Hypoxic-ischaemic encephalopathy (HIE) is one of the leading causes of newborn mortality and morbidity worldwide, and therapeutic hypothermia is often used as a treatment. A review in Developmental Medicine and Child Neurology highlights additional therapies for HIE that are being tested with and without concomitant therapeutic hypothermia.
Neonatal HIE is characterised by neurological dysfunction resulting from inadequate oxygen and blood flow to the brain near the time of birth. Therapeutic hypothermia is an established therapy in high-income countries, but many infants still die or experience neurodevelopmental consequences after treatment. Moreover, in low- and middle-income countries, where the burden of HIE is the highest, therapeutic hypothermia was recently shown to be ineffective.
The new review notes that investigational therapies for HIE include agents that block excessive activation of glutamate receptors, drugs that act as antioxidants or anti-inflammatories, and products that target multiple neuroprotective pathways.
“Therapeutic hypothermia for moderate-to-severe neonatal HIE is one of the success stories in newborn care, but there is an urgent need to identify additional therapies that are effective both with and without therapeutic hypothermia,” said corresponding author Natalie H. Chan, MD, MPH, of the University of California, San Francisco. “Our paper reviews the promising therapies being evaluated in clinical studies that could close the remaining gap in optimising outcomes in all babies with HIE.”
When patients kept at a body temperature of 37C with aggressive warming during surgery, there was no reduction cardiac complications compared to patients kept at 35.5C, finds a large new study reported in The Lancet. No differences was seen in number of infections or required blood transfusions in patients kept at cooler body temperatures.
An unintentional drop in body temperature is a normal side effect during surgery, due mostly to anaesthetic medications’ interference with the body’s temperature regulation processes. In Western countries, nursing staff typically use forced-air heaters to keep patients warm during surgery, with a target temperature of 36C. This trial, one of the largest to date, sought to determine whether even greater warming, to 37C, would reduce the risk of cardiac complications, a major cause of mortality in the first 30 days after surgery.
Results showed no significant differences between groups for the trial’s primary endpoint, a composite of troponin elevation due to ischemia (an indicator of heart injury), non-fatal cardiac arrest or death from any cause within 30 days after surgery. Researchers also reported no differences for any of the trial’s secondary endpoints.
“This trial tells us that there is no benefit to aggressively warming patients to 37 C during surgery. It is simply unnecessary, and it doesn’t improve any substantive outcomes,” said Daniel I. Sessler, MD, Michael Cudahy professor and chair of the Department of Outcomes Research at Cleveland Clinic and the trial’s lead author. “Also, the results show that 36C should not be considered the threshold for defining mild hypothermia since there was no harm at 35.5C.”
The researchers enrolled 5050 patients, mostly in Chinese centres. Participants had various major noncardiac surgical procedures, with a minimum duration of two hours and an average duration of four hours. Half of the patients were randomised to routine care, with a target body temperature of 35.5C, and the other half randomised to aggressive warming, with a target body temperature of 37C.
For patients assigned to routine care, nursing staff put a warming cover in position but did not activate it until the patient’s body temperature decreased to less than 35.5C, resulting in an average group body temperature of 35.6C. With the more aggressive warming protocol, nurses covered patients with a heated blanket for 30 minutes before surgery and then used two forced-air heaters to keep patients warmed to a mean of 37.1 C during surgery.
In addition to seeing no benefit in terms of the composite primary endpoint, the trial reported no significant differences between groups in terms of serious wound infections, length of hospitalization, hospital re-admissions or the need for blood transfusions. The investigators were surprised that rates of wound infections and transfusions were similar to previous studies, which suggested that both were more common in patients maintained at lower body temperatures.
While most patients were enrolled in China, Dr Sessler said, the results should still be generalisable to patients and health care settings in other countries.
“This study shows that it is reasonable to keep patients warm, but we saw no evidence whatsoever that it makes a difference if they’re just above or just below 36C,” Dr Sessler said. “Surgical patients should still be warmed, but there’s no need to be super-aggressive about the warming.”
Less serious or non-medical outcomes, such as patient comfort or shivering was not assessed. Dr Sessler said that patients maintained at a lower body temperature may shiver or feel cold after surgery, but both are temporary and unlikely to have a meaningful health impact.
Oxygen-deprived newborns who undergo hypothermia therapy have a higher risk of seizures and brain damage during the rewarming period, according to a new study. The finding, published online in JAMA Neurology, could lead to better ways to protect these vulnerable patients during an often overlooked yet critical period of hypothermia therapy.
“A wealth of evidence has shown that cooling babies who don’t receive enough oxygen during birth can improve their neurodevelopmental outcomes, but few studies have looked at events that occur as they are rewarmed to a normal body temperature,” said study leader Lina Chalak, MD, MSCS, Professor at UT Southwestern. “We’re showing that there’s a significantly elevated risk of seizures during the rewarming period, which typically go unnoticed and can cause long-term harm.”
Millions of newborns around the world are affected by neonatal hypoxic-ischaemic encephalopathy (HIE), brain damage initially caused by hypoxia during birth. Although the World Health Organization estimates that birth asphyxia is responsible for nearly a quarter of all neonatal deaths, those babies that survive oxygen deprivation are often left with neurological injuries, Dr Chalak explained.
To help improve outcomes, babies diagnosed with HIE are treated with hypothermia, using a cooling blanket that brings the body temperature down to as low as 33.5°C, said Dr. Chalak.
Studies initially showed that during cooling, babies with HIE commonly have symptomless seizures, which are neurological events that can further damage the brain, prompting the addition of electroencephalographic (EEG) monitoring to the hypothermia protocol. However, Dr Chalak explained, babies typically haven’t been monitored during the rewarming period, in which the temperature of the blanket is increased by 0.5°C every hour.
To better understand seizure risk during rewarming, Dr. Chalak and colleagues studied 120 babies who were enrolled in another study that compared two different cooling protocols, one longer and colder than the other. The babies in the study were also monitored with EEG to check for seizures both during the cooling and the rewarming phases of hypothermia.
When the researchers compared data from the last 12 hours of cooling and the first 12 hours of rewarming, they found that rewarming roughly tripled the odds of seizures. Additionally, babies who had seizures during rewarming, there was twice the risk of mortality or neurological disability by age 2, compared with those who didn’t have seizures during this period. This finding held true even after adjusting for differences in medical centers and the newborns’ HIE severity.
While it is not known how to prevent seizures from occurring in babies with HIE, treating seizures when they do occur can help prevent further brain damage, Dr Chalak said. Thus, monitoring during both cooling and rewarming can help protect the babies’ brains from further insults while they heal.
“This study is telling us that there’s an untapped opportunity to improve care for these babies during rewarming by making monitoring a standard part of the protocol,” said Dr Chalak.
