A dissertation on
“URINARY URIC ACID TO CREATININE RATIO AS A BIOCHEMICAL MARKER OF PERINATAL ASPHYXIA AND ITS
CORRELATION WITH ARTERIAL BLOOD GAS VALUES”
Dissertation submitted to
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY CHENNAI
In partial fulfillment of regulations for award of the degree of M.D.PAEDIATRICS BRANCH- VII
DEPARTMENT OF PAEDIATRICS,
GOVERNMENT KILPAUK MEDICAL COLLEGE, CHENNAI - 10
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY CHENNAI-TAMILNADU
MAY 2020
BONAFIDE CERTIFICATE
This is to certify that this dissertation entitled “URINARY URIC ACID TO CREATININE RATIO AS A BIOCHEMICAL MARKER OF PERINATAL ASPHYXIA AND ITS CORRELATION WITH ARTERIAL BLOOD GAS VALUES” is the original and bonafide work done by Dr. PRIYA SHARMA under the guidance of Prof. Dr. K. DEVI MEENAKSHI, M.D., DCH., Professor, Department of Paediatrics, Government Kilpauk Medical College & Hospital, Chennai – 600 010, during the tenure of her course in M.D. Paediatrics from May-2017 to May-2020 held under the rules and regulations of the Tamilnadu Dr. M.G.R Medical University, Guindy, Chennai – 600 032, in partial fulfilment for the award of the degree of M.D Paediatrics, branch VII.
Prof. Dr. P.VASANTHAMANI,
MD., DGO., MNAMS., DCPSY., MBA
DEAN
Government Kilpauk Medical College &
Hospital,
Chennai – 600 010.
Prof.Dr.V.E.VIVEKANANDAN,
M.D,DCH.,
Professor and Head,
Department of Paediatrics, Govt. Kilpauk Medical College, Chennai- 600 010.
Date :
Place : Chennai
CERTIFICATE BY THE GUIDE
This is to certify that this dissertation titled “URINARY URIC ACID TO CREATININE RATIO AS A BIOCHEMIVAL MARKER OF PERINATAL ASPHYXIA AND ITS CORRELATION WITH ARTERIAL BLOOD GAS VALUES” is the original and bonafide work done by Dr. PRIYA SHARMA under my guidance and supervision at the Govt.
Kilpauk Medical College & Hospital, Chennai – 600 010, during the tenure of her course in M.D. Paediatrics from May-2017 to May-2020 held under the regulation of the Tamil Nadu Dr. M.G.R. Medical University, Guindy, Chennai – 600 032.
Prof. Dr K DEVI MEENAKSHI, M.D, DCH., Professor & Chief,
Department of Pediatrics,
Govt. Kilpauk Medical College, Chennai- 600 010.
Date :
Place : Chennai
DECLARATION BY THE CANDIDATE
I solemnly declare that this dissertation title “URINARY URIC ACID TO CREATININE RATIO AS A BIOCHEMICAL MARKER OF PERINATAL ASPHYXIA AND ITS CORRELATION WITH ARTERIAL BLOOD GAS VALUES” is the original and bonafide work done by me at Govt. Kilpauk Medical College & Hospital, Chennai –600010.
This is submitted to the Tamil Nadu Dr. M. G. R. Medical University, Chennai in partial fulfilment of the rules and regulations for the award of M.D.
Degree in PAEDIATRICS, BRANCH VII.
Signature by the candidate
Dr PRIYA SHARMA
Date :
Place : Chennai
CERTIFICATE – II
This is to certify that this dissertation work titled “URINARY URIC ACID TO CREATININE RATIO AS A BIOCHEMICAL MARKER OF PERINATAL ASPHYXIA AND ITS CORRELATION WITH ARTERIAL BLOOD GAS VALUES” of the candidate Dr.PRIYA SHARMA, post graduate in PAEDIATRICS with registration Number 201717154 for the award of M.D. PAEDIATRICS in the Branch VII. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 11 percentage of plagiarism in the dissertation.
GUIDE AND SUPERVISOR SIGN WITH SEAL
Date :
Place : Chennai
ACKNOWLEDGEMENT
It gives me immense pleasure to express my sincere thanks and deep gratitude to my Dean, Prof. Dr. P. VASANTHAMANI, M.D.,DGO., MNAMS., DCPSY, MBA, for permitting me to utilise the infrastructure and resources needed to conduct this study in Government Kilpauk Medical College & Hospital..
I express my sincere gratitude to Prof. Dr. T.ARUNA, M.D., Vice Principal for her support and encouragement to conduct this study.
I extend my sincere thanks to my HOD, Prof. Dr. V. E.
VIVEKANANDAN M.D., DCH.,for his valuable support, guidance, support and encouragement during this dissertation.
I take this opportunity to express my heartfelt gratitude to my guide Prof.Dr. K. DEVI MEENAKSHI, M.D., DCH., Professor and chief, Department of Pediatrics, Govt. Kilpauk Medical College & Hospital, Chennai for her keen interest, guidance, constant encouragement, and valuable suggestions throughout this study. Her constant motivation and support were the key factors for the construction of this study. I am extremely grateful to her.
I also express my gratitude towards DR SRIDEVI A. NARAYANAN, Associate Professor of Dept of Paediatrics, Govt Kilpauk medical college and Hospital for her valuable input and guidance during this study.
I would also like to thank my assistant professors of the department of Paediatrics, Govt kilpauk medical college and Hospital Dr. M. SUGANYA M.D, DCh, Dr N ADALARASAN, M.D, DCh, Dr RAJI, M.D, Dr SRIDEVI M.D, DCh, Dr SUNDAR M.D., Dr SELVAKUMAR M.D.,Dr PADMAVATHI M.D, for their guidance and constant inputs throughout this study.
I sincerely thank the Head of the department of Biochemistry in Govt KIlpauk Hospital for guiding and supporting me.
I am grateful to the staff nurse, interns and fellow post graduates of Department of Paediatrics, Government Kilpauk Hospital, who were an immense help.
I would like to thank all the newborns and their parents who participated in this study.Finally, I would like to thank God for His blessings.
CONTENTS
S.NO TITLE PAGE NO.
1. INTRODUCTION
2. AIMS AND OBJECTIVES
3. REVIEW OF LITERATURE
4. NEED OF THE STUDY
5. MATERIALS AND METHODS
6. OBSERVATION AND ANALYSIS
7. DISCUSSION
8. SUMMARY
9. CONCLUSION
10. BIBLIOGRAPHY
11. ANNEXURES
ABBREVIATIONS PROFORMA CONSENT FORM
URKUND PLAGIARISM ANALYSIS REPORT
ETHICAL COMMITTTEE CLEARANCE FORM
MASTER CHART
KEY TO MASTER CHART
1
URINARY URIC ACID TO CREATININE RATIO AS A BIOCHEMICAL MARKER OF PERINATAL ASHPYXIA AND ITS
CORRELATION WITH ARTERIAL BLOOD GAS VALUES
1.INTRODUCTION
Perinatal asphyxia is a leading cause ..of morbidity and mortality in developing countries. In perinatal asphyxia cerebral blood flow is compromised causing acidosis, hypoxia and hypercapnea .In worldwide asphyxia accounts for 26% of the 3.2 million stillbirths and 23% of 4 million.. neonatal deaths each year(1).
It is difficult to estimate the actual burden of asphyxia because of the different definitions used in various studies. The reported incidence varies from 2 to 16.2% in community based studies(2), with case fatality rates ranging from 38.5 to 74%.About 2.8 and 5.6% of all live births had moderate and severe asphyxia respectively, although the case fatality rate was relatively low at 8.7%(3).
In a term infant with perinatal asphyxia, renal, neurological, cardiac and lung dysfunction occurs in 50%, 28%, 25% and 23% respectively(4).The extent of the mutiorgan damage determines the survival of the neonate.
2
HIE refers to the CNS dysfunction associated with perinatal asphyxia.It is of utmost concern as it has the potential to cause serious long term neuromotor sequelae among survivors.
Birth asphyxia is an important cause of neurological handicap in preterm as well as term neonates. About 3 to 13% neonates among the neurologically impaired infants have some evidence of intrapartum asphyxia(5).
Cellular metabolism requires adequate oxygen supply. Brief periods of hypoxia can impair cerebral oxidative metabolism causing anaerobic glycolysis to generate ATP. During anaerobic metabolism, one molecule of glucose yields just 2 molecules of ATP in comparison to the 38 molecules of ATP during aerobic conditions.Anaerobic metabolism results in a number of degradation products like lactic acid(6,7,8,9,10)
.During prolonged hypoxia, there is a fall in the cardiac output, cerebral blood flow is affected and causes further celluar damage. Lack of ATP causes accumulation of ADP and AMP which is then catabolized to adenosine, inosine and hypoxanthine(6,7,8,9,10)
. If there is continued tissue hypoxia, there is also reperfusion injury during which hypoxanthine is oxidized to xanthine and uric acid in presence of xanthine oxidase causes an increase in uric acid production which is excreted in urine(6,7,8,9,10)
.
3
Figure 1:
Mechanism of degradation of adenosine and formation of uric acid
4
There are no specific cut off values for defining asphyxia based purely on arterial blood gas values.Generally it is agreed that an umbilical cord pH of
< 7 is associated with severe asphyxia.It has been shown in a number of previous studies that there is a strong association between urinary uric acid to creatinine ratio among asphyxiated neonates in comparison to non asphyxiated neonates.
This study will help in ascertaining the utility of urinary uric acid to creatinine ratio as a non invasive, easy and cheap as well as biochemical means of diagnosing asphyxia. This study will also help in finding the correlation between UUA/Cr ratio and umbilical cord arterial blood gas values.
2.AIMS AND OBJECTIVES
The aim of the study is to evaluate the utility of urinary uric acid to creatinine ratio as a marker of perinatal asphyxia and its correlation with arterial blood gas values.
OBJECTIVES
To assess the significance of UUA/Cr ratio as a marker of perinatal asphyxia.
To evaluate the correlation between UUA/Cr ratio and umbilical cord arterial blood gas values in asphyxiated group.
Correlation between UUA/Cr ratio and severity of severity of asphyxia.
5
3. REVIEW OF LITERATURE HISTORICAL REVIEW
The examination of perinatal asphyxia from a historical point of view poses a myriad of intriguing problems. This is because, first, there is no satisfactory definition. Dr. Eastman of Hopkins called asphyxia “an infelicity of etymology” as asphyxia in Greek meant “without pulse”.
Secondly, each speciality forms a definition of hypoxia, which has enormous exceptions. For example, according to a pathologist, an “asphyxial”
lesion may be present in the absence of any history of asphyxia. The term asphyxia in the textbooks of physiology describes both hypoxia and hypercarbia. Sometimes, biochemical evidence of asphyxia is present in enormous number of neonates who are absolutely normal clinically.
A recent pair of papers published from the Pittsburgh University describes the effects of perinatal asphyxia on the newborn. A study was conducted on38,405 consecutive deliveries. The study showed the correlation between prematurity and asphyxia, and demonstrated a positive relationship between survival and gestational age.(11) The study reconfirmed that the incidence and severity of birth asphyxia were not having any relation with gestational age. The interesting part about these studies is the criterion used for the diagnosis of asphyxia. Nowadays, where technological advance is a routine occurrence, and detailed cellular physiology is being studied, these investigators used , “infants requiring more than one minute positive pressure
6
ventilation before sustained respiratory efforts.” as the sole criteria for asphyxia. It is not mentioned about the etiology leading to the absence of voluntary respiratory effort. Also no reference is made to blood biochemistry.
In 1861, Dr. William Little presented a paper demonstrating a causal relationship between abnormal parturition and CNS damage. Dr. Little showed that although the difference between apoplexy, asphyxia and asthenia was not known, but in asphyxia, failure of circulation was a clear factor as well as an important cause of the CNS pathology.(12) Dr William‟s talk to the Obstetric Society of London was actually the culmination of a long series of studies published in Lancet, several years earlier. He discussed about other authors who had given comments on the immediate postnatal period. According to him these authors seemed to be quite unaware that besides the abnormal parturition ending in death or recovery, also has termination in other diseases. The terms to describe birth asphyxia in Little's time were“asphyxia neonatorum” and
“suspended animation”. These were descriptive terms that were not entirely different from the Pittsburgh authors of 1980. He made a comparison between the appearance of the asphyxiated neonates to adult drowning victims. Little's thesis alsoincluded the difference between “asphyxia pallida” and “asphyxia livida” with asphyxia pallida the more deleterious event. A view that deserves a special mention from the historical perspective is Dr William‟s observation that “ the great majority of apparently stillborn neonates whose lives are saved by the attendant recover unharmed from the condition”.
7
In the history of birth asphyxia, one name that is central to perinatal medicine is that of Dr N. J. Eastman. Dr. Eastman began his work in the early 1930's.His study was based on the sound physiologic principles that were derived from the work of eminent physiologists who were conducting studies in the field of respiration at that time. According to Dr. Eastman asphyxia is defined as “an inability of the newborn to breathe and apnea associated with oxygen deficiency during .labour”. In fact, the concept of initiation of respiration at birth ignited Dr. Eastman's original contributions. He was keenly interested in the dilemma whether it was the hypercarbia or hypoxia that was responsible for the initial breath.(13) He came to the realization that only by understanding the process of normal initiation of respiration and the biochemistry involved in the process, one can know the problems associated with abnormal respiration as in asphyxia. His studies were compiled in a series of five articles that were published between 1931 and 1936.
He initially studied the concentration and delivery of oxygen through the maternal andfetal blood through the umbilical vein and its return to the placenta via the umbilical artery in 16 patients.(13) His subsequent paper used these 16 patients as controls to identify the variations from normal. He measured the lactate levels in the cord blood of 24 patients, out of which 7 had birth asphyxia. Three of these infants died and as per his report, the autopsy revealed no evidence of trauma or hemorrhage.(14) He showed the relationship between maternal and fetal lactate and inferred that this was most likely a measure of mild deficiency of oxygen. He came to a conclusion that the lack of
8
hyperlactatemia indicated adequacy of fetal oxygen. He provided a quote from a paper by a German investigator, Heinbicken, who demonstrated that acidic products of the cellular metabolism generated from anoxia can cause damage to the cell. The summary of the above two studies and their application is encompassed by Dr Eastman's third paper.(15) He took the reference of the Kane and Kreiselman study(1930) which showed increased levels of carbon dioxide in the blood of adult patients who were asphyxiated. Dr. Eastman made a measurement of the carbon dioxide and pH in normal and abnormal fetal as well as maternal blood. Finally, he demonstrated that neonatal acidosis is accompanied by asphyxia.
In 1928, Schmidt had published a theory about “Reversal”.(16) According to Schmidt, following prolonged deprivation of oxygen and acidemia and hypercarbia, cerebral cells along with the respiratory center, can no longer utilize oxygen and instead of stimulating the respiratory activity, respiratory depression occurred. In 1910, Mathison demonstrated the effect of asphyxia on reduction of cardiac output. Dr. Eastman derived from this pathophysiological observation that the ominousprocess of “asphyxia pallida” was equal to circulatory failure.(17,18). Dr Eastman concluded that neither high carbon dioxide nor low oxygen were the primary initiators of breathing. He also made it crystal clear that the resuscitation end points are evident. He explained that that there appears to be only one indication in the management of asphyxia neonatorum, and that is the introduction of oxygen into the circulation of the newborn ”. He also stated that the usual methods of stimulation which includes
9
slapping, carbon dioxide inhalation and bathing may produce depression and even result in irreparable damage to cerebral cells.
Dr. Eastman's investigations then made him to inquire about the role of anesthesia in perinatal depression and asphyxia.(18) In the 1930's, there was tremendous suspicion that part of hypoxia was due to the administration of anesthetic agents and also that hypoxia as well as the anaesthetic agent were responsible for the central nervous system depression. Dr. Eastman further looked at the concentrations of oxygen in mothers as well asbabies and concluded that in most circumstances, the perinatal depression seen after anesthesia administration is, in fact, not related to deficiency of oxygen but depends on the drug used. He, however, agreed that the incorrect drug concentrations caused apnea due to asphyxia, not due to the anesthesia. This distinction was probably one of the the first scientific distinction made in the present day perinatal medicine regarding neonatal respiatory depression.(18,19)
Dr. Apgar, in a paper published by her in 1953, was very disturbed by the lacunae found in the specificity of resuscitation.(30) She described the absence of systematic examination of neonates which placed limitation in evaluating the methodology of resuscitation. She selected the criteria, in order to overt the requirement for intervention at the time of resuscitation and asserted that her criteria could be precise without any compromise in care. She then assessed the correlation of her score with a number of variables such as perinatal mortality as well as method of anaesthesia, and demonstrated that the
10
score was inversely related to the need for resuscitation. She clarified that her score was not intended to be used for more than focussing attention on the baby and the immediate needs, and for the objectifying and systematizing the process of observer communications.
Dr. L.S. James with his coworkers implemented the pathophysiology of the Apgar score into acid and base biochemical correlates.(21)As one of the weak links in the historical description of asphyxia is the scarcity of interplay among clinical, pathological and biochemical phenomena, this work is deemed to be of critical importance.
Dr.William. Windle deserves a particular mention mainly due to of his system of methods and the decision to utilise a primate as a model, which made most of the pathogenesis of the outcomes of perinatal asphyxia clearer. This work is especially worthy of being noted since it summates the most important correlation among clinical condition, biochemical measurements and pathology.(22)
Another study by Dr. Meyers tells about the cycle of events in hypoxia leading to cellular damage mediated by lactate that most likely causes brain damage. Due to the secondary loss of membrane integrity, there is resultant cellular swelling. Subsequently, ischemia causes further reduction in the delivery of oxygen. There is further hypoperfusion as the cardiac muscle gets affected and cardiac output reduces.(23) Hence it can be derived that the findings obtained from the study by Dr Little, clinical observation by Dr. Eastman and
11
systemic evaluation by Dr Apgar, have resulted in novel approaches to both resuscitation as well as prevention.
Since the ultimate goal should be prevention, a plethora of markers have been studied to identify perinatal asphyxia such as electronic fetal cardiac monitoring, fetal scalp blood pH, Apgar scores, cord blood pH, CT, MRI scans and Doppler studies.A lot of studies have evaluated the markers that distinguish between an asphyxiated and a non-asphyxiated baby and assess how severe is the birth asphyxia.
REVIEW OF LITERATURE
Patel KP et al.did a study on urinary uric acid/creatinine ratio-A marker for perinatal asphyxia.Among the 80 newborns ( 40 in each group- case and control), the mean UA/Cr (2.75±0.18 vs. 1.78 ±0.23) is significantly higher inyhe asphyxiated group than in control(p<0.0001).urinary UA/Cr had a negative correlation with blood pH.(24).
Choudhary et al. studied Urinary uric acid and creatinine ratio as a marker of perinatal asphyxia and its correlation with different stages of hypoxic ischemic encephalopathy.Results showed that the value of UUA/Cr was significantly higher in asphyxiated compared to control group.ratios were also significantly higher with severe HIE(3.61±0.61) when compared with moderate HIE (2.95±0.98) and with mild HIE(2.64±0.25; p < 0.01).(25)
Sreekrishna Y, Eregowda a\A., Sharma AHL studied urinary uric acid to creatinine ratio as a biochemical marker of perinatal asphyxia and its
12
correlation with APGAR score.Results showed a significant increase in UUA/Cr ratio in asphyxiated newborns compared to non asphyxiated newborns (p value <0.001).It also showed a negative correlation between UUA/Cr ratio and AGAR score at 1, 5 and 10 minutes.(p value <0.001).(26)
Krishnana et al studied urinary uric acid to creatinine ratio as a marker of neonatal asphyxia for babies born in a tertiary care hospital.The results showed that the mean UUA/Cr ratio was 2.58±1.09 and 0.86±0.17 in case and control group respectively.(27)
Pallab Basu along with his colleagues did a study in which they found that the uric acid to creatinine ratio in the urine within 24 hours of life was higher in newborns suffering from perinatal asphyxia in comparison to non asphyxiated newborns(28)
Another study by G Ciler Erdag and A vitrine proved that the mean UUA to Cr ratio was more in asphyxiated compared to non asphyxiated babies(29)
It has been shown by Hsing Jin chen that the urinary uric acid to creatinine ratio may be used as a marker of perinatal asphyxia and that this ratio is higher in both term as well as preterm babies who are asphyxiated.(30)
In a study by Lofty M El- Sayed et al, it was shown that UUA to Cr ratio was significantly higher in both term as well as preterm newborns.It was also proved by this study that this ratio had an accuracy of 80%,sensitivity of 86.6%,a positive predictive value of 82.1% and 78.1% as a negative predictive
13
value, hence showing that this test allows rapid detection of asphyxia and also can predict short term outcome as well as long term outcome(31)
According to akisu M et al, the ratio of urinary uric acid to creatinine was higher significantly in babies with asphyxia and implemented it as a simple screening tool for assessment of perinatal hypoxia(32)
David bader et al showed that UUA to Cr ratio maybe used as a marker of perinatal asphyxia and also to indicate the severity of asphyxia.(33)
Conclusion by C banupriya et al showed that excretion of uric acid is more in asphyxiated babies and can act as a biochemical marker for evaluation of morbidity and moratality of perinatal asphyxia.(34)
Study by Reem Mahmoud andDina El Abd. of Ciaro university found that there was a significant correlation between the UUA/Cr ratio with HIE severity with a p value of <0.001 and r=0.94.(35)
Another study by Dong en bin et al also showed that urinary uric acid to creatinine ratio was higher in asphyxiated babies and that it can be used to assess severity and post asphyxia renal injury in newborns suffering from asphyxia.(36)
A novel research by Tekgul et al showed that measurement of interleukin 6 in the cerebrospinal fluid with a cut off value of 25.9 pg/ml has the greatest positive predictive value among all the markers of perinatal asphyxia.In fact, they suggested that it is a better indicator of asphyxia than the
14
ratio of urinary uric acid to creatinine.The disadvantage being that the method is sophisticated, expensive and invasive whereas the UUA/Cr ratio is a simple and non invasive test for indicating asphyxia.(37)
Studies by Naithani M, dept of biochemistry and Dr Ashish Kumar simalti of military hospital in Agra identified that neuron specific enolase, Il 6, brain specific creatine kinase and urinary uric acid are promising markers in hypoxic ischaemic encephalopathy.(38)
Laing et al did a study in which they found that 24 hour urinary hypoxanthine to creatinine ratios in moderate to severe asphyxia were higher compared to mild asphyxia.(39)
Studies by Jensen et al(40) and Hasday and Grum(41) found the direct link of the increased urinary uric acid to hypoxia which is the basis of this study.
PERINATAL ASPHYXIA DEFINITION
Perinatal asphyxia refers to a condition in which there is impaired gas exchange during the first and second stage of labour leading to fetal hypoxemia and hypercarbia.It can be identified by fetal acidosis as measured in umbilical artery blood.(42)
The umbilical artery pH that defines asphyxia is actually the predominant determinant of brain injury.The widely accepted definition of fetal
15
acidosis is pH <7, but the likelihood of brain injury even with this acidosis is quite low.(42)
Since hypoxia and ischaemia occur concurrently, the term hypoxic ischaemic insult is preferred nowadays than perinatal asphyxia.Hypoxic insult results in a insult to the brain but not all cases result in cerebral palsy.Evidence shows that 70 to 80% of all cerebral palsy cases are due to antenatal factors and that only in < 10% cases, there is a role of birth asphyxia(43)
The fetus as well as the newborn are equipped with a range of mechanisms for adaptation to survive an episode of asphyxia.The initial injury triggers a cascade of processes resulting in a secondary damage such as seizures, edema and wound repair over the next few days.(42)
Perinatal asphyxia contributes significantly to morbidity as well as mortality in the neonatal period. The incidence of birth asphyxia is approximately 1-1.5% of the live births.
WHO, as per their latest statistics, nearly 40 lac newborns die every year even before they complete the age of four weeks and developing countries are responsible for 98% of these deaths. Among these deaths, 29% are due to perinatal asphyxia and birth injuries put together.
As far as the definition of birth asphyxia is considered, there is no agreement or consensus.It is also very difficult to confirm the incidence of asphyxia due to different definitions given by different workers in the field.
Definition of birth asphyxia as per WHO is “the failure to initiate and to sustain breathing at birth”.
16
According to WHO, APGAR system is the basis for the definition of birth asphyxia in the International classification of diseases (ICD 10): APGAR at 1 min of birth: 0-3 is an indicator of severe birth asphyxia 4-7 indicates moderate asphyxia.
The NNPD 2000 used a similar definition for perinatal asphyxia and defined moderate asphyxia as slow gasping breathing or an Apgar score of 4-6 and severe asphyxia as no breathing or an Apgar score of 0-3 at one minute of life. The National Neonatology Forum of India has defined asphyxia as
“gasping or ineffective breathing or lack of breathing at one minute of life”.
Definitions based on Apgar scores may be useful as it can be used for formulating guidelines for post-asphyxial treatment of neonates. Apgar scores are also useful for predicting long term outcome in infants with perinatal asphyxia.
The NNF(National Neonatology Forum) of India has defined asphyxia as “gasping or ineffective respiration or lack of respiration at one minute of life”. The required criteria for the diagnosis of perinatal asphyxia as per ACOG and AAP are as follows:
Prolonged mixed or metabolic acidosis (i.e pH <7.0 in the cord arterial blood).
Persisting Apgar of <3 for 5 min or more.
Clinical manifestations in the form of convulsions, reduced tone, coma, encephalopathy .
17
Evidence of dysfunction in multiorgan system in the immediate postnatal period.
The Burden of Perinatal asphyxia
Of the total approximate 130 million births worldwide, four million suffer from birth asphyxia; of these approximately 1 million die and another 1 million suffer from some form of neurological sequelae.98% of these occur in countries limited in resources. This leads to a disparity in the resource rich countries having a neonatal mortality of 4-5 per 1000 compared to resource limited countries where the rates are 10 times more than this rate.(44)
Figure 2:
Estimated causes of 4 million neonatal deaths ( Lawn 2005)
18
The incidence of perinatal asphyxia is somewhere between 1% to 1.5%
of the total live births in the West and it is inversely related to the gestational age and the weight of the baby at birth.
Perinatal asphyxia occurs in about 0.5% of live born newborns >36 weeks of gestation and and contributes for nearly 20% of the perinatal mortality which goes up to50% if stillborns are also included.(45)
It has been observed that a higher incidence of perinatal asphyxia is seen in:
Term infants of diabetic or toxemic mothers.
Infants with IUGR (intrauterine growth restriction).
Breech presentation.
Post dated infants.
Out of the 26 million births every year in India, 4-6 % of newborns are unable to establish a spontaneous respiration at birth.(46).About 8.4% of the inborn neonates have an Apgar score less than 7 at one minute and of these, 1.4%
newborns suffer from HIE.(47)
Global statistics reveal that birth asphyxia or stillbirth account for 23%
of mortality in the 4 million neonatal deaths and it also contributes to 26% of the 3.2 million stillborn neonates each year.(48)
19
Recent terminologies include „birth depression‟, which is a term used to indicate a neonate with reduced Apgar score but without defining the specific etiology for this depression.. The use of word “perinatal” is preferred as it encompasses the pathological processes that begin before birth itself and continue for many hours afterwards. There are numerous causes, and the clinical manifestations vary. Infants who experience mild asphyxia may show no neurological injury. However, severe asphyxia may be fatal in utero, or immediately afterbirth, with survivors showing extensive neurological sequelae, with or without cognitive deficits.(49)
The following terms may be used in evaluating a term infant at risk for brain injury in the perinatal period.(50)
A. Neonatal depression
It is a general term used to describe an infant who has a prolonged transition from an intrauterine to an extrauterine environment. These infants usually have low 1- and 5-minute Apgar scores.
B. Neonatal encephalopathy
It is a clinical term used to describe an abnormal neurobehavioral state that consists of a decreased level of consciousness with abnormalities in neuromotor tone. It characteristically begins within the first postnatal day and may be associated with seizure-like activity, hypoventilation or apnea, depressed primitive reflexes and the appearance of brain stem reflexes. It does not imply a specific etiology, nor does it imply irreversible neurologic injury.
20
C. Hypoxic-ischemic encephalopathy (HIE)
It is an abnormal neurobehavioral state in which the predominant pathogenic mechanism is impaired cerebral blood flow.
D. Hypoxic-ischemic brain injury
It refers to neuropathology attributable to hypoxia and/or ischemia as evidenced by biochemical (such as serum creatinine kinase brain bound [CK- BB]), electrophysiologic (EEG), neuroimaging (cranial ultrasonography, MRI, CT), or postmortem abnormalities.
ETIOLOGY
In term infants, 90% of asphyxial events occur in the antepartum or intrapartum period as a result of impaired gas exchange across the placenta that leads to the inadequate provision of oxygen (O2) and removal carbon dioxide (CO2) and H+ from the fetus. The remainder of these events occurs in the postpartum period and is usually secondary to pulmonary, cardiovascular, or neurologic abnormalities.(51)
A. Factors that increase the risk of perinatal asphyxia include the following:
1. Impairment of maternal oxygenation.
2. Decreased blood flow from mother to placenta.
3. Decreased blood flow from placenta to fetus.
21
4. Impaired gas exchange across the placenta or at the fetal tissue level.
5. Increased fetal O2 requirement.
B. CAUSES
90% of asphyxial events in term newborns occur during the prepartum or intrapartum period due to impairment in exchange of gas across the placenta leading to the decreased supply of oxygen (O2) and carbon dioxide (CO2)and H+disposal from the fetus. The rest of the events occur in the postpartum period and is generally due to pulmonary, neurologic or cardiovascular derangements.(51)
I. Factors causing perinatal asphyxia:
1. Defect in maternal oxygenation.
2. Impairment of placental gas exchange or defective exchange at the fetal tissue level.
3. Reduced blood flow from mother to the placenta.
4. Reduced flow of blood from placenta to the fetus.
5. Increased requirement of O2 by the fetus.
Risk Factors Associated With Perinatal Asphyxia
It is broadly classified as maternal and fetal risk factors.
22
1. Maternal conditions
Toxemia of pregnancy
Eclampsia
Gestational Diabetes
Bad obstretic history
Cephalopelvic disproportion
Medical disease complicating pregnancy such as pulmonary or renal diseases
Rh isoimmunisation
Antepartum haemorrhage
Multiple gestation
Maternal drugs such as sedatives, anaesthetics etc
Fetal conditions
Prematurity
Post term
Intrauterine growth restriction
Meconium stained liquor
Abnormal fetal heart rates
Obstructed labor
Abnormal lie or position in utero and during labour.
B. Predisposing factors for perinatal hypoxia-ischemia are:
23
1. Maternal factors:
Acute or chronic hypertension
Maternal infections
Gestational or overt diabetes
Hypotension
Vascular disease
Use of drugs
Hypoxia secondary to pulmonary,cardiac or neurological disorders.
2. Placental factors:
Placental infarction
Placental fibrosis
Abruption
Hydrops.
3. Uterine rupture.
4. Umbilical cord accidents:
Prolapse
Cord entanglement
True knot
Cord compression.
24
5. Abnormalities of umbilical vessels.
6. Fetal factors:
Fetal anaemia
Intrauterine infections
Cardiomyopathy
Severe cardiac insufficiency
7. Neonatal factors:
Cyanotic congenital heartdisease,
Persistent pulmonary hypertension of the newborn.
Assessment of Fetal well-being
There are a number of parameters which are used to assess and predict the well being of the fetus intrapartum as well as following the delivery These include the following:
Passage of meconium in utero
Fetal heart rate monitoring with the help of cardiotocograph (CTG),
Apgar score
Acid-base balance
Meconium stainined amniotic fluid
When the amniotic fluid is thickly stained with meconium, it is considered as a marker of prolonged asphyxia. Meconium staining of amniotic
25
fluid is seen at an average rate of15% among all deliveries.Meconium staining is also seen in 11% of labour where there are no signs of asphyxia.(52)It has been shown in studies that only about 0.4% of term babies with meconium stained liquor at the time of labour developed cerebral palsy.(53).In a study byRichey, there was no correlation between the meconium stained liqour and pH of umbilical artery, lactate and hypoxanthine levels.(54)Therefore, this sign is not a very good predictor of adverse outcome. Also, in one study, more than 50% of newborns who had early neonatal convulsions with a possible history of intrapartum asphyxia had no evidence of meconium staining of liquor.
Further, if cerebral palsy is taken as the final result of a major asphyxia, then almost 99.6% of newborns with meconium staining of amniotic fluid had no evidence of cerebral palsy.(55)
Electronic fetal monitoring (EFM)
Despite the consesnsus that continuous electronic fetal monitoring is not any better in reducing the perinatal mortality in comparison to the traditional auscultation by the trained physician, it is still being widely used.In the contrary, it has increased the number of operative deliveries.(51) In this method, both the fetal heart rate and uterine activity are evaluated.
Parameters in fetal electronic monitoring(51)
1.The baseline normal fetal heart rate is between 110 to 160 beats per minute. The baseline should be apparent at least for of 2 minutes in any 10 minute segment and should not include any episodic variations/ marked heart
26
rate variability or segments of baseline of heart rate that differ by more than 25 beats per minute.
Baseline fetal bradycardia is defined as a fetal heart rate <110 beats per minute.It may be due to congenital heart block secondary to congenital cardiac malformation or maternal SLE(systemic lupus erythematosus).
Baseline tachycardia is defined as a fetal heart rate >160 beats per minute. It may result from fetal arrhythmias, maternal fever,hyperthyroidism or chorioamnionitis.
2. Beat-to-beat variability is another such important parameter. The autonomic nervous system of a normal, awake and term fetus constantly changes the heart rate from beat to beat at an average of 5 to 25 beats/minute.
Decreased beat to beat variability may result due to:
Depression of the fetal central nervous system
Fetal immaturity
Hypoxia
Fetal sleep
Certain maternal medications such as narcotics, β-blockers, sedatives and intravenous magnesium sulfate.
3. Accelerations of the FHR are a sign of reassurance during non stress test.
27
4. Decelerations in the fetal heart rate may be benign or it may indicate a fetal compromise. This is assessed on the basis of their characteristic shape as well as timing in relation to the uterine contractions.
Early Deceleration Late deceleration Symmetric in shape
Closely mirror the uterine contractions Benign
Accompanied by good beat to beat variability
Due to head compression in active phase
Visually apparent decrease in association with contractions
Peak during the nadir of contraction As a result of uteroplacental insufficiency or hypoxia
As the intrauterine hypoxia worsens:
(i) Loss of beat-to-beat variability (ii) Longer lasting decelerations
(iii) Decelerations will begin sooner after the onset of a contraction and will take longer to return to baseline after a contraction.
(iv) The rate at which the fetal heart slows down will be lower.
Late decelerations occurring repeatedly warrant urgent attention.
28
Variable decelerations
These vary in their shape and in their timing in relation to uterine contractions.Usually, they occur as a result of fetal umbilical cord compression.
These generally should be considered as a cause for concern if they are severe defined as a heart rate down to 60 beats/minute or deceleration lasting for 60 seconds or longer or both.
Umbilical cord compression occurring secondary to oligohydramnios may be corrected by intrapartum amnioinfusion of saline into the uterine cavity.
It has been seen that a normal intrapartum fetal heart rate tracing appears to be a reliable indicator that there is no metabolic acidosis. On the other hand, an abnormal tracing with late decelerations is associated with significant acidosis in the fetus in only about 50% of the cases. A recent Cochrane review(56) proved that there was a statistically significant decrease in the rate of neonatal convulsions when electronic fetal monitoring is used, but it has no protective effect over the 1 minute Apgar scores, admission rates to neonatal intensive care units, perinatal mortality or cerebral palsy.
Fetal response to hypoxia-ischemia(57)
A normal, healthy fetus is able to mount a number of adaptive responses to overcome the hypoxic-ischemic insult. These include:
29
Reduction in body movements, breathing movements as well as rapid eye movement sleep. This reduces the energy consumption and oxygen demand.
Increased extraction of oxygen from the blood: This is achieved by the fact that almost twice the amount of oxygen is extracted by the fetal hemoglobin before cardiac output can increase. There is an increase in the erythropoietin concentrations stimulating the fetal RBC production.
Redistribution of blood supply to the central nervous system, adrenals and myocardium at the expense of the kidneys, gastrointestinal tract and muscle.
Preferential oxygenation in the brain is maintained by diverting the flow of the blood to the brainstem, midbrain and cerebellum.
Sympathetic response: High catecholamine levels seen during ischemiaincrease peripheral vascular resistance and contractility of the myocardium inorder to maintain the perfusion. It also accelerates the anaerobic glycolysis along with mobilization glycogen stores from the liver, thereby providing energy for the CNS and myocardium.
The immature CNS of the newborns utilizes the lactate, pyruvate andketones generated by anaerobic glycolysis more readily as an alternative to glucose. On the other hand, in babies with hyperinsulinemia , the ability to utilise these alternative energy sources is limited and are hence are at greater risk from hypoxic-ischemic injury.
30
Hypoxia, and under perfusion of placenta which are the hallmarks of asphyxia, are relatively common events during labor. The fetus is well adapted to these changes. These are the physiological responses to the deviations in the fetal environment.
Important physiological changes in response to short episodes of fetal hypoxia(58)
Cardiovascular responses:
· „Diving seal‟ reflex :Redistribution of the blood flow to brain, myocardium and adrenals diverting from gut,lungs
· Bradycardia
· Hypertension
Regional cerebral blood flow changes:
· Increased blood supply to brainstem
· Decreased blood supply cerebral cortex Autonomic responses:
· In premature animals : There is a net parasympathetic response
· In full-term animals: Sympathetic response
Biochemical response: Switch from aerobic to anaerobic metabolism occurs
31
DIVING REFLEX
Some marine mammals have the ability to divert their cardiac output to vital organs and can also slow down their heart rate to very low levels in order to remain under water for up to one hour in certain cases. The fetus has also been proved to have similar adaptive mechanisms during episodes of hypoxic stress during labor in some way to that of the diving seal. There is a decrease in the blood flow through the descending aorta along with reflex bradycardia.(58) Redistribution of blood flow
During hypoxia, there is a decrease in the fetal heart rate and a rise in blood pressure. This leads toa significant fall in the cardiac output during the episode hypoxia. This reduction in the cardiac output is adequately compensated by a simultaneous redistribution of blood flow to vital organs with increase in blood flow to the fetal brain, heart and adrenals at the expense of organs like the liver, lungs, skin and muscles (Figure:3).
32
Figure 3:
Showing redistribution of blood in hypoxia(59)
Blood flow to the brain is distributed towards the more primitive regions, particularly the brainstem, compromising the cerebral cortex thereby protecting function in the most 'vital' centers.(60) At the times of fetal stress, high levels of cortisol are produced that mediate the vascular effects seen in the fetus at the time of hypoxia. The autonomic nervous system also plays an important role in the fetal responses to hypoxic stress.(58)
Glycolytic activity
The major metabolic fuels for the developing brain are glucose and oxygen. Metabolism can switch to anaerobic glycolysis at the times of hypoxia resulting in the production of lactic acid. This constitutes the normal metabolic adaptation. It is a known fact that the immature animal is more resistant to the
33
effects of asphyxia compared to mature animals of the same species. This is due to the increased resilience of the mature cardiovascular system as well as brain. This in turn maybe due to either reduced glycolytic ability or reduced use of glucose by the brain.(58)
Stress vs. distress
The fetus is beautifully adapted with a number of mechanisms to protect it from the stress of labor, both hypoxic as well as ischemic. Stress is an invariable component of the birth process and the one which the fetus can withstand under most circumstances. Distress may occur as a result of response to prolonged stress. It is extremely difficult to differentiate fetal stress from distress using the currently available methods. Fetal distress may occur due to a single episode of prolonged, or frequent episodes of brief hypoxia.
Currently,the methods used in the detection of fetal distress such as CTG and fetal scalp pH measurements help in detecting severity of fetal stress. An understanding of the fetal responses to the stress of labour might encourage that there is no assistance required.(58)
Apgar score and perinatal Asphyxia
The Apgar score was first described by Dr. Virginia Apgar in 1952, an obstetric anesthesiologist. Her aim was to develop a scoring system using the signs traditionally observed by anesthesiologists that would help to assess a newborn‟s transition after birth, particularly keeping in view the fetal presentation, type of delivery and anesthetics used in obstetrics. It was used as
34
an objective tool that measured the five signs of physiological adaptation. The score is the sum of the values assigned to infant at first and fifth minutes of life, with a score of 7 or more which indicates that the baby is in good to excellent condition. The scoring system soon gained near universal acceptance after it was shown that it could predict survival, especially at 5 minutes.
The validity of the Apgar score has been criticized for its utility in clinical assessment and predictive abilities. It has become outdated as a result of the prompt application of modern resuscitation and neonatal care. Also, the score does not take into account preterm or newborn who are intubated, who often are given lower scores. Apgar scoreis most controversial when used as a predictor of birth asphyxia and long-term neurologic sequelae.(61)
It is essential to recognize that the components of the Apgar score, which are tone, color and grimace, are actually partially dependent on the physiologic maturity of the infant. This may result in a low score for a healthy preterm healthy with no evidence of hypoxic insult, acidosis or cerebral depression, only due to prematuity.
A number of maternal medications as well as infant conditions may influence Apgar scores, including neuromuscular malformations that may result in decreased tone and respiratory effort. Certain cardiorespiratory conditions also may cause decrease in the newborn‟s heart rate, respiration and tone. Intrauterine infections may affect with tone, color and response to resuscitation.(62)
35
Apgar scores when used alone have a poor correlation with the outcome, which limits their utility in epidemiological studies. Extended Apgar score which is recorded 20 minutes after birth was much more specific for the prediction of both early death as well as disability.(63)
It is obvious that continuing depression of the newborn even after the first minutes of life is more significant compared to the responses immediately after birth.
In the literature, there is an lack of a consistent correlation of low Apgar score with biochemical evidence of asphyxia. In earlier studies, a 4 times increase in the neurologic abnormalities in neonates with low Apgar scores at 5 min has been documented, but recent studies prove that the fetal or cord blood pH is a better indicator of asphyxia and that hypoxic ischemic encephalopathy is a better predictor of long term prognosis than presence of low Apgar scores alone.(64)
Persistence of low Apgar scores like0 to 3 at 10, 15 and 20 minutes have been observed that they have a fair correlation with long term outcome.
Generally, with prolonged persistence of low Apgar scores, there is increased risk of mortality and probability of long term neurologic sequelae among the survivors.
36
Table 1: Apgar Evaluation of Newborn Infants(65)
Factors affecting the APGAR score:
False positive: It refers to a low apgar score in the absence of hypoxia or academia.
It is seen in:
Prematurity
Use of analgesics or sedatives
Precipitate delivery
CNS anomaly
Congenital myopathy or neuropathy
Spinal cord trauma
Congenital lung or airway anomalies
Sepsis
37
False negative: Normal APGAR in the presence of acidosis.
Maternal acidosis
High levels of catecholamine in the fetus
Pathophysiology of Birth Asphyxia
Perinatal asphyxia is an important cause of perinatal mortality and morbidity. The term “asphyxia” is used to imply an abnormal process, which if left untreated, may cause a permanent injury.
Apnea at the time of birth can be as a result of intrapartum asphyxia or drugs depressing the respiratory centres administered to the mother. A newborn who has not taken breath atbirth suffers from lack of oxygen, carbon dioxide built up and fall in blood pH leading to acidosis. This increase in the hydrogen ion concentration is partly due to the rise in carbon dioxide concentration but mainly due to the anaerobic breakdown of glucose as a result forming lactic acid.
At the pathophysiological level, asphyxia is the combination of both hypoxia plus reduced perfusion, which causes impairment in the tissue gas exchange leading to acidosis. At the time of normal labor, transient hypoxemia occurs during uterine contractions, but the healthy fetus can tolerate this well.
38
Basically, there are five causes of intrapartum asphyxia:
1. Interruption in umbilical blood flow such as in cord compression.
2. Defect in the gas exchange across the placenta as seen in abruptio placentae.
3. Reduced perfusion on the maternal side of the placenta seen in severe maternal hypotension.
4. A compromised fetus who can no further tolerate the intermittent hypoxia during uterine contractions such as in anaemia and IUGR.
5. Failure to inflate the lungs and to undergo the change in ventilation as well as lung perfusion that must occur shortly after birth.
A healthy fetus is equipped with a range of adaptive mechanisms to reduce the overall consumption of oxygen in order to protect the vital organs such as the heart and brain at the time of asphyxia. Acute injury takes place when the asphyxia is too severe and exceeds the capacity to maintain the cellular metabolism. Since the damage to the tissue occurs as a result of inadequate delivery of oxygen and substrate, that are determined, by the degree of hypoxia and ischemia, these injuries are classified as hypoxic ischemic injuries.
Asphyxia in a newborn is a progressive and reversible process. But the speed at which it progresses and its extent are highly variable. Profound asphyxia can be lethal even within 10 min whereas mild asphyxia may gradually worsen over
39
30 min or even more. Recurrent episodes of brief and mild asphyxia may revert spontaneously but it produces a net effect of progressive asphyxia.
In the initial stages, asphyxia will usually reverse spontaneously if the cause is corrected. If the asphyxia is severe, spontaneous reversal is less likely due to the changes in circulatory and neurological function that occur along with it.(66)
The Pathophysiology of hypoxia-ischemia Cell damage
When a cell gets exposed to hypoxia or ischemia, the consequence depends on the degree as well as the duration of the insult. If the insult is brief, the cellular injury may be reversible whereas if it is prolonged, the cell will be damaged irreversibly and undergoes cell death. The two main pathways of cell death are necrosis and apoptosis.
Necrosis: It is generally seen after there is a loss of blood supply to the cell but it can also occur if there is exposure to toxins.
Apoptosis: It is seen in both physiological as well as pathological conditions. Hypoxia/ ischemia leads to decrease in oxidative phosphorylation that inturn leads to a decrease in ATP production. Reduction in ATP production affects the cell membrane in the following way:
40
Figure 4:
Schema of events in hypoxic cell injury
41
Figure 5:
Mechanism of cell membrane changes in asphyxia
The mechanism of the damage of cellular membranes during an insult is multifactorial. Influx of calcium activates the phospholipases and proteases that cause the breakdown of membrane phospholipids. Phospholipids and cytoskeletons are an essential part of cell membranes. Since the membranes lose their integrity, there is a chance that there will be irreversible damage due to the massive influx of calcium and the leakage if the cellular enzymes into the peripheral circulation.(67)
42
Figure 6:
Cellular and biochemical sites in cell damage
Specific insight into the pathophysiology of perinatal asphyxia
During labour, there is a normal transient fetal hypoxia at the time of each uterine contraction. This causes the fetus to become more acidemic as the labor further progresses. These changes have been confirmed by correlating with intrapartum serial fetal scalp blood pH measurements during the first and second stages. A number of hormones and other biochemical markers of asphyxia are released in response to stress. Generally, the more the stress of the labour, higher is the level of hormones released. Surprisingly, despite these processes going on for a long time, most newborn infants are pink, vigorous and breathe spontaneously at a regular rate by 1 to 2 minutes after birh.
43
Some babies may require certain assistance to make this transition to the extrauterine environment. The treatment given at right time in such babies can make a great difference.
Markers of stress or hypoxia in a neonate in normal labour(68)
Catecholamines
Arginine vasopressin
Renin
Angiotensin
Endothelin I
Cortisol
Hypoxanthine
Endorphins
Plasma CK-BB
Clinical features after birth
Hypoxic-ischemic encephalopathy (HIE)
Neonatal encephalopathy refers to the abnormality in the neurological behavior in the neonatal period. It may be due to a wide range of conditions.
When the full-term brain has undergone compromise by asphyxia during delivery, it is very likely that the newborn will show a deviation in the neurological behaviour, a state that is referred to as HIE. It is not clear to what extent the similar clinical features are manifested in the premature babies after a hypoxic-ischemic injury in comparison to the term babies.(55) Neonates often
44
show a sequence of a transient encephalopathy lasting often for days which is depends on the severity and duration of the asphyxia. Grading systems have been established to grade the degree of encephalopathy.
NEUROLOGICAL SIGNS IN ASPHYXIATED NEONATES
Encephalopathy: characterized by abnormal consciousness.In mild cases, there is a jittery or hyperalert state. Moderate and severe are characterized by impaired responses to light, touch or noxious stimuli.
Brainstem and cranial nerve abnormalities: Abnormal brainstem reflexes, dysconjugate gaze, ocular bobbing etc.
MOTOR ABNORMALITIES: In very severe encephalopathy, there is greater hypotonia, weakness and abnormal posture with lack of flexor tone, usually symmetric. Gradually, this hypotonia evolves into spasticity and hyperreflexia,.If the neonte shows hypertonia within first day of life, there is a significant HI insult in antepartum period itself.
Seizure: Occurs in upto 50% of newborns with HIE and usually start within 24 hours after HI insult.Seizures maybe subtle, tonic or clonic.
EEG remains the gold standard in the diagnosis of neonatal seizures Sarnat and Sarnat(69) introduced a grading system to explain the hypoxic ischaemic encephalopathy i.e. HIE.
.
45
TABLE 2: Sarnat and sarnat stages of hypoxic ischaemic encephalopathy
46
TABLE 3: This classification has further been modified by Levene MI.(70).
NEUROLOGICAL CONSIDERATIONS (51)
a. An increase in the intracranial pressure, defined as >10 mmHg or cerebral edema is considered as an effect of brain damage. Cerebral edema occurs at its peak at around 36 to 72 hours after the asphyxial insult. It often reflects prior cerebral necrosis, making this finding consistent with a poor prognostic outcome. Attempts to alleviatethe intracranial pressure and cerebral edema include phenobarbitone, steroids, mannitol and other hypertonic solutions. But these have no effect on the outcome.
b. Seizures are reported to occur in about 20% to 50% of neonates with asphyxia, and usually start between 6 to 24 hours after the insult. They are most often seen in the Stage 2 of sarnat staging of HIE. Seizures occur rarely in stage 3 and almost never in stage 1of HIE.
47
The seizures in HIE are usually subtle, tonic or multifocal clonic. Generalized seizures do not occur due to comparatively incomplete myelinization and synapsis formation in the neonatal brain.
Seizures are associated with increase in the cerebral metabolic rate, whichleads to further cerebral injury. Seizures compromise the ventilation and oxygenation, especially ininfants who are not on ventilator support. In newborns who areput on neuromuscular blockade for the sake of mechanical ventilation, seizures are manifested as changes in the blood pressure, heart rate and saturation.
Seizures that occur as a result of HIE are often very resistant. Whether seizures alone can lead to brain injury in the absence of metabolic or cardiopulmonary is a topic of debate.
Prognosis of HYPOXIC ISCHAEMIC ENCEPHALOPATHY
In a study showing the meta-analysis, assessing the outcome of newborns with different grades of HIE, it is shown that stage I does not impose an increased risk of morbidity or mortality.(71) (Table: 4).
There is a significant decrease in the IQ at 8 years of age in children who were diagnosed with stage II HIE but were neurologically normal, in comparison to children with stage I HIE.(72)In a comparison between the depressed Apgar scores with HIE staging in predicting the outcome of asphyxia, an Apgar score of 5 or lower at l0 minutes after birth was found to be a more specific in the prediction of death or other major neurological sequelae
48
than the staging of HIE as stages II and III (95% and 78% respectively),but apgar scores were less sensitive than HIE staging (57% and 96%
respectively).(73)
The fetus can cope with an asphyxial event by many protective reflexes to preserve the function to the vital organs. Tissues with compromised perfusion are particularly vulnerable to the ischemic injury. In a term infant, renal, neurological, cardiac and pulmonary dysfunction occurs in 50%, 28%, 25% and 23% of cases respectively.(74)The renal system appears to be the most vulnerable, followed by the brain and the heart. Gastrointestinal complications are quite uncommon (Table: 5).
Recent reports have published that neonates with HIE who later developed cerebral palsy, did not show evidence of multi organ dysfunction.(75)
49
Table 4:
Risk of death or severe handicap in the survivors associated with HIE stages
Lungs
The fetus commonly passes meconium during intrapartum asphyxia and gasping or irregular breaths may occur due to brainstem compromise. This causes the meconium to be aspirated deep into the lungs and causes chemical pneumonitis.Severe pulmonary hypertension can occur.It is also associated with a high risk of air leak. The newborns who are pharmacologically paralyzed to facilitate mechanical ventilation in cases of meconium aspiration syndrome will not display any clinical signs of encephalopathy.Hence, coincidental cerebral injury may go unrecognized. These infants should be put under continuous EEG monitoring to assess the cerebralfunction.(76)
50
TABLE 5:
MULTISYSTEM EFFECTS OF ASPHYXIA
The Cardiovascular system
During asphyxial episodes, blood flow to the myocardium is relatively preserved, still cardiac compromise is a common aftermath of asphyxial injury.
Myocardial dysfunction detected by Doppler ultrasound studies has been reported in 28-40% of asphyxiated infants.(74) Common complications are cardiogenic shock and hypotension, tricuspid valve incompetence due to cardiac dilation, arrhythmias and myocardial ischemia that can be diagnosed by the electrocardiogram. The ECG may show ST depression and T-wave inversion in the left precordium. Echocardiographic findings commonly
