Therapeutic Hypothermia Treatment Research Articles

Urinary metabotypes of newborns with perinatal asphyxia undergoing therapeutic hypothermia.

Perinatal asphyxia (PA) still occurs in about three to five per 1,000 deliveries in developed countries; 20% of these infants show hypoxic-ischemic encephalopathy (HIE) on brain magnetic resonance imaging (MRI). The aim of our study was to apply metabolomic analysis to newborns undergoing therapeutic hypothermia (TH) after PA to identify a distinct metabotype associated with the development of HIE on brain MRI. We enrolled 53 infants born at >35 weeks of gestation with PA: 21 of them showed HIE on brain MRI (the "HIE" group), and 32 did not (the "no HIE" group). Urine samples were collected at 24, 48 and 72 hours of TH. Metabolomic data were acquired using high-resolution mass spectrometry and analyzed with univariate and multivariate methods. Considering the first urines collected during TH, untargeted analysis found 111 relevant predictors capable of discriminating between the two groups. Of 35 metabolites showing independent discriminatory power, four have been well characterized: L-alanine, Creatine, L-3-methylhistidine, and L-lysine. The first three relate to cellular energy metabolism; their involvement suggests a multimodal derangement of cellular energy metabolism during PA/HIE. In addition, seven other metabolites with a lower annotation level (proline betaine, L-prolyl-L-phenylalanine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E, 2,6 dimethylheptanoyl carnitine, Octanoylglucuronide, 19-hydroxyandrost-4-ene-3,17-dione) showed biological consistency with the clinical picture of PA. Moreover, 4 annotated metabolites (L-lysine, L-3-methylhistidine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E) retained a significant difference between the "HIE" and "no HIE" groups during all the TH treatment. Our analysis identified a distinct urinary metabotype associated with pathological findings on MRI, and discovered 2 putative markers (L-lysine, L-3-methylhistidine) which may be useful for identifying neonates at risk of developing HIE after PA.

Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild-Moderate Neonatal Hypoxia-Ischemia Brain Injury Model.

Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2–3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3–10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate–severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild–moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild–moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild–moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild–moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild–moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.

Therapeutic Hypothermia on Transport: The Quest for Efficiency: Results of a Quality Improvement Project.

Introduction:Therapeutic hypothermia (TH) within 6 hours after birth is known to improve both survival and neurodevelopmental outcomes in neonates with hypoxic ischemic encephalopathy (HIE). Meeting this recommended target temperature for neonates who require transport for TH treatment can be complex for various reasons. This study aimed to reduce the time from birth to the initiation of TH and target temperature, thereby increasing the proportion of transported neonates reaching target temperature within 6 hours to >50%.Methods:We evaluated the effect of three quality improvement interventions, including revised transport team processes, outreach education/resources, and the use of a servo-controlled cooling device on land transports. We compared key outcome TH metrics for cohorts before and after implementation.Results:The study team compared baseline data for 77 to 102 neonates born between 2009 and April 2015 (preintervention) and September 2015 and September 2020 (postintervention(s)). We observed reductions in both the time from birth to the initiation of passive cooling (38%) and time to reach target TH temperature (23%), with an increase in the proportion of neonates reaching target temperature by 6 hours of age from 50% to 71%.Conclusions:We used quality improvement methodology to identify key areas for intervention(s) and improvement. Targeted interventions have successfully and consistently improved the timing and delivery of TH to neonates with hypoxic ischemic encephalopathy within the transport environment, with a 20% increase in neonates reaching target temperature by 6 hours of age.

Fluid Supply and Feeding Practices in Cooled Asphyxiated Newborns.

Therapeutic hypothermia (TH) for 72 h is the standard treatment to reduce neurological deficits in term newborns with hypoxic-ischemic encephalopathy. There is a large variability regarding nutritional supply during TH treatment in asphyxiated newborns. We performed a retrospective multicentre study in four level I (highest level of care in Germany) NICUs, including 135 asphyxiated term newborns undergoing TH. We analyzed enteral and parenteral nutritional supply during and after TH. We correlated nutritional supply with risk factors for encephalopathy, pH, Sarnat score, mechanical ventilation, seizures, and sedation. A total of 120 of 135 neonates received enteral nutritional supply within the first 24 h, and the majority of children were fully enterally fed within the first 10 days. The grade of encephalopathy and mechanical ventilation had a significant influence on the amount of enteral fluids (p = 0.01), whereas the pH and appearance of seizures did not affect the amount of nutritional supply significantly. Furthermore, we did not observe any correlation between enteral intake and abdominal complications such as necrotizing enterocolitis. We observed a large variability of feeding regimes in the four participating NICUs. Early enteral feeding among newborns undergoing TH was performed in each NICU and was well tolerated without increased rates of complications.

Process variations between Swiss units treating neonates with hypoxic-ischemic encephalopathy and their effect on short-term outcome

ObjectiveTo compare therapeutic hypothermia (TH) treatment of term and near-term neonates with hypoxic-ischemic encephalopathy (HIE) between neonatal units.Study designPopulation-based, retrospective analysis of TH initiation and maintenance, and of diagnostic imaging. The comparison between units was based on crude data analysis, indirect standardization, and adjusted logistic regression.ResultsTH was provided to 570 neonates with HIE between 2011 and 2018 in 10 Swiss units. We excluded 121 off-protocol cooled neonates to avoid selection bias. Of the remaining 449 neonates, the outcome was favorable to international benchmarks, but there were large unit-to-unit variations in baseline perinatal data and TH management. A total of 5% neonates did not reach target temperature within 7 h (3–10% between units), and 29% experienced over- or undercooling (0–38%).ConclusionAlthough the neonates had favorable short-term outcomes, areas for improvement remain for Swiss units in both process and outcome measures.

Therapeutic hypothermia effect on asphyxial cardiac arrest-induced renal ischemia/reperfusion injury via change of Nrf2/HO-1 levels.

The present study aimed to investigate the renoprotective effect of therapeutic hypothermia (TH) on renal ischemia-reperfusion injury (RI/RI) induced by asphyxial cardiac arrest (CA) in rats. A total of 48 male rats were randomly divided into five groups: i) Sham (n=6); ii) Normothermia + CA (Normo.) (n=14); iii) Normo. and 2 h of TH after return of spontaneous circulation (ROSC) (n=12); iv) Normo. and 4 h of TH after ROSC (n=9); and v) Normo. and 6 h of TH after ROSC (n=7). All rats except the Sham group underwent asphyxia CA and were sacrificed 1 day after ROSC. The survival rate increased from 42.8% in the Normo. group to 50, 66.6 and 85.7% in the groups with 2, 4 and 6 h of TH after CA, respectively. TH attenuated the histopathological changes of the renal tissues following ROSC and the levels of blood urea nitrogen, serum creatinine and malondialdehyde in renal tissues. On immunohistochemistry, the relative optical density of nuclear erythroid-related factor-2 (Nrf2) and heme oxygenase (HO-1) expression in renal tissues increased in the Normo. group compared with that in the Sham group and exhibited further significant increases at 6 h of TH after ROSC. In conclusion, TH attenuated renal injury and increased the expression of Nrf2 and HO-1 in a TH treatment time-dependent manner.

A Comparison of MRI Scoring Systems Predictive Ability for Two-Year Neurodevelopmental Outcome in Neonatal Encephalopathy

Background: MRI scoring systems are used in the perinatal period to predict later neurodevelopmental outcome in infants with neonatal encephalopathy (NE). Our objective was to compare the predictive ability of 3 MRI scoring systems for neurodevelopmental outcome at 2 years of age in infants with NE. Methods: We retrospectively analysed MRI scans from term-born neonates with NE in the first two weeks of life between February 2011 and June 2015 using three scoring systems: Barkovich, NICHD-NRN and Weeke. Neurodevelopmental outcome was assessed using Bayley Scales of Infant and Toddler Development, third edition (Bayley-III) 2 years later. After adjusting for postmenstrual age at MRI scan and therapeutic hypothermia, the relationship between scoring systems and Bayley-III composite scores was assessed by regression analysis and logistic regression was used to calculate the predictive value of MRI scoring systems for adverse outcome (Bayley-III score of <85 in any domain). Findings: Of the 136 infants recruited, MRI was performed in 99 infants. 66 infants (cooled n=49; non-cooled n=17) were assessed at two years of age, of which 16 (24%) had adverse outcomes. NICHD-NRN and Weeke scores were associated with cognitive, language and motor scores and Barkovich scores were associated with cognitive, and motor scores. In predicting adverse outcome at 2 years, sensitivity and specificity was 0.56 and 0.82 for conventional-based Barkovich, 0.56 and 0.96 for Barkovich with DWI, 0.69 and 0.80 for NICHD-NRN, and 0.50 and 0.96 for Weeke. Subcortical brain injury was highly predictive of cognitive and motor deficits, as well as adverse outcome. MRI scores in cooled infants had lower predictive ability for adverse outcome compared with non-cooled infants. Interpretation: Our results show MRI scoring systems demonstrated high specificity, however, we were not able to identify which system best predicted adverse outcome at 2 years. Therapeutic hypothermia treatment seems to reduce the predictive value of MRI scores for neurodevelopmental outcome. Funding Statement: National Children’s Research Centre, Tallaght, Ireland. Declaration of Interests: None to declare. Ethics Approval Statement: Approval was granted by the Ethics Committee of the National Maternity Hospital, Dublin, and Children’s University Hospital, Temple Street, Dublin. Written informed consent was not required in this retrospective cohort study and all patient data were processed anonymously.

Early clinical outcome and complications associated in neonates with hypoxic ischemic encephalopathy grade II/III who underwent treatment with servo controlled whole-body therapeutic hypothermia: A prospective observational study

Background: There are limited data regarding servo-controlled whole-body therapeutic hypothermia (TH) for neonates with hypoxic-ischemic encephalopathy (HIE) Stage II/III in the Indian setting. The objectives of this study were to determine the early clinical outcome of neonates with HIE Stage II/III treated with TH and to determine the mortality rate and associated complications. Methods: This study was a prospective observational study done at a Level 3A National Neonatology Forum accredited tertiary care neonatal intensive care unit (NICU). Term neonates with HIE Grade II/III admitted to NICU within 6 h of birth were enrolled in the study. Subjects underwent servo-controlled whole-body therapeutic cooling as per the research protocol. Results: Out of 54 subjects, 22 (40.7%) had stage II HIE and 32 (59.3%) had Stage III. The mortality rate was 24% (n = 13), with all having Stage 3. Direct breastfeeds was achieved in 65.9% of successfully cooled babies within 48 h after TH treatment. About 85.4% of babies who were successfully cooled had good early clinical outcomes as evidenced by good activity, normal tone, successful direct breastfeeding, and early discharge within 72 h post treatment with TH. Coagulopathy was observed in 70.4%, raised liver enzymes in 96.3% and thrombocytopenia in 9.3%. Conclusion: There is a significant correlation of grade of encephalopathy and blood gas abnormality at admission with the outcome in babies with HIE treated with TH. Majority of babies with HIE stage 2/3 who successfully completed TH had good early clinical outcomes at the time of discharge.

Analysis of microRNA expression in cerebral ischemia/reperfusion after mild therapeutic hypothermia treatment in rats.

BackgroundThis study aimed to explore the molecular mechanism of mild hypothermia in in the treatment of cerebral ischemia, microRNA (miRNA) microarrays and bioinformatics analysis were employed to examine the miRNA expression profiles of rats with mild therapeutic hypothermia after middle cerebral artery occlusion (MCAO).MethodsMCAO was induced in Male Sprague–Dawley rats. Mild hypothermia treatment began from the onset of ischemia and maintained for 3 hours. miRNA expressions following focal cerebral ischemia and mild hypothermia treatment were profiled using microarray technology. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the functions of the target genes in mild therapeutic hypothermia after MCAO. 60 min before MCAO, mimics and inhibitor of miR-291b were injected into the right lateral ventricle respectively, then the infarct volume and neuronal apoptosis were analyzed.ResultsSix upregulated miRNAs and 6 downregulated miRNAs were detected 4 hours after mild therapeutic hypothermia, and after 24 hours, 41 and 10 miRNAs were upregulated and downregulated, respectively. The target genes of the differentially expressed genes were mainly related with multicellular organism development and the mucin type O-glycan biosynthesis pathway was the most enriched KEGG pathway. Among the differentially expressed miRNAs, miR-291b was selected to assess the effects of mild therapeutic hypothermia in MCAO rats. At 24 hours after mild therapeutic hypothermia, miR-291b overexpression was proved to exhibit neuroprotective effects.ConclusionsThe results showed that miRNAs might play a pivotal role in mild therapeutic hypothermia in cerebral ischemia/reperfusion injury. Further understanding of the mechanism and function of miRNAs would help to illuminate the mechanism of mild therapeutic hypothermia in cerebral ischemia/reperfusion injury.

Guidelines for Assessment and Initiation of Therapeutic Hypothermia (Cooling) Treatment for Moderate or Severe Hypoxic Ischaemic Encephalopathy

Aims of the Guideline To ensure that babies with suspected HIE are appropriately assessed to see whether therapeutic hypothermia (cooling) is appropriate. To ensure that cooling is initiated in a safe and timely manner. To outline the care pathway for ongoing cooling treatment.

Early exit from neonatal therapeutic hypothermia: A single institution experience using MRI to guide decision-making.

To evaluate the feasibility of a protocol using combined magnetic resonance imaging (MRI), clinical data, and electroencephalogram (EEG) to identify neonates with mild neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH) who are eligible for "early exit". Retrospective chart review of TH cases at a single Level III NICU over a 5-year period was used to describe the demographic, clinical, and outcome data in neonates that received early exit in contrast to 72 hour TH treatment. Two hundred and eight TH cases, including 18 early exit cases (9%) and 9 cases (4%) evaluated for early exit with MRI but continued on 72 hours of TH, were identified. Early exit and 72 hour treatment groups did not differ in demographics or cord gas measures, although early exit neonates had a shorter length of stay (p < 0.05). Consistent with the early exit protocol, no early exit infants had evidence of moderate or severe encephalopathy on EEG or evidence of hypoxic ischemic injury on MRI at 24 hours of life. Neurology follow up between age 1 and 18 months was available for 10 early exit infants, 8 of whom had a normal examination. Early MRI at 24 hours of age, alongside clinical and EEG criteria, is feasible as part of a protocol to identify neonates eligible for early exit from therapeutic hypothermia.

The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep.

High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (n = 5) or cerebral ischemia for 30 min followed by treatment with vehicle (n = 4), rEPO (n = 8) or combined treatment with rEPO and hypothermia (n = 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (n = 1) or complete umbilical cord occlusion for 25 min followed by i.v. infusion of vehicle (n = 8) or rEPO (n = 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5 h in preterm and near-term fetuses. A further group of preterm fetal sheep received repeated bolus injections of rEPO (n = 8). The plasma concentrations of rEPO were best described by a pharmacokinetic model that included first-order and mixed-order elimination with linear maturation of elimination with gestation age. There were no detectable effects of therapeutic hypothermia, cerebral ischemia, global asphyxia or exogenous treatment on rEPO pharmacokinetics. The increase in rEPO elimination with gestation age suggests that to maintain target exposure levels during prolonged treatment, the dose of rEPO may have to be adjusted to match the increase in size and growth. These results are important for designing and understanding future studies of neuroprotection with high-dose rEPO.

Additive Protective Effects of Delayed Mild Therapeutic Hypothermia and Antioxidants on PC12 Cells Exposed to Oxidative Stress.

Mild therapeutic hypothermia is protective against several cellular stresses, but the mechanisms underlying this protection are not completely resolved. In the present study, we used an in vitro model to investigate whether therapeutic hypothermia at 33°C applied following a peroxide-induced oxidative stress would protect PC12 cells. A 1-hour exposure to tert-butyl peroxide increased cell death measured 24 hours later. This cell death was dose-dependent in the range of 100-1000 μM tert-butyl peroxide with ∼50% cell death observed at 24 hours from 500 μM peroxide exposure. Cell survival/death was measured with an alamarBlue viability assay, and propidium iodide/Hoechst imaging for counts of living and dead cells. Therapeutic hypothermia at 33°C applied for 2 hours postperoxide exposure significantly increased cell survival measured 24 hours postperoxide-induced stress. This protection was present even when delayed hypothermia, 15 minutes after the peroxide washout, was applied. Addition of any of the three FDA-approved antioxidants (Tempol, EUK134, Edaravone at 100 μM) in combination with hypothermia improved cell survival. With the therapeutic hypothermia treatment, a significant downregulation of caspases-3 and -8 and tumor necrosis factor-α was observed at 3 and 24 hours poststress. Consistent with this, a cell-permeable pan-caspase inhibitor Z-VAD-FMK applied in combination with hypothermia significantly increased cell survival. Overall, these results suggest that the antioxidants quenching of reactive oxygen species likely works with hypothermia to reduce mitochondrial damage and/or apoptotic mechanisms. Further studies are required to confirm and extend these results to other cell types, including neuronal cells, and other forms of oxidative stress as well as to optimize the critical parameters of hypothermia treatment such as target temperature and duration.

The influence of therapeutic hypothermia on the outcomes of cardiac arrest survivors: a retrospective cohort study

AimTo determine whether therapeutic hypothermia (TH) improves survival and neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors.MethodsThis retrospective cohort study enrolled patients treated for OHCA with a return of spontaneous circulation admitted to the Cardiac Intensive Care Unit from October 2000 until March 2019. Data were collected from medical archives. Propensity score matching was used. The primary endpoint was death during hospital stay and secondary endpoint was cerebral performance category (CPC) score at discharge.ResultsOut of 152 patients included in the study, 58 (38.7%) underwent TH treatment. After matching (which left 70 patients in the analysis), death during hospital stay occurred less often in TH group (28.6% vs 57.1%, P = 0.029), while the difference in CPC score was not significant. Cox proportional hazards model showed the predictors of death during hospital stay to be TH (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.13-0.68, P = 0.004), initial Glasgow Coma Scale score of 3 (HR 7.55, 95% CI 1.44-39.63, P = 0.017), and heart failure (HR 2.35, 95% CI 1.02-5.34, P = 0.045). TH was not an independent predictor of CPC score. Mann-Whitney U test and linear regression model showed that TH was associated with higher gain in GCS.ConclusionTH was associated with better survival and certain variables suggesting improved neurological outcomes, suggesting that TH is a vital treatment option for comatose OHCA survivors.

Targeted temperature management: State of the Art

One of the indicated elements of post-resuscitation care is therapeutic hypothermia or temperature treatment management. the survivability of out-of-hospital cardiac arrest (OHCA) till admission to hospital is only 23%. Efficient thermoregulatory mechanisms are the basis for maintaining optimal body temperature. Therapeutic hypothermia shows normalizing effect on metabolic processes disturbed in ischaemic conditions, including improving metabolism and maintaining glucose balance in the brain, lowering the concentration of lactates, limiting the secretion of free radicals in damaged neurons, lowering the production of pro-inflammatory cytokines, stabilizes the blood-brain barrier and reduces endothelial dysfunction preventing ischaemic damage to tissues and organs. Hypothermia has a wide multidirectional effect on the human body, which can be useful in patients. Most available scientific studies show the efficacy and benefits of hypothermia in patients with out-of-hospital sudden cardiac arrest, including especially with ventricular fibrillation. The delay in the initiation of therapeutic hypothermia and reaching target temperature significantly increased the odds of a poor neurological outcome. Current American Heart Association (AHA) and European Resuscitation Council (ERC) resuscitation guidelines recommend that targeted temperature management should be implemented in all adult coma patients with return of spontaneous circulation (ROCS) after sudden cardiac arrest. The target temperature should be between 32°C and 36°C and then maintained for at least 24 hours. In patients with coma after TTM, fever should be actively prevented. For patients with out-of-hospital cardiac arrest, it is not recommended to routinely cool patients in prehospital conditions with a rapid intravenous infusion of cold fluids after ROSC.

Potential protective effects of bilirubin following the treatment of neonatal hypoxic-ischemic encephalopathy with hypothermia therapy.

Background: Therapeutic hypothermia (TH) is the standard therapy for hypoxic-ischemic encephalopathy (HIE) and is associated with a wide range of physiological changes. Objective: We re-evaluated the effects of HIE and TH on bilirubin measurements following HIE in a center involved in the China cooling randomized controlled trial (RCT). Methods: Serial serum bilirubin concentrations measured during the first week of life were compared among the HIE + NT (normothermia) group, HIE + TH treatment group and control group (without HIE). Survivors of HIE were followed and assessed at approximately 2 years of age, and the results were correlated with peak bilirubin levels during the first week of life. Results: One hundred and thirty-eight infants were available for analysis. Significantly lower bilirubin levels were recorded in the HIE + NT group than in the controls (P<0.05). Significant differences were not observed among the patients in the HIE + NT group (mild to severe) or between the HIE + TH group and the HIE + NT group at any time point (P>0.05). The peak serum bilirubin concentrations recorded at 96 h of age showed a good correlation with the results of the Bayley Scales of Infant and Toddler Development, third edition (BSID-III) (P=0.02). Conclusion: Bilirubin potentially exerts a neuroprotective effect during the first week of life, and low temperature does not affect the possible antioxidant function of bilirubin during TH following HIE.

Attention and visuo-spatial function in children without cerebral palsy who were cooled for neonatal encephalopathy: a case-control study

ABSTRACTObjectives: Dorsal-stream functions are vulnerable to early brain injury associated with neonatal encephalopathy (NE) following perinatal asphyxia, even in children not developing cerebral palsy (CP). Since therapeutic hypothermia (TH) became the standard treatment for NE, the incidence of CP is reduced but the impact on dorsal-stream functions is unknown. We aimed to compare dorsal-stream functions in TH-treated survivors of NE, without CP, with those of matched controls.Methods: We administered tests of dorsal-stream function to 29 case children aged 6-to-8 years treated with TH for NE and without CP, and 20 age, sex and social class matched controls. We used the Conner’s Continuous Performance Test (CPT) 2nd Edition to assess attentiveness, based upon Hit Reaction Time (HRT) percentile score and HRT standard error percentile, the CPT HRT block change measure to assess sustained attention and the NEPSY-II block construction and arrows tests to assess visuo-spatial performance and mental rotation.Results: Case children performed significantly worse than controls on measures of attention and visuo-spatial function.Conclusions: Children given TH treatment for NE can have subtle attention difficulties with slower reaction times and reduced visuo-spatial processing. These findings illustrate the continued vulnerability of dorsal-stream functions following NE despite the use of TH.

The Therapeutic Hypothermia in Treatment of Hyperammonemic Encephalopathy due to Urea Cycle Disorders and Organic Acidemias.

Hyperammonemic encephalopathy in newborns with urea cycle disorders and certain organic acidurias can cause severe brain injury, coma and death. Standard therapy includes protein restriction, nitrogen-scavenging drugs, prevention of catabolism and hemodialysis. Neuroprotective hypothermia as part of the treatment has been reported only 3 times. It has been suggested that mild systemic hypothermia can contribute to better neurological outcomes in hyperammonemic encephalopathy. However, the limited experience precludes accurate conclusions on safety and efficacy. Whole body therapeutic hypothermia was included in the standard treatment of hyperammonemic encephalopathy in 4 neonates with urea cycle disorder or organic aciduria. Two patients survived the initial crisis. One patient has a developmental quotient of 0.8, while the other shows severe developmental delay. The cooling protocol had to be discontinued in 3 patients due to the otherwise untreatable complications (hypotension and hemorrhage). The efficacy and safety of therapeutic hypothermia in the treatment of neonatal hyperammonemic encephalopathy depend on various factors, requiring further evaluation.

Response to antiseizure medications in neonates with acute symptomatic seizures.

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM.

Therapeutic hypothermia in treatment of different cerebral injuries

There is an increasing incidence of various cerebral eventsin Russia, as well as throughout the world. At the same time, despite of all the successes of modern medicine, the treatment outcomes of these patient groups haven’t improved. The main successes are based on faster patient delivery to hospitals and on the creation of specialized centers for this cohort of patients. At the same time, the effectiveness of pharmacological agents with neuroprotective activity is questionable. On the other hand, therapeutic hypothermia techniques have proven to be an effective method of neuroprotection in various cerebral events. These methods can be divided into local and general hypothermia. Each of these options has its own advantages and indications. Thus, the use of general hypothermia techniques maintains the target temperature of the whole body, these techniques are more controllable, but at the same time, the methods of local craniocerebral hypothermia allows to affect the target organ. The methods of hypothermia and thermostabilization have been proven to improve the treatment results of patients post-CPR and in children with neonatal hypoxia. The effectiveness of hypothermia in the remaining pathological conditions of the brain has not yet been investigated. Studies of the last 5 years have not revealed high efficacy of general hypothermia at TBI, so almost of all studies indicated that normothermia and hypothermia are equally effective. Studies are ongoing in patients with subarachnoid hemorrhage, subdural hematomas and ischemic stroke. Identifying groups of patients who are recommended for these methods for complex treatment can lead to progress in improving survival and neurological outcome.