I read Dr Anderson's article with interest because the removal of
codeine from the pharmacopeia for children under 12 years of age has
caused difficulty in my clinical practice.
I am a paediatric haematologist and in my unit in Manchester there
are over 420 children registered with bleeding disorders and another 100
or so on long term warfarin. The use of non-steroidal analgesics (NSAID)
is contra-indicated in...
I read Dr Anderson's article with interest because the removal of
codeine from the pharmacopeia for children under 12 years of age has
caused difficulty in my clinical practice.
I am a paediatric haematologist and in my unit in Manchester there
are over 420 children registered with bleeding disorders and another 100
or so on long term warfarin. The use of non-steroidal analgesics (NSAID)
is contra-indicated in all of these patients because of the effect that
NSAIDs have on platelet function. Yet painful muscle bleeds and joint
haemorrhages are a relatively common problem in children with inherited
bleeding disorders. As of now I can only use paracetamol that is often
relatively ineffective in these patients or immediately escalate to
morphine to help with their pain. How can this be safer for my patients
than having codeine as an intermediate step?
Manchester is only one of many paediatric centres for bleeding
disorders in the UK and this ban potentially affects thousands of children
and yet it would appear that their needs have not been considered in
making this rather sudden decision. Perhaps wider consultation would have
led to a more considered approach to this important clinical problem.
Morinis et al conclude that there remains a significant adverse
effect on verbal abilities in children born to teenage mothers at age five
years of age after adjustment for sociodemographic circumstances and
perinatal risk. However there appears to be a flaw in the methodology of
the study which undermines its findings.
In the characteristics of the study population by age group (table 1), the
response "Father at home- No...
Morinis et al conclude that there remains a significant adverse
effect on verbal abilities in children born to teenage mothers at age five
years of age after adjustment for sociodemographic circumstances and
perinatal risk. However there appears to be a flaw in the methodology of
the study which undermines its findings.
In the characteristics of the study population by age group (table 1), the
response "Father at home- No" rises from 51.7% at 9 months to 53.5% at 5
years. Implausibly, reading across the data for all age groups, the
parental relationships involving teenage mothers would appear more stable
over this period than those in any other age group. The presence of the
father at home falls for the other age groups by between 3 and 6%.
Clinical experience indicates that a substantial proportion of the young
mothers will have separated from the child's father and have begun a new
relationship in the 4 year interval. It would appear that the study
equates the presence of any male partner with having the child's father in
the home.
The Institute of Fiscal Studies, also using a sample of the Millennium
Cohort Study, found that 20% and 27% of unmarried cohabiting parents had
separated by the time the child was three and five years old respectively.
This is of no small consequence for the Morinis study because the IFS also
found that the separation of the birth parents was the most significant
adverse influence on the cognitive outcomes for children.
If, as it appears, any male partner has been considered as the father, and
the effect of the separation of a child's natural parents has not been
taken into account, the conclusions by Morinis are unsafe.
Goodman, A. and Greaves, E. (2010) Cohabitation, Marriage and Child Outcomes, IFS Commentary C114, Institute of Fiscal Studies.
We welcome the interest in our study reviewing the epidemiology and
referral patterns for boys with cryptorchidism.
We are in agreement with Dr Hadziselimovic that the retractile testis
is often misdiagnosed as undescended testis. However, we do not share his
experience that over half of patients 'sent' for treatment meet the
criteria for retractile testis. In our study, only 5% of boys had
retractile testis. In...
We welcome the interest in our study reviewing the epidemiology and
referral patterns for boys with cryptorchidism.
We are in agreement with Dr Hadziselimovic that the retractile testis
is often misdiagnosed as undescended testis. However, we do not share his
experience that over half of patients 'sent' for treatment meet the
criteria for retractile testis. In our study, only 5% of boys had
retractile testis. In addition, when comparing congenital with acquired
testis, we only included those who had documented scrotal findings from
the neonatal period. Our study does not attempt to draw conclusions about
the 'results'of 'treatment', merely to evaluate trends of referral and
management in relation to current recommended practice (References 4,5,6
in main article). We do not routinely offer surgery for retractile testes,
but continue to follow them up as many later ascend resulting in acquired
cryptorchidism( Agarwal)
We note the reservations of Dr Hadziselimovic regarding the impact of
orchidopexy on fertility, and indeed share them, as stated in our paper.
Although the final two statements in Dr Hadziselimovic's letter appear to
directly contradict each other, we certainly acknowledge that orchidopexy
at an early age may not prevent infertility and studies with much longer
follow-up are required. Again, this is beyond the scope of our study.
Additional Reference
Agarwal PK, Diaz M, Elder JS. Retractile testis--is it really a normal
variant? J Urol. 2006 Apr;175(4):1496-9.
The authors recommend that children on long term aspirin therapy for
complications of Kawasaki Disease should be immunised with varicella
zoster vaccine because of the risk of Reye's syndrome (RS) if they acquire
chicken pox. It is equally important that they receive influenza vaccine
annually because influenza is also associated with the development of RS
in children taking aspirin. In fact one of the groups listed as el...
The authors recommend that children on long term aspirin therapy for
complications of Kawasaki Disease should be immunised with varicella
zoster vaccine because of the risk of Reye's syndrome (RS) if they acquire
chicken pox. It is equally important that they receive influenza vaccine
annually because influenza is also associated with the development of RS
in children taking aspirin. In fact one of the groups listed as eligible
for annual routine flu vaccine in both the United States and South Africa,
is children and teenagers on aspirin.
I read with interest the paper by Drs Nah and colleagues on;
Undescended testis;513 patients' characteristics, age at orchidopexy and
patterns of referral (1).
The objective of this study was to describe current practice at the time
of orchidopexy . The results obtained should help to identify the
corrections necessary to optimize the treatment
Several principal questions should be raised:
1. The greatest challenge in a d...
I read with interest the paper by Drs Nah and colleagues on;
Undescended testis;513 patients' characteristics, age at orchidopexy and
patterns of referral (1).
The objective of this study was to describe current practice at the time
of orchidopexy . The results obtained should help to identify the
corrections necessary to optimize the treatment
Several principal questions should be raised:
1. The greatest challenge in a discussion regarding undescended testicles
is to exclude the retractile testis, for which no treatment would be
required except categorical reassurance. Examination in older boys has
certainly fooled many doctors and even experienced surgeons many times.
Over half of the patients sent for treatment could be expected to meet the
criteria for retractile testis and ff such cases are "treated", of course,
the "results" would be good. Therefore, it is vital to exclude such cases
from the discussion. The comparison of histology and hormonal levels
exemplify hypogonadotropic hypogonadism in the majority of cryptorchid
boys.(2) Importantly, only histological examination of the testicular
biopsy can distinguish a true cryptorchid testis from retractile one.
Therefore, to conclude that only congenital cryptorchid testes were
treated because these boys had surgery is inappropriate.
2. Most importantly, an early and seemingly successful orchidopexy
does not improve fertility in a substantial number of cryptorchid males
because it does not address the underlying pathophysiology of
cryptorchidism, namely, the impaired transformation of gonocytes into Ad
spermatogonia (impaired mini-puberty). It has been demonstrated that all
males having had an early (timely) and successful surgery but belonging to
the high infertility risk group develop severe oligospermia, with 20%
being azoospermic.(3) Furthermore, it has been demonstrated that
infertility caused by cryptorchidism, which is believed to be a congenital
malformation, can be successfully corrected if adequately treated. (4)
In conclusion, the recommendation to perform orchidopexy at an early age
gives the wrong impression that performing orchidopexy at an early age
will prevent development of infertility.
1 . Nah SA, Yeo CH, How G et al. Undescended testis: 513 patients'
characteristics, age at orchidopexy and patterns of referral Arch. Dis.
Child. 2013 0:Archdischild-2013-305225v1-archdischild-2013-305225;
doi:10.1136/archdischild-2013-305225
2. Hadziselimovic F, Hoecht B: Testicular histology related to
fertility outcome and postpubertal hormone status in cryptorchidism. Klin
P?diatr (2008) 220: 302-307
3. Hadziselimovic F, Hadziselimovic NO, Demougin
P, et al. Testicular gene expression in cryptorchid boys at risk of
azoospermia.
(2011).Sex Dev 5: 49-59 .
4. Hadziselimovic F: Successful treatment of unilateral cryptorchid boys
risking infertility with LH-RH analogue. Int Braz J Urol (2008).34: 319-
326
We thank Dr Hemila for sharing his work on Vitamin C with us. Dr
Hemila draws our attention to his analysis of the work by Karlowski et
al., which we read with interest. We are certainly in agreement with Dr
Hemila that "technically the Karlowski study is not among the best" with
regards to blinding.
In our paper, the referenced Karlowski article was an example of how
inadequate blinding can lead to questions...
We thank Dr Hemila for sharing his work on Vitamin C with us. Dr
Hemila draws our attention to his analysis of the work by Karlowski et
al., which we read with interest. We are certainly in agreement with Dr
Hemila that "technically the Karlowski study is not among the best" with
regards to blinding.
In our paper, the referenced Karlowski article was an example of how
inadequate blinding can lead to questions being raised on trial validity.
We are neither agreeing nor disagreeing on the original authors' analysis
of their own work.
More than half a century ago, M. J. Moroney pointed out that ". . .
the Poisson distribution may only be applied in cases where the
expectation, z, is constant from trial to trial. Thus, it does not apply
to the number of suicides per year in a given community, because the
temptation to commit suicide varies with the stress of the times, . . ."
(Facts from figures, 1956, pp 100-101.
More than half a century ago, M. J. Moroney pointed out that ". . .
the Poisson distribution may only be applied in cases where the
expectation, z, is constant from trial to trial. Thus, it does not apply
to the number of suicides per year in a given community, because the
temptation to commit suicide varies with the stress of the times, . . ."
(Facts from figures, 1956, pp 100-101.
In their short review, Wan et al. refer to the Karlowski et al.
(1975) study (1) as an example of problems caused by shortcomings in
blinding. Karlowski et al. found that vitamin C significantly shortened
the duration of colds; however, they proposed that the benefit of vitamin
C was causd by the placebo effect (1).
However, the placebo-effect explanation of Karlowski et al. was shown
to be erroneous 2 decades a...
In their short review, Wan et al. refer to the Karlowski et al.
(1975) study (1) as an example of problems caused by shortcomings in
blinding. Karlowski et al. found that vitamin C significantly shortened
the duration of colds; however, they proposed that the benefit of vitamin
C was causd by the placebo effect (1).
However, the placebo-effect explanation of Karlowski et al. was shown
to be erroneous 2 decades ago (2,3). The Karlowski et al. study has been
used as an evidence for the importance of blinding and for the claim that
vitamin C is not effective against the common cold. It is not a valid
evidence for either of those claims (2-4).
Refs.
1. Karlowski TR, et al. Ascorbic acid for the common cold. A
prophylactic and therapeutic trial. JAMA 1975;231:1038-42
2. Hemila H. Vitamin C, the placebo effect, and the common cold: a
case study of how preconceptions influence the analysis of results.
Journal of Clinical Epidemiology 1996;49:1079-84 [Discussion in:
1996;49:1085-7]
http://dx.doi.org/10.1016/0895-4356(96)00189-8
http://dx.doi.org/10.1016/0895-4356(96)00191-6
3. Hemila H. Do vitamins C and E affect respiratory infections?
Thesis. Medical Faculty, University of Helsinki, 2006: pp. 21-4
http://hdl.handle.net/10138/20335
4. Hemila H, Chalker EB. Vitamin C for preventing and treating the
common cold.
Cochrane Database of Systematic Reviews 2013; CD000980
http://dx.doi.org/10.1002/14651858.CD000980.pub4
We would like to thank Drs Jakob and Hentschel for their response to
our recent paper concerning the use of balloon occlusion catheters. Their
experience of single lung ventilation of preterm infants is very useful.
Our paper covered the use of balloon occlusion across a wider age range:
from preterm infants up to 6 years age. The mainstem bronchi are so short
in preterm infants that a balloon has only a small 'foothold'...
We would like to thank Drs Jakob and Hentschel for their response to
our recent paper concerning the use of balloon occlusion catheters. Their
experience of single lung ventilation of preterm infants is very useful.
Our paper covered the use of balloon occlusion across a wider age range:
from preterm infants up to 6 years age. The mainstem bronchi are so short
in preterm infants that a balloon has only a small 'foothold'. In these
patients there is no real difference between balloon occlusion and single
lung ventilation achieved by selective intubation of a bronchus. With
older and larger children, a few more options are available, but there
will never be big enough numbers to allow detailed studies of management
techniques. Common sense backed by clinical experience is the best guide -
the reason we welcome discussion based on the experiences of other
centres.
While there may be an increased risk of mucosal injury with use of a
balloon catheter, it did not occur in our case series, and is not reported
in the published literature. In our patients the catheter was inserted
over a guidewire placed down (1 patient) or alongside (5 patients) the
endotracheal tube (ETT). Inserting the catheter down the ETT avoids the
risk of damage to the upper airway. With modern dedicated thin catheters
and soft balloons, we believe a catheter can be passed down a 4.5 Fr
uncuffed ETT without excessive airway occlusion. Deflating the balloon for
5 minutes every hour is an arbitrary way to ensure mucosal safety, but it
does add the new risk of excessive re-inflation volumes during one of the
many re-inflation episodes. This re-emphasises the absolute need for very
careful nursing of these patients.
Modes of ventilation were too variable to give recommendations
suitable for every child. In the two children with bronchopleural
fistulae, several different modes (including high frequency oscillation
and jet ventilation) were used in an attempt to stabilise the patients
prior to bronchial balloon occlusion. One child had the added complication
of needing extracorporeal life support (ECLS) prior to balloon insertion.
Once the balloons were in place, ventilation could be weaned rapidly to
conventional techniques, and both patients made excellent recoveries.
In conclusion, we found endobronchial balloon occlusion to be a
minimally invasive, reversible and safe technique in the management of
complex pulmonary air leaks in children Careful selection of cases,
performance by skilled operators, and meticulous nursing care are all of
paramount importance.
References:
1. Jakob A, Hentschel R. Air leaks and pulmonary emphysema in
infants: selective bronchial intubation or balloon occlusion? Arch Dis
Child 2013;98(8):649.
2. Hathorn C, Armitage N, Wensley D, Seear M. Bronchial balloon
occlusion in children with complex pulmonary air leaks. Arch Dis Child
2013;98:136-140.
With pleasure we read the article by Allegaert et al(1) on the use of
paracetamol for ductus arteriosus closure with high doses of paracetamol
(15mg/kg q6h) and the response by Mazer-Amishahi(2). The authors propose
to initiate a prospective randomized controlled trial. Before embarking on
such a 'Proof of Concept' (POC) study, translational considerations may
provide usefull insights.
With pleasure we read the article by Allegaert et al(1) on the use of
paracetamol for ductus arteriosus closure with high doses of paracetamol
(15mg/kg q6h) and the response by Mazer-Amishahi(2). The authors propose
to initiate a prospective randomized controlled trial. Before embarking on
such a 'Proof of Concept' (POC) study, translational considerations may
provide usefull insights.
The considered mode of action for ductus closure is inhibition of
arachidonic acid metabolism by Prostaglandin-H2-synthetases (PGHS)(1,3-5).
By measuring prostaglandin or tromboxane generation rate, in-vitro, or ex-
vivo studies indicate that PGHS is inhibited with an IC50 (i.e.
concentration with 50% inhibition) of at least 5 - 10 mg/L(3,4,5). Because
of tissue specificity and a lack of direct measurement in ductus tissue,
it might be interesting to confirm this assumption in an ex-vivo setting
before embarking on a POC-study.
According to Allegaert average plasma concentrations in preterm
infants will range between 10 - 20 mg/L, i.e. a factor 2 above the
expected IC50's. This means inhibition of PGHS is expected to be just over
50%.
In a POC study this 50% inhibition is rather low. To provide an
answer to the question whether inhibiting an enzyme results in a clinical
response, one should aim for >90% inhibition. Ibuprofen, also used to
inhibit PGHS in the same indication has an IC50 around 0.4 mg/L with
neonatal plasmaconcentrations around 4 - 40 mg/L (taking protein binding
into account roughly a factor 10 higher).
If safety considerations limit the possibility to increase the dose
further as indicated in the mentioned response(2), the use of paracetamol
for this indication should be reconsidered.
Edwin Spaans, PharmD(1,2), Daniella Roofthooft, MD(3), Saskia de
Wildt MD, PhD(1)
1) Erasmus MC Sophia Children's Hospital, Dept of Pediatric Surgery and
Intensive Care
2) Kinesis-Pharma BV, Clinical Research
3) Erasmus MC Sophia Children's Hospital, Dept of Neonatology
Correspondence to:
Edwin Spaans, PharmD, Clinical Pharmacologist
ErasmusMC Sophia Children's Hospital
Dept of Intensive Care (SK-3232)
Dr Molewaterplein 60, 3015 GJ Rotterdam
Mail: e.spaans@erasmusmc.nl
References:
(1) Allegaert K, Anderson B, Simons S, et al. Paracetamol to induce ductus
arteriosus closure: is it valid? Arch dis Child 2013; 98: 462-6. Letter in
Response:
(2) Mazer-Amishahi M, van den Anker J. Arch Dis child 2013: doi:
10.1136/archdischild2013-304630
(3) Ouellet M, Percival MD. Mechanism of Acetaminophen Inhibition of
Cyclooxygenase Isoforms. Archives of Biochemistry and Biophysics?2001; 387
(2): 273-280
(4) Boutaud O, Aronoff DM, Richardson HJ, Marnet LJ, Oates JA.
Determinants of the cellular specificity of acetaminophen as an inhibitor
of prostaglandin H2 synthases. PNAS 2002, 99; 10: 7130-7135
(5) Hinz B, Cheremina O, Brune K. Acetaminophen (paracetamol) is a
selective cyclooxygenase-2 inhibitor in man. FASEB journal 2007; 22: 1 - 8
I read Dr Anderson's article with interest because the removal of codeine from the pharmacopeia for children under 12 years of age has caused difficulty in my clinical practice.
I am a paediatric haematologist and in my unit in Manchester there are over 420 children registered with bleeding disorders and another 100 or so on long term warfarin. The use of non-steroidal analgesics (NSAID) is contra-indicated in...
Morinis et al conclude that there remains a significant adverse effect on verbal abilities in children born to teenage mothers at age five years of age after adjustment for sociodemographic circumstances and perinatal risk. However there appears to be a flaw in the methodology of the study which undermines its findings. In the characteristics of the study population by age group (table 1), the response "Father at home- No...
We welcome the interest in our study reviewing the epidemiology and referral patterns for boys with cryptorchidism.
We are in agreement with Dr Hadziselimovic that the retractile testis is often misdiagnosed as undescended testis. However, we do not share his experience that over half of patients 'sent' for treatment meet the criteria for retractile testis. In our study, only 5% of boys had retractile testis. In...
The authors recommend that children on long term aspirin therapy for complications of Kawasaki Disease should be immunised with varicella zoster vaccine because of the risk of Reye's syndrome (RS) if they acquire chicken pox. It is equally important that they receive influenza vaccine annually because influenza is also associated with the development of RS in children taking aspirin. In fact one of the groups listed as el...
I read with interest the paper by Drs Nah and colleagues on; Undescended testis;513 patients' characteristics, age at orchidopexy and patterns of referral (1). The objective of this study was to describe current practice at the time of orchidopexy . The results obtained should help to identify the corrections necessary to optimize the treatment Several principal questions should be raised: 1. The greatest challenge in a d...
We thank Dr Hemila for sharing his work on Vitamin C with us. Dr Hemila draws our attention to his analysis of the work by Karlowski et al., which we read with interest. We are certainly in agreement with Dr Hemila that "technically the Karlowski study is not among the best" with regards to blinding.
In our paper, the referenced Karlowski article was an example of how inadequate blinding can lead to questions...
More than half a century ago, M. J. Moroney pointed out that ". . . the Poisson distribution may only be applied in cases where the expectation, z, is constant from trial to trial. Thus, it does not apply to the number of suicides per year in a given community, because the temptation to commit suicide varies with the stress of the times, . . ." (Facts from figures, 1956, pp 100-101.
Conflict of Interest:
...In their short review, Wan et al. refer to the Karlowski et al. (1975) study (1) as an example of problems caused by shortcomings in blinding. Karlowski et al. found that vitamin C significantly shortened the duration of colds; however, they proposed that the benefit of vitamin C was causd by the placebo effect (1).
However, the placebo-effect explanation of Karlowski et al. was shown to be erroneous 2 decades a...
We would like to thank Drs Jakob and Hentschel for their response to our recent paper concerning the use of balloon occlusion catheters. Their experience of single lung ventilation of preterm infants is very useful. Our paper covered the use of balloon occlusion across a wider age range: from preterm infants up to 6 years age. The mainstem bronchi are so short in preterm infants that a balloon has only a small 'foothold'...
With pleasure we read the article by Allegaert et al(1) on the use of paracetamol for ductus arteriosus closure with high doses of paracetamol (15mg/kg q6h) and the response by Mazer-Amishahi(2). The authors propose to initiate a prospective randomized controlled trial. Before embarking on such a 'Proof of Concept' (POC) study, translational considerations may provide usefull insights.
The considered mode of acti...
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