Dr Asumang in her eletter, in response to my recently published audit
of peripherally inserted central venous catheters (PICCs) in neonates,
questions the details of the location of line tips, and the determination
and recording of tip positions.
Tip positions were – right atrium (1282),
SVC (239), subclavian vein (203), limb vein (100), IVC (98), jugular vein
(71), innominate vein (61), ne...
Dr Asumang in her eletter, in response to my recently published audit
of peripherally inserted central venous catheters (PICCs) in neonates,
questions the details of the location of line tips, and the determination
and recording of tip positions.
Tip positions were – right atrium (1282),
SVC (239), subclavian vein (203), limb vein (100), IVC (98), jugular vein
(71), innominate vein (61), neck vein (11), iliac vein (9), aorta (8 –
removed on recognition), chest wall vein (7), cephalic vein (4), axillary
vein (2), ascending lumbar vein (2), abdominal wall vein (1), pulmonary
artery (1), not recorded (73) and unknown – record not traced (14).
As detailed in the methods section of the paper, line tip positions
are recorded prospectively, initially in the medical chart notes. Since
1996, these have been recorded then into the computerised neonatal
database. While preparing this paper, needing as described to retrieve
some such details from medical charts in the 1991-1995 time period, I
realised that the chart records of line insertions were not always as
complete as I would desire, and unsuccessful attempts were virtually never
recorded. Therefore in late 2001 we introduced a ‘procedure stamp’ to be
placed into the chart and filled in for every attempted line insertion.
For central venous lines, line tip positions recorded are those determined
by the clinical medical staff who insert the line, not those in imaging
department reports. I hold very strongly to the view that any imaging
report of a vascular catheter or endotracheal tube that describes the tip
position as ‘satisfactory’ is an unsatisfactory report. Imaging reports,
and chart medical records, should record anatomical tip positions. It is
the responsibility of clinical medical staff to decide whether the
position is ‘satisfactory’ or not, and to clearly document this opinion
and any action taken when it is deemed to be ‘unsatisfactory’.
As an addendum to my paper, I might now add that while that issue
of your journal was being printed, in a recent one month period I twice
saw the complication of pleural effusion, manifest as sudden onset of
respiratory distress, in babies with central venous catheters in place.
In my paper I stated correctly that I had not ever seen that complication.
One catheter was a surgically inserted catheter, the other a ‘PICC’. The
tips of both catheters were clearly demonstrated to be well outside the
heart, in the region of the superior vena cava. Both complications were
dealt with swiftly and effectively with no detriment to the baby. One
required needle thoracocentesis and line removal, the other simply line
removal. These observations do not alter the main conclusion of my paper
– that central venous catheters ‘with their tips in the right atrium and
not coiled do not cause pericardial effusion’. They do emphasise that
catheters placed with their tips in and around the heart are inherently
risky, we must know accurately where their tips are located, and we must
be eternally vigilant while such catheters are in place and balance their
continued presence against demonstrable positive need.
We read with great interest the review by Dorling et al [1]. on
neonatal illness severity score systems (NISS), in which the authors have
thoroughly examined the strengths and weaknesses of the existing methods.
We would like to add a few points to the ongoing debate [2] on the
usefulness and limitations of the NISS.
Assessment of illness severity in
the newborn is of paramount impo...
We read with great interest the review by Dorling et al [1]. on
neonatal illness severity score systems (NISS), in which the authors have
thoroughly examined the strengths and weaknesses of the existing methods.
We would like to add a few points to the ongoing debate [2] on the
usefulness and limitations of the NISS.
Assessment of illness severity in
the newborn is of paramount importance, especially in neonatal intensive
care unit (NICU) environment, certainly justifies the ongoing efforts
in the search for easy-to-use, reproducible, and accurate methods.
Potential limitations may arise from the concepts on which the currently
available methods are based.
Firstly, it should be noted that treatment
modalities could not only influence neonatal outcomes, as indicated by the
report of increased mortality odds among inborn infants 32 weeks'
gestation admitted to NICUs at night compared with during daytime [3], but
also the relationship between NISS and neonatal morbidity and mortality.
To this regard, we have recently shown that CRIB and CRIB-II scores have
similar accuracy values in predicting in-hospital neonatal mortality in a
population of VLBW infants and that neither score offers an advantage in
predicting mortality compared to gestational age or birth weight when
applied to a minimal intubation policy NICU setting [4].
The potential
relevance of these findings, far from being interpreted as a specific
criticism to the CRIB scores, is that treatment modalities can modify both
predictive accuracy of illness severity scores and neonatal outcomes.
Secondly, the potential effects of perinatal conditions on postnatal
disease severity should be taken into account. For instance, histologic
chorioamnionitis (HCA) is a major challenge in perinatology, often
subclinical and associated with high rates of preterm birth leading to
fetal/neonatal morbidity and mortality [5]. HCA is likely to be mediated
by a fetal inflammatory response syndrome, and can be considered a natural
model for neonatal illness severity in high-risk newborns [6]. Our group
has recently demonstrated that, after adjustment for potential confounders
in a multivariable logistic regression analysis, HCA is an independent
predictor of high illness severity in very low birth weight infants [7].
Thirdly, and most important, it should be noted that the calculation of a
risk assigned to a measured score is an epidemiologic tool, and never
should be used as a single patient prevision tool [8]. As a consequence,
there is urgent need for new, non-invasive, accurate, and real time risk-
adjustment indices of neonatal illness severity, based on different
concepts. We have previously reported on the potential value of skin
colorimetry [9,10], skin spectrophotometry [11], and pulse oximetry-
derived perfusion index [12] in identifying higher-severity newborns.
Emerging evidence indicates that the dynamic analysis of heart rate (R-R)
variability provides relevant information and is applicable to the health
status assessment in a neonatal population [13, 14].
Several
homeostatically controlled systems show nonrandom, nonperiodic, systematic
variations in time. This is likely to be related to the fact that, in
living organisms, essential natural rhythms should maintain sufficient
regularity to preserve function and sufficient flexibility in stress
adaptation. We have applied a nonlinear dynamic (NLD) approach, based on
the chaos theory, to real-time monitoring of pulse oximetry-derived
signals, and our preliminary results indicate the occurrence of an early
loss in chaotic behaviour for pulse-to-pulse and perfusion index
variability in newborns with higher illness severity [15].
Moreover,
recent evidence suggests the feasibility of a methodology based on NLD
analysis of fetal heart rate, and found to be helpful in identifying
pathological states [16]. These data suggest:
(i) the importance of an
integrated obstetric-neonatological approach to the issue of neonatal
illness severity, with a particular emphasis toward a better understanding
of illness severity already in the fetus;
(ii) and the need for novel,
real-time indices, which should enable the neonatologist to identify
higher-severity newborns, monitoring the evolution of their health
status, and possibly applying potential preventive and/or specific
therapeutic strategies.
References
(1). Dorling JS, Field DJ, Manktelov B Neonatal disease severity score
systems. Arch Dis Child Fetal Neon Ed 2005;90 F11-F16
(2). Meadow W, Frain L, Ren Y, et al. Serial assessment of mortality in the
neonatal intensive care unit by algorithm and intuition: certainty,
uncertainty, and informed consent. Pediatrics 2002;109:878-86.
(3). Lee SK, Lee DS, Andrews WL, Baboolal R, et al.; Canadian Neonatal
Network. Higher mortality rates among inborn infants admitted to neonatal
intensive care units at night. J Pediatr 2003;143:592-7.
(4). De Felice C, Del Vecchio A, Latini G. Evaluating illness severity for
very low birth weight infants: CRIB or CRIB-II? J Mat Fet Neon Med. In
press.
(5). Hagberg H, Wennerholm UB, Savman K. Sequelae of chorioamnionitis. Curr
Opin Infect Dis 2002;15:301-6
(6). Gomez R, Romero R, Ghezzi F, et al. The fetal inflammatory response
syndrome Am J Obstet Gynecol 1998;179:194-202
(7). De Felice C, Toti P, Parrini S, et al. Histologic chorioamnionitis and
severity of illness in very low birth weight newborns. Pediatr Crit Care
Med. In press.
(8). Lemeshow S, Le Gall JR. Modeling the severity of illness of ICU
patients. A systems update. JAMA. 1994;272:1049-55
(9). De Felice C, Flori ML, Pellegrino M, et al. Predictive value of skin
color for illness severity in the high-risk newborn. Pediatr Res.
2002;51:100-5.
(10). De Felice C, Vacca P, Del Vecchio A, et al. Early postnatal skin
colour changes in term newborns with subclinical histologic
chorioamnionitis. Eur J Pediatr. 2004;163(9):550-4.
(11). De Felice C, Mazzieri S, Pellegrino M, et al. Skin reflectance changes
in preterm infants with patent ductus arteriosus. Early Hum Dev 2004;78:45
-51.
(12). De Felice C, Latini G, Vacca P, et al. The pulse oximeter perfusion
index as a predictor for high illness severity in neonates. Eur J Pediatr
2002;161:561-562.
(13). Griffin MP, O'Shea TM, Bissonette EA, et al. Abnormal heart rate
characteristics are associated with neonatal mortality. Pediatr Res
2004;55:782-8.
(15). De Felice C, Bianciardi, G, Parrini S, et al. Pulse oximetry signals
chaotic analysis in the evaluation of neonatal illness severity. Pediatr
Res 2004;56:475.
(16). Signorini MG, Magenes G, Cerutti S, Arduini D. Linear and nonlinear
parameters for the analysis of fetal heart rate signal from
cardiotocographic recordings. IEEE Trans Biomed Eng 2003;50:365-74.
Reynolds et al report on a very immature newborn infant who suffered
severe skin damage after periumbilical administration of an alcohol-based
antiseptic [1]. The burned skin may serve as a microbial entry port and
give rise to lasting scars [2]. After topical skin application, ethanol or
propanol cause substantial decreases of functional capillary density and
red blood cell velocity, which is...
Reynolds et al report on a very immature newborn infant who suffered
severe skin damage after periumbilical administration of an alcohol-based
antiseptic [1]. The burned skin may serve as a microbial entry port and
give rise to lasting scars [2]. After topical skin application, ethanol or
propanol cause substantial decreases of functional capillary density and
red blood cell velocity, which is less pronounced after administration of
hexamethylenbiguanide (Lavasept) and absent after 2-
phenoxyethanol/octenidine (Octenisept) administration [3].
When the
commercially available 2-phenoxyethanol/octenidine solution was tested in
24 consecutive preterm infants born at 24-27 weeks gestational age, we
found only one infant to have a transient erythematous rash.[2] As shown
by quantification of 2-phenoxyethanol and 2-phenoxyacetic acid in urine,
the 2-phenoxyethanol absorbed through the infants' skin is readily
detoxified by oxidative metabolism and urinary excretion.
While iodine-
containing antiseptics may cause subclinical hypothyroidism in preterm
infants,[4] a combination of phenoxyethanol and octenidine in water may be
a safe alternative to alcohol-based antiseptics prior to insertion of
intravenous or intraarterial lines in very immature newborn infants.
References
(1). Reynolds PR, Banerjee S, Meek JH. Alcohol burns in extremely low
birthweight infants: still occurring. Arch Dis Child Fetal Neonatal Ed
2005;90:F10.
(2). Bührer C, Bahr S, Siebert J, Wettstein R, Geffers C, Obladen M.
Use of 2% 2-phenoxyethanol and 0.1% octenidine as antiseptic in premature
newborn infants of 23-26 weeks gestation. J Hosp Infect 2002;51:305-7.
(3). Langer S, Sedigh Salakdeh M, Goertz O, Steinau HU, Steinstraesser
L, Homann HH. The impact of topical antiseptics on skin microcirculation.
Eur J Med Res 2004;9:449-54.
(4). Linder N, Davidovitch N, Reichman B, Kuint J, Lubin D, Meyerovitch
J, Sela BA, Dolfin Z, Sack J. Topical iodine-containing antiseptics and
subclinical hypothyroidism in preterm infants.J Pediatr 1997;131:434-9.
Omari and Cameron are not quite right when they extrapolate from the
literature on knotted cords in singleton pregnancies to the particular
situation of monochorionic monoamniotic twins. It is true to point out
that a single true knot in the cord is rarely of significance when there
is one baby, although on occasion even these can tighten and cause
hypovolaemic shock and/or hypoxic ischaemia.
Omari and Cameron are not quite right when they extrapolate from the
literature on knotted cords in singleton pregnancies to the particular
situation of monochorionic monoamniotic twins. It is true to point out
that a single true knot in the cord is rarely of significance when there
is one baby, although on occasion even these can tighten and cause
hypovolaemic shock and/or hypoxic ischaemia.
However, in the very rare
situation of a monoamniotic pregnancy (only 1% of monozygotic twins) the
risk of fetal death or brain damage from cord entanglement is very real.
Indeed, many reputable UK centres electively delivery monoamniotic twins
at 32 weeks precisely because of this risk, which is estimated to be
greater than the risk of prematurity at this gestation (Allen et al.
2001). Some studies estimate the risk of fetal death in this situation as
50-70% although Allen et al report a better outcome with active
intervention.
The twins in Glan Clwyd were lucky, and even though they both
survived they should be offered neuroimaging.
Reference
(1). Allen, V. M., Windrim, R., Barrett, J., & Ahlsson, A. 2001,
"Management of monoamniotic twin pregnancies: a case series and systematic
review of the literature", British Journal of Obstetrics &
Gynaecology, vol. 108, pp. 931-936.
We read with interest the study by Heikkinen et al [1] and the letter
by Bala, Ryan and Murphy [2] on bronchiolitis hospital admissions and of
Palivizumab prophylaxis. We would like to add our experience on the issue.
Our retrospective study covered the period from 01.01.1995 to 31.12.2000
i.e. a 6-year period before Palivizumab prophylaxis became available in
Greece. We looked into hosp...
We read with interest the study by Heikkinen et al [1] and the letter
by Bala, Ryan and Murphy [2] on bronchiolitis hospital admissions and of
Palivizumab prophylaxis. We would like to add our experience on the issue.
Our retrospective study covered the period from 01.01.1995 to 31.12.2000
i.e. a 6-year period before Palivizumab prophylaxis became available in
Greece. We looked into hospital admissions with the clinical diagnosis of
bronchiolitis of infants born less than 32 weeks of gestation within one
year after discharge from our NICU. We did not specifically look for RSV
diagnosis as in Greece rapid laboratory testing for this virus became
widely available as late as 1999.
Information was collected and analysed
using NICU and follow up medical notes; medical notes of the hospital
the infants were admitted in case of bronchiolitis as well as parental
questionnaire and direct telephone contact.
During the study period 289 infants were discharged and 5 deaths (1.7%)
occurred following discharge, all unrelated to respiratory disease. Of the
remaining 284 infants, 242 (85%) were traced and were included in this
analysis. The median gestational age was 29 weeks (24-31 weeks) and the
median birthweight was 1200g (550-1810g). Mechanical ventilation received
161 (66.5%) and oxygen administration at 36 weeks required 11 (4.5%). No
infant was discharged home on oxygen. Total admissions to hospital within
one year of discharge involved 56 infants (23.1%), while 25 (10.3%) were
admitted with the clinical diagnosis of bronchiolitis. None of these
infants required intensive care including mechanical ventilation and the
median length of hospitalisation was 7 days (5-14 days). There were no
deaths.
Using logistic regression analysis of probable factors influencing
bronchiolitis hospital admission revealed that the presence of older
siblings at home significantly increased the chance of admission (OR 5.5
95%CI 2.69 13.82, p<_0.001 particularly="particularly" if="if" the="the" older="older" sibling="sibling" was="was" attending="attending" nursery="nursery" or="or" school="school" _6.25="_6.25" _95ci="_95ci" _2.63="_2.63" _16.67="_16.67" p0.001.="p0.001." eighty="eighty" percent="percent" of="of" _25="_25" infants="infants" had="had" siblings.="siblings." no="no" association="association" found="found" with="with" other="other" factors="factors" such="such" as="as" peri="peri" neonatal="neonatal" gestational="gestational" age="age" birthweight="birthweight" prenatal="prenatal" administration="administration" steroids="steroids" mechanical="mechanical" ventilation="ventilation" surfactant="surfactant" oxygen="oxygen" dependency="dependency" at="at" _28="_28" days="days" _36="_36" weeks="weeks" maternal="maternal" milk="milk" family="family" history="history" asthma="asthma" parental="parental" smoking="smoking" pet="pet" in="in" household="household" sleeping="sleeping" arrangement.="arrangement." p="p"/>
Since no information regarding RSV infection was available we hypothesised
that all episodes of bronchiolitis necessitating admission to hospital
were due to RSV. Using American Academy recommendations [3] and the
results of the Impact Study [4], prophylaxis of 17.1 infants with the
monoclonal antibody (Palivizumab) would be required to avert 1 hospital
admission. It was estimated that Palivizumab prophylaxis would reduce
hospital costs by 29400€ but would have cost 575000€. Prophylaxis of the
infants with older sibling(s) i.e. 36% of 242 infants of this study would
have included 20 out of 25 hospitalised infants (80%) because of
bronchiolitis.
We entirely endorse the conclusions by Heikkinen et al [1] and Bala et al
[2]
References
(1). Heikkinen T, Valkonen H, Lehtonen L et al. Hospital admission of
high risk infants for respiratory syncytial virus infection: implications
for palivizumab prophylaxis. Arch Dis Child Fetal Neonatal Ed 2005; 90:F64
-F68
(2). Bala P, Ryan CA, Murphy BP. Hospital admissions for bronchiolitis
in preterm infants in the absence of respiratory syncytial virus
prophylaxis. Arch Dis Child Feta Neonatal Ed 2005;90:92
(3). American Academy of Pediatrics. Prevention of respiratory
syncytial virus infections: indications for the use of palivizumab and
update on the use of RSV-IGIV. Pediatrics 1998;102:1211-16
(4). The Impact-RSV Study Group. Palivizumab, a humanized respiratory
syncytial virus monoclonal antibody, reduces hospitalisation from
respiratory syncytial virus infection in high risk infants. Pediatrics
1998;102:531-7
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
Dear Editor,
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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)...
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