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Congratulations to Behrendt and team for introducing yet another
infection marker in premature babies [1]. However, there are several flaws
in the study design which could render the study conclusions not
clinically useful.
The authors repeatedly mention the aim of their study was to look at
lipopolysaccharide binding protein (LBP) levels in premature babies.
Results quoted however includ...
Congratulations to Behrendt and team for introducing yet another
infection marker in premature babies [1]. However, there are several flaws
in the study design which could render the study conclusions not
clinically useful.
The authors repeatedly mention the aim of their study was to look at
lipopolysaccharide binding protein (LBP) levels in premature babies.
Results quoted however include data on term infants (23%) and appear to
have combined data for preterm and term infants. Authors have also
excluded 26% of the eligible population introducing further potential
bias.
The authors consider one of the gold standards for diagnosing
neonatal bacterial infection as at least 3 clinical symptoms from a
detailed list and a CRP of > 5mg/dl. The majority of newborns with mild
respiratory distress syndrome or transient tachypnea would have all of
these symptoms and could have a CRP of 5-10mg/dl. The use of CRP in the
diagnosis of neonatal bacterial infection is a controversial area. Most
studies have reported positive likelihood ratios of CRP in diagnosing
bacterial infection in the range of 1-4 and negative likelihood ratios 0.5
-1, showing limited clinical utility [2]. Do the authors have any data from
their population showing likelihood ratios of CRP for diagnosis of
bacterial infection, to substantiate their claim that a CRP > 5 mg/dl
indicates bacterial infection? Many studies have actually taken CRP <
10 mg/dl as normal [2-4]. What proportion of the infants fell within this
uncertain 5-10mg/dL group?
The second criterion for gold standard is a positive blood culture
and at least 3 clinical symptoms. This would exclude a baby with apnoea,
whose blood culture has grown a pathogenic organism. Authors do not
mention if they have cultured any other body fluids (urine or CSF). It
would be interesting to know what the LBP levels were in the 2 babies with
a positive blood culture. The test would be much more usefully evaluated
in a cohort of babies with positive cultures, since these at least would
have harder evidence of infection. The blood culture positivity rate in
the study was low (2 positives in 74 babies = 2.7%)
The authors’ initial hypothesis was that LBP might fill the
diagnostic gap between IL-6 and CRP. Unfortunately the time to maximum
median value of LBP falls outside of this critical period. Despite this
the authors conclude LBP may be useful diagnostic marker of infection in
premature babies. It is not clear why, as infants with risk factors will
already have been started on antibiotics by this time. Did the authors
look at tests for diagnostic utility of LBP (e.g. sensitivities,
likelihood ratios) to support this claim. Larger studies using more a
stringent gold standard comparing LBP with traditional markers [5] for
diagnostic accuracy of neonatal bacterial infection will be needed before
LBP becomes routine neonatal practice.
References
(1). Behrendt D, Dembinski J, Heep A, Bartmann P. Lipopolysaccharide
binding protein in preterm infants. Arch Dis Child 2004; 89: F551-F554
(2). Fowlie PW, Schmidt B. Diagnostic tests for bacterial infection
from birth to 90 days: a systematic review. Arch Dis Child.1998;78:F92-F98
(3). Laborada G, Rego M, Jain A, Guliano M, Stavola J, Ballabh P,
Krauss AN, Auld PA, Nesin M. Diagnostic value of cytokines and C-reactive
protein in the first 24 hours of neonatal sepsis. Am J Perinatol.
2003;20(8):491-501
(4). Franz AR, Kron M, Pohlandt F, Steinbach G Comparison of
procalcitonin with interleukin 8, C-reactive protein and differential
white blood cell count for the early diagnosis of bacterial infections in
newborn infants. Pediatr Infect Dis J. 1999;18(8):666-71.
(5). Pavcnik-Arnol M, Hojker S, Derganc M. Lipopolysaccharide-binding
protein in critically ill neonates and children with suspected infection:
comparison with procalcitonin, interleukin-6, and C-reactive protein.
Intensive Care Med. 2004;30 (7):1454-60
The study on storage of breastmilk and its effect on antioxidant levels [1] was well designed and provided some interesting information. However, the conclusions that the authors drew are based on conjecture about the clinical relevance of the findings. There is a potential risk to infant health if mothers follow their recommendations and abandon the pumping and storage of their milk.
The study on storage of breastmilk and its effect on antioxidant levels [1] was well designed and provided some interesting information. However, the conclusions that the authors drew are based on conjecture about the clinical relevance of the findings. There is a potential risk to infant health if mothers follow their recommendations and abandon the pumping and storage of their milk.
The authors demonstrated that term and preterm human milk had high levels of antioxidant activity but that some of this activity was lost with refrigeration while even more was lost with freezing, especially after 7 days. It should be noted, however, that antioxidant levels only decreased by 5% and 11% at 48hrs and 7 days of refrigeration respectively, while the corresponding drops for freezing were 13% and 19%. These drops may be statistically significant, but their clinical significance is unknown. For example, the authors cited necrotising enterolitis as one condition that could be prevented by antioxidants. One of the earliest studies demonstrating a protective effect against necrotising enterocolitis [2] used pooled, banked, pasteurised donor human milk. Presumably the processing and storage of this type of donor milk was much harsher on the antioxidants than the conditions under which the authors tested their mothers' milk samples, and yet there was significant protection conferred on the infants who consumed it.
The authors compared the antioxidant levels of various infant formulas against human milk, finding that even though formula did not lose antioxidant activity with storage, its levels were consistently significantly lower than those of human milk. Even at 7 days of freezing, human milk had 25% greater antioxidant activity than formula.
Despite their findings, the authors recommend: "To preserve antioxidant capacity, [human] milk should only be stored for a short time at refrigerator temperature and not frozen." Human milk has been demonstrated to retain many of its beneficial immunoprotective properties with refrigeration for as long as 8 days [3,4] and also to a lesser extent with pasteurization and freezing for donor banking [5]. The current study shows that human milk also retains most of its antioxidant activity to the extent that even after 7 days of freezing it still has significantly more than formula. Whether due to its antioxidant activity or its many other immunoprotective factors, the fact remains that human milk protects infants against a variety of illnesses.
Pumping milk is a time-consuming endeavour, especially for mothers of premature infants. In order to maintain an adequate milk supply by pumping, mothers must pump frequently and in the early weeks their infants often don't consume as much milk as their mothers produce. The excess must be stored. It would be unfortunate if mothers who read the authors' recommendation concluded that their milk had no value if not fed within a couple of days. There are too many other beneficial factors that are stable for longer periods of storage, and even the levels of antioxidants preserved with longer storage are still better than formula.
Instead of recommending that mothers' milk be refrigerated for only brief periods and not frozen, it would be better to acknowledge that freshly expressed milk is ideal and should be fed whenever available, but that in its absence refrigerated milk, followed by frozen milk, are the next best alternatives. That way, the babies would get the most beneficial milk during their most vulnerable period but still have many benefits of their mothers' milk later on.
References
(1) N Hanna et al. Effect of storage on breast milk antioxidant activity. Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F518-F520
(2) Lucas A and Cole T. Breast milk and neonatal necrotizing enterocolitis. Lancet 1990;336:1519-23. Letters Lancet 1991;337:435-6.
(3) Pardou et al. human milk banking: influence of storage processes and of bacterial contamination on some milk constituents. Biol Neonate 1994;65:302-9.
(4) Hamosh M. Bioactive factors in human milk. Pediatr Clin North Am 2001;48:69-86.
(5) Arnold LDW. Donor Human Milk Banking. Chapter 14 in Breastfeeding and Human Lactation, Riordan J, Ed, 3rd ed. 2005. Jones and Bartlett. Pp 424-5.
Drs. De Silva, Jones and Spencer have provided a timely review of
issues relating to studies of breastmilk feeding for VLBW infants and
rates of infection [1]. We would appreciate the opportunity to clarify
some points they have raised regarding our study [2]. We believe our
results clearly support our conclusion: that intake of greater than 50
ml/kg/day of maternal milk through week four of life...
Drs. De Silva, Jones and Spencer have provided a timely review of
issues relating to studies of breastmilk feeding for VLBW infants and
rates of infection [1]. We would appreciate the opportunity to clarify
some points they have raised regarding our study [2]. We believe our
results clearly support our conclusion: that intake of greater than 50
ml/kg/day of maternal milk through week four of life decreases the rate of
sepsis in VLBW infants.
de Silva et al state that, “… a major flaw noted in all the studies
was the lack of a consistent definition of HM fed groups or methods used
to quantify HM intake.” We were able to provide a concise definition of
maternal milk intake, which was classified by mean ml/kg/day through week
four of life, and included groups fed 1-24 ml/kg/day, 25-49 ml/kg/day and
>50 ml/kg/day. These groups were compared to a reference group
receiving 0 ml/kg/day of maternal milk. We also describe the maternal milk
intake of our population in two week increments by daily volume, by total
volume, as a percent of total intake, and as a percent of enteral intake.
We agree that when human milk intake is measured only as a proportion of
enteral intake, infants may be misclassified, and state this in our
discussion.
de Silva et al criticize our and others’ work for not including an
exclusively HM fed cohort. The realities of breast milk feeding for VLBW
infants, including months of milk expression, make attaining a cohort of
exclusively HM fed infants extremely difficult. As de Silva et al point
out, not having such a cohort is likely to lead to an underestimate of the
beneficial effects of human milk, and strengthens rather than weakens our
(and others’) conclusion that human milk reduces infection rates.
We agree that including a wide range of infections other than sepsis,
such as urinary tract infection and pneumonia, may confuse rather than
clarify an effect of maternal milk. We examined solely the rate of
sepsis, and defined it as “a positive blood culture obtained in the
presence of clinical signs and/or symptoms of infection, treated for five
or more days with antibiotics”. This is the gold standard. Since
inflammatory response to infection in VLBW infants may be lacking, may
lag, and is not always an accurate measure of illness severity, the
addition of data regarding inflammatory markers and changes in cell counts
would not be expected to provide clarification.
We also agree with de Silva et al that the timing of maternal milk
intake in relation to onset of infection is important, and we examined
rates of sepsis after weeks two, four and six of life according to
cumulative volume of maternal milk received prior to these ages. In a
logistic regression that adjusted for birth weight, we found that “the
greater the average volume of maternal milk intake (ml/kg/day), the lower
the rate of sepsis after weeks two and four (both p<_.05 though="though" not="not" after="after" week="week" six.="six." we="we" also="also" excluded="excluded" throughout="throughout" the="the" study="study" all="all" episodes="episodes" of="of" sepsis="sepsis" occurring="occurring" prior="prior" to="to" day="day" _5="_5" life="life" since="since" enteral="enteral" intake="intake" was="was" minimal="minimal" this="this" time.="time." p="p"/> De Silva et al are correct that postnatal steroid intake may impact
the rate of infection, and we did not control for this in our study.
Since 27% of our population received postnatal steroid therapy, which was
standard of care at the time, this is an important consideration and a
valid criticism. We have re-done the Poisson regression analysis that
examines the effect of maternal milk on the rate of sepsis. While also
controlling for birth weight, race and sex as in the original analysis, we
additionally controlled for postnatal steroid treatment. This resulted in
negligible changes in the relative risk and confidence intervals for each
(maternal milk intake) group. The effect of postnatal steroid treatment
in this analysis was not significant, and our original conclusions are
unchanged.
Finally, there is no question that future research should include
larger numbers of infants. When our project was submitted for funding, we
calculated our sample size based on rate of sepsis as the primary outcome
measure of interest. Specifically our proposal read: “Based on the sample
size of 60 infants in each group, we will have the ability to detect a 50%
decrease in the rate of sepsis, i.e. from 40% to 20% (power = .78, alpha
one tailed = .05)”. de Silva et al state that “…64 [infants] are required
in each group with an addition for drop out…” Their and our calculations
are quite similar. The difficulty we encountered is that while more than
half of mothers intended to breastfeed (87 mothers, 73%), 18 had
discontinued lactation by 3 weeks postnatal age, and 39 more discontinued
by 40 weeks corrected age [3]. Other centers experienced similar rates of
discontinuation during the same time period [4,5]. Not only is a
randomized trial of breastfeeding unethical, it remains a challenge simply
to support those mothers who have enrolled and chosen to breastfeed.
Further work is needed.
We believe that our study demonstrates clearly that VLBW infants who
receive greater than 50 ml/kg/day of maternal milk through the first four
weeks of life have a decreased rate of sepsis, and thus maternal milk
feeding is beneficial for these infants.
References
(1). de Silva A, Jones PW and Spencer SA. Does human milk reduce
infection rates in preterm infants? A systematic review. Arch Dis Child
Fetal Neonatal Ed 2004; 89: F509-F513.
(2). Furman L, Taylor G, Minich N and Hack M. The effect of maternal milk
on neonatal morbidity of very low birth weight infants. Arch Pediatr Adol
Med 2003; 157:66-71.
(3). Furman L, Minich N and Hack M. Correlates of lactation in mothers of
VLBW infants. Pediatr. 2002;109 (4). URL:
http://www.pediatrics.org/cgi/content/full/109/4/e57
(4). Bier JB, Ferguson AE, Morales Y, et al. Breastfeeding infants who were
extremely low birthweight. Pediatrics. 1997;100(6). URL:
http://www.pediatrics.org/cgi/content/full/100/61/e3
(5). Richards MT, Lang MD, McIntosh C, et al. Breastfeeding the VLBW infant:
successful outcome and maternal expectations. Pediatr Res. 1996;39:383A
We appreciate the interest of Dr Gupta and his thoughtful comments.[1]
1. Primary disease of the neonates included in the study: Our original submission to the journal included a complete table describing in many more details the patient population. At the request of the reviewers/editors to shorten the paper, we removed the table which is now attached at the end of this letter.
We appreciate the interest of Dr Gupta and his thoughtful comments.[1]
1. Primary disease of the neonates included in the study: Our original submission to the journal included a complete table describing in many more details the patient population. At the request of the reviewers/editors to shorten the paper, we removed the table which is now attached at the end of this letter.
2. Antibiotics were started on day 1 in every baby of this study. Thus, we are not able to discuss the impact of starting or not starting antibiotics on the occurrence of cutaneous abscesses.
3. The fact that blood cultures became negative within 24 hours of abscess drainage, does not tell us how long antibiotic therapy should be continued. Although no written recommendation exist, we believe that in order to prevent recurrence, the usual rules for antibiotic therapy in neonates should be applied, i.e., longer therapy for gram negative than for gram positive bacteria. The question of topical antimicrobial preparations remains wide open. However, neonatal infections are usually systemic (as in every single patient in our study). Thus while topical therapy might shorten the clinical course, we doubt seriously whether it would suffice when used alone.
Table. Clinical characteristics. Data are expressed as mean ± SD or n (%),
except for Apgar scores which are expressed as median (range).
With abscess
(n=10)
Without abscess
(n=36)
Survived
(n=36)
Died
(n=13)
Birthweight (g)
1490±782
1134±614
1364 ±719
823 ±180
Gestational age (wks)
31±4
*
26±6
29
± 4
26
± 2
1-min Apgar
7 (0-9)
5 (1-9)
6 (0-9)
4 ( 1-8)
5-min Apgar
9 (4-10)
8 (5-10)
9 (4-10)
8 (5-10)
Age at sepsis (wks)
10±4
12±10
12
± 8
7 ±
6
Subcutaneous abscess
10 (100)
0 (0)
9 (27.2)
1 (7.7)
Presence of UVC
3 (30)
11 (92)
20 (60)
11 (92)
Duration of UVC (days)
1±1.5
**
4±2.5
3 ±
3
4 ±
2
Presence of UAC
7(70)
30 (83)
22 (69)
13 (100)
Duration of UAC (days)
3±2.5
4±2.3
4 ±
2
4 ±
2
Mechanical ventilation
7(70)
34 (90)
28 (85)
13 (100)
Days of ventilation
4±3
10±10
8 ±
9
11
± 9
TPN
9 (90)
36 (100)
32 (97)
13 (100)
Duration of TPN (days)
8±2.3
9±8
10
± 8
6 ±
4
Received Blood transfusions
6 (60)
28 (78)
22 (69)
12 (91)
Presence of PDA
7 (70)
25 (96)
22 (67)
11(83)
Appropriate therapy
10 (100)
35 (97)
33 (100)
12 (92)
* p<0.017; ** p<0.001
Reference
1. Girish Gupta, Vishal Sondhi, Kinley Tshering, Suprabha Patnaik. Septic Infants: Pandora box reopens [electronic response to D Mandel et al. Nosocomial cutaneous abscesses in septic infants] fn.bmjjournals.com 2004http://fn.bmjjournals.com/cgi/eletters/89/2/F161#420
Chappell and Newman [1] have asked for urgent initiatives needed to ensure the manufacture of neonatal targeted products to reduce the risks associated with intravenous drug administration. We endorse their view and report a little recognized problem with use of adult formulations in neonatal nurseries
This investigation was conducted after we noticed symptoms of Digoxin overdose (brady-arrhythmia)...
Chappell and Newman [1] have asked for urgent initiatives needed to ensure the manufacture of neonatal targeted products to reduce the risks associated with intravenous drug administration. We endorse their view and report a little recognized problem with use of adult formulations in neonatal nurseries
This investigation was conducted after we noticed symptoms of Digoxin overdose (brady-arrhythmia) in a neonate. Retrospective review of the case suggested that the overdose received was due to the unaccounted-for drug, in the dead space of a 1ml syringe.
The nursing drug-dose-manual "Pediatric Drugs and Nursing implications" [2] , gives the maintenance dose of intravenous Digoxin as 2.5 microgram /Kg /dose. The nursing instruction [3] states that the dose must be diluted, with at least four times the volume, using normal saline or 5% dextrose and the drug must be given over five minutes. In practice, for a 2 Kg neonate who is to receive 5 microgram Digoxin intravenous injection (250 micrograms/ml), the drug volume required is 0.02 ml. This is drawn up in a 1 ml syringe up to the 0.02 ml mark. The nursing practice in our nursery was to draw up normal saline to dilute this four times and give it intravenously, slowly over five minutes. Cognizance is not taken of the dead space in the needle hub and syringe.
We estimated this dead space by drawing up saline in the one ml syringe and flushing out the syringe{ Syringe and Precision Glide TM Needle, 1 ml 26 G 1/2 " , Becton Dickinson, Singapore }. The syringe piston was then withdrawn again, and the volume of saline in the dead space, was drawn into the syringe barrel. This volume was noted. The dead space volume is 0.07 ml in this syringe. When the diluent is drawn up, the drug in the dead space is also drawn up resulting in toxicity. In the case of Digoxin, the baby received 0.09 ml Digoxin instead of 0.02 ml.
Ordinarily if the Digoxin is drawn up to the 0.02-ml mark and injected directly, the drug in the dead space, is retained in the syringe, and there is no overdose delivered. However when the diluent is drawn up into the syringe for dilution, the drug in the dead space also is drawn up and this results in the overdosing.
We looked at the magnitude of error induced by the dead space in some of the medications routinely used in the nursery. The Table shows the standard volume of drug required for a 2 Kg neonate and magnitude of error introduced by the dead space of a 1 ml syringe. Its is assumed that these drugs were first drawn in a 1 ml syringe and then diluted in the same syringe. The neonate will get 4.5 times the recommended dose if Digoxin - 250 micrograms/ml is used and 2.4 time the recommended dose, if Digoxin - 100 micrograms/ml is used. The inadvertent extra dosing factor using 1 ml syringe for different drugs used in the neonatal unit have been calculated. The dose of Adrenaline can be exceeded by a factor of 2.16, for Furosemide by 1.35, for Dexamethasone by 2.4 and for Midazolam by a factor of 2.75.
To avoid this inadvertent overdosing of neonates, pre-diluted drug formulations are required. Till such drug formulations are more widely available especially in developing countries, awareness of this error can help circumvent the problem.
A method that can be employed to circumvent the problem is to draw up the required volume in a 1ml syringe and transfer it to a larger volume syringe, leaving the dead-space-drug behind in the first syringe. This is a crude method and it is not a closed system (as it requires transferring the drug from one syringe to another).
The insulin syringe (U-40 INSULIN, 29 G 1/2 " ULTRA-FINE 1ml Needle, Becton Dickinson Consumer Products , Franklin Lakes, N.J , USA) does not have a dead space and its needle is fixed to the syringe. Use of this syringe can also obviate the problem.
Another way would be to add the drug contained in this dead space (0.07 ml) to the calculation for dilution.
Although no reports of life threatening adverse effects have been reported in literature, this inadvertently dosing error has the potential of being serious.
Table shows the inadvertent overdose for different drugs *
Drug (Concentration of drug in vial /ampoule)
Dose
Amount of drug for a neonate weighing 2Kg in mg
Drug volume taken in a 1-ml syringe
Volume of drug in dead space
Amount of drug in dead space (mg)
Total amount of drug
neonate is getting (mg)
Inadvertent overdose factor
Digoxin **
(1ml=0.25mg)
0.025mg/Kg/
dose
0.005mg
0.02ml
0.07ml
0.0175mg
0.005+0.0175
=0.0225 mg
4.5
Digoxin **
(Iml=0.1mg)
0.025mg/Kg/
dose
0.005mg
0.05ml
0.07ml
0.007mg
0.005+0.007
=0.012mg
2.4
Adrenaline
(1ml=1mg) (1:1000)
0.03mg
/Kg/
dose
0.06mg
0.06ml
0.07ml
0.07mg
0.06+0.07=0.13mg
2.16
Furosemide
(1ml=10mg)
1mg/Kg/dose
2mg
0.2ml
0.07ml
0.7mg
2+0.7=2.7mg
1.35
Dexamethasone
(1ml=4mg)
0.1mg/Kg/dose
0.2mg
0.05ml
0.07ml
0.28mg
0.2+0.28=0.48
2.4
Midazolam
(1ml=5mg)
0.1mg/Kg/dose
0.2mg
0.04ml
0.07ml
0.35mg
0.2+0.35=0.55mg
2.75
Assuming medication for a 2 Kg neonate is drawn up in a 1 ml syringe and the drug is diluted by drawing up the diluent into the same syringe.
* Doses of drugs taken from "Pediatric Drugs and Nursing implications" [2]
** Digoxin is available in two formulations – 250 micrograms/ml
100 micrograms/ ml
I have read with interest a systematic and well-referenced review of
causes of neonatal coagulation disorders in recent Archives [1].
However, amongst non-haematological causes of the coagulopathies the
author has failed to mention a small, but significant subgroup of patients
with neonatal liver failure (NLF).
This condition could often be difficult
to diagnose due to presence of jaundice (ea...
I have read with interest a systematic and well-referenced review of
causes of neonatal coagulation disorders in recent Archives [1].
However, amongst non-haematological causes of the coagulopathies the
author has failed to mention a small, but significant subgroup of patients
with neonatal liver failure (NLF).
This condition could often be difficult
to diagnose due to presence of jaundice (easily confused with
physiological jaundice), sepsis and subtle, non-specific symptoms of
encephalopathy, such as poor feeding or drowsiness. The commonest
conditions causing NLF are vertically acquired herpes infection, perinatal
haemochromatosis, haemophagocytic lymphohistiocytosis and mitochondrial
cytopathies [2]. Furthermore, some liver-based metabolic conditions
such as PiZZ alpha-1-antitrypsin deficiency or galactosaemia could cause a
life-threatening late haemorrhagic disease of the newborn [5]. Need
for a better awareness of these conditions has also been recently
recognised by British Paediatric Surveillance Unit, which has conducted a
prospective epidemiological study on incidence of vitamin K non-responsive
haemorrhagic disease of the newborn.
Management of NLF has significantly improved in the recent years, not
only following a success of liver transplantation [3], but also by
early introduction of antioxidant medications for perinatal
haemochromatosis [4], prompt use of intravenous acyclovir [3],
even in the absence of obvious maternal symptoms, and, to some extent,
immunosuppressive treatment for haemophagocytic lymphohistiocytosis. The
outcome of these rare, but previously uniformly fatal conditions may not
need to be that bleak provided they are suspected early and referred to
specialist centres.
(2). Durand P, Debray D, Mandel R et al. Acute liver failure in infancy: a
14-year experience of a paediatric liver transplantation center. J Pediatr
2001;130;871-6.
(3). Twagira M, Hadzic N, Smith M et al. Disseminated neonatal herpes
simplex virus (HSV) type 2 infection diagnosed by HSV DNA detection in
blood and successfully managed by liver transplantation. Eur J Pediatr.
2004 Mar;163:166-9.
(4). Israels SJ, Gilfix BM. Alpha-1-antitrypsin deficiency with fatal
intracranial haemorrhage in a newborn. J Pediatr Hematol Oncol 1999;21:447
-50.
(5). Flynn DM, Mohan N, McKiernan P, et al. Progress in treatment and and
outcome for children with neonatal haemochromatosis. Arch Dis Child
2003;88:F124-7.
I read with interest the publication of the audit on the use of central venous lines(CVL) by DW Cartwright.
He reported that 58.6% of the catheters were postioned in the right atrium, but there was no breakdown of where the other 41.8% tips were located. Probably this was because he was interested in only catheters in the right atrium. I would have liked to know as well if this information was i...
I read with interest the publication of the audit on the use of central venous lines(CVL) by DW Cartwright.
He reported that 58.6% of the catheters were postioned in the right atrium, but there was no breakdown of where the other 41.8% tips were located. Probably this was because he was interested in only catheters in the right atrium. I would have liked to know as well if this information was initially recorded or radiographs had to be reviewed to ascertain the anatomical
position of these catheter tips.
In my experience, catheter tips have been reported as
"satisfactory" without anatomical description of the position of the tip. Since most of the serious problems with CVL are related to the position of the catheter tip, this needs to be appropriately recorded. This will help with audits and subsequent formulation of guidelines on the insertion of CVLs.
Professor Shah has submitted a comprehensive and well-documented
response that agrees and disagrees with my letters. With clarification of
a few points, I find that we may be very close to complete agreement, and
to major improvement in neonatal outcome.
Regarding the definition of “asphyxia,” for want of a better, I use
the term to describe the sum total of pathologies produced by compressi...
Professor Shah has submitted a comprehensive and well-documented
response that agrees and disagrees with my letters. With clarification of
a few points, I find that we may be very close to complete agreement, and
to major improvement in neonatal outcome.
Regarding the definition of “asphyxia,” for want of a better, I use
the term to describe the sum total of pathologies produced by compression
of the umbilical cord. This may not fit the definition of “the so-called
International Consensus Statement”, but it focuses elucidation onto the
single, most common cause of fetal/neonatal “asphyxia,” namely, cord
compression. It also eliminates confusion with pathologies generated by
other causes of birth “asphyxia” such as placental abruption and meconium
aspiration.
Professor Shah cites many papers on birth asphyxia/acidosis that have
apparent contradictions regarding placental blood volume, placental
transfusion and cord compression, pH, hemoglobin and hematocrit readings.
He correctly defines “infants to which Dr. Morley refers” as acute
intrapartum asphyxia (cord compression) plus immediate cord clamping (ICC)
resulting in neonatal hypovolemia These fetuses have large blood volume
shifts TO the placenta just prior to delivery, and the phenomenon was
described by Linderkamp [1] as “intrapartum asphyxia.” Linderkamp also
differentiates “intrauterine asphyxia” (prior to labor, or in early labor)
that causes a marked shift of blood volume from the placenta. These
peculiar reverse effects of “asphyxia” and most of the conflicting
reference studies are readily explained on the degree and chronicity of
the cord compression “asphyxia”.
Cord venous compression engorges the placenta, raises placental intra
-capillary hydrostatic pressure and thus forces fluid into the mother,
dehydrating the fetus. If the cord compression is not intermittently
relieved, as in oligohydramnios where the cord has no fluid buffer between
fetal parts and the uterine wall, fetal dehydration and hemoconcentration
may become extreme; hypovolemia with very high hematocrit values results.
The fetus responds to hypovolemia / dehydration with generalized
vasoconstriction that ,i>includes placental and cord vessels. Such babies
are born limp and ashen white, covered in “pea soup” meconium and the cord
often appears white with three “pencil streaks” of vessels. Placental
transfusion has already occurred and little placental function is
available; the correct treatment is immediate cord clamping followed by
immediate intravenous correction of the dehydration, acidosis and
electrolyte imbalance with pulmonary resuscitation. [2] This is
Linderkamp’s “intrauterine asphyxia.” I completely concur with Professor
Shah’s statement that: “Likewise, delay in resuscitation of a severely
asphyxiated infant to await a placental transfusion that is unlikely to
occur owing to constricted umbilical arteries is likely to cause more harm
than benefit.”
With acute intrapartum cord compression with intermittent relief,
(late decelerations) dehydration is a very variable factor, but a
significant one in the more severe cases. By relieving the cord
compression at birth (releasing a tight nuchal cord on delivery of the
head) and permitting third stage placental circulation to continue,
placental oxygenation, placental correction of acidemia and placental re-
hydration with restoration of electrolyte balance rapidly restore the
physiological state while the neonatal blood volume is adjusted by
placental transfusion. The mandatory clinical factor in this procedure is
a vigorously pulsating cord; a factor that Professor Shah agrees should
not be destroyed. This is Linderkamp’s “intrapartum asphyxia.”
However, if the intrapartum cord compression has been more chronic,
without much intermittent relief, more severe dehydration and placental /
cord vasoconstriction may have shifted blood volume to the fetus, and the
birth condition approaches that of “intrauterine asphyxia.” Management
depends on the condition of the cord vessels at birth. If they are
constricted, placental function is marginal and immediate clamping and
I.V. hydration with resuscitation is the choice. If there is active cord
pulsation above 100 b.p.m. and the vein is filled, placental function
should be used to correct hypoxia, acidemia, dehydration, electrolyte
imbalance and hypovolemia while ventilation is being established. In
severely acidotic, hypoxic neonates (cord arterial blood values) the cord
venous blood is usually well oxygenated with a normal pH. With release of
cord compression at birth, circulation through the massive placental /
maternal interface will rapidly correct the pathologies created by cord
compression and with much greater accuracy and efficiency than procedures
done after immediate amputation of the placenta.
In the case of preterm infants, it is very encouraging to find a
neonatologist stating:
“Late clamping of preterm infants is probably safer than early clamping.”
and in regard to umbilical cord blood sampling:
“If necessary its treatment, a sample can be taken from the infant rather
than the cord.”
The following critique of blood loss and blood transfusion is from an
obstetrician’s perspective and does not concur with current Neonatolgy
philosophy. Obstetrical blood loss (maternal hemorrhage) is rapid and
often massive. Obstetrical management is rapid and massive. The adequacy
of residual blood volume after blood loss is measured in terms of blood
pressure, pulse rate, central venous pressure and urine output; hemoglobin
and hematocrit values (unless extreme) are irrelevant. Acute blood loss
mandates rapid blood volume replacement to avoid hypovolemic sequelae.
Whole blood is the best replacement; otherwise plasma volume expanders are
supplemented with red cells.
The following statement illustrates conflict:
“Based on the eligibility and exclusion criteria of our study, and on the
haemoglobin and haematocrit values reported here, we are confident that
immediate cord clamping did not cause significant blood losses in the
great majority of our cases.”
Blood loss into the placenta is silent, invisible and occasionally
massive. Hemoglobin and hematocrit values near birth (or at the time of
acute hemorrhage) have no relation at all to circulating blood volume or
to blood loss and are usually misleading (as in dehydration – high
hematocrit, low blood volume.) Taken two weeks post-partum after hemo-
dilution, they do reflect blood loss during delivery.
“Sick neonates are one of the most heavily transfused groups of
patients in modern medicine.” [3]
The neonatal criterion for transfusion (of red cells only) is Hg<_10 gms="gms" dl="dl" the="the" blood="blood" plasma="plasma" volume="volume" _40="_40" of="of" total="total" has="has" been="been" restored="restored" by="by" child="child" over="over" a="a" period="period" days="days" _="_" weeks.="weeks." hg10="hg10" at="at" one="one" weeks="weeks" life="life" indicates="indicates" major="major" loss="loss" birth="birth" and="and" error="error" in="in" management="management" or="or" cord="cord" clamping.="clamping." even="even" preemies="preemies" draws="draws" do="do" not="not" remove="remove" volume.="volume." these="these" hypovolemic="hypovolemic" neonates="neonates" after="after" are="are" hypotensive="hypotensive" oliguric="oliguric" pale="pale" hypothermic="hypothermic" many="many" exhibit="exhibit" retraction="retraction" respiration.="respiration." our="our" experience="experience" term="term" infants="infants" can="can" tolerate="tolerate" acute="acute" losses="losses" up="up" to="to" percent="percent" professor="professor" peltonen="peltonen" _4="_4" agrees="agrees" with="with" shah="shah" but="but" recommends="recommends" against="against" it.="it." most="most" parents="parents" would="would" consent="consent" practice.="practice." p="p"/> Regarding Professor Peltonen’s review, [4] the exact quotation in a
paragraph devoted to “clamping before the first breath” is:
“It would seem that the closing of the umbilical circulation before the
aeration of the lungs has taken place is a highly unphysiological measure,
which should thus be avoided. Although the normal infant survives without
harm, in certain unfavourable circumstances, the consequences may be
fatal.”
Peltonen concludes the paragraph with:
“There is thus good reason in cases of resuscitation to keep the placental
circulation intact.”
Profesor Shah’s response makes no mention of retraction respiration
(RR) that is an integral part of my postulation that hypovolemia and
deficient perfusion of brain tissue are the primary cause of neuron
necrosis. In the adverse outcome group, 69 of 80 neonates had defined
“pulmonary dysfunction.” If all those neonates had RR, they all were
hypovolemic at birth. Record review should be able to settle the question
of this common and frequently misunderstood symptom in the “risk” neonate.
Regarding hyperviscosity and polycythemia, neither is pathological in
the normovolemic child. The basic concept of the “hyperviscosity
syndrome” is pathology caused by inadequate perfusion of tissues – “sticky
blood” causing diminished blood flow through vessels. Blood flow
(perfusion) is inversely proportional to viscosity, directly proportional
to the pressure differential (blood pressure) and proportional to the fourth power of the diameter of the vessel. (Arteriole) Thus an adequate
blood pressure alone should counteract increased viscosity; vaso-
dilatation from 1 to 2 increases perfusion 16 times! Vaso-dilatation from
1 to 1.2 doubles perfusion. Rapid hydration of the intra-uterine
asphyxiated, dehydrated, polycythemic, hyperviscous neonate will dilate
the arterioles and prevent the hyperviscosity syndrome. Fortunately
nowadays, amnio-infusion usually corrects the pathology prior to birth.
The “hyperviscosity syndrome” is the product of hypovolemia,
hemoconcentration and primarily, vasoconstriction.
Professor Shah’s statement “ it is likely that the umbilical cord had
lost its function in the great majority of our cases by the time that the
cord was clamped.” is contradicted by one of the eligibility criteria in
the original study – “metabolic acidosis (cord arterial blood or blood gas
analysis within the first hour after birth) indicated by a base deficit
>16mmol/l”. This blood is obtained routinely on “risk” neonates from
cord arteries by immediate cord clamping. [5] A cord that has lost its
function has no available blood in the arteries. All cases with cord
arterial blood analysis had actively functioning cords.
Myocardial contractility is dependent on an oxygenated blood supply;
hypoxia at some degree stops the heartbeat, and, after this point,
infarction of all tissues will occur. A pulsating cord indicates that
functional cardiac oxygenation and viable tissue perfusion are still
active. Whatever pathology and dysfunction is present in a “cord
compressed” neonate with a pulsating cord, placental function is, and has
been maintaining life. That placental function should be used to maintain
life, correct pathology and dysfunction, and supplement resuscitation
during the third stage of labor.
Overall, in managing the cord-compressed, “asphyxiated” neonate,
there appears to be a consensus that leaving a pulsating cord alone to the
point of spontaneous closure of the cord vessels, (allowing placental
function to restore physiology,) and using immediate clamping of an
obviously mal-functioning cord to facilitate neonatal correction of
pathologies are beneficial for optimal survival. With this agreement,
disputes over transfusion and placental function become moot. Correction
of the present situation demands that obstetrical and neonatal management
of the risk neonate concur and overlap. Placental respiration normally
continues until pulmonary respiration is established. Oxygenation of
aortic blood closes the umbilical arteries. Do the two specialties have
to have a wall of cord clamps between their turfs? At c-section, would
not placental transfusion (generated by uterine contraction) be handled
best by the obstetrician while the neonatologist is managing the receiving
end?
“To our knowledge, a comprehensive health outcome has not been
studied in relation to placental transfusion.” This enormous “gap” in
perinatal knowledge is readily closed. On the premise that physiological
cord closure results in a physiological blood volume, several hundred
normal (preemie and term) deliveries should be allowed to proceed through
the third stage of labor without severing the cord until the placenta is
delivered. (Many midwives do this routinely.) Gunther’s method of
continuous weight recording [6] to measure placental transfusion could be
done on many selected cases. Placental and neonatal blood studies and
urine output are recorded; as are blood pressure, pulse and respiration
rates, oxygen saturation, suckling, weight change etc. One or two MRI
studies on the brain would be invaluable in providing radiologists with
records of normal perfusion of the neonatal brain. By establishing these
standards and parameters – physiological norms – correction of
abnormalities in the compromised neonate is greatly facilitated and put on
a rational, objective basis.
Professor Shah and his colleagues are in a unique position to
accomplish this goal of optimal neonatal resuscitation.
References
(1). Linderkamp O. Placental transfusion: determinants and effects.
Clinics in Perinatology 1982;9:559-592
(2). Morley GM. Letters to the Editor. OBSTETRICS & GYNECOLOGY
Vol.97 No. 6 June 2001 1024.
(3). N A Murray and I A G Roberts. Neonatal transfusion practice Arch.
Dis. Child. Fetal Neonatal Ed., Mar 2004; 89: F101 – 107
(5). ACOG Committee Opinion Number 138 - April 1994, published in the
International Journal of Gynaecology and Obstetrics 45:303-304 [54],
reaffirmed 2000, and listed as current in OBSTETRICS & GYNECOLOGY,
February 2002
(6). Gunther M. The transfer of blood between the baby and the placenta
in the minutes after birth. Lancet 1957;I:1277-1280.
Wright and Lee's article [1] provides an excellent overview of the
options to consider when parents decline the offer of conventional autopsy
following perinatal death.
Although a less invasive autopsy (LIA), such as one based on MRI, may
be more acceptable to many parents, the provision of such a service could
have significant implications, not just with regard to the availability of
a scar...
Wright and Lee's article [1] provides an excellent overview of the
options to consider when parents decline the offer of conventional autopsy
following perinatal death.
Although a less invasive autopsy (LIA), such as one based on MRI, may
be more acceptable to many parents, the provision of such a service could
have significant implications, not just with regard to the availability of
a scarce resource, in terms of availability of MRI services but also with
regard to how such a service should be provided.
Just as perinatal autopsy has largely become a regional specialist
service, it could be argued that MRI LIA (if offered) should also be a
regional specialist service, as smaller centres are unlikely to acquire
the expertise with smaller local numbers of perinatal deaths. In addition,
as experience is being acquired, conventional post-mortem should be
performed on referrals for MRI autopsy, and therefore probably restricted
to research studies, with appropriate informed consent.
If LIA was indeed more acceptable to parents, this would have
significant implications for audit and counselling. As Wright and Lee
highlight, current evidence suggests that MRI autopsy may not detect
clinically significant anomalies in different organ systems including the
gastrointestinal tract and the heart. Other abnormalities such as
anomalous lung lobation may also go undetected, and the quality of
counselling by obstetricians and neonatologists could be reduced. Genetic
syndromes may not be recognised, or be misdiagnosed, with false-negative
findings.
The loss of the 'gold-standard' autopsy would also have implications
for audit within fetal medicine and obstetric ultrasound services.
Although published work on post-mortem MRI of the fetal CNS is
encouraging [2], with regard to its specificity and sensitivity, we need
more data with which to counsel parents who are seeking a less-invasive
autopsy, but also potentially to explain its limitations in the apparent
absence of abnormality on MRI (even after one was suspected on antenatal
ultrasound, for example). Absence of evidence of abnormality (normal MRI
autopsy) cannot be at present equated with evidence of absence of
abnormality (normal conventional autopsy), and parents must be aware of
this when making choices at this difficult time. Consent for a
conventional or less-invasive autopsy, must therefore be sought by a
skilled clinician aware of these difficulties, as well as insight into
organ and tissue retention issues.
The proposed DoH-funded Less Invasive Autopsy studies [3] will make a
welcome contribution to our understanding of this area.
References
(1). Wright, C and Lee, REJ. Investigating perinatal death: a review of
the options when autopsy consent is refused
Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F285-F288
(2). Griffiths, P.D., et al., Postmortem MR imaging of the fetal and
stillborn central nervous system. AJNR Am J Neuroradiol, 2003. 24(1): p.
22-7.
The primary immunisation schedule in the UK is about to change for
the seventh time since the accelerated schedule was introduced in 1990.
The latest change, to a combined DTPaHibIPV vaccine (Pediacel), provoked a
flurry of lay concern.
Given the rapid advancement of vaccine technology that has prompted
such frequent changes to our primary immunisation policy it is inevitable
that we would...
The primary immunisation schedule in the UK is about to change for
the seventh time since the accelerated schedule was introduced in 1990.
The latest change, to a combined DTPaHibIPV vaccine (Pediacel), provoked a
flurry of lay concern.
Given the rapid advancement of vaccine technology that has prompted
such frequent changes to our primary immunisation policy it is inevitable
that we would have lessons to learn along the way. Amongst the important
ones are that not all populations respond to vaccines alike, (preterm
populations are different from those born at term [1], and ethnicity
matters [2]), interactions occur if vaccines are combined [3], and ‘minor’
changes may have ‘major’ consequences (DTPaHib combinations result in far
poorer Hib protection than DTPwHib combinations [4]).
It is sometimes impossible to determine precisely which immunisations
have been given to a study population, and how they were administered –
for example whether as separate or combined immunisations. Whilst we read
with great interest further data from Clarke and Robinson [5] on the
effect of steroid treatment on preterm infants’ immunisation responses
several important points are illustrated. The twelve infants reported
share identical demographic characteristics with (and are presumably the
same infants as) 12 infants previously reported in this journal after a
fourth dose of conjugate Haemophilus influenzae type b (Hib) vaccine (PRP-
T), where the implication was that a booster dose of PRP-T in such infants
would not increase Hib protection [6]. In the original paper no mention is
made of the fact that the extra PRP-T dose was actually administered with
DTPw, a fact only deducible with care 18 months later, yet one which may
alter the interpretation of the original paper. Likewise, the historical
data from both Ramsay [7] and Booy [8] predate the introduction of Hib and
Men C into the schedule. Comparison of the post primary immunisation GMTs
presented by Clarke [5] (immunised with the Trivax AD DTP vaccine) with
those of a more contemporaneous group of preterm steroid treated infants
(immunised with the Pasteur Meriuex DTPHib vaccine [9]) shows that only
the 95% confidence intervals for FIM and FHA overlap:
Vaccine Study
GMT
(95% CI)
Trivax AD(9)
ActHibDTP(5)
Diphtheria
0.424 (0.29-0.6)
2.08 (1.39-3.10)
Tetanus Pertussis
0.62 (0.42-0.91)
3.15 (1.67-5.93)
FIM
5085 (3360-7697)
15922 (6869-36908)
PT
264
(185-375)
1567 (613-4005)
FHA
1382 (1025-1863)
3011 (1806-5022)
As the schedule changes yet again may we suggest that future
publications ensure clear and explicit identification by name,
manufacturer and method of administration of all vaccines administered to
study subjects, whether or not the antibody response to a particular
component is the major focus of the paper. Such information would clearly
aid interpretation of the data.
References
(1). Slack MH, Schapira D, Thwaites RJ, Burrage M, Southern J, Andrews
N, et al. Immune response of premature infants to meningococcal serogroup
C and combined diphtheria-tetanus toxoids-acellular pertussis-Haemophilus
influenzae type b conjugate vaccines. Journal of Infectious Diseases
2001;184(12):1617-20.
(2). Ward J, Brenneman G, Letson G, Heyward W, and the Alaskan
Haemophilus influenzae group. Limited efficacy of a Haemophilus influenzae
type b conjugate vaccine in Alaskan native infants. New England Journal of
Medicine 1990;323:1393-1401.
(3). Bell F, Martin A, Blondeau C, Thornton C, Chaplais J and Finn A.
(1996) Combined diphtheria, tetanus, pertussis, and Haemophilus influenzae
type b vaccines for primary immunisation. Archives of Disease in
Childhood;75(4):298-303.
(4). Eskola J, Olander RM, Hovi T, Litmanen L, Peltola S, Kayhty H.
Randomised trial of the effect of co-administration with acellular
pertussis DTP vaccine on immunogenicity of Haemophilus influenzae type b
conjugate vaccine. Lancet 1996;348(9043):1688-92.
(5). Clarke P, Robinson M. DTP immunisation of steroid treated preterm
infants. Archives of Disease in Childhood Fetal & Neonatal Edition
2004;89:F468-470.
(6). Clarke P, Powell P, Goldblatt D, Robinson M. Effect of a fourth
Haemophilus influenzae type b immunisation in preterm infants who received
dexamethasone for chronic lung disease. Archives of Disease in Childhood
2003;88(S1):58-61.
(7). Ramsay ME, Miller E, Ashworth LA, Coleman TJ, Rush M, Waight PA.
Adverse events and antibody response to accelerated immunisation in term
and preterm infants. Archives of Disease in Childhood 1995;72(3):230-2.
(8). Booy R, Aitken SJ, Taylor S, Tudor-Williams G, Macfarlane JA,
Moxon ER, et al. Immunogenicity of combined diphtheria, tetanus, and
pertussis vaccine given at 2, 3, and 4 months versus 3, 5, and 9 months of
age. Lancet 1992;339(8792):507-10.
(9). Robinson M, Heal C, Gardener E, Powell P, Sims D. Antibody
response to diphtheria-tetanus-pertussis immunisation in preterm infants
who receive dexamethasone for chronic lung disease. Pediatrics
2004;113(4):733-737.
Dear Editor,
Congratulations to Behrendt and team for introducing yet another infection marker in premature babies [1]. However, there are several flaws in the study design which could render the study conclusions not clinically useful.
The authors repeatedly mention the aim of their study was to look at lipopolysaccharide binding protein (LBP) levels in premature babies. Results quoted however includ...
Dear Editor,
The study on storage of breastmilk and its effect on antioxidant levels [1] was well designed and provided some interesting information. However, the conclusions that the authors drew are based on conjecture about the clinical relevance of the findings. There is a potential risk to infant health if mothers follow their recommendations and abandon the pumping and storage of their milk.
The authors...
Dear Editor,
Drs. De Silva, Jones and Spencer have provided a timely review of issues relating to studies of breastmilk feeding for VLBW infants and rates of infection [1]. We would appreciate the opportunity to clarify some points they have raised regarding our study [2]. We believe our results clearly support our conclusion: that intake of greater than 50 ml/kg/day of maternal milk through week four of life...
Dear Editor
We appreciate the interest of Dr Gupta and his thoughtful comments.[1]
1. Primary disease of the neonates included in the study: Our original submission to the journal included a complete table describing in many more details the patient population. At the request of the reviewers/editors to shorten the paper, we removed the table which is now attached at the end of this letter.
2. Antibiot...
Dear Editor,
Chappell and Newman [1] have asked for urgent initiatives needed to ensure the manufacture of neonatal targeted products to reduce the risks associated with intravenous drug administration. We endorse their view and report a little recognized problem with use of adult formulations in neonatal nurseries
This investigation was conducted after we noticed symptoms of Digoxin overdose (brady-arrhythmia)...
Dear Editor,
I have read with interest a systematic and well-referenced review of causes of neonatal coagulation disorders in recent Archives [1]. However, amongst non-haematological causes of the coagulopathies the author has failed to mention a small, but significant subgroup of patients with neonatal liver failure (NLF).
This condition could often be difficult to diagnose due to presence of jaundice (ea...
Dear Editor,
I read with interest the publication of the audit on the use of central venous lines(CVL) by DW Cartwright.
He reported that 58.6% of the catheters were postioned in the right atrium, but there was no breakdown of where the other 41.8% tips were located. Probably this was because he was interested in only catheters in the right atrium. I would have liked to know as well if this information was i...
Dear Editor,
Professor Shah has submitted a comprehensive and well-documented response that agrees and disagrees with my letters. With clarification of a few points, I find that we may be very close to complete agreement, and to major improvement in neonatal outcome.
Regarding the definition of “asphyxia,” for want of a better, I use the term to describe the sum total of pathologies produced by compressi...
Dear Editor,
Wright and Lee's article [1] provides an excellent overview of the options to consider when parents decline the offer of conventional autopsy following perinatal death.
Although a less invasive autopsy (LIA), such as one based on MRI, may be more acceptable to many parents, the provision of such a service could have significant implications, not just with regard to the availability of a scar...
Dear Editor,
The primary immunisation schedule in the UK is about to change for the seventh time since the accelerated schedule was introduced in 1990. The latest change, to a combined DTPaHibIPV vaccine (Pediacel), provoked a flurry of lay concern.
Given the rapid advancement of vaccine technology that has prompted such frequent changes to our primary immunisation policy it is inevitable that we would...
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