Multi Organ Dysfunction in Term Neonates with Perinatal Asphyxia

Introduction: Multiorgan dysfunction (MOD) is one of the four consensus based criteria for the diagnosis of intrapartum asphyxia. The theoretical concept behind MOD is the diving reflex -conservation of blood flow to vital organs at the cost of non-vital organs. The objective of this study was to assess the patterns of involvement of each major organ/system in term asphyxiated neonates. Material and Methods: This was a hospital based prospective study. Sixty term neonates who had suffered perinatal asphyxia were assessed for central nervous system, kidney, cardiovascular system, gastrointestinal system and liver dysfunction. Results: Out of 60 eligible neonates, 57 (95%) had evidence of at least one organ dysfunction. Cardiovascular system involvement (95%) was most common, followed by renal system (37%), hepatic system (22%), central nervous system and hematological system (20% each) and finally, gastrointestinal tract (8%). Conclusion: MOD is frequently associated with perinatal asphyxia with cardiovascular system being the most commonly affected.


Introduction
P erinatal asphyxia refers to a condi on during the fi rst and second stage of labor in which impaired gas exchange leads to fetal hypoxemia and hypercarbia 1 .Obstetric and pediatric associa ons have opined that dysfunc on of organs other than the central nervous system is a common feature of perinatal asphyxia. 2The phenomenon of mul organ dysfunc on (MOD) is due to asphyxia induced diving refl ex that leads to shun ng of blood from non-vital organs like skin to vital organs like heart, adrenals and brain to protect these organs from hypoxic-ischemic (HI) injury.
The presence of MOD in every neonate with neonatal asphyxia has been ques oned by some authors 3 .Human and animal studies have demonstrated diff erences in the involvement of the various organs which would suggest an inconsistency in the ac va on of diving refl ex.The objec ve of the study was to assess the frequency and pa ern of involvement of each major organ system and combina on of organs in infants with post-asphyxial encephalopathy.

Material and Methods
This is a prospec ve study carried out on 60 asphyxiated term neonates who were admi ed on their fi rst day of life to the neonatal intensive care unit (NICU) of a ter ary care hospital in Pune over a period of two years from September 2012 to September 2014.

Inclusion criteria:
• Term neonates born intramural requiring resuscita on (bag and mask ven la on for 30 sec and above) and admi ed to NICU.
• Term neonates born outside with history of not having cried a er birth, having required resuscita on and referred within 24 hours of life.

Collection of data:
• Detailed birth history including all major events, resuscita on details, other neonatal and maternal data were recorded.
• Gesta onal age was assessed by last menstrual period and new Ballard score.
• All babies were thoroughly examined at the me of admission and each baby was followed up ll discharge with special emphasis on the aff ected organ system.
• Basic inves ga ons for evalua on of MOD were done as per NICU protocol.

Criteria for organ dysfunction:
• Central nervous system involvement: Detailed neurological examina on was done and features of CNS involvement like seizures, abnormal tone and altered sensorium were noted.Clinical classifi ca on of neurological status for HIE staging was done by modifi ed Sarnat and Sarnat's staging.Ultrasonography (USG) of brain was done within 48 hours of admission.Magne c Resonance Imaging (MRI) of brain and electroencephalogram (EEG) were done before discharge for babies who were HIE stage II or more.
• Cardiovascular system involvement: Hypotension (mean BP < 40 mm Hg) treated with inotropes and/or serum CPK-MB more than 25 IU/l.
• Hepa c involvement: Serum SGPT more than 60 IU/l at 24 hours of life.
• Gastro-intes nal tract: RT aspirates more than 30 % of total intake in last 6 hours.
Microso Excel 2007 and Microso Windows 2007 were used for analysis.Percentage of involvement of individual organs was calculated.

Results
From September 2012 through September 2014, 60 babies met the eligibility criteria.Data enabling the evalua on of all six organ systems was collected.Seven babies were excluded from the study.Four were referred a er 24 hours of life, one had congenital malforma on and resuscita on details were unavailable for two babies.

Discussion
As in our study, a high male to female ra o was also observed in studies conducted by Mar n-Ancel et al 3 , Mohammed LH et al 4 , Lin MH et al 5 , Shireen N et al 6 and Dalal EA et al 7 .These results concur with Futrakul et al found a sta s cally signifi cant rela onship between HIE and male gender 8 .Our study revealed a greater incidence of asphyxia in infants born to mul parous mothers as opposed to primi mothers in studies conducted by Dalal EA et al 7 and Shireen N et al 6 .Incidence of meconium stained liquor in our study was 40%.Mar n-Ancel et al 3 and Dalal EA et al 7 reported meconium stained liquor in 42% and 42.2% babies respec vely.
The pa ern of organ involvement in our study has been illustrated in Table 2. Mar n-Ancel et al found CNS, renal and cardiac involvement in 72%, 42.1% and 29% infants respec vely 3 .The variability in the reported incidence of MOD may be explained by diff erences in the inclusion criteria for studies, defi ni on of MOD and sample size of encephalopathic babies in our study.
Encephalopathy with seizures was present in 20% babies.Lin MH et al reported clinical seizures in 11.5% of term asphyxiated infants 5 .Five out of seven babies who underwent neuroimaging showed changes consistent with HIE.Neurosonography was normal in 29 (60%) babies without encephalopathy.Abnormali es detected included cerebral edema and bilateral germinal matrix hemorrhage.Noman F et al documented a normal ultrasound study of brain in 80% term neonates 9 .EEGs done in nine babies revealed evidence of mul focal epilep form discharges over various areas of the brain in six babies.Ajay Kumar et al 10 studied clinic-e ological and EEG profi le of 90 babies with seizures, demonstrated asphyxia as the cause for seizures in 40 babies and an abnormal EEG in 8(20%) babies.
Twenty (33%) babies had raised serum crea nine of which two also had raised blood urea.We observed oliguria in only 5(8%) babies which improved a er giving an intravenous normal saline bolus.Three babies showed rising serum crea nine but two of them showed a rise by 0.1 mg/dl which was considered insignifi cant.Serum crea nine levels showed a decreasing trend with subsequent normaliza on in all except one baby who developed non-oliguric acute kidney injury.The involvement of kidneys in 67% of cases in this cohort was comparable to the reported incidence in representa ve studies by Shah P et al 11 (70%) and Mohammed LH et al 4 (63.5%)refl ec ng the severity of asphyxia although we chose the middle of the spectrum of published defi ni ons and our sample size was small.Anomalies like hydronephrosis, pelviureteric junc on obstruc on and adrenal hemorrhage were found on abdominal sonography in 14% infants.Gupta BD et al demonstrated abnormali es on renal sonography in 6.6% cases in form of increased size, altered echo texture and loss of cor comedullary diff eren a on 12 .
GIT involvement was found in 13% neonates and had feed intolerance.Mar n-Ancel el al reported an incidence of 21% taking into account various features like presence of gastric residuals, vomi ng, abdominal distension or tenderness and gastrointes nal bleeding 3 .Hepa c in involvement was observed in 22% babies with 50% involvement among those with HIE and 14% among those without encephalopathy.Shah P et al 11 , Mohammed LH et al 4 and Tarcan A et al 13 demonstrated elevated liver enzymes at any me during the fi rst week of life in 85%, 35.1% and 39% infants with HIE.Lin MH et al concluded that there was no signifi cant diff erence in the eleva on of liver enzymes in babies with both mild and severe asphyxia 5 .Five (8.33%) babies had clinically appreciable murmurs.Hypotension was observed in 11 (18%) babies and all of them required inotropic support for maintaining blood pressures within normal range.Serum CPK -MB was elevated in 57 (95%) babies.Func onal 2D Echo showed structural abnormali es (patent ductus arteriosus, ventricular septal defect and patent foramen ovale) and func onal defects like tricuspid regurgita on in 13 (22%) babies.The high percentage of cardiovascular system involvement in our study is possibly due to inclusion of serum CPK-MB as one of the criteria which is a sensi ve marker of heart involvement.Primhak et al studied serial electrocardiogram and CK-MB in term infants and found that CK-MB was associated with myocardial injury in asphyxiated infants 14 .However, Omokhodion et al concluded that specifi city of CK-MB as a marker of myocardial injury in asphyxiated newborns is possible but remains uncertain 15 .
Our study showed a survival rate of 87%.Eight (13%) babies had taken discharge against medical advice.Among them, three had HIE and were on inotropic support.All of them had involvement of two or more organ systems.Lin MH 5 , Shireen N et al 6 , Khatoon 17 and Etuk 18 also demonstrated mortality rates of 9.8%, 16%, 25.4% and 20.8% in their respec ve studies.

Conclusion
Cardiovascular system involvement was most common, followed by renal, hepa c, central nervous, renal systems and lastly, the gastrointes nal tract.Babies with and without encephalopathy both showed highest incidence of cardiovascular system involvement.Survival rate was good.

Table 1 :
Showing the basic perinatal characteris cs of all the babies.

Table 2 :
Perinatal characteris cs, pa ern of organ involvement and outcome among babies with encephalopathy and without encephalopathy