Education Research:
Cognitive performance is preserved in
sleep-deprived neurology residents
M. Reimann, PhD
R. Manz, MD
S...
medical specialties and that 2) vigilance as well
as cognitive performance is more compromised
after 24 hours overnight on...
measurements. We revealed significant correlations
with r values ranging from 0.763 to 0.904 (p Ͻ
0.001). Based on these r...
tion as a motivational incentive, which tends to offset
sleepiness effects on performance.13
Alternatively, the applied me...
brain injury: modality-specific factors. J Head Trauma Re-
habil 2000;15:943–956.
16. Wills S, Leathem J. The effects of t...
The new engl and jour nal of medicine
n engl j med 361;14  nejm.org  october 1, 2009 1349
original article
Moderate Hypoth...
The new engl and jour nal of medicine
n engl j med 361;14  nejm.org  october 1, 20091350
P
erinatal asphyxial encephalopat...
Moderate Hypothermia for Perinatal Asphyxial Encephalopathy
n engl j med 361;14  nejm.org  october 1, 2009 1351
vention pe...
The new engl and jour nal of medicine
n engl j med 361;14  nejm.org  october 1, 20091352
ables, as means (±SD) for normall...
Moderate Hypothermia for Perinatal Asphyxial Encephalopathy
n engl j med 361;14  nejm.org  october 1, 2009 1353
as well as...
The new engl and jour nal of medicine
n engl j med 361;14  nejm.org  october 1, 20091354
the noncooled group; relative ris...
Moderate Hypothermia for Perinatal Asphyxial Encephalopathy
n engl j med 361;14  nejm.org  october 1, 2009 1355
come but h...
The new engl and jour nal of medicine
n engl j med 361;14  nejm.org  october 1, 20091356
the target temperatures varied: t...
Moderate Hypothermia for Perinatal Asphyxial Encephalopathy
n engl j med 361;14  nejm.org  october 1, 2009 1357
were rare ...
n engl j med 361;14  nejm.org  october 1, 20091358
Moderate Hypothermia for Perinatal Asphyxial Encephalopathy
References
...
Articles
www.thelancet.com Vol 373 March 28, 2009 1105
Long-term risk of epilepsy after traumatic brain injury in
children...
Articles
1106 www.thelancet.com Vol 373 March 28, 2009
Danish National Hospital Register. Specialists in neurology
working...
Articles
www.thelancet.com Vol 373 March 28, 2009 1107
log-linear Poisson regression18
with the GENMOD
procedure in SAS (v...
Articles
1108 www.thelancet.com Vol 373 March 28, 2009
5·19–9·91) and the ICD-10 period (7·51, 6·02–9·38;
p=0·82). For sku...
Articles
www.thelancet.com Vol 373 March 28, 2009 1109
low relative risk of post-traumatic epilepsy in young age
groups.
P...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
Education Research: Cognitive performance is preserved in sleep ...
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  1. 1. Education Research: Cognitive performance is preserved in sleep-deprived neurology residents M. Reimann, PhD R. Manz, MD S. Prieur H. Reichmann, Prof T. Ziemssen, MD ABSTRACT Objective: To test the hypotheses that sleep deprivation in neurology residents is associated with performance deficits and that vigilance and cognitive performance is more compromised after overnight on-call duty compared to night shift. Methods: Thirty-eight neurology residents of a university teaching hospital participated in a prospec- tive single-blind comparison study. Residents were recruited according to their working schedule and divided into 3 groups: 24 hours overnight on-call duty, night shift, and regular day shift (controls). All participants underwent serial measurements of sleepiness and cognitive performance in the morning directly after or before their shift. Pupillary sleepiness test and Paced Auditory Serial Addition Test were applied. Perceived sleepiness was assessed by a questionnaire. Results: Sleepiness was increased in residents after night shift and overnight call compared to controls while the type of night duty was not associated with the extent of sleepiness. Sleep- deprived residents did not show any performance deficits on the Paced Auditory Serial Addition Test. Cognitive performance was not associated with sleepiness measures. Conclusions: Night shift and overnight call duty have a similar impact on alertness in neurology residents. Sleep-deprived neurology residents may be able to overcome sleep loss–related per- formance difficulties for short periods. Neurology® 2009;73:e99 –e103 GLOSSARY PASAT ϭ Paced Auditory Serial Addition Test; PST ϭ Pupillography Sleepiness Test; PUI ϭ pupillary unrest index; SSS ϭ self-stated sleepiness. Despite recent changes in working schedule regulation for clinicians, long working hours remain a common feature in health care.1-3 Associated sleep deprivation and fatigue present not only a serious concern for patient safety, but also places the health of health care professionals at risk. Serious problems resulting from sleep loss range from performance deficits and erroneous decision making to increased risk for motor vehicle accidents.2,4 The majority of sleepiness studies have been performed in certain medical specialties with a reputation for demanding schedules, such as surgery or intensive care.2 Neurologists are frequently underrated in terms of intensity and heaviness of their working schedules due to their mistakenly close relationship to psychiatry. Call rotation on the neurology ward and night shifts at the neurol- ogy intensive care unit are as common as in internal medicine or surgery. Actually, neurologists are frequently challenged by the high prevalence of life-threatening strokes in the Western society, where any delay in action or poor performance may be fatal for the patient. This prompted us to investigate sleepiness and cognitive performance in sleep-deprived and alert neurologists working at a large university neurology clinic. We hypothesized that 1) sleep depriva- tion in neurologists is associated with performance deficits as previously demonstrated for other Address correspondence and reprint requests to Dr. Manja Reimann, ANF Laboratory, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307 Dresden, Germany manjareimann@uniklinikum-dresden.de From the Autonomic and Neuroendocrinological Laboratory, Department of Neurology (M.R., R.M., S.P., H.R., T.Z.), and Research Group Neuro- Metabolism, Department of Neurology and Internal Medicine III (M.R., T.Z.), University Hospital Carl Gustav Carus, Dresden University of Technology, Germany. Supported by the University Hospital Carl Gustav Carus, Dresden, Germany. Disclosure: Author disclosures are provided at the end of the article. RESIDENT & FELLOW SECTION Section Editor Mitchell S.V. Elkind, MD, MS Copyright © 2009 by AAN Enterprises, Inc. e99
  2. 2. medical specialties and that 2) vigilance as well as cognitive performance is more compromised after 24 hours overnight on-call duty compared to night shift. METHODS This pilot study included 38 neurology residents (19 women and 19 men, mean age 30 Ϯ 2 years) recruited from the Department of Neurology at the University Hospital Carl Gustav Carus, Dresden, Germany. We screened residents for exclusion cri- teria such as current use of medication known to affect the sleep/ wake cycle or daytime alertness, current psychiatric illness, and sleep disorder diagnosis. We then stratified eligible residents according to their working schedule into 3 groups: group 1, 24 hours overnight on-call duty; group 2, night shift; and group 0, regular day shift (control). Definitions of groups. Residents in group 1 (24 hours over- night on-call duty) performed their regular shift from 8 AM–4 PM followed by overnight call until 8 AM the next day. During their overnight duty, they were allowed to sleep but there was no scheduled coverage. Residents have usually 3 to 4 overnight calls per month. Residents in group 2 (night shift) worked at the intensive care unit for 7 consecutive days daily from 8 PM to 8 AM the following morning. Afterwards they had 1 week off. Sleeping was not permitted during their shifts. From experience, residents have on average 2 admissions and 30 internal and 3 outpatient consultations per night. Night shift rotation was every 5 to 6 weeks over a period of 1 year. Residents in group 0 (day shift) regularly worked from 7:30 AM to 3:30 PM. However, residents on day shift frequently work overtime. Standard protocol approvals, registrations, and patient con- sents. The Ethics Committee on human experimentation of the Dresden University of Technology approved the study and the in- vestigation conformed with the principles outlined in the Declara- tion of Helsinki. We informed all participating residents about the objectives and procedures of the study and obtained written in- formed consent prior to their inclusion. The serial data collection was performed at the Autonomic and Neuroendocrinological Labo- ratory of the University Clinic. We measured all residents before 9 AM directly after their (night) shift rotation or just before day shift commenced (controls). The assistant performing the measurements was blinded. We measured objective sleepiness by Pupillography Sleepiness Test (PST) and cognitive performance by Paced Audi- tory Serial Addition Test (PASAT). We instructed the residents to abstain from drinking alcoholic beverages, smoking, and drinking coffee for at least 4 hours before the measurements. The residents rated their sleepiness on a 5-point Likert scale based on the state- ment “Currently I feel.” We also recorded the number of hours slept in the previous 24 hours and assessed the perceived recovery effect due to sleep on a 5-point Likert scale. All measurements were serially repeated up to a maximum of 13 times. Measurement frequency, however, varied between individuals according to the rotation schedules (4.8 Ϯ 3.3). Pupillary Sleepiness Test. We performed the PST (AMTech, Dossenheim, Germany) in a quiet and darkened room after an ini- tial dark-adapting phase of 15 minutes. During PST, residents wore goggles equipped with infrared light transmitting filter glasses im- pervious to visible light. They were seated on a comfortable chair and head position was adjusted by a chin rest fixed on a table. An infrared video camera was fixed at a distance of 70 cm from the examination subject. We instructed the clinicians to maintain fixa- tion on a set of infrared light-emitting diodes. We then recorded spontaneous pupillary oscillations over a period of 11 minutes by infrared video pupillography and evaluated the recording by 25-Hz real-time analysis as published elsewhere.5 Pupillary unrest index (PUI) is a measure of pupillomotor hippus in darkness and calcu- lated as an integrated sum of slow movements of the pupillary mar- gin during the measurement period.6 This value is usually low in alertness and increases with progressive sleepiness. We also calcu- lated the mean pupil diameter over the entire recording period of 11 minutes. During sleepiness the initial diameter is reduced and the mean pupil size falls below the initial diameter toward the end of the measurement. Paced Auditory Serial Addition Test. The validated and computer-aided PASAT allows for measuring the capacity and velocity of information processing within the auditory-verbal do- main (cognitive performance).7,8 The test system entails the sub- ject to continuously add the last 2 numbers of consecutive series and to announce the sum aloud. Numbers from 1 to 9 are an- nounced acoustically in random order by a PC with the screen remaining dark. To avoid practice effects, clinicians were trained on the PASAT at least 3 times before commencing the study. We applied the 60-item short version of the test (maximal score of 60). Lower scores (small numbers of correct answers) indicate worse cognitive performance. Statistical analysis. We used the SPSS software package ver- sion 16.0 for Windows (SPSS Inc., Chicago, IL) for all statistical evaluation. Data are presented as median and 25th–75th percen- tile unless otherwise stated. Owing to the small sample size we assumed non-Gaussian distribution, and hence applied nonpara- metric tests with Bonferroni correction for comparing groups. Spearman correlation coefficients were calculated. A two-tailed p Ͻ 0.05 was regarded as the level of significance. RESULTS Before we started the comparison among the 3 groups, we assessed the strength of association between the first measurement and the mean of serial Table Sleepiness and cognitive performance of neurology residents by type of night duty Parameters Overnight call (n ‫؍‬ 17) Night shift (n ‫؍‬ 6) Control (n ‫؍‬ 15) ␹2 (p*) Pupil diameter (mm) 7.51 (6.25–7.75) 7.23 (5.18–7.54) 7.21 (6.61–8.00) 0.59 (0.744) Pupillary unrest index (mm/min) 7.00 (4.96–9.44)a 10.34 (7.78–15.07)a 4.72 (3.86–5.09)b 12.88 (0.002) PASAT score† 56 (49–58) 51 (42–58) 54 (48–56) 0.67 (0.715) Self-stated sleepiness‡ 2.3 (1.7–2.7)a 2.6 (2.2–3.1)a 1.0 (0–1.0)b 20.24 (Ͻ0.001) Data are median (interquartile range). Unequal superscript letters indicate significant differences (Mann-Whitney U test). *Kruskal-Wallis test. †Paced Auditory Serial Addition Test (number of correct answers/60). ‡Categorical value. e100 Neurology 73 November 24, 2009
  3. 3. measurements. We revealed significant correlations with r values ranging from 0.763 to 0.904 (p Ͻ 0.001). Based on these results, we continued our analysis using the mean values. PUI and self-stated sleepiness (SSS) were signifi- cantly affected by type of night duty while pupil diame- ter and the PASAT score remained unaffected (table). It appeared that PUI and SSS were significantly higher after the night shift and the 24 hours overnight on-call duty compared to a normal night at home. Residents after night shift and 24 hours overnight on-call duty did not differ with respect to sleepiness measures. Neurology residents on 24 hours overnight on- call duty had slept on average 4.3 (2.8–4.6) hours (midshift nap) in the last 24 hours, which was signif- icantly less compared to their colleagues on night shift (5.9 [4.9–7.0] hours, p ϭ 0.006) or on day shift (controls) (6.5 [6.0–7.0] hours, p Ͻ 0.001). The longest sleeping phase during 24 hours overnight on- call duty was 3.0 (2.0–3.8) hours. Residents had on average a mean (minimum–maximum) of 2 (1–3) admissions, 2 (0–7) consultations, and 3 (1–5) tele- phone inquiries during overnight on-call duty. Figure 1 illustrates the proportion of respective responses to the statement “Currently I feel . . .” Fig- ure 2 depicts the self-stated recovery effect due to sleep in the 24 hours preceding the examination. Correlation analyses did not reveal any association between the PUI and the PASAT score. However, the PUI increased (r ϭ 0.507, p ϭ 0.001) and the PASAT score decreased (r ϭ Ϫ0.335, p ϭ 0.04) with increased SSS in the total sample. The perceived level of sleepiness decreased as the number of sleeping hours in the past 24 hours increased (r ϭ Ϫ0.527, p ϭ 0.001). The above associations could not be confirmed in subgroups (p Ͼ 0.05). DISCUSSION Rotating shift work in clinics to pro- vide 24-hour patient care has come increasingly under scrutiny due to negative effects associated with sleep loss, fatigue, and circadian disruption.9,10 Although night shift and 24 hours overnight on-call duty consid- erably differ in terms of number of working hours, per- mission for midshift naps, and rotation frequency, their effect on sleepiness and cognitive performance has never been distinguished. We hypothesized that residents on 24 hours call rotation would be more affected by sleep loss due to a longer and more irregular working sched- ule. We investigated this hypothesis in neurology resi- dents of a large university clinic. This specialty group is often underrated in terms of heaviness and intensity of labor and therefore has never been investigated in sleep- iness studies. Importantly, previous sleepiness studies in selected medical specialties explicitly emphasized that results must not be extrapolated to other medical spe- cialty groups.3,4,11 Although we could not verify the above hypothesis, our results clearly demonstrate that sleepiness is a common problem among neurology resi- dents undergoing night shift and 24 hours overnight on-call duty. We additionally demonstrated that vigilance mea- sured by PST is in good agreement with SSS. This finding corresponds with previous studies suggesting the PST as a valid and objective tool to detect sleepi- ness in healthy subjects.6 The lack of significant performance decrements in sleep-deprived neurology residents vs controls is intrigu- ing since an association between performance and acute sleep deprivation was found in previous studies.2,4,12 Differences in study design, medical specialty, and methods for vigilance testing limit comparisons across studies. However, one study also failed to show a signif- icant performance decrement on the complex PASAT test in sleep-deprived normal subjects.13 The investiga- tors concluded that university-based research may func- Figure 1 Self-stated sleepiness of neurology residents by type of night duty Figure 2 Self-stated recovery effect due to sleep in the past 24 hours Neurology 73 November 24, 2009 e101
  4. 4. tion as a motivational incentive, which tends to offset sleepiness effects on performance.13 Alternatively, the applied method for performance testing may have been suboptimal for our population since its clinical utility is mainly proven in neuropsycho- logical syndromes. However, more recent studies also employed the PASAT in healthy adults with satisfactory results.7,14 Originally assumed to measure rate of infor- mation processing, the PASAT is now recognized as tapping into different types of cognitive processes.15 This multifactorial nature may complicate the interpre- tation of test result from sleep-deprived subjects espe- cially under the assumption that sleep loss affects different cognitive pathways differentially. The consis- tently high PASAT score across all study groups sug- gests that sleep-deprived neurology residents are able to overcome performance difficulties for a limited time pe- riod. This assumption seems plausible since stressful working situations are routine in the clinic and thus may facilitate partial conditioning. Although there is ev- idence that sleep-deprived resident doctors are prone to committing medical errors,4,9 tasks of short duration may be less likely to detect performance deficits in chronically sleep deprived individuals.2 Importantly, we adequately controlled for prac- tice effects8 first by using a control group and sec- ondly by training the clinicians on the PASAT prior to the study. Consequently, we obtained a very good agreement between the first measurement and the mean of serial measurements. In addition, major confounders of the PASAT such as age, gender, edu- cation, and ethnicity14,16 were accounted for by creat- ing a homogenous study sample. Nevertheless, it must be considered that our results are compromised by a questionable rested control group. Correspondingly, the average amount of sleep in our controls was equivalent to the accepted core sleep requirement of 6.5 hours (many were also below).17 In addition, nearly two thirds of the controls felt fairly to poorly rested, which indicates chronic partial sleep de- privation (figure 3). This finding is relevant as chronic partial sleep deprivation appears to be cumulative with respect to performance decrements.18 Neurology residents on night shift and overnight call are affected to a similar extent by sleepiness. In- creased sleepiness, however, did not affect performance on the complex PASAT test. It seems that sleep- deprived neurology residents may be able to overcome sleep loss–related performance difficulties for short peri- ods. This, however, may not necessarily apply for more demanding procedures outside the laboratory. AUTHOR CONTRIBUTIONS Statistical analysis was conducted by Dr. Manja Reimann. ACKNOWLEDGMENT The authors thank all neurology residents for their participation in this study. DISCLOSURE Dr. Reimann, Dr. Manz, and S. Prieur report no disclosures. Dr. Reich- mann serves on scientific advisory boards, receives speaker honoraria, and/or receives funding for travel from Cephalon, Inc., Novartis, Teva Pharmaceutical Industries Ltd., Lundbeck Inc., GlaxoSmithKline, Boehr- inger Ingelheim, Bayer Schering Pharma., UCB/Schwarz Pharma, Desitin Pharmaceuticals, GmbH, Pfizer Inc., and Solvay Pharmaceuticals, Inc. Dr. Ziemssen has received speaker honoraria from Biogen Idec, Sanofi- Aventis, Merck Serono, Novartis, Teva Pharmaceutical Industries Ltd., and Bayer Schering Pharma; serves as a consultant for Teva Pharmaceuti- cal Industries Ltd., Novartis, and Bayer Schering Pharma; and receives research support from the Roland Ernst Foundation. REFERENCES 1. Reddy R, Guntupalli K, Alapat P, Surani S, Casturi L, Subramanian S. Sleepiness in medical ICU residents. Chest 2009;135:81–85. 2. Veasey S, Rosen R, Barzansky B, Rosen I, Owens J. Sleep loss and fatigue in residency training: a reappraisal. JAMA 2002;288:1116–1124. 3. Surani S, Subramanian S, Aguillar R, Ahmed M, Varon J. Sleepiness in medical residents: impact of mandated reduc- tion in work hours. Sleep Med 2007;8:90–93. 4. Arnedt JT, Owens J, Crouch M, Stahl J, Carskadon MA. Neurobehavioral performance of residents after heavy night call vs after alcohol ingestion. JAMA 2005;294:1025–1033. 5. Ludtke H, Wilhelm B, Adler M, Schaeffel F, Wilhelm H. Mathematical procedures in data recording and processing of pupillary fatigue waves. Vision Res 1998;38:2889–2896. 6. Wilhelm B, Wilhelm H, Ludtke H, Streicher P, Adler M. Pupillographic assessment of sleepiness in sleep-deprived healthy subjects. Sleep 1998;21:258–265. 7. Diehr MC, Cherner M, Wolfson TJ, Miller SW, Grant I, Heaton RK. The 50 and 100-item short forms of the Paced Auditory Serial Addition Task (PASAT): demo- graphically corrected norms and comparisons with the full PASAT in normal and clinical samples. J Clin Exp Neuro- psychol 2003;25:571–585. 8. Tombaugh TN. A comprehensive review of the Paced Au- ditory Serial Addition Test (PASAT). Arch Clin Neuro- psychol 2006;21:53–76. 9. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med 2005;352:125–134. 10. Gold DR, Rogacz S, Bock N, et al. Rotating shift work, sleep, and accidents related to sleepiness in hospital nurses. Am J Public Health 1992;82:1011–1014. 11. Saxena AD, George CF. Sleep and motor performance in on- call internal medicine residents. Sleep 2005;28:1386–1391. 12. Grantcharov TP, Bardram L, Funch-Jensen P, Rosenberg J. Laparoscopic performance after one night on call in a surgical department: prospective study. BMJ 2001;323: 1222–1223. 13. Hood B, Bruck D. A comparison of sleep deprivation and narcolepsy in terms of complex cognitive performance and subjective sleepiness. Sleep Med 2002;3:259–266. 14. Diehr MC, Heaton RK, Miller W, Grant I. The Paced Auditory Serial Addition Task (PASAT): norms for age, education, and ethnicity. Assessment 1998;5:375–387. 15. Madigan NK, DeLuca J, Diamond BJ, Tramontano G, Averill A. Speed of information processing in traumatic e102 Neurology 73 November 24, 2009
  5. 5. brain injury: modality-specific factors. J Head Trauma Re- habil 2000;15:943–956. 16. Wills S, Leathem J. The effects of test anxiety, age, intelli- gence level, and arithmetic ability on Paced Auditory Serial Addition Test performance. Appl Neuropsychol 2004;11: 180–187. 17. Bonnet MH, Arand DL. We are chronically sleep de- prived. Sleep 1995;18:908–911. 18. Dinges DF, Pack F, Williams K, et al. Cumulative sleepi- ness, mood disturbance, and psychomotor vigilance per- formance decrements during a week of sleep restricted to 4–5 hours per night. Sleep 1997;20:267–277. Neurology 73 November 24, 2009 e103
  6. 6. The new engl and jour nal of medicine n engl j med 361;14  nejm.org  october 1, 2009 1349 original article Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy Denis V. Azzopardi, F.R.C.P.C.H., Brenda Strohm, R.G.N., A. David Edwards, F.Med.Sci., Leigh Dyet, M.B., B.S., Ph.D., Henry L. Halliday, F.R.C.P.H., Edmund Juszczak, M.Sc., Olga Kapellou, M.D., Malcolm Levene, F.Med.Sci., Neil Marlow, F.Med.Sci., Emma Porter, M.R.C.P.C.H., Marianne Thoresen, M.D., Ph.D., Andrew Whitelaw, F.R.C.P.C.H., and Peter Brocklehurst, F.F.P.H., for the TOBY Study Group* From the Division of Clinical Sciences and Medical Research Council (MRC) Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, Lon- don (D.V.A., A.D.E., L.D., O.K., E.P.); the National Perinatal Epidemiology Unit, Uni- versity of Oxford, Oxford (B.S., E.J., P.B.); the Department of Perinatal Medicine, Royal Maternity Hospital and Depart- ment of Child Health, Queen’s University, Belfast (H.L.H.); the University of Leeds and Leeds General Infirmary, Leeds (M.L.); the Academic Division of Child Health, Queen’s Medical Centre, Nottingham (N.M.); and the Department of Clinical Science, University of Bristol, St. Michael’s Hospital (M.T.) and Southmead Hospital (A.W.), Bristol — all in the United King- dom. Address reprint requests to Dr. Az- zopardi at the Division of Clinical Scienc- es and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom, or at d.azzopardi@ imperial.ac.uk. *The members of the Total Body Hypo- thermia for Neonatal Encephalopathy Trial (TOBY) study group are listed in the Ap- pendix. N Engl J Med 2009;361:1349-58. Copyright © 2009 Massachusetts Medical Society. Abstr act Background Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain. Methods We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5°C for 72 hours and in- tensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes. Results Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 under- went intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 in- fants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P = 0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P = 0.003). Among survivors, cooling resulted in reduced risks of cere- bral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P = 0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P = 0.03 for each) and the Gross Motor Function Classification System (P = 0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associ- ated with cooling. Conclusions Induction of moderate hypothermia for 72 hours in infants who had perinatal as- phyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors. (Current Controlled Trials number, ISRCTN89547571.) Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  7. 7. The new engl and jour nal of medicine n engl j med 361;14  nejm.org  october 1, 20091350 P erinatal asphyxial encephalopathy is associated with high morbidity and mor- tality rates worldwide and is a major burden for the patient, the family, and society. There is an urgent need to improve outcomes in affected in- fants. Experimentally, reducing body temperature to 3 to 5°C below the normal level reduces cerebral injury and improves neurologic function after as- phyxia.1-6 Preliminary clinical studies have found no serious adverse effects of cooling.7-9 Two ran- domized, controlled trials, the CoolCap trial10 and the National Institute of Child Health and Hu- man Development (NICHD) trial,11 have reported outcomes among infants at 18 months of age who had asphyxial encephalopathy, after slightly dif- ferent cooling regimens. Only the NICHD trial showed a significant reduction in the composite primary outcome of death or disability with hypo- thermia. Neither trial had sufficient power to de- tect significant differences in important individu- al neurologic outcomes, and several systematic reviews and an expert workshop did not reach a consensus in recommending hypothermia as stan- dard treatment.12-17 To clarify the role of hypothermia, we carried out the Total Body Hypothermia for Neonatal En- cephalopathy Trial (TOBY), a multicenter, random- ized trial comparing intensive care plus total-body cooling for 72 hours with intensive care without cooling among term infants with asphyxial en- cephalopathy. Methods The TOBY protocol was approved by the London Multicenter Research Ethics Committee and the local research ethics committee of each participat- ing hospital. Conduct of the study was overseen by an independent trial steering committee with advice from an independent data monitoring and ethics committee. Study Design and Procedures TOBY was a randomized, controlled trial, involv- ing term infants, comparing intensive care plus total-body cooling for 72 hours with intensive care without cooling. Infants were eligible if they were born at or after 36 completed weeks’ gestation. They also had to have, at 10 minutes after birth, either an Apgar score of 5 or less or a continued need for resuscitation or, within 60 minutes after birth, acidosis (defined as any occurrence of um- bilical-cord, arterial, or capillary pH of <7.00 or base deficit of ≥16 mmol per liter). In addition, they had to have moderate-to-severe encephalopa- thy (indicated by lethargy, stupor, or coma) and either hypotonia, abnormal reflexes (including oc- ulomotor or pupillary abnormalities), an absent or weak suck, or clinical seizures. Finally, they had to have abnormal background activity of at least 30 minutes’ duration or seizures on amplitude- integrated electroencephalography.18 We excluded infants expected to be more than 6 hours of age at the time of randomization and those with major congenital abnormalities known at randomization that required surgery or were suggestive of chromosomal anomaly or syndromes that involve brain dysgenesis. Written informed consent was obtained from a parent of each infant after explanation of the study, and consent was reaffirmed within the sub- sequent 24 hours.19 Assignment to a treatment group was performed by means of central tele- phone randomization or a secure Web-based sys- tem (provided by the National Perinatal Epide- miology Unit Clinical Trials Unit, Oxford, United Kingdom). Minimization was used to ensure bal- ance of treatment assignment among infants with various grades of abnormality on amplitude-inte- grated electroencephalography and within each participating center. Clinical Management All recruited infants were cared for in partici- pating centers. Infants from referring hospitals were assessed by trained retrieval teams who per- formed amplitude-integrated electroencephalog- raphy, sought consent if the infant was eligible, performed randomization, and for infants assigned to the cooled group, began cooling by discontinu- ing warming and applying cooled gel packs, if nec- essary, until the infant was admitted to a partici- pating center. To minimize potential confounding from dif- ferential use of cointerventions, uniform guidance was provided on ventilatory and circulatory care, management of seizures, sedation, and fluid re- quirements. All infants underwent sedation with morphine infusions or with chloral hydrate if they appeared to be distressed. Skin temperature and rectal temperature (measured at least 2 cm within the rectum) were monitored continuously and re- corded hourly in all infants throughout the inter- Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  8. 8. Moderate Hypothermia for Perinatal Asphyxial Encephalopathy n engl j med 361;14  nejm.org  october 1, 2009 1351 vention period. Clinical staff were made aware of the treatment assignments so that they could man- age cooling appropriately. Intensive Care Alone Infants assigned to the noncooled group received the current standard of care and were placed un- der radiant heaters or in incubators, which were servo-controlled according to the abdominal skin temperature to maintain the rectal temperature at 37.0±0.2°C. Intensive Care with Cooling Infants assigned to the cooled group were treated in incubators with the power turned off. Hypo- thermia was maintained by nursing the infant on a cooling blanket in which fluid whose tempera- ture was regulated by a manually adjusted thermo- stat (Tecotherm TS 200, Tec-Com) was circulated. The target rectal temperature was 33 to 34°C, and typically, the thermostat was set from 25 to 30°C. Rewarming Procedures When the period of cooling concluded, 72 hours after randomization, the rectal temperature was monitored for at least 4 hours to prevent rebound hyperthermia. The rectal temperature was allowed to rise by no more than 0.5°C per hour, to a max- imum of 37±0.2°C. Cranial ultrasonography was performed daily for the first 4 days after birth, and magnetic resonance imaging (MRI) was con- ducted, according to a specified protocol, within 5 to 14 days after birth. Outcomes The primary outcome at 18 months of age was a composite of death or severe neurodevelopmental disability in survivors. Severe neurodevelopmental disability was defined as a score of less than 70 on the Mental Developmental Index of the Bayley Scales of Infant Development II (BSID-II) (on which the standardization mean [±SD] is 100±15 and higher scores indicate better performance), a score of 3 to 5 on the Gross Motor Function Classifica- tion System20 (GMFCS) (on which scores can range from 1 to 5, with higher scores indicating greater impairment), or bilateral cortical visual impairment with no useful vision. Adverse outcomes included intracranial hemor- rhage, persistent hypotension, pulmonary hemor- rhage, pulmonary hypertension, prolonged blood coagulation time, culture-proven sepsis, necrotiz- ing enterocolitis, cardiac arrhythmia, thrombocy- topenia, major venous thrombosis, renal failure treated with dialysis, pneumonia, pulmonary air leak, and duration of hospitalization. (Most out- comes are defined in the Supplementary Appen- dix, available with the full text of this article at NEJM.org.) Secondary outcomes at 18 months, specified before data analysis, included death and severe neurodevelopmental disability (components of the composite primary outcome), the score on the Psychomotor Developmental Index of BSID-II (on which the standardization mean [±SD] is 100±15 and higher scores indicate better performance), cerebral palsy, hearing loss, seizures treated with anticonvulsant agents, microcephaly (i.e., age- and sex-standardized head circumference of more than 2 SD below the mean), multiple neurodevelop- mental abnormalities (i.e., more than one of the following: a GMFCS score of 3 to 5, a score of <70 on the Mental Developmental Index of BSID-II) (on which the standardization mean [±SD] is 100±15 and higher scores indicate better performance, seizures, or cortical visual impairment and hear- ing loss), and survival without neurologic abnor- mality (i.e., a Mental Developmental Index score >84, a Psychomotor Developmental Index score >84, no abnormalities on GMFCS assessment, and normal vision and hearing). Neurologic Assessment Infants were assessed at approximately 18 months of age, through a structured examination by one of five trained assessors who were unaware of the treatment assignments. Neurologic signs and func- tion were scored,20,21 and the presence and type of cerebral palsy were determined. Neurodevel- opmental outcome was assessed according to the BSID-II.22 Statistical Analysis We estimated that a sample of 236 infants would be required to detect a relative risk of 0.6 to 0.7 for the primary outcome in the cooled group as com- pared with the noncooled group, with a statistical power of 80%, at a two-sided significance level of 5% and assuming a 10% loss to follow-up. This sample size was achieved ahead of schedule, and enrollment was continued after the CoolCap and NICHD trial results suggested that a larger sam- ple would be valuable. Demographic and clinical characteristics were summarized at baseline as counts and percentages of the total numbers of infants for categorical vari- Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  9. 9. The new engl and jour nal of medicine n engl j med 361;14  nejm.org  october 1, 20091352 ables, as means (±SD) for normally distributed continuous variables, and as medians and ranges or interquartile ranges for other continuous vari- ables. Data were analyzed in the groups to which pa- tients had been assigned regardless of either de- viation from the protocol or treatment received. Consistent with previous reports,10,11 neurologic outcomes are presented for survivors who had available follow-up data. Comparative statistical analysis entailed calcu- lating the relative risks plus the 95% confidence intervals for all dichotomous outcomes, the mean differences plus 95% confidence intervals for nor- mally distributed, continuous outcomes (using analysis of covariance where appropriate), and the median differences plus 95% confidence intervals for skewed continuous variables. In addition, or- dered categorical variables were examined with the use of the chi-square test for trend. An adjusted analysis of the primary outcome was performed to investigate the effect of known prognostic fac- tors. All statistical tests were two-sided and were not adjusted for multiple comparisons. Prespecified subgroup analyses were performed with stratification on the basis of the grade of abnormality on amplitude-integrated electroen- cephalography at randomization and duration of the interval between birth and randomization (0 to <4 hours vs. 4 to 6 hours). The consistency of the effect of the treatment group across subgroups was explored by means of the statistical test of interaction. Results From December 1, 2002, through November 30, 2006, 494 infants were screened and 325 were recruited from 42 hospitals (Fig. 1). The infants were from the United Kingdom (277), Hungary (24), Sweden (18), Israel (4), and Finland (2). Base- line characteristics of the infants (including ma- ternal characteristics) were broadly similar between the two groups (Table 1). Compliance with Cooling Protocol Rectal temperatures were similar between the two groups at the time of randomization (Table 1). Mean rectal temperatures at 6 to 72 hours after randomization were 33.5±0.5°C and 36.9±0.6°C in the cooled and noncooled groups, respectively (Fig. 2). Among the 162 infants who were not cooled, during the treatment period the tempera- ture rose above 38°C on one occasion in 14 (9%) and on more than one occasion in 23 (14%). Primary Outcome In the cooled group, 42 infants died and 32 sur- vived with severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (Table 2) (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P = 0.17). The result was materi- ally unchanged when adjusted for severity of ab- normality on amplitude-integrated electroenceph- alography, sex, or age at randomization. Adverse Outcomes The incidence of adverse events was similar in the two groups (Table 3). Hypotension, thrombocy- topenia, prolonged coagulation time, and intra­ cranial hemorrhage (seen only on MRI) were fre- quently observed in both groups. Serious adverse events other than death were uncommon and were not associated with cooling. Two infants in the cooled group and one in the noncooled group had sinus thrombosis noted on MRI. Another infant in the cooled group had a thrombus in the aorta, 22p3 325 Underwent randomization 494 Patients were assessed for eligibility 169 Were excluded 94 Did not meet inclusion criteria 30 Declined to participate 45 Had other reasons 163 Were assigned to undergo intensive care plus cooling 162 Were assigned to undergo intensive care without cooling 1 Was lost to follow-up (unable to collect outcome data) 42 Died 120 Survivors were assessed 1 Was lost to follow-up (unable to collect outcome data) 44 Died 117 Survivors were assessed 163 Were analyzed 162 Were analyzed AUTHOR: FIGURE: JOB: ISSUE: 4-C H/T RETAKE SIZE ICM CASE EMail Line H/T Combo Revised AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. REG F Enon 1st 2nd 3rd Azzopardi 1 of 2 xx-xx-09 ARTIST: ts 360xx Figure 1. Enrollment and Follow-up of the Study Infants. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  10. 10. Moderate Hypothermia for Perinatal Asphyxial Encephalopathy n engl j med 361;14  nejm.org  october 1, 2009 1353 as well as an umbilical arterial catheter and a he- matocrit of 70%. No case of renal failure requir- ing dialysis occurred. Secondary Outcomes at 18 Months The mortality rate was similar in both groups. Forty-two infants in the cooled group died, as did 44 infants in the noncooled group; in each group, 39 of those died before hospital discharge. Death occurred after the withdrawal of care in 34 of the 39 (87%) in the cooled group and 29 of the 39 (74%) in the noncooled group. Outcomes were significantly improved in the cooled group with regard to 5 of the 12 second- ary neurologic outcomes assessed (Table 2). The rate of survival without a neurologic abnormality was significantly increased in the cooled group (71 of 163 infants [44%], vs. 45 of 162 [28%] in Table 1. Baseline Characteristics of the Infants.* Characteristic Cooled Group (N = 163) Noncooled Group (N = 162) P Value Male sex — no. (%) 101 (62) 88 (54) 0.16 Gestational age — wk Median 40.3 40.1 0.22 IQR 39.1–41.3 38.8–41.1 Birth weight — g Median 3450 3350 0.18 IQR 2957–3873 3044–3729 Head circumference — cm Median 35.0 35.0 0.53 IQR 34.0–36.0 34.0–35.9 Age at randomization Median — hr 4.7 4.7 0.88 IQR — hr 3.8–5.4 3.5–5.5 0 to <4 hr — no. (%) 48 (29) 57 (35) 0.27 4 to 6 hr — no. (%) 115 (71) 105 (65) Maternal pyrexia during labor — no. (%)† 10 (6) 10 (6) 0.94 Delivery complications — no. (%) 115 (71) 119 (74) 0.55 Apgar score at 10 min Median 4 4 0.15 IQR 2–5 2–5 <5 — no. (%) 110 (83) 105 (77) 0.21 Resuscitation required at 10 min of age — no. (%) 149 (91) 151 (93) 0.54 Clinical seizures — no. (%) 92 (56) 83 (51) 0.35 Temperature at randomization Mean ±SD — °C 36.6±1.1 36.5±1.2 0.24 <35.5°C — no. (%) 18 (11) 25 (16) 0.24 Abnormality on aEEG at randomization — no. (%) Moderate 65 (40) 67 (41) Severe 98 (60) 95 (59) 0.79 * Data were unavailable for some patients: for gestational age, 16 patients in the cooled group and 17 in the noncooled group; for birth weight, 1 patient in the cooled group and 1 in the noncooled group; for head circumference, 41 pa- tients in the cooled group and 44 in the noncooled group; for maternal pyrexia, 2 patients in the cooled group and 6 in the noncooled group; for delivery complications, 2 patients in the cooled group and 2 in the noncooled group; for Apgar score at 10 minutes, 31 patients in the cooled group and 26 in the noncooled group; and for temperature at ran- domization, 2 patients in the noncooled group. The term aEEG denotes amplitude-integrated electroencephalography, and IQR interquartile range. † Pyrexia was defined as a temperature of 37.6°C or more. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  11. 11. The new engl and jour nal of medicine n engl j med 361;14  nejm.org  october 1, 20091354 the noncooled group; relative risk, 1.57; 95% CI, 1.16 to 2.12; P = 0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P = 0.03) and ab- normal GMFCS score (relative risk, 0.63; 95% CI, 0.45 to 0.89; P = 0.007) and resulted in improve- ments in the Mental Developmental Index and Psychomotor Developmental Index scores (P = 0.03 for each), and the GMFCS score (P = 0.01). The rate of multiple neurodevelopmental abnormali- ties was 21 of 112 in the cooled group, as com- pared with 33 of 110 in the noncooled group (relative risk, 0.63; 95% CI, 0.39 to 1.01; P = 0.05). Results from the complete analysis of the neurode- velopmental assessments are provided in the Sup- plementary Appendix. Subgroup Analyses More infants with severely abnormal results on amplitude-integrated electroencephalography at the time of randomization died or had a severe disability than did those with moderately abnor- mal results (109 of 193 [56%] vs. 50 of 132 [38%]; relative risk, 1.49; 95% CI, 1.16 to 1.91; P = 0.001). However, the effect of cooling did not significant- ly vary according to the severity of abnormality on amplitude-integrated electroencephalography (P = 0.23 for interaction). The results were similar when the analysis was carried out with the results of amplitude-integrated electroencephalography classified as in the CoolCap study.10 The effect of treatment group did not vary significantly on the basis of time to randomization: among the 105 infants randomly assigned to a group less than 4 hours after birth, the relative risk for the primary outcome with cooling was 0.77 (95% CI, 0.44 to 1.04), whereas among the 220 remaining infants who were randomly assigned between 4 and 6 hours after birth, the relative risk was 0.95 (95% CI, 0.72 to 1.25; P = 0.21 for interaction). Discussion In this trial of near-term infants with perinatal asphyxia, we found no significant difference in the risk of the primary outcome, the combined rates of death or severe disability, between the cooled group and the noncooled group. However, cooling resulted in consistent improvement in second- ary outcomes, including a significant increase in the rate of survival without neurologic abnormal- ities and improved neurodevelopmental outcomes among survivors. The primary outcome of TOBY, as in the CoolCap and NICHD trials, was a composite end point, chosen because of concerns that cooling might increase survival with additional disability. Results of all three trials are consistent with re- spect to this primary outcome, with point esti- mates supporting a benefit from hypothermia: the relative risk associated with cooling (vs. no cool- ing) was 0.82 (95% CI, 0.66 to 1.02) in the CoolCap study, 0.72 (95% CI, 0.71 to 0.93) in the NICHD trial (which included infants with moderate dis- ability), and 0.86 (95% CI, 0.68 to 1.07) in the present trial. Our categorization of neurologic outcomes is consistent with that used in the CoolCap and NICHD trials and previous systematic reviews,12-17 facilitating the comparison of our findings with previous results. We found a significant increase in the rate of survival without neurologic abnor- mality with cooling (relative risk, 1.57; 95% CI, 1.16 to 2.12); the NICHD and CoolCap trials, which were smaller than the present trial, showed nonsignificant benefits with regard to this out- 22p3 40 MeanRectalTemperature(°C) 38 39 37 36 34 33 30 35 32 31 0 0 4 8 12 16 20 24 28 32 36 40 48 52 56 60 64 68 72 76 80 8444 88 Cooling No cooling Hours since Randomization AUTHOR: FIGURE: JOB: 4-C H/T RETAKE SIZE ICM CASE EMail Line H/T Combo Revised AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. REG F Enon 1st 2nd 3rd Azzopardi 2 of 2 xx-xx-09 ARTIST: ts 360xx ISSUE: Figure 2. Mean Rectal Temperatures during the Study, According to Treatment Group. The vertical bars indicate 2 SDs. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  12. 12. Moderate Hypothermia for Perinatal Asphyxial Encephalopathy n engl j med 361;14  nejm.org  october 1, 2009 1355 come but had similar point estimates. The relative risk in the NICHD trial was 1.51 (95% CI, 0.94 to 2.42),23 and the relative risk in the CoolCap trial was 1.48 (95% CI, 0.89 to 2.45) (Gunn A, University of Auckland, New Zealand: personal communication). Although there is striking homogeneity among results of these three trials, there are also some differences. Only the NICHD trial detected a sig- nificant effect of hypothermia on the primary outcome, and only TOBY detected significant im- provements in specific neurologic outcomes. Both TOBY and the CoolCap trial showed that the in- creased risk of death or severe disability in infants with the most abnormal grade on amplitude- integrated electroencephalography was unaffect- ed by cooling, but the CoolCap results suggested a reduction of the risk in the subgroup with less severely abnormal findings. These discrepancies among results may be ex- plained in part by differences in the trial proto- cols. In all three trials, the whole-body tempera- ture (as measured in the rectum or esophagus) was reduced, but the strategies for cooling and Table 2. Main Neurodevelopmental Outcomes at 18 Months. Outcome Cooled Group Noncooled Group P Value Relative Risk (95% CI) no./total no. (%) Primary outcome Combined death and severe neurodevelopmental disability 74/163 (45) 86/162 (53) 0.17 0.86 (0.68–1.07) Secondary outcomes* Death 42/163 (26) 44/162 (27) 0.78 0.95 (0.66–1.36) Severe neurodevelopmental disability 32/120 (27) 42/117 (36) 0.13 0.74 (0.51–1.09) Survival without neurologic abnormality 71/163 (44) 45/162 (28) 0.003 1.57 (1.16–2.12) Multiple neurodevelopmental disabilities 21/112 (19) 33/110 (30) 0.05 0.63 (0.39–1.01) BSID-II Mental Developmental Index score 0.03 for trend <70 28/115 (24) 38/110 (35) 0.09 0.70 (0.47–1.06) 70–84 6/115 (5) 12/110 (11) ≥85 81/115 (70) 60/110 (55) 0.01 1.29 (1.05–1.59) BSID-II Psychomotor Developmental Index score 0.03 for trend <70 27/114 (24) 37/109 (34) 0.09 0.70 (0.46–1.06) 70–84 9/114 (8) 14/109 (13) ≥85 78/114 (68) 58/109 (53) 0.02 1.29 (1.04–1.60) GMFCS score 0.01 for trend No abnormality 85/120 (71) 63/117 (54) 0.007 1.32 (1.07–1.61) 1–2 11/120 (9) 18/117 (15) 3–5 24/120 (20) 36/117 (31) 0.06 0.65 (0.41–1.02) Cerebral palsy 33/120 (28) 48/117 (41) 0.03 0.67 (0.47–0.96) Hearing loss not corrected by aids 4/114 (4) 7/108 (6) 0.31 0.54 (0.16–1.80) No useful vision 8/119 (7) 12/114 (11) 0.30 0.64 (0.27–1.50) Seizures requiring anticonvulsant agents at time of assessment 12/116 (10) 16/116 (14) 0.42 0.75 (0.37–1.51) Head circumference at follow-up >2 SD below the mean 24/114 (21) 28/112 (25) 0.48 0.84 (0.52–1.36) * Scores on the Bayley Scales of Infant Development II (BSID-II) are assessed relative to a standardization mean (±SD) of 100±15, with higher scores indicating better performance. Scores on the Gross Motor Function Classification System (GMFCS) can range from 1 to 5, with higher scores indicating greater impairment. CI denotes confidence interval. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  13. 13. The new engl and jour nal of medicine n engl j med 361;14  nejm.org  october 1, 20091356 the target temperatures varied: temperature was decreased to 33 to 34°C with the use of cooling blankets in TOBY and the NICHD trial and to 34 to 35°C by means of scalp cooling in the CoolCap study. The NICHD trial recorded slight- ly higher temperatures in the control group than did the other two trials. In TOBY, but not the other two trials, cooling was initiated during transport to the treatment center. In TOBY and the CoolCap trial, but not the NICHD trial, pa- tients were selected on the basis of the presence of abnormalities on amplitude-integrated electro- encephalography in addition to clinical criteria. Differences in local practices for withdrawal of care may also have affected outcomes. Withdrawal was slightly more common in the control group than in the cooled group in the NICHD study but was more common in the cooled group than in the control group in TOBY; these results may par- tially account for the greater apparent effect of hypothermia on mortality rate in the NICHD study as compared with TOBY. Elevation of body temperature to greater than 38°C was observed in several noncooled infants in the NICHD and CoolCap trials and was associ- ated with a worse outcome in the CoolCap trial.11,24 A rectal temperature of more than 38°C was also noted in some noncooled infants in TOBY. Experi- mental data showing that pyrexia may adversely affect neurodevelopment support the possibility that increased temperatures may contribute to the poorer outcomes seen in the noncooled groups; however, it is also possible that the relationship between higher elevation of body temperature and poor outcome reflects reverse causation (i.e., as- phyxia resulting in impairment of temperature regulation). Consistent with findings in the earlier trials, in our study, minor respiratory and cardiovascular events were common, but serious adverse events Table 3. Adverse Outcomes, According to Treatment Group.* Outcome Cooled Group (N = 163) Noncooled Group (N = 162) P Value Relative Risk or Median Difference (95% CI)† Total duration of hospital care — days Median 12 13 0.13 1 (0–4) IQR 8–18 9–25 Persistent hypotension — no./total no. (%)‡ 126/163 (77) 134/162 (83) 0.22 0.93 (0.84–1.04) Prolonged coagulation time — no./total no. (%) 67/163 (41) 72/161 (45) 0.51 0.92 (0.71–1.18) Thrombocytopenia — no./total no. (%) 94/163 (58) 80/161 (50) 0.15 1.16 (0.95–1.42) Intracranial hemorrhage — no./total no. (%)§ 25/64 (39) 21/67 (31) 0.35 1.25 (0.78–1.99) Pulmonary diagnoses — no./total no. (%) Pneumonia 5/163 (3) 5/162 (3) 0.99 0.99 (0.29–3.37) Pulmonary air leak 9/163 (6) 3/162 (2) 0.08 2.98 (0.82–10.80) Pulmonary hemorrhage 5/163 (3) 3/162 (2) 0.48 1.66 (0.40–6.82) Pulmonary hypertension 16/163 (10) 9/162 (6) 0.15 1.77 (0.80–3.88) Necrotizing enterocolitis — no./total no. (%) 1/163 (<1) 0/162 Cardiac arrhythmia — no./total no. (%)¶ 8/163 (5) 3/162 (2) 0.13 2.65 (0.72–9.81) Culture-proven sepsis — no./total no. (%) 20/163 (12) 20/162 (12) 0.98 0.99 (0.56–1.78) * No case of renal failure requiring dialysis occurred. CI denotes confidence interval, and IQR interquartile range. † Values are relative risks except for total duration of hospital care, for which the median difference is shown. ‡ Hypotension was defined as a mean blood pressure of 40 mm Hg or less. § Intracranial hemorrhage was identified on magnetic resonance imaging (MRI); 39 of the 46 cases were subdural (10 moderate and 29 mild). No intracranial hemorrhage was identified on cranial ultrasonography. Two cases of sinus thrombosis in the cooling group, and one case in the noncooled group, were also noted on MRI. ¶ All but three cases of cardiac arrhythmia consisted of sinus bradycardia of less than 80 beats per minute. The other three cases consisted of ventricular arrhythmia; two of these occurred in the noncooled group. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  14. 14. Moderate Hypothermia for Perinatal Asphyxial Encephalopathy n engl j med 361;14  nejm.org  october 1, 2009 1357 were rare and were not associated with cooling. Mild-to-moderate intracranial hemorrhage that was not visible on cranial ultrasonography was frequently seen on MRI in both groups, and sinus thrombosis occurred very infrequently in both groups. No trial, to our knowledge, has yet reported neurologic outcomes at ages older than 18 months. Neurodevelopmental assessments at 18 months may not reliably predict later outcomes.25 Although it is likely that severe neuromotor disability will have been correctly identified at 18 months, less severe impairments are not reliably assessable at this age. Assessment later in childhood (e.g., at 6 to 7 years of age) is necessary for accurate, com- prehensive evaluation of cognitive function, be- havior and learning, fine motor development, at- tention, and psychosocial health.26 In conclusion, TOBY did not show a significant reduction in the combined rates of death and se- vere disability with cooling, as compared with no cooling, but did show a significant improvement in several secondary neurologic outcomes among survivors. Whether this improvement is main- tained in the longer term needs to be ascertained. Supported by grants from the U.K. Medical Research Council and the U.K. Department of Health. No potential conflict of interest relevant to this article was re- ported. We thank the Imperial College Healthcare Biomedical Research Centre and Bliss, the Special Care Baby Charity, for their advice and support, as well as all the parents and infants who took part in the study. Appendix Members of the TOBY Study Group are as follows: Project Management Group — D. Azzopardi (chief investigator), P. Brocklehurst (chief investigator), A.D. Edwards (principal investigator), H. Halliday (principal investigator), M. Levene (principal investigator), M. Thoresen (principal investigator), A. Whitelaw (principal investigator), S. Ayers (National Perinatal Epidemiology Unit [NPEU] informa- tion technology coordinator), U. Bowler (NPEU Clinical Trials Unit [CTU] senior trials manager), M. Gallagher (NPEU data manager), E. Juszczak (NPEU CTU head of trials), C. Mulhall (NPEU TOBY study coordinator), B. Strohm (NPEU TOBY research nurse and study coordinator); Writing Committee — D. Azzopardi (chief investigator), P. Brocklehurst (chief investigator), A.D. Edwards (principal in- vestigator), E. Juszczak (NPEU CTU head of trials); Trial Steering Committee — N. McIntosh (chair), Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom (UK); D. Azzopardi, Imperial College London, London; H. Baumer, Derriford Hospital, Plymouth, UK; P. Brocklehurst, NPEU, University of Oxford, Oxford, UK; C. Doré, Medical Research Council (MRC) CTU; D. Elbourne, London School of Hygiene and Tropical Medicine, London; R. Parnell, Scope Data Monitoring and Ethics Committee; R. Cooke (chair), Liverpool Women’s Hospital, University of Liverpool, Liverpool, UK; H. Davies, National Research Ethics Service; A. Johnson, Univer- sity of Oxford, Oxford, UK; S. Richmond, Sunderland District General Hospital, University of Newcastle, Newcastle, UK; P. Yudkin, Division of Public Health and Primary Health Care, University of Oxford, Oxford, UK; Trial Statisticians (NPEU) — S. Gates, Edmund Juszczak, M. Quigley; TrialHealthEconomists(NPEU) — O. Eddama, J. Henderson, S. Petrou; ClinicalResearchFellow — O. Kapellou; Follow-up Pediatricians — L. Dyet, E. Porter, Imperial College London, London; G. Mero, Jósa András County Hospital, Nyíregyháza, Hungary; B. Vollmer, Karolinska Institutet, Stockholm; E. Goldstein, Soroka Medical Center, Beersheeva, Israel; SpecialistAdviser — B. Hutchon, Royal Free Hospital, London; Cranial Ultrasonography Interpretation — C. Hagmann, University College London, London; Bayley Scales of Infant Development II (BSID-II) Training — S. Johnson, University of Nottingham, Nottingham, UK; MRI Evaluation — L. Ramenghi, University of Milan, Milan; M. Rutherford, MRC Clinical Sciences Centre, Imperial College London, London; Centers for Recruitment and Data Collection for MRI Evaluation (in descending order of no. of infants recruited, in parentheses) — Hammer- smith Hospital, London (54) — D. Azzopardi, A.D. Edwards, O. Kapellou, P. Corcoran; First Department of Pediatrics, Semmelweis University Hospital, Budapest, Hungary (24) — M. Szabó, A. Róka, E. Bodrogi; Homerton Hospital, London (20) — E. Maalouf, C. Harris; Southmead Hospital, Bristol, UK (20) — A. Whitelaw, S. Lamburne; University College Hospital, London (19) — N. Robertson, A. Kapetanakis; St. George’s Hospital, London (18) — K. Farrer, L. Kay-Smith; Royal Maternity Hospital, Belfast, UK (17) — H. Hal- liday, D. Sweet; Liverpool Women’s Hospital, Liverpool, UK (15) — M. Weindling, A.S. Burke; St. Michael’s Hospital, Bristol, UK (14) — M. Thoresen, J. Tooley, J. Kemp; Leicester Royal Infirmary, Leicester, UK (12) — A. Currie, M. Hubbard; Royal Sussex County Hos- pital, Brighton, UK (10) — P. Amess; Queen Silvia’s Hospital, Gothenburg, Sweden (9) — K. Thiringer, A. Flisberg; Leeds General Infirmary, Leeds, UK (8) — M. Levene, A. Harrop; Nottingham City Hospital, Nottingham, UK (8) — S. Watkin, D. Jayasinghe; John Radcliffe Hospital, Oxford, UK (7) — E. Adams; Karolinska Institutet, Stockholm (6) — C. Lothian, M. Blennow; Medway Maritime Hospital, Gillingham, UK (6) — S. Rahman, B. Jani, K. Vandertak; Luton and Dunstable Hospital, Luton, UK (5) — S. Skinner, Y. Mil- lar; Queen’s Medical Centre, Nottingham, UK (5) — N. Marlow, S. Wardle; Jessop Wing, Sheffield, UK (4) — M. Smith; Royal Victoria Infirmary, Newcastle, UK (4) — J. Berrington; Soroka Medical Center, Beersheva, Israel (4) — K. Marks; Bradford Royal Infirmary, Bradford, UK (3) — S. Chatfield; Heartlands Hospital, Birmingham, UK (3) — S. Rose; New Cross Hospital, Wolverhampton, UK (3) — B. Kumararatne, L. Greig; Norfolk and Norwich University Hospital, Norwich, UK (3) — P. Clarke; Lund University Hospital, Lund, Sweden (3) — V. Fellman; Wishaw General Hospital, Wishaw, UK (3) — R. Abara; City Hospital, Birmingham, UK (2) — D. Armstrong; Erinville Hospital–Cork University Hospital, Cork, Ireland (2) — D. Murray; Hospital for Children and Adolescents, Helsinki (2) — M. Metsaranta; Queen Mother’s Hospital, Glasgow, UK (2) — J. Simpson; Singleton Hospital, Swansea, UK (2) — J. Matthes; Southern General Hospital, Glasgow, UK (2) — P. MacDonald; University Hospital of Wales, Cardiff, UK (2) — S. Cherian; Princess Royal Ma- ternity Hospital, Glasgow, UK (1) — L. Jackson; Royal Cornwall Hospital, Truro, UK (1) — P. Munyard; Royal Devon and Exeter Foundation Trust, Exeter, UK (1) — M. Quinn; St. Mary’s Hospital, Manchester, UK (1) — S. Mitchell; James Cook University Hospital, Middlesbrough, UK (0) — S. Sinha; Derriford Hospital, Plymouth, UK (0) — J. Eason; Department of Pediatrics, Oulu University Hos- pital, Oulu, Finland (0) — M. Hallman. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  15. 15. n engl j med 361;14  nejm.org  october 1, 20091358 Moderate Hypothermia for Perinatal Asphyxial Encephalopathy References Thoresen M, Penrice J, Lorek A, et al.1. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed ce- rebral energy failure in the newborn pig- let. Pediatr Res 1995;37:667-70. Sirimanne ES, Blumberg RM, Bossa-2. no D, et al. The effect of prolonged modi- fication of cerebral temperature on outcome after hypoxic-ischemic brain injury in the infant rat. Pediatr Res 1996;39:591-7. Amess PN, Penrice J, Cady EB, et al.3. Mild hypothermia after severe transient hypoxia-ischemia reduces the delayed rise in cerebral lactate in the newborn piglet. Pediatr Res 1997;41:803-8. Edwards AD, Yue X, Squier MV, et al.4. Specific inhibition of apoptosis after cere- bral hypoxia-ischaemia by moderate post- insult hypothermia. Biochem Biophys Res Commun 1995;217:1193-9. Bona E, Hagberg H, Loberg EM, Bå-5. genholm R, Thoresen M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res 1998;43:738-45. Colbourne F, Corbett D, Zhao Z, Yang6. J, Buchan AM. Prolonged but delayed post­ ischemic hypothermia: a long-term out- come study in the rat middle cerebral ar- tery occlusion model. J Cereb Blood Flow Metab 2000;20:1702-8. Gunn AJ, Gluckman PD, Gunn TR.7. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102:885-92. Azzopardi D, Robertson NJ, Cowan8. FM, Rutherford MA, Rampling M, Edwards AD. Pilot study of treatment with whole body hypothermia for neonatal encepha­ lopathy. Pediatrics 2000;106:684-94. Eicher DJ, Wagner CL, Katikaneni LP,9. et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol 2005;32:18-24. Gluckman PD, Wyatt JS, Azzopardi D,10. et al. Selective head cooling with mild sys- temic hypothermia after neonatal enceph- alopathy: multicentre randomised trial. Lancet 2005;365:663-70. Shankaran S, Laptook AR, Ehrenkranz11. RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic enceph- alopathy. N Engl J Med 2005;353:1574-84. Shah PS, Ohlsson A, Perlman M. Hy-12. pothermia to treat neonatal hypoxic ische­ mic encephalopathy: systematic review. Arch Pediatr Adolesc Med 2007;161:951-8. Schulzke SM, Rao S, Patole SK. A sys-13. tematic review of cooling for neuropro- tection in neonates with hypoxic ischemic encephalopathy — are we there yet? BMC Pediatr 2007;7:30. Jacobs S, Hunt R, Tarnow-Mordi W,14. Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007;4: CD003311. Higgins RD, Raju TN, Perlman J, et al.15. Hypothermia and perinatal asphyxia: ex- ecutive summary of the National Institute of Child Health and Human Development workshop. J Pediatr 2006;148:170-5. Barks JD. Current controversies in hy-16. pothermic neuroprotection. Semin Fetal Neonatal Med 2008;13:30-4. Kirpalani H, Barks J, Thorlund K,17. Guyatt G. Cooling for neonatal hypoxic ischemic encephalopathy: do we have the answer? Pediatrics 2007;120:1126-30. al Naqeeb N, Edwards AD, Cowan FM,18. Azzopardi D. Assessment of neonatal en- cephalopathy by amplitude-integrated elec- troencephalography. Pediatrics 1999;103: 1263-71. Allmark P, Mason S. Improving the19. quality of consent to randomised con- trolled trials by using continuous consent and clinician training in the consent pro- cess. J Med Ethics 2006;32:439-43. Palisano RJ, Hanna SE, Rosenbaum20. PL, et al. Validation of a model of gross motor function for children with cerebral palsy. Phys Ther 2000;80:974-85. Haataja L, Mercuri E, Regev R, et al.21. Optimality score for the neurologic exami- nation of the infant at 12 and 18 months of age. J Pediatr 1999;135:153-61. Bayley N. Bayley scales of infant devel-22. opment. 2nd ed. San Antonio, TX: Psy- chological Corporation, 1993. Shankaran S, Pappas A, Laptook AR,23. et al. Outcomes of safety and effective- ness in a multicenter randomized, con- trolled trial of whole-body hypothermia for neonatal hypoxic-ischemic encepha­ lopathy. Pediatrics 2008;122(4):e791-e798. Wyatt JS, Gluckman PD, Liu PY, et al.24. Determinants of outcomes after head cooling for neonatal encephalopathy. Pe- diatrics 2007;119:912-21. Barnett AL, Guzzetta A, Mercuri E, et25. al. Can the Griffiths scales predict neuro- motor and perceptual-motor impairment in term infants with neonatal encepha­ lopathy? Arch Dis Child 2004;89:637-43. Voss W, Neubauer AP, Wachtendorf M,26. Verhey JF, Kattner E. Neurodevelopmental outcome in extremely low birth weight in- fants: what is the minimum age for reliable developmental prognosis? Acta Paediatr 2007;96:342-7. Copyright © 2009 Massachusetts Medical Society. powerpoint slides of journal figures and tables At the Journal’s Web site, subscribers can automatically create PowerPoint slides. In a figure or table in the full-text version of any article at NEJM.org, click on Get PowerPoint Slide. A PowerPoint slide containing the image, with its title and reference citation, can then be downloaded and saved. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WASHINGTON on December 10, 2009 .
  16. 16. Articles www.thelancet.com Vol 373 March 28, 2009 1105 Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study Jakob Christensen, Marianne G Pedersen, Carsten B Pedersen, Per Sidenius, Jørn Olsen, MogensVestergaard Summary Background The risk of epilepsy shortly after traumatic brain injury is high, but how long this high risk lasts is unknown. We aimed to assess the risk of epilepsy up to 10 years or longer after traumatic brain injury, taking into account sex, age, severity, and family history. Methods We identified 1605216 people born in Denmark (1977–2002) from the Civil Registration System. We obtained information on traumatic brain injury and epilepsy from the National Hospital Register and estimated relative risks (RR) with Poisson analyses. Findings Risk of epilepsy was increased after a mild brain injury (RR 2·22, 95% CI 2·07–2·38), severe brain injury (7·40, 6·16–8·89), and skull fracture (2·17, 1·73–2·71). The risk was increased more than 10 years after mild brain injury (1·51, 1·24–1·85), severe brain injury (4·29, 2·04–9·00), and skull fracture (2·06, 1·37–3·11). RR increased with age at mild and severe injury and was especially high among people older than 15 years of age with mild (3·51, 2·90–4·26) and severe (12·24, 8·52–17·57) injury. The risk was slightly higher in women (2·49, 2·25–2·76) than in men (2·01, 1·83–2·22). Patients with a family history of epilepsy had a notably high risk of epilepsy after mild (5·75, 4·56–7·27) and severe brain injury (10·09, 4·20–24·26). Interpretation The longlasting high risk of epilepsy after brain injury might provide a window for prevention of post-traumatic epilepsy. Funding Danish Research Agency, P A Messerschmidt and Wife’s Foundation, Mrs Grethe Bønnelycke’s Foundation. Introduction Traumatic brain injury raises the risk of epilepsy,1 but little is known about the duration of the increased risk and the factors that modify the risk, especially in children and young adults.2 In hospital-based case series, the risk of epilepsy 1–2 years after moderate to severe brain injury is related to some CT or MRI findings and is high in people who had had neurosurgical procedures.2–6 In a population-based study, age in people who had traumatic brain injury at age 65 years or older and time since and severity of injury were significant risk factors for epilepsy,1 but only a few studies have included children and young adults.1–4 In some of these studies,2,4 acute seizures in the first week after brain injury were associated with a high risk of epilepsy. Studies of epilepsy related to level of consciousness (eg, assessed with the Glasgow coma scale) and duration of post-traumatic amnesia after brain injury have given conflicting results.1,3,4 No effective prophylaxis for epilepsy after traumatic brain injury is available, and trials with preventive drug have been discouraging.7 However, better information about prognostic factors might help the development of new prevention strategies and treatment.5 We studied the risk of epilepsy in a large population-based cohort of children and young adults and considered time since injury, sex, age, severity, and family history of epilepsy. Methods Study population We used data from the Danish Civil Registration System (CRS)8 to identify all people born in Denmark between Jan 1, 1977, and Dec 31, 2002. All liveborn children and new residents in Denmark are assigned a unique personal identification number (CRS number) together with information on vital status, emigration from Denmark, and CRS numbers of mothers, fathers, and siblings. The CRS number links individual information in all national registries and provides identification of family members and links parents with their children. Identity of individuals in the study was blinded to the investigators, and the study did not involve contact with individual patients. The study therefore did not need approval from the ethics committee according to Danish laws, but the project was approved by the Danish Data Protection Agency. Data collection Information about brain injury and epilepsy was obtained from the Danish National Hospital Register,9 which contains information on all discharges from Danish hospitals since 1977; outpatients have been included in the register since 1995. All treatment is free of charge for Danish residents. Patients admitted to the only private epilepsy hospital in Denmark are also recorded in the Lancet 2009; 373: 1105–10 Published Online February 23, 2009 DOI:10.1016/S0140- 6736(09)60214-2 See Comment page 1060 Department of Neurology, Aarhus University Hospital, Aarhus, Denmark (J Christensen MD, P Sidenius MD); Department of Clinical Pharmacology (J Christensen) and National Centre for Register-based Research (M G Pedersen MSc, C B Pedersen MSc), University of Aarhus, Denmark; Southern California Injury Prevention Research Centre (SCIPRC), School of Public Health, UCLA, CA, USA (J Olsen MD), Department of Epidemiology (J Olsen) and Department of General Practice (MVestergaard MD), Institute of Public Health, University of Aarhus, Aarhus, Denmark Correspondence to: Dr Jakob Christensen, Department of Neurology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark jakob@farm.au.dk
  17. 17. Articles 1106 www.thelancet.com Vol 373 March 28, 2009 Danish National Hospital Register. Specialists in neurology working in private outpatient clinics also treat patients with epilepsy, but these contacts are not recorded in the Danish National Hospital Register. Diagnostic information in the National Hospital Register is based on the International Classification of Diseases, 8th revision (ICD-8) from 1977–93, and ICD-10 from 1994–2002. Cohort members, their parents and siblings were classified with epilepsy if they had been hospitalised or in outpatient care with a diagnosis of epilepsy (ICD-8: 345; ICD-10: G40,G41).10–13 By use of the CRS numbers, we linked parents and siblings registered with an epilepsy diagnosis in the National Hospital Register. A person was recorded as having a family history of epilepsy if the date of first epilepsy diagnosis in a parent or sibling preceded their epilepsy diagnosis. Cohort members were classified with mild brain injury (concussion: ICD-8 850.99; ICD-10 S06.0), severe brain injury (structural brain injury: ICD-8 851.29-854.99; ICD-10S06.1-S06.9),orskullfracture(ICD-8800.99–801.09, 803.99; ICD-10: S02–S02.1, S02.7, S02.9), respectively, if they had been admitted or been in outpatient care with the relevant diagnosis.14,15 Time of onset of epilepsy and brain injury was defined as the first day of the first contact to the hospital with the relevant diagnosis. The definition of mild brain injury (concussion) in Denmark is based on the definition given by the American Congress of Rehabilitation Medicine.16 The diagnostic criteria include a relevant direct trauma against the head manifesting with changed brain function (ie, loss of consciousness, amnesia, confusion/disorientation, or focal [temporary] neurological deficit). Severity of mild brain injury should not include loss of consciousness longer than 30 min, a Glasgow coma scale of 13 or less after 30 min, or post-traumatic amnesia longer than 24 h.17 Severe brain injury (structural brain injury) includes brain contusion or intracranial haemorrhage. Skull fracture liable to be associated with disruption of brain function can occur alone or be associated with other types of brain injury and usually requires verification with a radiograph or CT. Brain injuries recorded in the same patient within 14 days were categorised as the same event according to the hierarchy of brain injury—severe brain injury, skull fracture, and mild brain injury. For each type of brain injury, we calculated the age at first brain injury (0–5, 5–10, 10–15, and ≥15 years), the length of first admission (0, 1–6, 7–13, 14–27, and ≥28 days), and time since first brain injury (0–6 months, 6 months to 1 year, 1–2, 2–3, 3–5, 5–10, and ≥10 years). Statistical analyses People were followed from birth until onset of epilepsy, death, emigration from Denmark, or Dec 31, 2002, whichever came first. The incidence rate ratio (for these analyses a good approximation of the relative risk, the term used in this Article) of epilepsy was estimated by Patients diagnosed with epilepsy New cases (per 1000 person-years) Adjusted relative risk (95% CI) p value Time (years) since mild brain injury 0·0–0·5 162 4·67 5·46 (4·67–6·37) <0·0001 0·5–1·0 78 2·37 2·91 (2·33–3·64) <0·0001 1·0–2·0 109 1·78 2·26 (1·87–2·73) <0·0001 2·0–3·0 99 1·79 2·33 (1·91–2·84) <0·0001 3·0–5·0 138 1·50 1·99 (1·68–2·36) <0·0001 5·0–10·0 154 1·14 1·56 (1·33–1·83) <0·0001 ≥10·0 97 1·00 1·51 (1·24–1·85) <0·0001 No mild injury 16633 0·87 1·00 ·· Time (years) since severe brain injury 0·0–0·5 35 19·62 21·26 (15·25 to 29·62) <0·0001 0·5–1·0 19 11·52 13·45 (8·57 to 21·09) <0·0001 1·0–2·0 18 6·06 7·42 (4·68 to 11·79) <0·0001 2·0–3·0 11 4·26 5·40 (2·99 to 9·76) <0·0001 3·0–5·0 11 2·69 3·52 (1·95 to 6·35) <0·0001 5·0–10·0 15 3·22 4·40 (2·65 to 7·30) <0·0001 ≥10·0 7 2·94 4·29 (2·04 to 9·00) 0·0001 No severe injury 17354 0·89 1·00 ·· Time (years) since skull fracture 0·0–0·5 6 2·90 2·96 (1·33 to 6·60) 0·0078 0·5–1·0 6 2·99 3·51 (1·58 to 7·83) 0·0021 1·0–2·0 13 3·38 4·30 (2·50 to 7·41) <0·0001 2·0–3·0 5 1·39 1·81 (0·75 to 4·35) 0·1845 3·0–5·0 9 1·36 1·78 (0·93 to 3·42) 0·0838 5·0–10·0 16 1·21 1·55 (0·95 to 2·54) 0·0781 ≥10·0 23 1·46 2·06 (1·37 to 3·11) 0·0005 No fracture 17392 0·89 1·00 ·· Each form of injury led to a significant (p<0·0001) increase in risk of epilepsy relative to people without brain injury. Relative risk (RR) was adjusted for age and interaction with sex and calendar year. RR of epilepsy in people with brain injury was modified by time since first admission with brain injury for mild (p<0·0001) and severe (p<0·0001) brain injury but not skull fracture (p=0·16). Table 1: Time since first admission with brain injury and relative risk (RR) of epilepsy 35 30 25 20 15 10 5 0 Relativeriskofepilepsy 0 1 2 3 4 5 6 7 8 9 ≥10 Years after injury Mild brain injury Severe brain injury Skull fracture Reference Figure: Relative risk of epilepsy after brain injury in Denmark (1977–2002)
  18. 18. Articles www.thelancet.com Vol 373 March 28, 2009 1107 log-linear Poisson regression18 with the GENMOD procedure in SAS (version 8.1). Because incidence of epilepsy depends on age, sex, and calendar year,10 all the relative risks were adjusted for these factors. Age, calendar year, age at first brain injury, duration of first admission with brain injury, time since first brain injury, and history of epilepsy in a parent or sibling were time dependent variables;19 all other variables were treated as time independent. Age was categorised in quarter year age levels from birth to the first birthday, in 1 year age levels from the first birthday to the 20th birthday, and as 20–21 years and ≥22 years. Calendar year was categorised in 1 year periods from 1977 to 2002. Likelihood ratio tests were used to calculate p values and 95% CIs were calculated by use of Wald’s test.19 The adjusted-score test20 suggested that the regression models were not subject to overdispersion. Role of the funding source The sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of the Article. All authors had full access to the data and approved the decision to submit the Article for publication in The Lancet. Results We followed-up 1605216 for a total of 19527337 person-years. During this study period, 78572 people had at least one traumatic brain injury, and in the same period, 17470 people developed epilepsy, of whom 1017 had a preceding brain injury. Follow-up was stopped before the end of the study period for 45677 people (2·9%) because of emigration from Denmark (30362 [1·9%]) or death (15 315 [1·0%]). Relative to no brain injury, the risk of epilepsy was two times higher after mild brain injury (RR 2·22, 95% CI 2·07–2·38); seven times higher after severe brain injury (7·40, 6·16–8·89); and two-times higher after skull fracture (2·17, 1·73–2·71). Tables 1–3 show the risk of epilepsy after brain injury according to time since first admission with brain injury, age at first brain injury, and duration of first hospital stay with brain injury. The risk of epilepsy after mild (p<0·0001) and severe (p<0·0001) brain injury was highest during the first years after injury, but remained high for more than 10 years after the injury as compared with people without such a history (table 1, figure). For patients with skull fractures, risk of epilepsy did not vary significantly with time since injury (p=0·16; table 1). Brain injury was associated with an increased risk of epilepsy in all age groups (table 2). The risk increased with age for mild (p<0·0001) and severe (p=0·02) brain injury and was highest among people older than 15 years at injury. Patients who had a long duration of hospital stay with severe brain injury (p<0·0001) and skull fracture (p=0·02) had a notably high risk of epilepsy (table 3). For people with mild brain injury there was no association between duration of hospital stay and risk of epilepsy (p=0·73; table 3). Table 4 shows the relative risk of epilepsy after brain injuries subdivided by family history of epilepsy. The relative risk of epilepsy with a family history of the disorder and mild brain injury is between what would have been predicted from a multiplicative model (3·37×2·24=7·54) and from an additive model (3·37+2·24–1=4·61; table 4). The relative risk estimate associated with severe brain injury and family history of epilepsy of is almost the same as would have been predicted from an additive model (3·35+7·81–1=10·16; table 4). We had very few people with epilepsy with skull fracture and a family history of epilepsy (table 4). The relative risk of epilepsy after mild brain injury was higher among women (2·49, 2·25–2·76) than among men (2·01, 1·83–2·22; p=0·003). There was no interaction with sex for patients with skull fractures (p=0·59) or severe brain injury (0·22). We calculated the risk of epilepsy for patients registered with brain injury according to ICD-8 and ICD-10 (ie, patients diagnosed in the time period 1977 to 1993 and 1994 to 2002, respectively). For patients with mild brain injury, the risk of epilepsy was lower in the ICD-8 period (RR 1·89, 1·71–2·10) than in the ICD-10 period (2·61, 2·37–2·87; p<0·0001). For severe brain injury, the risk of epilepsy was almost the same in the ICD-8 period (7·17, Number of patients with epilepsy* New cases (per 1000 person-years) Adjusted relative risk (95% CI) p value Age (years) at mild brain injury 0–5 365 1·64 2·06 (1·86–2·29) <0·0001 5–10 243 1·56 2·12 (1·87–2·41) <0·0001 10–15 117 1·54 2·25 (1·88–2·71) <0·0001 ≥15 112 2·03 3·51 (2·90–4·26) <0·0001 No mild injury 16633 0·87 1·00 ·· Age (years) at severe brain injury 0–5 51 6·26 7·20 (5·47–9·48) <0·0001 5–10 24 4·96 6·18 (4·14–9·23) <0·0001 10–15 11 3·56 4·91 (2·72–8·87) <0·0001 ≥15 years 30 7·47 12·24 (8·52–17·57) <0·0001 No severe injury 17354 0·89 1·00 ·· Age (years) at skull fracture 0–5 52 1·53 1·95 (1·49–2·56) <0·0001 5–10 17 2·12 2·86 (1·78–4·60) <0·0001 10–15 5 1·81 2·55 (1·06–6·12) 0·0368 ≥15 years 4 1·71 2·75(1·03–7·34) 0·0433 No skull fracture 17392 0·89 1·00 ·· Each form of injury led to a significant (p<0·0001) increase in risk of epilepsy relative to people without brain injury. Relative risk (RR) was adjusted for age and interaction with sex and calendar year. RR of epilepsy in people with brain injury was modified by age at first admission with brain injury for mild (p<0·0001) and severe (p=0·02) brain injury but not skull fracture (p=0·55). Table 2: Age at first admission with brain injury and relative risk of epilepsy
  19. 19. Articles 1108 www.thelancet.com Vol 373 March 28, 2009 5·19–9·91) and the ICD-10 period (7·51, 6·02–9·38; p=0·82). For skull fracture, the risks of epilepsy were comparable in the ICD-8 period (2·00, 1·54–2·58) and ICD-10 period (2·87, 1·85–4·46; p=0·17). Discussion As previously shown in studies smaller than ours,1,2,6,21 risk of epilepsy increased after brain injury in relation to severity of brain injury. Risk was high for more than 10 years after the brain injuries even for mild brain injury (concussion), a finding in contrast to that of a previous study showing no increased risk of epilepsy 5 years after a mild brain injury.1 The discrepancy might result from different inclusion criteria for mild brain injury and epilepsy,1,11 and an insufficient sample size to identify a moderate increase in risk.1 Our results suggest that time from brain injury to clinically overt symptoms (seizures) can span several years, leaving room for clinical intervention.5 However, animal studies suggest that a specific time window exists shortly after injury in which appropriate drugs might stop the epileptogenic process,22 and antiepileptogenic trials after brain injury in human beings have not shown drug treatment to be effective.7 In Denmark, seizure prophylaxis with antiepileptic drugs after brain injury was not used routinely in the study period.23 We defined the onset of epilepsy as the first day of the first contact, although this is only an approximation. There may be a delay from the first seizure to diagnosis of epilepsy. We have previously validated the epilepsy diagnosis in a sample from the Danish National Hospital Register and found that 64% were registered in the Danish National Hospital Register within 1 year of first seizure, and 90% were registered within 5 years.11 Diagnostic delay might, therefore, explain part of the increased risk of epilepsy after the brain injury. Likewise, a delay between brain injury and diagnosis (eg, in patients with chronic subdural haematoma), could bias the estimates of epilepsy shortly after a brain injury diagnosis, but this effect is likely to be small, especially in children. Brain injury might be the first presentation of epilepsy, in which the patient has a head trauma during an unwitnessed seizure (reverse causation). In a subanalysis, we excluded patients diagnosed with epilepsy within the first 6 weeks of first brain injury diagnosis and found that the high risk of epilepsy remained for all types of brain injury, albeit in an attenuated form (data not shown). Although patients with infrequent seizures might remain undiagnosed more than 6 weeks, this problem probably affects only a small part of the delayed association between brain injury and epilepsy. The risk of epilepsy increased slightly with age at time of mild brain injury, and was highest for people over 15 years of age, indicating that susceptibility to epilepsy after brain injury increases with age. This finding is in line with results of a previous study identifying people aged 65 or more as being at high risk of epilepsy after brain injury.1 Alternatively, the severity of brain injuries might increase with age, or doctors might be more likely to hospitalise younger children with less severe brain injuries, resulting in a Number of patients with epilepsy New cases (per 1000 person-years) Adjusted relative risk# (95% CI) p value Hospital stay (days) for mild brain injury 0 256 1·73 2·22 (1·96–2·51) <0·0001 1–6 563 1·60 2·20 (2·02–2·40) <0·0001 7–13 9 2·08 3·01 (1·56–5·78) 0·0010 14–27 4 2·54 3·68 (1·38–9·82) 0·0091 ≥28 5 2·05 2·94 (1·22–7·07) 0·0159 No mild injury 16633 0·87 1·00 ·· Hospital stay (days) for severe brain injury 0 12 1·73 2·09 (1·19–3·68) <0·0108 1–6 24 3·71 4·82 (3·23–7·20) <0·0001 7–13 15 7·04 9·42 (5·68–15·63) <0·0001 14–27 18 13·11 18·01 (11·34–28·60) <0·0001 ≥28 47 14·86 20·07 (15·06–26·74) <0·0001 No severe injury 17354 0·89 1·00 ·· Hospital stay (days) for skull fracture 0 8 2·13 2·72 (1·36–5·45) 0·0046 1–6 48 1·35 1·77 (1·33–2·35) <0·0001 7–13 10 1·99 2·70 (1·45–5·03) 0·0017 14–27 4 3·08 4·01 (1·51–10·69) 0·0055 ≥28 8 5·59 6·69 (3·35–13·38) <0·0001 No fracture 17392 0·89 1·00 ·· Each form of injury led to a significant (p<0·0001) increase in risk of epilepsy relative to people without brain injury. Relative risk (RR) was adjusted for age and interaction with sex and calendar year. RR of epilepsy in people with brain injury was modified by duration of first hospital stay with brain injury for severe brain injury (p<0·0001) and skull fracture (p=0·02) but not mild brain injury (p=0·73). Table 3: Duration of first hospital stay with brain injury and relative risk of epilepsy No family history of epilepsy Family history of epilepsy Number of patients with epilepsy Adjusted relative risk (95% CI) p value Number of patients with epilepsy Adjusted relative risk (95% CI) p value Mild brain injury No 15511 1·00 ·· 1122 3·37 (3·17–3·58) <0·0001 Yes 766 2·24 (2·08–2·41) <0·0001 71 5·75 (4·56–7·27) <0·0001 Severe brain injury No 16166 1·00 ·· 1188 3·35 (3·16–3·56) <0·0001 Yes 11 7·81 (6·48–9·42) <0·0001 5 10·09 (4·20–24·26) <0·0001 Skull fracture No 16202 1·00 ·· 1190 3·35 (3·16–3·55) <0·0001 Yes 75 2·28 (1·81–2·86) <0·0001 3 2·71 (0·87–8·41) 0·0842 Any brain injury No 15338 1·00 ·· 1115 3·39 (3·19–3·61) <0·0001 Yes 939 2·47 (2·31–2·65) <0·0001 78 5·73 (4·58–7·16) <0·0001 Patients might have been exposed to more than one type of brain injury at separate admissions/outpatient visits. Relative risk adjusted for age and its interaction with sex and calendar year. Table 4: Family history and relative risk of epilepsy after traumatic brain injury
  20. 20. Articles www.thelancet.com Vol 373 March 28, 2009 1109 low relative risk of post-traumatic epilepsy in young age groups. Post-traumatic epilepsy is thought to be typical of symptomatic epilepsy (ie, determined by environmental factors). However, twin studies suggest that genetic factors also play a part in localisation-related epilepsies, most of which are thought to be symptomatic or probably symptomatic.24 Family history of epilepsy and mild brain injury independently contribute to the risk of epilepsy.25 Thus, people genetically predisposed to epilepsy (ie, with a family history of epilepsy) have a higher risk of epilepsy than do people without genetic predisposition when exposed to mild brain injury. To our knowledge, no previous studies have studied the risk of epilepsy after brain injury in first degree relatives to patients with epilepsy. In animals, variation in the susceptibility of various rat strains to post-traumatic epilepsy might lend some support to the hypothesis of an underlying genetically determined tendency to develop post-traumatic epilepsy.26 Our registration of family history is not complete because some parents and older siblings might have been diagnosed before the Danish National Hospital Register was established (Jan 1, 1977). This mis- classification is likely to cause an underestimation of the effect of family history on the risk of epilepsy. The relative risk of epilepsy after mild brain injury was slightly higher in female than in male patients perhaps because female patients with epilepsy are more likely registered in the National Hospital Register because of sex-specific factors, such as pregnancy. Alternatively female brains might be more susceptible to epilepsy after mild brain injury than are male brain, as supported by a previous study showing that localisation-related epilepsy with no apparent structural cause is more prevalent in women than in men.27 The sex difference was not present for the other types of brain injury, suggesting that other mechanisms might be involved in post-traumatic epilepsy after skull fracture and more severe brain injuries. The length of first hospital stay with brain injury was associated with an increased risk of epilepsy for severe brain injury and cranial fractures. The length of admission is probably related to severity of brain injury. Despite the length and completeness of follow up, the size of the study cohort, and the population-based nature of the study,8 we had limited clinical information. In a recent study, we validated the epilepsy diagnosis in the Danish National Hospital Register.11 We found a positive predictive value of an ICD-8 or ICD-10 epilepsy diagnosis according to ILAE criteria28 of 81% for epilepsy and 89% for single seizures, but identified no epilepsy diagnoses based on acute symptomatic seizures.11 Thus, some patients registered with epilepsy in the present study do not fulfil the diagnostic criteria, but the misclassification would only bias the results of the present study away from the null hypothesis if the quality of the epilepsy registration differs between patients with and without brain injury, which we find unlikely. The Danish Hospital Register does not capture all patients with epilepsy, because some outpatients might be treated in private practice. However, estimates of incidence (68·8 per 100000 people per year) and prevalence (0·6%) of epilepsy in Denmark based on data from the Danish National Hospital Register were similar to those found in other developed countries and indicate a high completeness.10 If cases with epilepsy are missed in the Danish National Hospital Register, the relative risk of epilepsy would be affected only if the incomplete capture of patients differs between those with and without brain injury. Patients with head injury may be followed more closely than the general population, which might increase the completeness and overestimate the relative risk of epilepsy after brain injury. However, the effect of this bias is likely to decrease over time. Although, most patients with epilepsy are cared for on an outpatient basis, the incidence estimate only increased by 17% after inclusion of outpatients.10 Hence, most outpatients with epilepsy are also admitted to hospital for that or other reasons and, thereby, included in the National Hospital Register. Some patients with severe brain injury live in care homes in the community after their condition has stabilised, but these patients have the same access to the hospital system as patients without brain injury, and thus we think that they do not have a decreased likelihood of being registered with epilepsy in the Danish National Hospital Register. People were censored when they died or left Denmark permanently, but less than 3% of the entire cohort did so.8 Some people may have had a brain injury or epilepsy during a short stay abroad; but numbers are likely to be very low, and most of these will be treated in Danish hospitals or outpatient clinics when they return to Denmark. Bias due to selection of study participants is therefore an unlikely explanation for our findings. In comparison, 1139 (25%) patients of a total population of 4541 in the Rochester study were lost to follow-up due to migration from Minnesota.1 A previous study assessed the validity of the hospital codes for brain injury (ICD-8: 851–854) showing that the diagnoseswereconfirmedinabout88%ofcases.29 However, clinical discrimination between different types of brain injury is difficult and the definitions vary between countries.14 Brain injuries that at first seem mild can turn outtobesevere.Inastudyof24patientswithpost-traumatic amnesia lasting more than 1 week, four had initially been diagnosed with skull fracture and four with concussion.14 Although, there is debate about the importance of post-traumatic amnesia in the diagnosis of patients with mild brain injury,14,30 some patients diagnosed with mild head injury might actually suffer from more severe brain injury, which would likely lead to an overestimated risk of epilepsy associated with mild brain injury.

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