebral oxygen delivery. The increase in TOI

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With increased MABP in some seizures might, in part, repre-

Sent impaired cerebral autoregulation. However, assessment

Of cerebral autoregulation using TOI and MABP requires the




E u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 4e3 0 7306

Fig. 1 e simultaneous bedside recording of 2-channel EEG, c

Pressure (MABP) and arterial oxygen saturation (sao2) in an

Seizure on EEG and corresponding TOI and MABP changes. S

A prolonged subclinical seizure, MABP increased along with dec

Ceased. B: during a brief seizure, both MABP and TOI stayed st

Bral tissue oxygenation index (TOI), mean arterial blood

Ant who suffered HIE. Arrows indicate start of subclinical

2 was steady throughout the recordings.Nanoxia ncore retro A: during

Reased TOI which slowly returned to baseline when seizure


Assumed condition of constant cerebral metabolic demand.8

Given the changes in cerebral metabolic demand from the

Frequent seizures, it is difficult to accurately assess the

Autoregulatory ability.

It remains controversial what TOI valuesmay be harmful to

Below which significant cerebral hypoxia with poor neurologic

Outcome occurs. However, infants with HIE with worse


Dr. R. Silas was supported by the ritchie clinical fellowship.

Dr. F. Y. Wong was supported by the kathleen tinsley

E u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 4e3 0 7 307

Outcomewere reported tohaveparadoxicallyhighertoi values

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Than those with better outcome, possibly due to secondary

Energy failure and/or “luxury perfusion” due to cerebral vaso-

Paralysis,12 as also shown in the similar higher baseline TOI

Values in our case. It remains unknownwhat the lower “safety

Margin” is for cerebral oxygenation in HIE infants.

As neonatal seizures in HIE are often difficult to control, an

Important unresolved question for neonatologists is whether

Aggressive anticonvulsant treatment of all seizures, especially

Subclinical seizures, is warranted. Our results may have

Implication for refininguse of anticonvulsants. Animal studies

Have raised concern that anticonvulsantsmay cause neuronal

Apoptosis in the immature brain.13 therefore anticonvulsants

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For neonatal seizure should be considered with caution

Because of their potential adverse effects. Importantly, seizure

Reduction with prophylactic use of anticonvulsants did not

Improve outcome in HIE.14 A recent study15 did not show less

Brain injury evident onmri or difference inmedianmri scores

In infants treated for both clinical and subclinical seizures,

Comparedwith those treated for clinical seizures only. Our TOI

Findings suggest that not all subclinical seizures contribute to

Cerebral hypoxia and perhaps not all seizures should be

Treated. This is particularly important in the context of

Potential adverse effects of aggressive and prolonged use of


While most clinical trials of treatment of neonatal seizures

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Use beside EEG findings as treatment criteria and clinical end

Points, it might also be useful to take into account the degree

Of cerebral hypoxia. Continuous, simultaneous NIRS and aeeg

Monitoring has been used in HIE infants,4 and may be utilized

Not only in research on neonatal seizures but extended to

Refine treatment strategies. An important issue for further

Experimental and clinical studies would be to delineate the

Effects of seizure severity and anticonvulsant treatment on

Cerebral oxygenation and their relationships to develop-

Mental outcome.

Conflict of interest statement


The immature brain. Previous studies in preterm infants sug-

Gested a 10% reduction in mixed cerebral oxygenation to be of

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Clinical concern,9 while animal studies using NIRS have found

A mixed cerebral oxygenation of 40e50%10,11 to be the limits

Fellowship. This work is supported by the victorian

Government’s operational inftrastructure support program.

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Cerebral oxygenation during subclinical seizures in neonatal hypoxic-ischaemic encephalopathy

nanoxia ncore retro

1. Introduction

2. Case report

2.1. Seizure management

2.2. Cerebral and cardiorespiratory monitoring

3. Results

4. Discussion

Conflict of interest statement