This document discusses current controversies around the use of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). While three randomized controlled trials showed cooling decreases death and disability, adoption has been slow. Reasons include wanting more data on death vs disability outcomes, longer-term follow-up, and concerns about trial size. Practical barriers to implementation include cost of equipment, off-label use of available devices, and complexity of protocols. Widespread adoption may increase as additional large trials report and low-cost options are developed.
How ebp enable healthcare professionals to provide informed decision - PubricaPubrica
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Neurological Pupil Index as an Indicator of Irreversible Cerebral Edema: A Ca...NeurOptics, Inc.
Assessing the pupillary light reflex (PLR) is acore component of neurological assessments. Changes in pupil size and reactivity can provide early recognition of neurological decline and facilitate lifesaving interventions.
How ebp enable healthcare professionals to provide informed decision - PubricaPubrica
Regular steps in EBP
Feature of EBP
Necessity of EBP
Quality of the research publication
Advantages & Disadvantages of EBP
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Continue Reading: https://bit.ly/3dOLWqq
For our services: https://pubrica.com/services/physician-writing-services/clinical-literature-review-for-an-evidence-based-medicine/
Why Pubrica:
When you order our services, We promise you the following – Plagiarism free | always on Time | 24*7 customer support | Written to international Standard | Unlimited Revisions support | Medical writing Expert | Publication Support | Biostatistical experts | High-quality Subject Matter Experts.
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Neurological Pupil Index as an Indicator of Irreversible Cerebral Edema: A Ca...NeurOptics, Inc.
Assessing the pupillary light reflex (PLR) is acore component of neurological assessments. Changes in pupil size and reactivity can provide early recognition of neurological decline and facilitate lifesaving interventions.
Comparison of Tympanic and Rectal temperature in febrile pediatric patients a...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
A risk indicator can be any metric used to identify your risk exposure over time. It becomes a KRI when it tracks an important risk, or does so especially well because of its predictive value.
Dr Andrianov, CEO Cyntegrity, discusses the importance of keeping KRIs simple, the link to specific risks, and the emerging common industry KRIs.
A full recording of this webinar is available to MCC members: https://metricschampion.org/
Successful Pediatric Studies: Key Study Design and Site Selection Considerationsjbarag
The industry recognizes the importance of ensuring the safety and well‐being of children involved in research studies. Medical and regulatory bodies have worked to provide a framework to support appropriately designed studies through regulations and guidance documents in this vulnerable population. However, it is crucial to understand the nuances associated with pediatric trials, for the site, patient and family, in order to manage them to successful completion.
During the 2012 ACRP Annual Meeting, Dr. Charlene Sanders and Angi Robinson from Premier Research reviewed topics including the evaluation of study design considerations such as duration of treatment, required assessments, use of placebo, and inclusion of specific age groups; selection of appropriate sites for pediatric trials and the unique needs of these sites; identification of pediatric recruitment/retention hurdles and site specific strategies to overcome these as well as a reflection on ethical concerns related to pediatric research.
For more information, go to http://www.premier-research.com/pediatrics.
A forensic analysis of the FEAST trial - Kathryn Maitland - SSAI2017scanFOAM
A talk by Kathryn Maitland at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All of the conference content can be found here: https://scanfoam.org/ssai2017/
Developed in collaboration between scanFOAM, SSAI and SFAI.
Cooling of sepsis patients - Morten Bestle - SSAI2017scanFOAM
A talk by Morten Bestle at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Content delivered in collaboration between scanFOAM, SSAI & SFAI.
Clinical, ethical and legal considerations in the treatment of newborns 2008Dominique Gross
Non-ketotic hyperglycinaemia (NKH) is a devastating neurometabolic disorder leading, in its classical form, to early death or severe disability and poor quality of life in survivors. Affected neonates may need ventilatory support during a short period of respiratory depression. The transient dependence on ventilation dictates urgency in decision-making regarding withdrawal of therapy.
The occurrence of patients with apparent transient forms of the disease, albeit rare, adds uncertainty to the prediction of clinical outcome and dictates that the current practice of withholding or withdrawing therapy in these neonates be reviewed. Both bioethics and law take the view that treatment decisions should be based on the best interests of the patient.
The medical-ethics approach is based on the principles of non-maleficence, beneficence, autonomy and justice. The law relating to withholding or withdrawing life-sustaining treatment is complex and varies between jurisdictions. Physicians treating newborns with NKH need to provide families with accurate and complete information regarding the disease and the relative probability of possible outcomes of the neonatal presentation and to explore the extent to which family members are willing to take part in the decision making process. Cultural and religious attitudes, which may potentially clash with bioethical and juridical principles, need to be considered.
2008 Elsevier Inc
Patient Advocate Stephen Dolle's FDA Stamp Conference RecommendationsStephen Dolle
This is a paper of FDA STAMP Conference recommendations FDA patient advocate and CNS shunt user Stephen Dolle, which he wrote for this 1999 Conference in Bethesda, MD, a conference he was responsible for, yet was not invited to speak on panel, nor was his new solution oriented DiaCeph Test included in the conference. STAMP was held in part due to Dolle's 1996 FDA petition on anti siphon shunts, of which he was an affected user, and FDA upheld, but oddly withheld their Sept. 1998 ruling from the Federal Register. Dolle did everything he could possibly do to bring progress in CNS shunts, yet wasn't allowed.
You can read from his recommendations back in 1999 that he had a vision to bring progress in this area. Since 1999, CNS shunts have been plagued by widespread device failures, more notably programmable shunts.
CNS shunts users today face new risks from years of over use of CT scanning, which DiaCeph would have reduced. Some patients have had as many as 100 and 200.
I can be reached at contact[at]dollecommunications[dot]com and via my blog.
With @Atreja at the NODE Health Conference - Digital Medicine http://digitalmedicineconference.com/ on the events and studies which moved the field forward
How many patients does case series should have .in comparison to case reports...Pubrica
Case reports are defined as the scientific documentation of a single clinical observation and have a time-honored and rich tradition in medicine and scientific publication. Pubrica has extensive experience in developing a detailed clinical case report that highlights the symptoms, signs, diagnosis, treatment and follow-up of an individual patient.
Continue Reading: https://bit.ly/34RO9vU
For our services: https://pubrica.com/services/research-services/case-report-writing/
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When you order our services, We promise you the following – Plagiarism free | always on Time | 24*7 customer support | Written to international Standard | Unlimited Revisions support | Medical writing Expert | Publication Support | Biostatistical experts | High-quality Subject Matter Experts.
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Comparison of Tympanic and Rectal temperature in febrile pediatric patients a...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
A risk indicator can be any metric used to identify your risk exposure over time. It becomes a KRI when it tracks an important risk, or does so especially well because of its predictive value.
Dr Andrianov, CEO Cyntegrity, discusses the importance of keeping KRIs simple, the link to specific risks, and the emerging common industry KRIs.
A full recording of this webinar is available to MCC members: https://metricschampion.org/
Successful Pediatric Studies: Key Study Design and Site Selection Considerationsjbarag
The industry recognizes the importance of ensuring the safety and well‐being of children involved in research studies. Medical and regulatory bodies have worked to provide a framework to support appropriately designed studies through regulations and guidance documents in this vulnerable population. However, it is crucial to understand the nuances associated with pediatric trials, for the site, patient and family, in order to manage them to successful completion.
During the 2012 ACRP Annual Meeting, Dr. Charlene Sanders and Angi Robinson from Premier Research reviewed topics including the evaluation of study design considerations such as duration of treatment, required assessments, use of placebo, and inclusion of specific age groups; selection of appropriate sites for pediatric trials and the unique needs of these sites; identification of pediatric recruitment/retention hurdles and site specific strategies to overcome these as well as a reflection on ethical concerns related to pediatric research.
For more information, go to http://www.premier-research.com/pediatrics.
A forensic analysis of the FEAST trial - Kathryn Maitland - SSAI2017scanFOAM
A talk by Kathryn Maitland at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All of the conference content can be found here: https://scanfoam.org/ssai2017/
Developed in collaboration between scanFOAM, SSAI and SFAI.
Cooling of sepsis patients - Morten Bestle - SSAI2017scanFOAM
A talk by Morten Bestle at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Content delivered in collaboration between scanFOAM, SSAI & SFAI.
Clinical, ethical and legal considerations in the treatment of newborns 2008Dominique Gross
Non-ketotic hyperglycinaemia (NKH) is a devastating neurometabolic disorder leading, in its classical form, to early death or severe disability and poor quality of life in survivors. Affected neonates may need ventilatory support during a short period of respiratory depression. The transient dependence on ventilation dictates urgency in decision-making regarding withdrawal of therapy.
The occurrence of patients with apparent transient forms of the disease, albeit rare, adds uncertainty to the prediction of clinical outcome and dictates that the current practice of withholding or withdrawing therapy in these neonates be reviewed. Both bioethics and law take the view that treatment decisions should be based on the best interests of the patient.
The medical-ethics approach is based on the principles of non-maleficence, beneficence, autonomy and justice. The law relating to withholding or withdrawing life-sustaining treatment is complex and varies between jurisdictions. Physicians treating newborns with NKH need to provide families with accurate and complete information regarding the disease and the relative probability of possible outcomes of the neonatal presentation and to explore the extent to which family members are willing to take part in the decision making process. Cultural and religious attitudes, which may potentially clash with bioethical and juridical principles, need to be considered.
2008 Elsevier Inc
Patient Advocate Stephen Dolle's FDA Stamp Conference RecommendationsStephen Dolle
This is a paper of FDA STAMP Conference recommendations FDA patient advocate and CNS shunt user Stephen Dolle, which he wrote for this 1999 Conference in Bethesda, MD, a conference he was responsible for, yet was not invited to speak on panel, nor was his new solution oriented DiaCeph Test included in the conference. STAMP was held in part due to Dolle's 1996 FDA petition on anti siphon shunts, of which he was an affected user, and FDA upheld, but oddly withheld their Sept. 1998 ruling from the Federal Register. Dolle did everything he could possibly do to bring progress in CNS shunts, yet wasn't allowed.
You can read from his recommendations back in 1999 that he had a vision to bring progress in this area. Since 1999, CNS shunts have been plagued by widespread device failures, more notably programmable shunts.
CNS shunts users today face new risks from years of over use of CT scanning, which DiaCeph would have reduced. Some patients have had as many as 100 and 200.
I can be reached at contact[at]dollecommunications[dot]com and via my blog.
With @Atreja at the NODE Health Conference - Digital Medicine http://digitalmedicineconference.com/ on the events and studies which moved the field forward
How many patients does case series should have .in comparison to case reports...Pubrica
Case reports are defined as the scientific documentation of a single clinical observation and have a time-honored and rich tradition in medicine and scientific publication. Pubrica has extensive experience in developing a detailed clinical case report that highlights the symptoms, signs, diagnosis, treatment and follow-up of an individual patient.
Continue Reading: https://bit.ly/34RO9vU
For our services: https://pubrica.com/services/research-services/case-report-writing/
Why Pubrica:
When you order our services, We promise you the following – Plagiarism free | always on Time | 24*7 customer support | Written to international Standard | Unlimited Revisions support | Medical writing Expert | Publication Support | Biostatistical experts | High-quality Subject Matter Experts.
Contact us:
Web: https://pubrica.com/
Blog: https://pubrica.com/academy/
Email: sales@pubrica.com
WhatsApp : +91 9884350006
United Kingdom: +44 1618186353
Perioperative Management of the Pediatric Organ Donorasclepiuspdfs
Introduction: For bereaved families, organ donation does not take away from the pain and loss of death, but it does give some meaning at the time and a great deal of comfort later. Each and every family whose child has suffered brain stem death should be offered the chance to donate. When a diagnosis of brain death has been made in a child, it may be possible for organ donation to occur, but it requires optimization of the donor and meticulous planning. There are a number of medical, nursing, ethical, psychological, and administrative issues which must be addressed in the perioperative period to facilitate the procurement of organs in good condition. Aim: This review aims to provide up to date information and provides the clinical pathway used in our tertiary level, university-affiliated children’s hospital for the management of the child in the critical care unit before organ donation, and intraoperative anaesthetic management. Method: This review was prepared using literature and clinical guidelines which were obtained from Medline and EMBASE databases, using the following search terms: Organ donation; intensive care management of organ donor; paediatric; neonatal; transplant outcome; and graft outcome. The focused literature search was carried out in 2017 by the five authors involved in the project. Results: The Society of Critical Care Medicine published consensus based guidelines for donor management in adult patients in 2015. Many of the core critical care principles in this document are similar in infants and children; although there are different considerations with respect to the diagnosis of brain death, consent, and pharmacological management. Full-text papers were employed by the project group to update our clinical pathway for the perioperative management of the infant or child who is a potential organ donor. Providing critical care medical and nursing staff with a pathway may improve communication, confidence, and delivery of care to the deceased child, their family and the graft recipients in this challenging situation.
European Pharmaceutical Review: Trials and Errors in NeuroscienceKCR
With many shifts in legislature, and advances in science and technology affecting clinical development in neurology and its clinical studies, it has never been more important to stay up to date with the latest regulations and trends
Hello guys, bringing to you the concept of golden hour of neonatology. As in trauma, the first hour of neonatal life is most precious and this ppt is an attempt to highlight a few key aspects of this resuscitative strategy in premature infants.
Experience the thrill of Progressive Puzzle Adventures, like Scavenger Hunt Games and Escape Room Activities combined Solve Treasure Hunt Puzzles online.
Orpah Winfrey Dwayne Johnson: Titans of Influence and Inspirationgreendigital
Introduction
In the realm of entertainment, few names resonate as Orpah Winfrey Dwayne Johnson. Both figures have carved unique paths in the industry. achieving unparalleled success and becoming iconic symbols of perseverance, resilience, and inspiration. This article delves into the lives, careers. and enduring legacies of Orpah Winfrey Dwayne Johnson. exploring how their journeys intersect and what we can learn from their remarkable stories.
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Early Life and Backgrounds
Orpah Winfrey: From Humble Beginnings to Media Mogul
Orpah Winfrey, often known as Oprah due to a misspelling on her birth certificate. was born on January 29, 1954, in Kosciusko, Mississippi. Raised in poverty by her grandmother, Winfrey's early life was marked by hardship and adversity. Despite these challenges. she demonstrated a keen intellect and an early talent for public speaking.
Winfrey's journey to success began with a scholarship to Tennessee State University. where she studied communication. Her first job in media was as a co-anchor for the local evening news in Nashville. This role paved the way for her eventual transition to talk show hosting. where she found her true calling.
Dwayne Johnson: From Wrestling Royalty to Hollywood Superstar
Dwayne Johnson, also known by his ring name "The Rock," was born on May 2, 1972, in Hayward, California. He comes from a family of professional wrestlers, with both his father, Rocky Johnson. and his grandfather, Peter Maivia, being notable figures in the wrestling world. Johnson's early life was spent moving between New Zealand and the United States. experiencing a variety of cultural influences.
Before entering the world of professional wrestling. Johnson had aspirations of becoming a professional football player. He played college football at the University of Miami. where he was part of a national championship team. But, injuries curtailed his football career, leading him to follow in his family's footsteps and enter the wrestling ring.
Career Milestones
Orpah Winfrey: The Queen of All Media
Winfrey's career breakthrough came in 1986 when she launched "The Oprah Winfrey Show." The show became a cultural phenomenon. drawing millions of viewers daily and earning many awards. Winfrey's empathetic and candid interviewing style resonated with audiences. helping her tackle diverse and often challenging topics.
Beyond her talk show, Winfrey expanded her empire to include the creation of Harpo Productions. a multimedia production company. She also launched "O, The Oprah Magazine" and OWN: Oprah Winfrey Network, further solidifying her status as a media mogul.
Dwayne Johnson: From The Ring to The Big Screen
Dwayne Johnson's wrestling career took off in the late 1990s. when he became one of the most charismatic and popular figures in WWE. His larger-than-life persona and catchphrases endeared him to fans. making him a household name. But, Johnson had ambitions beyond the wrestling ring.
In the early 20
Unveiling Paul Haggis Shaping Cinema Through Diversity. .pdfkenid14983
Paul Haggis is undoubtedly a visionary filmmaker whose work has not only shaped cinema but has also pushed boundaries when it comes to diversity and representation within the industry. From his thought-provoking scripts to his engaging directorial style, Haggis has become a prominent figure in the world of film.
Tom Selleck Net Worth: A Comprehensive Analysisgreendigital
Over several decades, Tom Selleck, a name synonymous with charisma. From his iconic role as Thomas Magnum in the television series "Magnum, P.I." to his enduring presence in "Blue Bloods," Selleck has captivated audiences with his versatility and charm. As a result, "Tom Selleck net worth" has become a topic of great interest among fans. and financial enthusiasts alike. This article delves deep into Tom Selleck's wealth, exploring his career, assets, endorsements. and business ventures that contribute to his impressive economic standing.
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Early Life and Career Beginnings
The Foundation of Tom Selleck's Wealth
Born on January 29, 1945, in Detroit, Michigan, Tom Selleck grew up in Sherman Oaks, California. His journey towards building a large net worth began with humble origins. , Selleck pursued a business administration degree at the University of Southern California (USC) on a basketball scholarship. But, his interest shifted towards acting. leading him to study at the Hills Playhouse under Milton Katselas.
Minor roles in television and films marked Selleck's early career. He appeared in commercials and took on small parts in T.V. series such as "The Dating Game" and "Lancer." These initial steps, although modest. laid the groundwork for his future success and the growth of Tom Selleck net worth. Breakthrough with "Magnum, P.I."
The Role that Defined Tom Selleck's Career
Tom Selleck's breakthrough came with the role of Thomas Magnum in the CBS television series "Magnum, P.I." (1980-1988). This role made him a household name and boosted his net worth. The series' popularity resulted in Selleck earning large salaries. leading to financial stability and increased recognition in Hollywood.
"Magnum P.I." garnered high ratings and critical acclaim during its run. Selleck's portrayal of the charming and resourceful private investigator resonated with audiences. making him one of the most beloved television actors of the 1980s. The success of "Magnum P.I." played a pivotal role in shaping Tom Selleck net worth, establishing him as a major star.
Film Career and Diversification
Expanding Tom Selleck's Financial Portfolio
While "Magnum, P.I." was a cornerstone of Selleck's career, he did not limit himself to television. He ventured into films, further enhancing Tom Selleck net worth. His filmography includes notable movies such as "Three Men and a Baby" (1987). which became the highest-grossing film of the year, and its sequel, "Three Men and a Little Lady" (1990). These box office successes contributed to his wealth.
Selleck's versatility allowed him to transition between genres. from comedies like "Mr. Baseball" (1992) to westerns such as "Quigley Down Under" (1990). This diversification showcased his acting range. and provided many income streams, reinforcing Tom Selleck net worth.
Television Resurgence with "Blue Bloods"
Sustaining Wealth through Consistent Success
In 2010, Tom Selleck began starring as Frank Reagan i
Modern Radio Frequency Access Control Systems: The Key to Efficiency and SafetyAITIX LLC
Today's fast-paced environment worries companies of all sizes about efficiency and security. Businesses are constantly looking for new and better solutions to solve their problems, whether it's data security or facility access. RFID for access control technologies have revolutionized this.
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Get an intimate look at Dinah Mattingly’s life alongside NBA icon Larry Bird. From their humble beginnings to their life today, discover the love and partnership that have defined their relationship.
Matt Rife Cancels Shows Due to Health Concerns, Reschedules Tour Dates.pdfAzura Everhart
Matt Rife's comedy tour took an unexpected turn. He had to cancel his Bloomington show due to a last-minute medical emergency. Fans in Chicago will also have to wait a bit longer for their laughs, as his shows there are postponed. Rife apologized and assured fans he'd be back on stage soon.
https://www.theurbancrews.com/celeb/matt-rife-cancels-bloomington-show/
Barbie Movie Review - The Astras.pdffffftheastras43
Barbie Movie Review has gotten brilliant surveys for its fun and creative story. Coordinated by Greta Gerwig, it stars Margot Robbie as Barbie and Ryan Gosling as Insight. Critics adore its perky humor, dynamic visuals, and intelligent take on the notorious doll's world. It's lauded for being engaging for both kids and grown-ups. The Astras profoundly prescribes observing the Barbie Review for a delightful and colorful cinematic involvement.https://theastras.com/hca-member-gradebooks/hca-gradebook-barbie/
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Current Controversies in Hypothermic Neuroprotection
1. Seminars in Fetal & Neonatal Medicine (2008) 13, 30e34
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Current controversies in hypothermic
neuroprotection
John D.E. Barks*
C. S. Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, MI 48109, USA
KEYWORDS Summary In 2005, three randomised controlled trials (RCTs) showed that treating infants
Hypoxiceischaemic with hypoxiceischaemic encephalopathy (HIE) with hypothermia decreased the combined out-
encephalopathy; come of death or disability at 12e18 months, although treatment effects were modest. More
Neonatal recently, the US Food and Drug Administration (FDA) approved a device for selective head cool-
encephalopathy; ing. In addition, the protocol from another of the three trials, using equipment available in
Newborn infant; many hospitals, has been in the public domain for over a year. Why has this not led to a con-
Perinatal asphyxia; sensus that hypothermia is the standard of care for HIE? This is explored. Important questions
Therapeutic for future research will focus on ways to improve on initial results with cooling, such as drug
hypothermia plus hypothermia combination therapy and refining duration and depth of cooling or duration
of rewarming. Although the latter are important questions for future clinical trials, those who
are convinced by the evidence to date should focus on safe implementation of cooling using
protocols with established safety and efficacy and should consider ways to increase access
to cooling for eligible babies.
ª 2007 Published by Elsevier Ltd.
Introduction Why is everyone not convinced?
More than 2 years have passed since the results of three Until recently, the most definite sign that the neonatal
randomised controlled trials (RCTs), which individually and community was not universally convinced of the efficacy
collectively demonstrated the efficacy of hypothermia for of hypothermia was that an RCT (the ICE trial), with a
the treatment of perinatal hypoxiceischaemic encephalop- non-hypothermic control group, continued to enroll pa-
athy (HIE) in term or late preterm infants, were publish- tients in several countries. It would be logical to suppose
ed.1e4 Yet, to date, there is still no general consensus that that investigators who participated in the published or
hypothermia is the standard of care for such infants. Why is completed trials are most likely to be convinced of the
this the case? This review aims to address some of the cur- safety and efficacy of cooling, and that this conviction
rent controversies surrounding hypothermia as a treatment would be demonstrated by their centres now offering
for HIE. hypothermia to infants meeting their original trial criteria.
This appears to be true for the National Institute of Child
Health and Human Development (NICHD) and Neonatal
* Tel.: þ1 734 763 4109; fax: þ1 734 763 7728. Research Network trial centres. Furthermore, many of the
E-mail address: jbarks@med.umich.edu centres in the Brain Cooling RCT also participated in the
1744-165X/$ - see front matter ª 2007 Published by Elsevier Ltd.
doi:10.1016/j.siny.2007.09.004
2. Current controversies in hypothermic neuroprotection 31
subsequent FDA-approved continued access protocol and trial device, has never been ‘tested’ on a human infant
are now transitioning to the commercial Cool Capâ device. prior to its commercial release. The Cool Capâ System
One commonly expressed reservation about the early now features a graphical, touch-screen, user interface
completed trials is that none of them was powered to that walks the user through the entire cooling process. Al-
address the death versus disability question, i.e. clinicians though the Cool Capâ system is quite expensive compared
may still need to be convinced that cooling is not simply to the Blanketrol cooling mattress, economic modelling in-
permitting more babies to survive with severe handicaps, dicates that, from a societal perspective, the Cool Capâ
without increasing the number of non-handicapped survi- system would be cost-effective under several different re-
vors. It is likely that the results of the three pending RCTs gional implementation strategies in the state of Massachu-
(see below) will provide enough patients to evaluate sepa- setts.8 Despite its cost-effectiveness at a regional/societal
rately the effects of hypothermia on death and on disability level, individual hospitals might be deterred from cooling
in survivors by using meta-analysis. A related concern is that by price concerns.
outcome in later childhood, e.g. cognitive outcome at school The NICHD body cooling protocol is publicly available on
age, is unknown; interestingly, other new therapies in the Internet as a written protocol at https://neonatal.
neonatology, like surfactant or inhaled nitric oxide, have rti.org/studies_hypothermia.cfm. Unlike the FDA-approved
not been held to such a high standard before becoming head cooling system, the equipment used in the NICHD pro-
accepted therapies. Both the NICHD trial and the Brain tocol, the Blanketrol IIâ Hypo/hyperthermia system (Cin-
Cooling trial are planning school-age follow-up evaluations. cinnati Sub-Zero), was not designed or FDA-approved for
For others, an important question is, ‘have enough neonates. Thus, its use for treatment of HIE in neonates
patients been studied to be reasonably certain that hypo- constitutes an ‘off-label’ use, and for some hospitals in par-
thermia is really effective?’ In simple terms, the concern is ticularly litigious settings, this may be a deterrent to its use
that combining early ‘smaller’ trials of a new therapy in in the treatment of HIE. Yet, it might be argued that many
a meta-analysis is similar to taking multiple ‘peeks’ at data medications commonly used in neonatology are used ‘off-
and prematurely stopping a prospective trial e it increases label’ without hesitation. Although many neonatologists
the chance of a type I error. One way of addressing this has may not be familiar with the Blanketrolâ, it is likely to be
recently been proposed, using the ‘optimal information size’ found at least in limited numbers in the operating rooms
concept to calculate the number of infants needed in pooled and/or patient equipment departments of many North
trials to confirm that a treatment effect exists and that American hospitals and it is sold in other parts of the world,
estimates of the treatment effect size are reasonable.5 Inves- including Europe and the Middle East. Thus, some neonatal
tigators in the Brain Cooling and NICHD trials would probably intensive care units (NICUs) would be able to implement the
dispute their characterisation as ‘small’ given the time and NICHD cooling protocol after investing the time necessary
effort involved in accruing over 200 patients each, but in to find and connect the equipment and supplies within their
fact compared to some adult clinical trials in conditions of own institution, and adapting the NICHD protocol for their
greater prevalence, they are relatively small trials. The re- own use (e.g. creating a graphic presentation of the proto-
sults of three additional large RCTs that have closed enroll- col), as we have done at the University of Michigan Health
ment (the Chinese selective head cooling trial, the TOBY System. Others would need to purchase at least two of the
trial and the ICE trial) should provide sufficient numbers of pa- devices, one for the patient and one for back-up. It must be
tients to address the concern about optimal information size.5 emphasised that safe use of the Blanketrolâ device for hy-
pothermia in neonates depends on strict adherence to the
NICHD protocol, including use of a second, adult-sized mat-
What are the practical barriers to tress suspended from a pole to damp out temperature fluc-
implementation? tuations that would otherwise occur with use of a system
overpowered for neonates. The equipment setup and the
At the time of writing, there is no consensus that hypo- protocol are sufficiently complicated that body cooling
thermia should be the standard of care for infants with should not be undertaken on the spur of the moment, but
suspected HIE. The advice from authoritative sources that only after advance planning.
hypothermia should only be undertaken using established In Europe, the TOBY trial hypothermia protocol is in the
protocols with known safety and efficacy is still sound.6,7 public domain on the Internet, but the hypothermia device
For those convinced by the published evidence, cost and/ used was not available for purchase at the time of writing,
or limited equipment availability may be barriers to imple- and safety and efficacy data have not yet been reported.
mentation of cooling within an individual centre, while ge- Geographical barriers to cooling are relevant in some
ography may pose an additional barrier to implementation regions, because there is a consensus amongst all published
of neonatal cooling at a regional level. However, lack of protocols that cooling needs to be initiated within 6 h of
availability of detailed cooling protocols should no longer birth. This 6-h limit in clinical trials was based on animal
be an issue. data, which suggest that the effectiveness of cooling dimin-
The Olympic Cool Capâ System for selective head cooling ishes as time increases from the hypoxiceischaemic insult to
is the only FDA-approved device for treatment of perinatal initiation of cooling, with the closing of the ‘window’ at
HIE with hypothermia. It is relatively expensive compared a time between 5.5 and 8 h after the insult.9 In many larger
with other cooling systems. Its availability is limited at the countries, babies may be born at great distances from
present time due to the manufacturer’s phased roll-out, regional NICUs, so that they could not possibly reach a
which has been made necessary by the fact that the ‘cooling centre’ within 6 h of birth. If such infants are to ben-
commercial device, a substantial update of the clinical efit from therapeutic hypothermia, practical strategies will
3. 32 J.D.E. Barks
be needed to evaluate and initiate cooling in the birth hos- not influence the effect of cooling on outcome. In a post
pital, in collaboration with a regional referral NICU and prior hoc analysis, data from the NICHD body cooling trial were ex-
to neonatal transport. Such strategies were implemented in amined to determine whether there were factors identifi-
the published trial of Eicher et al., which demonstrated able prior to 6 h of life that could be incorporated into
overall efficacy1,10; cooling, prior to and/or during trans- either a scoring scheme or a decision tree scheme to deter-
port, was also incorporated into the TOBY and ICE trial pro- mine which infants were likely to benefit from cooling and
tocols. Until the results of the latter two trials are which would not.13 Although both approaches yielded means
published, individual centres are left to consider whether of identifying infants in the NICHD study population that
the results of the Eicher trial and the experimental evidence would not benefit from cooling, very few infants (2e3%)
are compelling enough to support implementation of a trans- had such scores, and neither scheme has yet been validated
port cooling protocol and, as we have done, they may prospectively in a new patient population. Thus, these scor-
choose to adapt Eicher’s transport cooling protocol to fit ing systems are not currently suitable as a tool for excluding
their centre’s cooling strategy. Given the limited evidence, infants from hypothermic intervention. Similarly, the Brain
safety concerns should be paramount in developing proto- Cooling investigators have not advocated use of aEEG criteria
cols for initiation of cooling at birth hospitals without NICUs to exclude infants from cooling. To date, the most that can
and/or during neonatal transport. In particular, there must be said, based on common sense and consistent with clinical
be a method of safely measuring core (oesophageal or rec- trial protocols, is that infants judged to be in extremis are
tal) temperature; standard bedside digital thermometers not cooling candidates.
may not register temperatures in the target range for the All currently published cooling protocols limit initiation
established cooling protocols. of treatment to within 6 h of birth. There is no human data
An often-overlooked barrier to cooling is denial of, or to support efficacy of cooling initiated >6 h after birth. This
failure to recognise, an infant’s birth depression and/or may be an important question for future study. However,
encephalopathy. Some practitioners delivering babies per- the question could become largely irrelevant if recognition
sist in paradoxically responding to a litigious environment of eligibility improves as evidence for, and acceptance of,
by not drawing umbilical cord blood gases, in a misguided cooling increase, and if protocols for evaluation and initia-
effort to ‘protect’ themselves. This omission eliminates tion of cooling at birth hospitals become more widely
valuable information that could identify an infant requiring disseminated.
further evaluation for cooling, or that might suggest a non-
hypoxiceischaemic explanation for neonatal depression.
Although not every infant 36 weeks’ gestation with a cord How might we improve upon our results with
pH 7 is a candidate for cooling, all need evaluation for cooling?
signs of encephalopathy. Sometimes, evaluation for enceph-
alopathy and consideration for cooling may be overlooked in For those convinced by the current evidence, this is an
the flurry of managing other critical complications associ- important question, which will be the focus for future re-
ated with birth depression, such as hypotension, blood search. Several possible strategies include combinations of
loss, meconium aspiration syndrome and persistent pulmo- potentially neuroprotective drugs with hypothermia; earlier
nary hypertension. initiation of cooling; increased depth or duration of cooling;
Even if the need to evaluate for encephalopathy is and prolonged rewarming. There is some experimental
recognised, clinicians vary in their level of experience evidence supporting additive or synergistic effects of drugs
and confidence in performing the neonatal neurological with hypothermia, including some FDA-approved drugs (top-
examination, and the signs of encephalopathy can be iramate, N-acetylcysteine).14,15 Many other FDA-approved
subtle, may not always fit neatly into published grading drugs, e.g. anticonvulsants and anti-inflammatories, still
schemes, can evolve over time, or may be mistaken for the need to be evaluated experimentally in combination with
side-effects of sedatives or of severe systemic illness.11 Am- cooling, to provide a foundation for future human studies.
plitude-integrated EEG (aEEG), which was originally used in Although experimental evidence indicates that cooling is
the Cool Cap trial to exclude infants anticipated to do well more effective when initiated earlier after the insult,9 the
without intervention, might become a useful way of decid- therapeutic time window for the benefit of cooling appears
ing whether an infant with equivocal findings on examina- to decrease as the severity of the initial insult increases.16
tion is ‘encephalopathic enough’ to benefit from cooling. The two largest trials to date were unable to detect an ef-
fect of time of initiation on outcome, perhaps because
cooling of most infants was started relatively late in the
Who should be cooled? Who should not be time window in both trials, between 4 and 5 h after birth.2,3
cooled? In the Eicher trial, cooling was initiated with ice packs prior
to or during transport, and enrollment time was thus earlier
The results of the Cool Cap trial indicated that the subgroup than in the two larger trials1; it is tempting to speculate
of infants with the most severe aEEG tracings (severe that earlier time of initiation facilitated detection of effi-
suppression plus seizures) did not improve with cooling, cacy, despite a smaller sample size than either the Brain
whereas the majority of infants, who had less severe aEEG Cooling or the NICHD trial. Perhaps the results of the re-
abnormalities, showed improved outcome with cooling.2 In maining RCTs or analysis of data from the VermonteOxford
contrast, a post hoc analysis from the Cool Cap trial,12 consis- Neonatal Encephalopathy registry will shed additional light
tent with the results of the NICHD body cooling trial,3 showed on the importance of initiation time. There is no evidence
that clinical encephalopathy grade (Sarnat II versus III) did to indicate that longer durations of cooling or rewarming,
4. Current controversies in hypothermic neuroprotection 33
or greater depth of cooling will result in better outcomes safety should be a priority, and data on cooled infants
(nor that they are safe), so the use of these approaches should be collected systematically, e.g. via the Vermonte
should be limited to evaluation in RCTs. Oxford Network Neonatal Encephalopathy registry or the
TOBY Register.
Neurodevelopmental outcome
As indicated earlier, it is not yet known whether the early Practice points
promising results with hypothermia based on evaluation at
12e24 months will translate into improved performance at Therapeutic hypothermia safely decreases the
school age. However, given the lack of any other therapies combined outcome of death or disability at 12e
for HIE on the immediate horizon, this limitation is not likely 24 months, in infants with apparent HIE.
to present a barrier to implementation for many neonatol- Published protocols and the necessary equipment
ogists, nor is it likely to deter parents from accepting the are available.
therapy. Use of therapeutic hypothermia for HIE is not yet
Of more immediate concern, neonatologists and pediat- the standard of care.
ric neurologists should remember that what we think we Only protocols with established safety and efficacy
know about the prognostic implications of early neurolog- should be used.
ical findings and early neuroimaging, such as magnetic
resonance imaging (MRI) is based almost entirely on data
from the pre-cooling era. As a neonatologist, who has
participated in the cooling of over 50 infants, using both
selective head cooling and the NICHD body cooling pro-
tocol, the author has noted that even infants that ulti- Research directions
mately do well at 18e24 months do not always show
a dramatic improvement in neurological status after re- Does hypothermia reduce disability in survivors,
warming, but rather many seem to show a gradual recovery independent of its effect on mortality?
over several days. Does hypothermia change the prognostic implica-
Regarding the prognostic implications of early MRI, e.g. tions of post-hypothermic neurological examina-
at 7e10 days after birth, there is tantalising (but inconsis- tion or MR imaging?
tent) preliminary data to suggest that cooling is associated Does earlier initiation of cooling, within the first
with a change in the pattern and/or extent of injury,17,18 6 h of life, improve outcome?
but this has so far not been evaluated in large numbers of Can drug plus hypothermia combinations safely
patients nor are there any reports so far of the correlation improve outcome?
of early MRI findings in cooled infants with 18e24 months’ Could longer duration or lower target temperature
neurodevelopmental outcome. It is possible that MRI find- safely improve outcome?
ings at 7e10 days in infants with encephalopathy treated
with cooling may represent reversible changes in evolution.
The latter question is likely to be addressed by the NICHD
trial investigators in a secondary analysis. In the meantime,
neonatologists and neurologists should exercise some cau-
References
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