Hypothermia therapy for neonatal encephalopathy
Hypothermia therapy for neonatal encephalopathy | |
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Specialty | neonatologist(pediatrician) |
Mild total body hypothermia, induced by cooling a baby to 33-34°C for three days after birth, is nowadays a standardized treatment after moderate to severe
Hypoxic ischemic encephalopathy has many causes and is defined essentially as the reduction in the supply of blood or oxygen to a baby's brain before, during, or even after birth. It is a major cause of death and disability, occurring in approximately 2–3 per 1000 births and causing around 20% of all cases of cerebral palsy. A 2013 Cochrane review found that therapeutic hypothermia is useful in full term babies with encephalopathy.[3]
Medical uses
Extended follow-up of trial participants
Studies have been undertaken to determine the effects of
The most significant follow-up study published so far is the assessment of the NICHD trial participants at 6–7 years.
These results were not quite conclusive, as the effect in the NICHD trial appears to be on mortality rather than neurological function, but they gave considerable confidence that the therapeutic effects of hypothermia following birth asphyxia are sustained into later childhood, and when the Toby trial childhood follow up was published in the New England Journal of Medicine it confirmed the persistence of the effect [6]
Current state of the evidence
Hypothermic neural rescue therapy is an
At present data relate only to full term infants, and all human studies of hypothermia treatment have so far been restricted to infants >36 weeks out of an expected 40 weeks gestation. There are both more potential side effects on the developing
Since the prerequisites regarding immediate closeness after giving birth radically chances, researchers have become curious regarding parent's experiences and how to improve the nursing care around effects families. In interviews made by different researchers in different countries it has been clear the parents want clear communication with the NICU staff, but also in between the NICU staff and the obstetrics staff.[7] They also described a strong wish touching and being really close to their baby but also actively participate in the baby's care [8]
There remains much that is unknown. Recognition of infants with marginal external signs of asphyctic damage at birth, who still develop moderate hypoxic ischemic encephalopathy would be enhanced by finding more reliable bio-markers or physiologic tests accurately predicting the risk for progressive damage. These tests could also prevent unwarranted, expensive treatment of many infants. Long-term follow-up has yet to demonstrate show persisting benefit, but available data together with an imaging study nested in TOBY also found reduced brain tissue damage in cooled infants are encouraging.[9]
The simplicity that attracted empiricists to cooling centuries ago now makes hypothermic neural rescue with accurate patient selection a potentially transforming therapy for low-resource environments where birth asphyxia remains a major cause of death and disability. Ironically this brings back the problem of cooling infants in an environment where modern resuscitation and intensive care are not available.[10]
Mechanisms of action
Much of what is known about the mechanisms of hypothermic neuroprotection is gathered from studies in mature and adult models. What follows uses some of these data while trying to focus on the immature brain.
Hypoxia-ischaemia
Several adverse biological events contribute to this secondary deterioration, including: release of excitatory amino acids which activate
Newborn hypoxic-ischaemic brain injury differs from injury in the adult brain in several ways:
Actions of hypothermia
Mild hypothermia helps prevent disruptions to cerebral metabolism both during and following cerebral insults. Hypothermia decreases the cerebral metabolic rate for glucose and oxygen and reduces the loss of high energy phosphates during hypoxia-ischaemia[27] and during secondary cerebral energy failure,[28] and reduces delayed cerebral lactic alkalosis.[29] The simultaneous increase in cytotoxic oedema and loss of cerebral cortical activity that accompanies secondary energy failure is also prevented.[30]
Hypothermia appears to have multiple effects at a cellular level following cerebral injury. Hypothermia reduces vasogenic oedema, haemorrhage and neutrophil infiltration after trauma.[31] The release of excitatory neurotransmitters is reduced, limiting intracellular calcium accumulation.[32][33][34] Free radical production is lessened, which protects cells and cellular organelles from oxidative damage during reperfusion.[35] In addition mild hypothermia may reduce the activation of the cytokine and coagulation cascades through increased activation of suppressor signalling pathways, and by inhibiting release of platelet activating factor.[36]
Many of the effects induced by mild hypothermia may help to reduce the number of cells undergoing apoptosis. Experimental and clinical studies indicate that the number of apoptotic neurons is reduced caspase activity is lessened and cytochrome c translocation is diminished by mild hypothermia,[37][38] and there may be an increase in expression of the anti-apoptotic protein BCl-2.[39]
History
Many physicians over the centuries have tried to resuscitate babies after birth by altering their body temperatures, essentially aiming to animate the infant by inducing the onset of breathing.[40] Little thought was given to brain protection, because cerebral hypoxia during birth was not linked with later neurological problems until William John Little in 1861,[41] and even then this was controversial; Sigmund Freud, for example, famously disagreed, and when scientific studies of neonatal therapeutic hypothermia were begun in the 1950s researchers like Bjorn Westin still reported their work in terms of re-animation rather than neuroprotection.[42] Investigators such as James Miller and Clement Smith carried out clinical observations and careful physiological experiments,[43][44][45][46] but although some babies were conscientiously followed up, they were not mainly concerned with long term neurological outcome.
However, by the 1960s physicians saw hypothermia after delivery as something to be avoided. The problem of infants who failed to breathe at birth had been solved by the invention of mechanical ventilation, so any benefit cooling might have for re-animation was no longer needed, and an influential trial showed that keeping small and preterm infants warm increased survival.[47] These results, together with observational[48] and experimental[49] data made it an article of medical faith for decades that babies should not be allowed to get cold.
Consequently, during the next two decades studies of neonatal hypothermia in Europe and the USA were sporadic and often unsuccessful. An interest in cooling for brain protection was beginning to emerge, but contemporary neuroscience provided few useful concepts to guide this research and little progress was made.[50][51][52][53][54][55][56] Although across the Iron Curtain in the Soviet Union cooling was being applied empirically following birth asphyxia,[57] the language barrier, cold war politics and the Russians' failure to carry out randomised controlled trials contributed to an almost total ignorance of this work in the West. Indeed, a group of Russian neonatologists who described hypothermic neural rescue during a visit to the Neonatal Unit in Bristol, UK, met with little interest.[58]
Neural rescue
In the late 1980s the development of a new set of concepts and problems led to a re-examination. A new generation of neonatal researchers were influenced by the growing evidence that protecting the brain against the effects of oxygen deprivation during labour might be possible. These researchers were aware that cooling produced powerful intra-ischaemic neuroprotection during cardiac surgery but a new concept of hypothermic post-insult neural rescue developed. This shift in thinking was possible because of at least three major new ideas that were developing at the same time: delayed post-ischaemic cell death; excitotoxicity; and apoptosis.
Delayed cell death
The first paradigm shift that affected neonatal researchers in particular was the idea that if a baby was resuscitated after cerebral hypoxia-ischaemia there was a period of time before brain cells started to die. Osmund Reynolds at
Delayed brain injury (called 'secondary energy failure' by Reynolds) was a critical new idea. If brain cells remained normal for a time and the mechanism of the delayed death could be unravelled, it opened the possibility of therapeutic intervention in what had previously seemed an impossible situation.[63]
Excitotoxicity
The new and transforming concept of
Apoptosis
However, it was still a mystery how and why cells triggered by hypoxia-ischaemia should die hours or days later, particularly when it became clear that glutamate levels were not particularly high during secondary energy failure. The next critical idea came with the discovery of programmed cell death, a novel form of cell suicide. Originally observed as a pathological appearance and named apoptosis ("falling off", as of leaves) in the 1970s,[67] Horvitz,[68] Raff[69] and Evan[70] provided a molecular understanding and showed that apoptosis could be triggered by cellular insults. The radical idea that hypoxia-ischaemia triggered a cell suicide programme which could explain the perplexing phenomenon of delayed cell death was soon supported by experimental[71][72] and human data,[73] and many researchers believe this helps explain why neural rescue works in the newborn. However the picture is complex: both apoptosis and necrosis are present in variable proportions;[74] and there seems to be prolonged neurodegeneration after an insult.[75] Research into this problem continues.
Neonatal neural rescue
These ideas flowed through the perinatal research community, producing a new belief that neural rescue after birth asphyxia should be possible. Amongst the first to have attempt neonatal neural rescue in animals were Ingmar Kjellmer and Henrik Hagberg in Gothenburg,[76][77] and Michael Johnston in Baltimore.[78] The potential began to draw in other neonatal researchers from diverse fields to begin neuroprotection research, including those who came to form the informal neonatal hypothermia research group:
Peter Gluckman and Tania Gunn were endocrinologists in the
There were many potential therapies around which might achieve neural rescue, and most of these workers did not immediately move to hypothermia.
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