Multi-Organ Dysfunction in Neonates with Hypoxic-Ischemic Encephalopathy

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1 Med. J. Cairo Univ., Vol. 78, No., December , Multi-Organ Dysfunction in Neonates with Hypoxic-Ischemic Encephalopathy LAILA H. MOHAMMED, M.D.; MAI A.KHAIRY, M.D.; NAGY A. EL-HUSSIENY, M.D.*; MOHAMMED H. ZAAZOU, M.D.* and RAGHDAA M. ALY, M.D.* The Departments of Pediatrics, Faculty of Medicine, Cairo University and Ahmed Maher Teaching Hospital*. Abstract Perinatal hypoxic-ischemic cerebral injury remains an important recognized cause of cerebral palsy. Most cases of hypoxic-ischemic encephalopathy (HIE) result from injury in the prenatal period secondary to intrauterine asphyxia, with disturbance of gas exchange across the placenta. The aim of this study was to assess the patients of hypoxicischemic encephalopathy regarding the patterns of each organ/ system dysfunction in relation to the outcome and also assessment of occurrence of multi-organ/system dysfunction and its relation to outcome and the severity of acidosis. Our study included full term neonates diagnosed as HIE. Data wre collected from patients files including full maternal history, detailed neonatal history, general and systemic examination, laboratory studies and the outcome of each one. Some risk factors associated with HIE were assessed among our patients. Meconium staining of the amniotic fluid was found to be the most common risk factor in our study. Multi-organ dysfunction occurred in 74% of cases, with the renal dysfunction being the commonest to occur followed by pulmonary dysfunction. While regarding the outcome, cardiovascular dysfunction was associated with the highest incidence of mortalities followed by pulmonary dysfuncction. We also found that two-organ dysfunction was the commonest to occur followed by one-organ dysfunction. Highly significant relation was found between the number of organ dysfunction and the occurrence of death. Among all our patients ( patients), death occurred in 4% of cases, while 6% of cases were discharged. On the other hand, death occurred in 39 cases (5.7%) among the the multi-organ dysfunction (MOD) group (74 patients) while 35 patients (47.9%) were discharged. Key Words: Organ Dysfunction MOD Neonates Hypoxic ischemic encephalopathy. Correspondence to: Dr. Laila H. Mohammed, the Department of Pediatrics, Faculty of Medicine, Cairo University. Introduction NEONATAL hypoxic-ischemic encephalopathy (HIE), the most common neurologic complication in the perinatal period, is a major cause of chronic disability in childhood []. HIE is termed as neonatal encephalopathy that results from systemic hypoxemia and decreased cerebral perfusion leading to ischemia []. Etiology of perinatal HIE includes those circumstances that can affect the cerebral blood flow in the fetus and neoborn compromising the supply of oxygen to the brain. They may develop antepartum (%), intrapartum (3%), intrapartum and antepartum (35%), or postpartum (%). HIE develops in the setting of perinatal asphyxia, which is a multi-organ system disease [3]. Hypoxia and ischemia can cause damage to almost every tissue and organ of the body and various target involved have been reported to the kidneys in 5%, followed by central nervous system (CNS) in 8%, cardiovascular system (CVS) in 5% and lungs in 3% cases [4]. Multi-organ dysfunction (MOD) is one of 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 at the cost of non-vital ) (Shah et al., 4). Excessive stimulation of glutamate receptors appears to play an important role in the pathogenesis of neonatal brain injuries caused by lack of oxygen [5]. Improved understanding of the pathophysiological mechanism involved in perinatal brain lesions 46

2 46 Multi-Organ Dysfunction in Neonates with Hypoxic-Ischemic Encephalopathy helps to identify potential targets for neuroprotective interventions [6]. Aim of the work: To assess the patterns of involvement of each major organ/system and combinations of involvement in infants with post-asphyxial hypoxicischemic encephalopathy. Patients and Methods This is a retrospective study carried out on hypoxic-ischemic neonates who were admitted on their first day of life to the Neonatal Intensive Care Unit (NICU) in Kasr El-Aini University and Ahmed Maher Teaching Hospitals, Cairo, Egypt, over a period of 8 months from June 7 to December 8. Inclusion Criteria (Neonates with HIE criteria): - Having one or more of the followings: Five minutes Apgar score of <5, and/or metabolic acidosis indicated by a base deficit >_ 6mmol/L, and/or delayed onset of respiration for five or more minutes. - Neonates who needed mechanical ventilation. 3- Neonates with evidence of encephalopathy as altered consciousness and/or seizures. Exclusion Criteria: - Preterm babies (<37 weeks gestation). - Babies with congenital anomalies including dysmorphism, congenital viral infections, inborn errors of metabolism,and hemorrhagic shock without evidence of intrapartum asphyxia. Data were collected from patients files as follows: - Full maternal history including personal (name, age, gravidity and parity) and medical (anemia, hypertension, diabetes mellitus and drug intake). - Detailed obstetric history (duration of pregnancy, number of births, mode of delivery and occurrence of complications as APH, PROM, MSAF and cord around the neck). 3- Neonatal history (estimated gestational age, sex, Apgar score at and 5 minutes and method of resuscitation if needed). 4- Clinical examination including general (RR, HR, ABP and TEMP.) and systemic (neurological, chest, heart and abdominal). 5- Laboratory studies: CBC, ABG, liver function tests (ALT, AST, SB), kidney function tests (BUN, S.CREAT., Na + and K + ). 6- Cranial ultrasonography (whenever available). 7- Outcome whether death or discharge. Outcome was studied in relation to individual organ dysfunctions and in relation to number of organ/system involved. All patients were then divided into two groups, the first group included patients with PH<7, and the second one included patients with PH >_7. Both groups were then compared regarding mode of delivery, risk factors, distribution of organ affection, the occurrence of multi-organ affection and the relation to the outcome. Criteria for organ/system dysfuncyion: Renal dysfunction: Anuria or oliguria (.5<ml/Kg/hr) for 4 hours or more, and/or serum creatinine concentration more than mg%, and/or serum urea concentration more than 4mg%. Cardiovascular dysfunction: Hypotension treated with ionotropes for more than 4 hours to maintain blood pressure within the normal range. Pulmonary dysfunction: Need for ventilatory support with oxygen requirement more than 4% during the first 4 hours of life. Hepatic dysfunction: Aspartate aminotransferase > IU/I or alanine aminotransferase > IU/I at any time during the first week after birth. Gasteroinetestinal dysfunction: GIT bleeding with or without vomiting or abdominal distention. Hematologic dysfunction: Signs of DIC with bleeding tendency. Statistical Analysis: We used computer programs Microsoft Excel 3 (Microsoft corporation, NY, USA) and SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version for Microsoft Windows.

3 Laila H. Mohammed, et al. 463 Results Table (): Sex distribution among cases. Sex distribution Number Percentage Males 57 Females 43 Table (): Mode of delivery among cases. Mode of Vaginal delivery Cesarean section delivery N=54 N=46 ph 7 46 (5.%) 4 (47.8%) 8 (66.7%) 4 (33.3%) p-value: % 43% total 88 (88%) (%) Table (3): Maternal and obstetric problems among cases. Obstetric problems n=88 n= n= p-value Maternal diseases (88.9)% (.%) (8%) Placental abnormalities (66.7%) (33.3%) (6%) Table (5): Mean and standard deviation of laboratory parameters among the studied cases. Laboratory parameters Minimum Maximum Mean Std. deviation ph po pco HCo BE Hb TLC PLT BUN Creatinine Na K Bilirubin ALT AST Table (6): Occurrence of multi-organ dysfunction (MOD) among cases. MOD yes n=88 63 (85.3%) n= (4.86%) n= 74 (74%) PROM (84.6%) (5.4%) (3%) No 5 (96.5%) (3.84%) 6 (6%) Meconium staining (85.3%) (4.7%) (34%) Cord around neck (%) (4%) Obstructed labor (84.%) (5.8%) (9%) Table (4): Clinical presentation of the studied neonates. Clinicalpresentation Number percentage -Neurological: a-convulsions 9 9% b-lethargy 48 48% c-irritability 4 4% -Respiratory: a-delayed initiation of respiration 5 5% b-respiratory distress 4 4% c-meconium aspiration 34 34% 3-Renal: a-anuria 6 6% b-oliguria 4 4% 4-Gastrointestinal: a-abdominal distention % b-vomiting 5 5% c-git bleeding 4 4% 5-Cardiac: a-hypotension % b-tachycardia 5 5% 74% MOD Fig. (): Occurrence of multi-organ dysfunction (MOD) among cases. Table (7): Distribution of organ dysfunction among MOD group. Organ/system N=63 N= N=74 p-value Renal (89.3%) (.7%) (63.5%) Pulmonary (85.7%) (4.3%) (47.3%) Hepatic (84.7%) (5.3%) (35.%) Cardiac (9.4%) (9.6%) (8.4%) Gastrointestinal 4.3 (5%) (5%) (5.4%) Hematological.6 (%) (.35%)

4 464 Multi-Organ Dysfunction in Neonates with Hypoxic-Ischemic Encephalopathy Table (8): Distribution of organ dysfunction in relation to outcome. Organ/system Renal Pulmonary Hepatic Cardiac Gastrointestinal Hematological Discharge N=35 5 (3.8%) (5%) N=39 6 (76.9%) (5%) (%) N=74 (8.4%) 4 (5.4%) (.35%) p-value Four (46.8%) (53.9%) (63.5%) Five (37.4%) (6.85%) (47.3%) Fig. (3): Number of organ dysfunction among the MOD group (46.5%) (53.84% (35. %) Table (): Relation between number of organ dysfunction and outcome Number of organ affection One organ Two Dischage N=35 (7.4%) 3 (36.%) N=39 8 (8.6%) 3 (63.9%) One organ Two Three n= Renal pulmonary Hepatic Cardiac Gastrointestinal Fig. (): Relation between organ dysfunction and outcome. Hematological Three Four Five p-value: < (4.3%) (%) 6 (85.7%) (%) Table (9): Number of organ dysfunctions among MOD group. Number of organ dysfunction n=63 n= One organ 3 5 (3.8%) (6.75%) Two 3 5 (4.89%) (6.75%) Three 7 (9.45%) Four (.35%) (.35%) Five (.35%) n=74 Fig. (4): Relation between number of organ dysfunction and outcome. Table (): Relation between ph and outcome among the whole group. Outcome n=88 n= One organ p-value:. Two N=4 3 (34%) (83%) Three Four Discharge N=6 58 (66%) (7%) Five N= 88 (88%) (%)

5 Laila H. Mohammed, et al. 465 Table (): Relation between ph and outcome among the MOD group. Outcome p-value:.6 N=39 Discharge N=35 N= (46%) (54%) (85.3%) (9.9%) (9.%) (4.87%) Discussion Hypoxic ischemic brain injury during the perinatal period remains the single major cause of acute mortality and chronic disability in newborn infants, leading to permanent neurodevelopmental sequelae [7]. In spite of major advances in technology and knowledge of fetal and neonatal pathology and pathophysiology, HIE remains a serious condition leaving significant handicaps in % of survivors of severe HIE and in 3% of survivors of moderate HIE [8]. This retrospective study included hypoxic ischemic neonates who were admitted on their first day of life to the NICU at Kasr El Aini university and Ahmed Maher Teaching Hospitals over a period of 8 months from june 7 to december 8. In our study, 57% of our patients were males, while 43% were females. These results concur with Futrakul et al. [9], who studied the risk factors of HIE in 84 neonates and found out that there was a statistically significant relationship between HIE and male gender. Parkash and Das [], also found a significant relationship between HIE and male gender and their study under the risk factors of HIE. Concerning the mode of delivery in our study, 54% of our patients were delivered by vaginal delivery, while 46% of them were delivered by cesarean section. This agrees with Butt et al. [] who carried out the study on the risk factors of HIE on 53 neonates diagnosed as hypoxic ischemic encephalopathy, and they found that vaginal delivery occurred in 76.5% of cases while cesarean section occurred in 3.5% of cases. On the other hand, our results disagree with Kaye [] who stated that cesarean section was highly associated with HIE. According to Milsom et al. [3], emergency cesarean section was more frequent in HIE. The variation in different studies concerning the mode of delivery may be explained by the fact that neonatal encephalopathy may originate early in the antepartum period in some cases of HIE. The recorded risk factors in our study were maternal diseases, placental abnormalities, PROM, meconium staining, cord around the neck and obstructed labour. Our results revealed that meconium staining was the commonest risk factor (34%). This is in agreement with Ross and Gala [4] who considered the presence of meconium-stained amniotic fluid a strong evidence of fetal distress. Also, Shrestha et al. [5] studied the risk factors of HIE and showed that meconium staining of the amniotic fluid was the commonest risk factor reaching up to 65% of cases. On the contrary, Majeed et al. [6] found that absence of antenatal care was the commonest risk factor among their study which included 5 neonates with HIE. It occurred in 64% of cases, while meconium stained amniotic fluid occurred only in 9.6% of cases. Absence of antenatal care was also the commonest risk factor of HIE according to West et al. [7]. Since our study is a retrospective one, this makes it difficult to discuss antenatal care as a risk factor for HIE due to lack of data about the antenatal period. In our study the clinical presentations of the patients showed evidence of encephalopathy with or without manifestations of other organ dysfunction where convulsions were the commonest presentation recorded in 9% of cases, followed by lethargy in 4% of cases. Our results disagree with Afzal et al. who carried out a study analyzing the risk factors of HIE, they found that lethargy was the commonest neurological presentation (5%) followed by irritability (36%) while convulsions were the least to occur (8%). Concerning the occurrence of multi-organ dysfunction in our study, 74% of our patients had at least one-organ dysfunction in addition to the CNS affection. This result agrees with Shankaran et al. [8]who studied the occurrence of multi-organ dysfunction in 6 hypoxic ischemic neonates and they found that 73% of their patients had evidence of multi-organ dysfunction while Wheeler et al. [9]recorded higher incidence of multi-organ dysfunction in their study. They found that multi-organ dysfunction occurred in 95% of their patients. The distribution of organ dysfunction among the MOD group was studied. Our results revealed that renal dysfunction was the commonest to occur (64%) followed by pulmonary dysfunction (47%). This agrees with Zlatnik et al., who found that renal dysfunction was the commonest to occur (4%) followed by pulmonary dysfunction (6%). According to Tekin [9], renal dysfunction was also the commonest to occur followed by pulmonary dysfunction. On the other hand, our results disagree

6 466 Multi-Organ Dysfunction in Neonates with Hypoxic-Ischemic Encephalopathy with Higgins et al. [] who carried out a retrospective study on 3 term neonates with perinatal asphyxia, they found that pulmonary dysfunction was the commonest to occur (86%, followed by hepatic dysfunction in (85%) of cases, the renal dysfunction in (7%) of cases and the least organ/system dysfunction was cardiovascular dysfunction in 6% of cases. The range of organ involvement varies among different studies, depending in part upon definitions used for perinatal asphyxia and upon criteria of organ dysfunction. Despite the fact that the cause of death in MODS is multi-factorial, our study revealed that the occurrence of death was the highest among patients with cardiovascular dysfunction (76%) followed by pulmonary dysfunction (63%) and then renal dysfunction (53%). The p-value was statistically significant in the cases of renal dysfunction and was highly significant in cases of cardiovascular and pulmonary dysfunctions. On the contrary, Chauhan et al., found that renal dysfunction was associated with the highest adverse outcome (67%) followed by cardiovscular dysfunction (63%). These differences may be explained by the fact that adverse outcomes according to them referred to death or CP while in our study adverse outcome refers to death only. Also, Devarajan and Woroniecki [] found that mortality rate in the presence of renal dysfunction was 8% when associated with multi-organ failure, although death was almost never caused by renal failure. The number of organ/system dysfunction was also studied and we found that two organ dysfunction was the commonest to occur (49%) followed by one organ dysfunction (38%). In a similar study carried out by Shah et al. [], one-organ dysfunction occurred in 5% of cases, two-organ dysfunction occurred in 5% of cases, three-organ dysfunction occurred in 33% of cases and four-organ dysfunction occurred in 37% of cases. Another similar study was carried out by Bennet et al. [3], they found one-organ dysfunction occurred in 47% of cases, two-organ dysfunctioon occurred in 7% of cases, three-organ dysfunction occurred in 3%of cases and four-organ dysfunction occurred in % of cases. The relation between additional dysfunction and adverse outcome "death" was also studied. It was found that the highest incidence of death occurred in cases of four-organ dysfunction representing % of cases followed by three-organ dysfunction representing 86% of cases showing a high statistical significance. Despite the difference in defining the term "adverse outcomes", Chauhan et al. [4] recorded nearly the same results. Finally, the outcomes (whether death or discharge) were studied in relation to the ph of the whole group and the MOD group. Regarding the whole group, the relation between death and ph was statistically highly significant with p-value less than. and it was significant in the MOD group with p-value.6. In conclusion, we found evidence in support of the MOD criterion in the definition of asphyxia, with renal dysfunction being the most commonly occuring dysfunction. Increased number of organ dysfunctions was strongly associated with increased incidence of mortalities. No correlation was found between the severity of acidosis and increased number of organ dysfunctions. Recommendations: Prevention of hypoxic ischemic encephalopathy in utero by proper antepartum and intrapartum surveillance of all deliveries specially high risk groups. Optimizing obstetric care is important to limit many neurological damages by using new techniques to detect fetal distress. Special care should be directed for early recognition of symptoms and signs of target organ expected to be affected by hypoxia. Special care should be directed towards neonates with multi-organ dysfunction. Applying new approaches in treatment specially the neuroprotective techniques as hypothermia and other new modalities of treatment. References - YONEDA S., IBARA S., KOBAYASHI K., KATO E., MARUYAMA Y., MARUYAMA H., SUMIDA Y., SU- NAMI R., SAKAI M., IKENOUE T. and SAITO S.: Low adjusted serum ionized calcium shortly after birth predicts poor outcome in neonatal hypoxic-ischemic encephalopathy: J. Obstet. Gynecol. Res., 3 (): pp 57-64, 5. - FAHEY J.O. and KING T.L.: Intrauterine asphyxia; neonatal encephalopathy, hypoxic-ischemic encephalopathy and cerebral palsy. J. Midwife Women s health, 5 (6): pp , LEGIDO A., KATSETOS C., MISHRA O. and DELIVOR- IA-PAPADOPOULOS M.: Perenatal hypoxic ischemic encephalopathy; current and future treatments. International pediatrics, 5 (3): pp 43-5,. 4- GUPTA B.D., SHARMA P., BALGA J., PARAKH M. and SONI J.P.: Renal Failure In Asphyxiated Neonates. Indian pediatrics, 4: pp 98-34, JOHNSTON M.V.: Excitotoxicity in neonatal hypoxia. Ment. Retard. Dev. Disabil. Res., 7: pp 9-34,.

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