Therapeutic Hypothermia Group Research Articles

General movement assessment efficacy for assessment of nervous system integrity in children after hypoxic-ischemic encephalopathy in middle income countries

BackgroundMany infants who survive hypoxic-ischemic encephalopathy (HIE) face long-term complications like epilepsy, cerebral palsy, and developmental delays. Detecting and forecasting developmental issues in high-risk infants is critical. AimThis study aims to assess the effectiveness of standardized General Movements Assessment (GMA) and Hammersmith Infant Neurological Examinations (HINE) in identifying nervous system damage and predicting neurological outcomes in infants with HIE. DesignProspective. Subjects and measuresWe examined full-term newborns with perinatal asphyxia, classifying them as Grade 2 HIE according to Sarnat and Sarnat. The study included 31 infants, with 14 (45.2 %) receiving therapeutic hypothermia (Group 1) and 17 (54.8 %) not (Group 2). We evaluated general movements during writhing and fidgety phases and conducted neurological assessments using the HINE. ResultsAll infants exhibited cramped-synchronized - like movements, leading to cerebral palsy (CP) diagnosis. Three children in Group 1 and four in Group 2 lacked fidgety movements. During active movements, HINE and GMA showed high sensitivity and specificity, reaching 96 % and 100 % for all children. The ROC curve's area under the curve (AUC) was 0.978. ConclusionOur study affirms HINE and GMA as effective tools for predicting CP in HIE-affected children. GMA exhibits higher sensitivity and specificity during fidgety movements. However, study limitations include a small sample size and data from a single medical institution, necessitating further research.

The Neuroprotective Effect of Therapeutic Hypothermia in Cognitive Impairment of an Ischemia/Reperfusion Injury Mouse Model.

Background and Objectives: Therapeutic hypothermia (TH) shows promise as an approach with neuroprotective effects, capable of reducing secondary brain damage and intracranial pressure following successful mechanical thrombectomy in the acute phase. However, its effect on cognitive impairment remains unclear. This study investigated whether TH can improve cognitive impairment in a mouse model of transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R). Materials and Methods: Nine-week-old C57BL/6N mice (male) were randomly assigned to three groups: sham, tMCAO/R, and tMCAO/R with TH. Cognitive function was assessed 1 month after model induction using the Y-maze test, and regional cerebral glucose metabolism was measured through positron emission tomography with fluorine-18 fluorodeoxyglucose. Results: tMCAO/R induced cognitive impairment, which showed improvement with TH. The TH group exhibited a significant recovery in cerebral glucose metabolism in the thalamus compared to the tMCAO/R group. Conclusions: These findings indicate that TH may hold promise as a therapeutic strategy for alleviating ischemia/reperfusion-induced cognitive impairment.

Erythropoietin in Neonates with Perinatal Asphyxia Undergoing Therapeutic Hypothermia—A Prospective Cohort Study

Aims: To assess the safety and feasibility of erythropoietin (EPO) in asphyxiated neonates undergoing therapeutic hypothermia (TH). Subjects and methods: This study enrolled 60 neonates with HIE undergoing TH. 30 neonates were divided into EPO with TH group, where neonates received EPO (dose), at a dose rate of 1000 IU/kg/48 hours, for four doses and the remaining 30 neonates undergoing TH were into control group. Magnetic resonance imaging brain was undertaken between 10 and 14 days of life in surviving neonates. The Bayley Scales of Infant (BSI) Development IV was performed at regular intervals up to the age of 12 months. Results: Amplitude-integrated electroencephalogram (aEEG) showed burst suppression (19% vs. 11%), low voltage (10% vs. 4%), and flat trace (7% vs. 3%) in control group in comparison with EPO concurrent with TH group which was statistically significant. Brain magnetic-resonance imaging (MRI) done at 12 days (±2 days) showed significant brain injury patterns such as severe brain injury (4% vs. 9% P = .05) and regional specific HIE (7% vs. 13%, P = .03) in control group of only TH neonates. At 12 months, neurodevelopment outcomes in EPO with TH group neonates showed a favorable outcome. Conclusion: rhEPO concurrent with TH in HIE neonates resulted in significantly less severe brain injuries in MRI brain in HIE neonates. aEEG changes were less statistically significant in EPO with TH group with favorable neurodevelopmental outcomes at 12 months of age.

Growth and developmental outcomes of infants with hypoxic ischemic encephalopathy

Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed.

Short-Term Outcomes of Neonates with Hypoxic-Ischemic Encephalopathy Receiving Active Versus Passive Cooling During Transport.

Therapeutic hypothermia (TH) is the only currently approved treatment for neonatal hypoxic-ischemic encephalopathy (HIE) and must be started within 6 hours to optimize effectiveness. This narrow therapeutic window often requires initiation of TH before or during transport. The goal of this study was to assess the effects of servo-controlled TH versus passive hypothermia during transport on short-term outcomes in newborns with HIE. This was a single-center retrospective case-control study of neonates with HIE treated with active or passive TH during transport. Primary outcomes included brain injury on magnetic resonance imaging (MRI) and presence of seizures. Seventy-six neonates were included-13 active and 63 passive. The active TH group was more likely to arrive within goal temperature. No difference was noted between groups in seizures or TH complications. Active TH was associated with increased injury on MRI. Active TH resulted in tighter temperature control, but no improvement in short-term outcomes in our cohort. The MRI findings may be due to differences in overall disease severity, which could not be adjusted for, given the modest sample size.

Therapeutic Hypothermia Is Limited in Preventing Developmental Impairments after Neonatal Hypoxia-Ischemia

The only current treatment for neonatal hypoxia-ischemia (HI) is therapeutic hypothermia (TH), which still shows some limitations. Specific effects of TH in the several processes involved in brain injury progression remain unclear. In this study, the effects of TH treatment on developmental parameters, behavioral outcomes, and peripheral leukocytes were evaluated in neonatal male and female rats. In P7, animals were submitted to right common carotid artery occlusion followed by hypoxia (8% oxygen). TH was performed by reducing the animal scalp temperature to 32°C for 5 h. Behavioral parameters and developmental landmarks were evaluated. Animals were euthanized at P9 or P21, and cerebral hemispheres, spleen, and thymus were weighed. White blood cells (WBCs) were counted in blood smears. There was a reduction in the weight of the brain hemisphere ipsilateral to the carotid occlusion in HI and TH groups, as well as a reduction in body weight gain and a delay in the opening of the ipsilateral eye. Latency in negative geotaxis was increased by HI at P12. TH did not prevent brain weight loss, developmental impairments, or WBC number changes but prevented negative geotaxis impairment and spleen weight reduction. These data reinforce that a better understanding of the events that occur after HI and TH in both males and females is necessary and would allow the development of more adequate and sex-specific therapeutic approaches.

Safety and efficacy of therapeutic hypothermia in neonates with mild hypoxic-ischemic encephalopathy

BackgroundThough there has been an increase in the number of neonates with hypoxic-ischemic encephalopathy (HIE) treated by therapeutic hypothermia (TH) in recent years, the effect of therapeutic hypothermia on mild HIE neonates is still uncertain.ObjectivesThis study aims to explore the safety and efficacy of therapeutic hypothermia in neonates with mild HIE.MethodsRetrospectively collected between January 2010 to December 2022 at Children’s Hospital of Fudan University, neonates with mild HIE were divided into TH and non-TH groups. Clinical data of the mild HIE neonates and their mothers’ general information during pregnancy were collected. SPSS 23.0 was used to compare the general condition, the incidence of adverse events, and efficacy in the two groups.ResultsA total of 71 neonates with mild HIE were included, including 31 in the TH group and 40 in the non-TH group. Compared with the non-TH group, the TH group had significantly lower 5-minute Apgar scores [6 (5–7) points vs. 7 (5–8) points, p = 0.033 ], but a higher rate of tracheal intubation at birth (68%, 21/31 vs. 40%, 16/40, p = 0.02), a higher rate of chest compressions > 30 s (39%, 12/31 vs. 15%, 6/40, p = 0.023), the later initiation enteral feeding [4 (3–4) days vs. 1 (1–2) days, p < 0.001], a higher usage rate of analgesic and sedative drugs (45%, 14/31 vs. 18%, 7/40, p = 0.011) and the longer hospital stay [12.5 (11–14) days vs. 9 (7-13.9) days, p = 0.003]. There was no death in 71 mild HIE neonates. TH group had lower incidence of brain injury (16%, 5/31 vs. 43%, 17/40, p = 0.017) and encephalopathy progression (10%, 3/31 vs. 45%, 18/40, p = 0.001) than the non-TH group. There was no statistical significance in the incidence of adverse events between the two groups.ConclusionTherapeutic hypothermia can reduce the incidence of brain injury in neonates with mild HIE.

Conflicting findings on the effectiveness of hydrogen therapy for ameliorating vascular leakage in a 5-day post hypoxic-ischemic survival piglet model

Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in newborns in both high- and low-income countries. The important determinants of its pathophysiology are neural cells and vascular components. In neonatal HIE, increased vascular permeability due to damage to the blood–brain barrier is associated with seizures and poor outcomes in both translational and clinical studies. In our previous studies, hydrogen gas (H2) improved the neurological outcome of HIE and ameliorated the cell death. In this study, we used albumin immunohistochemistry to assess if H2 inhalation effectively reduced the cerebral vascular leakage. Of 33 piglets subjected to a hypoxic-ischemic insult, 26 piglets were ultimately analyzed. After the insult, the piglets were grouped into normothermia (NT), H2 ventilation (H2), therapeutic hypothermia (TH), and H2 combined with TH (H2-TH) groups. The ratio of albumin stained to unstained areas was analyzed and found to be lower in the H2 group than in the other groups, although the difference was not statistically significant. In this study, H2 therapy did not significantly improve albumin leakage despite the histological images suggesting signs of improvement. Further investigations are warranted to study the efficacy of H2 gas for vascular leakage in neonatal HIE.

Insight into the mechanisms of therapeutic hypothermia for asphyxia cardiac arrest using a comprehensive approach of GC-MS/MS and UPLC-Q-TOF-MS/MS based on serum metabolomics

Cardiac arrest (CA) is a severe worldwide health problem. Therapeutic hypothermia is widely used to reduce the cardiac injury and improve the neurological outcomes after CA. However, a few studies have reported the changes of serum metabolic characteristics after CA. The healthy male New Zealand Rabbits successfully resuscitated from 10-min asphyxia-induced CA were divided randomly into the normothermia (NT) group and mild therapeutic hypothermia (HT) group. The sham group underwent sham-operation. Survival was recorded and neurological deficit score (NDS) was assessed. The serum non-targeted metabolomics were detected using ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS/MS) at 15 min, 3 h, 6 h and 24 h after return of spontaneous circulation (ROSC). Our study showed that the heart rate (HR) significantly slowed down during 0.5–6 h post ROSC, consistent with the decreasing trend of body temperature in the HT group. Compared with the NT group, the levels of Lac and PCO2 at 24 h post ROSC were lower, while a significant increase in PO2 level at 24 h post ROSC was observed in the HT group. The survival rate of the HT group was significantly higher than that of the NT group, and NDS scores were remarkably increased at 24 h post ROSC in the NT group. Significant differences in metabolic profiles at 15 min, 3 h, 6 h and 24 h post ROSC were observed among the Sham, NT and HT groups. The differential metabolites detected by UPLC-Q-TOF-MS/MS and GC-MS/MS were screened for further study between every two groups (NT vs sham, HT vs sham and HT vs NT) at 15 min, 3 h, 6 h and 24 h post ROSC. Phenylalanine metabolism, alanine, aspartate and glutamate metabolism and tricarboxylic acid (TCA) cycle were enriched in NT vs sham, HT vs sham and HT vs NT respectively. Our study demonstrated that therapeutic hypothermia improves the survival and neurological outcomes in rabbit model of cardiac arrest, and firstly represents the dynamic metabolic changes in the hypothermia therapy for CA by comprehensive UPLC-Q-TOF-MS/MS- and GC-MS/MS-based metabolomics.

Therapeutic hypothermia can cause non-infective C-reactive protein elevating.

To analyze the relationship between therapeutic hypothermia (TH) and whole blood high-sensitivity C-reactive protein (hs-CRP) in neonates with hypoxic-ischemic encephalopathy (HIE). Retrospective analysis was made on the clinical data of hospitalized infants diagnosed with asphyxia in our neonatal intensive care unit from January 2014 to June 2021. According to whether TH was performed, they were divided into two groups, the control group (missed the time in other hospitals and did not receive TH) and the treatment group (TH group). In their first ten days, analysis was made on the hs-CRP, white blood cell (WBC) count, neutrophil percentage, platelet count (PLT), and brain MRI. The correlation analysis was carried out based on the severity of brain injury displayed by the brain MRI and the time of hs-CRP elevation to summarize the relationship between TH and the time of hs-CRP elevation and the severity of HIE. 83 infants were included, 28 in the control group and 55 in the TH group. After birth, 33 infants (60.0%) in the TH group and 2 patients (7.1%) in the control group had elevated hs-CRP, which was statistically significant (P < 0.05). The time window for CRP elevation after TH was 72-96 h after the end of treatment; The results of the brain MRI showed 23 in the TH group and 11in the control group with moderate and severe HIE. 21 infants (all in the TH group) had elevated hs-CRP. MRI showed that the number of infants with mild injury or regular infants whose hs-CRP raised in the TH group was 12, and the rate of hs-CRP elevation was 37.5%; in the control group, the rate was 11.8%. The difference was significant. TH can decrease PLT and WBC, but no significance in the two groups. Blood and sputum cultures were negative in all infants, and there were no signs of infection. TH can increase the blood hs-CRP of HIE neonates, and the probability of its occurrence is related to the severity of HIE. The heavier the HIE, the higher the risk of hs-CRP elevation after TH; The hs-CRP elevation has little to do with infection, and it doesn't recommend using antibiotics actively.

Hypothermia as an Adjunctive Therapy in Cardiogenic Shock: A Systematic Review and Meta-Analysis.

In the setting of out-of-hospital cardiac arrest, therapeutic hypothermia (TH) has been shown to improve clinical outcomes. However, trials showing the advantage of TH did not include patients with cardiogenic shock (CS). We performed a comprehensive literature search for studies that evaluated the efficacy and safety of adjunctive TH compared with the standard of care (SOC) in patients with CS. The primary outcome was the mortality rate (in-hospital, short-, and mid-term). The secondary outcomes were the TH-related complications, duration of Intensive Care Unit (ICU) stay, duration of mechanical ventilation (MV-days), and improvement in cardiac function. Relative risk (RR) or the standardized mean difference (SMD) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. A total of 7 clinical studies (3 RCTs included), and 712 patients (341 in the TH group and 371 in the SOC group) were included. As compared with the SOC, TH was not associated with a statistically significant improvement in the in-hospital (RR: 0.73%, 95% CI: 0.51-1.03; p = 0.08), short-term (RR: 0.90%, 95% CI: 0.75-1.06; p = 0.21), or mid-term (RR: 0.93%, 95% CI: 0.78-1.10; p = 0.38) mortality rates. Despite the improvement in the cardiac function in the TH group (SMD: 1.08, 95% CI: 0.02-2.1; p = 0.04), the TH strategy did not significantly shorten the MV days, or the ICU stay (p-values >0.05). Finally, there was a trend toward higher risks for infection, major bleeding, and the need for blood transfusion in the TH group. According to our meta-analysis of published clinical studies, TH is not beneficial in patients with CS and has a marginal safety profile. Larger-scale RCTs are needed to further clarify our results.

Effects of erythropoietin in neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia.

Minimizing multiple organ dysfunction-related mortality and morbidity is a critical issue for patients with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH). Although erythropoietin (EPO) has demonstrated protective effects on various hypoxic-ischemic organs in animal studies and clinical trials in adults, its effects on neonates with HIE require further investigation. This study retrospectively analyzed the medical records of neonates with HIE who received TH with or without EPO (TH+EPO vs TH groups) administration in a tertiary referral hospital from January 2016 to January 2021. Data regarding patient characteristics, medical treatment, and clinical (neurological, cardiac, respiratory, gastrointestinal, hepatic, and renal) function assessments were collected. To control for confounding factors and selection bias between the two groups, a 1:1 propensity matching method was applied. A total of 45 neonates with HIE received TH during the study period, with 24 patients (53%) in the TH+EPO group. After matching, each group enrolled 13 cases. No significant difference in mortality or hospital stay between the two groups was noted. During the first 3 days, the patients in the TH+EPO group showed significantly higher blood pressure (BP) than those in the TH group ( p < 0.05 on day 1). The TH+EPO group showed trends of higher blood hemoglobin ( p > 0.05) and creatinine ( p > 0.05) levels and lower estimated glomerular filtration rate ( p > 0.05) and urine output ( p > 0.05) during the first 2 weeks than TH group. The use of EPO in addition to TH is safe for neonates with HIE. The neonates with moderate or severe HIE who received EPO may have a lesser risk of hypotension than those who received TH alone. Further clinical studies on renal and cardiac functions and long-term neurological effects of EPO are required.

Short-term effects of therapeutic hypothermia following hypoxia-ischemia in neonatal male and female rats.

Nowadays, the only treatment for human babies suffering from hypoxia-ischemia (HI) is therapeutic hypothermia (TH). However, a better understanding of the specific effects of TH in males and females is important to improve its clinical application. The present study evaluated the short-term effects of TH on the brain injury and behavioral outcomes in male and female neonatal rats submitted to neonatal HI. Seven-day-old Wistar rats underwent a surgery for unilateral occlusion of the right common carotid artery and were exposed to a hypoxic atmosphere (8% oxygen) for 75 min. Then, the animals in the TH group were submitted to TH (scalp temperature of 32°C) for 5 h. In the behavioral tests, no remarkable differences triggered by HI or TH were observed relative to SHAM animals. Only females of the HI group presented lower latency to complete the righting reflex test. TH reduced the volume of brain injury in males, but not in females. The animals of the HI group showed a reduction in the number of neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus and TH partially prevented neuronal death. In the CA1 region of the hippocampus, animals from the HI group showed more degenerating cells relative to the SHAM, which was reversed by TH. In the DG, animals from the HI group showed an increase in the number of degenerating neurons, which was partially reversed by TH only in males. Our data show that HI leads to a brain injury, which was attenuated by TH in a sex-dependent way and clarify the importance of the assessment of males and females in order to outline specific strategies for the treatment of each sex in newborns suffering from HI.

Moderate systemic therapeutic hypothermia is insufficient to protect blood-spinal cord barrier in spinal cord injury.

Blood-spinal cord barrier (BSCB) disruption is a pivotal event in spinal cord injury (SCI) that aggravates secondary injury but has no specific treatment. Previous reports have shown that systemic therapeutic hypothermia (TH) can protect the blood-brain barrier after brain injury. To verify whether a similar effect exists on the BSCB after SCI, moderate systemic TH at 32°C was induced for 4 h on the mice with contusion-SCI. In vivo two-photon microscopy was utilized to dynamically monitor the BSCB leakage 1 h after SCI, combined with immunohistochemistry to detect BSCB leakage at 1 and 4 h after SCI. The BSCB leakage was not different between the normothermia (NT) and TH groups at both the in vivo and postmortem levels. The expression of endothelial tight junctions was not significantly different between the NT and TH groups 4 h after SCI, as detected by capillary western blotting. The structural damage of the BSCB was examined with immunofluorescence, but the occurrence of junctional gaps was not changed by TH 4 h after SCI. Our results have shown that moderate systemic TH induced for 4 h does not have a protective effect on the disrupted BSCB in early SCI. This treatment method has a low value and is not recommended for BSCB disruption therapy in early SCI.

Abstract 13426: Efficacy and Safety of Hypothermia as Adjuvant Therapy for Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis

Objective: Randomized control trials (RCT) conducted on myocardial infarction (MI) patients regarding the efficacy of therapeutic hypothermia (TH) as an adjunct to percutaneous coronary intervention (PCI) have shown inconsistent results. This study aims to compare the use of TH in patients with MI undergoing PCI with control groups. Methods: We systematically searched four databases; PubMed, Scopus, Web of Science, and Cochrane for studies conducted until March 2022. The inclusion criteria were any study design that compared TH in patients with MI undergoing PCI with a control group. Infarct size percentage and recurrent MI were primary efficacy outcomes. Mortality, major adverse cardiovascular events (MACE), and overall bleeding complications were primary safety outcomes. The risk of bias assessment of the included RCTs was conducted through Cochrane tool, while the quality of the included cohort studies was assessed by the NIH tool. The meta-analysis was performed on RevMan. Results: A total of 19 studies were included; 15 RCTs, one case-control, and three cohort studies. Infarct size percentage was significantly reduced in TH group as compared to control (MD= -1.76, 95% CI [-3.04, -0.47), p=0.007), but the TH group had a higher incidence of bleeding complications (OR= 1.88, 95% CI [1.11, 3.18), p=0.02). There were no significant differences between TH and control groups in mortality (OR= 1.06, 95% CI [0.75, 1.50), p=0.73) or recurrent MI (OR= 1.21, 95% CI [0.64, 2.30), p=0.56). Conclusion: In patients with MI, TH reduces infarct size while increasing bleeding complications. Mortality and recurrent MI outcomes are not significantly reduced.

Abstract 14498: Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK)

Introduction: Despite advances in revascularization and mechanical support, cardiogenic shock (CS) remains a highly morbid clinical state with 30-day mortality approaching 50%. Therapeutic hypothermia (TH) has been demonstrated to improve hemodynamics and reduce inflammation in small studies, but prospective randomized data is limited. We aimed to assess the safety and hemodynamic effects of TH (33 °C for 24 hours) in patients with CS. Methods: A total of 20 patients in CS were randomized to either TH plus standard therapy or standard therapy alone in this pilot study. Patients randomized to TH were cooled and rewarmed via intravenous cooling catheter. The primary safety endpoint was a composite of bradycardia requiring treatment, bleeding requiring transfusion as a result of catheter placement or secondary to resulting coagulopathy, shivering, hyperglycemia requiring insulin for non-diabetic patients, electrolyte derangement unexplained by other therapies, and complications from cooling catheter insertion. Secondary endpoints included hemodynamic parameters (cardiac output, pulmonary artery pressure, systemic vascular resistance, and cardiac power index). Results: There were no statistically significant differences in the composite analysis of prespecified safety outcomes (3 events in TH group vs 0 events in control group, p = 0.24). Patients randomized to TH demonstrated a statistically significant increase in cardiac index (3.6 [3.1, 3.9] L/min/m 2 vs 2.6 [2.5, 3.2] L/min/m 2 , p = 0.03) and cardiac power index (0.61 [0.55, 0.70] W/m 2 vs 0.53 [0.44, 0.57] W/m 2 , p = 0.03) compared to the control group at 48-96 hours after randomization. There were no statistically significant differences between the two groups for other collected hemodynamic variables. Conclusions: TH is a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters. Larger studies are necessary to better understand the clinical benefits of TH in patients presenting with CS.

Abstract 10566: Hypothermia as an Adjunctive Therapy to Percutaneous Intervention in St-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Control Trials

Introduction: In the setting of acute ST-elevation myocardial infarction (STEMI), several randomized control trials (RCTs) suggested a potential benefit with the use of Therapeutic hypothermia (TH). However, results from previous studies are contradictory. Method: We performed a comprehensive literature search for studies that evaluated the efficacy and safety of adjunctive TH compared to the standard percutaneous coronary intervention (PCI) in awake patients with STEMI. The primary outcome was the infarct size (IS) and microvascular obstruction (MVO) assessed by cardiac imaging at the end of follow-up. The secondary outcomes were major adverse cardiovascular events (MACE), procedure-related complications, and door to balloon time. Relative risk (RR) or the mean difference (MD) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. Results: A total of 10 RCTs, including 706 patients (mean age: 58±9.6 years, 364 patients managed with adjunctive TH vs. 342 with standard PCI), were included. As compared to standard PCI, TH was not associated with a statistically significant improvement in the IS (MD: -0.87 %, 95%CI: -2.97, 1.23; P = 0.42) or in the MVO (MD: 0.11 %, 95%CI: -0.06, 0.27; P = 0.21). MACE and its individual components were comparable between the two groups. However, the TH approach was associated with an increased risk of infection and prolonged door to balloon time. Furthermore, there was a trend in the TH group toward an increased incidence of stent thrombosis and paroxysmal atrial fibrillation. Conclusions: According to our meta-analysis of published RCTs, the benefit of TH in STEMI patients is modest, with a marginal safety profile and potential for care delays. Larger-scale RCTs are needed to further clarify our results.

Hypothermia as an Adjunctive Therapy to Percutaneous Intervention in ST-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Control Trials

IntroductionIn the setting of acute ST-elevation myocardial infarction (STEMI), several randomized control trials (RCTs) suggested a potential benefit with the use of therapeutic hypothermia (TH). However, results from previous studies are contradictory. MethodWe performed a comprehensive literature search for studies that evaluated the efficacy and safety of adjunctive TH compared to the standard percutaneous coronary intervention (PCI) in awake patients with STEMI. The primary outcomes were the infarct size (IS) and microvascular obstruction (MVO) assessed by cardiac imaging at the end of follow-up. The secondary outcomes were major adverse cardiovascular events (MACE), procedure-related complications, and door-to-balloon time. Relative risk (RR) or the mean difference (MD) and corresponding 95 % confidence intervals (CIs) were calculated using the random-effects model. ResultsA total of 10 RCTs, including 706 patients were included. As compared to standard PCI, TH was not associated with a statistically significant improvement in the IS (MD: -0.87 %, 95%CI: −2.97, 1.23; P = 0.42) or in the MVO (MD: 0.11 %, 95%CI: −0.06, 0.27; P = 0.21). MACE and its components were comparable between the two groups. However, the TH approach was associated with an increased risk of infection and prolonged door-to-balloon time. Furthermore, there was a trend in the TH group toward an increased incidence of stent thrombosis and paroxysmal atrial fibrillation. ConclusionsAccording to our meta-analysis of published RCTs, TH is not beneficial in awake patients with STEMI and has a marginal safety profile with potential for care delays. Larger-scale RCTs are needed to further clarify our results.

Comparing the effect of different loading doses of phenobarbitone on serum phenobarbitone levels in babies with neonatal seizures and effect of therapeutic hypothermia on phenobarbitone levels.

With current recommendation for phenobarbitone dosing, we have noted that babies are extremely sedated with elevated serum phenobarbitone levels. We postulate that asphyxiated neonates with hypoxic liver injury have impaired drug metabolism and renal injury affects drug elimination, thus elevating serum drug levels. Therapeutic hypothermia (TH) could further affect the drug levels. To determine the serum levels of the phenobarbitone in babies receiving different loading doses of phenobarbitone for neonatal seizures and to study the effect of asphyxia and TH on drug levels. Prospective observational cohort study. Term neonates with seizures of any cause were given phenobarbitone up to a maximum loading of 40 mg/kg followed by maintenance dose of 5 mg/kg/day. Serum phenobarbitone levels were assessed after 4 h of the initial loading dose and subsequently at 24, 48 and 72 h from the time after maximum loading dose. Babies were divided into three groups Group 1 (HIE + TH-hypoxic ischemic encephalopathy undergoing TH), Group 2 (HIE - TH-hypoxic ischemic encephalopathy without TH) and Group 3 (non-HIE group). A total of 47 babies completed the study. Twenty-three (49%) received 20 mg/kg, 14 (30%) received 30 mg/kg and 10 (21%) received 40 mg per kg of phenobarbitone as loading dose. HIE was the major cause of seizures 28 (59%) followed by hypoglycemia 7 (14%), cerebral malformations 4 (8%), inborn errors of metabolism 2 (4%) and hypocalcemia 1 (2%) while the cause of seizures was not known in 6 (13%). Median (IQR) Phenobarbitone levels at 72 h in babies who received 20 mg/kg loading dose of phenobarbitone was 46.72 (44.02-50.49) mcg/ml in HIE + TH group, 40.53 (28.66-65.09) mcg/ml in HIE - TH group and 49 (37-65) mcg/ml in non-HIE group. After a loading dose of 30 mg/kg, phenobarbitone level was 63.76 (59.5-65.94) mcg/ml in HIE + TH group, 42.5 (34.75-48.75) mcg/ml in HIE - TH group and 42.07 (40-49.05) mcg/ml in non-HIE group. After 40 mg/kg loading dose, it was 62.3 (60.2-64.9) mcg/ml in HIE + TH group, 57.0 (49.8-60.2) mcg/ml in HIE - TH group and 48.15 (40.8-50.97) mcg/ml in non-HIE group. In babies who received &gt;20 mg/kg loading dose, 100% of HIE + TH, 80% of HIE - TH and 60% of non-HIE had supratherapeutic levels of phenobarbitone. At higher loading doses of 30 and 40 mg/kg, steady state concentration of serum phenobarbitone is higher in babies with hypoxic ischemic encephalopathy who underwent TH than in babies with non-HIE causes of seizures. Loading dose beyond 20 mg/kg should be used with close monitoring of serum drug level.

Thyroid Function in Neonates with Hypoxic Ischemic Encephalopathy.

We aimed to examine heel prick (capillary) and serum thyroid function test (TFT) results in neonates with hypoxic ischemic encephalopathy (HIE) to evaluate the effect of asphyxia and therapeutic hypothermia (TH) on thyroid functions. This retrospective chart review included infants who were born after 34 weeks of gestation, were diagnosed and treated for HIE. The patients were divided into those who did and did not undergo TH and the groups were compared in terms of demographic characteristics, laboratory results, capillary thyroid-stimulating hormone (cTSH) levels, and serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels. A total of 111 neonates were included in the study. There was no difference between the TH group (n = 90) and the nonhypothermia group (n = 21) in terms of median gestational age (38.3 ± 2.1 weeks vs. 38.6 ± 1.8 weeks, p = 0.42) or birth weight (3182 ± 509 g vs. 3174 ± 573 g, p = 0.72). Serum TFT was performed at a median of 10 days (range, 2-43) and capillary TSH analyzed at a median of 6 days (range, 1-26). Capillary TSH at 96 hours was analyzed in 36 patients in the TH group and 19 patients in the nonhypothermia group. Serum TSH and fT4 levels were similar in both groups (p = 0.29, p = 0.1). Overall cTSH and cTSH obtained in the first 4 days were 2.2 (0.5-10) and 4.3 (0.5-94), p = 0.059; 2 (0.5-22) and 5 (0.5-94), p = 0.04, respectively, whereas cTSH obtained after day 4 was similar in both groups (p = 0.058). Abnormal serum TSH (>5.5 mU/mL) was more frequent in the hypothermia group (44.4% vs. 19%, p = 0.026). Our results suggest that TH may cause some alterations on TFTs. Therefore, it may be reasonable to repeat TSH screening after TH.