Dear Editor,
We read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that...
Dear Editor,
We read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that found insufficient evidence supporting the routine use of therapeutic hypothermia in NE. According to our results, we need high quality and stronger RCTs to improve the knowledge on an important topic.
References
1. Kariholu U, Montaldo P, Markati T, et al. Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and meta-analysis. Archives of Disease in Childhood - Fetal and Neonatal Edition 2020;105:225-228
2. Ridgeon EE, Young PJ, Bellomo R, et al. The Fragility Index in multicenter randomized controlled critical care trials. Crit Care Med 2016;44:1278–1284
3. Vargas M, Servillo G. The End of Corticosteroid in Sepsis: Fragile Results From Fragile Trials. Crit Care Med 2018 46:e1228
4. Vargas M, Servillo G. Liberal versus conservative oxygen therapy in critically ill patients: using the fragility index to determine robust results. Crit Care 2019;23:132
5. Vargas M, Buononanno P, Marra A et al. Fragility Index in Multicenter Randomized Controlled Trials in Critical Care Medicine That Have Shown Reduced Mortality. Crit Care Med. 2020;48:e250-e251
All of these extubation-readyness tests assess respiratory drive / lungs. However, it may be for many preterms that they struggle to maintain their airway despite good drive and lungs that are relatively healthy. This aspect can't be tested and could explain why so many infants who seem able to breath don't do so once the ETT has been taken out.
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3),...
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3), and speculated that this was due to lack of sedation. On the other hand, Gunn et al. demonstrated significant improvement in neuropathology scores in fetal lambs cooled for 72 hours without sedation compared with those that were not(4).
Secondary analysis from the National Institute of Child Health and Human Development (NICHD) (5)and Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE) (6)studies examined the effect of sedation in term infants during therapeutic hypothermia. Routine sedation was not associated with neuroprotection, but increased the hospital stay.
There are many difficulties in quantifying pain in neonates undergoing therapeutic hypothermia. Often shivering is equated to stress, which may only indicate depletion of brown fat(7). Clinicians tend to use sedation to stop shivering, although the evidence to support this practice is unclear(8). We are only suggesting that the jury is still out on pre-emptive opioid sedation during therapeutic hypothermia, and at present, it is unclear whether this practice beneficial or harmful. This issue can be answered only by developing better markers for quantifying stress in infants with encephalopathy and rigorously evaluating the safety and efficacy of opioid therapy during therapeutic hypothermia in clinical trials.
References
1. Anand KJ, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet (London, England) 2004; 363(9422): 1673-82.
2. Montaldo P, Vakharia A, Ivain P, et al. Pre-emptive opioid sedation during therapeutic hypothermia. Archives of disease in childhood Fetal and neonatal edition 2020; 105(1): 108-9.
3. Thoresen M, Satas S, Loberg EM, et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatric research 2001; 50(3): 405-11.
4. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. The Journal of clinical investigation 1997; 99(2): 248-56.
5. Natarajan G, Shankaran S, Laptook AR, et al. Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy. Journal of perinatology : official journal of the California Perinatal Association 2018; 38(8): 1060-7.
6. Liow N, Montaldo P, Lally PJ, et al. Preemptive Morphine During Therapeutic Hypothermia After Neonatal Encephalopathy: A Secondary Analysis. Therapeutic hypothermia and temperature management 2019.
7. Hu HH, Wu TW, Yin L, et al. MRI detection of brown adipose tissue with low fat content in newborns with hypothermia. Magnetic resonance imaging 2014; 32(2): 107-17.
8. Pitoni S, Sinclair HL, Andrews PJ. Aspects of thermoregulation physiology. Current opinion in critical care 2011; 17(2): 115-21.
Sir,
In their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the...
Sir,
In their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the risk of drug accumulation by using novel dosing recommendations.
References
1. Favie LMA, Groenendaal F, van den Broek MPH, et al. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia. PLoS One 2019;14(2):e0211910.
2. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;1(8527):243-8.
3. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326(1):1-9.
4. May TL, Seder DB, Fraser GL, et al. Moderate-dose sedation and analgesia during targeted temperature management after cardiac arrest. Neurocrit Care 2015;22(1):105-11.
Floris Groenendaal and Richard van Lingen, 7 January 2020
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
In their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestati...
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
In their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestation.[5]
Undoubtedly, neurological development is a multi-factorial process with a multitude of influencing factors. The above described clear association between neonatal sepsis and neurological sequelae from previous studies is not only contrary to the results by Baud et al.[1], but further emphasizes the significance of their findings from the PREMILOC trial. As the authors had not discussed this relevant issue in their publications,[1] we would like to point that out.
REFERENCES
1. Baud O, Trousson C, Biran V, et al. Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth. Arch Dis Child Fetal Neonatal Ed 2019;104(1):F30–5. doi: 10.1136/archdischild-2017-313756.
2. Baud O, Maury L, Lebail F, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet 2016;387(10030):1827–36. doi: 10.1016/S0140-6736(16)00202-6.
3. Alshaikh B, Yusuf K, Sauve R. Neurodevelopmental outcomes of very low birth weight infants with neonatal sepsis: systematic review and meta-analysis. J Perinatol 2013;33:558–64. doi: 10.1038/jp.2012.167.
4. Mitha A, Foix-L'Hélias L, Arnaud C, et al. Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants. Pediatrics 2013;132:e372–80. doi: 10.1542/peds.2012-3979.
5. Alshaikh B, Yee W, Lodha A, et al. Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome. J Perinatol 2014;34:125–9. doi: 10.1038/jp.2013.155.
Dear Editor
We read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early...
Dear Editor
We read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early stage the very few who develop sepsis(7, 8).
References:
1. Goel N, Shrestha S, Smith R, et al. Screening for early onset neonatal sepsis: NICE guidance-based practice versus projected application of the Kaiser Permanente sepsis risk calculator in the UK population. Arch Dis Child Fetal Neonatal Ed. 2019 Online First Jul 11. DOI: 10.1136/archdischild-2018-316777.
2. Puopolo KM, Benitz WE, Zaoutis TE. AAP Committee on Fetus and Newborn, AAP Committee on Infectious Diseases. Management of Neonates Born at ≥35 0/7 Weeks’ Gestation with Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2018;142(6):e20182894
3. Mukhopadhyay S, Puopolo KM. Risk assessment in neonatal early onset sepsis. Semin Perinatol. 2012 Dec; 36(6):408-15.
4. Benitz W.E., Han M.Y., Madan A., et al: Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998; 102: E41.
5. Benitz WE. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin Perinatol. 2010;37: 421–438.
6. Neonatal infection (early onset): antibiotics for prevention and treatment. Clinical guideline [CG149]. Published August 2012.https://www.nice.org.uk/guidance/cg149/evidence/full-guideline-pdf-18817....
7. Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, et al. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr.2017 Apr 1;171(4):365-371.
8. Berardi A, Tzialla C, Travan L et al. Secondary prevention of early-onset sepsis: a less invasive Italian approach for managing neonates at risk. Ital J Pediatr. 2018; 44: 73
We were impressed by the conduct and results of Reynolds et al.’s randomised controlled cross-over trial comparing Vapotherm’s IntellO2 device with manual control of inspired oxygen, showing improvement in the proportion of time spent within the target oxygen saturation range (automated arm mean 80% of time in 90-95% range vs. manual 49%). The findings are consistent with a meta-analysis referenced within their paper [1].
The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) shows that targeting oxygen saturations of 91–95% with an oximeter with a correctly configured algorithm, carries a 38% survival advantage [2]. The co-ordinator of the NeOProM collaboration has stated that the “Infants born extremely preterm … should have their oxygen saturation levels targeted between 91% and 95%” [3].
The difference between the saturation targeting approach adopted by Reynolds et al., and NeOProM may appear small but, on account of the sigmoidal shape of the haemoglobin–oxygen dissociation curve, significant hypoxic shifts will occur with small changes in oxygen saturation.
Given the rigor of the NeOProM findings, would Reynolds et al. agree that targeting oxygen saturations of 91-95% is an important first step, whilst we wait for products which will allow improved titration of oxygen delivery?
References:
[1] Mitra S, Singh B, El-Naggar W, McMillan DD. Automated versus manual control of inspired oxygen to target oxygen saturation in prete...
We were impressed by the conduct and results of Reynolds et al.’s randomised controlled cross-over trial comparing Vapotherm’s IntellO2 device with manual control of inspired oxygen, showing improvement in the proportion of time spent within the target oxygen saturation range (automated arm mean 80% of time in 90-95% range vs. manual 49%). The findings are consistent with a meta-analysis referenced within their paper [1].
The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) shows that targeting oxygen saturations of 91–95% with an oximeter with a correctly configured algorithm, carries a 38% survival advantage [2]. The co-ordinator of the NeOProM collaboration has stated that the “Infants born extremely preterm … should have their oxygen saturation levels targeted between 91% and 95%” [3].
The difference between the saturation targeting approach adopted by Reynolds et al., and NeOProM may appear small but, on account of the sigmoidal shape of the haemoglobin–oxygen dissociation curve, significant hypoxic shifts will occur with small changes in oxygen saturation.
Given the rigor of the NeOProM findings, would Reynolds et al. agree that targeting oxygen saturations of 91-95% is an important first step, whilst we wait for products which will allow improved titration of oxygen delivery?
References:
[1] Mitra S, Singh B, El-Naggar W, McMillan DD. Automated versus manual control of inspired oxygen to target oxygen saturation in preterm infants: a systematic review and meta-analysis. Journal of Perinatology. 2018; 38, 351–360 doi:10.1038/s41372-017-0037-z
[2] Askie LM, Darlow BA, Finer N, et al. Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-Analysis Collaboration [published correction appears in JAMA. 2018 Jul 17;320(3):308]. JAMA. 2018;319(21):2190–2201. doi:10.1001/jama.2018.5725
[3] Askie LM., Meta-analysis of Oxygenation Saturation Targeting Trials Do Infant Subgroups Matter? Clin Perinatol 2019 doi.org/10.1016/j.clp.2019.05.003
Thank you for an interesting case but the position of the arterial catheter after the perforation suggests to me that this was from an umbilical artery rather than the aorta (compare the path on the abdominal wall on the 2 x-rays).
This may therefore be why you were able to successfully manage this conservatively.
We kindly thank Da Lozzo et al. for their reaction to our paper. Indeed, many variables may be of influence on the incidence of thrombosis in our study group.
The authors are correct that the incidence of necrotizing enterocolitis in our study group (12.5%, 5/40) is higher than expected based on literature. As shown by Battersby et al. comparing NEC incidences internationally is challenging (1). The incidence of NEC in our study group does not reflect the NEC incidence of last 15 years at our department (which was 3.7% (98/2626) in infants with a gestational age <32 weeks). Possibly, the higher incidence of NEC led to a higher incidence of thrombosis in our study. However, care should be taken when interpreting our results due to the small sample size (n=40).
Da Lozzo et al. make a valuable point about the diameter of central venous catheters. Most (25/40) umbilical venous catheters (UVCs) used in our study-group were 4Fr Vygon catheters, single or double lumen, with an external diameter of 1.5 and 1.4 mm, respectively (strange enough double lumen is smaller than single lumen). In 3/40 infants 5Fr Vygon catheters (external diameter 1.7 mm) were used and in 10/40 infants 3.5Fr Vygon catheters (external diameter 1.16 mm). In 2/40 infants the size of the catheter was not registered. We found no association between the risk of thrombosis and the size of the catheter (p=0.59). However, as stated in the discussion of our paper, the sample size of our group is too...
We kindly thank Da Lozzo et al. for their reaction to our paper. Indeed, many variables may be of influence on the incidence of thrombosis in our study group.
The authors are correct that the incidence of necrotizing enterocolitis in our study group (12.5%, 5/40) is higher than expected based on literature. As shown by Battersby et al. comparing NEC incidences internationally is challenging (1). The incidence of NEC in our study group does not reflect the NEC incidence of last 15 years at our department (which was 3.7% (98/2626) in infants with a gestational age <32 weeks). Possibly, the higher incidence of NEC led to a higher incidence of thrombosis in our study. However, care should be taken when interpreting our results due to the small sample size (n=40).
Da Lozzo et al. make a valuable point about the diameter of central venous catheters. Most (25/40) umbilical venous catheters (UVCs) used in our study-group were 4Fr Vygon catheters, single or double lumen, with an external diameter of 1.5 and 1.4 mm, respectively (strange enough double lumen is smaller than single lumen). In 3/40 infants 5Fr Vygon catheters (external diameter 1.7 mm) were used and in 10/40 infants 3.5Fr Vygon catheters (external diameter 1.16 mm). In 2/40 infants the size of the catheter was not registered. We found no association between the risk of thrombosis and the size of the catheter (p=0.59). However, as stated in the discussion of our paper, the sample size of our group is too small to confirm the influence of risk factors, such as catheter size. As suggested by Barone et al. (2), the external diameter of the catheter should not exceed 1/3 of the internal diameter of the vein to reduce the risk of thrombosis. Since the most frequently used catheter in our study was a double-lumen 4Fr catheter, these catheters would preferably have to be placed in veins with an internal diameter of least 4.2 mm to reduce the risk of thrombosis. Unfortunately, Barone et al. (2) did not report diameters of veins in the umbilical venous catheter route, nor did we measurements of these diameters in our study. Eifinger et al. (3) analyzed the diameter of the umbilical vein and its further course with use of spiral-CT examinations on stillborns. They report an umbilical vein diameter increasing from 3.4 to 11 mm, a ductus venosus diameter of 2.5 mm and an umbilical recess diameter of 5 mm and conclude the umbilical vein and its extensions are wide enough to admit a 4Fr catheter. However, diameters of veins in stillborns, without flow, may not be the same as in living children.
Ultrasonography is nowadays increasingly being used in various NICUs, including our department, to evaluate the position of UVCs during and after insertion. We agree with Da Lozzo et al. that it may be beneficial to use ultrasonography before catheterization to check the internal diameter of the venous route in order to choose the most appropriate sized catheter.
(1) Battersby C, Santhalingam T, Costeloe K, Modi N. Incidence of neonatal necrotising enterocolitis in high-income countries: a systematic review. Arch Dis Child Fetal Neonatal Ed 2018;103(2):F182-F189.
(2) Barone G, D’Andrea V, Vento G, Pittiruti M: A Systematic Ultrasound Evaluation of the Diameter of Deep Veins in the Newborn: Results and Implications for Clinical Practice. Neonatology 2019;115:335-340.
(3) Eifinger F, Fuchs Z, Koerber F, Persigehl T, Scaal M. Investigation of umbilical venous vessels anatomy and diameters as a guideline for catheter placement in newborns. Clin Anat 2018;31(2):269-274.
We appreciated the paper by Dubbink-Verheij et al. evaluating the incidence of thrombosis in newborns who underwent umbilical catheterization in comparison with a control group of infants without umbilical venous catheter (UVC). While the paper highlights specific issues about UVC-related thrombosis in NICU, regarding the sites, the time of onset and the outcomes of this condition, we suggest that some relevant variables have not been taken fully in account.
Some of the comorbidity rates of the patients in the study group are not consistent with data from literature and might have had a role in the unusual high rate of thrombosis and poor outcome in the study group. The reported rates of necrotizing enterocolitis (NEC; 12.5% in the study group, 10% in the total population of the study) is significantly higher compared with that of the Vermont Oxford Network (VON); VLBW infants between 2000 and 2009 based on the VON showed a NEC incidence of 4.6-6.1%. (1)
The study reported 30 thrombotic episodes in defined locations but, remarkably, the type and the diameter of catheter utilized was not stated by the Authors. Neonates, and especially preterm neonates, have an unfavorable catheter-to-vessel diameter ratio, which is a recognized risk factor for the development of catheter-related thrombosis in CVCs. In a in vitro model Nifong and McDevitt (2) quantified the impact of the catheter to vein size ratio on fluid flow unraveling the mechanism by which risk of catheter-...
We appreciated the paper by Dubbink-Verheij et al. evaluating the incidence of thrombosis in newborns who underwent umbilical catheterization in comparison with a control group of infants without umbilical venous catheter (UVC). While the paper highlights specific issues about UVC-related thrombosis in NICU, regarding the sites, the time of onset and the outcomes of this condition, we suggest that some relevant variables have not been taken fully in account.
Some of the comorbidity rates of the patients in the study group are not consistent with data from literature and might have had a role in the unusual high rate of thrombosis and poor outcome in the study group. The reported rates of necrotizing enterocolitis (NEC; 12.5% in the study group, 10% in the total population of the study) is significantly higher compared with that of the Vermont Oxford Network (VON); VLBW infants between 2000 and 2009 based on the VON showed a NEC incidence of 4.6-6.1%. (1)
The study reported 30 thrombotic episodes in defined locations but, remarkably, the type and the diameter of catheter utilized was not stated by the Authors. Neonates, and especially preterm neonates, have an unfavorable catheter-to-vessel diameter ratio, which is a recognized risk factor for the development of catheter-related thrombosis in CVCs. In a in vitro model Nifong and McDevitt (2) quantified the impact of the catheter to vein size ratio on fluid flow unraveling the mechanism by which risk of catheter-related thrombosis increases with the size of the catheter. On that basis, in 2009 Barone et al. (3) performed a systematic ultrasound evaluation of the diameter of deep veins in newborns, suggesting that the external diameter of the catheter should not exceed 1/3 of the internal diameter of the vein to reduce the risk of thrombosis. According to these evidences, we believe that catheter caliber is a relevant variable that should be reported in studies aiming to assess the risk of CVCs-related thrombosis.
(1) Jeffrey D. Horbar, et al. Mortality and Neonatal Morbidity Among Infants 501 to 1500 Grams From 2000 to 2009, Pediatrics Jun 2012; 129; 1019
(2) Nifong TP, McDevitt TJ. The effect of catheter to vein ratio on blood flow rates in a simulated model of peripherally inserted central venous catheters. Chest. 2011 Jul; 140(1): 48–53.
(3) Barone G, D’Andrea V, Vento G, Pittiruti M: A Systematic Ultrasound Evaluation of the Diameter of Deep Veins in the Newborn: Results and Implications for Clinical Practice. Neonatology 2019;115:335-340.
Prisca Da Lozzo MD. Cristina Bibalo MD. Francesca Galdo MD. Francesco Maria Risso MD. Neonatal Intensive Care Unit, Institute for Child Health IRCCS Burlo Garofolo, Trieste, Italy.
Dear Editor,
Show MoreWe read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that...
All of these extubation-readyness tests assess respiratory drive / lungs. However, it may be for many preterms that they struggle to maintain their airway despite good drive and lungs that are relatively healthy. This aspect can't be tested and could explain why so many infants who seem able to breath don't do so once the ETT has been taken out.
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3),...
Show MoreSir,
Show MoreIn their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the...
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
Show MoreIn their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestati...
Dear Editor
Show MoreWe read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early...
We were impressed by the conduct and results of Reynolds et al.’s randomised controlled cross-over trial comparing Vapotherm’s IntellO2 device with manual control of inspired oxygen, showing improvement in the proportion of time spent within the target oxygen saturation range (automated arm mean 80% of time in 90-95% range vs. manual 49%). The findings are consistent with a meta-analysis referenced within their paper [1].
The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) shows that targeting oxygen saturations of 91–95% with an oximeter with a correctly configured algorithm, carries a 38% survival advantage [2]. The co-ordinator of the NeOProM collaboration has stated that the “Infants born extremely preterm … should have their oxygen saturation levels targeted between 91% and 95%” [3].
The difference between the saturation targeting approach adopted by Reynolds et al., and NeOProM may appear small but, on account of the sigmoidal shape of the haemoglobin–oxygen dissociation curve, significant hypoxic shifts will occur with small changes in oxygen saturation.
Given the rigor of the NeOProM findings, would Reynolds et al. agree that targeting oxygen saturations of 91-95% is an important first step, whilst we wait for products which will allow improved titration of oxygen delivery?
References:
Show More[1] Mitra S, Singh B, El-Naggar W, McMillan DD. Automated versus manual control of inspired oxygen to target oxygen saturation in prete...
Thank you for an interesting case but the position of the arterial catheter after the perforation suggests to me that this was from an umbilical artery rather than the aorta (compare the path on the abdominal wall on the 2 x-rays).
This may therefore be why you were able to successfully manage this conservatively.
We kindly thank Da Lozzo et al. for their reaction to our paper. Indeed, many variables may be of influence on the incidence of thrombosis in our study group.
Show MoreThe authors are correct that the incidence of necrotizing enterocolitis in our study group (12.5%, 5/40) is higher than expected based on literature. As shown by Battersby et al. comparing NEC incidences internationally is challenging (1). The incidence of NEC in our study group does not reflect the NEC incidence of last 15 years at our department (which was 3.7% (98/2626) in infants with a gestational age <32 weeks). Possibly, the higher incidence of NEC led to a higher incidence of thrombosis in our study. However, care should be taken when interpreting our results due to the small sample size (n=40).
Da Lozzo et al. make a valuable point about the diameter of central venous catheters. Most (25/40) umbilical venous catheters (UVCs) used in our study-group were 4Fr Vygon catheters, single or double lumen, with an external diameter of 1.5 and 1.4 mm, respectively (strange enough double lumen is smaller than single lumen). In 3/40 infants 5Fr Vygon catheters (external diameter 1.7 mm) were used and in 10/40 infants 3.5Fr Vygon catheters (external diameter 1.16 mm). In 2/40 infants the size of the catheter was not registered. We found no association between the risk of thrombosis and the size of the catheter (p=0.59). However, as stated in the discussion of our paper, the sample size of our group is too...
We appreciated the paper by Dubbink-Verheij et al. evaluating the incidence of thrombosis in newborns who underwent umbilical catheterization in comparison with a control group of infants without umbilical venous catheter (UVC). While the paper highlights specific issues about UVC-related thrombosis in NICU, regarding the sites, the time of onset and the outcomes of this condition, we suggest that some relevant variables have not been taken fully in account.
Show MoreSome of the comorbidity rates of the patients in the study group are not consistent with data from literature and might have had a role in the unusual high rate of thrombosis and poor outcome in the study group. The reported rates of necrotizing enterocolitis (NEC; 12.5% in the study group, 10% in the total population of the study) is significantly higher compared with that of the Vermont Oxford Network (VON); VLBW infants between 2000 and 2009 based on the VON showed a NEC incidence of 4.6-6.1%. (1)
The study reported 30 thrombotic episodes in defined locations but, remarkably, the type and the diameter of catheter utilized was not stated by the Authors. Neonates, and especially preterm neonates, have an unfavorable catheter-to-vessel diameter ratio, which is a recognized risk factor for the development of catheter-related thrombosis in CVCs. In a in vitro model Nifong and McDevitt (2) quantified the impact of the catheter to vein size ratio on fluid flow unraveling the mechanism by which risk of catheter-...
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