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The Trouble with Informed Consent
I read with great interest the commentary by John D. Lantos on the SUPPORT study controversy. Dr. Lantos makes a compelling argument that the OHRP was misguided in its criticism of SUPPORT, primarily because both arms of the trial were within standard of care.1-2
Eligible infants whose parents refused to participate in SUPPORT received the same medical care, but instead of randomization via protocol, they were subject to "idiosyncratic clinical judgments in the absence of good evidence."1 That is a frightening concept. How can it be easier for a physician to change clinical practice on a whim than it is for her to study those very same differences in practice using the scientific method?
I agree that the informed consent process needs to change, but I propose that we change the entire system. If both intervention arms of a clinical trial are within standard practice, the IRB should not require written informed consent at all. "In such situations," according to Dr. Lantos, "there may be no incremental risk to being in a study. There may even be some benefit." 1 Of course, these studies would continue to require verbal assent from parents and prior approval from the IRB, but shifting to an opt-out rather than an opt-in regime would significantly benefit the progress of medicine. Indeed, some institutions outside of the United States have already adopted this policy.3
No one wants to get rid of oversight for clinical research entirely, but too much oversight has had a measurable and significant chilling effect on scientific advancement.4 In my opinion, there is no doubt that the obstacles to initiating and conducting clinical research would be more navigable without the burden of universal written informed consent.
REFERENCES 1. Landtos JD. Learning the right lessons from the SUPPORT study controversy. Arch Dis Child Fetal Neonatal Ed. 2013;epub ahead of print. 2. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremey preterm infants. N Engl J Med. 2010;362:1959-1969. 3. Reignier J, Mercier E, Le Gouge A, et al. Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial. JAMA. 2013;309:249-56 4. O'Herrin JK, Kudsk K, Frost N. Health insurance portability Accountability Act (HIPAA) regulations: effect on medical record research. Ann Surg. 2004;239:772-776.
Conflict of Interest:
I enjoyed reading this paper, but I have some comments about the statistics, which I think should have been picked up in the peer review process.
In the paper it is stated that the Bland Altman plot showed good correlation. Correlation should produce a coefficient and a p-value.
The paper does not report the value for the mean difference between the two methods. From the graph it looks about -0.01 mmol/L. The limits of agreement look to be about 0.49 mmol/L to -0.49 mmol/L.
I estimate the standard deviation of the differences to be around 0.25 mmol/L, making the standard error of the mean about 0.02 mmol/L. Thus there is no systematic difference between the two methods as the 95% confidence intervals for the mean difference are approximately 0.03 mmol/L to -0.05 mmol/L, crossing zero.
If you want to replace one measure with another you must demonstrate that there is no a systematic difference. While it is implicit in the figures and text it is not stated.
More importantly 95% of the differences are within 0.5 mmol/L. However, once the glucose value in the baby is only 2 to 2.5 this has massive clinical importance. I think there are 2 ways of addressing this issue. First whatever your unit's lower limit of glucose acceptability is you must add the limits of agreements to that (0.5 mmol/L in this case). However, would it be better, given the consequences of prolonged hypoglycaemia, to calculate the 99% confidence interval, or even higher and add that to your usual lower limit. If enough samples were collected it is possible to calculate a minimum acceptable value for the new test.
There is another method to address the accuracy of the new instrument, although seemingly constant, but possibly significantly clinically less reliable at lower glucose readings. We note that the spread of difference is reasonably constant over the range of measurements, as suggested in the graph. However, at 8 mmol/L the limits of agreement of 0.5 mmol/L represent a margin of error of around 6%, but at 2 mmol/L it is 25%. I have seen studies re-plot the Bland Altman graph with the differences as a percentage of the mean value. In this case it would emphasise how at clinically important low values, an in house guideline must be in place to ensure that hypoglycaemia is not undiagnosed.
It is my firm belief that these issues should have been picked up in the peer review. The authors could have then have shown the data I have estimated and concluded that their validation is useful for their unit, but your unit would need to do its own testing before adopting this new method of measuring glucose in preterm arterial samples.
Simon J Clark Neonatal Consultant
Conflict of Interest:
Preterm twins and singletons differ in their neurodevelopment at 5 years of age.
We read with interest the thought provoking paper written by Dr. Bodeau-Livinecr and colleagues on behalf of the EPIPAGE. They concluded that compared with very preterm singletons, twins had higher mortality, no difference in severe deficiencies, but slightly lower Mental Processing Composite scores at 5 years. 1
The Authors suggest that although all the infants studied who were born preterm had been exposed to a pregnancy complication that had led to their early birth, these may not be the same (i.e. in utero death of the co-twin, being born second, monochorionic placenta, and birthweight discordance) and may not have the same neurodevelopmental consequences in singletons and twins. 1
Accumulating evidence indicates that the prenatal environment plays a significant role in shaping children's neurodevelopment. Some authors hypothesize that prenatal psychological distress on the part of the mother is a risk factor for children's neurocognitive development. 2 We have been assessing subjective states in singleton and twin pregnant women using L?scher's 8-color test. 3 According to test results, singleton and twin pregnant women share feelings denoting a particular emotional state, idealizing their status, although perceiving it as stressful. Twin pregnant women are afraid of building a relationship with their infants and those women who became pregnant with twins following assisted reproduction technologies perceive their pregnancy as exhausting, characterized by a deep-seated anxious state and by the wish to give birth soon. This is a particularly complex situation in which mothers are at risk for anxiety, depression, and unsatisfactory postnatal bonding.
Studies specifically including maternal psychological distress in their design will be able to assess the relative and/or synergistic impact of these prenatal experiences on developmental trajectories. Once again, we would like to thank the Authors for bringing these considerations to the forefront and hope to read other articles on this timely subject.
1. Bodeau-Livinec F, Zeitlin J, et al. Do very preterm twins and singletons differ in their neurodevelopment at 5 years of age? Arch Dis Child Fetal Neonatal Ed. 2013 Jul 17.
2. Monk C, Georgieff MK, Osterholm EA. Research review: maternal prenatal distress and poor nutrition - mutually influencing risk factors affecting infant neurocognitive development. J Child Psychol Psychiatry 2013;54:115-30.
3. L?scher, M. The L?scher Colour Test. Translated and edited by Ian. A. Scott. London: Pan Books, 1972.
Conflict of Interest:
Another reason to deliver babies with CCHD at local NICU's
The authors are to be thanked for looking into outcomes of fetuses identified with Critical Congenital Heart Disease (CCHD) based on the location of birth. Bennett et al (1) came to the same conclusion: that birth hospital had little impact on survival. As the authors point out, 75% of CCHD may be missed during prenatal evaluations. This means that the physicians at the non-specialty hospitals have to be able to recognize and stabilize these critically ill babies. Based on the data from Anagnostou et al and Bennett, I argue that it is better to deliver these babies wherever the mother wants and provide local support as necessary. These episodes of planned care will help the local staff remain competent to care for the majority of patients with CCHD who will arrive unexpectedly.
(1) Influence of Birth Hospital on Outcomes of Ductal-Dependent Cardiac Lesions Tellen D. Bennett, Matthew B. Klein, Mathew D. Sorensen, Anneclaire J. De Roos and Frederick P. Rivara DOI: 10.1542/peds.2009-2829 ; originally published online November 22, 2010; 2010;126;1156 Pediatrics
Conflict of Interest:
Re: In vitro comparison of neonatal suction catheters using simulated 'pea soup' meconium
Dear Editor, The paper by Zareen et al. recently published in Archives, evaluates the effectiveness for suctioning meconium of various catheters and bulb syringes. The data provide useful information for caregivers of infants in the delivery room.  The authors describe meconium suctioning as a routine procedure. They quote: "However, recent guidelines recommend that, if the baby born with meconium stained fluid has a normal respiratory effort, normal muscle tone and a heart rate greater than 100 bpm, one should simply use a bulb syringe (BS) or large bore catheter to clear secretions and any meconium from the mouth and nose as needed". They further comment: "There is still some debate regarding whether or not suctioning in this setting confers any benefit to the infant, who does not require intubation".  The Neonatal Resuscitation Program of the AAP and ILCOR do not recommend any longer routine suction of meconium stained infants. Suction should be neither performed with clear nor with meconium stained amniotic fluid (MSAF) if the infant is vigorous, has normal respiratory effort, normal muscle tone and a heart rate greater than 100 bpm. The guidelines emphatically recommend that, with clear or MSAF, suction should be exclusively performed if the infant's airway appears evidently obstructed by secretions or, in infants with MSAF who are not breathing, just before intubation The authors should have referred to the latest recommendations. [2, 3] ILCOR and other institutions base their guidelines in serious scientific evidence, directed toward improving clinical practice. For many years, literature search failed to yield randomized controlled trials addressing topics related to therapies used during the birth process. Fortunately in the last decade, several studies performed in the delivery room followed appropriate evidence based medicine design allowing for rational changes to which all clinicians should progressively adapt. [4, 5]
Adriana M. Aguilar Nestor E. Vain
FUNDASAMIN (Fundaci?n para la Salud Materno Infantil) Honduras 4160, Buenos Aires, Argentina (1180) Tel/ Fax 54-11-4863-4102
Correspondence to: Nestor E. Vain E- Mail address: email@example.com
1. Zareen, Z., C.P. Hawkes, E.R. Krickan, E.M. Dempsey, and C.A. Ryan, In vitro comparison of neonatal suction catheters using simulated 'pea soup' meconium. Arch Dis Child Fetal Neonatal Ed, 2013. 98(3): p. F241-3. 2. Kattwinkel, J., Textbook of Neonatal Resuscitation. 6th edition. 6 ed. Vol. 1. 2011: American Academy of Pediatrics and American Heart Association. 3. Perlman, J.M., J. Wyllie, J. Kattwinkel, D.L. Atkins, L. Chameides, J.P. Goldsmith, et al., Part 11: Neonatal Resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation, 2010. 122(16 Suppl 2): p. S516-38. 4. Vain, N.E., E.G. Szyld, L.M. Prudent, T.E. Wiswell, A.M. Aguilar, and N.I. Vivas, Oropharyngeal and nasopharyngeal suctioning of meconium- stained neonates before delivery of their shoulders: multicentre, randomised controlled trial. Lancet, 2004. 364(9434): p. 597-602. 5. Saugstad, O.D., S. Ramji, R.F. Soll, and M. Vento, Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology, 2008. 94(3): p. 176-82.
Conflict of Interest:
Re:Procalcitonin for early diagnosis of neonatal nosocomial sepsis
Dear Editor, Thank you for the opportunity of answering to the comments of Chiesa (1) about our paper (2). First, the assay: Procalcitonin (PCT) was measured with an immunoluminometric, quantitative method, as in studies cited by us and by Chiesa. We used reagents Brahms and Berthold LB9507 luminometer (Dasit). The analytical signal, proportional to the concentration of the PCT in the sample, was converted into continuous concentration values. The definitive results were available in 5-6 hours from the blood collection, that we considered as "fast".
Second: the first blood sample was taken on admission of all patients to NICU (time 0), in the absence of clinical and laboratory signs of infection, to check the increase of PCT during the subsequent infection, when it would be manifested. These results were never included in the calculation of the maximum value of PCT during infection. Infants with maternal-fetal infections were excluded from the study. In neonates who developed signs of nosocomial sepsis at least 48 h after the admission in NICU, PCT levels were further measured, as stated in the methods, at least within 24 and 48 h after the onset of the infection. These data only were used to calculate the median value of the highest PCT levels during the infection. PCT was also measured in 762 (GA 34+/-4 weeks, BW 2130+/-863 g) critically ill, but uninfected, patients; 205 of them were VLBW (29+/-3 weeks, BW 1123+/-258g), admitted to NICU in the first three days of life. Our unpublished data confirm a physiologic increase in PCT levels during the first days of life (3-5). Considering all uninfected neonates, the median values of PCT by day of life were: 0.40 ng/ml (IQR 0.21-1.20), in the first , 2.38 ng/ml (IQR 0.77-8.76), in the second and 0.52 ng/ml (IQR 0.28 -1.37), in the third. We obtained similar results in VLBW infants. Stratifying for BW (collinear with gestational and postnatal age), the accuracy of PCT did not differ significantly in neonates with a BW 1500- 2500 gr from that of heavier BW: a cut-off of 2.4 ng/ml. yielded a sensitivity of 55%, a specificity of 84% and a positive Likelihood Ratio of 3.4. Finally, in the first study of Chiesa, cited in his letter, (3) PCT was measured in healthy neonates, and a nomogram was established with statistical cut-offs. Despite this, when the problem of late-onset sepsis was investigated, a matched case-control design was adopted. (4) In this study cases and controls were defined, on clinical grounds, as we did, apparently ignoring statistical cut-offs and postnatal age, that was one of the variables of matching. Turner introduced as well a nomogram by gestational age in the first 4 days of life (5). However he has published results about PCT accuracy in another study (6), with the current, evidence-based approach, where different cut-offs were explored to establish the most appropriate for clinical application in a given context,. A number of biological or clinical reasons (e.g. concomitant diseases, age, labour, drugs etc.) can lead to misdiagnosis, measured by sensitivity, specificity and the other values of accuracy, that we hold as meaningful with our approach.
Dr.ssa Cinzia Auriti Dr. Vincenzo M. Di Ciommo
1). Chiesa C, Pacifico L, Osborn JF, Natale F, De Curtis M Procalcitonin for early diagnosis of neonatal nosocomial sepsis Arch Dis Child Fetal Neaonatal Ed Published 31 March 2011 2). Auriti C, Fiscarelli E, Ronchetti MP, at al. Procalcitonin in detecting neoanatal nosocomial sepsis. Arch Dis Child Fetal Neaonatal Ed 2011.Published online First: 15 March 2011 doi:10.1136/adc.2010.194100 3) Chiesa C, Panero A, Rossi N, et al. Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. Clin Infect Dis 1998;26:664-72. 4) Chiesa C, Natale F, Pascone R, et al. C reactive protein and procalcitonin: Reference intervals for preterm and term newborns during the early neonatal period. Clin Chim Acta 2011; 412: 1053-59 5) Turner D, Hammerman C, Rudensky B, et al. Procalcitonin in preterm infants during the first few days of life: introducing an age related nomogram. Arch Dis Child Fetal Neonatal Ed 2006;91:F283-6 6) Turner D, Hammerman C, Rudensky B, et al. The role of procalcitonin as a predictor of nosocomial sepsis in preterm infants. Acta Paediatr 2006;95:1571-6
Conflict of Interest:
Survey of management of patent ductus arteriosus in neonatal units across England
We read with great interest the review "Patent ductus arteriosus-time to grasp the nettle" (Smith, Kissack, ADC F&N 2013; 98) which highlighted the controversies in PDA management and variation in management. Evidence to support the routine closure of the ductus arteriosus to improve neonatal morbidity remains inconclusive1. We recently conducted a survey on PDA management in neonatal units across England to understand current clinical practice. A structured questionnaire was emailed with an online hyperlink to consultant neonatologists working in tertiary neonatal units in England.Fourteen questions addressed work load, management strategies, fluid management, drugs used, threshold for treatment of PDA, cardiology service available in their unit. The survey was conducted from August 2012 to November 2012. The response rate was 75%.The majority (68%) of neonatologists felt that a symptomatic strategy best describes their practice for treating PDA, while 25% felt that they practised a presymptomatic/ echo directed targeted strategy. Only two neonatologists (at the same unit) practice a prophylactic treatment strategy and two neonatologists felt that their practice does not fit in any of above categories. Significant variation was observed when percentage of preterm babies treated for PDA/year was compared within different units practising same symptomatic strategy (7% to 75%).The drug of choice for treating PDA was ibuprofen for 74% of neonatologists, with only 26% using indomethacin. Fluid intake is restricted in PDA by18 neonatologists out of 63 (28%); 16 of these restrict fluids only in symptomatic babies while two restrict fluid in all babies with PDA. Most neonatologists continue feeds during medical treatment of a PDA with only 6 (10%) stopping. Just over half of neonatologists restrict fluids while treating baby for PDA (53%). We asked clinical questions to all the neonatologists to understand the threshold for treatment. Previously a similar question was asked to neonatologists in the United States of America2. Neonatologists from UK are much more conservative when compared to neonatologists from United States when it comes to treating PDAs in preterm babies. Interestingly 18% neonatologists from England said that they would treat a moderately large PDA in a preterm baby, even if the baby is extubated and on CPAP with 5% going on to surgical ligation if medical treatment fails or is contraindicated. No neonatologists from the UK would treat a moderate to large PDA in a baby who is self-ventilating in air as opposed to one third of Neonatologists from United States. A second course of medical treatment is given by 80% neonatologists before ligating PDA while 11% would give only one course of treatment before ligating the duct if baby hasn't responded. Of those that responded, only one neonatologist would give three courses of medical treatment before ligating while 5 neonatologists felt that they would very rarely ligate a PDA in preterm babies (1-5/every 5 years). Echocardiography was performed by 79% of neonatologists themselves to diagnose and treat PDA. In 46% of units there is no cardiology service and the decision to treat PDA is made based on echocardiography findings of the neonatologists. In these units babies require transfer to cardiology centre for cardiology input. Onsite cardiology services are available in 18% of the units, with 20% of units having a paediatric cardiologist visiting twice a week. Two units get cardiology input within 24 hrs of request and a further two units have a paediatric cardiology visiting twice a month. In conclusion, significant variations exist in practice amongst neonatologists when it comes to management of PDA in preterm babies. There are significant variations in the number of babies treated on different units by neonatologists claiming to follow same treatment strategy suggesting different thresholds for treatment. The use of a prophylactic treatment strategy is becoming rare. Most of neonatologists do echocardiography themselves to make a decision regarding treatment of PDA, with a half of units responding not having access to specialist cardiology services on site. Reference: 1. Bose CL, Laughon MM (2007) Patent ductus arteriosus: lack of evidence for common treatments. Arch Dis Child Fetal Neonatal Ed 92:F498-F502 2. Jhaveri N et al: Feeding practices and patent ductus arteriosus ligation preferences-are they related? Am J Perinatol 27: 667-674, 2009
Conflict of Interest:
This may due to Low Maternal DHEA
It is my hypothesis that evolution selected dehydroepiandrosterone(DHEA) because it optimizes replication and transcription of DNA. Therefore DHEA levels affect all tissues and life span. (I think selection for DHEA produced mammalia. "Hormones in Mammalian Evolution," Rivista di Biologia / Biology Forum 2001; 94: 177- 184).
A case may be made that sufficient maternal DHEA is necessary both for conception and full term pregnancy. A mother must produce sufficient DHEA for herself as well as a fetus, until such time that the fetus starts to produce DHEA sufficient to initiate birth and support for itself.
A mother who has difficulty initiating and supporting conception and pregnancy may be low DHEA. If DHEA levels do affect all tissues, growth and development of the child may be impaired, especially for the brain. This may explain the findings of Seggers, et al.
Conflict of Interest:
End of life decision making
End of Life Decision Making (EoL DM) in NICU is an extremely sensitive issue. In our unit we have practiced shared DM for a long time however as the authors write we did not come across any large studies looking into parents perceptions of EoL DM in the long term.
1. We appreciate that telephonic interviews were discarded in this paper to ensure accurate assessment of parent's self-perceived role. Also interviews were conducted by three skilled interviewers and to ensure reliability of themes extracted, however it is not clear if each parent was interviewed three times, which if it did appeared a bit excessive. Also it was not clear where the interview happened. 2. We noted that only 145 out of 258 eligible families were contacted. We wonder whether inclusion of non-French speaking families would improve the sample size? 3. As noted by the authors there were limitations in the sample with overrepresentation of certain categories leading to limited possibility of generalization of results. Overall we appreciate the large amount of work into this study and hope that such studies will prompt further large projects to improve our strategies of decision making for these babies and families in times of extreme grief.
Conflict of Interest:
Positioning of neonates for lumbar puncture
Lumbar puncture is a blind procedure (no guidance about the path of the lumbar puncture needle except for the sensory information that the performer obtains about interspinous distance before inserting the needle and upon puncturing the duramater). 1. We feel that the for a successful procedure, besides ensuring adequate interspinous space to insert the needle by ensuring optimum position of the patient it is very important to ensure that the patient is as calm and comfortable as possible so that we donot have to chase a moving target with a sharp needle. In our unit we use a few drops of 24% sucrose just before positioning in lateral recumbent position. The observation in the study that heart rate increases the most in sitting position (with or without flexed hips) in itself suggests that the baby is far from calm at that point. 2. The authors have concluded that 'Sitting flexed position of hips, which seems to be suffciently safe and serve to enhance the success rate of a LP' appears to be misrepresented as the authors have themselves recognized that one of the limitations of this study is that there is absence of performed lumbar puncture so success of the procedure cannot be gauged in this study. 3. Sitting position may not be practically feasible in preterm and sick ventilated neonates who have cardiovascular instability
Conflict of Interest:
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