The Neonatal Resuscitation Program: The Evidence Evaluation Process and Anticipating Edition 6 John Kattwinkel and Jeffrey

Perlman Neoreviews 2010;11;e673 DOI: 10.1542/neo.11-12-e673

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Article

emergency care

The Neonatal Resuscitation Program:

John Kattwinkel, MD,* Jeffrey Perlman, MD

The Evidence Evaluation Process and Anticipating Edition 6

Abstract
The Neonatal Resuscitation Program (NRP), published by the American Academy of Pediatrics (AAP) and American Heart Association (AHA), has been in existence for 23 years, and the 6th edition of the NRP Textbook will be published soon. Today, more than 3 million perinatal health professionals have received NRP participation cards, and many hospitals are now requiring evidence of NRP completion before permitting physicians to admit newborns or staff to work in delivery areas. This article describes the evolution of the evidence evaluation process, the questions that have been posed over the past 5 years about the most appropriate neonatal resuscitation techniques, the process that the AAP and AHA have implemented to address those questions, and the major changes that have been incorporated into the upcoming edition of the NRP Textbook.

Author Disclosure Drs Kattwinkel and Perlman have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Objectives

After completing this article, readers should be able to:

1. Delineate the important recommendations in the new edition of the NRP Textbook. 2. Review the recommendations for appropriate teaching of neonatal resuscitation.

Introduction
The NRP, published by the AAP and AHA, has been in existence for 23 years, and the 6th edition of the NRP Textbook will be published soon. The original goal in 1987 was to try to assure that at least one person trained in the techniques of neonatal resuscitation be present at each of the deliveries that occurred in the approximately 5,000 hospitals with licensed delivery services that existed in the United States at the time. (1) The program has far surpassed its goals, as evidenced by the observation that more than 3 million perinatal health professionals have received NRP participation cards and many hospitals are now requiring evidence of NRP completion before permitting physicians to admit newborns or staff to work in delivery areas. This enthusiastic endorsement has placed a heavy responsibility on those developing and updating the NRP to be certain that the recommendations reect the best scientic evidence available at the time of publication. This article describes the evolution of the evidence evaluation process, the questions that have been posed over the past 5 years about the most appropriate neonatal resuscitation techniques, the process that the AAP and AHA have implemented to address those questions, and the major changes that have been incorporated into the upcoming edition of the NRP Textbook. For detailed descriptions of specic issues, readers are encouraged to consult the various resources that have been published and are referenced throughout the article, as well as the unpublished worksheets that are readily available on the AAP NRP website and the AHA Resuscitation website. Although summaries of the details recently were published in the International Liaison Committee on Resuscitation (ILCOR) statement on Consensus on Science and Treatment Recommendations (COSTR) (2) and the AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, (3) these are both large documents, and the neonatal portions are easily lost among the pediatric and adult text. The neonatal scientic and treatment portions of those documents have been reprinted in Pediatrics, (4)(5) and the neonatal portion of Guidelines will be reprinted in the back of the NRP Textbook, Edition 6.
*Editor, NRP Textbook; Charles Fuller Professor of Neonatology, University of Virginia, Richmond, Va. Co-Chair, Neonatal Task Force, International Liaison Committee on Resuscitation; Professor of Pediatrics, Weill Medical College, New York, NY. NeoReviews Vol.11 No.12 December 2010 e673

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Evolution of the Evidence Evaluation Process

The AHA has published guidelines for resuscitation since 1966, (6) and the recommendations for neonates were embedded within the general pediatric sections. In the late 1970s, children began to be recognized as distinctly different physiologically from adults, neonatology was emerging as a recognized specialty, and newborns were recognized as unique from older infants and children. Similarly, the physiologic adaptations imposed by undergoing transition from a uid-lled intrauterine environment to an extrauterine environment requiring air breathing present unique challenges for resuscitation of compromised newborns compared with adults and older children. In the latter, the cause of many, if not most, arrests was a cardiac rather than a respiratory event. The rst edition of the NRP Textbook was published in 1987 and was modeled after a resuscitation chapter from a larger neonatal respiratory-focused program from a single institution. Although neonatology experts recruited by the AAP and AHA made adaptations to the Bloom and Cropley document, the recommendations in that rst edition largely reected expert opinion rather than well-documented, peer-reviewed, and widely debated evidence. Over the past 2 decades, there has been an increasing effort to improve the scientic foundation of resuscitation recommendations by carefully reviewing all published evidence, to debate that evidence in a forum involving diverse expertise, and to reach consensus on interpretation of that evidence. The agreed-on science forms the basis for making or modifying treatment recommendations appropriately to match recognized clinical resources while also gradually challenging delivery facilities to obtain the necessary personnel and equipment resources to permit implementation of the recommendations. During this process, it has become clear that many of the recommended steps of neonatal resuscitation are based on little-to-no scientically validated published evidence. Therefore, another purpose of the review process has been to identify the areas needing more evidence and to stimulate investigators to conduct the necessary research to address those areas. By the 3rd edition, the evidence gathering had been expanded to include countries outside the United States. (7) The review process now occurs in 5-year cycles and literally involves many hundreds of scientists, clinicians, and health-care organizers from around the world.

Debate the evidence through a series of ILCOR meetings Reach consensus with ILCOR on the scientic evidence (COSTR) Reach consensus within the NRP Steering Committee (NRPSC) on the appropriate application of the science to dene appropriate treatment recommendations for NRP Publish COSTR and Treatment Recommendations documents and a new edition of the NRP Textbook

The Evidence Evaluation Process

The 5-year process occurs in stages:

Dene the issues for consideration in the new cycle Conduct an in-depth review of the literature

The process of dening the issues to be researched begins within 6 months of the publication of a new edition of the textbook and takes place over approximately 1 year. Neonatologists, nursing organizations, and NRP instructors are surveyed, from which the NRPSC selects those issues that are judged most likely to result in improved outcome. For the current cycle, 33 questions were selected and each was assigned to a minimum of two experts to conduct an in-depth review of the literature. Each expert was to work independently to create a detailed worksheet for his or her assigned topic. Each worksheet followed a strictly dened format, including a detailed description of the search strategy, the numbers of articles identied and reasons for any rejections, a classication of the quality of the study and level of evidence (Table), the reviewers critique of each publication, a summary of the conclusions regarding the evidence, and a recommendation for any implications regarding resuscitation treatment guidelines. Each worksheet was critiqued by the cochairs of the neonatal task force as well as two ILCOR senior reviewers and revised to satisfaction before being presented and debated at a series of meetings that took place over years 2 to 4. Both authors of each worksheet topic were invited to present their respective worksheets, and presenters and discussants unable to attend the meetings could participate via webinar conferencing. Where possible, the two authors assigned to each topic were encouraged to negotiate a unied set of recommendations for that topic. All worksheets were posted to a restricted website for review by all authors and committee members. In February 2010, a 1-week ILCOR conference was held in Dallas, where all worksheet authors and other invited experts heard presentations of the worksheet summaries, following which the conclusions were debated until a consensus on science could be reached. In some cases, a consensus also was reached about a treatment recommendation appropriate for international implementation. It was from the 33 conclusions reached at this ILCOR Evidence Evaluation Conference that the

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C2010 Levels of Evidence (LOE) for Studies of Therapeutic Interventions

Table.

Assessment of the need for and management of supplemental oxygen:

LOE 1: Randomized, controlled trials (or meta-analyses of randomized, controlled trials) LOE 2: Studies using concurrent controls without true randomization (eg, pseudo-randomized) LOE 3: Studies using retrospective controls LOE 4: Studies without a control group (eg, case series) LOE 5: Studies not directly related to the specic patient/population (eg, different patient/population, animal models, mechanical models)

What is the reliability of oximeters (type, probe placement, timing of achieving signal, limitations)? How much oxygen should be used (room air versus 100% versus blended O2)? What are the appropriate indications for supplemental oxygen use (eg, color versus SpO2; CO2 production)?

Ventilation

COSTR document (2) was drafted and eventually approved through electronic communication, conference calls, and one subsequent meeting of the writing groups. The individual resuscitation councils, all of which had sent representatives to ILCOR, returned to their countries for further rening and expansion of the treatment recommendations deemed appropriate for their respective countries. The NRPSC, consisting of neonatologists and liaisons from respiratory therapy, neonatal nursing, maternal-fetal medicine, and education from the United States and Canada subsequently met by e-mail communication and two 2-day meetings to reach consensus on the treatment recommendations to be published in the Guidelines. (3) These recommendations were incorporated into the new edition of the NRP Textbook, with associated instructional materials scheduled for release in early 2011.

How should functional residual capacity (FRC) be established with positive-pressure ventilation (PPV) (eg, long inations, positive end-expiratory pressure [PEEP], pressure guidelines)? Is pressure the appropriate parameter to consider in PPV or should we measure and display volume? Is continuous positive airway pressure (CPAP) preferable to intubation and PPV in the delivery room? What are the alternative airway interfaces to intubation (masks, prongs, laryngeal mask airway)? What are the alternatives to PPV devices (eg, mouthto-mouth, mouth-to-tube, mouth-to-mask)?

Chest compressions

What is the optimum technique (two-nger, twothumb-encircling, best chest placement; how deep)? What is the most effective compression:ventilation ratio (3:1, 15:2, 30:2, continuous compressions)?

Drugs

Questions Selected for Review During the 2006 to 2010 Cycle

The following were selected for review and were assigned worksheets, all of which may be viewed at http://www. americanheart.org/presenter.jhtml?identier 3060114. Assessment of need for and measures of efcacy of resuscitation:

Which drugs (epinephrine, sodium bicarbonate, naloxone)? What route (endotracheal, intravenous, intraosseous)? What dose of epinephrine is appropriate according to route?

Cord clamping

Early versus late (routine versus with resuscitation)? Is there an advantage to milking of the cord?

Postresuscitation care

Anticipation (accuracy of risk factors, role of gestation)? How accurate are clinical/physical ndings (heart rate, respiratory effort, skin color) for assessing the need for and efcacy of neonatal resuscitation? What adjunct measures are there that might improve clinical ndings (eg, pulse oximetry, exhaled CO2, electronic determination of heart rate)?

How often should glucose be monitored and how managed? When, if, and how should asphyxiated babies be given therapeutic hypothermia?

Ethics

What are the appropriate indications for nonresuscitation?

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What are the thresholds of viability and the parents role? How long should one attempt resuscitation before stopping?

Resuscitation environment

What are appropriate strategies for temperature management of very low-birthweight infants (eg, delivery room temperature, polyethylene wraps/bags, exothermic mattresses)? Is iatrogenic hyperthermia a problem after asphyxia; what about febrile mothers? What are appropriate personnel needs for nonemergent cesarean sections?

supplemental oxygen is believed to be necessary, particularly for babies born preterm. The newer pulse oximeters report both heart rate and oxygen saturation reliably, although they may not be able to achieve a signal during periods of profound bradycardia and hypoperfusion, at which time the clinician must rely on traditional clinical signs.

Assessment of the Need for and Management of Supplemental Oxygen

At the time of the last review and since then with an additional publication, six randomized, controlled clinical studies have demonstrated that beginning resuscitation with 100% supplemental oxygen offers no apparent advantage over 21% oxygen. Evidence from two metaanalyses shows that room air may be associated with a slightly lower mortality and, from a few additional investigations, that proinammatory cytokine generation may be lower when room air is used. More recently, additional studies in preterm infants have evaluated the efcacy of using pulse oximetry and blended oxygen to try to match the gradual increase in preductal SpO2 that has been demonstrated following the birth of healthy term babies (Fig. 1). (9) Importantly, irrespective of the starting FiO2 (ie, room air or supplemental oxygen), evidence has shown that most preterm infants require approximately 30% FiO2 before transfer to the neonatal intensive care unit. There was considerable debate during the ILCOR process and during NRPSC review as to the best method of translating the many observations from the numerous studies into clinically appropriate recommendations and

Education methodology

Are debrieng sessions effective and are they different from briengs? Is simulation as effective as traditional teaching?

Highlights of Recommendations for 2011 to 2015

A summary of the consensus on science for all of the questions, as debated by ILCOR, may be found in the COSTR document, (2) with details available in individual worksheets. The worksheets present references and summaries of the original studies on which the consensus was based, with commentaries by the respective reviewers. A summary of the NRP treatment recommendations developed following debate may be found in the Guidelines document, (3) with details also available by reading the worksheets and the NRP Textbook. The following is a description of some of the more controversial or provocative topics that led to changes in the NRP resuscitation guidelines.

Assessment of Measures of Resuscitation Efcacy

A review of all the animal and human neonatal studies published in the past 50 years was unable to nd new evidence to refute the ndings of Dawes (8) that an improvement in heart rate is the most sensitive indicator of a clinical response to resuscitative efforts. However, several studies demonstrated that clinical assessment of heart rate can be misleading and inaccurate, while pulse oximetry display of an accurate heart rate and SpO2 can be achieved reliably within 90 seconds of birth. This nding, coupled with a need for tighter control of oxygen management (see next section) has led to a strong recommendation that pulse oximetry be employed whenever resuscitation is anticipated or administration of
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Figure 1. Change of SpO2 following birth of babies born at

term. Reprinted with permission from Mariani et al, 2007. (9)

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have the recommendations reliably reect the evidence. Some members of the committees were of the opinion that exposure to even a brief period of hyperoxemia for a baby who had recently experienced a hypoxic-ischemic insult could result in irreversible injury and should be aggressively avoided, even at the expense of possibly exposing such babies to a brief period of hypoxemia when compared with the healthy term norms. Conversely, others argued that the studies demonstrating long-term effects of brief exposure had been conducted only by a well-dened group of investigators and had not been independently conrmed sufciently by others and that animal studies suggest there is possible harm from a similarly brief period of hypoxemia, particularly in the infant who has profound bradycardia and a hypoperfused state. Therefore, the NRPSC has observed the following compromise guidelines during preparation of NRP Edition 6:

Every delivery area should have an oximeter readily available but not necessarily physically present at every delivery. Supplemental oxygen should be administered using a blender, allowing adjustment of variable concentration, and should be titrated to maintain SpO2 within the interquartile range dened for uncomplicated term babies. NRP will advocate (but not mandate) starting resuscitation of a term baby with 21% oxygen and something greater than 21%, but less than 100%, oxygen for a preterm baby (which would encourage having the blender attached for all preterm deliveries). An oximeter is recommended whenever supplemental oxygen, positive ventilation, or CPAP is used.

of experience with ventilating babies during the immediate neonatal period has provided sufcient evidence to support the use of PEEP once a baby has been intubated for respiratory distress. Surprisingly, there is a paucity of data regarding the use of CPAP/PEEP in the delivery room in the term newborn. Thus, evidence to recommend any particular ination strategy over another is insufcient. The new NRP guidelines reect this uncertainty and describe the concept and techniques for administering CPAP, PEEP, and variable ination times following birth but leave the decision of when and which particular strategy to implement to local preferences. Although resuscitation of adults appears to be focusing more on re-establishing cardiac output and less on ventilation, the evidence continues to support assisting ventilation as the most important and effective action leading to successful resuscitation of the neonate. Both the neonatal committee of ILCOR and the NRPSC believed that additional emphasis should be placed on securing the airway and assuring adequate ventilation before a resuscitator begins to initiate chest compressions or administration of epinephrine. Therefore, the new algorithm developed for NRP now includes an extra 30-second period (Fig. 2) and a six-step mnemonic (Fig. 3) for assuring adequate chest movement and encourages consideration of endotracheal intubation before beginning chest compressions. Also, more publications have reported the safety and efcacy of using the laryngeal mask airway (LMA) in the larger newborn, so the NRP recognizes the LMA as a reasonable alternative to endotracheal intubation when endotracheal intubation is unsuccessful or not feasible.

Chest Compressions
The adult ILCOR group and the Advanced Life Support, Basic Life Support, and First Aid groups of the AHA have markedly decreased their emphasis on ventilation and changed their recommendations about compression: ventilation ratios from 15:2 to 30:2 for multiple resuscitators, eliminating ventilations entirely for the single resuscitator. However, the neonatal ILCOR and NRP committees, recognizing the importance of ventilation in resuscitation of the newborn, have maintained the 3:1 recommendation and strongly recommend endotracheal intubation by the time that compressions are started. Because the increased focus on compressions has also been adopted by Pediatric Advanced Life Support (PALS), to clarify the differences between the NRP and PALS recommendations, both NRP and PALS recommend that when resuscitating young infants, the likely cause of the arrest should be the driving force when
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Modes of Ventilation and Airway Devices Used During Resuscitation of the Newborn
The most effective and least traumatic method of establishing FRC in babies who have compromised ventilation at birth has been the subject of much debate over the past 2 decades. Although several randomized trials have evaluated the early postdelivery use of CPAP versus elective intubation and some human and animal studies have examined the use of long ination times, with and without PEEP to establish and maintain an FRC, the optimum strategy remains unclear. The early use of CPAP has been enthusiastically advocated by many clinicians, but a recent randomized, controlled trial suggests no advantage over selective intubation, and those receiving CPAP may have an increased incidence of pneumothoraces. (10) A consensus was reached that the many years

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Figure 2. New algorithm for NRP Edition 6.

deciding which ratio to use. The NRPSC also increased the time for interrupting compressions to assess heart rate from every 30 seconds to at least 45 to 60 seconds. This change was based on animal studies indicating that more than 30 seconds is required to re-establish effective coronary perfusion pressures after resuming compressions.
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Epinephrine Route and Dosing

Recent clinical studies have shown that when the recommended intravenous (IV) dose of 0.01 to 0.03 mg/kg epinephrine is administered endotracheally, the result is often unpredictable, and one animal study showed no effect at all. Therefore, the new NRP Textbook strongly recommends the IV route for epinephrine and has iden-

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1 minute for newborns who do not require resuscitation. However, there is insufcient evidence to support or refute a recommendation to delay cord clamping in babies requiring resuscitation. This strategy impinges on obstetric practice but is worthy of discussion, and management will likely reect local practices.

Discontinuing Resuscitation
An important area that was hotly debated during the ILCOR process and at the NRPSC meetings was the management of babies who do not Figure 3. Mnemonic for remembering the six steps for improving efcacy of positivehave a detectable heart rate after pressure ventilation. 10 minutes. The available evidence, albeit involving relatively small numtied placement of an umbilical venous catheter as a bers, suggests that such babies are likely to either die or have procedure to be considered early in the resuscitation severe neurologic disability. However, one study with a process if a major resuscitation is underway. If epinephlarge contemporary cohort of infants (some randomized to rine is administered endotracheally while the IV line is receive postresuscitation hypothermia) indicates that the being placed, a higher dose (0.05 to 0.1 mg/kg) should lack of return of spontaneous circulation after 10 minutes of be used, although the evidence for a specic higher dose age in babies born without detectable heart rate is associis lacking. ated with survival without severe neurologic decit in a small number of the survivors. (12) However, data were not Induced Therapeutic Hypothermia available on the number of infants who were deemed too Edition 5 of NRP recognized that early institution of sick for study entry or died before enrollment. These factors induced hypothermia following intrapartum hypoxiamay have resulted in a signicant overestimation of the rate ischemia likely was efcacious in reducing the severity of of intact survival among infants who had Apgar scores of 0 subsequent brain injury. Since that publication, addiat 10 minutes. The new NRP guidelines suggest that it is tional randomized, controlled trials have been comstill appropriate to consider stopping resuscitation in a newpleted, and the evidence now is consistent that early born who has no detectable heart rate that remains undeinduced hypothermia is effective at reducing the incitectable for 10 minutes. However, the guidelines recognize dence and severity of hypoxic-ischemic encephalopathy, that the decision to continue resuscitation efforts beyond whether induced by whole-body or selective head cool10 minutes of no heart rate is often complex and may be ing. Therefore, the new edition recommends using this inuenced by issues such as the presumed cause of the therapy when it can be implemented according to dearrest, the gestational age of the baby, the presence or ned protocols and with coordination by facilities that absence of complications, the potential role of therapeutic have multidisciplinary resources and the ability to prohypothermia, and the parents previously expressed feelings vide longitudinal follow-up. (11) about acceptable risk of morbidity.

Delayed Cord Clamping

Several studies have demonstrated a benet to delaying cord clamping for the uncomplicated birth for a minimum time ranging from 1 minute until the cord stops pulsating following delivery. Particularly in the uncomplicated preterm birth, delayed clamping was associated with higher blood pressures during stabilization and a lower incidence of intraventricular hemorrhage. Thus, ILCOR recommends delaying umbilical cord clamping for at least

Teaching Neonatal Resuscitation

The ILCOR process dealt with the issue of structural programs to teach neonatal resuscitation. Most studies indicate that use of simulation-based learning methodologies enhances performance in both real-life clinical situations and simulated resuscitations. In addition, use of briengs or debriengs of resuscitation team performance generally have been found to result in improved knowledge or skills. Based on the available evidence, the
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NRPSC suggests adopting simulation, brieng, and debrieng techniques in designing an effective education program for the acquisition and maintenance of the skills necessary for effective neonatal resuscitation.

References
1. Bloom RS, Cropley C, eds. Textbook of Neonatal Resuscitation.
Dallas, Tex; Elk Grove Village, Ill: American Heart Association; American Academy of Pediatrics; 1987 2. The International Liaison Committee on Resuscitation (ILCOR) consensus on science with treatment recommendations. Circulation. 2010;122:S250 S275 3. 2010 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC). Circulation. 2010;122:S640 S656 4. Perlman JM, Wyllie J, Kattwinkel J, et al. The International Liaison Committee on Resuscitation (ILCOR) consensus on science with treatment recommendations for pediatric and neonatal patients: neonatal resuscitation. Pediatrics. 2010;126: e1319 e1344 5. Kattwinkel J, Perlman JM, Aziz K, et al. 2010 guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of pediatric and neonatal patients: neonatal resuscitation guidelines. Pediatrics. 2010;126:e1400 e1413 6. Cardiopulmonary resuscitation: statement by the Ad Hoc Committee on Cardiopulmonary Resuscitation, of the Division of Medical Sciences, National Academy of Sciences, National Research Council. JAMA. 1966;198:3723799 7. Nadkarni V, Hazinski MF, Zideman D, et al. Pediatric resuscitation: an advisory statement from the Pediatric Working Group of the International Liaison Committee on Resuscitation. Circulation. 1997;95:21852195 8. Dawes GS. Foetal and Neonatal Physiology. Chicago, Ill: Year Book Medical Publishers; 1968:149 9. Mariani G, Dik PB, Ezquer A, et al. Pre-ductal and post-ductal O2 saturation in healthy term neonates after birth. J Pediatr. 2007;150:418 421 10. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008;358:700 708 11. Perlman J, Davis P, Wyllie J, Kattwinkel J. Therapeutic hypothermia following intrapartum hypoxia ischemia. An advisory statement from the Neonatal Task Force of the International Liaison Committee on Resuscitation. Resuscitation. 2010; 81:1459 1461 12. Laptook AR, Shankaran S, Ambalavanan N, et al. Outcome of term infants using Apgar scores at 10 minutes following hypoxic-ischemic encephalopathy. Pediatrics. 2010;124: 1619 1626

Conclusions
Neonatal clinicians are encouraged to read both the COSTR and Guidelines documents as well as the individual worksheets (http://www.americanheart.org/ presenter.jhtml?identier 3060114) for the details and to note the several hundreds of references related to the full complement of topics reviewed for the current edition. Although some of the recommendations may reect significant change from those presented in earlier editions, readers should be assured that major efforts were made to base any changes on documented evidence. Despite the absence of evidence in most aspects of resuscitation, the NRPSC believed that guidelines should be developed for all of the elements of the resuscitation process to assist the clinicians who must make decisions in the real world. Where no evidence existed, recommendations were made only after extensive debate involving large numbers of highly respected experts. We hope that clinicians will not hesitate to notify the AAP or the AHA wherever recommendations are viewed to be inappropriately based on inadequate evidence or if there are areas where the recommendations should be even more prescriptive.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Know indications for and proper administration of supplemental oxygen in the delivery room. Know the proper approach to airway management in the delivery room. Know the indications for, techniques, and potential complications of chest compression in the delivery room. Know the indications, contraindications, and methods of administration of drugs used for neonatal resuscitation.

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The Neonatal Resuscitation Program: The Evidence Evaluation Process and Anticipating Edition 6 John Kattwinkel and Jeffrey Perlman Neoreviews 2010;11;e673 DOI: 10.1542/neo.11-12-e673

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