Outcome of infants with hypoxic ischemic encephalopathy treated with brain hypothermia

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1 bs_bs_banner doi: /jog J. Obstet. Gynaecol. Res. Vol. 41, No. 2: , February 2015 Outcome of infants with hypoxic ischemic encephalopathy treated with brain hypothermia Takuya Tokuhisa 1, Satoshi Ibara 1, Hisanori Minakami 2, Yoshinobu Maede 1, Chie Ishihara 1 and Takako Matsui 1 1 Department of Neonatology, Perinatal Medical Center, Kagoshima City Hospital, Kagoshima, and 2 Department of Obstetrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan Abstract Aim: The aim of this study was to determine perinatal factors associated with cerebral palsy (CP) in infants treated with brain hypothermia (BHT). Material and Methods: We carried out a retrospective review of 23 infants with hypoxic ischemic encephalopathy in whom BHT was applied within 6 h after birth. Outcome regarding the presence or absence of CP was assessed at the age of 18 months. Oxygen extraction fraction (OEF) was measured before, during and after BHT at the jugular sinus. Results: Three infants died and 12 developed CP (poor outcome group). The remaining eight infants did not have CP at 18 months old (favorable outcome group). There were no differences in gestational age, birthweight, ph, base deficit, or lactate level between infants with favorable and poor outcomes. Infants with flat trace on electroencephalography on admission were less likely to have favorable outcome (0.0% [0/8] vs 53% [8/15], respectively, P = 0.02), while those with Apgar score at 10 min 5 (57% [8/14] vs 0.0% [0/9], P = 0.007) or 6 (70% [7/10] vs 7.7% [1/13], P = 0.002), OEF 13.3% during BHT (64% [7/11] vs 8.3% [1/12], P = 0.009), and OEF 18.5% after BHT (73% [8/11] vs 0.0% [0/12], P = 0.002) were more likely to have favorable outcome compared with those with counterpart characteristics. Conclusion: Infants with an Apgar score at 10 min 5, activity on electroencephalography on admission, and higher OEF during and after BHT were likely to have a favorable outcome. Key words: brain hypothermia, cerebral palsy, neonatal encephalopathy, hypoxemia, hypoxic ischemic encephalopathy. Introduction Although recent advances in perinatal medicine have improved perinatal and neonatal mortality rates, the outcome of neonatal hypoxic ischemic encephalopathy (HIE) associated with complications such as placental abruption and cord prolapse is unsatisfactory, often resulting in death or serious sequelae, such as cerebral palsy. 1,2 As the prevalence of cerebral palsy is 1 2 in 1000 live births 3,4 and intrapartum HIE accounts for approximately 10% of all cases of cerebral palsy, 5,6 HIEassociated cerebral palsy is uncommon, but is a serious issue when it does occur. Initial treatment may be important to avoid cerebral palsy associated with HIE. Brain hypothermia (BHT) is a treatment option for neonates with intrapartum HIE, and has been shown to be effective in some patients In a randomized trial of neonates born at or after 36 gestational weeks with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe Received: March Accepted: June Reprint request to: Dr Takuya Tokuhisa, Department of Neonatology, Perinatal Medical Center, Kagoshima City Hospital, Kajiya-chou, Kagoshima city, Japan. tokutaku0305@nifty.com 2014 The Authors 229

2 T. Tokuhisa et al. encephalopathy, 8 the risk of death or moderate or severe disability was reduced by 28% in neonates with whole-body hypothermia compared those with conventional care. 8 In another randomized trial of term neonates with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aeeg), 7 although induced head-cooling was not protective in a mixed population of infants with neonatal encephalopathy, it improved survival without severe neurodevelopmental disability among infants with less severe aeeg changes. 7 This retrospective study was conducted to determine perinatal factors significantly associated with neuromotor development among infants treated with BHT for HIE. Methods BHT was introduced in the treatment of infants with intrapartum HIE at Kagoshima City Hospital in This retrospective study was conducted with the approval of the institutional review board of Kagoshima City Hospital. Patient selection During the study period between January 2000 and July 2008, 5531 infants were admitted to the Neonatal Intensive Care Unit (NICU), Perinatal Medical Center, Kagoshima City Hospital, Japan (Fig. 1). Of the 5531 infants, 38 underwent BHT for treatment of HIE. All 38 infants fulfilled all of the following inclusion criteria: (i) gestational age at birth 36 weeks, weighing 2000 g with Apgar score 5 at10min,ph < 7.00 in initial blood sample, or requirement of resuscitation with assisted ventilation for 10 min; (ii) disturbance of consciousness, such as excitement and stupor, or neurological symptoms, such as hypotonia, abnormal reflex, and convulsions; (iii) abnormal tracing on the initial electroencephalogram (EEG) exhibiting a flat trace of 0 5 μv in background activity (maximal depression), burst suppression pattern (marked depression), or low amplitude of 5 20 μv in background activity (moderate depression); (iv) initiation of BHT within 6 h after birth; and (v) consent was given by parents. Exclusion criteria included chromosomal abnormalities, congenital heart disease, and intracranial hemorrhage. Figure 1 Patient selection. Patients in shaded column were analyzed in this study. BHT, brain hypothermia; NICU, neonatal intensive care unit The Authors

3 BHT in infants with HIE Of the 38 infants with BHT, three died at 7, 23, and 94 days old, and the remaining 35 survived to the neonatal period, but 14 infants were less than 18 months old at the analyses for this study (Fig. 1). Clinical data for the 23 patients, including 20 patients aged 18 months and three that died, were analyzed in this study after excluding 14 patients aged less than 18 months old at the analyses for this study (including one that was lost to follow-up). Blood levels of aspartate transaminase, creatinine, and creatine kinase were 193 ± 362 IU/L (median, 71 IU/L), 1.0 ± 0.3 mg/dl (1.1 mg/dl) and 2356 ± 4422 IU/L (685 IU/L), respectively, soon after birth in the 23 infants. Cooling methods and monitoring of core temperature BHT was initiated within 6 h after birth and continued for 72 h. Two types of BHT, the intravascular cooling method using extracorporeal membrane oxygenation (ECMO) and the surface cooling method using a cooling blanket, were applied according to the patient s condition. Of the 23 infants, five were treated with the intravascular method and 18 with the surface-cooling method. Intravascular cooling method (Fig. 2) The intravascular cooling method with ECMO was used in patients requiring cardiopulmonary support due to persistent fetal circulation. The internal jugular sinus was cannulated cephalad from the right internal jugular vein with a catheter (Fem-Flex, 8 12 F; Edwards Lifesciences) for application of ECMO. Whole-body hypothermia was achieved by passing the cooled blood back into the infants. The temperature of the internal jugular sinus (cephalic vein) and jugular venous oxygen saturation (Sj O2) were monitored with the blood withdrawn from the internal jugular sinus. The temperature of the internal jugular sinus was maintained between 34 C and 35 C. Surface-cooling method (Fig. 3) The surface cooling method was used in patients with stable cardiopulmonary status. The temperatures of the head and body were managed separately using a cooling blanket (Medi-Therm 2 Hyper/Hypothermia Machine MTA 5900 Series; Gaymar Industries). A fiberoptic catheter (Opticath, 5.5 F; Hospira) was inserted cephalad from the internal jugular vein. The catheter (Opticath) has sensor probes for measurement of temperature and oxyhemoglobin saturation and a Figure 2 Intravascular cooling method using extracorporeal membrane oxygenation (ECMO). Patients with persistent fetal circulation were treated with this cooling method. The internal jugular sinus was cannulated cephalad from the right internal jugular vein with a catheter (Fem-Flex, 8 to 12 F; Edwards Lifesciences) for application of ECMO. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. tip for blood sampling. The temperature of the internal jugular sinus (cephalic vein) was maintained between 34 C and 35 C. Rewarming was conducted at 0.5 C per 8 h after cessation of BHT and the infants were placed at 36 C for 24 h. Then, rewarming was started again at 0.5 C per 8 h until the temperature at the internal jugular sinus (cephalic vein) reached 37 C. EEG EEG was performed for 30 min on admission before initiation of BHT (8-channel electroencephalograph, NeuroFax EEG-5514; Nihon Kohden Corporation). The findings of EEG on admission were classified into the following five categories: (i) minimal depression (flattening of the low amplitude portion of the trace alternant); (ii) mild depression (disappearance of high voltage [ μv] slow wave); (iii) moderate depression (low voltage pattern [5 20 μv]); (iv) marked depression (appearance of burst suppression); and (v) maximal depression (flat trace [0 5 μv]). Moderate, marked, and maximal depressions were defined as abnormal EEG. 11 Only infants with an abnormal EEG were eligible for BHT in this study. Monitoring of oxygen delivery to the brain Arterial and jugular venous blood samples were obtained at the same time for determination of oxygen 2014 The Authors 231

4 T. Tokuhisa et al. Figure 3 Surface cooling method using a cooling blanket. Patients with stable cardiorespiratory status were treated with this cooling method. Left arrow indicates the tip of the fiberoptic catheter (Opticath, 5.5 F; Hospira) with a thermosensor, SO 2 sensor, and blood sampling port. The temperatures of the head and body were managed separately using a cooling blanket (Medi-Therm 2 Hyper/Hypothermia Machine MTA 5900 Series; Gaymar Industries). A fiberoptic catheter (Opticath) was inserted cephalad from the internal jugular vein (right arrow). saturation. The oxygen extraction fraction (OEF) was calculated as follows: OEF = (1 Sj O2/Sa O2) 100. The OEF is used to monitor the adequacy of cerebral oxygen delivery and is normally between 25% and 45% in adults. 12 Assessment of outcomes Infant neuromotor development was assessed at the age of 18 months regarding the presence or absence of cerebral palsy (CP). Poor outcome was defined as any of the following: death within 18 months after birth or development of CP, including hypotonic CP, athetoid CP, spastic diplegia, and spastic quadriplegia. Infants without CP at the age of 18 months were defined as having a favorable outcome. Statistical analysis Data are presented as means ± standard deviation. Statistical analyses were performed using jmp7. Differences between the means were tested using the Tukey Kramer honestly significant difference test between groups. Categorical variables were compared using Fisher s exact probability test. In all analyses, P < 0.05 was taken to indicate statistical significance. Results Of the 23 infants analyzed in this study, 15 exhibited poor outcomes (poor outcome [PO] group); three died and 12 developed CP (five developed hypotonic CP, two athetoid CP, three spastic diplegia, and two spastic The Authors

5 BHT in infants with HIE Table 1 Comparison of characteristics between the two groups divided by outcome Favorable group (n = 8) Poor group (n = 15) P-value Gestational week at delivery 37.9 ± ± Birthweight (g) 2723 ± ± < (25%) 4 (27%) (0.0%) 2 (13%) 0.53 ph 6.94 ± ± <6.8 1 (13%) 8 (53%) 0.09 Base deficit (mm) 18.9 ± ± >20 2 (25%) 9 (60%) 0.64 Lactate (mm) 10.6 ± ± >12 1 (13%) 5 (33%) 0.37 Time interval until BHT after birth (h) 4.0 ± ± >5.0 2 (25%) 6 (40%) 0.65 Apgar score 5 (1 min) 2 (25%) 1 (7%) (5 min) 5 (63%) 5 (33%) (10 min) 8 (100%) 6 (40%) (10 min) 7 (88%) 3 (20%) Determined in the arterial cord blood or arterial blood on admission to the neonatal intensive-care unit. quadriplegia) (Tables 1 and 2). The remaining eight infants did not have CP at 18 months old, and had a favorable outcome (favorable outcome [FO] group). There were no significant differences in: gestational age at birth, birthweight, ph, base deficit, lactate level determined in the arterial cord blood or arterial blood on admission to the NICU, or time interval until initiation of BHT after birth between the two groups (Table 1). Percentage of neonates with Apgar scores 5 at 1 and 5 min did not differ between two groups, but those with Apgar scores of 5 and 6 at 10 min were significantly higher in the FO group than the PO group (Table 1, Fig. 4). Thus, infants with an Apgar score of 5 at 10 min (57% [8/14] vs 0.0% [0/9], P = 0.007) or those with an Apgar score of 6 at 10 min (70% [7/10] vs 7.7% [1/13], P = 0.002) were significantly more likely to have a favorable outcome than those with counterpart characteristics (Fig. 4). On EEG at admission to the NICU, nine (four with favorable outcome and five with poor outcome), six (four with favorable outcome and two with poor outcome), and eight (none with favorable outcome and eight with poor outcome) infants showed moderate depression (low voltage pattern), marked depression (burst suppression pattern), and maximal depression (flat trace), respectively (Table 2). Thus, infants with maximal depression (flat trace with no background activity) on admission EEG were significantly less likely to have a favorable outcome than those with moderate or marked depression (0.0% [0/8] vs 53.3% [8/15], respectively, P = 0.01). The OEF monitored at the jugular sinus was 34.3% ± 12.3%, 18.0% ± 4.0%, and 32.1% ± 10.1% before, during, and after BHT in the FO group, respectively, while corresponding values were 26.1% ± 8.2%, 8.0% ± 5.3%, and 14.6% ± 7.7% in the PO group (Table 3, Fig. 5). The OEF decreased significantly after initiation of BHT and increased significantly after cessation of BHT in both the FO and PO groups (Table 3). Although the mean OEF before BHT did not differ significantly, those during and after BHT were significantly higher for the FO group than the PO group. Median OEF value for the 23 neonates was 29.4% before BHT, 13.3% during BHT, and 18.5% after BHT. The numbers of infants with OEF 13.3% during BHT and OEF 18.5% after BHT were significantly greater in the FO group than in the PO group (Table 3). Thus, infants with OEF 13.3% during BHT (64% [7/11] vs 8.3% [1/12], respectively, P = 0.009), and OEF 18.5% after BHT (73% [8/11] vs 0.0% [0/12], respectively, P = 0.002) were significantly more likely to have a favorable outcome. Correlations between OEF levels after BHT, Apgar score at 10 min, maximal depression on EEG, and infant outcome are shown in Figure 6. Among 14 patients with Apgar score 5 at 10 min, four patients 2014 The Authors 233

6 T. Tokuhisa et al. Table 2 Clinical details of 23 patients undergoing brain hypothermia Case GW BW FHR BHT ph BD Lactate Apgar EEG Outcome (g) (mm) (mm) (1, 5, & 10 min) Brad IV , 3, 5 Mod Favorable Brad S , 4, 6 Mod Favorable Brad S , 5, 7 Marked Favorable LD S , 2, 6 Marked Favorable LD S , 7, 7 Mod Favorable Brad S , 6, 6 Marked Favorable Brad S , 7, 7 Marked Favorable LD S , 7, 7 Mod Favorable Brad IV , 4, 4 Max HCP Brad IV , 4, 4 Max HCP Brad IV , 2, 4 Mod HCP Brad S , 0, 4 Mod HCP Brad S , 4, 5 Max ACP Brad S , 7, 7 Max HCP SVD S , 6, 6 Mod ACP SVD S , 4, 4 Marked SD SVD S , 5, 5 Mod SQ SVD S , 6, 7 Mod SD SVD S , 5, 5 Marked SD S , 2, 2 Max SQ Brad IV , 1, 2 Max Death SVD S , 0, 0 Max Death Brad S , 1, 1 Max Death Determined in the arterial cord blood or arterial blood on admission to the neonatal intensive-care unit. ACP, athetoid cerebral palsy; BD, base deficit; BHT, brain hypothermia; Brad, prolonged bradycardia; BW, birthweight; EEG, electroencephalogram; FHR, fetal heart rate monitoring; GW, gestational week at delivery; HCP, hypotonic cerebral palsy; IV, intravascular cooling method; LD, repeated late deceleration; Marked, marked depression; Max, maximal depression; Mod, moderate depression; S, surface cooling method; SD, spastic diplegia; SQ, spastic quadriplegia; SVD, severe variable deceleration. Figure 4 Correlations of Apgar scores at 1, 5, and 10 min with infant outcome. Open, shaded, and closed circles indicate infants with favorable outcome, cerebral palsy, and death, respectively. Patients with maximal depression on electroencephalography The Authors

7 BHT in infants with HIE Table 3 Changes in oxygen extraction fraction monitored at the jugular sinus in the two groups Favorable group (n = 8) Poor group (n = 15) P-value Before BHT 34.3% ± 12.3% 26.1% ± 8.2% (63%) 7 (47%) 0.67 During BHT 18.0% ± 4.0%* 8.0% ± 5.3%* (88%) 4 (27%) After BHT 32.1% ± 10.1% 14.6% ± 7.7% (100%) 3 (20%) *P < 0.05 vs values obtained before and after BHT within group. Median value of 23 infants. BHT, brain hypothermia. Figure 5 Oxygen extraction fraction (OEF) monitored at the jugular vein before, during, and after brain hypothermia. Open, shaded, and closed circles indicate infants with favorable outcome, cerebral palsy, and death, respectively. Patients with maximal depression on electroencephalography. with the lower four OEF levels developed CP exclusively, even though two (Cases 15 and 19 in Table 2) of the four exhibited an EEG activity on admission. Five infants who met all three conditions, including Apgar score 6 at 10 min, no maximal depressions on EEG, and OEF 35% after BHT, did not have CP at 18 months old (Fig. 6). Discussion Figure 6 Correlations between oxygen extraction fraction (OEF) after brain hypothermia (BHT), Apgar score at 10 min, maximal depression on electroencephalography (EEG), and infant outcome. Open, shaded, and closed circles indicate infants with favorable outcome, cerebral palsy, and death, respectively. Patients with maximal depression on EEG. BHT is an established therapy in term neonates to reduce death and disability due to HIE. 13,14 However, it is very important to determine reliable early predictors as they may allow both selection of infants for therapy and guide withdrawal of care. The present study demonstrated that higher OEF at the jugular sinus during and after BHT were significantly associated with favorable outcome among infants who underwent BHT for treatment of HIE, suggesting that the OEF during and after BHT were predictive of later mortality and the development of cerebral palsy. To our knowledge, there have been no previous reports of brain OEF in infants undergoing BHT for treatment of HIE. In this study, 73% (8/11) of infants with OEF 18.5% after cessation of BHT showed a favorable outcome without cerebral palsy at age 18 months, whereas infants with OEF < 18.5% exclusively showed poor outcome (Table 3, Fig. 5). Oxygen consumption and oxygen metabolism are reduced in brain-dead organ donors. 15,16 As expected from the equation for determination of OEF, a high Sj O2 results in a low OEF in the presence of constant Sa O2. In adults, global cerebral hyperemia and ischemia are defined as Sj O2 > 75% and 2014 The Authors 235

8 T. Tokuhisa et al. <55%, respectively. An extremely high Sj O2 with an extremely low OEF was suggested to be a signal of irreversible brain damage and near brain death. 17 High Sj O2 values with low OEF are probably primarily a consequence of a decrease in cerebral oxygen consumption. Indeed, high Sj O2 was reported in adult patients with severe brain damage. 18 Adult patients with favorable outcome after resuscitation from cardiopulmonary arrest show a decrease in Sj O2 and increase in OEF during BHT. 12 Thus, OEF may reflect the degree of brain injury. Patients with a low OEF < 18.5% after cessation of BHT may have had irreversible brain damage and therefore died or developed cerebral palsy exclusively in this study. As oxygen consumption, oxygen metabolic rate, and OEF in the brain are considered to decrease with decreasing body temperature, 19,20 the present observations that the OEF decreased significantly after initiation of BHT and increased significantly after cessation of BHT were expected. Although not verified in this study, this hypothermia-induced decrease in OEF may be involved in the neuroprotective effect of BHT. After brain injury due to hypoxia and ischemia (initial brain damage), secondary brain damage is exacerbated by cerebral reperfusion (with oxygen) caused by resuscitation. 21 Although brain damage is caused by various factors, including release of excitatory amino acids and Ca 2+ influx into cells, 22 an increase in free radical production derived from oxygen reduced by one electron may also play a role in secondary brain damage. Decrease in OEF and low oxygen consumption during BHT may have contributed to the lesser degree of oxygen-induced secondary brain injury in the present study. There are currently three major predictors of mortality and morbidity in cases of HIE: Apgar score, 23 EEG, 24,25 and clinical severity of encephalopathy. 8,9 In this study, all of the nine infants with an Apgar score <5 at 10 min died or developed cerebral palsy, while 57% of 14 infants with Apgar score 5 exhibited a favorable outcome (Tables 1 and 2), consistent with the results of a recent study 23 in which Apgar score at 10 min was shown to be a useful prognostic indicator before other evaluations are available for infants with HIE; 23 each point decrease in Apgar score at 10 min was associated with a 45% increase in the odds of death or disability, and death or disability occurred in 76%, 82%, and 80% of infants with 10-min Apgar scores of 0, 1, and 2, respectively. 23 The predictive correlation between the 5-min Apgar score and neonatal mortality was already established among a cohort of singleton preterm and term newborns in a retrospective study from a single institution. 26 Thus, although the interobserver reliability of assigning Apgar scores and equal weighting of the components of the Apgar score remain a concern, the 10-min Apgar score is also clinically useful for predicting outcome as the Apgar score uses readily available observations and can be acquired without interfering with delivery room care. In this study, a flat trace on early EEG within 6 h after birth was predictive of poor outcome; death or disability occurred in 100% (8/8) of infants with maximal depression (flat trace [0 5 μv]), while less severe depression, such as moderate and marked depression on EEG, could not differentiate between patients with favorable and poor outcomes. Poor outcome occurred in 56% (5/9) and 33% (2/6) of infants with moderate and marked depression, respectively, in this study. Pathological amplitudeintegrated EEG (aeeg) as well as classical EEG (ceeg) background as early as 3 6 h after birth, were shown to be correlated with poor prognosis in HIE infants before the BHT era. 19,20,27,28 However, after the clinical introduction of BHT for treatment of HIE, only those with aeeg abnormalities persisting at and beyond 24 h after birth showed poor neurological outcome. 24 Early normalization of aeeg and early onset of sleep wake cycle predict good outcome among HIE infants treated with BHT. 25 Thus, early aeeg patterns can be used to predict outcome among infants treated with normothermia, but not hypothermia. 25 Infants with good outcome had normalized background pattern by 48 h when treated with BHT. 25 However, it has been shown that BHT had no effect in infants with the most severe aeeg changes, but was beneficial in infants with less severe aeeg changes. 7 In the eight patients with maximal depression on early ceeg in this study, ceeg findings may not have changed to normalized background pattern by 48 h, and therefore they died or developed cerebral palsy. In conclusion, eight of the 23 HIE infants treated with BHT exhibited favorable outcome without CP at 18 months old. Apgar score 5 at 10 min, no maximal depressions of EEG on admission, and higher OEF of 13.3% and 18.5% during and after BHT, respectively, were associated with favorable outcome. None of the five infants with all three conditions, including Apgar score 6 at 10 min, no maximal depressions of EEG on admission, and OEF 35% after BHT, had CP at 18 months old The Authors

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