- Email: [email protected]
Selective head cooling after neonatal encephalopathy
Correspondence
acknowledged in the context of research in which their very vulnerability makes them “ideal” participants. We thank Andrew Hunter for his contribution to this letter. We declare that we have no conflict of interest.
*Bebe Loff, Carol Jenkins, Melissa Ditmore, Cheryl Overs, Rosanna Barbero [email protected] *Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Victoria 3004, Australia (BL); and Network of Sex Work Projects, Hong Kong (BL, CJ, MD, CO, RB) 1 2
3
4
The Lancet. The trials of tenofovir trials. Lancet 2005; 365: 1111. Vonthanak Saphonn, Heng Sopheab, Ly Penh Sun, et al. Current HIV/AIDS/STI epidemic: intervention programs in Cambodia, 1993–2003. AIDS Educ Prevent 2004; 16 (suppl A): 64–77. Lowe D. Documenting the experiences of sex workers: perceptions of the Cambodian 100% Condom Use Program. Phnom Penh: Policy Project, 2003. Duan D. Listening to consumers and HIV vaccine preparedness. Lancet 2005; 365: 1119–21.
Selective head cooling after neonatal encephalopathy Peter Gluckman and colleagues’ multicentre randomised trial on selective head cooling with mild systemic hypothermia after neonatal encephalopathy (Feb 19, p 663)1 is a landmark study. However, a few points need clarification. Why did Gluckman and colleagues not adjust for Apgar scores in the logistic regression analysis? The “cooled” group was at a disadvantage, since 70% had 10-min Apgar scores of 0–3, whereas only 55% in the control group had such scores. Apgar scores are clinically relevant with wide applicability and the difference was more stark than other parameters that were included in the regression analysis. Gluckman and colleagues had sufficient numbers to be able to include this variable in the regression model. Even if one argues that the independent variables for the www.thelancet.com Vol 365 May 7, 2005
model had been decided a priori, surely Apgar scores should have been included up front. We have also not been provided with data about antenatal events. Therefore it is difficult to judge whether or not some babies had intrauterine hypoxia and if so of what duration. If hypoxic damage had already occurred before birth, the postnatal head cooling would have been insufficient to prevent injury. We declare that we have no conflict of interest.
*Sourabh Dutta, G C M Pradeep, Anil Narang [email protected] Newborn Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India 1
Gluckman PD, Wyatt JS, Azzopardi D, et al, on behalf of the CoolCap Study Group. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663–70.
Data from the study by Peter Gluckman and colleagues1 on treatment of neonatal hypoxic ischaemic neonatal encephalopathy with head cooling reveal a reassuring unadjusted odds ratio of 0·61 (95% CI 0·34–1·09). However, the window for intervention and the management options in this disorder are quite narrow.2,3 Data from studies on such illnesses may require assessment beyond statistical significance. The wide confidence intervals in Gluckman and colleagues’ study might suggest statistical insignificance, but they also reveal that the treatment could reduce the risk of the endpoints under consideration by as much as 66% or increase the risk by only 9%. The treatment effect after adjustment is even more reassuring (0·57, 0·32–1·01) and suggests essentially no risk from the treatment. Also, given the nature of the illness, an level of 0·05 may have been too conservative. Predetermined subgroup analysis might not have been a good idea in this study because it is intuitive that hypothermia could act by at least decelerating damaging inflammatory
responses more than it does favourable responses and that this influence could be absent in severe injuries. During intervention, this intuition could have introduced bias against patients with more severe abnormalities on amplitudeintegrated electroencephalography (aEEG). A post-hoc subgrouping and analysis might have controlled such potential bias. Taken as they stand, the data still reveal a potential 51% reduction in risk in the more compromised neonates (1·8, 0·49–6·4). This finding is quite reassuring considering that the right side of the risk (6·4-fold increase) is not inconsistent with the risk from no intervention. Overall, the result of the study suggests a potentially clinically important benefit of head cooling in neonatal hypoxic-ischaemic encephalopathy as a group, and could be of high clinical usefulness in developing economies where neonatal hypoxic-ischaemic encephalopathy is more common4 and where aEEG might not be available but head cooling could be feasible. I declare that I have no conflict of interest.
Shaibu Oricha Bello [email protected] Department of Obstetrics and Gynecology, Al Azhar University Teaching Hospital, Sayed Galal University Hospital, Bab El Shariah, Cairo, Egypt 1
2
3
4
Gluckman PD, Wyatt JS, Azzopardi D, et al, on behalf of the CoolCap Study Group. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663–70. Aggarwal P, Chaudhari S, Bhave S, Pandit A, Barve S. Clinical predictors of outcome in hypoxic ischaemic encephalopathy in term neonates. Ann Trop Paediatr 1998; 18:117–21. Cowan F, Rutherford M, Groendaal F, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 2003; 361: 736–42. Kinotti SN. Asphyxia of the newborn in East, Central and Southern Africa. East Afr Med J 1993; 70: 422–33.
Authors’ reply As Sourabh Dutta and colleagues note, we saw a chance bias in randomisation so that more infants in the treatment group than the comparison group showed a very low 5-min Apgar score. 1619
Science Photo Library
Correspondence
Rights were not granted to include this image in electronic media. Please refer to the printed journal
1620
This finding is also reflected in the fact that there were more infants with adverse modified Sarnat scores in the cooled group than in the control group. We chose not to include Apgar scores in the primary analysis because it is regarded by many as an imprecise measure of the severity of neonatal encephalopathy and a weak predictor of neurodevelopmental outcome.1 However, we agree that additional adjustment for illness severity might be informative, and we have therefore undertaken a further logistic regression analysis which includes the Apgar and modified Sarnat scores as well as the aEEG background and presence of seizures. This analysis revealed a significant overall effect of hypothermia on the primary outcome of death or disability at 18 months (odds ratio 0·52, 95% CI 0·28–0·70, p=0·04) in the full study population (n=218). Consistent with previous reports, in this analysis the modified Sarnat score showed significant predictive value (stage 3 vs stage 1 or 2: 3·37, 1·64–6·93, p=0·001),1–3 although the 5-min Apgar score did not (0·90, 0·76–1·06, p=0·21). As in earlier studies, the aEEG changes at randomisation (seizures: 1·96, 1·02–3·74, p=0·04; background amplitude: 2·06, 1·01–4·17, p=0·05) and Sarnat score seem to be independently predictive.3 We speculate that clinical examination and aEEG recordings in the early hours after birth could provide complementary information on the severity of the perinatal insult and on how far advanced the process of injury was at the time of recruitment. Since the period from birth to enrolment varied little between infants, the stage of evolution of damage would mainly be influenced by the timing of intrauterine hypoxia. As Dutta and colleagues note, a prolonged period between hypoxia and treatment could be expected to reduce the effect of the treatment. Unfortunately the routine clinical data collected before study enrolment and our general ability to
monitor fetal state are not sufficient to allow this hypothesis to be tested. We appreciate Shaibu Oricha Bello’s comments. The use of a “one in 20 chance” is of course completely arbitrary, although hallowed by common use. The additional analysis reported here might assist in interpreting the clinical significance of the study.
*Alistair J Gunn, Peter D Gluckman, John S Wyatt, Marianne Thoresen, A David Edwards, on behalf of the CoolCap Study Group
it appears from the mother’s womb”. Neuberger fails to alert us to the tensions or ambiguities within the Jewish tradition which might suggest a higher moral and legal status for the embryo. For example, under the law of Noah, a law given for gentiles (like myself), the destruction of the unborn child in the womb is a capital offence. “What is Rabbi Ishmael’s reason? Because it is written, Whoso sheddeth the blood of man within [another] man, shall his blood be shed. What is a man within another man?—An embryo in his mother’s womb”.2
[email protected]
I declare that I have no conflict of interest.
*Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1020, New Zealand (AJG); Liggins Institute, University of Auckland, Auckland, New Zealand (PDG); University College London, London, UK (JSW); University of Bristol, St Michael’s Hospital, Bristol, UK (MT); and Imperial College, London, UK (ADE)
David Albert Jones
1
2
We declare that we have no conflict of interest other than that stated in the original paper.
2
3
van de Riet JE, Vandenbussche FP, Le Cessie S, Keirse MJ. Newborn assessment and longterm adverse outcome: a systematic review. Am J Obstet Gynecol 1999; 180: 1024–29. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976; 33: 696–705. Shalak LF, Laptook AR, Velaphi SC, Perlman JM. Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics 2003; 111: 351–57.
Embryos and ensoulment Although The Soul of the Embryo is a “calm look at what Christians and others had to say”, it is a mistake to see the book as “a considered denial of the position taken by the Pope” (March 5, p 837).1 On the contrary, the book is ultimately a defence of precisely that position. In her book review, Julia Neuberger also suggests that there is “no absolute truth here” and calls for “less certainty” all round. However, at the same time she presents the Jewish tradition in curiously absolutist terms: “the unborn child does not . . . count as life”, it has “no legal status . . . until
[email protected] School of Theology, Philosophy, and History, St Mary’s College, Waldegrave Road, Twickenham TW1 4SX, UK 1
Embryos and ensoulment: when does life begin? Lancet 2005; 365: 837–38. Babylonian Talmud, tractate sanhedrin: 57b. http://www.come-and-hear.com/sanhedrin/ sanhedrin_57.html#PARTb (accessed March 23, 2005).
Department of Error Feenstra J, de Herder WW, ten Have SMTH, et al. Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet 2005; 365: 1644–46—In this Research Letter (May 7), the figure legend should read: “IGF-I concentration in serum of 19 patients with acromegaly, before and after 42 weeks of combined therapy”. The second sentence of the sixth paragraph should read: “The observed 95% efficacy at 42 weeks is similar to that of daily pegvisomant monotherapy”. Czupryniak L, Loba J. Route of corruption in Poland’s health-care system. Lancet 2004; 364: 1856—In this Correspondence Letter (Nov 20), the second sentence of the second paragraph should start: “Doctors’ monthly salaries. . .” Hardy R, Kuh D, Langenberg C, Wadsworth MEJ. Birthweight, childhood social class, and change in adult blood pressure in the 1946 British birth cohort. Lancet 2003; 362: 1178–83—In this Article (Oct 11), the estimate of the intercept (95% CI) for childhood manual social class in the unadjusted model for systolic blood pressure in tables 3 and 4 (p 1180) should be: “2·14 (1·12 to 3·14)”.
www.thelancet.com Vol 365 May 7, 2005
acknowledged in the context of research in which their very vulnerability makes them “ideal” participants. We thank Andrew Hunter for his contribution to this letter. We declare that we have no conflict of interest.
*Bebe Loff, Carol Jenkins, Melissa Ditmore, Cheryl Overs, Rosanna Barbero [email protected] *Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Victoria 3004, Australia (BL); and Network of Sex Work Projects, Hong Kong (BL, CJ, MD, CO, RB) 1 2
3
4
The Lancet. The trials of tenofovir trials. Lancet 2005; 365: 1111. Vonthanak Saphonn, Heng Sopheab, Ly Penh Sun, et al. Current HIV/AIDS/STI epidemic: intervention programs in Cambodia, 1993–2003. AIDS Educ Prevent 2004; 16 (suppl A): 64–77. Lowe D. Documenting the experiences of sex workers: perceptions of the Cambodian 100% Condom Use Program. Phnom Penh: Policy Project, 2003. Duan D. Listening to consumers and HIV vaccine preparedness. Lancet 2005; 365: 1119–21.
Selective head cooling after neonatal encephalopathy Peter Gluckman and colleagues’ multicentre randomised trial on selective head cooling with mild systemic hypothermia after neonatal encephalopathy (Feb 19, p 663)1 is a landmark study. However, a few points need clarification. Why did Gluckman and colleagues not adjust for Apgar scores in the logistic regression analysis? The “cooled” group was at a disadvantage, since 70% had 10-min Apgar scores of 0–3, whereas only 55% in the control group had such scores. Apgar scores are clinically relevant with wide applicability and the difference was more stark than other parameters that were included in the regression analysis. Gluckman and colleagues had sufficient numbers to be able to include this variable in the regression model. Even if one argues that the independent variables for the www.thelancet.com Vol 365 May 7, 2005
model had been decided a priori, surely Apgar scores should have been included up front. We have also not been provided with data about antenatal events. Therefore it is difficult to judge whether or not some babies had intrauterine hypoxia and if so of what duration. If hypoxic damage had already occurred before birth, the postnatal head cooling would have been insufficient to prevent injury. We declare that we have no conflict of interest.
*Sourabh Dutta, G C M Pradeep, Anil Narang [email protected] Newborn Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India 1
Gluckman PD, Wyatt JS, Azzopardi D, et al, on behalf of the CoolCap Study Group. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663–70.
Data from the study by Peter Gluckman and colleagues1 on treatment of neonatal hypoxic ischaemic neonatal encephalopathy with head cooling reveal a reassuring unadjusted odds ratio of 0·61 (95% CI 0·34–1·09). However, the window for intervention and the management options in this disorder are quite narrow.2,3 Data from studies on such illnesses may require assessment beyond statistical significance. The wide confidence intervals in Gluckman and colleagues’ study might suggest statistical insignificance, but they also reveal that the treatment could reduce the risk of the endpoints under consideration by as much as 66% or increase the risk by only 9%. The treatment effect after adjustment is even more reassuring (0·57, 0·32–1·01) and suggests essentially no risk from the treatment. Also, given the nature of the illness, an level of 0·05 may have been too conservative. Predetermined subgroup analysis might not have been a good idea in this study because it is intuitive that hypothermia could act by at least decelerating damaging inflammatory
responses more than it does favourable responses and that this influence could be absent in severe injuries. During intervention, this intuition could have introduced bias against patients with more severe abnormalities on amplitudeintegrated electroencephalography (aEEG). A post-hoc subgrouping and analysis might have controlled such potential bias. Taken as they stand, the data still reveal a potential 51% reduction in risk in the more compromised neonates (1·8, 0·49–6·4). This finding is quite reassuring considering that the right side of the risk (6·4-fold increase) is not inconsistent with the risk from no intervention. Overall, the result of the study suggests a potentially clinically important benefit of head cooling in neonatal hypoxic-ischaemic encephalopathy as a group, and could be of high clinical usefulness in developing economies where neonatal hypoxic-ischaemic encephalopathy is more common4 and where aEEG might not be available but head cooling could be feasible. I declare that I have no conflict of interest.
Shaibu Oricha Bello [email protected] Department of Obstetrics and Gynecology, Al Azhar University Teaching Hospital, Sayed Galal University Hospital, Bab El Shariah, Cairo, Egypt 1
2
3
4
Gluckman PD, Wyatt JS, Azzopardi D, et al, on behalf of the CoolCap Study Group. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663–70. Aggarwal P, Chaudhari S, Bhave S, Pandit A, Barve S. Clinical predictors of outcome in hypoxic ischaemic encephalopathy in term neonates. Ann Trop Paediatr 1998; 18:117–21. Cowan F, Rutherford M, Groendaal F, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 2003; 361: 736–42. Kinotti SN. Asphyxia of the newborn in East, Central and Southern Africa. East Afr Med J 1993; 70: 422–33.
Authors’ reply As Sourabh Dutta and colleagues note, we saw a chance bias in randomisation so that more infants in the treatment group than the comparison group showed a very low 5-min Apgar score. 1619
Science Photo Library
Correspondence
Rights were not granted to include this image in electronic media. Please refer to the printed journal
1620
This finding is also reflected in the fact that there were more infants with adverse modified Sarnat scores in the cooled group than in the control group. We chose not to include Apgar scores in the primary analysis because it is regarded by many as an imprecise measure of the severity of neonatal encephalopathy and a weak predictor of neurodevelopmental outcome.1 However, we agree that additional adjustment for illness severity might be informative, and we have therefore undertaken a further logistic regression analysis which includes the Apgar and modified Sarnat scores as well as the aEEG background and presence of seizures. This analysis revealed a significant overall effect of hypothermia on the primary outcome of death or disability at 18 months (odds ratio 0·52, 95% CI 0·28–0·70, p=0·04) in the full study population (n=218). Consistent with previous reports, in this analysis the modified Sarnat score showed significant predictive value (stage 3 vs stage 1 or 2: 3·37, 1·64–6·93, p=0·001),1–3 although the 5-min Apgar score did not (0·90, 0·76–1·06, p=0·21). As in earlier studies, the aEEG changes at randomisation (seizures: 1·96, 1·02–3·74, p=0·04; background amplitude: 2·06, 1·01–4·17, p=0·05) and Sarnat score seem to be independently predictive.3 We speculate that clinical examination and aEEG recordings in the early hours after birth could provide complementary information on the severity of the perinatal insult and on how far advanced the process of injury was at the time of recruitment. Since the period from birth to enrolment varied little between infants, the stage of evolution of damage would mainly be influenced by the timing of intrauterine hypoxia. As Dutta and colleagues note, a prolonged period between hypoxia and treatment could be expected to reduce the effect of the treatment. Unfortunately the routine clinical data collected before study enrolment and our general ability to
monitor fetal state are not sufficient to allow this hypothesis to be tested. We appreciate Shaibu Oricha Bello’s comments. The use of a “one in 20 chance” is of course completely arbitrary, although hallowed by common use. The additional analysis reported here might assist in interpreting the clinical significance of the study.
*Alistair J Gunn, Peter D Gluckman, John S Wyatt, Marianne Thoresen, A David Edwards, on behalf of the CoolCap Study Group
it appears from the mother’s womb”. Neuberger fails to alert us to the tensions or ambiguities within the Jewish tradition which might suggest a higher moral and legal status for the embryo. For example, under the law of Noah, a law given for gentiles (like myself), the destruction of the unborn child in the womb is a capital offence. “What is Rabbi Ishmael’s reason? Because it is written, Whoso sheddeth the blood of man within [another] man, shall his blood be shed. What is a man within another man?—An embryo in his mother’s womb”.2
[email protected]
I declare that I have no conflict of interest.
*Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1020, New Zealand (AJG); Liggins Institute, University of Auckland, Auckland, New Zealand (PDG); University College London, London, UK (JSW); University of Bristol, St Michael’s Hospital, Bristol, UK (MT); and Imperial College, London, UK (ADE)
David Albert Jones
1
2
We declare that we have no conflict of interest other than that stated in the original paper.
2
3
van de Riet JE, Vandenbussche FP, Le Cessie S, Keirse MJ. Newborn assessment and longterm adverse outcome: a systematic review. Am J Obstet Gynecol 1999; 180: 1024–29. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976; 33: 696–705. Shalak LF, Laptook AR, Velaphi SC, Perlman JM. Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics 2003; 111: 351–57.
Embryos and ensoulment Although The Soul of the Embryo is a “calm look at what Christians and others had to say”, it is a mistake to see the book as “a considered denial of the position taken by the Pope” (March 5, p 837).1 On the contrary, the book is ultimately a defence of precisely that position. In her book review, Julia Neuberger also suggests that there is “no absolute truth here” and calls for “less certainty” all round. However, at the same time she presents the Jewish tradition in curiously absolutist terms: “the unborn child does not . . . count as life”, it has “no legal status . . . until
[email protected] School of Theology, Philosophy, and History, St Mary’s College, Waldegrave Road, Twickenham TW1 4SX, UK 1
Embryos and ensoulment: when does life begin? Lancet 2005; 365: 837–38. Babylonian Talmud, tractate sanhedrin: 57b. http://www.come-and-hear.com/sanhedrin/ sanhedrin_57.html#PARTb (accessed March 23, 2005).
Department of Error Feenstra J, de Herder WW, ten Have SMTH, et al. Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet 2005; 365: 1644–46—In this Research Letter (May 7), the figure legend should read: “IGF-I concentration in serum of 19 patients with acromegaly, before and after 42 weeks of combined therapy”. The second sentence of the sixth paragraph should read: “The observed 95% efficacy at 42 weeks is similar to that of daily pegvisomant monotherapy”. Czupryniak L, Loba J. Route of corruption in Poland’s health-care system. Lancet 2004; 364: 1856—In this Correspondence Letter (Nov 20), the second sentence of the second paragraph should start: “Doctors’ monthly salaries. . .” Hardy R, Kuh D, Langenberg C, Wadsworth MEJ. Birthweight, childhood social class, and change in adult blood pressure in the 1946 British birth cohort. Lancet 2003; 362: 1178–83—In this Article (Oct 11), the estimate of the intercept (95% CI) for childhood manual social class in the unadjusted model for systolic blood pressure in tables 3 and 4 (p 1180) should be: “2·14 (1·12 to 3·14)”.
www.thelancet.com Vol 365 May 7, 2005