Cerebral Edema During Treatment of Diabetic Ketoacidosis:
Fall In Ketoacid Levels and Consequent Fall In Osmolality May Be A Culprit
Inward and Chambers[1] have called for a rethink of the management
of diabetic ketoacidosis. In their article they quote a study by Grove L M
and colleagues[2] suggesting that pediatricians overestimated the quantum
of dehydration in DKA. Over correction of dehydrat...
Cerebral Edema During Treatment of Diabetic Ketoacidosis:
Fall In Ketoacid Levels and Consequent Fall In Osmolality May Be A Culprit
Inward and Chambers[1] have called for a rethink of the management
of diabetic ketoacidosis. In their article they quote a study by Grove L M
and colleagues[2] suggesting that pediatricians overestimated the quantum
of dehydration in DKA. Over correction of dehydration is implicated in
precipitating cerebral edema.
On the face of it, it seems implausible that pediatricians who are so
adapt at estimating dehydration in the context of gastroenteritis,
diarrhea, and vomiting should err in estimating the dehydration in DKA,
unless the dehydration of DKA has special features. Hypertonicity may be
that special feature. We hypothesize that hypertonic dehydration can
result in the tongue appearing dry and parched and when this is combined
with acidotic respiration of DKA, the treating pediatrician may classify
the child as more severely dehydrated than he or she actually is.
In a study of DKA we found that the mean osmolality at admission was
318 (SD 12.9, Range 291-337).[3] Further we also found that the
calculated osmolality {Calculated osmolality=1.86(Na + + K + ) + Urea +
Glucose} [4] was only 289 (Range 282 - 304) . This suggests hypertonicity
is common in DKA and calculated osmolality underestimates the true
osmolality. The mean osmolar gap was 29 (Range 14-48).
The osmolar gap between true and the calculated osmolality, is made up of
unmeasured substances like ketoacids. The osmolality of ketoacids have
been ignored in the past, as they are considered to be osmotically
inactive and not contributing to osmotonicity.[5] A study done by us
(sent for publication) has demonstrated that ketoacids (acetoacetates)
are osmotically active. (Acetoacetate can influence fluid shifts across a
semipermeable membranes. This is in contrast to urea, which is not
osmotically active) Osmolality, osmolar gap and ketone bodies are not
measured routinely during the management of DKA. A rapid fall in ketone
body level can result in a fall in osmolality and osmoticity of the serum
and lead to cerebral edema.
In a recent paper looking at the risk factors for development of cerebral
edema in DKA[6] the author noted that since none of the ‘relevant
variables’ - serum glucose concentration at presentation, change in serum
glucose concentration during therapy, rate of fluid and sodium
administration were associated with the risk of cerebral edema, their data
did not support the theory that a rapid decrease in extra cellular
osmolality during treatment results in osmotic mediated swelling.
Osmolality and osmolar gap were not measured, nor was ketone body levels
studied (Personal communication Glaser N ). Our studies demonstrates that
the ketone level is probably a 'relevant variable ' that needs to be
estimated before we can be certain that rapid decrease in extra-cellular
osmolality did not occur.
In summary we suggest that changes in ketone body levels be considered, as
a factor that can be partially responsible for the cerebral edema often
seen during treatment of DKA .We will be glad to share our data at any
summit of experts convened to study the enigma of cerebral edema in DKA.
(2) Grove LM, Nobel-Jamieson CM, Barnes ND et al. Assessment of
dehydration, fluid balance and insulin requirement in diabetic
ketoacidosis. Proc Br Paediatr Assoc Annual Meet 1995; 67:26.
(3) Puliyel J, Puliyel M, Hincliffe R. Hypertonicity in diabetic
ketoacidosis. Proceedings of International Symposium on Diabetes. Chaing
Mai Thailand Jan 26 - 29 1997.
(4) Varley H, Gowenlock AH, Bell M. Practical Clinical Biochemistry. 5
Th ed. London, William Heinemann Medical Books Ltd, 1980: 776-777.
(5) Van der Meulen JA, Klip A, Grinstein S. Possible mechanism for
cerebral edema in diabetic ketoacidosis. Lancet 1987; ii 306-8.
(6) Glaser N, Bernett P, McCaslin I, et al. Risk factors for cerebral
edema in children with diabetic ketoacidosis. N Engl J Med 2001; 344: 264-
9.
I read with great interest Clarkson and Choonara’s paper on the fatal
suspected adverse drug reactions (ADRs) in the UK, and I strongly agree
with their conclusions, namely that an evidence-based approach to drug
therapy is needed to minimise fatalities due to drug toxicity in children.[1] However, recent evidence also suggests that we are now ready for a
gene based approach to drug therapy allowing...
I read with great interest Clarkson and Choonara’s paper on the fatal
suspected adverse drug reactions (ADRs) in the UK, and I strongly agree
with their conclusions, namely that an evidence-based approach to drug
therapy is needed to minimise fatalities due to drug toxicity in children.[1] However, recent evidence also suggests that we are now ready for a
gene based approach to drug therapy allowing to further minimise the
occurrence and the severity of adverse drug reactions.[2] Increasingly
complex genetic knowledge can be already used to elucidate mechanisms
underlying the adverse events of drugs, to identify biomarkers for
physiological events, and potentially even to predict adverse events
before human exposure.[3] In a recently published systematic review, the
authors found that more than half of the drugs cited in ADR studies are
metabolized by at least one enzyme with a variant allele known to cause
poor metabolism, suggesting that genetic variability in drug metabolizing
enzymes is likely to be an important contributor to the incidence and
severity of ADRs.[4]
In the Clarkson and Choonara’s paper it is reported that anticonvulsants
was the group of drugs most frequently associated with fatal ADRs.
Anticonvulsants are indeed among the drugs mostly concerned by enzymes
with variant alleles associated with poor metabolism. A number of
polimorfisms in the cytocrome P450 enzimes (CYPs), important in the
metabolism of anticonvulsants have been reported. For example, the enzyme
CYPIA2, which is one important metabolic pathway for carbamazepine and
phenitoin, has only one identified variant allele with poor metabolism,
but there is a significant prevalence of poor metabolisers for CYPIA2
among the general population. Other common polymorphisms concern the
enzyme CYP2C19, resulting in altered metabolism of both phenobarbital and
phenitoin.[5]
Substantial investments are being made within the pharmaceutical and
biotechnology industries to use genomic strategies for the development of
therapeutic agents targeted for specific subgroups of the population. Such
pharmacogenomic studies also permit a more rational and safer use of
existing therapies. It is my hope that this translation of functional
genomics into rational therapeutics will not neglect the right of children
to receive safer and more efficient pharmacotherapy, and that the pace of
this transformation will not be limited by the lack of adequate
pharmacogenomic information to practicing paediatricians.
References
(1) Clarkson A, Choonara I. Surveillance for fatal suspected adverse drug
reactions in the UK. Arch Dis Child 2002;87:462-7.
(2) Varmus H. Getting ready for Gene-Based Medicine. N Engl J Med
2002;347:1526-7.
(3) Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet
2000;356:1667-71.
(4) Phillips KA, Veenstra DL , Oren E, et al. Potential Role of
pharmacogenomics in reducing adverse drug reactions: a systematic review
JAMA 2001;286:2270-9.
(5) Holmes L. The interface of preclinical evaluation with clinical
testing of antiepileptic drugs: role of pharmacogenomics and
pharmacogenetics. Epilepsy Research 2002 50;1-2:41-54.
In an outstanding piece of medical detective work, Drs Fox, Palmer
and Davies lay to rest the widespread myth that bottom shuffling is a
dominantly inherited trait with such penetrance that it can be traced back
to mediaeval times by simple nomenclature. Thus Shufflebottoms do not
bottom-shuffle more than Walkers. Whether it is appropriate for doctors
from Luton to be examining such an area of Lancastri...
In an outstanding piece of medical detective work, Drs Fox, Palmer
and Davies lay to rest the widespread myth that bottom shuffling is a
dominantly inherited trait with such penetrance that it can be traced back
to mediaeval times by simple nomenclature. Thus Shufflebottoms do not
bottom-shuffle more than Walkers. Whether it is appropriate for doctors
from Luton to be examining such an area of Lancastrian sensitivity is one
matter. However, the authors announce their intention to go on to exonerate
other nomenclaturely-challenged souls from historical taint.
Am I alone in noticing that the surnames of two of the three authors
were associated with cheating and card sharping in years gone by? Surely
this warrants a declaration of Conflict of Interest.
The editorial by Russell [1] suggests that when high dose inhaled
steroids are being considered the use of fluticasone diproprionate should
be avoided, on the basis of this survey.[2] Clinical studies rather than
a questionnaire based survey should form the basis for such advice. Such
studies show no increased risk of hypothalamic pituitary axis (HPA)
suppression with fluticasone propionate when comp...
The editorial by Russell [1] suggests that when high dose inhaled
steroids are being considered the use of fluticasone diproprionate should
be avoided, on the basis of this survey.[2] Clinical studies rather than
a questionnaire based survey should form the basis for such advice. Such
studies show no increased risk of hypothalamic pituitary axis (HPA)
suppression with fluticasone propionate when compared with other inhaled
steroids.
The recent publication by the CSM "Current Problems in
Pharmacovigilance"[3] on inhaled steroids and adrenal suppression in
children emphasises that all inhaled steroids may cause side effects. As
such, cases of adrenal suppression are dose-related class effects,
associated with all inhaled steroids. Focussing on one inhaled steroid may
lead to children being switched inappropriately from one inhaled steroid
to another rather than highlighting the potential problems associated with
the prescribing of out of licence doses of drugs in children.[3]
The paper states that a considerable proportion of the patients are
likely to have been over-treated with inhaled steroids.[2] With reference
to children it should be noted that all (rather than a considerable
proportion) of the children reported in the paper were treated with doses
of fluticasone between 500-2000 mcg daily, which are up five times greater
than the maximum recommended dose.
In a published correspondence entitled "The side effects of high-dose
fluticasone propionate in children", Dr Todd highlighted that a survey of
specialist paediatric centres in the UK showed that when high doses of
inhaled corticosteroids (>1000mcg daily) were thought necessary, nearly
all choose fluticasone propionate.[4] This may explain the preponderance
of cases on fluticasone propionate in the article.
It is worth noting that reported cases of adrenal suppression are not
restricted to fluticasone diproprionate alone. Of eight cases reported by
Patel in 2001, three were receiving budesonide 400mcg/day, one
beclometasone 600mcg/day and the remainder Flixotide at doses of
500mcg/day and above.[5]
Individuals have differing sensitivities to inhaled corticosteroids.
It can be difficult to establish the cause of adrenal suppression through
survey methods, such studies are inadequate to determine safety.
Idiosyncratic responses to inhaled corticosteroids may occur even at
licensed doses.[2]
The authors state that the low response rate (24%) means that the
results are likely to underestimate the true scale of the problem. This
would appear to be an unsupported and probably unfounded assertion. It
cannot be assumed that the incidence in the centres that did not respond
would be the same as in those that did. As adrenal crisis is an unusual
event, the presence of such an event is more likely to be remembered by
clinicians and reported in response to a specific request, than cases
where such events did not occur.
Linda Pearce
Respiratory Nurse Consultant
Dr David Mabin
Consultant Paediatrician
West Suffolk Hospital
References
(1) Russell G. Inhaled corticosteroids and adrenal insufficiency
Arch Dis Child 2002; 87:455-456.
(2) Todd GRG, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance
D. Survey of adrenal crisis associated with inhaled corticosteroids in
the United Kingdom. Arch Dis Child 2002; 87: 457-461.
(3) Committee on the Safety of Medicines. Inhaled corticosteroids and
adrenal suppression in children. Current Problems in Pharmacovigilance
2002; 28: 7.
(4) Todd GRG. Side effects of high dose fluticasone propionate in
children. Eur Respir J 1999; 13: 707-709.
Statements of conflict of interest
Linda Pearce:
I have received fees for delivering lectures, hospitality at scientific meetings and/or payments for participation in clinical trials or other
asthma-related research from Astra-Zeneca, Boehringer Ingelheim, 3M Health Care, Glaxo SmithKline, MSD, Novartis, Schering Plough, Trinity Pharmaceuticals.
David Mabin:
I have received fees for providing professional advice and delivering lectures as well as hospitality at, and sponsorship to
attend, scientific meetings and/or payments (sometimes in kind, for example educational materiel and textbooks) to me
personally and my discretionary funds for participation in clinical trials or other asthma, allergic rhinitis and atopic
dermatitis-related research from Astra-Zeneca, GSK, Schering Plough, UCB Pharma and MSD.
I read with great satisfaction the paper by Galloway et al.[1]
concluding that the ITT test is a reliable and safe test. Having had the
experience of many hundreds of ITT tests between the years 1958-1992 as
Director of the Institute of Pediatric and Adolescent Endocrinology at the
Beilinson and Schneider Children's Medical Centers,[2] I was very
astonished and upset that so many centers stopped p...
I read with great satisfaction the paper by Galloway et al.[1]
concluding that the ITT test is a reliable and safe test. Having had the
experience of many hundreds of ITT tests between the years 1958-1992 as
Director of the Institute of Pediatric and Adolescent Endocrinology at the
Beilinson and Schneider Children's Medical Centers,[2] I was very
astonished and upset that so many centers stopped performing the ITT after
the report by Shah et al.[3] We always had a 10% glucose syringe at hand
but used it only once. In patients suspected to have GH deficiency we
used half the dose, that is, 0.05 U/kg i.v. The ITT test was first
introduced by Albright' group in 1941 [4] to test indirectly GH secretory
capacity based on the degree of induced hypoglycemia and hypoglycemia
responsiveness after the injection. With the introduction of specific
radioimmunoassays it was shown to be a reliable test for GH secretion.[5]
It is a very convenient test as it measures concomitantly also ACTH and
prolactin reserve and one can inject together with the insulin GnRH and
TRH and thus by one combined test obtain a wide endocrine profile.
Due to its many positive properties and low, if any risk (provided
preventions are taken) ITT is among the recommended tests by the GH
Research Society for children [6] and as the standard test for the
diagnosis of GH deficiency in adults.[7]
References
(1) Galloway PJ, McNeill E, Paterson WF, Donaldson MDC. Safety of the
insulin tolerance test. Arch Dis Child 2002;87:354-6.
(2) Josefsberg Z, Kauli R, Keret R, Brown M, Bialik O, Greenberg D, Laron Z. Tests for hGH secretion in childhood. In: Laron Z, Butenandt O, eds.
Evaluation of Growth Hormone Secretion. Pediat Adolesc Endocrinol
1983;12:66-74.
(3) Shah A, Stanhope R, Matthew D. Hazards of pharmacological tests of
growth hormone secretion in childhood. BMJ 1992;304:173-4.
(4) Fraser RW, Albright F, Smith PH. The value of the glucose tolerance
test, the insulin tolerance test, and the glucose insulin test in the
diagnosis of endocrinologic disorders of glucose metabolism. J Clin
Endocrinol 1941;1:297
(5) Roth J, Glick SM, Yalow RSS, Berson SA. Hypoglycemia: a potent
stimulus to secretion of growth hormone. Science 1963;140:987-988.
(6) Sizonenko PC, Clayton PE, Cohen P, Hintz RL, Tanaka T, Laron Z.
Diagnosis and management of growth hormone deficiency in childhood and
adolescence. Part 1: Diagnosis of growth hormone deficiency. GH & IGF
Res 2001;11:137-165.
(7) Growth Hormone Research Society (GRS). Consensus Guidelines for the
diagnosis and treatment of adults with GH deficiency: Statement of the GRS
Workshop on Adult GHD. J Clin Endocrinol Metab 1998;83:379-381
Drs Huicho, Singi and Bharti make the important points that
definitions of hypoxaemia should be based on altitude-specific normal
values and that further research at sea level and higher altitudes is
needed. An altitude-specific definition of hypoxaemia (being an arbitrary
value of SpO2 more than 2 [1] or 3 standard deviations below the normal
population mean) may be different from the th...
Drs Huicho, Singi and Bharti make the important points that
definitions of hypoxaemia should be based on altitude-specific normal
values and that further research at sea level and higher altitudes is
needed. An altitude-specific definition of hypoxaemia (being an arbitrary
value of SpO2 more than 2 [1] or 3 standard deviations below the normal
population mean) may be different from the threshold SpO2 for giving
oxygen. Other considerations for giving oxygen are at what level of SpO2
(at different altitudes) oxygen is beneficial, local resource
availability, and, in an individual child, confounding factors including
the duration of exposure to altitude, age, or co-existent disease such as
brain injury, severe anaemia, pulmonary hypertension and cardiac failure.
We studied Papua New Guinean neonates and children living at an
altitude of 1600m to determine normal range of oxygen saturation.[2]
Hypoxaemia in our study was a SpO2 less than 2SD below the mean. In
practice our threshold for giving oxygen to sick children (SpO2<_85:_ xmlns:_85="urn:x-prefix:_85" more="more" than="than" _3sd="_3sd" below="below" the="the" mean="mean" was="was" lower="lower" this="this" because="because" of="of" limited="limited" oxygen="oxygen" availability.="availability." however="however" there="there" is="is" evidence="evidence" that="that" safe="safe" and="and" effective.3="effective.3" we="we" stated="stated" without="without" further="further" evaluation="evaluation" should="should" not="not" be="be" applied="applied" to="to" hospitals="hospitals" at="at" substantially="substantially" altitudes="altitudes" _1600m="_1600m" or="or" in="in" areas="areas" where="where" availability="availability" greater.="greater." p="p"/> In comparing the prevalence of hypoxaemia between studies in
different health facilities referral and selection biases are likely.
Hypoxaemia will be more common in emergency departments of referral
hospitals than at primary care settings, and more common still among
children requiring hospital admission.[4] The prevalence of hypoxaemia in
hospitalized children will depend on thresholds for admission and case-
mix. The 491 children in our study constituted about 20% of all the
children admitted during the course of the study. A specialist
paediatrician, whose practice was to oversee the care of sicker children,
enrolled many of the patients, so this was a further source of selection
bias. The much lower overall prevalence of hypoxaemia seen by Drs Singhi
and Bharti in their emergency department population is therefore
understandable. Of note the prevalence of hypoxaemia among sick neonates
admitted to Goroka Hospital (43%) was similar to the prevalence among
young infants (<_2 months="months" of="of" age="age" attending="attending" the="the" emergency="emergency" department="department" in="in" chandigarh="chandigarh" _38.5.5="_38.5.5" p="p"/> It is interesting to consider the effects of altitude on hypoxaemia
in children with pneumonia. Some populations living at higher altitudes
have a greater tendency to pulmonary hypertension; this susceptibility may
be genetically determined [6] and supports Dr Huicho’s statement that
ethnic differences in SpO2 at the same altitude are important. At
altitude in response to hypoxaemia, pulmonary blood flow is shunted to the
lung apices associated with an exaggerated vasoconstriction in the basal
lung.[7] This may have an adverse effect on ventilation perfusion
matching in the supine position. In addition cardiac expression of
natriuetic peptides increases in parallel with pulmonary artery
pressure.[8] These and other pathophysiological changes may account for
the greater severity and prolonged duration of hypoxaemia seen at higher
altitudes.[3,9,10] It may be useful to evaluate the simple intervention of nursing children with pneumonia and hypoxaemia at high altitude in an
inclined head-up position, rather than supine, to determine if this reduces the severity of hypoxaemia.
There is a need for more evidence about the prevalence of hypoxaemia
at sea level and different altitudes; which children benefit from oxygen;
for how long oxygen should be given and the best ways to deliver oxygen in
remote settings. Controlled trials of oxygen in mild hypoxaemia may not
be justified for ethical reasons, but other evidence will be informative.
Before the introduction of pulse oximetry in Goroka we used the World
Health Organization guidelines for giving oxygen (cyanosis, inability to
feed or severe respiratory distress). With the introduction of pulse
oximetry we set a threshold for giving oxygen at SpO2 85%. The severe
pneumonia case-fatality rate fell from 10% (26 / 258) pre-pulse oximetry
to 5.8% (65 / 1116) 2 years later.[3,10] In highland PNG children
cyanosis was only detected in 44% of those with an SpO2 70-84%.[3]
Although there will be confounders in the before-and-after analysis of
outcome, we conclude that clinical signs must miss a significant
proportion of children who would otherwise benefit from supplemental
oxygen, and adherence to a protocol for the administration of oxygen based
on a threshold SpO2 of 85% (more than 3 SD below the mean for normal
children in Goroka) resulted in improved outcomes, and was within
available resources.
The costs of oxygen and logistics of transporting cylinders are major
problems in many developing countries; Dr Huicho is right that these are
important public health challenges. They call for innovative research and
development into how best to supply oxygen to children who need it. The
role of oxygen concentrators need to be further explored;[11] the
combination of concentrators with pulse oximetry would be appropriate
technology for many hospitals in developing countries. Increasing the
availability of any drug that is crucial to the management of more than
20% of children hospitalized worldwide should be a very high priority;
oxygen is one such drug.
Dr Trevor Duke
Centre for International Child Health
University Department of Paediatrics
Royal Children’s Hospital
Parkville, 3052
Victoria
Australia
References
(1) Reuland DS, Steinhoff MC, Gilman RH, Bara M, Olivares EG, Jabra A
et al. Prevalence and prediction of hypoxemia in children with respiratory
infections in the Peruvian Andes. J Pediatr 1991;119:900-6.
(2) Duke T, Blaschke AJ, Sialis S, Bonkowsky JL. Hypoxaemia in acute
respiratory and non-respiratory illness in neonates and children in a
developing country. Arch Dis Child 2002;86:108-12.
(3) Duke T, Frank D, Mgone J. Hypoxaemia in children with severe
pneumonia in Papua New Guinea. Int J Tuberc Lung Dis 2000;5:511-9.
(4) Lozano JM. Epidemiology of hypoxaemia in children with acute
lower respiratory infection. Int J Tuberc Lung Dis 2001;5:496-504.
(5) Rajesh VT, Singhi S, Kataria S. Tachypnoae is a good predictor of
hypoxia in acutely il infants under 2 months.Arch Dis Child 2000;82:46-9.
(6) Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV,
Mamanova LB et al. Characterisation of high-altitude pulmonary
hypertension in the Kyrgyz: association with angiotensin-converting enzyme
genotype. Am J Resp Crit Care Med 2002;166:1396-402.
(7) Hanaoka M, Tanaka M, Ge RL, Droma Y, Ito A, Miyahara T et al.
Hypoxia-induced pulmonary blood redistribution in subjects with a history
of high-altitude pulmonary oedema. Circulation 2000;101:1418-22.
(8) Nakanishi K, Tajima F, Itoh H, Nakata Y, Osada H, Hama N et al.
Changes in atrial natriuretic peptide and brain natriuretic peptide
associated with hypobaric hypoxia-induced pulmonary hypertension in rats.
Virchows Arch 2001;439:808-17.
(9) Shann F, MacGregor D, Richens J, Coakley J. Cardiac failure in
children with pneumonia in Papua New Guinea. Pediatr Infect Dis J
1998;17:1141-3.
(10) Duke T, Poka H, Frank D, Michael A, Mgone J, Wal T.
Chloramphenicol versus benzylpenicillin and gentamicin for the treatment
of severe pneumonia in children in Papua New Guinea: a randomised trial.
Lancet 2002;359:474-80.
(11) Dobson M, Peel D, Khallaf N. Field trial of oxygen concentrators
in upper Egypt. Lancet 1996;347:1597-9.
Paracetamol poisoning (PP) as we all know the commonest agent in UK
causing acute hepatic insult leading to many deaths as well.
One thing baffles us, 150mg/kg is the toxic dose. 10-15mg/kg/dose is the
therapeutic dose as an antipyretic and this may be repeated even 4-6 hourly.
Thus, if a child is given 15mg/k, 4 hourly he gets 90mg/k in 24 hours and if
given for 10 days at a stretch which may be quite com...
Paracetamol poisoning (PP) as we all know the commonest agent in UK
causing acute hepatic insult leading to many deaths as well.
One thing baffles us, 150mg/kg is the toxic dose. 10-15mg/kg/dose is the
therapeutic dose as an antipyretic and this may be repeated even 4-6 hourly.
Thus, if a child is given 15mg/k, 4 hourly he gets 90mg/k in 24 hours and if
given for 10 days at a stretch which may be quite common in multidrug
resistant typhoids, the child may get upto 900mg/k over 240 hours, of course
not at a time. Still, why do we not get to see so many paracetamol
poisonings in India really intrigues me?
Duke et al. are to be commended for their interesting report aimed to determine normal oxygen saturation values in healthy infants and children and to assess the performance of clinical signs for predicting hypoxaemia in sick neonates and children with and without acute lower respiratory infections (ALRI).[1]
Acute lower respiratory infections (ALRI) account for a substantial burden of diseas...
Duke et al. are to be commended for their interesting report aimed to determine normal oxygen saturation values in healthy infants and children and to assess the performance of clinical signs for predicting hypoxaemia in sick neonates and children with and without acute lower respiratory infections (ALRI).[1]
Acute lower respiratory infections (ALRI) account for a substantial burden of disease in children and adults, being pneumonia the leading cause of deaths in under five children, particularly in developing countries. Tachypnoea and chest retraction have been shown to be the most useful clinical signs for determining the presence of pneumonia and thus they are widely used in the diagnosis and management of this condition in children.[2] The World Health Organization pneumonia case-detection and management programme [3] which relies on these simple signs, seems to be justified by the existing body of evidence.
Varying degrees of hypoxaemia may be present in children with pneumonia. However, surprisingly few studies have been performed to assess normal values of haemoglobin oxygen saturation (SpO2) through the use of transcutaneous pulse oximetry, at both sea level and high altitude. Singhi’s response to Duke et al. rightly emphasizes that altitude of studies reported must be taken into account in the interpretation of their results.[4] There are some reports on SpO2 values at mid- and high altitude settings in healthy and sick children.[5-8] We previously reported normal values of SpO2 in 1264 healthy children and adolescents living at 4100 m.[9]
The main conclusions of these studies performed at different altitudes are: first, values considered abnormal at sea level are very frequently found at high altitude in healthy children; second, normal values vary for different altitudes; third, recommended SpO2 cut-offs for giving supplementary oxygen to sick children at sea level are clearly not applicable to high altitude settings, as according to these recommendations oxygen should be administered for values below 92%.[2] There is the need to perform more studies for determining which cut-off values for supplementary oxygen are related to better outcomes in sick children living at high altitude. Moreover, our study at 4100 m revealed that SpO2 values may be different according to different ethnic groups and history of exposure to high altitude. Higher SpO2 values in Quechua children suggest a better degree of adaptation to high altitude in native populations with a longer time to exposure to high altitude. This latter finding has obvious practical implications, as high altitude-native children, with higher baseline oxygen saturation levels than newcomers or resident non-native children, may need oxygen at higher cut-off SpO2 values when they are sick.
Singhi is justifiably concerned on the cost of giving oxygen to children who may not need it. Oxygen may be unacceptably expensive for health services in developing countries, particularly at primary level, where most sick children seek health care. However, hypoxaemia may be a serious, life-threatening problem in sick children, particularly at high altitude, and thus we need to extend the study of Duke et al. for different altitudes, in healthy and sick infants and children, to determine normal values of SpO2 and to identify highly predictive clinical signs of hypoxaemia. The potential aggravating role of co-existing prevalent childhood diseases other than ALRI, namely diarrhoea, malnutrition, malaria and HIV/AIDS, is also an area that warrants more attention. These data will allow providing both good quality and cost-effective health care to sick children with and without ALRI.
Millions of children and adults live at high altitude. Developing a medicine based on scientific evidence that can be applicable to this setting is a major public health challenge for all of us working in those parts of the world.
References
(1) Duke T, Frank D, Mgone J. Hypoxaemia in children with severe pneumonia in Papua New Guinea. Int J Tuberc Lung Dis 2000;5:511–19.
(2) British Thoracic Society of Standards of Care Committee. BTS Guidelines for the management of community acquired pneumonia in childhood. Thorax 2002;57:i1-i24.
(3) World Health Organization. Acute respiratory infections in children: case management in small hospitals in developing countries. Geneva: World Health Organization, 1994.
(4) Singhi S, Bharti B. Response to Duke et al [electronic response to Duke T et al, Hypoxaemia in acute respiratory and non-respiratory illnesses in neonates and children in a developing country]. archdischild.com 2002http://adc.bmjjournals.com/cgi/eletters/archdischild;86/2/108#307
(5) Reuland DS, Steinhoff MC, Gilman RH, Olivares EG, Jabra A, Finkelstein D. Prevalence and prediction of hypoxemia in children with respiratory infections in the Peruvian Andes. J Pediatr 1991;119:900-6.
(6) Nicholas R, Yaron M, Reeves J. Oxygen saturation in children living at moderate altitude. J Am Board Fam Pract 1993;6:452-56.
(7) Lozano JM, Steinhoff M, Ruiz JG, Meza ML, Martinez N, Dussan B. Clinical predictors of acute radiological pneumonia and hypoxaemia at high altitude. Arch Dis Child 1994;71:323-27.
(8) Gamponia MJ, Babaali H, Yugar F, Gilman RH. Reference values for for pulse oximetry at high altitude. Arch Dis Child 1998;78:461-65.
(9) Huicho L, Pawson IG, León-Velarde F, Rivera-Ch M, Pacheco A, Muro M, Silva J. Oxygen saturation and heart rate in healthy school children and adolescents living at high altitude. Am J Hum Biol 2001;13:761-70.
We thank Dr van der Wouden for his congratulations at our attempt at
validating this infant respiratory questionnaire.[1] We also welcome his
comments regarding our methodology and statistics. The method for
assessing test-retest reliability in the development of respiratory
questionnaires has been and recommended by Chinn et al.[2] They recommend
the use of the (weighted) kappa score and averag...
We thank Dr van der Wouden for his congratulations at our attempt at
validating this infant respiratory questionnaire.[1] We also welcome his
comments regarding our methodology and statistics. The method for
assessing test-retest reliability in the development of respiratory
questionnaires has been and recommended by Chinn et al.[2] They recommend
the use of the (weighted) kappa score and average correct classification
scores, which we have calculated for a two-week period and presented. We
accept that the respiratory symptoms may vary over that two-week period
and may not be stable, but the questionnaire does ask about the period
prevalence of the last three months and we feel that the symptom
variability over those two weeks would have minimal effect on the final
conclusions. We do not feel we have over interpreted these reliability
results. We have followed the recommendation by Altman [3] who suggests
that a kappa score above 0. 41 should be accepted as 'moderate', a score
of greater than 0.61 should be 'good' and a score of greater than 0.81
should be 'very good'.[4] In the results section of our abstract we
state 'good to moderate short-term reliability'. We felt that in our
initial assessment of the criterion validity of the questionnaire we
should choose subjects who were clearly felt to have asthma by a
respiratory pediatrician and compare this group to mildly affected or
asymptomatic children. The next stage of the examination of this
questionnaire is to collect more data on subjects with different wheezy
phenotypes to clarify if the questionnaire can identify these different
groups. This would need many more symptomatic subjects. Finally, the data
in table 1 are being reviewed in response to Dr van der Wouden’s comments.
References
(1) Powell CVE, McNamara P, Solis A, Shaw NJ. A parent completed
questionnaire to describe the patterns of wheezing and other respiratory
symptoms in infants and preschool children. Arch Dis Child 2002;87:376-
379.
(2)Chinn S , Burney PG. On measuring repeatability of data from self
administered questionnaires. In J Epidemiol 1987;16:121-127.
(3) Altman DG. Practical statistics for medical research. London: Chapman
and Hall, 1992.
(4) Landis JR, Koch GG. The measurement of observer agreement for
categorical data. Biometrics 1977;33:159-174.
Dear Editor
Cerebral Edema During Treatment of Diabetic Ketoacidosis: Fall In Ketoacid Levels and Consequent Fall In Osmolality May Be A Culprit
Inward and Chambers[1] have called for a rethink of the management of diabetic ketoacidosis. In their article they quote a study by Grove L M and colleagues[2] suggesting that pediatricians overestimated the quantum of dehydration in DKA. Over correction of dehydrat...
Dear Editor
I read with great interest Clarkson and Choonara’s paper on the fatal suspected adverse drug reactions (ADRs) in the UK, and I strongly agree with their conclusions, namely that an evidence-based approach to drug therapy is needed to minimise fatalities due to drug toxicity in children.[1] However, recent evidence also suggests that we are now ready for a gene based approach to drug therapy allowing...
Dear Editor
In an outstanding piece of medical detective work, Drs Fox, Palmer and Davies lay to rest the widespread myth that bottom shuffling is a dominantly inherited trait with such penetrance that it can be traced back to mediaeval times by simple nomenclature. Thus Shufflebottoms do not bottom-shuffle more than Walkers. Whether it is appropriate for doctors from Luton to be examining such an area of Lancastri...
Dear Editor
The editorial by Russell [1] suggests that when high dose inhaled steroids are being considered the use of fluticasone diproprionate should be avoided, on the basis of this survey.[2] Clinical studies rather than a questionnaire based survey should form the basis for such advice. Such studies show no increased risk of hypothalamic pituitary axis (HPA) suppression with fluticasone propionate when comp...
Dear Editor
I read with great satisfaction the paper by Galloway et al.[1] concluding that the ITT test is a reliable and safe test. Having had the experience of many hundreds of ITT tests between the years 1958-1992 as Director of the Institute of Pediatric and Adolescent Endocrinology at the Beilinson and Schneider Children's Medical Centers,[2] I was very astonished and upset that so many centers stopped p...
NOTE FROM SECTION EDITOR
Updates on the three topics covered by Archimedes have been requested.
Does nebulised adrenaline reduce admission rate in bronchiolitis?
Update published in full in Arch Dis Child 2002;87:548-50.
[Full Text]
Are routine chest x ra...
Dear Editor
Drs Huicho, Singi and Bharti make the important points that definitions of hypoxaemia should be based on altitude-specific normal values and that further research at sea level and higher altitudes is needed. An altitude-specific definition of hypoxaemia (being an arbitrary value of SpO2 more than 2 [1] or 3 standard deviations below the normal population mean) may be different from the th...
Dear Editor
Paracetamol poisoning (PP) as we all know the commonest agent in UK causing acute hepatic insult leading to many deaths as well. One thing baffles us, 150mg/kg is the toxic dose. 10-15mg/kg/dose is the therapeutic dose as an antipyretic and this may be repeated even 4-6 hourly. Thus, if a child is given 15mg/k, 4 hourly he gets 90mg/k in 24 hours and if given for 10 days at a stretch which may be quite com...
Dear Editor
Duke et al. are to be commended for their interesting report aimed to determine normal oxygen saturation values in healthy infants and children and to assess the performance of clinical signs for predicting hypoxaemia in sick neonates and children with and without acute lower respiratory infections (ALRI).[1]
Acute lower respiratory infections (ALRI) account for a substantial burden of diseas...
Dear Editor
We thank Dr van der Wouden for his congratulations at our attempt at validating this infant respiratory questionnaire.[1] We also welcome his comments regarding our methodology and statistics. The method for assessing test-retest reliability in the development of respiratory questionnaires has been and recommended by Chinn et al.[2] They recommend the use of the (weighted) kappa score and averag...
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