We have read with interest the response by Dr. Shabih Manzar on our article. The Thompson score is a clinical score consisting of nine items that are associated with neurologic dysfunction to assess the severity of neonatal encephalopathy (NE) in infants with perinatal asphyxia.[1] There are indeed important limitations that need to be considered; the assessment of infants by use of the Thompson score requires interpretation from the examiner, and the degree of NE may change over time.[2] It should be noted that these limitations are also applicable to other clinical grading tools, such as the modified Sarnat score, which is being widely applied to select infants for therapeutic hypothermia.[2,3] We would like to emphasize that the majority of the infants described in this study was born in a level-II-hospital. Amplitude-integrated electroencephalography (aEEG), another tool to select infants for therapeutic hypothermia, allows continuous monitoring, expert revision and the detection of subclinical seizures, but also requires well-trained staff for correct interpretation and is often not available in these hospitals. By design, the Thompson score did not require extensive training of the observer, which is why it is suitable to be used in smaller hospitals.[1] In a previous study, our study group demonstrated that the Thompson score and aEEG had a similar predictive value for an adverse outcome.[4] We however completely agree with Dr. Manzar that it is of concern that the...
We have read with interest the response by Dr. Shabih Manzar on our article. The Thompson score is a clinical score consisting of nine items that are associated with neurologic dysfunction to assess the severity of neonatal encephalopathy (NE) in infants with perinatal asphyxia.[1] There are indeed important limitations that need to be considered; the assessment of infants by use of the Thompson score requires interpretation from the examiner, and the degree of NE may change over time.[2] It should be noted that these limitations are also applicable to other clinical grading tools, such as the modified Sarnat score, which is being widely applied to select infants for therapeutic hypothermia.[2,3] We would like to emphasize that the majority of the infants described in this study was born in a level-II-hospital. Amplitude-integrated electroencephalography (aEEG), another tool to select infants for therapeutic hypothermia, allows continuous monitoring, expert revision and the detection of subclinical seizures, but also requires well-trained staff for correct interpretation and is often not available in these hospitals. By design, the Thompson score did not require extensive training of the observer, which is why it is suitable to be used in smaller hospitals.[1] In a previous study, our study group demonstrated that the Thompson score and aEEG had a similar predictive value for an adverse outcome.[4] We however completely agree with Dr. Manzar that it is of concern that the Thompson score was not available in more than half of our study population, although this could have been the result of a lack of documentation.
Seven infants in our study developed moderate NE <6 hours after birth, and therefore indeed qualified for therapeutic hypothermia.[5] Three of these infants showed a rapid cardiorespiratory recovery after birth, i.e. they were cardiorespiratory stable with a minimal amount of oxygen support after resuscitation and only a short period of ventilation. All three were born in a level-II-hospital without access to aEEG. Although one of these infants had a Thompson score of 13 at 1 hour after birth, hypothermia was not started because of a low Thompson score (1) at 3 hours after birth on arrival at the NICU. In the other two cases, the first signs of NE were recognized around 4-5 hours after birth, but hypothermia was not started because the infants arrived at respectively 8 hours and 11 hours after birth at the NICU.
As mentioned in our discussion, the large trials on therapeutic hypothermia used different eligibility criteria for this intervention, including various thresholds for Apgar scores and pH.[6] Some trials indeed included infants using a pH <7.0 and 10-minute Apgar score ≤5,[7,8] while others included infants with a pH <7.1 [9,10] or 5-minute Apgar score <7.[9] The systematic review by Jacobs et al. used a cord or arterial pH <7.1 within 60 minutes of birth as criterium for peripartum asphyxia.[6] We were interested whether the infants in our study population would have been eligible for hypothermia using different thresholds, and therefore separately reported the proportion of infants with and without a pH <7.0.
To conclude, we would like to emphasize that selection of infants for therapeutic hypothermia is difficult, especially as most infants are born in level-II-hospitals with different levels of clinical experience and often no access to aEEG. Even though seven infants in our study should have received hypothermia, the proportion of infants who developed an adverse outcome remains high (16/32, 50%) when these seven infants are excluded. Both clinical grading tools as well as aEEG have limitations in clinical practice, which is why further studies on optimizing the selection of infants for therapeutic hypothermia are needed. Until a better tool to select infants for therapeutic hypothermia becomes available, structural use of the Thompson score and early referral of infants with perinatal asphyxia for neuromonitoring, including those who seem to recover quickly from a perinatal insult, remains of great importance.
References
[1]. Thompson, CM, Outerman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, et al. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr. 1997 Jul;86(7):757-61.
[2]. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976 Oct;33(10):696-705.
[3]. Mrelashvili A, Russ JB, Ferriero DM, Wusthoff CJ. The Sarnat score for neonatal encephalopathy: looking back and moving forward. Pediatr Res. 2020 Dec;88(6):824-825.
[4]. Weeke LC, Vilan A, Toet MC, van Haastert IC, de Vries LS, Groenendaal F. A Comparison of the Thompson encephalopathy score and amplitude-integrated electroencephalography in infants with perinatal asphyxia and therapeutic hypothermia. Neonatology. 2017;112(1):24–9.
[5]. Groenendaal F, Casaer A, Dijkman KP, Gavilanes AWD, de Haan TR, ter Horst HJ, et al. Introduction of Hypothermia for Neonates with Perinatal Asphyxia in the Netherlands and Flanders. Neonatology. 2013;104(1):15-21.
[6]. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013 Jan 31;2013(1):CD003311.
[7]. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365(9460):663‐70.
[8]. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Whole‐body hypothermia for term and near‐term newborns with hypoxic‐ischemic encephalopathy: a randomized controlled trial. Archives of Pediatrics and Adolescent Medicine 2011;165(8):692‐700.
[9]. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102(4 Pt 1):885‐92.
[10]. Lin Z, Yu H, Lin J, Chen S, Liang Z, Zhang Z. Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit. Journal of Perinatology 2006;26(3):180‐4.
The article by Parmentier et al [1] highlights the role of Amplitude-integrated electroencephalography (aEEG) and early biomarkers in selecting infants for therapeutic hypothermia (TH). They also suggested the role of the Thompson score (TS) in asphyxiated infants. The problem with TS is that it is subjective. It consists of nine clinical signs: tone, level of consciousness, fits, posture, moro reflex, grasp, suck, respiration, and fontanelle, which could change over time [2]. Also, in the data presented by Parmentier et al [1], twenty-one (53%) infants did not have TS performed.
It was surprising to note that four cases that had moderate neonatal encephalopathy (NE) were not treated with TH despite having seizures within the first 6 hours. The reason for not treatment was rapid recovery. What was the definition of rapid recovery? According to the published flow diagram for NE, the onset of seizure within 6 hours warrants TH [3].
The definition of perinatal asphyxia used by Parmentier et al [1] was from a study in 2003 [4]. It was defined as an arterial cord blood pH <7.1, Apgar Score <7 at 5 min, or need for neonatal resuscitation. While the analysis was done with pH of < 7 and > 7 [(Table 1) 1]. A pH of 7.1 and Apgar of 7 at 5 min is higher than the definition/criteria used in the TH trial [5].
References:
1. Parmentier CEJ, Steggerda SJ, Weeke LC, Rijken M, De Vries LS, Groenendaal F. Outcome of non-cooled asphyxiated infants w...
The article by Parmentier et al [1] highlights the role of Amplitude-integrated electroencephalography (aEEG) and early biomarkers in selecting infants for therapeutic hypothermia (TH). They also suggested the role of the Thompson score (TS) in asphyxiated infants. The problem with TS is that it is subjective. It consists of nine clinical signs: tone, level of consciousness, fits, posture, moro reflex, grasp, suck, respiration, and fontanelle, which could change over time [2]. Also, in the data presented by Parmentier et al [1], twenty-one (53%) infants did not have TS performed.
It was surprising to note that four cases that had moderate neonatal encephalopathy (NE) were not treated with TH despite having seizures within the first 6 hours. The reason for not treatment was rapid recovery. What was the definition of rapid recovery? According to the published flow diagram for NE, the onset of seizure within 6 hours warrants TH [3].
The definition of perinatal asphyxia used by Parmentier et al [1] was from a study in 2003 [4]. It was defined as an arterial cord blood pH <7.1, Apgar Score <7 at 5 min, or need for neonatal resuscitation. While the analysis was done with pH of < 7 and > 7 [(Table 1) 1]. A pH of 7.1 and Apgar of 7 at 5 min is higher than the definition/criteria used in the TH trial [5].
References:
1. Parmentier CEJ, Steggerda SJ, Weeke LC, Rijken M, De Vries LS, Groenendaal F. Outcome of non-cooled asphyxiated infants with under-recognised or delayed-onset encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2022;107(4):364-370. doi:10.1136/archdischild-2020-321331
2. Thompson CM, Puterman AS, Linley LL, et al. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr. 1997;86(7):757-761. doi:10.1111/j.1651-2227.1997.tb08581.x
3. Chiang MC, Jong YJ, Lin CH. Therapeutic hypothermia for neonates with hypoxic ischemic encephalopathy. Pediatr Neonatol. 2017;58(6):475-483. doi:10.1016/j.pedneo.2016.11.001
4. Cowan F, Rutherford M, Groenendaal F, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet. 2003;361(9359):736-742. doi:10.1016/S0140-6736(03)12658-X
5. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584. doi:10.1056/NEJMcps050929
I agree with Yieh et al [1] that there is an overuse of therapeutic hypothermia (TH) in mild HIE resulting in increased resource utilization. The two main reasons we see this practice are the fear of litigation and scare that infant would later have neurological problems. DuPont et al [2] reported abnormal short-term neurologic outcomes in 20% of newborns with perinatal acidemia and mild HIE not treated with TH. However, in the same study they had 14% of infants that did not receive TH despite the neurological examination consistent with moderate and severe HIE.
Mehta et al [3] have earlier described overutilization of TH in mild HIE, recommending a robust review of the eligibility criteria definitions, especially the 10-min Apgar score. The subjectivity of TH criteria put the practitioner in a decision dilemma. For example, out of five components of Apgar score, only heart rate assessment is objective. A color score of 1 or 2 can change the Apgar from 5 to 6. Similarly, a slight variation in observer examination in obtaining Sarnat score could change it from mild to moderate. Therefore, using a combination of factors in deciding about TH would be a better approach [4].
One of the most important criterion for TH is presence of perinatal academia. Recently, Blecharczyk et al [5] have shown the benefits of standardized screening pathway for evaluating abnormal cord gases in neonates at risk for HIE. Following a structured pathway resulted in minimizing unnecess...
I agree with Yieh et al [1] that there is an overuse of therapeutic hypothermia (TH) in mild HIE resulting in increased resource utilization. The two main reasons we see this practice are the fear of litigation and scare that infant would later have neurological problems. DuPont et al [2] reported abnormal short-term neurologic outcomes in 20% of newborns with perinatal acidemia and mild HIE not treated with TH. However, in the same study they had 14% of infants that did not receive TH despite the neurological examination consistent with moderate and severe HIE.
Mehta et al [3] have earlier described overutilization of TH in mild HIE, recommending a robust review of the eligibility criteria definitions, especially the 10-min Apgar score. The subjectivity of TH criteria put the practitioner in a decision dilemma. For example, out of five components of Apgar score, only heart rate assessment is objective. A color score of 1 or 2 can change the Apgar from 5 to 6. Similarly, a slight variation in observer examination in obtaining Sarnat score could change it from mild to moderate. Therefore, using a combination of factors in deciding about TH would be a better approach [4].
One of the most important criterion for TH is presence of perinatal academia. Recently, Blecharczyk et al [5] have shown the benefits of standardized screening pathway for evaluating abnormal cord gases in neonates at risk for HIE. Following a structured pathway resulted in minimizing unnecessary evaluations, admissions to NICU and disruption of neonate–mother bonding.
In conclusion, the role of TH in mild HIE in reference to the long-term neurodevelopmental outcomes remain unclear. When using TH in mild HIE, healthcare cost and resource utilization should be considered.
References:
1. Yieh L, Lee H, Lu T, et al. Neonates with mild hypoxic-ischaemic encephalopathy receiving supportive care versus therapeutic hypothermia in California. Arch Dis Child Fetal Neonatal Ed. 2022;107(3):324-328. doi:10.1136/archdischild-2021-322250
2. DuPont TL, Chalak LF, Morriss MC, Burchfield PJ, Christie L, Sánchez PJ. Short-term outcomes of newborns with perinatal acidemia who are not eligible for systemic hypothermia therapy. J Pediatr. 2013;162(1):35-41. doi: 10.1016/j.jpeds.2012.06.042
3. Mehta S, Joshi A, Bajuk B, Badawi N, McIntyre S, Lui K. Eligibility criteria for therapeutic hypothermia: From trials to clinical practice. J Paediatr Child Health. 2017;53(3):295-300. doi:10.1111/jpc.13378
4. Bonifacio SL, Hutson S. The Term Newborn: Evaluation for Hypoxic-Ischemic Encephalopathy. Clin Perinatol. 2021;48(3):681-695. doi: 10.1016/j.clp.2021.05.014
5. Blecharczyk E, Lee L, Birnie K, et al. Standardized Evaluation of Cord Gases in Neonates at Risk for Hypoxic Ischemic Encephalopathy. Hosp Pediatr. 2022;12(1):29-37. doi:10.1542/hpeds.2021-006135
In this study Selvanathan et al [1] showed small birth head circumference (HC) to be associated with poorer neurodevelopment outcome, independent of postnatal illness and white matter injury. They concluded that normalisation of HC during NICU care appears to moderate this risk.
It was interesting to note that normal/small group had the highest chorioamnionitis (40%), lowest ROP (0) and highest NEC (30%) rates. They also received the highest Energy (kcal/kg/day), median 80. What could be the reason for the HC to regress from normal to small?
We need to investigate other factors that affect the head growth. The individual factors such as parental bonding and availability, environmental exposure to noise, light and other stimuli may have some role in slowing the head growth.
Interestingly, in the same issue of ADC, Ni et al [2] have shown poor HC growth in EPICure2 that was unchanged from EPICure, which is alarming.
1. Selvanathan T, Guo T, Kwan E, et al. Head circumference, total cerebral volume and neurodevelopment in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2022;107(2):181-187. doi:10.1136/archdischild-2020-321397
2. Ni Y, Lancaster R, Suonpera E, et al. Growth in extremely preterm children born in England in 1995 and 2006: the EPICure studies. Arch Dis Child Fetal Neonatal Ed. 2022;107(2):193-200. doi:10.1136/archdischild-2020-321107
Kamupira et al [1] presented a case of umbilical venous line extravasation that was confirmed by contrast study. To justify the contrast use they stated, “There is evidence routine contrast use in checking tip positions improves long line positioning (reference 3 on the paper) and British Association of Perinatal Medicine (BAPM) has included this in it's central access guidance (reference 4 on the paper)”. The caveats with this statement are that first umbilical lines are not synonymous to long lines and second that in BAPM executive summary statement there is no mention of contrast use, “The findings of the Working Group recommend that:
• Any clinical deterioration of a baby in whom a central venous catheter is present should raise the question of catheter-related complications, particularly infection, extravasation and tamponade.
• All central catheter tips should be positioned outside the cardiac silhouette.
• An umbilical venous catheter (UVC) tip should ideally be sited at T8-T9 (assuming this lies outside the cardiac silhouette). A UVC tip sited at or below T10 carries a significantly higher risk of extravasation. It may be necessary to use these catheters in the short term, but they should be replaced at the earliest opportunity”.
In fact, the use of contrast has been associated with hypothyroidism in neonates [2]. UVC misplacements happen either due to the wrong placement or due to the migration of UVC from a safe to wrong position. Th...
Kamupira et al [1] presented a case of umbilical venous line extravasation that was confirmed by contrast study. To justify the contrast use they stated, “There is evidence routine contrast use in checking tip positions improves long line positioning (reference 3 on the paper) and British Association of Perinatal Medicine (BAPM) has included this in it's central access guidance (reference 4 on the paper)”. The caveats with this statement are that first umbilical lines are not synonymous to long lines and second that in BAPM executive summary statement there is no mention of contrast use, “The findings of the Working Group recommend that:
• Any clinical deterioration of a baby in whom a central venous catheter is present should raise the question of catheter-related complications, particularly infection, extravasation and tamponade.
• All central catheter tips should be positioned outside the cardiac silhouette.
• An umbilical venous catheter (UVC) tip should ideally be sited at T8-T9 (assuming this lies outside the cardiac silhouette). A UVC tip sited at or below T10 carries a significantly higher risk of extravasation. It may be necessary to use these catheters in the short term, but they should be replaced at the earliest opportunity”.
In fact, the use of contrast has been associated with hypothyroidism in neonates [2]. UVC misplacements happen either due to the wrong placement or due to the migration of UVC from a safe to wrong position. The ways to confirm the UVC placement and monitor possible migration are x-rays and ultrasound. Contrast studies are rarely indicated. The radiographic landmarks used to detect UVC malposition include the vertebrae and the expected course of the UVC. A slight change in position in relation to vertebrae indicate migration (Figure 1) [3].
The other way of locating the tip of UVC is using real-time ultrasound using the inferior vena cava and right atrium as landmarks [4].
In conclusion, in the light of the emerging evidence and growing interest in the use of point of care ultrasound in neonatal care and proper use of radiological landmarks, UVC placement or migration could be easily monitored avoiding the use of contrast.
References:
1. Kamupira SR, Tarr JD, Kuruvilla M. Contrast study in umbilical venous line extravasation. Arch Dis Child Fetal Neonatal Ed. 2022;107(2):120. doi:10.1136/archdischild-2020-321081
2. Piatek M, Schneider DJ, Smith WJ, Hanna M, Abu Jawdeh EG. Hypothyroidism after Percutaneous Patent Ductus Arteriosus Device Closure in an Extremely Preterm Infant: Possible Role of Iodinated IV Contrast. Neonatology. 2020;117(6):776-779. doi:10.1159/000512110
3. Patel BS, Walyat N, Manzar S. Catheter related ascites in a preterm Infant. Neonatology Today. 2021 (2); 37-40
4. Rubortone SA, Costa S, Perri A, D'Andrea V, Vento G, Barone G. Real-time ultrasound for tip location of umbilical venous catheter in neonates: a pre/post intervention study. Ital J Pediatr. 2021;47(1):68. Published 2021 Mar 18. doi:10.1186/s13052-021-01014-7
Legend to Figure:
Figure: Panel A and B showing migration of the UVC over time, adapted from Patel et al. Catheter related ascites in a preterm Infant. Neonatology Today. 2021 (2); 37-40
We read with great interest this article published by Chandran et al. However, we have some critical
reservations on implementation of low dose diazoxide. The target blood glucose thresholds used for
management have been taken from Pediatric endocrine society guidelines of 2015, which are based
on adult neuroglycopenic effects. However, AAP guidelines recommend a lower treatment target of
<2.2 mmol/l (40 mg/dl) for asymptomatic,<2.5 mmol/l (45 mg/dl) for symptomatic neonates
during first 48 hours and <3.3 mmol/l (60mg/dl) thereafter (1, 2) . Moreover, in a recent multi-centric
trial published by Kempen et al; it was concluded that low treatment threshold of <2 mmol/l (36
mg/dl) was non inferior in terms of neurodevelopmental outcomes at 18 months of age in healthy
asymptomatic neonates (3) . Hence it is still debatable whether all the neonates being managed for
hypoglycemia warranted an intravenous glucose infusion therapy and diazoxide.
Authors have used a combination of starting dose of diazoxide along with hydrochlorothiazide for
management of SGA neonates; which are known to have a synergistic effect on increasing blood
glucose levels, hence actual dose of diazoxide required if used alone could have been potentially
higher in these neonates.
In the study design the authors have mentioned that this was an observational cohort study,
however neither the absence of compar...
We read with great interest this article published by Chandran et al. However, we have some critical
reservations on implementation of low dose diazoxide. The target blood glucose thresholds used for
management have been taken from Pediatric endocrine society guidelines of 2015, which are based
on adult neuroglycopenic effects. However, AAP guidelines recommend a lower treatment target of
<2.2 mmol/l (40 mg/dl) for asymptomatic,<2.5 mmol/l (45 mg/dl) for symptomatic neonates
during first 48 hours and <3.3 mmol/l (60mg/dl) thereafter (1, 2) . Moreover, in a recent multi-centric
trial published by Kempen et al; it was concluded that low treatment threshold of <2 mmol/l (36
mg/dl) was non inferior in terms of neurodevelopmental outcomes at 18 months of age in healthy
asymptomatic neonates (3) . Hence it is still debatable whether all the neonates being managed for
hypoglycemia warranted an intravenous glucose infusion therapy and diazoxide.
Authors have used a combination of starting dose of diazoxide along with hydrochlorothiazide for
management of SGA neonates; which are known to have a synergistic effect on increasing blood
glucose levels, hence actual dose of diazoxide required if used alone could have been potentially
higher in these neonates.
In the study design the authors have mentioned that this was an observational cohort study,
however neither the absence of comparison group nor the retrospective nature of study been
clearly disclosed in the methodology (4) .
Finally, to make the study findings more generalizable; it shall be of greater interest to know the
long-term neurodevelopmental outcomes in this group of neonates.
References
1. Committee on F, Newborn, Adamkin DH. Postnatal glucose homeostasis in late-preterm and
term infants. Pediatrics. 2011;127(3):575-9.
2. Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, et al.
Recommendations from the Pediatric Endocrine Society for Evaluation and Management of
Persistent Hypoglycemia in Neonates, Infants, and Children. The Journal of pediatrics.
2015;167(2):238-45.
3. van Kempen A, Eskes PF, Nuytemans D, van der Lee JH, Dijksman LM, van Veenendaal NR, et
al. Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia. N Engl J Med.
2020;382(6):534-44.
4. Chandran S, R PR, Mei Chien C, Saffari SE, Rajadurai VS, Yap F. Safety and efficacy of low-
dose diazoxide in small-for-gestational-age infants with hyperinsulinaemic hypoglycemia.
2021:fetalneonatal-2021-322845.
We thank the authors for the comments on the Economic Evaluation of SIFT (1) and we are grateful for the opportunity to respond to their comments.
Taking each of the authors’ points in the order in which they are presented:
1. In relation to the first point about the loss to follow up and the exclusion of such patients from the analysis, we point out that we used complete case analysis and accounted for the missing patients following best practice using a multiple imputation analysis which is provided in the supplementary materials. We state the following in the paper:
“Mean total costs for all infants, adjusting for missing data using multiple imputation, are found in the online supplementary table S3. When the missing values were accounted for, faster feed increments remain more costly in comparison to slower feed increments but at a slightly higher level (£378 more) per infant, reflecting the high level of uncertainty in the difference in costs, especially with regard to the healthcare resource use after discharge estimated by the multiple imputation” (last paragraph of methods))
2. In relation to the authors second concern, whilst death was slightly higher in the slower feeds arm during initial hospital stay there are two important points in response to this. First, we clarify that by definition economic analysis is not an exercise in accountancy where death is assumed to incur a zero cost, because economic evaluation focuses on costs and ou...
We thank the authors for the comments on the Economic Evaluation of SIFT (1) and we are grateful for the opportunity to respond to their comments.
Taking each of the authors’ points in the order in which they are presented:
1. In relation to the first point about the loss to follow up and the exclusion of such patients from the analysis, we point out that we used complete case analysis and accounted for the missing patients following best practice using a multiple imputation analysis which is provided in the supplementary materials. We state the following in the paper:
“Mean total costs for all infants, adjusting for missing data using multiple imputation, are found in the online supplementary table S3. When the missing values were accounted for, faster feed increments remain more costly in comparison to slower feed increments but at a slightly higher level (£378 more) per infant, reflecting the high level of uncertainty in the difference in costs, especially with regard to the healthcare resource use after discharge estimated by the multiple imputation” (last paragraph of methods))
2. In relation to the authors second concern, whilst death was slightly higher in the slower feeds arm during initial hospital stay there are two important points in response to this. First, we clarify that by definition economic analysis is not an exercise in accountancy where death is assumed to incur a zero cost, because economic evaluation focuses on costs and outcomes together in a ratio. Thus, death causes a severe penalty in the denominator of the analysis as fewer survivors in the denominator means the cost effectiveness is less favorable ( eg. Dividing an integer by a zero gives a result tending to infinity). Second, death alone was not the primary outcome. The primary outcome was neurodevelopmental disability at aged 2, since surviving with severe disability will incur substantial cost.
3. With respect to point 3, we refer to the response to point one - in accordance with best practice multiple imputation was carried out to account for missing data.
4. We do not exclude the parental nutrition costs - these are presented in the first line of Table 1 and are supported by the reference of Walter et al. (see reference 28) in the paper (1)
5. In terms of generalizability, whilst the transferability of healthcare resource use and costs will be affected by differences in clinical practice and relative prices across countries, varying costs alone may not be sufficient (2).
Finally, whilst our paper concluded that SIFT would not be deemed cost- effective, that result was not driven by the costs alone. The clinical paper showed no statistical difference in the primary outcome of survival without moderate or severe disability (3). The recommended approach to economic evaluation is not to use statistical significance but to estimate and quantify the uncertainty that is implied using simulation techniques. Following these techniques the analysis suggested that the Sift intervention of faster feeds had potential to be harmful as reported in the paper. To assume that the results of the paper are driven by cost is to misunderstand health economics and the definition of cost-effectiveness which is not based on cost alone but a ratio of the difference in costs divided by the difference in effects.
Yours sincerely
Tracy Roberts On behalf of all co authors
Sift authorship
References:
1. Tahir W, Monahan M, Dorling J, et al. Economic evaluation alongside the Speed of Increasing milk Feeds Trial (SIFT). Arch Dis Child Fetal Neonatal Ed. 2020 Nov;105(6):587-592. doi: 10.1136/archdischild-2019-318346.
2. Drummond M, Barbieri M, Cook J, Glick HA, Lis J, Malik F, et al. Transferability of economic evaluations across jurisdictions: ISPOR Good Research Practices Task Force report. Value in health. 2009; 12 (4):409–18. https://doi.org/10.1111/j.1524-4733.2008.00489.x PMID: 19900249).
3. Dorling J, Abbott J, Berrington J, et al; SIFT Investigators Group. Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants. N Engl J Med. 2019 Oct 10;381(15):1434-1443. doi: 10.1056/NEJMoa1816654.
Thanks for this excellent focus on visual abilities of infants following HIE.
More than three decades ago, at a time when brain imaging of newborns with HIE was limited to ultrasound and CT scanning, we have published impairments of visual functions at an early age (Early Hum Dev 1989;20:267-279 and Neuropediatrics 1990;21:76-78) .
We could do so using standardized, outpatient methods of visual assessment.
Further use of this relatively simple tools could and should be part of assessments of infants with HIE, in particular when (diffusion weighted) MRI indicates involvement of visual tracts.
We thank Dr. Khashu for his comments on our article Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences.
Below we provide responses to his comments.
1. The review is suggesting significant change to current UK practice but does not review any data to suggest that current practice is causing secondary hyperparathyroidism ( apart from an anecdotal case discussed). While the recommendations may have merit based on physiology , it seems suboptimal to recommend a significant change of practice without any data to clearly show that current practice is causing a problem.
Response: Our suggested approach on management of Metabolic Bone Disease of Prematurity (MBDP) is underpinned by pathophysiology of this disorder. The case discussed is not an anecdotal case but represents many such cases referred to our service. In all age groups calcipaenic state (Calcium deficiency) causes increase in PTH secretion while phosphopaenic states (inadequate Phosphate absorption from diet or primary urinary phosphate leak) do not. Therefore our approach is to measure PTH to guide mineral supplementation and more specifically to maintain appropriate oral Calcium (Ca) to Phosphate (PO4) ratio for adequate mineralisation of bones. It is our observation that PTH is not routinely measured in MBDP but, there are publications where PTH has been measured...
We thank Dr. Khashu for his comments on our article Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences.
Below we provide responses to his comments.
1. The review is suggesting significant change to current UK practice but does not review any data to suggest that current practice is causing secondary hyperparathyroidism ( apart from an anecdotal case discussed). While the recommendations may have merit based on physiology , it seems suboptimal to recommend a significant change of practice without any data to clearly show that current practice is causing a problem.
Response: Our suggested approach on management of Metabolic Bone Disease of Prematurity (MBDP) is underpinned by pathophysiology of this disorder. The case discussed is not an anecdotal case but represents many such cases referred to our service. In all age groups calcipaenic state (Calcium deficiency) causes increase in PTH secretion while phosphopaenic states (inadequate Phosphate absorption from diet or primary urinary phosphate leak) do not. Therefore our approach is to measure PTH to guide mineral supplementation and more specifically to maintain appropriate oral Calcium (Ca) to Phosphate (PO4) ratio for adequate mineralisation of bones. It is our observation that PTH is not routinely measured in MBDP but, there are publications where PTH has been measured and was found to be useful, both in diagnosis and management of MBDP1-5. Besides us Moreira et al have also demonstrated usefulness of PTH measurement and treatment using oral calcium supplements2. Oral phosphate supplementation reduces ionized calcium and therefore increases parathyroid hormone concentration. This pathophysiological concept is further elucidated in recent published case in Archives of Disease in Childhood education and practice section where pharmacological dose of oral phosphate in MBDP caused hypocalcaemia6. Our advice is to maintain oral Ca to PO4 ratio as unopposed supplementation with PO4 can cause secondary hyperparathyroidism and worsening of MBDP.
2. The review recommends measurement of plasma parathromone as a critical initial step and most of the subsequent practice is dictated by this. The authors state “measurement of plasma PTH both for screening and diagnosis is crucially important". In the very next line they however state "the reference range of plasma PTH in neonates is not well established" They then go to talk about a very small study of 20 preterm neonates. It does not make much sense to recommend a major change of practice without any data to back it up and then highlight plasma PTH as a critical investigation for decision making when we don't really have any robust normative data. Should we not instead be generating prospective data based on current practice and if there is evidence of secondary hyperparathyroidism to change treatment accordingly? Also should we not be generating normative data for various gestations and postnatal ages to be confident about the plasma PTH values?
Response: We agree that data on normal ranges of PTH in preterm infants was derived from 20 preterm neonates but, with 134 separate measurements7. This study is well conducted and in healthy neonates, PTH concentration using third-generation immunoassays demonstrated values similar to adult reference ranges with authors concluding that values above this should be considered as secondary hyperparathyroidism. Unlike serum PO4, Ca concentration is tightly maintained within a narrow range in all age groups and it would therefore appear that PTH, which is the primary hormone for Ca homeostasis, is also maintained within the normal range in all age groups. We believe therefore that current reference ranges of PTH in combination with measurement of serum Ca, PO4 and Alkaline Phosphatase are sensitive indicator of MBDP and will allow us to guide management with appropriate mineral supplementation. Of course a larger study will be most welcome specially looking at various gestational ages and corrected ages in premature infants taking into consideration infant’s dietary Ca intake and serum Vitamin D concentration.
3. In figure 1, the first part shows a right humerus at 3 months of age but the subsequent picture at 5 months which supposedly is to demonstrate healing following vitamin D and calcium therapy is of the left arm. Before and after pics ideally need to be same side and similar resolution to clearly demonstrate the change.
Response: The purpose of these images was to demonstrate consequences of secondary hyperparathyroidism when Ca to PO4 mineral ratio is not maintained. These manifestations are generalised and affects all long bones of infant. Through these images we have demonstrated improvement in bone mineralisation, healing of periosteal elevation and rickets following treatment with oral calcium and vitamin D supplementation. Even though, these images are of different arms, healing of above manifestations of MBDP are clearly demonstrated.
4. We don’t know what proportion of such preterms have secondary hyperparathyroidism and the case discussed in your paper may be a small minority. Rather than advising a significant change of practice would it not be more appropriate to actually prove presence or absence of sec hyperparathyroidism in a larger dataset and develop normative values for PTH for various gestations/postnatal age ranges etc?
Response: Please also refer to our response to comment 2. We agree that a larger dataset in preterm neonates would be appropriate. Given challenges of undertaking this study in sick preterm infants, we would have to rely on above mentioned well conducted study7 which has demonstrated that adult normative ranges are applicable in preterm neonates. In our clinical practise we have always found measurement of PTH extremely useful in diagnosis and monitoring of treatment in all cases of MBDP. Our clinical approach of maintaining oral Ca to PO4 ratio in management of rickets has allowed normalisation of serum PTH, PO4 and ALP, healing of rickets and prevented secondary hyperparathyroidism and associate complications such as hypocalcaemia and fractures.
References:
Lothe A, Sinn J, Stone M. Metabolic bone disease of prematurity and secondary hyperparathyroidism. J Paediatr Child Health. 2011;47(8):550–553.
Moreira A, February M, Geary C. Parathyroid hormone levels in neonates with suspected osteopenia. J Paediatr Child Health. 2013;49(1):E12–E16.
Yes¸iltepe Mutlu G, Kırmızıbekmez H, Ozsu E, et al. Metabolic bone disease of prematurity: report of four cases. J Clin Res Pediatr Endocrinol. 2014;6(2):111–115.
Dowa Y, Kawai M, Kanazawa H, et al. Screening for secondary hyperparathyroidism in preterm infants. Pediatr Int. 2016;58(10):988–992.
Patel M, Housley D, Ossuetta I. Serial serum parathormone (PTH) as a marker for monitoring metabolic bone disease of prematurity. Arch Dis Child. 2008;93:ps323.
Liddicoat INM, Tighe MP. Supplementation in hypophosphataemic rickets: the bare bones of management. Arch Dis Child Educ Pract Ed 2019;104:207-210. Matejek T ,
Navratilova M , Zaloudkova L , et al. Parathyroid hormone - reference values and association with other bone metabolism markers in very low birth weight infants - pilot study. J Matern Fetal Neonatal Med 2018:1–8.
In response to: "Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia".
We read with great interest the article by Dr Woods et al (1) that adds evidence to recent, large multicenter studies on lung ultrasound (LUS) as a predictive tool for bronchopulmonary dysplasia (BPD) (2-4). These studies, performed on a total of more than 600 infants, stem from a validated scoring system whose signs represent a progressive decrease in lung aeration in standardized ultrasound views (5). Notably, this approach is also well established in adult critical care (6).
The grading system adopted by Dr Woods and coworkers, has not been validated and its highest scores do not correspond to less air in the lung and therefore to a more severe pulmonary disease. Also, rather than the conventional sum of scores, Dr Woods et al. calculate a two-decimals mean score that may undermine the technique discrimination. None of these choices have ever been made for any other LUS scores, neither in neonates nor in older patients, despite ultrasound semiology and statistics needed to evaluate the predictive power are always the same (6). These factors may undermine the LUS prediction power for BPD.
Moreover, the authors needed a full ROC procedure to perform a formal diagnostic accuracy analysis, but even then, its strength would have been questionable with only 7 out 96 infants suffering from moderate-to-severe BPD (7) as target condition. This smal...
In response to: "Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia".
We read with great interest the article by Dr Woods et al (1) that adds evidence to recent, large multicenter studies on lung ultrasound (LUS) as a predictive tool for bronchopulmonary dysplasia (BPD) (2-4). These studies, performed on a total of more than 600 infants, stem from a validated scoring system whose signs represent a progressive decrease in lung aeration in standardized ultrasound views (5). Notably, this approach is also well established in adult critical care (6).
The grading system adopted by Dr Woods and coworkers, has not been validated and its highest scores do not correspond to less air in the lung and therefore to a more severe pulmonary disease. Also, rather than the conventional sum of scores, Dr Woods et al. calculate a two-decimals mean score that may undermine the technique discrimination. None of these choices have ever been made for any other LUS scores, neither in neonates nor in older patients, despite ultrasound semiology and statistics needed to evaluate the predictive power are always the same (6). These factors may undermine the LUS prediction power for BPD.
Moreover, the authors needed a full ROC procedure to perform a formal diagnostic accuracy analysis, but even then, its strength would have been questionable with only 7 out 96 infants suffering from moderate-to-severe BPD (7) as target condition. This small number of patients with the target disease reduces the diagnostic accuracy of any exam performed for an early prediction.
Finally, we agree with Dr Woods and colleagues that LUS is not a silver bullet, but adequate methodology should be followed to investigate it. According to data produced with this methodology LUS has a significant power for BPD prediction.
REFERENCES
1. Woods PL, Stoecklin B, Woods A, Gill AW. Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed. 2021 May 14;fetalneonatal-2020-320830.
2. Raimondi F, Migliaro F, Corsini I, Meneghin F, Dolce P, Pierri L, et al. Lung Ultrasound Score Progress in Neonatal Respiratory Distress Syndrome. Pediatrics. 2021 Apr;147(4):e2020030528.
3. Alonso-Ojembarrena A, Serna-Guerediaga I, Aldecoa-Bilbao V, Gregorio-Hernández R, Alonso-Quintela P, Concheiro-Guisán A, et al. The Predictive Value of Lung Ultrasound Scores in Developing Bronchopulmonary Dysplasia. Chest. 2021 Mar;S0012369221004682.
4. Loi B, Vigo G, Baraldi E, Raimondi F, Carnielli VP, Mosca F, et al. Lung Ultrasound to Monitor Extremely Preterm Infants and Predict BPD: Multicenter Longitudinal Cohort Study. Am J Respir Crit Care Med. 2020 Dec 22;rccm.202008-3131OC.
5. Brat R, Yousef N, Klifa R, Reynaud S, Shankar Aguilera S, De Luca D. Lung Ultrasonography Score to Evaluate Oxygenation and Surfactant Need in Neonates Treated With Continuous Positive Airway Pressure. JAMA Pediatr. 2015 Aug;169(8):e151797. doi: 10.1001/jamapediatrics.2015.1797.
6. Mongodi S, De Luca D, Colombo A, Stella A, Santangelo E, Corradi F, Gargani L, Rovida S, Volpicelli G, Bouhemad B, Mojoli F. Quantitative Lung Ultrasound: Technical Aspects and Clinical Applications. Anesthesiology. 2021 Jun 1;134(6):949-965. doi: 10.1097/ALN.0000000000003757.
7. Higgins RD, Jobe AH, Koso-Thomas M, Bancalari E, Viscardi RM, Hartert TV, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. The Journal of Pediatrics. 2018 Jun;197:300–8.
We have read with interest the response by Dr. Shabih Manzar on our article. The Thompson score is a clinical score consisting of nine items that are associated with neurologic dysfunction to assess the severity of neonatal encephalopathy (NE) in infants with perinatal asphyxia.[1] There are indeed important limitations that need to be considered; the assessment of infants by use of the Thompson score requires interpretation from the examiner, and the degree of NE may change over time.[2] It should be noted that these limitations are also applicable to other clinical grading tools, such as the modified Sarnat score, which is being widely applied to select infants for therapeutic hypothermia.[2,3] We would like to emphasize that the majority of the infants described in this study was born in a level-II-hospital. Amplitude-integrated electroencephalography (aEEG), another tool to select infants for therapeutic hypothermia, allows continuous monitoring, expert revision and the detection of subclinical seizures, but also requires well-trained staff for correct interpretation and is often not available in these hospitals. By design, the Thompson score did not require extensive training of the observer, which is why it is suitable to be used in smaller hospitals.[1] In a previous study, our study group demonstrated that the Thompson score and aEEG had a similar predictive value for an adverse outcome.[4] We however completely agree with Dr. Manzar that it is of concern that the...
Show MoreThe article by Parmentier et al [1] highlights the role of Amplitude-integrated electroencephalography (aEEG) and early biomarkers in selecting infants for therapeutic hypothermia (TH). They also suggested the role of the Thompson score (TS) in asphyxiated infants. The problem with TS is that it is subjective. It consists of nine clinical signs: tone, level of consciousness, fits, posture, moro reflex, grasp, suck, respiration, and fontanelle, which could change over time [2]. Also, in the data presented by Parmentier et al [1], twenty-one (53%) infants did not have TS performed.
It was surprising to note that four cases that had moderate neonatal encephalopathy (NE) were not treated with TH despite having seizures within the first 6 hours. The reason for not treatment was rapid recovery. What was the definition of rapid recovery? According to the published flow diagram for NE, the onset of seizure within 6 hours warrants TH [3].
The definition of perinatal asphyxia used by Parmentier et al [1] was from a study in 2003 [4]. It was defined as an arterial cord blood pH <7.1, Apgar Score <7 at 5 min, or need for neonatal resuscitation. While the analysis was done with pH of < 7 and > 7 [(Table 1) 1]. A pH of 7.1 and Apgar of 7 at 5 min is higher than the definition/criteria used in the TH trial [5].
References:
1. Parmentier CEJ, Steggerda SJ, Weeke LC, Rijken M, De Vries LS, Groenendaal F. Outcome of non-cooled asphyxiated infants w...
Show MoreI agree with Yieh et al [1] that there is an overuse of therapeutic hypothermia (TH) in mild HIE resulting in increased resource utilization. The two main reasons we see this practice are the fear of litigation and scare that infant would later have neurological problems. DuPont et al [2] reported abnormal short-term neurologic outcomes in 20% of newborns with perinatal acidemia and mild HIE not treated with TH. However, in the same study they had 14% of infants that did not receive TH despite the neurological examination consistent with moderate and severe HIE.
Show MoreMehta et al [3] have earlier described overutilization of TH in mild HIE, recommending a robust review of the eligibility criteria definitions, especially the 10-min Apgar score. The subjectivity of TH criteria put the practitioner in a decision dilemma. For example, out of five components of Apgar score, only heart rate assessment is objective. A color score of 1 or 2 can change the Apgar from 5 to 6. Similarly, a slight variation in observer examination in obtaining Sarnat score could change it from mild to moderate. Therefore, using a combination of factors in deciding about TH would be a better approach [4].
One of the most important criterion for TH is presence of perinatal academia. Recently, Blecharczyk et al [5] have shown the benefits of standardized screening pathway for evaluating abnormal cord gases in neonates at risk for HIE. Following a structured pathway resulted in minimizing unnecess...
In this study Selvanathan et al [1] showed small birth head circumference (HC) to be associated with poorer neurodevelopment outcome, independent of postnatal illness and white matter injury. They concluded that normalisation of HC during NICU care appears to moderate this risk.
It was interesting to note that normal/small group had the highest chorioamnionitis (40%), lowest ROP (0) and highest NEC (30%) rates. They also received the highest Energy (kcal/kg/day), median 80. What could be the reason for the HC to regress from normal to small?
We need to investigate other factors that affect the head growth. The individual factors such as parental bonding and availability, environmental exposure to noise, light and other stimuli may have some role in slowing the head growth.
Interestingly, in the same issue of ADC, Ni et al [2] have shown poor HC growth in EPICure2 that was unchanged from EPICure, which is alarming.
1. Selvanathan T, Guo T, Kwan E, et al. Head circumference, total cerebral volume and neurodevelopment in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2022;107(2):181-187. doi:10.1136/archdischild-2020-321397
2. Ni Y, Lancaster R, Suonpera E, et al. Growth in extremely preterm children born in England in 1995 and 2006: the EPICure studies. Arch Dis Child Fetal Neonatal Ed. 2022;107(2):193-200. doi:10.1136/archdischild-2020-321107
Kamupira et al [1] presented a case of umbilical venous line extravasation that was confirmed by contrast study. To justify the contrast use they stated, “There is evidence routine contrast use in checking tip positions improves long line positioning (reference 3 on the paper) and British Association of Perinatal Medicine (BAPM) has included this in it's central access guidance (reference 4 on the paper)”. The caveats with this statement are that first umbilical lines are not synonymous to long lines and second that in BAPM executive summary statement there is no mention of contrast use, “The findings of the Working Group recommend that:
Show More• Any clinical deterioration of a baby in whom a central venous catheter is present should raise the question of catheter-related complications, particularly infection, extravasation and tamponade.
• All central catheter tips should be positioned outside the cardiac silhouette.
• An umbilical venous catheter (UVC) tip should ideally be sited at T8-T9 (assuming this lies outside the cardiac silhouette). A UVC tip sited at or below T10 carries a significantly higher risk of extravasation. It may be necessary to use these catheters in the short term, but they should be replaced at the earliest opportunity”.
In fact, the use of contrast has been associated with hypothyroidism in neonates [2]. UVC misplacements happen either due to the wrong placement or due to the migration of UVC from a safe to wrong position. Th...
We read with great interest this article published by Chandran et al. However, we have some critical
Show Morereservations on implementation of low dose diazoxide. The target blood glucose thresholds used for
management have been taken from Pediatric endocrine society guidelines of 2015, which are based
on adult neuroglycopenic effects. However, AAP guidelines recommend a lower treatment target of
<2.2 mmol/l (40 mg/dl) for asymptomatic,<2.5 mmol/l (45 mg/dl) for symptomatic neonates
during first 48 hours and <3.3 mmol/l (60mg/dl) thereafter (1, 2) . Moreover, in a recent multi-centric
trial published by Kempen et al; it was concluded that low treatment threshold of <2 mmol/l (36
mg/dl) was non inferior in terms of neurodevelopmental outcomes at 18 months of age in healthy
asymptomatic neonates (3) . Hence it is still debatable whether all the neonates being managed for
hypoglycemia warranted an intravenous glucose infusion therapy and diazoxide.
Authors have used a combination of starting dose of diazoxide along with hydrochlorothiazide for
management of SGA neonates; which are known to have a synergistic effect on increasing blood
glucose levels, hence actual dose of diazoxide required if used alone could have been potentially
higher in these neonates.
In the study design the authors have mentioned that this was an observational cohort study,
however neither the absence of compar...
We thank the authors for the comments on the Economic Evaluation of SIFT (1) and we are grateful for the opportunity to respond to their comments.
Taking each of the authors’ points in the order in which they are presented:
1. In relation to the first point about the loss to follow up and the exclusion of such patients from the analysis, we point out that we used complete case analysis and accounted for the missing patients following best practice using a multiple imputation analysis which is provided in the supplementary materials. We state the following in the paper:
“Mean total costs for all infants, adjusting for missing data using multiple imputation, are found in the online supplementary table S3. When the missing values were accounted for, faster feed increments remain more costly in comparison to slower feed increments but at a slightly higher level (£378 more) per infant, reflecting the high level of uncertainty in the difference in costs, especially with regard to the healthcare resource use after discharge estimated by the multiple imputation” (last paragraph of methods))
2. In relation to the authors second concern, whilst death was slightly higher in the slower feeds arm during initial hospital stay there are two important points in response to this. First, we clarify that by definition economic analysis is not an exercise in accountancy where death is assumed to incur a zero cost, because economic evaluation focuses on costs and ou...
Show MoreDear authors, dear editors,
Thanks for this excellent focus on visual abilities of infants following HIE.
More than three decades ago, at a time when brain imaging of newborns with HIE was limited to ultrasound and CT scanning, we have published impairments of visual functions at an early age (Early Hum Dev 1989;20:267-279 and Neuropediatrics 1990;21:76-78) .
We could do so using standardized, outpatient methods of visual assessment.
Further use of this relatively simple tools could and should be part of assessments of infants with HIE, in particular when (diffusion weighted) MRI indicates involvement of visual tracts.
With kind regards,
Floris Groenendaal
Dear Editors,
Archives of Disease in Childhood
We thank Dr. Khashu for his comments on our article Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences.
Below we provide responses to his comments.
1. The review is suggesting significant change to current UK practice but does not review any data to suggest that current practice is causing secondary hyperparathyroidism ( apart from an anecdotal case discussed). While the recommendations may have merit based on physiology , it seems suboptimal to recommend a significant change of practice without any data to clearly show that current practice is causing a problem.
Response: Our suggested approach on management of Metabolic Bone Disease of Prematurity (MBDP) is underpinned by pathophysiology of this disorder. The case discussed is not an anecdotal case but represents many such cases referred to our service. In all age groups calcipaenic state (Calcium deficiency) causes increase in PTH secretion while phosphopaenic states (inadequate Phosphate absorption from diet or primary urinary phosphate leak) do not. Therefore our approach is to measure PTH to guide mineral supplementation and more specifically to maintain appropriate oral Calcium (Ca) to Phosphate (PO4) ratio for adequate mineralisation of bones. It is our observation that PTH is not routinely measured in MBDP but, there are publications where PTH has been measured...
Show MoreIn response to: "Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia".
We read with great interest the article by Dr Woods et al (1) that adds evidence to recent, large multicenter studies on lung ultrasound (LUS) as a predictive tool for bronchopulmonary dysplasia (BPD) (2-4). These studies, performed on a total of more than 600 infants, stem from a validated scoring system whose signs represent a progressive decrease in lung aeration in standardized ultrasound views (5). Notably, this approach is also well established in adult critical care (6).
Show MoreThe grading system adopted by Dr Woods and coworkers, has not been validated and its highest scores do not correspond to less air in the lung and therefore to a more severe pulmonary disease. Also, rather than the conventional sum of scores, Dr Woods et al. calculate a two-decimals mean score that may undermine the technique discrimination. None of these choices have ever been made for any other LUS scores, neither in neonates nor in older patients, despite ultrasound semiology and statistics needed to evaluate the predictive power are always the same (6). These factors may undermine the LUS prediction power for BPD.
Moreover, the authors needed a full ROC procedure to perform a formal diagnostic accuracy analysis, but even then, its strength would have been questionable with only 7 out 96 infants suffering from moderate-to-severe BPD (7) as target condition. This smal...
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