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Guest
Lectures
21
Guest Lectures
INTERNATIONAL PEDIATRIC UPDATE 2004
Proceedings & Abstract Book
Anemia Beyond Iron Deficiency
Dr. M R Lokeshwar
Anemia is defined as a reduction of the red
blood cell volume or hemoglobin
concentration and hematocrit below the
range of values occurring in healthy
persons, or two standard deviation below
the mean for the normal population, age and
sex1
Anemia is a global problem of immense
health significance affecting persons of all
ages and economic groups. It is ranked as
the commonest chronic malady mankind
has ever suffered. Approximately 1500
million people i.e. 30% of the world
population suffers from anemia most of them
suffer from iron deficiency state.2,3 It is more
common in developing countries like ours.
30-50% of pregnant ladies and 60 to 80% of
school going children are reported in some
studies to be iron deficient. The prevalence
of iron deficiency anemia in a developing
country like India has been found to be as
high as 63% in 1-3 years.age group and 44
% in the age group 3 to 6 years of children
as per study by I.C.M.R.in 1977.4 More
recent reports of N.F.H.S.-2 shows that the
prevalence has not much changed in 199899 and are still 74% among children 6-35
month age.5
(Fig. 1 shows the WHO criteria for diagnosis
of anemia)
Fig. 1
WHO Criterion for
Diagnosis of Anemia6
Age / Sex Group
Children 6 Mon - 6 yr
Children 6-14 yr.
Adult males
Adult females (non-pregnant)
Adult females (pregnant)
Grading of Anemia –
Mild Anemia
Moderate Anemia
Severe Anemia
Very Severe Anemia
Hb (g/dl)
Less than 11
Less than 12
Less than 13
Less than 12
Less than 11
10 gm%, But
< than Normal
For Age
7-10 gm%
< 7 gm%.
< 5 gm%
22
The anemia of childhood may be
classified into 2 broad groups:
1 Those resulting primarily from decreased
or ineffective production of red blood
cells or hemoglobin; and
2 Those in which increased destruction or
loss of red blood cells is the predominant
mechanism.
A morphologic classification :
It is often used on the basis of indices.
Anemia can be classified into three types.
1) Microcytic Hypo chromic anemia – M.C.V.
less than 75 cu.mm, M.C.H. is less than
29pg & M.C.H.C. less than 32%
2) Macrocytic anemia – Where M.C.V. is
greater than 98cmm
3) Normocytic Normochromic anemia –
Where M.C.V. is 75-98 cmm, M.C.H. is
29pg to 34pg and M.C.H.C. is 30-36%
(The Fig. 2, an Algorithm on next page
shows approach to microcytic hypochromic
anemia.)
Classification of anemia based on red
blood cell mean volume (M.C.V.) & (R.D.W.)
Anemia in childhood may also be classified
by variations in cell size and shape, as
reflected by alterations in the red blood cell
distribution width (RDW). A knowl­edge of
both the MCV and the RDW can be helpful
in the initial classification of the anemia of
childhood
RDW is the coefficient of variation of red cell
volume distribution
RDW is the objective documentation of
subjective anisocytosis
Normal range: 11.5 to 14.5 %
(Refer to Fig. 3 for RDW values in various
diseases)
As I.D.A. is very common and with few
clinical & physical findings and mimic other
types of anemia’s, many a times these
children are investigated extensively &
treated for I.D.A. without confirming the
diagnosis.
Few illustrative cases will help drive home
this point.
INTERNATIONAL PEDIATRIC UPDATE 2004
Fig. 2
Algorithm of approach to microcytic hypochromic anemia
P.S. Examination / Red Cell Indices
Hypo chromic, microcytic anemia
(MCV <75 u3, MCH <29 Pg., MCHC <32%)
S. Iron studies
Normal or decreased
Normal or increased
Iron store / Ferritin
EPP
Decreased
Increased
IDA
Anemia
TIBC increased
of chronic
Rectic increased
disorder
Normal or decreased
FEP Normal
Abnormal
Normal
Hemoglobinopathies
BM Examination
&
/ Iron stain
Thalassemia
Ring sideroblast
Sideroblastic Anemia
TIBC Normal
FEP increased
TS decreased
Fig. 3
RDW Values in various diseases
RDW
Normal
RDW
High
Low MCV
Thal
trait
Normal MCV
Normal
anemia
High MCV
Aplastic
IDA
Chronic liver
disease,
malignanies,
myelofibrosis,
myelotoxic
drugs
Megalo. An.,
Imm. Hem.
An.
Case 1 : Kamlesh, Age 8 yrs.
Child was referred for anemia of 7 gm%
O/E : Clinically NAD except pallor. No
lymphadenopathy, No hepatosplenomegaly,
No petechie / purpura
Investigations showed: Hypochormic,
microcytic anemia with MCV 60 u3, RBC 3.4
Mil. RDW 18%, T.S.: 8%
Diagnosis: I.D.A.
Child was treated with Syp. Tonoferron for
3 months Hb. increased from 7 to 9 gm% in
23
1 month but no further increase .
Smear repeated showed basophilic
stippling.
Father working in the standard battery,
father’s teeth showed blue lines
Further investigations confirmed the
diagnosis of Lead Poisoning in father &
the son
Case 2 : Gurdeep Singh 5 yrs. male child
C/o Pallor since early childhood H/o Cough,
cold – 10 days
No bleeds / Jaundice / Wt. Loss / Bl. Trans.
Punjabi community. No H/o consanguinity
Pallor+, No icterus. LN / Liver / Spleen NP,
S/E-NAD
Investigations:
Hb. 9.0 gm%, WBC 9800/cumm, P 60 % L 40%
MCV 60, MCH 25, RDW 12, RBC 6.5 mill
S. Iron: 35, TIBC: 350, TS: 10%, S. Ferritin:
25 ng/ml
HbF 0.6%, HbA2: 3.3%
Child was initially treated with oral iron &
folic acid with no response
Proceedings & Abstract Book
No single principle
can answer
All life’s complexities
- Felix Frankfurter
Experience may be
defined as the ability
To continue making the
same mistakes
With increasing
confidence.
- Dr. D. W. Webb
Investigations: repeated after 2 months
Hb. 10 gm%, WBC 9800/cumm,
MCV 60, MCH 25, RDW 12, RBC 6.5, Retic
1% P 60 L 40 Hypo / Micro +,
In view of High RBC count, low MCV, low
Hb,
Normal RDW, Nestroft: +ve
Hb F: 1%, Hb EPP: NAD, Hb A2 : 3.6%.
Sickling: Negative
Diagnosis : Thalassemia Minor
High RBC, low MCV, low Hb, normal RDW
suggestive of thalassemia minor.
Microcytic anemia – non-responding to
iron are due to
- Ineffective iron preparation / inappropriate
dose
- Malabsorption, Persistent bleeding
- Thalassemia minor
- Anemia of chronic infection
- Associated Folic acid B12 deficiency
- Sideroblastic anemia
Repeated investigations did not give any
clue to the diagnosis
No evidence of thalassemia minor, Coomb’s
test –ve,
Bone marrows : Mild erythroid hyperplasia,
no evidence of megaloblastosis.
On routine round BP was taken : 180/110
mmHg.
Further investigations –
Creatinine 4.0 mg%, BUN 79 mg/dl
Urine R : Albumin ++, Microscopic - Pus
cells 10-15/hpf.
Diagnosis : Chronic Renal Failure
Carry home message :
Routine –
thorough clinical examination must
evaluation like blood pressure must be
taken
CBC – Burr cells may be indicative of
underlying pathology
urine exam. must be done
Carry home message:
Nestroft test useful as screening test in
hypochromic, microcytic anemia to
suspect thalassemia minor. But not
diagnostic.
High RBC, low MCV, low Hb, normal RDW
suggestive of thalassemia minor.
HbA2 may be borderline low in thal minor
when associated with IDA. Repeat the test
after treatment.
Case 4 : Ganesh, Age 10 yrs
H/O Persistent anemia not responding oral
iron therapy since 6 months
H/O loose motion off &on Since 4-5 years.
Large bulky stools
Distention of abdomen ++, Failure to thrive/
No hepato splenomegaly.
Results of investigations Hb 7 gm%, MCV 60 cumm, R.D.W.18
RBC 3.4 m. T.S. 6% HbF 0.8%, HbA2 2.8%
Further investigations confirmed the
diagnosis of ‘Gluten Induced Enteropathy’
with Malabsorption Syndrome,
Anti-gliadin antibodies: +ve
Child was given parenteral iron and
correction of the diet, child responded well
and growth improved.
Case 3 : Master Mohd. Ashraf, Age 11 yrs.
C/o marked pallor noticed by the family
physician since 2 months
C/o Mild puffiness of the eyes
O/E : Conjunctiva and.nails : pale, No
lymphadenopathy, No hepatosplenomegaly,
No bony tenderness, No petechiae / purpura
/Ecchymosis
Investigations done :
Hb 5 gm%, Retic count 2%, MCV 80 u3,
MCH 27 Pg,
MCHC 33 %, RDW 18%, Platelet count
4,50,000/cmm.
PS Exam. : Micro +, Normo ++, Occasional
Macro +, Burr cells +,
Sr.Iron 35 ug/dl, TIBC 355 ug/dl. TS 10 %
Child was treated with oral iron therapy,
Hb increased upto 9 gm%, no further
improvement.
24
Case 5 : Rohit, 8 yrs male
C/o Pallor off & on : for 3 yrs
No H/o feverH/o jaundice : 2 yrs. back
O/E: Pallor +, No koilonychia / platynychia,
No generalized lymphadenopathy,
Liver : just palable, Spleen : 3 cm
Results of investigations done Hb 6.5 gm%, Retic 7.0%, MCV 82,
MCHC 37, MCH 27, RDW 16,
WBC 9600/cmm, Platelets 1,86,000/cmm
INTERNATIONAL PEDIATRIC UPDATE 2004
Liver profile : Within normal limits.
Multiple investigations : No conclusion
Child was referred for further management
PS Examination – Diagnostic.
Diagnosis : Spherocytosis
Mind is like a Parachute It works only when
it is open
What mind can think,
Eyes can see!
Case 6 : Baby Navita, Age 1 month
Referred by pediatrician for persistent
progressive anemia & enlarged liver &
spleen.
Antenatal period No H/o fever / rash during early antenatal
period in mother
No H/o lymphadenopathy in the mother
H/o fever with chills during 8th month of
pregnancy in mother
O/E : Wt.3.5 kg, AF 3 x 3cm, Conjunctiva /
Nail: Pale,
No lymphadenopathy, Liver 3 cm, Spleen 2
cm.
Results of investigations done:
Hb.10.8 gm%, WBC 20,800/cmm, P60%,
L40%,
Normoblasts 8-10/100 WBC, MCV 58 u3,
RDW 18%,
Platelet count 1.3 lac/cmm. K.B. test in
mother : -ve
Coomb’s test: Direct & Indirect –ve, G6PD:
Normal activity
Child was treated with Oral iron drops,
multivitamin drops
Child was brought again after 10 days with
further drop in Hb,
fever spiky ranging from 100 – 102 F,
persistence of hepatosplenomegaly
Differential diagnosis :
- Anemia due to intrauterineinfection
- Chronic feto-maternal Hg.
- Congenital spherocytosis
- Congenital / Neonatal Malaria
PS Exam : Microcytic, hypochromic anemia
P. Vivax present. Diagnosis malaria
Child was treated with Chloroquine &
packed cell transfusion was given
Carry home message: What mind can
think, eyes can see !
PS exam. is a key to diagnosis
Case 7 : Raghavendra, Age: 3 months
boy, Wt : 4 kg.
H/o Feer and cold cough off & on
25
Child was referred for progressive pallor :
noticed by family physician
O/E: Pallor, listlessness, Failure to thrive
Distension of abdomen
No jaundice, Occasional cervical gland –
non-specific
Liver = 3 cm, Spleen = 3 cm
Results of investigations done Hb
5.0 gm%
Retic
1.8 %
MCV 68 cumm
MCHC 30 %
MCH 21 Pg.
RDW
18 %
WBC 3500/cmm
Plat.
88,000
Child was treated with Iron and folic acid
without much response
Further investigations done to rule out
abnormal hemoglobinopathy,
Child’s HbF 8%, HbA2 : 3.2%,
Mother & Father : HbA2 : 2.3% & 3.1%,
No evidence of thalassemia
Peripheral smear examination did not show
any spherocytes
TORCH titre in mother
child
CMV IgM
+ve
+ve
CMV IgG
+ve
+ve
Rubella IgM
-ve
-ve
Rubella IgG
+ve
-ve
Toxo IgM
-ve
-ve
Toxo IgG
-ve
-ve
Diagnosis: CMV Infection in Mother &
Child
Carry home message:
High index of suspicion is key to the
diagnosis
Proper history of the mother gives a clue
to the diagnosis
H/o fever with rash in the mother may be
present.
Anemia & hepatosplenomegaly in early
infancy
– Keep in mind intrauterine infection (after
ruling out other common causes)
Case 8 : Baby Kajal, Age 2,1/2 yr.
Child was admitted on surgical side for
swelling over the hand. ? cellulitis
X-ray hand showed osteomyelitis
CBC showed : Hb 6 gm%, WBC 22,300/
cmm, P70%, L28%, M1%, E1%,
Child was referred for correction of anemia,
as was to be taken up for surgery
Proceedings & Abstract Book
P.S. examination showed sickle cells. No
surgery required.
References
(1) M.R. Lokeshwar V.P. Choudhry - Introduction to
anemia in children I.A.P. Text book of pediatrics.
I.C.M.R.Technical report series no. 26. National
Institute of nutrition. 1977. Hyderabad.
(2) DeMayer E.H. Adiels – Tegman M The prevalence
of anemia in the world, World health statistics
1985, 38, 302-316.
(5) N.F.H.S (2000) India 1998-1999. National Family
Health Survey-2, Key finding’s Anemia among
women and children. International Institute for
Population Science Mumbai 2000-19.
(3) Agarwal D.K., Upadhyay S.K., Tripathi A.M., et.al.
Nutritional status, physical work capacity & mental
function in school children, New Delhi Nutrition
foundation of India Scientific report No.6. 1987.
(4) I.C.M.R. Studies on preschool children.
(6) Dallaman P.R. Iron deficiency and related
nutritional anemia In Nathan D, G., Oski F.A
Hematology of infancy and childhood. W.B.
Saunders 1987, 274-314.
Evaluation and Management of
Intractable Epilepsy
Dr. Vrajesh Udani, Consultant Pediatric Neurologist,
P D Hinduja National Hospital & Medical Research Center, Mumbai
In the majority of children epilepsy remains
a mild disorder with 60 – 80% remitting
spontaneously or with treatment 123 .
Epidemiological data suggest that there is
a 68% probability of achieving a 5 year
remission 1. Seizure control, however,
remains poor in about 15 – 20 %. Though
Indian studies suggest a higher incidence
(40 – 70%) of intractability4 , these are from
tertiary care centers with an inherent bias
towards more difficult cases. If a minimum
of 20% were taken along with a minimum
point prevalence of epilepsy of 5 / 1000 (in
India figures vary from 4 -7/1000), the load
of intractable epileptics would be about 1
million persons. The psychosocial,
intellectual, financial and human cost of this
is considerable for a developing nation.
Medical Intractability :
There is no consensus defining intractability.
Some have used frequency of seizures as a
criterion5. However, less frequent severe
status episodes are as devastating as more
frequent brief seizures. Others have used a
time-bound (usually 2 years) lack of
response to at least two frontline AEDs and
a newer agent as monotherapy and even
as rational polytherapy6. However, so called
26
catastrophic epilepsies of infancy and
childhood can dramatically disrupt normal
development in a few weeks to months,
making a time-bound definition impractical.
Other vague definitions call epilepsy
intractable if it ‘interrupts normal activities
of life’ despite ‘relevant therapy’.
Epileptic encephalopaties like LandauKleffner syndrome (LKS) and electrical
status in slow wave sleep (ESES) defy the
definition as seizures may be absent or very
few; however, the epileptic process has a
similar devastating effect on language and
cognition as conventional intractable
epilepsy syndromes.
Associated neurological and developmental
impairments must be considered as well.
Weekly or monthly seizures in a high
functioning adolescent obviously are more
disruptive than daily brief seizures in a
severely handicapped patient. The practical
importance of these definitions is to decide
appropriate alternative therapies, both
medical and surgical. New anti-epileptic
drugs (AEDs), the ketogenic diet and
resective surgery are easily available in more
developed nations. In the developing work
the treatment gap is estimated to be high7
INTERNATIONAL PEDIATRIC UPDATE 2004
and specialized services are available in only
a few centers.
Risk Factors for Intractability:
Age of Onset of seizures
This is probably the most consistent risk
factor in almost all studies 2,3,5,8,9,10. It is
significant throughout the age spectrum in
childhood8. Even in the MR population age
of onset is significantly earlier in the
intractable group as compared to the
controlled group5.
Remote Symptomatic Seizures:
This is again consistent throughout
studies 2,3,8,9,10 .
Static neurological
impairments and mental retardation make
intractability more likely. In mentally
retarded children with epilepsy intractability
is seen in about half5, a figure probably
threefold higher than those with normal
intelligence2. This probably emphasizes the
importance of the underlying neurological
substrate in deciding the severity of the
epilepsy. 10% of children become retarded
due to intractable epilepsy5,11.
Types of Seizure and Syndromes:
Tonic 3,5, myoclonic2,3,5,9 seizures are the
ones difficult to control. Atypical absence2,5,
complex partial and even generalized tonicclonic (GTC)9 have been identified in some
studies only. Typical absence seizures on
the other hand are negatively correlated with
intractability3. Infantile spasms (IS)2,8 and
Lennox-Gastaut syndrome (LGS)2 are the
most common syndromes identified in this
group.
Table 1 lists etiologies and
syndromes associated with poor control.
Other Factors:
Studies have found male sex 9, status
epilepticus 8 as important predictors.
However, these have not been consistent.
Analysis of 123 childhood cases9 revealed
intractable epilepsy more in males with an
age of onset of seizures below 2 years, with
static or progressive neurological disease
in the form of mental retardation / regression,
and / or abnormal neurological findings,
myoclonic, mixed seizure types of known
epileptic syndromes.
Prognosis:
A 5-20 year follow up study of 145 children
with medically resistant seizures revealed a
seizure remission rate of 4% per year in
normal / borderline intelligent children and
27
only 1.5% remission rate in retarded
children10, implying that worst epilepsies
may remit and must be considered when
treatment decisions are taken. Several
observers have documented lower mean IQ,
poor academic performance, behavioral
abnormalities and later, higher rates of
unemployment and other psychosocial
impairments in chronic active epilepsy11,12.
In a prospective study of medically
intractable complex partial seizures starting
in childhood followed up for several years,
only one-third achieved seizure free and full
independent living13.
What is responsible for this adverse
outcome is still not clear. The consensus is
that the abnormal neurological substrate,
the seizures themselves, the EEG epileptic
activity, the AEDs and the psychological
effects of a chronic illness all play a role
although to different degrees in different
Understanding the
individuals 11 .
mechanisms of seizures induced changes
in the developing CNS has been helped by
the study of surgically obtained brain tissue.
It is now accepted that in some, prolonged
febrile status epilepticus triggers off
hippocampal neural cell loss12 possibly
through excitatory neurotransmitter release.
The immature hippocampus appears
particularly susceptible and may explain the
learning / memory disorders seen in such
children. A child with repeated status
epilepticus demonstrated bilateral
hippocampal atrophy on serial MRI with
progressive intellectual deterioration. Many
studies failed to demonstrate intellectual
decline in intractable epileptics12. Another
mechanism for intellectual decline is
disruption of normal neural networks by
severe paroxysmal EEG abnormalities
classically seen in IS and in LGS12. This
often improves with appropriate therapy.
Factors In Pseudo Intractability:
Errors in Diagnosis:
These are seen in 20 – 30 % of patients
referred to specialty clinics in the developed
world3. However, in the only Indian study
from Kerala4, 10 non-epileptic cases were
detected from more than 1000 referrals on
epilepsy. Common non –epileptic disorders
include pseudoseizures in the older
adolescent and young adult and atypical
migraine episodes, breath holding spells
and sleep disorders in younger children.
Proceedings & Abstract Book
Sometimes the underlying etiology is
overlooked e.g. neurometabolic disorders,
biotin and pyridoxine dependent disorders
and the occasional poliodystrophy like
Alpers and Menkes syndromes. We have
occasionally
identified
recurrent
hypoglycemia and hypocalcemia /
hypomagnesemia causing chronic epilepsy,
emphasizing the need of always doing these
basic tests. In the older child one must
consider SSPE and rarely, childhood onset
progressive myoclonic epilepsy syndromes
like neuronal ceroid lipofuscinosis etc.
Cortical dysplasias (CD) and other neuronal
migration abnormalities are often missed on
routine CT scans.
Syndromic and seizure type misdiagnosis
are more the rule than the exception in the
developing world because of lack of
awareness and technology. Infantile
spasms are often labeled as GTC seizures
and treated inappropriately with drugs like
Phenobarbital (PB). Staring spells cause
confusion between complex partial and
absence seizures leading to inappropriate
treatment of the later with drugs like
carbamazepine (CBZ). Many juvenile
myoclonic epilepsies (JME) have associated
GTC seizures leading to treatment with CBZ
and PHT rather than valproate (VPA). It must
be realized that up to 96% of all childhood
epilepsies can be classified into syndromes2
and those treating epilepsies must routinely
do this diagnostic exercise.
The careful history form the witness
describing the episode details can avoid
most errors. EEG is useful to confirm the
clinical suspicion but is marred with
problems like poor tracings and wrong
interpretations. As far as possible MRI
should be performed rather than CT in
intractable epilepsies as subtle
abnormalities are picked up only by this
technique14 .
Errors in Therapy:
The plethora of drugs and irrational drug use
are a recipe of errors of both omission and
commission. The level of treatment
competence is compounded by biased
information from drug companies. Many
epilepsies remain intractable because of
simple mistakes which are easy to rectify4, 9.
Inappropriate choice of drug:
Wrong diagnosis of syndromes and seizures
type often leads to errors. Often CBZ and
28
PB are used in infantile spasms and absence
seizures leading to no response. Recent
observations on AED induced seizures
indicate the most common offenders being
CBZ, PHT and VGB15. Often myoclonic,
absence and drop attacks are precipitated.
Inappropriate doses and dosing intervals:
The most common error is to rely on mg /
kg or serum drug levels to decide the
maximum dose. In case of good clinical
tolerance the dosage can be increased to
higher than average dosage and level. On
the other hand, serum levels help in
identifying patients with ineffective
absorption and rapid metabolism6. In those
patients referred for epilepsy surgery,
therapy omissions and inadequate dosage
are noted in as many as 1/3 rd of patients6.
Dosage intervals are different at different
ages especially when polytherapy is used.
For instance phenytoin which is often given
at a dose of 5-6 mg / kg in a single dose in
adolescence and adulthood needs higher
and multiple doses in infancy and early
childhood. VPA and CBZ likewise need
thrice daily dosing for optimum effect unless
one is using the controlled release
formulations.
Inappropriate polytherapy:
Since the 1980’s advantages of
monotherapy have been disseminated
widely in the literature. The biggest
disadvantage of polytherapy is troublesome
interactions necessitating frequent blood
levels – a facility often unavailable or
expensive. Use of low dose polytherapy
appears to be the rule in refractory epilepsy
in India. In one study4, 57% were on low
dose polytherapy at entry and at the end
76% were successfully switched to
monotherapy resulting in an increase in the
seizures free rate from 29% to 44%. The
annual savings were estimated at
approximately Rs. 700/- per patient just by
this simple and effective adjustment. In India
combination pills are still sold (e.g. PBI and
PHT), a practice which should be strongly
discouraged. Polytherapy is some times
necessary in severe epilepsies; however
drugs with minimum interactions and
different mechanism of action should be
used so called ‘rational polytherapy’. In the
Mumbai study9, about 40% of patients who
improved were on rational polytherapy
regimens. In practice often inappropriate
INTERNATIONAL PEDIATRIC UPDATE 2004
combinations like CBZ & PHT (both Na
channel blockers) or PB & CLP (both GABA
ergic) are used leading to virtually no
increase in efficacy and a dramatic increase
in adverse effects.
Medical Treatment:
This is described in a series of steps usually
employed by the author. It is meant to be a
general guideline and needs to be
individualized.
Complete Diagnosis:
The initial task is to identify the clinical
seizure type / types and if possible the
epileptic syndrome and etiololgy. Clinical
details are most important along with a sleep
deprived EEG. EEG abnormalities are seen
in more than 80% of children with
intractability and a normal EEG should
prompt a rethink of the diagnois 5,9 .
Sometimes a video-EEG needs to be done
to simultaneously capture clinical seizures
and the ictal EEG. This is possible only
when there are frequent, usually daily
seizures and obviously can be performed
in only a few referral centres. Ideally, a MRI
should be done in all cases of intractable
epilepsy. Recent studies 3,14 have shown that
in refractory childhood epilepsy neurological
substrates include developmental tumors
like dysembryopathic neuroectodermal
tumor (DNET) and ganglioglioma, focal and
diffuse migration abnormalities like cortical
dysplasia16,17 and lissencephaly and finally
hippocampal sclerosis12,14 which may be the
cause and sometimes the effect of frequent
seizures. These lesions are often invisible
on CT and usually need special MRI
techniques like thin cuts, FLAIR imaging18
etc for best results. Many of these are
amenable to surgical treatment. Functional
neuroimaging like SPECT18 or PET17may
demonstrate abnormalities in MRI negative
cases as has been shown by Chugani &
colleagues in infantile spasms 17. The
diagnosis of the epileptic syndrome
facilitates choice of drugs (Table 2). Long
term realistic goals are also set at this time.
For instance seizure freedom is not very
essential in a severely handicapped child
where the seizures are but one small part of
the total problem.
Drug History Review:
This is critical for treatment planning. Often
this is not possible due to non-availability of
complete records. Uneducated parents are
29
often not even aware of the names of the
different medications used. However, one
must obtain information form the
prescription and the parents to help select
‘target’ drugs3 which would be tried one by
one in a systematic manner with the aim of
deciding their efficacy. As patients already
come with 3-4 drugs on board, simultaneous
with drawl of apparently ineffective drugs is
carried out with slow upward titration of each
target drug. Withdrawal of sedative drugs
like CBZ or VGB seems to increase seizure
control in many patients. Only two drugs
should be used at any one time so that
adverse effects do not outweigh the benefits.
Parents must be counseled about the small
risk of increasing seizures during this
changeover and the physician must resist
making hasty decisions during short term
seizures exacerbations, concentrating rather
on the broader picture and treatment plan.
Each target drug should be stepped up to
maximally tolerated doses, preferably
confirmed by drug levels, before switching
to the next target drug. A good response
here points to a monotherapy regimen. The
least favorable strategy using first line drugs
is a change of drugs 3,9 while the most
successful is higher than average dose
monotherapy or rational polytherapy 9,
though this is not consistent in all studies6.
New AEDs:
Before using newer drugs one must confirm
both availability and affordability.
Pharmacologically, these drugs have fewer
drug interactions and side effects and more
relatively easy to use. Though there are
more than ten molecules available in the
more developed nations, this review will
concentrate on the five drugs available freely
in the Indian metropolises i.e. clobazam
(CLB), lamotrigine (LTG), gabapentin (GBP),
vigabatrin (VGB) and topiramate (TPM). The
last two are available only through the gray
market at an exorbitant cost.
Intractable partial epilepsies:
All 5 drugs improve seizures though CLB,
VGB and TPM are the most effective19, 20,21,22.
Seizure freedom, however, is rarely
obtained. CLB achieves almost full control
in as many as 40%20 and our experience with
this cheap easily available agent is similar.
VGB has been reported21 to help as many
as 50% of childhood refractory partial
seizures achieving full control in about one
third. Topiramate appears to be powerful in
Proceedings & Abstract Book
partial epilepsies though pediatric
experience is at present limited.
Intractable generalized epilepsies:
LTG is the clear winner here with as many
as 60% of children with severe epilepsy
showing some response 23. There seems
to be synergism with VPA and up to 35%
become seizure free when both are used.
All types of refractory generalized seizures
respond including tonic, myoclonic-atonic,
refractory absence and GTCs. CLB is also
fairly effective though tonic seizures
probably respond less favourably20. TPM
seems to be effective though some evidence
suggests better control in partial seizures
vis-à-vis generalized seizures23. VGB and
GBP are best avoided because of poor
efficacy and a tendency to exacerbate
myoclonic seizures15, 21.
West syndrome:
VGB has almost replaced steroids as first
line treatment in infantile spasms in Europe22,
24.
The results in various studies suggest an
equal if not better response with fewer side
effects. The response is rapid and is best
in infants with tuberous sclerosis (TS) 25. In
our experience of 12 cases, every child’s
seizure had completely resolved. TPM has
been used in refractory infantile spasms at
high doses and can be of help in half the
cases26.
Lennox Gastaut syndrome:
LTG & VPA in combination have shown fairly
good results in LGS with a response rate of
about 50% and with some becoming seizure
free27. CLB is also effective though tonic
seizures may not respond well. TPM has
shown promise28.
Limitations:
Most new AEDs are well tolerated.
Neurobehavioral changes are some-times
noted with CLB, VGB, GBP and TPM 19.
Cognitive changes may be a real problem
with TPM, especially if this is rapidly
increased. Rash is seen in upto 10% of
children with LTG, and more when given with
VPA19, 21. In a developing nation many of
these newer drugs remain elusive because
of the high cost (barring CLB).
Alternative Therapies:
Ketogenic diet:
In the 1920s it was shown that maintenance
30
of ketosis by a high fat, low carbohydrate
diet has an anti-epileptic effect. In a recent
‘intent to treat’ study 29 on 150 children
followed for one year, 27% had more than a
90% decrease in seizure frequency.
However, 45% stopped the diet either due
to inefficacy or poor tolerance. Use of this
diet in 22 children yielded > 90% seizure
reductions in 7 children. Initial fears of how
to use this diet in vegetarian children were
unfounded. The main group of children in
whom the diet is really helpful are young
and / or handicapped children in whom
compliance is assured. An added bonus is
that behavior is vastly and almost universally
improved. Parents often opt to continue the
diet for this reason alone. Though it is safe
in the majority, serious nutritional, metabolic
and other effects are seen in about 10%30.
Surgery for Epilepsy:
This is possible due to advances such as
simultaneous video-EEG and imaging
techniques like the MRI, SPECT and PET,
which have allowed a clear identification of
the epileptogenic zone (EZ). If this is
unifocal, it is often amenable to surgical
treatment. In adult life the most common
surgically remediable syndrome is mesial
temporal lobe epilepsy (MTLE) usually
caused by hippocampal sclerosis (HS).
Anterior temporal lobectomy is the
commonest surgical procedure and has
already been established at two centers in
South India with a surgical experience of
over 100 cases.
Surgery for childhood epilepsy is more
complicated. It is often difficult to decide
how long to wait with medical management
as childhood epilepsies can be
unpredictable at times with a small but
definite remission rate 10 . More often,
however, catastrophic epilepsies are
allowed to continue with all their devastating
effects because of the hesitancy of operating
in very young children. Childhood
epilepsies involve a complex interaction
between the epileptic and rapid
developmental processes making
localization of the EZ difficult which is often
extratemporal or multilobar 31 with rapid
seizure propagation and therefore often
difficult lateralization. On evaluation, the EZ
may appear more diffuse than is classically
seen in infantile spasms where focal lesions
often give rise to a generalized epileptic
syndrome and focal resections often
INTERNATIONAL PEDIATRIC UPDATE 2004
ameliorate the epilepsy17. Developmental
lesions are not uncommonly missed by MRI
and when seen, the extent is often
underestimated leading to sub-optimal
resection and poor results. What helps in
childhood epilepsy surgery is the
developmental neuronal plasticity allowing
large amounts of apparently functional
critical cortex e.g. language to be resected
with out permanent deficits31.
Over the last few years’ epilepsy surgery in
childhood and even infancy has established
itself in specialized pediatric epilepsy
centers and several surgically remediable
syndromes (Table 3) have been identified.
Three procedures are commonly done.
Focal cortical resections, hemispherectomy
and corpus callosotomy, a palliative
procedure mainly done for recalcitrant drop
attacks31. Seizure freedom is achieved in
60 – 70% overall with 0 – 20 % having only
rare seizures32. Temporal lobe resections
do better than extratemporal with a seizure
free rate of 75 – 80%32. Not surprisingly
adolescents do better than infants. We have
a small experience of 17 children and
adolescents operated in the last two years.
Over a follow up period from 4m-18m, 12
are seizure free, 2 have markedly improved
and 3 have done poorly. Though successful
surgery does not necessarily improve
intelligenc12 or employment33, there seems
to be an improvement in behavior and
quality of life34.
References:
1.
Cockerell OC et. Al. Prognosis of epilepsy: a
review and further analysis of the first nine years
of the British National General Practice Study of
Epilepsy, a prospective population-based study.
Epilepsia 1997; 38(1): 31-46.
2.
Eriksson KJ, Koivikko MJ. Prevalence.
Classification and severity of epilepsy and
epileptic syndromes in children. Epilepsia 1997;
38(12); 1275-1282.
3.
Aicardi J, Shorvon S. Intractable epilepsy In: Engel
J, Pedley T (Eds). Epilepsy: A comprehensive
textbook 1st edn. 1998; 1325 – 1331
4.
Radhakrishnan K et al. Profile of antiepileptic
pharmacotherapy in a tertiary referral centre in
South India: a pharmacoepidemiologic and
pharmacoeconomic study. Epilepsia, 1999; 40(2):
179-185.
5.
Steffenburg Ulf. Intractable epilepsy in a
population-based series of mentally retarded
children. Epilepsia 1998; 39(7): 767-775.
6.
Gilman JT et al. Medical intractability in children
evaluated for epilepsy surgery. Neurology 1994;
44: 1341-1343
7.
Bharucha NE, Shorvon S. Epidemiology in
developing countries. In: Engel J, Pedley T (Eds)
Epilepsy: A comprehensive Textbook 1 st edn.
1998; 105-117.
8.
Berg AT et al. Predictors of intractable epilepsy
in childhood: a case-control study. Epilepsia,
1996; 87(1): 24-30.
9.
Udani VP et al. Difficult to control epilepsy in
childhood – A long term study of 123 cases. 1993;
30: 1199-1206.
10. Huttenlocher PR et al. A follow-up study of
intractable seizures in childhood. Ann Neurol
1990; 28: 699-705
11. Bourgeois FDB. Antiepileptic drugs, learning and
behaviors in childhood epilepsy, Epilepsia 1998;
39(9): 913-921.
12. Duchowny M et al. Neurobiologic considerations
in early surgery for epilepsy. J. Child Neurol 1994;
9(Suppl): 42-48.
13. Lindsay J et al. Long term outcome in children
31
with temporal lobe seizures I: Social outcome and
childhood factors. Dev Med Child Neural 1979;
21: 285-298.
14. Zupanc ML. Neuroimaging in the evaluation of
children and adolescents with intractable
epilepsy: I. Magnetic resonance imaging and the
substrates of epilepsy. Pediatr Neurol 1997; 17:
19-26.
15. Guerrini R et al. Antiepileptic drug-induced
worsening of seizures in children. Epilepsia 1998;
39: 352-10.
16. Palmini A et al. Focal neuronal migration disorders
and intractable partial epilepsy: a study of 30
patients. Ann Neural 1991;30:741-749
17. Chugani H et. Al. Infantile spasms: I. PET identifies
focal cortical dysgenesis in cryptogenic cases for
surgical treatment. Ann Neurol 1990; 27: 406-413.
18. Zupanc ML. Neuroimaging in the evaluation of
children and adolescents with intractable
epilepsy: II. Neuroimaging and pediatric epilepsy.
Pediatr Neurol 1997;17:111-121.
19. Cramer JA et al. New antiepileptic drugs;
comparison of key clinical trials. Epilepisa 1999;
40(5): 590-600.
20. Sheth RD. Clobazam for intractable pediatric
epilepsy. J. Child Neurol 1995; (10): 205-208.
21. Belanger S. et al. Role of vigabatrin and
Iamotringine in treatment of childhood epilepsy
syndromes. Epilepsia 1998; 39(8): 878-883.
22. Moreland EC et al. Topiramate for intractable
childhood epilepsy. Seizure 1999; 8(1): 38-40.
23. Eriksson AS et al. The efficacy of lamotrigine in
children and adolescents with refractory
generalized epilepsy: A randomized, double
blind, crossover study. Epilepsia 1998; 39(5): 495501.
24. Vivegano F, Cilio MR. Vigabatrin versus ACTH as
first line treatment for infantile spasms: A
randomized prospective study. Epilepsia 1997;
38(12): 1270-1274.
25. Hancock E, Osborne JP. Vigabatrin in the
treatment of infantile spasms in tuberous
sclerosis; literature review. J Child Neurol 199;
Proceedings & Abstract Book
14(2):71-74.
26. Glauser TA et al. A pilot study of topiramate in the
treatment of infantile spasms. Epilepsia
1998;39(12): 1324-1328.
27. Donaldson JA et al. Lamotrigine adjunctive
therapy in childhood epileptic encephalopathy
(the Lennox Gastaut Syndrome) 1997; 38(1): 6873.
28. Glauser TA. Topiramate use in pediatric patients.
Can J Neurol SC 1998;25(3): 58-12.
29. Freeman JM et al. The efficacy of the ketogenic
diet-1998 A prospective evaluation of intervention
in 150 children. Pediatrics 1998; 102(6): 13581363.
30. Ballaban –Gil K et al. Compliations of the
ketogenic diet. Epilepsia 1998; 39(7): 744-748.
31. Wyllie E. Surgical treatment of epilepsy in
children. Pediatr Neurol 1998; 19(3):179-188.
32. Wyllie E. et al. Seizure outcome after epilepsy
surgery in children and adolescents. Ann Neurol
1998; (44): 740 – 748.
33. Reeves AL ET al. Factors associated with work
outcome after anterior temporal lobectomy for
intractable epilepsy. Epilepsia 1997; 38(6): 689695.
34. Gilliam F et al Epilepsy surgery outcome:
comprehensive assessment in children.
Neurology 1997: 48: 1368-1374.
Table 1: Clinical factors associated with Intractability
Factors
Examples
Epileptic syndromes
West syndrome, LGS, severe myoclonic epilepsy,
progressive myoclonic epilepsy, Kojeknikow’s
syndrome.
Etiologies
Tuberous sclerosis, Sturge-Weber syndrome, tumors
cortical developmental malformations, brain damage
following ischemia, hypoglycemia, trauma,
Rasmussens encephalitis.
Seizure types
Tonic seizures, myoclonic-atonic seizures, atypical
absence seizures, mixed seizures.
Associated clinical features
Mental retardation, neurologic abnormalities, early age
of seizure onset, status epilepticus.
Modified from Aicardi J, Shorvon SD, ‘Intractable Epilepsy’ chapter in Epilepsy A
Comprehensive Text book, Vol. 2; 1325-1331.
Table 2: Choice of Antiepileptic Drugs in different syndromes and seizure types
West syndrome
ACTH, prednisone, VGB*, NZP, CLP, VPA, TPM
Lennox Gastaut syndrome
VPA, CLB, LTG, TPM, FBM, CBZ**, PHT**
Severe myoclonic epilepsy
VPA, CLB, PB, VGB, stiripentol
Generalized seizures
VPA***, CLB, LTG, TPM ESM+, CLP, NGP,
acetazolamide
Partial seizures
CBZ, PHT, VPA, PB, CLB, VGB, TPM, LTG, GBP,
acetazolamide
* First choice in TS
** May increase myoclonic, atonic & absence seizures
***High doses may be needed
VPA = Valproate, CBZ = Carbamazepine, PHT = Phenytoin, PB = Phenobarbital,
CLP = Clonazepam, NZP = Nitrazepam, ESM = Ethosuxamide, CLB = Clobazam,
LTG = Lamotrigine, VGB = Vigabatrin, TPM = Topiramate, GBP = Gabapentin.
32
INTERNATIONAL PEDIATRIC UPDATE 2004
Table 3 : Surgically Remediable syndromes (Indian context)
Epileptic syndrome / Etiology
Procedure
Mesial temporal lobe epilepsy
(Hippocampal sclerosis)
Anterior temporal lobectomy
Lesions – tumors, hamartoma, vascular
malformations, acquired*, cortical dysplasia*#
Lesionectomy
Hemispheric syndromes; Strokes, Sturge-Weber
syndrome, Hemimegalencephaly, Rasmussens
syndrome
Hemispherectomy
Drop attacks
Corpus callosotomy
* Will need electrocorticography guided resection
*# Only MRI positive cases
Use of Cough Mixtures in Children
Dr. Suhas V. Prabhu, Visiting Consultant Pediatrician,
P D Hinduja National Hospital & Medical Research Center, Mumbai
Cough is one of the commonest symptoms
with which a child is presented to the
pediatrician who then reflexly prescribes a
“cough mixture”. However one must not lose
sight of the fact that the cough reflex
basically serves a protective and useful
purpose. Also the cough may be of varying
etiology and of different types. Therefore any
cough merits a thorough analysis before
deciding on the need and type of therapy
required.
The Cough Reflex:
Cough is a reflex generated from 3 different
groups of receptors.1 The afferents of all the
three are carried by the IXth & Xth cranial
nerves. The locations of these 3 groups of
receptors are:
a) Those lining the respiratory mucosa right
from the pharynx down to the terminal
bronchioles
b) Those lining the pleura
c) Interstitial (‘J’) receptors inside the lung
parenchyma.
In addition, cough may also result from
direct stimulation of the cough centre in the
33
medulla oblongata by various drugs and
even by inputs form the higher centres
(cortex). This type of cough is called the
psychogenic cough or more preferably
“habit cough”.
Types of Cough:
From the point of view of management
however, cough can be divided into two
types: Dry cough and Wet (or productive)
cough:
Dry cough: Cough which is not associated
with the production and expelling of sputum
is described as non-productive or dry
cough. Stimulation of the pleural or ‘J’
receptors always evokes this type of cough.
Cough which is central in origin, i.e. because
of direct stimulation of the cough centre is
also of this type. Sometimes dry cough can
also be produced by stimulation of those
receptors lining the respiratory mucosa (as
for example in an impacted bronchial foreign
body or bronchial asthma.) Such cough
may only be distressing to the child and
does not really serve any physiological
purpose. These types of cough are therefore
Proceedings & Abstract Book
termed as useless and of no benefit to the
patient. They therefore may need to be
suppressed by cough suppressant drugs or
“anti-tussives”.
Productive Cough : Cough may be
productive i.e. associated with the expelling
of sputum. Sputum consists of a mixture of
mucus, inflammatory exudates, debris, etc.
from the lower respiratory tract (i.e. the
tracheobronchial tree). The purpose of the
cough is to aid tracheo-bronchial toilet and
clear the airway. Clinical situations with this
type of cough are chronic bronchitis,
bronchiectasis, resolving pneumonia, etc.
Sputum may also be produced due to
cardiac or haemodynamic causes such as
left ventricular failure or pulmonary oedema.
If the cough is successful in expelling the
sputum, it helps to clear the respiratory tract
and improve gaseous exchange and
therefore is a useful cough. Many young
children will not expectorate i.e. bring out
the sputum by mouth; instead they swallow
it. Nevertheless, the purpose of expelling it
from and thereby clearing the respiratory
tract is still achieved.
Using a cough suppressant in such patients
with useful cough causes sputum retention
which can have harmful effects. However,
sometimes the sputum may be so thick or
tenacious that the cough is unsuccessful in
expelling the sputum. The cough is then no
longer useful and soon becomes exhausting
for the patient. In such cases, it can be made
useful by medicines that liquefy the sputum
and enable it to be expelled. Such
medications are termed as expectorants or
“pro-tussives”. Sometimes however, even in
a wet cough, it is not possible to facilitate
expectoration, because the sputum is too
tenacious. Then this cough, although wet,
needs to be suppressed. A good example
of this is Pertussis.
Therefore, generally speaking, wet or
productive cough performs a useful
physiological function and may need to be
aided to make it more effective rather than
using cough suppressant drugs. However,
in certain clinical situations, such a cough,
although beneficial in clearing the
respiratory tract may have other ill-effects
and therefore need to be suppressed with
anti-tussives. Examples are increased
intracranial tension, after eye surgery, in a
child with cough syncope or to allow an
exhausted child a short rest. They may also
34
be considered in a run-down terminally ill
patient.
Cough Medications:
One of the reasons why there is so much
confusion and uncertainty about cough
medications is that clinical assessment of
their efficacy is difficult. No experimental
cough produced by inhalation of irritants
(commonly capsaicin) can properly
represent the cough of disease. Also judging
the efficacy in clinical trials is prone to error.
It has been well shown that subjective
assessment by the patient is not a reliable
method of judging the frequency or severity
of cough. Interestingly also, the cough reflex
is under substantial voluntary control and
there can be a lot of psychological factors
affecting cough. This adds to the difficulty
of objective assessment. Thus there are
enough studies documenting the
effectiveness of placebos in a wide variety
of causes of cough from pharyngitis to
chronic bronchitis. This does not mean that
all cough medicines act by a placebo effect;
there are also definite controlled studies
showing the beneficial effect of drugs esp.
opiates in reducing cough.2
As discussed above, cough medications are
basically of two types:
I} Cough suppressants
(which suppress the cough reflex)
II} Expectorants
(which ease expectoration of sputum).
I} Cough suppressants (Anti-tussives):
It is quite obvious from the earlier discussion
that these are useful primarily in dry cough
which is distressing to the patient and are
only rarely to be used in wet or productive
cough. These drugs may act by:
A] Reducing the sensitivity of the cough
receptors or
B] Suppressing the cough centre in the
medulla oblongata directly or via the
cerebral cortex and the sub-cortical paths.
A] Drugs reducing the sensitivity of the
cough receptors:
i) Anaesthetic agents : One such example
is local anaesthetic agents such as
lignocaine which have to be applied directly
onto the respiratory epithelium. They are
useful, for example, as a spray prior to
procedures such as a bronchoscopy but are
unsuitable for use in clinical practice for
relieving dry cough. Benzonatate is another
INTERNATIONAL PEDIATRIC UPDATE 2004
local anaesthetic, related to amethocaine
that may reduce cough by depressing
pulmonary stretch receptors and so
moderating the response to the lung inflation
that is the first stage of the act of cough.
The adult dose is 100 mg t.d.s. However,
the effect of this drug comes on after 5 to 7
days of administration so that occasional
single doses are useless. This has effectively
made this drug unattractive and it has not
been fully evaluated. Ambroxol
hydrochloride, which is primarily believed
to be an expectorant, has in some studies
shown to have a local anaesthetic effect on
the pharyngeal mucosa when administered
in 20 mg doses in lozenge form (in adults).3
ii) Demulcents: Demulcents are drugs that
glutinously coat the pharynx and reduce
cough. It is thought that the coating of the
mucosa protects the receptors from the
effects of irritants and therefore reduces the
cough.
Demulcents
are
usually
administered in form of lozenges to the
chewed or sucked on. It is well known that
simple swallowing (of liquids or solids)
inhibits cough by an unknown mechanism.4
This may be the principle on which
demulcents work. They are however useful
only when the cough arises from above the
larynx i.e. in upper airway disease such as
tonsillitis or post-nasal drip.
Demulcents have long been a part of homeremedies for cough. The classic example
of a demulcent is liquorice which has been
apart of folk medicine for cough since many
centuries. It continues is an ingredient of
many home remedies as well as over-thecounter cough preparations. Another
ingredient of the same type is honey which
again is often used as a home remedy or
an ingredient of many cough mixtures
(Honeytus). Others of doubtful benefit are
various syrups, glycerol, etc.
iii) Humidification: When cough arises from
below the larynx, steam inhalations and a
warm moist environment give relief of cough.
This is based on the experimental fact that
cold dry air is a known stimulant of the
cough receptors lining the pharynx, larynx
and trachea. (This in fact is the mechanism
by which patients with adenoidal
enlargement who are mouth breathers get
cough.) It is traditional to add tincture
benzoin to the inhalation. It is postulated
that the benzoin may promote secretion of
dilute mucus and so help to give a protective
35
coating to the inflamed respiratory mucosa.
In fact, it may only to make the steam smell
therapeutic and add to the psychological
effect.
iv) Bronchodilators: In cough due to
bronchial asthma, the cough is caused by
the bronchoconstriction itself and in such
cases “cough mixtures” will not relieve the
cough. Simple use of bronchodilators, such
as beta-agonistic or anticholinergic drugs
(usually by inhalation) or theophyllines will
itself relieve the cough.
B] Antitussives acting on the CNS:
These act as mentioned earlier on the cough
centre or via higher centres. They can be
divided into the opioid group of drugs and
the non-opiates.
The Opiates: The basic opiates like
morphine, heroin and methadone are not
used because of their respiratory depression
and addictive properties.
a) The earliest prototype opiate drug for
cough is of course codeine (an ingredient
of Corex, Tossex, Phensedyl cough linctus,
Mit’s linctus codeinae, etc.).5 Codeine is
used in the dose of 1 mg/kg per dose and
probably acts on the medullary cough
“centre”. Drawbacks of this drug are:
1) There is a potential for drug addiction
and abuse esp. in older children.
2) They dry the mucosa and thicken the
sputum; so are unsuitable in wet cough.
3) Can cause constipation and other G-I
side effects.
4) Higher doses (esp. in small infants) can
cause respiratory depression.
In order to counteract this respiratory
depression of opioids, they have been on
occasion combined with a respiratory
stimulant; e.g. combination of leptazol & dihydrocodeione (Cardiozol-Dicodid drops)
but these have to still be used with caution.
These side-effects have led to the restricted
usage of codeine in pediatric practice. It is
usually reserved for children with severe
cough who have failed to respond to other
anti-tussives listed below.
b) Dextromethorphan is the standard antitussive agent for use in children (Alex,
Deletus, Tuspress, Ascoril-D, Chericof,
Benylin, Tuspel-D, etc.). It is the only antitussive recommended by the World Health
Organization for the routine treatment of
cough in children. It is the d-isomer of
Proceedings & Abstract Book
codeine analog levorphanol.6 It has antitussive effect almost on par with codeine but
does not have the drawbacks of codeine
listed above. (In very high doses in infants
however, they may be significant respiratory
depression). It is recommended to start with
0.5 mg/kg per dose but doses 3 times higher
be safely given to provide relief. It however
has a short half-life of 5 hours necessitating
dosing 3 to 4 times a day. This also makes
it unsuitable for providing the prolonged
action required for night-time relief of cough.
However, there is a sustained release
preparation available (Lastuss-LA), that
reduces the dosing to once or twice a day,
which is therefore much more useful.
c) Pholcodeine. (Tixylix) This drug has been
promoted over dextromethorphan as being
more potent and having a longer half-life.
These two properties together help this drug
provide better nocturnal relief and it needs
to be administered just once or twice a day.
d) Noscapine. (Coscopin) Has action
similar to dextromethorphan but is a potent
releaser of histamine and this can have
undesirable side-effects and make it
unsuitable for use particularly in asthmatic
children.
The non-opiates: A great many synthetic
centrally acting non-opiate anti-tussives
have been introduced. 7 They include
carbapentane, piperiodone (Sedulon),
pipazethate (Selvigon), chlorphedianol
(Detigon) and levopropoxyphene. Their
advantage is the claim that they are not
addictive. They are not as effective as the
opioid derivates listed above and have
therefore not managed to replace them.
II} Expectorants:
Expectorants are drugs that help to liquefy
and reduce the tenacity of respiratory
secretions, thereby easing expectoration.
The rationale behind the use of expectorants
(which have also been termed as protussives)1 is that they reduce the amount of
coughing needed by increasing its
efficiency. Reliable experimental data on
expectorants particularly in children is
scarce.8 Studies on some commonly used
expectorants like ammonium chloride are
non-existent. Also, different studies yield
contradictory data and many animal studies
are irrelevant.
The methods by which these drugs ease
expectoration fall into four main groups:7
36
A] Those acting reflexly via the stomach:
These include ammonium chloride,
citrates, iodides, ipecac, etc. Although
they are common adjuvants in many cough
mixtures, hard data from controlled trials on
their efficacy is lacking.
B] Direct stimulation of secretion by
bronchial mucosal glands: These include
guaiacols (such as guaiphenesin), volatile
oils (such as menthol, eucalyptus oil),
creosote and perhaps iodide.
The most popular of this group is
guaiphenesin which is the ingredient of
many cough syrups. Some studies have
shown significant improvement in ease of
sputum expectoration, decrease in sputum
viscosity and earlier clearance of secretions
when compared to placebo.9 Adult doses
typically are 200 mg thrice a day; there is
not enough data on children. In spite of its
widespread use even in the U.S., it does not
have FDA approval.
Volatile oils such as menthol, camphor,
terpineiol, and chlorothymol and
eucalyptus oil are extremely popular as an
ingredient of home remedies or “ayurvedic”
cough syrups. They are often found as an
adjuvant in allopathic preparations as well.
Because of their volatile nature they can also
be taken as an inhalation with steam or from
evaporation from balms and rubs applied
on the chest, nose or personal belongings.
C] Reducing viscosity of secretions:
i) Humidifying inhalations of water (steam).
This is another traditional home remedy for
cough with a sound physiological basis.
Besides its anti-tussive effect (described
earlier), steam helps to liquefy sputum and
aids expectoration. It can be administered
using a simple “steamer” but using a
nebulizer increases the effectivity by
reducing the particle size, allowing it to
penetrate deeper down into the tracheobronchial tree.
ii) Altering the secretion chemically e.g. Nacetylcysteine. This molecule has a free
sulphydryl group which opens the
disulphide bonds in the mucus; this
markedly reduces its viscosity, enabling
easy expectoration. It is effective in both,
normal individuals as well as patients with
abnormally viscid mucus secretions (cystic
fibrosis). It has to be administered by
inhalation or instillation and there is data that
its presence in the respiratory tract can
INTERNATIONAL PEDIATRIC UPDATE 2004
interfere with the action of some antibiotics.
This has led to restrictions in its use for short
periods in selected cases of patients on
ventilators, in the care of tracheostomies and
home care of chronic bronchitis and noninfected cystic fibrosis.
Other more commonly used mucolytics,
claimed to have properties of promoting the
secretion of liquefied secretions, are
bromhexine and its metabolite ambroxol.
A traditional home remedy, the extract of the
leaves of the Asian plant (Adhatoda vasica)
used for decades as vasaka contains
precursors of these two molecules. 10
Another home remedy the leaves of the
“tulsi” plant (Ocimum sanctum) also
contains similar compounds. There are
several studies showing some improvement
in adult patients with chronic bronchitis in
doses of 60-120 mg/day. 11,12 There are
however no adequate trials in children
documenting unequivocal benefit. To this
day both these drugs do not have US FDA
approval for use either in children or adults.
iii) Enzymes e.g. trypsin which directly
attacks and breaks down the mucus (but
not the pus). Their action is not as effective
as that of acetylcysteine. Like the latter, they
also have to be administered directly into
the respiratory tract. Oral Chymotrypsin
although widely used, has not been shown
to be beneficial.
iv) Iodides. Iodides alter proteins so that
they are more readily hydrolysed by
enzymes derived from leucocytes in the
sputum. Small doses of iodides are useless.
It must be given to the limits of its tolerance;
this makes its use unpopular.
D] Drugs which directly stimulate the vagus
centre such as centrally acting emetics and
cholinergic drugs that stimulate the
parasympathetic nerve endings on the
bronchial glands are generally not used
because of their undesirable side effects.
Cough Mixtures:
Most cough medications in the market are
mixtures. Single ingredient medications for
cough are rarely available. Many a times the
combination of drugs in the mixture is
irrational, e.g. a bronchodilator with a cough
suppressant or an anti-tussive with an
expectorant. It is therefore important to
choose the cough mixture carefully before
prescribing. A combination of a demulcent
37
with an antitussive may be desirable (in
pharyngitis) and a mucolytic with a
bronchodilator may find rational use in a
patient with chronic bronchitis.
Many cough mixtures have other ingredients
such as nasal decongestants, anti-pyretics,
anti-histaminics etc. These other ingredients
may have a role to play in the associated
symptoms that the patient with cough may
also have.
a) Nasal decongestants such as
psuedoephedrine, phenylephrine or
phenylpropranolamine (PPA) are added
for relieving associated nose block. Caution
has been advised in using the latter (PPA)
because of data suggesting increased
chances of stroke in teenage children who
have received PPA.
b) Although anti-histaminics (such as
diphenhydramine or chlorpheniramine
maleate or cetrizine) have been touted to
have anti-tussive effects, these have not
been proved in controlled trials.13 However
their use in cough syrups may be justified
for taking care of the associated symptoms
such as sneezing or nasal watering.
Besides, some anti-histaminics, particularly
the traditional ones like chlorpheniramine
maleate have a drying effect on the
respiratory mucosa which has a deleterious
effect.
c) Antipyretics like acetaminophen
(paracetamol) are often added to the cough
mixture. The justification for this is to take
care of the associated symptoms of
headache, body ache or fever.
Quite often, the combination of such
ingredients is not in the correct proportion
to ensure correct dosing of all the
ingredients. A careful examination of the
composition must be done before opting to
use such combination cough mixtures.
Choice of therapy in cough:
The choice of therapy depends on several
factors, but primarily depends on the type
and severity of the cough. Based on the
above discussion, the following guidelines
can be formulated:
1) Cough is a protective reflex. It is not
required (and in fact may be dangerous) to
treat it as an undesirable symptom that must
be completely eliminated at any cost. Cough
that is mild, productive and not distressing
to the patient may best be left alone.
Proceedings & Abstract Book
2) If the cough is due to the bronchospasm
of asthma, no cough syrup is required,
simple bronchodilators will effectively relieve
the cough.
3) In dry cough which is useless, simple
measures like frequent fluid intake,
humidification and use of demulcent
lozenges, are very beneficial and may suffice
in many cases. If the cough is very
distressing or disturbing to the patient,
Dextromethorphan is probably the drug of
choice in such cases. Pholcodeine or
Codeine may be required for more severe
cases such as in Pertussis but must be used
judiciously.
4) In case of wet cough, increased fluid
intake and steam inhalation should be
encouraged. If available, nebulization with
simple saline solution may help. Local
application or inhalations of volatile oils is
probably useful. In severe cases,
expectorants like ammonium chloride,
citrates, menthol, bromhexine or ambroxol
although unproven in clinical settings in
children may be used.
5) Other ingredients in the “cough mixture”
must be judiciously examined and such
syrups may be used for the beneficial effects
of such ingredients on the associated
symptoms such as running nose, sneezing,
throat pain, fever, etc. Care must be taken
to see that these ingredients are in the
correct proportion and do not have an
adverse effect on the cough.
In summary, drug therapy of cough is not
always necessary and “home remedies”
may suffice for mild cases. With proper
evaluation and thought, rational drug
therapy of cough is possible with full
pharmacological knowledge of all the
ingredients of the “cough mixture” and the
associated symptoms in the patient. Also it
must be remembered that cough is not a
disease but a symptom and the underlying
cause of the cough should also be
simultaneously evaluated and treated.
References:
1.
Irwin RS, Widdicombe J. Cough in Text Book of
Respiratory Medicine W.B. Saunders Co. 2nd Ed.
1994 Ed. Murray JF & Nadel JA. Vol 1, pp 52941.
2.
3.
4.
8.
Parvez L. Vaidya M. et. al. Evaluation of antitussive agents in man. Curr. Med Res and Opinion
3(2) 1975 pp. 63-67.
Schroeder K , Fahey T. Over-the-counter
medications for acute cough in children and
adults. Cochrane Database of Systematic
Reviews CD001831, 2001. Last updated Sept
2003.
9.
Fischer J, Pschorn U et. al. Efficacy and tolerability
of ambroxol hydrochloride lozenges in sore
throat. Randomised, double-blind, placebo
controlled trials regarding the local anaesthetic
properties. Arzneimittel-Forschung 52(4) 2002 pp.
256-63.
Rubin BK . An in vitro comparison of the
mucoactive properties of guaphenesin, iodinated
glycerol, surfactant and albuterol. Chest 116(1):
Jul 1999 pp 195-200.
10. Sehgal SK, Mohan M. Bromhexine. Ind Pediatr
27 (5) 1990 pp. 479-83.
Haslett C. Lung Defences and Immunology in
Crofton and Douglas’ Respiratory Diseases. 5th
Ed. Ed. Seaton A, Seaton D, Leitch AG. Blackwell
Science 2000. Vol. 1 pp 83-84.
5.
Monthly Index of Medical Specialities Ed. Gulati
CM. 24(3) Mar 2004 pp 237-45.
6.
Goodman & Gilman’s The Pharmacological Basis
of Therapeutics. 9th Ed. Ed. Hardmann JG, Limbird
LE. Mc-Graw-Hill 1996. pp 551-2.
7.
Laurence DR. Clinical Pharmacology 3 rd Ed.
ELBS, J.W. Churchill Ltd. 1969. pp 322-6.
38
11. Germouty J, Jirou-Najou et. al. Clinical efficacy
of ambroxol in the treatment of bronchial stasis.
Clinical trial in 120 patients at two different doses.
Resp. 51 1987 Suppl 1. pp 37-41
12. Ericsson CH, Juhasz J. et. al. Influence of
Ambroxol on tracheobronchial clearance in
simple chronic bronchitis. Eur J Resp Dis. 70
(3):Mar 1987 pp. 163-70.
13. Paul IM, Yoder KE et. al. Effect of
Dextromethorphan, Diphenhydramine, and
placebo on nocturnal cough and sleep quality
for coughing children and their parents.
Pediatrics, Jul 2004; 114: pp 85 - 90.
INTERNATIONAL PEDIATRIC UPDATE 2004
Non-Invasive Ventilation in
Pediatric Age
Dr. Giuseppe A. Marraro, Department of Anesthesia & Intensive Care - Pediatric
Intensive Care Unit, Fatebenefratelli & Ophthalmiatric Hospital - Corso di Porta
Nuova, 23 –Milano, Italy
The feasibility to apply a ventilatory mode
capable of avoiding airway invasion has
been evaluated and tested for long time. Two
modes have had large consensus, which
uses different methodologies to attain
respiration, i.e. 1. Negative Pressure
Ventilation by means of either iron lung or
chest cuirass, and 2. Positive Pressure
Ventilation in spontaneous breathing, with
CPAP, or Non-invasive Positive Pressure
Ventilation with mask. A new ventilatory
mode has been recently introduced in
clinical practice, which uses a biphasic
negative and positive external pressure to
obtain gas exchange.
Negative ventilation has been used in the
treatment of neuromuscular and chronic
obstructive pulmonary disease, to reduce
respiratory fatigue and put respiratory
muscles to rest. Relevant beneficial effects
were not observed in home assistance of
these patients.1,2
The use of non-invasive ventilation has been
implemented with the arrival of CPAP and
the use of masks instead of tracheal tube to
apply positive pressure ventilation (NPPV).
The advantages deriving from CPAP in the
treatment of Acute Respiratory Failure (ARF)
are: increase of PaO 2 and Functional
Residual Capacity (FRC), “open lung”
approach and reduction of cardiac
transmural pressure. CPAP can also reduce
work of breathing and inspiratory threshold
load if CPAP is less than 85% of static
intrinsic PEEP (PEEPi, stat).
NPPV is obtained increasing alveolar and
intramural pressure of the lung. Beneficial
effects of its application are: increase of
alveolar ventilation, improvement of gas
exchange, reduction of hypoxemia and
acidosis, reduction of muscle fatigue and
elastic lung work when external PEEP is
used to counterbalance PEEPi due to
dynamic hyperinflation.
39
General criteria for NPPV application in
pediatric age are:
• Moderate or severe dispnea;
• Tachypnea (respiratory frequency double
than expected for the specific child);
• Use of accessory muscles and
paradoxical abdominal respiration;
• Severe deterioration of gas exchange with
PaCO2 >45 and/or pH <7.35 or PaO2/FiO2
<300.
Eligibility criteria are : awake and
collaborative child, hemodynamical stability,
not abundant secretions, presence of airway
protective reflexes, absence of facial trauma
or anatomical malformation, and not
gastrointestinal bleeding.
Exclusion criteria are : unconsciousness, not
collaborating or agitated patient, respiratory
arrest,
hemodynamic
instability
(hypotension, arrhythmia, etc.), insufficient
protection of airways (lack of cough,
abundant secretions), airway obstruction,
vomiting, trauma, burns and face
malformation, pneumothorax not drained.
There is a high evidence-based efficacy in
the treatment of chronic lung disease3-5, in
cardiogenic pulmonary edema 6 , in
immunocompromised patients,7,8 in difficult
weaning from ventilator9 and in restrictive
lung pathology.10,11
There is a moderate evidence-based
efficacy in cystic fibrosis, asthma,
postoperative respiratory failure12-14 and in
“do not intubate” patients.15-16 Extubation
failure, ARDS and pneumonia have shown
evidence-based efficacy.
There are indispensable factors resulting in
NPPV efficacy:
1. Patient selection;
2. Early treatment;
3. Comfortable ventilator-patient interface;
4. Psychological patient support;
Proceedings & Abstract Book
5. Continuous monitoring;
6. Skilled and motivated team.
Respiratory-patient interface can be either
the facial mask, or the nasal mask, or, more
recently, the helmet. There is not agreement
on the ideal interface to be applied during
NPPV.
The characteristics of the mask should be
lightness, transparency, adherence, perfect
sealing and adaptability to anatomical
conformation. Nasal mask has reduced
dead space, provokes less claustrophobia,
reduces vomiting stimulation, and allows
secretion elimination, easy feeding without
removal of interface and better speech. For
these reasons it is better tolerated by the
patient. Efficacy is limited if nasal resistance
is more than 5 cmH2O/l/s.
Facial mask is preferable in severe
respiratory failure because improves minute
ventilation and bypasses nasal resistances.
Using <25 cmH2O of pressure, aerophagia
is rare and nasogastric tube is not
necessary.
Recently, the helmet has been tested in
clinical practice and appears to have
advantages compared to masks for the
absence of facial decubital necrosis
(occurring in more than 7% of cases using
masks!) but can create arm-pit decubitus
due to the securing system. In preliminary
reports, it appears to be more comfortable
because of the possibility for patients to see,
speak and read. Its application is possible
independent of facial anatomy.17-18
Non-invasive ventilators use different
systems:
â Single tube system;
â Two levels of pressure (BiPAP);
â Active expiration through an expiratory
valve (increase of work of breathing);
â Passive expiration, a part of EPAP flow;
â Need of CO2 re-breathing using a special
valve “non-re-breather” or applying EPAP
of 8 cmH 2 O in presence of high
respiratory rates.
â Flow trigger.
Some ventilators, like Respironics BiPAP
and Puritan Bennett PB-335, compensate
automatically the air leakage due to interface
and open mouth;
Characteristics of NPPV ventilators are:
1. Basic
Ability to reach 30 cmH2O pressure (control
40
pressure)
Ability to provide 60 l/min of inspiratory flow
Assisted/controlled ventilation mode
Bilevel PSV modality
Ability to reach a respiratory rate of 40
breaths /min
Flow trigger.
2. Optional
Rapid increase in pressurization time
Possibility to modify pressurization curve
Possibility to modify inspiratory and
expiratory trigger
Possibility to modify I:E ratio in ACV
Easy alarms suspension.
Criteria for NPPV withdrawal are:
â Inability to tolerate the interface
(discomfort, pain)
â Dyspnea or no gas exchange
improvement
â Need for tracheal intubation to perform
bronchosuctioning and to protect
airways
â No improvement in mental status after
30 min of NPPV application in case of
coma due to CO2 retention or in presence
of psychomotorial agitation connected
with hypoxemia.
Non-invasive ventilation using external
bi-phasic negative-positive ventilator.
A new mode of non-invasive ventilation,
similar to spontaneous breathing, is under
clinical research for the treatment of several
acute and chronic lung diseases in children
and adults.
To attain inspiration and expiration, this
ventilatory model uses an external cuirass
positioned on the chest and abdomen.
Positive and negative pressures are applied
alternatively inside this cuirass and are
regulated electronically by a software
program. The inspiratory phase is obtained
by generating a negative intrathoracic
pressure, like in physiological condition, and
similarly to the iron lung, but with limited total
involvement. During the negative phase, the
air flows into the lung if patency and stability
of upper airway is present. The expiratory
phase is passive but is favored by external
chest19 and diaphragm compression.20
This ventilatory mode does not need an
interface to link patient airways to ventilator
and does not apply positive pressure to the
INTERNATIONAL PEDIATRIC UPDATE 2004
lung, resulting in better clearance of
secretions. Moreover, it reduces those
specific hemodynamic variations deriving
from conventional positive pressure
ventilation.21-23
This new concept of ventilation is
implemented by the RTX Respirator
(Medivent Ltd), which is able to perform
Controlled Ventilation, Synchronized
Ventilation, HFO, and Triggered ventilation
[e.g. from ECG24] and Continuous Negative
Ventilation in spontaneous breathing. This
latter ventilatory mode is similar to CPAP, in
increasing functional residual capacity and
maintaining bronchioles and alveoli
continuously open. Not applying positive
pressure inside the lung, hemodynamic
stability is bigger.
The ventilator is able to change I:E ratio, to
facilitate secretion clearance using a special
system to assist the cough. Movement of
secretions is obtained using HFO, while
expulsion of secretions is achieved using
assisted cough with a high inverted ratio
(5:1).
There are several experiences in the use of
this new respiratory mode in different acute
and chronic lung pathologies in pediatric
age25,26: The ventilator is able to reduce the
need of intubation and conventional
mechanical ventilation.
References
1. Celli B, Lee H, Crimer G, et al. Controlled trial of
external negative pressure ventilation in patients with
severe chronic airflow obstruction. Am Rev Resp Dis
1989; 140:1251-1256
pressure (BiPAP) on extravascular lung water after
extubation of the trachea in patients following coronary
artery bypass grafting. Int Care Med 1996; 22: 13451350
2. Zibrak JD, Hill NS, Federman EC, et al. Evaluation
of intermittent long-term negative-pressure ventilation
in patients with severe chronic obstructive pulmonary
disease. Am Rev Respir Dis 1988; 138:1515-1518
13. Matte P, Jacquet L, Van Dyck M, Goenen M. Effects
of conventional physiotherapy, continuous positive
airway pressure and no-invasive ventilatory support
with bilevel positive airway pressure after coronary
artery bypass grafting. Acta Anaesth Scand 2000;
44:75-81
3. Meecham Jones DJ, Paul EA , Jones PW,
Wedzicha JA. Nasal pressure support ventilation plus
oxygen compared with oxygen therapy alone in
hypercapnic COPD. AJRCCM 1995; 152:538-544
4. Clini E, Sturani C, Rossi A, et al. The Italian
multicetre study on nonnvasive ventilation in chronic
obstructine pulmonary disease patients. Eur Respir J
2002; 20:529-538
5. Keenan SP, Kernerman PD, Cook DJ, et al. Effect
of noninvasive positive pressure ventilation on
mortality in patients admitted with acute respiratory
failure: a meta-analysis. Crit Care Med 1997; 25:16851692
6. Mehta S, Jay GD, Woolard RH, et al. Randomized
prospective trial of bilevel versus continuous positive
airway pressure in acute pulmonary edema. Crit Care
Med 1997; 25:620-628
7. Antonelli M, Conti G, Bufi M, et al. Noninvasive
ventilation for treatment of acute respiratory failure in
patients undergoing solid organ transplantation: a
randomized trial. JAMA 2000; 12:235-241
8. Hilbert G, Gruson D, Vargas F, et al. Non invasive
ventilation in immunosuppressed patients with
pulmonary infiltrates, fever and acute respiratory
failure. N Engl J Med 2001; 344:481-487
9. Ferrer M, Esquinas A, Leon M, Gonzalez G,
Alarcon A, Torres A. Non-invasive ventilation in severe
hypoxemic respiratory failure: a randomized clinical
trial. Am J Respir Crit Care Med 2003;168:1438–1444
10. National Association for Medical Direction of
Respiratory Care, Consensus Conference. Chest 1999
11. Bach JR, Ishikawa Y, Kim H. Prevention of
pulmonary morbidity for patients with Duchenne
muscular dystrophy. Chest 1997; 112:1024-1028
12. Gust R, Gottschalk A, Schmidt H, et al. Effects of
continuous (CPAP) and bi-level positive airway
41
14. AuriantI, Jallot A, Herve P, et al. Noninvasive
ventilation reduces mortality in acute respiratory failure
following lung resction. Am J Respir Crit Care Med
2001; 164:1231-1235
15. Freichels T. Noninvasive positive pressure
ventilation for patients with terminal respiratory
failure:The ethical and economical costs of dealing
with the inevitable are too great. Am J Crit Care 1994;
3:162
16. Meduri GU, Fox RC, Abou-Shala N, et al.
Noninvasive mechanical ventilation via face mask in
patients with acute respiratory failure who refused
endotracheal intubation. Crit Care Med 1994; 22:15841590
17. Klein M, Weksler N, Bartal C, Gurman GM. Helmet
noninvasive ventilation for weaning from mechanical
ventilation. Respir Care 2004; 49:1035-1037
18. Piastra M, Antonelli M, Chiaretti A, et al. Treatment
of acute respiratory failure by helmet-delivered noninvasive pressure support ventilation in children with
acute leukemia: a pilot study. Intensive Care Med
2004; 30:472-476
19. Zidulka A, Gross D, Minami H, et al.Ventilation by
high-frequency chest wall compression in dogs with
normal lungs. Am Rev Respir Dis. 1983;127:709-713
20. Kacmarek RM, “Home Mechanical Ventilation
Equipment” in Respiratory Care Equipment 2nd
Edition, Branson et al. eds. (New York: Lippincott,
1999)
21. Al-Saady NM, Fernando SS, Petros AJ, et al.
External high frequency oscillation in normal subjects
and in patients with acute respiratory failure.
Anaesthesia 1995; 50:1031-1035
22. Shekerdemian LS, Bush A, Shore DF, et al.
Proceedings & Abstract Book
Cardiopulmonary interactions after Fontan operations:
augmentation of cardiac output using negative
pressure ventilation. Circulation 1997; 96:3934-3942
23. Shekerdemian LS, Schulze-Neick I, Redington AN,
et al. Negative pressure ventilation as haemodynamic
rescue following surgery for congenital heart disease.
Intensive Care Med 2000; 26:93-96
24. Plein S, Bulugahapitiya S, Jones TR, et al. Cardiac
RM imaging with external respirator: synchronizing
cardiac and respiratory motion. Radiology
2003;227:887-882.
25. Marraro GA, Luchetti M, Cereda G, Galassini EM,
Mazza G. Non-invasive ventilation of acute respiratory
failure in infants with spinal muscular atrophy (SMA)
type 1. PCCM J 2003, abstracts’ book
26. Marraro GA. La ventilazione non invasiva in età
pediatrica. Proc. Of Congress “Il neonato con
sofferenza respiratoria”. Brescia 2003, 10-14.
Food Hypersensitivity and
Allergic Disease
Prof. R. K. Chandra, Université Internationale des Sciences de la Santé, Switzerland.
Introduction :
Allergic disease continues to increase in
prevalence worldwide. There is preliminary
data from India to suggest that both eczema
and asthma, especially the latter, are on the
ascendant. It is important for physicians to
understand the clinical features,
pathophysiology, diagnosis, management
and prevention of allergies.
I wish to emphasize the concept of “allergic
march”. By this is meant the sequence of
events that leads to clinical allergic disease.
The first step is the development of
sensitization to foods, which is followed by
gastrointestinal symptoms, skin rashes,
wheezing, asthma and rhinitis. This concept
means that if we can prevent food allergy in
the first few months of life, we can expect to
prevent the later manifestations
Clinical features:
Virtually all organs of the body can be
affected. As noted above, the earliest
manifestation is usually gastrointestinal
features such as colic, vomiting, diarrhoea,
and blood in stools and malabsorption. This
is followed in the second half of the first year
with skin rashes including frank atopic
eczema. Wheezing may follow and then
42
frank asthma. Hay fever usually does not
occur until after 8 years of age.
Diagnosis:
In addition to a detailed history, skin tests
can be done. It is best to do scratch or prick
tests rather intradermal tests. In India, there
are very few qualified allergists. The other
methods include testing blood for IgE
antibodies, cytotoxic IgG antibodies,
immune complexes and cell-mediated
reactions. Food challenge is the “gold
standard”.
Management:
Avoidance of involved foods is the best way
to reduce symptoms. However, the correct
diagnosis must be established first.
Otherwise, iatrogenic malnutrition may
result- Self-administered adrenaline is to be
kept for the medical emergency of
anaphylaxis. The management of eczema,
asthma and hay fever is on standard lines.
Precautions to Prevent Allergic Disease:
It is established that genetic factors,
especially history of allergy among parents,
is important. However, we cannot control this
because we do not choose our parents. In
addition, certain environmental factors such
INTERNATIONAL PEDIATRIC UPDATE 2004
as diet, nutrition, pollution, cigarette smoke,
pets such as cats, dust and pollen, play a
crucial role in development of allergy among
children.
The following precautions during
pregnancy, lactation and early childhood
help in reducing the risk of allergy in babies.
The earlier one can start these measures,
the better.
1. During pregnancy, avoiding exposure to
cigarette smoke, cats, birds, dust, and
to large quantities of certain foods that
cause problems in babies (dairy
products – milk, cheese, nuts especially
peanut and tree nuts, egg), would help.
2. The same dietary and other precautions
should be continued during the first 6
months of life. It is helpful to breast feed
the baby exclusively, for as long as
possible, but about 4 months is ideal.
3. From 6 months onwards, introduce new
foods one at a time every week, starting
with vegetables, fruits, cereals (rice is the
best) and grains. Meat can be given from
9 months, egg from 12 months, fish from
18 months.
Both the mother and the baby should be
given an ideal preparation of vitamins
and minerals. From all the research
available, IMMUNOBOOST-Y (for young
adults) and IMMUNOBOOST-C (for
children), both available in the metro
areas of Delhi and Kolkata (or by
email:[email protected]) are
the best to optimize the immune system
and to prevent allergies from developing.
Those with clinical features of allergic
disease, the regular administration of
these multivitamin preparations will
reduce the need for anti-asthma
mediations and visits to doctors and
hospitals.
Basics of Neonatal
Mechanical Ventilation
Surg Cdr Girish Gupta, Neonatologist,
INHS Dhanvantari, Port Blair, Andamans, India - 744 103
Learning Objectives: After reading this
article the reader should be able to:
1. Decide need for ventilation
2. Set up ventilator
3. Monitor neonate on ventilator
4. Identify complications
5. Wean and extubate from ventilator
Mechanical Ventilation (MV) is an
intervention which facilitates management
of respiratory dysfunction in neonates with
resultant improved survival and outcome.
The goals of ventilation are as follows:
1. Appropriate oxygenation
2. Appropriate ventilation
3. Prevent organ injuries
4. To ensure intact survival
43
DECISION MAKING FOR INITIATING MV
Before commencing MV several factors
need consideration in addition to clinical
condition. These include likely outcome,
financial effects and ethical issues. The
decision has to be made after detailed
discussion with parents. If more babies need
MV than the number of ventilators available,
then the baby with better likely outcome
should be given higher priority for
ventilation.
REQUIREMENTS FOR MV
Trained Resource : One should have
adequately trained personnel viz. doctors,
nurses, respiratory therapist, physiotherapist,
radiographers etc., well versed in their
respective roles in neonatal MV.
Proceedings & Abstract Book
Investigative modalities : One should have
functioning and adequate monitoring and
investigative facilities of Pulse-oximetry,
multisystem monitors, ABG machine,
Portable X Ray machine, Trans-cutaneous
capnometry, BP measurement, FiO2, USG
machine.
NICU setup: Before starting MV, NICU
should have well established level II
neonatal care with special attention to
infection prevention. There must be central
oxygen supply if not then a manifold room
to be created before starting MV in the unit.
It is also desirable to have central
compressed air supply.
INDICATIONS FOR MECHANICAL
VENTILATION [1]
i. Clinical criteria –
1. Respiratory disorders – conditions with
impending respiratory failure manifesting as
a. Retractions – moderate to severe
b. Tachypnoea
c. Central cyanosis with FiO2 > 40%
Clinical scoring systems may be used to
initiate MV.
2. CNS disorders
3. CVS disorders including shock states
4. GIT: NNEC, Postoperative neonates
5. Babies < 28 weeks, may be ventilated or
given CPAP electively.
ii. Blood gas criteria
1. PaCO2 > 50 mm Hg
2. PaO2 < 40 – 50 mm Hg, on O2 by hood
or CPAP at FiO2 > 60 %
3. pH <7.2 with respiratory distress.
VENTILATOR
Make the choice of a ventilator, preferably,
having pressure-limited, time-cycled and
continuous flow with SIMV. Buy it from an
authentic dealer with good after sales
service. One can enquire from the local units
who are using a ventilator and verify about
the ventilator performance and after sales
maintenance service provided by the
supplier. Always keep the dealer’s and
maintenance engineer’s contact numbers in
the unit for tackling emergency equipment
failures. Ventilator should have an UPS as
power back up. The electrical connections
should have a good power supply and
proper earthing, to prevent electrical
44
equipment accidents. Ventilator should be
placed in such a way that there is enough
space for nursing procedures, air circulation
and resuscitation. It should not be placed
too close to the walls, as it will get
overheated.
PARTS OF A VENTILATOR
They are following:
1. Compressor
2. Oxygen source
3. Ventilator
4. Breathing circuit
5. Humidifier
6. Test lung
GETTING THE INFANT READY FOR THE
VENTILATOR
• Place the infant on the firm surface.
• Position the infant in such a way that the
chin, sternum and umbilicus are all lined
up in a single plane.
• Equipments needed for intubation should
always be kept ready.
• Size of Endo-tracheal tube depends on
weight of the neonate and has been
shown below
Wt (grams)
Sizes (ID mm)
<1000
2.5
1000 - 2000
3
2000-4000
3.5
>4000
4
• Correct depth of tube to be inserted :
An endotracheal tube has a black portion
at the tip, called as vocal cord guide. The
tube should, therefore, be inserted to the
point where the complete vocal cord
guide has just passed the glottis. The tube
also has numerical markings in cms. The
reading visible on the tube at the lip
should be equal to weight of the baby in
kg + 6. e.g. for a baby weighing 3 Kg,
the reading at the lip should be 3+6 = 9.
• Confirming the correct position of the
tube
• Fixing the tube: Fixing the tube,
traditionally, is done by cutting the
adhesive (Elastoplast) into shapes of Y
or H. The main point to be ensured in
tube fixation is that it must prevent tube
displacement and minimize skin trauma
secondary to adhesive application.
Adhesives at times, are not only
INTERNATIONAL PEDIATRIC UPDATE 2004
associated with ineffective fixation of tube
but also result in micro abrasions, and
secondary infection. Girisam ETAT
(Endotracheal Tube and Auxiliary Tube)
fixator is a device, which supports the
baby’s head, allows effective tube fixation
with zero tube mobility and does not
traumatize skin. It also has additional
openings for passage of orogastric tube
and oropharyngeal care. It may be used
if available.
• Position in which the babies are to be
ventilated: The important thing to
practice is that whichever may be the
position, the shoulders must be gently
elevated, so as to push the diaphragm
down and facilitate MV.
SETTING THE CONTROL PANEL
The following parameters are required to be
set on Ventilator which is conventionally
pressure limited, timed cycled continuous
flow in neonates, after deciding the mode
of Ventilation.
• Fraction of inspired oxygen (FiO2): I t
determines the percentage of oxygen
being delivered to the lungs in each
breath. Changes in FiO2 alter alveolar
oxygen pressure and thus, oxygenation.
• Peak inspiratory pressure (PIP):
Changes in PIP affect both PaO 2 (by
altering MAP) and PaCO2 (by its effects
on tidal volume and thus, alveolar
ventilation). Therefore, an increase in PIP
improves oxygenation and decreases
PaCO2. Use of a high PIP may increase
the risk of barotrauma with resultant air
leaks and BPD; thus, exercise caution
when using high levels of PIP. The level
of PIP required in an infant depends
largely on the compliance of the
respiratory system. Starting PIP can be
approximately set at the pressures
required during bag mask ventilation. A
useful clinical indicator of adequate PIP
is gentle chest rise with every breath,
which should not be much more than the
chest expansion with spontaneous
breathing. While absent breath sounds
may indicate inadequate PIP (or a
blocked and/or displaced ETT or even
ventilator malfunction), the presence of
breath sounds is not very helpful in
determining optimal PIP. Always use the
minimum effective PIP.
Positive End expiratory pressure (PEEP):
It is the pressure in the lung at the end of
45
expiration. Adequate PEEP helps to prevent
alveolar collapse, maintains lung volume at
end-expiration, and improves V/Q matching.
Increases in PEEP usually increase
oxygenation associated with increases in
MAP. However, in infants with RDS, a high
PEEP (>6 cm H 20) may not improve
oxygenation further and, in fact, may
decrease venous return, cardiac output, and
oxygen transport along with decrease in
pulmonary perfusion by increasing
pulmonary vascular resistance. By reducing
ä pressure (PIP minus PEEP), an elevation
of PEEP may decrease tidal volume and
increase PaCO2.While both PIP and PEEP
increase MAP and may improve
oxygenation, they usually have opposite
effects on PaCO2. Generally, older infants
with chronic lung disease tolerate higher
levels of PEEP without carbon dioxide
retention and with improvements in
oxygenation. PEEP also has a variable effect
on lung compliance and may impact the PIP
required. With RDS, an improvement in
compliance occurs with low levels of PEEP,
followed by a worsening of compliance at
higher levels of PEEP (>6 cm H20).
A minimum PEEP of 2-3 cm H 2 0 is
recommended, since endotrachael
intubation eliminates the active maintenance
of FRC accomplished by vocal cord
adduction and closure of the glottis. This
mechanism of vocal cord adduction is
responsible for production of grunt and
hence, is the natural mechanism of elevating
PEEP in a neonate with respiratory
malfunctioning.
• Ventilatory Rate (VR)[2] Changes in
frequency alter alveolar minute ventilation
and, thus, PaCO2. Increases in rate and,
therefore, in alveolar minute ventilation
decrease PaCO 2 proportionally, and
decreases in rate increase PaCO 2 .
Frequency changes alone (with a
constant I/E ratio) usually do not alter
MAP nor substantially alter PaO 2. Any
changes in inspiratory time that
accompany frequency adjustments may
change the airway pressure waveform
and thus alter MAP and oxygenation.
MV= TV X VR
TV∝ (PIP – PEEP)
v MV=Minute Ventilation
v TV=Tidal Volume
v VR=Ventilatory Rate
Respiratory rate of 40-60/min. is usually
Proceedings & Abstract Book
adequate. Higher respiratory rates may be
required in case of PPHN.
• Flow rate : Flow rates of 5-8 l/min are
sufficient. Flow rate should be around
eight to ten times of minute ventilation. It
is also machine specific, some machines
may need higher flow rates. To maintain
an adequate tidal volume, high flows are
needed when inspiratory time is
shortened.
• Inspiratory and expiratory times (Ti, Te):
Ti of 0.3 to 0.4 is generally sufficient for
most disorders. Do not change Ti unless
there is persistent hypoxemia
unresponsive to changes in PEEP, PIP
and FiO2.
The major effect of an increase in the I/E
ratio is to increase MAP and thus improve
oxygenation. However, when corrected
for MAP, changes in the I/E ratio are not
as effective in increasing oxygenation as
are changes in PIP or PEEP. A reversed
(inverse) I/E ratio (inspiratory time longer
than expiratory time) has been
demonstrated to be effective in increasing
PaO 2; however, adverse effects may
occur. Changes in the I/E ratio usually do
not alter tidal volume, unless inspiratory
and expiratory times become relatively
too short. Thus, carbon dioxide
elimination usually is not altered by
changes in I/E ratio unless Te is so small
that it results in auto PEEP with resultant
CO2 retention.
• Mean Airway Pressure (MAP): MAP can
be calculated by dividing the area under
the airway pressure curve by the duration
of the cycle as follows:
TI
MAP = K (PIP – PEEP) ---------------- + PEEP
TI + T E
This formula includes the constant
determined by the flow rate and the rate of
rise of the airway pressure curve (K). This
equation indicates that MAP increases with
increasing PIP, PEEP, TI and flow (increases
K by creating a more square waveform).
PATHOPHYSIOLOGY-BASED
VENTILATORY STRATEGIES
Respiratory distress syndrome (RDS)
RDS is characterized by
• Low compliance
• Low FRC
An optimal conventional ventilation
46
strategy may include:
• Early ventilation
• Lowest PIP and tidal volume
• PEEP (3-5 cm H20)
• Permissive hypercapnia (PaCO2 45-60 mm
Hg) to prevent barotraumas and subsequent
CLD (2)
• Judicious use of narcotic analgesia
Meconium aspiration syndrome (MAS)
MAS is characterized by
• Air trapping
• High risk of Persistent pulmonary
hypertension (PPHN)
Strategy for ventilation would involve
• Commence ventilation after careful
evaluation.
• Minimal handling
• Attaching one pulse-oxymeter to right
upper limb and one pulse-oxymeter to
lower limb for early detection of PPHN.
• Tele-monitoring
• Preventing any condition that may disturb
the baby.
• Analgesia / Paralysis.
Persistent pulmonary hypertension
(PPHN): Persistent pulmonary hypertension
of the newborn may be primary or
associated with aspiration syndrome,
prolonged intrauterine hypoxia, congenital
diaphragmatic hernia, or other causes.
Ventilatory treatment of infants often is
controversial and varies markedly among
centers. In general, following should be the
strategy for ventilatory parameters:
• Adjust FiO2 to maintain PaO2 at 80-100
mm Hg to minimize hypoxia-mediated
pulmonary vasoconstriction;
• Adjust ventilatory rates and pressures to
maintain an arterial pH of 7.45
(sometimes combined with bicarbonate
infusion).
• Prevent low PaCO2 (<25 mm Hg), which
can cause cerebral vasoconstriction and
subsequent neurologic injury.
• Use Narcotic analgesia / paralysis
judiciously
• Minimal handling
• Dimming the lights
• Talking in low tone or whispers
• Attaching one pulse-oxymeter to right
INTERNATIONAL PEDIATRIC UPDATE 2004
upper limb and one pulse-oxymeter to
lower limb for early detection of PPHN.
• Tele monitoring
• Preventing any condition which may
disturb the baby.
Chronic lung disease (CLD): CLD usually
has heterogeneous time constants among
lung areas. Resistance may be increased
markedly, and frequent exacerbations may
occur. The ventilatory parameters suggested
are:
• PEEP (4-6 cm H20)
• Longer inspiratory and expiratory times
• Low rates are preferred
Hypercarbia (PaCO2= 45-55 mmHg) with
compensated respiratory acidosis often is
tolerated to avoid lung injury secondary to
aggressive mechanical ventilation. PaO 2
>50 mmHg prevents cor pulmonale.[3]
Avoid PaO 2 >80 mmHg to prevent O 2
mediated lung injury.
MANAGEMENT AFTER INITIATING
VENTILATION
The following need to be monitored
diligently during ventilation. The best
monitors are the dedicated bedside nurse
and resident doctor.
1. Look at the baby.
• Is the chest expansion adequate?
• Is there adequate air entry?
• Is the baby struggling on the ventilator?
• Is the baby having significant retractions?
• Is the baby having spontaneous
respiratory efforts?
• What is the SpO2? Aim to keep SpO2
between 87-93%.
• What are the heart rate, capillary refilling
time, blood pressure and colour of the
baby?
• What is the neurological state of the
baby?
• Ensure shoulder elevation.
Do not be in haste to change settings till the
baby stabilizes. It may take some time for
the infant to synchronize breaths with that
of the ventilator and for retractions to
disappear, but if retractions persist then the
settings need to be adjusted.
2. Look at the blood gases: The goal is to
try and maintain the blood gases as close
to normal as possible, while keeping the
47
barotrauma and oxytrauma to a minimum.
• Surrogate non-invasive: Blood gas
approximation is done with pulseoximetry
and
transcutaneous
capnometry. The end-tidal capnography
is not useful in neonates because of
smaller tidal volume and higher
respiratory rates but may be useful in
interpreting the trend of CO2.
3. Look at the ventilator
• Is it cycling?
• Is the ventilator delivering the set
parameters?
• What tidal volume (VT) is the baby
getting?
• Is there a significant leak?
4. Look at the humidifier
• Is it on?
• Does it have adequate water?
• Is there any loose or open connection?
5. Look at the circuit / water traps : Ensure
that the water traps are emptied frequently
of the condensed water else it might make
ventilation more erratic
6.Look at the nursing flow chart
• How stable has the baby been?
• How is the baby handling? Are there lots
of secretions?
7. Look at the X-ray
X-ray chest should be done to see
• Position of the tube
• State and expansion of lung
• Progression / course of disease / effect
of treatment.
• One should see to it that the X ray
technician understands the concept of
asepsis and observes asepsis strictly. It
is important that the patient is restrained
properly so as to get a good centralized
exposure.
8. Heamtological monitoring
9. Bacteriological monitoring
10. Miscellaneous monitoring
CHANGING THE VENTILATION
SETTINGS
Don’t forget to tell the bedside nurse what
changes you have made, and don’t forget
to document your changes as shown in the
following table.
Proceedings & Abstract Book
Table:1. Proposed solutions to blood gas abnormalities
Problem
Possible solutions
Comment
Low Oxygenation
Increase the FiO2
The easiest solution.Remember that babies whose oxygen
requirements are changing significantly need to be
clinically reassessed and consider a radiograph if the FiO2
increases by more than 10%.
Increase MAP
Increase the PIP Increase the PEEP.Increase the inspiratory
time (but this may just hold the lungs fully inflated at a high
pressure). Ensure that the inspiratory time is shorter than
the expiratory time.
Decrease the FiO2
Unless the baby is already in room air
Decrease the MAP
If the PEEP is higher than 5, then we can drop this down (if
the reason for the high PEEP - e.g. pulmonary haemorrhage
- has resolved)
Decrease the PIP (but this may adversely affect ventilation
Decrease the Ti.
Decrease the tidal
volume. Do this first
if the baby has good
chest movement
and/or high tidal
volumes
Decrease the difference between the PIP and PEEP (usually
by decreasing the PIP)
Note: that there are no rules on how much to drop the PIP
by - you need to look at the chest movement and look at
the delivered tidal volume on the ventilator. In general,
drop the PIP by decrements of 2 cms and monitor VT
Decrease the
frequency
Drop the rate. If the gas is alkalotic, drop by a fraction that
you want the pH to drop
Note that for modes where every breath is assisted (e.g.
PSV, SIPPV), it is futile to reduce the rate if the baby is
breathing above the back up rate. So wean the pressure
(or VT) instead.
Ensure Tube patency
and correct position.
Increase the PIP till you get some chest movement but
look at the tidal volume too
Increase the tidal
volume
In general, you should not increase the PIP too high as
you may find that the tidal volume increases significantly. But you need to give enough pressure to get chest
movement.
Remember that if you are having to put the PIP up a lot to
get the same tidal volume in that you were giving previously,
compliance is going down. Ask yourself “Why?” Look at
the baby, listen to the air entry, and think about a
radiograph, particularly if the FiO2 is going up.
Increase the
frequency
Increase the rate. If acidotic, increase by a fraction that
you want the pH to increase.
High Oxygenation
Over ventilation
(Low PaCO2)
Under ventilation
(Low pH with
a High PaCO2)
48
INTERNATIONAL PEDIATRIC UPDATE 2004
NURSING CARE
1. Change position every 4hrs
2. Record 1-2 hourly on ventilation chart.
3. Refill water in humidifier 8-12 hrly and
SOS.
4. Remove condensed water from circuit
and water traps 3-4 hrly and SOS
5. ETT care and suctioning with full aseptic
precautions as shown in appendix B.
6. CPT, Percussion, Vibration, Postural
drainage SOS as shown in appendix C.
7. Keep additional stand-by source of O2
8. Fluids adjustment for ventilated babies:
• Give 2/3rd of required maintenance
fluids initially
• Keep on dynamically adjusting the
fluids based on continuous
assessment of weight, CFT and urine
output, electrolytes, etc.
9. Nebulisation, if required
10. Tube feedings for ventilated babies:
• Initiate tube feeds once the baby is
hemodynamically stable; abdomen is
soft and not distended; increase
feeds gradually.
• If neonate’s condition does not permit
adequate enteral nutrition, trophic
feeds may be administered.
• Withhold feeding for 4-6 hours prior
to extubation
11. Weight records: Should be done daily
or more often as required by clinical
condition. However, it should be done
with the help of either online weighing
scale (ideally) or on a stand-alone
weighing machine without adversely
affecting the baby.
COMPLICATIONS
Mechanical ventilation can give rise to
following complications. Therefore it is
essential to prevent or minimize their
sequelae.
UPPER AIRWAY
1. Nasal septum necrosis
2. Palatal groove
3. Nasofacial cellulitis
4. Subglottic edema
5. Subglottic tracheal stenosis
6. Necrotizing tracheobronchitis
LOWER AIRWAYS
1. CLD
49
2.
3.
4.
5.
Air leaks
Pulmonary haemorrhage
Atelectasis
Pneumonia
EXTRAPULMONARY
1. ROP
2. Sepsis
3. IVH
4. PDA
5. NNEC
ROLE OF ANALGESICS / SEDATIVES/
PARALYTICS
Having an endotracheal tube in-situ, IV lines
and other invasive monitoring, is stressful
and painful to the baby. A smooth uneventful
ventilation is more likely to occur if the baby
is calm, comfortable and pain free. Such a
baby synchronizes well with the ventilator
and is less likely to fight the ventilator.[4]
This can be ensured with the use of low dose
analgesic infusions. Sedatives alone are not
as effective as they do not reduce pain
sensation. However, they may be used in
conjunction with analgesics. It is better to
use narcotic analgesics for comprehensive
action.
1. Morphine:
Supplied : Inj. 10mg per mL
Dose : Bolus dose 0.1 – 0.5 mg /Kg .
Repeat doses every 2 to 6 hrs.
Infusion : 0.025-0.05 mg/Kg/hr after initial
loading infusion of 0.1mg/Kg/hr.
Maximum dose : 20 µg/Kg/hr.
Side effects : Resp depression, decreased
gut motility, urinary retention.
2. Fentanyl:
Supplied : 0.05 mg/ mL in a 2mL vial.
Dose : Bolus : 1-2 µg/Kg IV. IV to be
administered over 3-5 min.
Repeat dose : every 1-2 hrs
Infusion : 1-2 µg/Kg/hr
3. Midazolam:
Supplied: Inj 1 mg./ml in 2ml
Dose : Bolus : 0.1 mg/Kg IV.
Repeat dose : every 2-4 hrs.
Infusion dose : 0.4-0.6 micrograms /Kg/min
4. Lorazepam:
Supplied as: Inj 2mg/mL
Dose : Bolus : 0.1 mg/Kg
Repeat dose : every 2-4 hrs. IV
Proceedings & Abstract Book
5. Pancuronium:
Initial dose : 0.1 mg/kg
Repeat dose : 1-4 hourly.
It is not to be used for continuous infusion.
6. Vecuronium:
Loading dose of 0.1mg/kg followed by 0.050.1 mg/kg/ hr.
Paralytic agents should be used for the
minimum possible duration.
Side effects of paralysis:
1. Loss of spontaneous respiration in the
case of accidental extubation.
2. V/Q mismatch.
3. Analgesics need to be given, as pain is
not alleviated.
WEANING
When to start?
• Satisfactory blood gas levels
pH
> 7.25
PaCO2 = 40 - 50 torr
PaO2
= 60-80 torr
• Stable baby at this levels for 6 – 24 hrs
• No respiratory distress
• No radiological complications
• Haematocrit > 35- 40 %
• Metabolically stable:
calcium /
magnesium /potassium / phosphate /
nitrogen balance
Transferring of respiratory load from
machine to neonate should be in a careful
and controlled manner with close
observation
How to execute?
Various modes and sequence of execution
available for weaning are:
• Low rate IMV - Extubation ± nasal /
nasopharyngeal CPAP / BIPAP
• IMV - Patient Triggered Ventilation Extubation ± nasal / nasopharyngeal
CPAP / BIPAP.
Steps to be taken prior to extubation –
• Nil orally for atleast 12 hours
• Stop sedatives / narcotic analgesics 24
hours prior to extubation
• Start methylxanthine in a < 1 kg and <
7 days old neonate
• Theophylline - 5 mg / kg / day
• Caffeine - 10 mg / kg / day
50
• Start Dexamethasone @ 0.5 mg / kg /
day; 24 hours prior to extubation and
continue for 24 to 48 hours there after. It
is usually started when there has been
repeated intubations or when the baby
has been ventilated for more than 5-7
days.
• Usual settings on which extubation is
done:
• PIP - 15
• PEEP - 4
• FiO2: 0.25-0.35
• Ventilatory rates: 20-30
EXTUBATION
• Has to be electively planned and
executed.
• Preferably in the morning hours so that
there is sufficient staff for after care.
• Attempt when electrolytes, acid base
status are normal with a haematocrit of
greater than 35%.
• Increase FiO2 prior to extubation
• Gently do endotracheal suctioning under
direct vision with full asepsis.
• Do bag to tube ventilation prior to
extubation and then come out with the
tube after giving a positive pressure.
• Send the tip of the tube for culture and
sensitivity
POST EXTUBATION CARE
• Do gentle bag and mask ventilation for
few times.
• Do gentle oropharyngeal suctioning.
• Give warm and humidified oxygen @ >
5 litres / min under hood while titrating
FiO2 with the clinical condition.
• Change neonates position 2 hourly.
• Gently do chest physiotherapy using a
nipple /cushioned soft face mask/cupped
hands.
• No feeds for atleast next 12 - 24 hours
CONCLUSION
This write up primarily addresses
conventional mechanical ventilation &
should facilitate a relatively less experienced
doctor to perform mechanical ventilation of
neonates safely. However, in reality,
mechanical ventilation requires the use of
both science and art and is best learnt sitting
next to the baby. It is important to remember
that mechanical ventilation has to be carried
INTERNATIONAL PEDIATRIC UPDATE 2004
out not in isolation but with comprehensive
care of all the systems of a neonate, only
then it will be successful with optimal intact
outcome of a neonate.
References:
1. Spitzer AR, Greenspan JS, Fox WW. Positive
pressure ventilation: Pressure limited and time
cycled ventilation. In: Goldsmith JP, Karotkin EH,
editors.Assisted ventilation of the neonate.4th ed.
Philadelphia: Saunders,2003;149-70
2. Beresford MW, Shaw NJ, Manning D: Randomised
controlled trial of patient triggered and
conventional fast rate ventilation in neonatal
respiratory distress syndrome. Arch Dis Child Fetal
Neonatal Ed 2000 Jan; 82(1): F14-8
3. Mariani G, Cifuentes J, Carlo WA: Randomized trial
of permissive hypercapnia in preterm infants.
Pediatrics 1999 Nov; 104(5 Pt 1): 1082-8
4. Bernstein G, Mannino FL, Heldt GP, et al:
Randomized multicenter trial comparing
synchronized and conventional intermittent
mandatory ventilation in neonates. J Pediatr 1996
Apr; 128(4): 453-63.
Acellular Pertussis Vaccines
Dr. Rémy Teyssou, Epidemiology Senior Director, Medical Affairs Department,
Sanofi-Aventis, Lyon
In worldwide terms of morbidity and
mortality, Pertussis (Whooping cough) is
one the most important of the vaccine
preventable diseases. In industrialized
countries, pertussis incidence is higher in
infants, adolescents and adults. In the
developing world, millions of cases occur
annually, mostly in children.
The first pertussis vaccines were whole cell
vaccines, prepared using bacterial cells
harvested from cultures. The efficacy of
these vaccines has been clearly
demonstrated in clinical trials, through
epidemiological surveillance systems and
from clinical experience in countries where
routine Pertussis vaccination was withdrawn
which lead to dramatic increases in Pertussis
disease incidence.
In several countries, Pertussis vaccination
was withdrawn following concerns over the
reactogenicity of whole cell vaccines. Fever,
drowsiness, fretfulness are the most
frequent adverse events, while convulsion/
seizures and acute encephalopathy account
respectively for 1 case per 1,750 children
vaccinated and 1/100,000.
These concerns directly lead to the
development of a new generation of cellfree (acellular pertussis) vaccines, based on
51
purified antigenic components involved in
the pathogenesis of B. pertussis infection.
Five distinct virulence factors have been
described and studied in the vaccine
perspective1:
• Pertussis toxin (PT), which produces a
wide range of physiological effects, such
as T and B-lymphocyte stimulation,
lymphocytosis, inhibition of neutrophil
chemotaxis and monocytes migration. PT
is a major contributor to the pathogenesis,
and as such is a major component of all
current acellular vaccines
• Filamentous hemagglutinin (FHA), which
is hypothesized to interact with pertactin
in establishing binding to respiratory tract
epithelium. It may also facilitate the
intracellular infection, stimulate
suppressor T-cells.
• Fimbriae (Fim) 2 and 3, which promote
attachment to monocytic cells and to the
respiratory epithelium. These induce
serotype-specific immunity.
• Pertactin (Prn), which is located on
bacterial surface. It acts as an adhesin,
probably in conjunction with FHA.
Different acellular pertussis (acP) vaccines
have been developed, including one (PT
alone), two, three four or five of these
Proceedings & Abstract Book
components. Currently there are licensed
formulations containing two (PT, FHA), three
(PT, FHA, Prn) or five components (PT, FHA,
Prn, Fim2 and Fim3). These acP vaccines
are administrated in combination with other
antigens: diphtheria and tetanus toxoids
(DTacP). In many countries they are also
administrated with additional antigens:
Hepatitis B, inactivated polio vaccine and/
or Haemophilus influenzae b.
Numerous studies have clearly established
that adverse events following administration
of acP are less severe and occur less
frequently than with whole cell pertussis
vaccines .1
All currently licensed acP vaccines have
been confirmed to be effective in numerous
clinical trials and surveillance studies. They
have a similar range of efficacy, with only
minor differences.2,3,4,5
However, efficacy is not the only approach
for assessing the potency of the vaccine.
Measuring the effectiveness represents a
more pertinent alternative, as vaccine
effectiveness describes the vaccine impact
on disease when used under the real-world
circumstances of medical and public health
practice, rather than under the ideal
conditions of a clinical efficacy trial. The
ongoing Swedish surveillance program,
which has been implemented since 1990,
provides unique information about
effectiveness of acP vaccines routinely used
in this country (2 and 3 components) since
their introduction in 1996 3. All children born
since January 1st 1996, and continuing to
live in Sweden, have been followed; each
notified and confirmed case has been
tracked by telephone contacts to document
vaccination status and clinical course. The
information gathered allows the calculation
of incidence in vaccinated and nonvaccinated children and hence the vaccine
effectiveness. The most recent available
data on the two-component vaccines (PT,
FHA) showed an effectiveness of about 91%
after 2 doses, increasing to 98% after the
third dose.
In conclusion, acellular pertussis vaccines
have proven high efficacy, and have superior
safety profiles compared to the whole cell
vaccines. Whatever the strategy
implemented and the vaccine used,
epidemiological surveillance warrants a
long-term follow-up of the incidence and the
effectiveness.
References:
1. M. J. Corbel and D. K. L. Xing. Toxicity and potency
evaluation of Pertussis vaccines. Expert Review
Vaccines. 2004 ; 3 (1) : 89 –101
Vaccine. 2003 ; 21 : 2015 - 2021
2. L. Gustafsson, H. Hallander, P. Olin, E. Reizenstein
and J. Storsaeter. A controlled trial of a twocomponent acellular, a five-component acellular
and a whole-cell Pertussis vaccine. New England
Journal of Medicine. 1996 ; 334(6) : 349 – 355
4. F. Simondon, MP Preziosi, A. Yam, C. Toure Kane,
L. Chabirand, I. Iteman, G. Sanden, S. Mboup, A.
Hoffenbach, K. Knudsen, N. Guiso, S. Wassilak and
M. Cadoz. A randomized double-blind trial
comparing a two-component acellular to a wholecell Pertussis vaccine in Senegal. Vaccine. 1997;
15 : 1606 – 1612.
3. P. Olin, L. Gustafsson, L. Barreto, L. Hessel, T. C.
Mast, A. Vanrie, H. Bogaerts; J. Storsaeter.
Declining Pertussis incidence in Sweden following
the introduction of acellular Pertussis vaccine.
5. S. Torvaldsen, J. M. Simpson and P. McIntyre.
Effectiveness of Pertussis vaccination in New
south Wales, Australia, 1996-1998. European
Journal of Epidemiology. 2003; 18 : 63 – 69
52
INTERNATIONAL PEDIATRIC UPDATE 2004
Adverse Reactions to
MMR Vaccines
Dr. A. K Dutta, Director Prof. & HOD Pediatrics,
Lady Hardinge Medical College, New Delhi
Introduction
Immunization is the most cost effective and
widely used public health interventions. A
higher standard of safety is generally
expected of vaccines than other medical
interventions since it is always given in
healthy individuals to prevent diseases. This
lower risk tolerance for vaccines translates
into a need to investigate the possible
causes of much rarer adverse events after
vaccinations than would be acceptable for
other pharmaceutical products. No vaccine
is perfect in its safety and efficacy. As the
incidence of vaccine preventable diseases
are becoming less due to universal
immunization, adverse vaccine reactions
(true vaccine reactions) and those
associated with vaccination only by
coincidence, become increasingly frequent
and prominent. World Health Organization
Expanded Program on Immunization
recommended in 1991 that all National
Programs implement surveillance for
adverse events following immunization.
As the evidence of the vaccine preventable
diseases are declining, more so in
developed countries, there is a general trend
to blame vaccines for the etiology of several
diseases. In the United Kingdom whole cell
pertussis vaccine fell into disrepute because
of encephalopathy. However, the hypothesis
has been proven to be not true. Similarly
MMR vaccine especially Urabe strains has
been incriminated to cause large number
of aseptic meningitis syndrome. Autism and
other neurological complications of MMR
vaccine were in the headlines of several print
and electronic media in the west. In Indian
market several vaccine-manufacturing
companies are marketing MMR vaccine with
different strains.
An attempt has been made in this review to
analyze the possible adverse reactions of
MMR vaccine containing different strains of
measles, mumps and rubella vaccine.
53
Measles Vaccine
Measles is a relatively safe vaccine
irrespective of the strains used for its
preparation either as monovalent or in
combination (MMR). Fever with a
temperature of more than 39.50C occurs in
approximately 5-15% of cases. Fever usually
develops 7-12 days after vaccination and is
of relatively mild in nature. Occasionally,
febrile seizure can cause in vaccine
recipients. Rash occurs in approximately 5%
of the cases 7-10 days after vaccination and
is transient in nature and usually disappears
in two days. Side effects following second
dose of measles containing vaccines are
generally less frequent than the first one,
because most children would be immune
from the initial vaccination. The Institute of
Medicine in 1994 in USA after examining the
possible adverse reactions of licensed
vaccine observed that there is causal
relationship between measles containing
vaccine and thrombocytopenia, anaphylaxis
and death.
The incidence of thrombocytopenic purpura
from MMR is estimated to be 1 per 30,000
doses. There are reports of documented
death from vaccine strain viral infection in
severely immuno-compromised children
including AIDS. Severe progressive vaccine
associated measles pneumonitis in a child
with AIDS, 1 year after the dose is reported
from U.S.A.
The possible causal relationship of central
nervous system involvement such as
encephalitis and encephalopathy and MMR
vaccination is debatable. There is
inadequate data to accept or reject the
hypothesis.
The
incidence
of
encephalopathy and encephalitis as
observed by CDC in U.S.A. following
measles containing vaccine was found to
be 0.4 per million doses. This rate is lower
than that noted for severe neurological
disorders of unknown etiology in
Proceedings & Abstract Book
unimmunized children of the same age
range. This suggests a chance temporal
association rather than cause and effect for
most cases.
The National Childhood Encephalopathy
study group however did find an increased
risk of encephalopathy or prolonged
convulsion within 7-14 days of vaccination,
but none of the children had any serious
permanent sequelae. There is very little or
no evidence of SSPE following measles
vaccination. The epidemiological data has
not documented a direct risk from the
vaccine.
Other side effects which are attributed to
measles vaccine are Gullain-Barre
Syndrome, Reye syndrome, oculomotor
palsy, optic neuritis, retinopathy, hearing
loss, cerebellar ataxia, autism and
inflammatory bowel disease. It is very
difficult to determine whether these events
are truly vaccine related or represent a
chance temporal relation.
Mumps Vaccine
Mumps vaccines prepared by various
laboratories in the world contain following
strains e.g. Jeryl-Lynn, Leningrad-Zagreb,
Leningrad-3, Urabe, Hoshino, Torri,
Miyahara, Chiba, and Rubini.
The most common adverse events to
mumps vaccine are parotitis and low-grade
fever, which occurs 10-14 days after
vaccination. Transient rash, purpura and
pruritis also have been reported following
mumps vaccination. In one study, Parotid
and or submaxillary swelling was observed
in 1.6% of children receiving Jeryl Lynn
strain and 1-2% in Urabe strain. Following
Hoshino strain, parotid swelling was
observed 14-24 days after vaccination.
Assessment of adverse reaction following
mumps vaccine is difficult to assess since
MMR is a combined vaccine. However, there
have been very rare reports of orchitis,
arthritis, sensorineural deafness and acute
myositis. There is a theoretical risk of diffuse
retinopathy, joint disturbances and
thrombocytopenia.
Mumps and Aseptic Meningitis
Natural mumps virus infection has a high
incidence of aseptic meningitis. All the
available mumps vaccine has been
implicated to cause aseptic meningitis.
However, the rates of this complication vary
54
according to the strains used in the vaccine.
The Urabe strain as well as Leningrad-3
strains have been attributed the most for the
causation of aseptic meningitis. In the United
Kingdom, a total of 23 cases of aseptic
meningitis following Urabe strain containing
MMR vaccine (1 in 11,000 doses) raised a
doubt regarding the safety of the strain in
early eighties. The same vaccine was
attributed to cause convulsion 15-35 days
after vaccination in 1 of 2600 doses.
Following this, Urabe strain has been
withdrawn from use in several countries in
the west.
It is very difficult to attribute mumps vaccine
for all cases of aseptic meningitis since
coincidental aseptic meningitis after MMR
vaccination may occur due to other viruses
and even due to wild mumps virus. However,
confirmation of the causative role of the
vaccine virus can be made by definitive
identification methodology of the mumps
virus isolate as vaccine strain. There is a
definite causal relationship between mumps
vaccine and aseptic meningitis.
Data regarding association of mumps
vaccine and aseptic meningitis are available
from United States, U.K., Canada, Germany,
Japan and France where a meticulous
surveillance system for adverse reactions of
vaccination is practiced. The reported
occurrence of aseptic meningitis following
vaccination is a rare event and reported to
be 1 in 1.8 million doses. In a nested casecontrol study, receipt of MMR within 30 days
was not demonstrated to be risk factor for
hospitalization for aseptic meningitis. In
Germany, the reported incidence is 1 per
million doses. The rates of aseptic meningitis
from Japan using Hoshino, Torii, Miyahara
and Chibha strains were found to be 1 in
1,20,000; 30,000; 20,000 and 5,000
respectively.
Leningrad Zagreb strain is being used in
India and Croatia. Reported incidence of
aseptic meningitis as per WHO (weekly
epidemiological report No. 45, 9th Nov. 2001)
is 1 per 1,00,000 doses in Bahamas and 2
per 1,00,000 doses in Slovenia. This strain
is widely used in India and since 1999; MMR
vaccine has been introduced in Delhi States
immunization schedule. No deaths have
been reported from Delhi after
administration of 500,000 doses of MMR
vaccine containing L-Zagreb strain. There
was one case of anaphylaxis and two cases
of aseptic meningitis. The causal
INTERNATIONAL PEDIATRIC UPDATE 2004
relationship of aseptic meningitis could not
be ascertained.
Urabe strain has been incriminated with
aseptic meningitis in Japan and United
Kingdom. In Japan the rate of aseptic
meningitis following MMR Urabe strain was
found to be 1 in 2,000 doses and isolation
of vaccine virus in CSF in 1:9,000 cases. In
Canada, the observed rate of meningitis
following MMR was calculated to be 1 in
62,000 doses. In France, the rate of aseptic
meningitis observed with Urabe strain
manufactured by Pasteur Meriux and
GlaxoSmithKline was 1: 28,400 and 1:
12,000 doses respectively. The Public
Health Laboratory Services Surveillance
from United Kingdom suggested a rate of 1
in 11,000 doses with Urabe strain and none
with Jeryl Lynn strain.
Brown and co-workers demonstrated that
the strain isolated from cases of aseptic
meningitis was one of two variants present
in the Urabe vaccine. The meningitisassociated variant had a mutation from
guanine to adenine at base 1081, which
resulted in a glutamine to lysine change in
amino acid 335 of the HN protein.
In view of the controversy over Urabe strains
association with aseptic meningitis WHO in
2001 stated that currently available mumps
vaccine vary in terms of adverse reactions
and protective efficacy but there is ample
evidence that these vaccines are highly
efficacious and safe. MMR vaccine with
available strains can be safely introduced
in the National Immunization program of any
country. However, WHO policy recommends
that Rubini strain should not be used and
those previously immunized with this strain
should receive one more dose of an effective
mumps vaccine to ensure protection.(WHO
position paper on Mumps Virus vaccines,
weekly epidemiological report No. 45, 9th
Nov. 2001)
and incidence of radiculoneuritis, other
neuropathies and thrombocytopenia. A
review of adverse events in Canada
observed an incidence of 0.3 per 1,00,000
doses for arthritis or arthralgia. The adverse
reaction of joint involvement was found to
be more with earlier strain of HPV-77 and
Candehill vaccine. However, Polk and
associates have reported an incidence of
13-15% arthralgia or arthritis with RA 27/3
strain of rubella vaccine.
The mechanism of joint involvement is
probably because of direct infection of the
synovial tissue by the virus. Tingle and coworkers reported in their prospective study
of 268 women in British Columbia following
complications e.g. sore throat, cervical
lymphadenopathy, rash, myalgia,
parasthesia, arthralgia and arthritis in a large
number of cases. The side effects of rubella
vaccine in the form of mild rubella vary
directly with age, being almost absent in
infants and present up to 50% in women. A
double blind study of vaccination with MMR
in children revealed 1% incidence of
arthropathy and little evidence of other
reactions.
Other complications e.g. polyneuropathy,
optic neuritis and diffuse myelitis, transverse
myelitis and Guillain-Barre syndrome have
been reported following rubella vaccination.
The complications are more with earlier
HPV-77 and Candehill vaccines. However,
cases of diffuse myelitis are reported with
RA 27/3 strains. Thrombocytopenia is a
known complication of natural rubella with
an incidence of 1 in 3000 infection and
following vaccination, the reported
incidence is 1 in 3,00,000 vaccinees. Rubella
vaccines have been noted to depress
nonspecific cellular immunity transiently
including tuberculin reaction, cell mediated
immunity to Candida and delayed type of
hypersensitivity to recall antigen.
Rubella Vaccine
The National Academy of Medical Sciences
in U.S.A. in 1991 published the report of the
committee in which four possible adverse
effects of rubella vaccine e.g. acute arthritis,
chronic arthritis, neuropathies and
thrombocytopenia were described. The
report found a definite causal relationship
between RA 27/3 strains and acute arthritis
and chronic arthritis in adult women. There
is still insufficient evidence to indicate a
causal relationship between use of vaccine
Summary
Although adverse side effects following
MMR vaccine is well known, most of the
reactions are of trivial and transient nature.
Some of the adverse reactions are related
to a particular strain in the MMR vaccine.
However, the benefit of the vaccine far
outweighs the side effects and therefore
universal immunization with MMR vaccine
is recommended for all infants in National
Immunization Program. If the MMR vaccine
is given early in life as primary immunization,
55
Proceedings & Abstract Book
the adverse reactions are minimum. The
present knowledge and review of the subject
clearly indicates that for measles vaccine
either Schwarz or E-Z strain can be safely
used, for mumps Jeryl Lynn strain,
Leningrad Zagreb or Urabe strain and for
rubella RA 27/3 are the strains which can
be incorporated. Universal immunization
with MMR vaccine would prevent several
million children deaths from measles,
eliminate congenital rubella syndrome and
ameliorate the misery of morbidity of
mumps.
References
1. Chen RT, Rastogi Se, Mullen JR, et al. The vaccine
adverse event reporting system (VAERS). Vaccine
1994; 12 : 542-550.
2. World Health Organizaztion. Vaccine supply and
quality. Surveillance of adverse events following
vaccination. Wkly Epidemiol Rec 1996; 71 : 237242.
3. Report of a WHO scientific group on measles
vaccine. WHO Technical Report Series 1963; 263
: 5-37.
4. Peltola H, Heinonen OP. Frequency of true adverse
reactions to MMR vaccine. A double blind placebo
control trial in twins. Lancet 1986; 1 : 939-942.
5. Isozaki M, Kuno Sakai H, Hoshi N, et al. Effects
and side effects of a new trivalent combined MMR
vaccine. J Exp clin Med 1982; 7 : 547-550.
6. Katz SL. Immunization with live attenuated measles
virus vaccines. Five years experience. Arch Virus
Forsch 1965; 16 : 222-230.
7. Griffin MR, Ray WA, Mortimer EA, et al. Risk of
seizures after MMR immunization. Pediatrics 1991;
88 : 881-885.
8. Landrigan PJ, Witte JJ. Neurological disorders
following live measles virus vaccine. JAMA 1973;
275 : 1459-1462.
9. Oski FA, Naiman JL. Effect of live measles vaccine
on the platelet count. N Eng J Med 1956; 275 :
352-356.
10.Wilhelm DJ, Paegle RD. Thrombocytopenia
purpura and pneumonia following live measles
vaccine. Am J Dis Child 1967; 113 : 283-285.
11.Stratton K, Howe CJ, Johnson RB Jr. Adverse
events associated with childhood vaccinations.
56
Evidence bearing on casuality. Washington DC.
National Academy Press 1994.
12.Miller C, Miller E, Rowe K, et al. Surveillance of
symptoms following MMR vaccine in children.
Practitioner 1989; 233 : 69-73.
13.Nakayama T, Oka S, Komase K, et al. The
relationship between the mumps vaccine strain
and parolitis after vaccination. J Infect Dis 1992;
165 : 186-187.
14.Griffin MR, Ray WA, Mortimer EA, et al. Risk of
seizures after MMR vaccination. Pediatrics 1991;
88 : 881-885.
15.Ueda K, Miyazaki C, Hidaka Y, et al. Aseptic
meningitis caused by MMR vaccine in Japan.
Lancet 1995; 346 : 701-702.
16.Miller E, Goldacre M, Pugh S, et al. Risk of aseptic
meningitis after MMR vaccine in U.K. children.
Lancet 1993; 341 : 979-982.
17.Peltola H. Mumps vaccination and meningitis.
Lancet 1993; 341 : 994-995.
18.Tingle AJ, Chanter JK, Pot KH, et al. Post partum
rubella immunization : Association with
development of prolonged arthritis, neurological
sequalae and chronic rubella viremic. J Infect Dis
1985; 152 : 606-612.
19.Tingle A, Mitchell L, Grace M, et al. Randomized
double blind placebo controlled study on adverse
effects of rubella immunization in seronegative
women. Lancet 1986; 349 : 1277-1281.
20.Centre for disuse control. Adverse events following
immunization. Surveillance Report No.1 19791982. US Dept. of Health and Human Services.
Public Health Services. Atlanta CDC, August 1984.
INTERNATIONAL PEDIATRIC UPDATE 2004
MMR Vaccines :
Which One to Use?
Dr. Y. K Amdekar, Consultant Pediatrician, Jaslok Hospital, Mumbai.
MMR vaccine is available in combination of
different strains. Each manufacturer stresses
superiority of his brand and brings out points
against other brands. This offers equal
opportunities for physicians to learn
worthiness of each combination. However
contradictory claims by the industry confuse
the practitioner to choose the ideal brand
for routine use. Most of the times, half-truth
is put forward by the industry and hence
need for unbiased study to make right
choice.
Every vaccine in the market is assured to
be reasonably safe and effective. There is
no reason to believe one vaccine far superior
than the other. But there are few
considerations that may decide a vaccine
more appropriate in our setting than another
is. Ideal MMR vaccine is expected to offer
protection against all three diseases to an
acceptable extent. It should be adequately
immunogenic to administer at the earliest
age of susceptibility to ensure protection to
all age groups of children. It should result
in sustained immunity and should have
capability of producing good booster effect
on revaccination. It should be of course safe
enough not to cause any serious side
effects. Finally cost of the vaccine must be
affordable to the majority. Vaccine for the
“rich” is not a sound idea as “poor” feels
obligatory to do the best for his child as well,
at any cost.
Edmonston-Zagreb Measles strain is shown
to be more immunogenic in early infancy
than Schwarz strain and is therefore an ideal
vaccine to administer at 6 months of age.
Immunity induced by EZ vaccine is also
unaffected by previously administered
vaccine and thus it is also ideal for
revaccination. However, Schwarz vaccine
induces higher antibody response amongst
children with low levels of maternally
transmitted antibodies. Antibody response
induced by Moraten strain is as good.
In general, different strains of Mumps
57
vaccine (Leningrad-Zagreb, Jeryl Lynn and
Urabe) produce equal immune response,
though it is claimed that side effects are least
with Jeryl Lynn strain, particularly in
reference to aseptic meningitis. However,
unbiased studies have estimated incidence
of vaccine induced aseptic meningitis to be
as low as 0.8 per 100,000 doses. Moreover
vaccine induced aseptic meningitis is a
benign disease with complete recovery
without treatment. In fact, mumps virus
induced disease presents with encephalitis
more than mere meningitis. Other side
effects are minor and include parotitis,
lymphadenitis and purpura.
Cost factor is an important consideration in
selecting an ideal vaccine. As of now, costeffectiveness of “safe” MMR vaccine is not
in favor of its universal use. Developed world
may consider even the smallest advantage
good enough to change to new vaccine. It
would be long before we could do that. The
only worry in this game of vaccine
manufacturers is the fact that industry would
rule how we should behave and the obvious
beneficiary may not be the child.
Proceedings & Abstract Book
Behavioural Diagnosis in
Office Practice
Dr. Gautam Koppikar, Consultant Pediatrician, Nasik.
Developmental-Behavioural Paediatrics is
an emerging subspeciality of Paediatrics,
and in past, not much emphasis was given
on this subject in undergraduate or
postgraduate curriculum and teaching.
However in office practice, behavioral
diagnosis is an essential skill and it fully
decides the choice of therapy and the
outcome. Behavioral diagnosis is difficult,
as it requires a thorough understanding of
the diagnostic criteria. Also there is a need
to periodically revise your diagnosis in view
of the dynamic nature of developmentalbehavioural disorders. A thorough
knowledge of co-morbid conditions is also
essential for proper office diagnosis.
The various diagnostic pitfalls, dilemmas
and difficulties are illustrated in this talk
in the form of various Case Scenarios.
Dilemmas in Chronic
Viral Hepatitis
Sheena Sharma*, Anupam Sibal**
*Dr. Med., Aerztliche Pruefung, LMU Germany, Research Fellow
**Senior Consultant Pediatric Gastroenterologist and Hepatologist,
Director Medical Services, Apollo Centre for Advanced Pediatrics, Indraprastha
Apollo Hospital, New Delhi.
Dilemmas in chronic viral hepatitis:
Chronic viral hepatitis is an important life
limiting liver disease requiring proper
management and appropriate timing of
treatment. Without treatment, there is a high
risk of reactivated infection and
development of hepatocellular carcinoma.
Also, untreated patients form a reservoir for
further spread of infection. On the other
hand however, limited treatment options
exist with side effects ranging from general
clinical complaints to treatment resistance
with virological rebound and exacerbation
of hepatitis. The goal of treatment is to
achieve viral clearance and normalization of
elevated serum transaminases beyond the
end of therapy.
The most difficult questions confronted by
the clinician are: who really needs to be
treated and when.
58
Hepatitis B
The natural history of hepatitis B in children
varies from spontaneous viral clearance to
prolonged latency and progressive liver
damage. Therefore, the aim of treatment in
children is prevention of complications in
later life. Treatment indications for hepatitis
B are HBsAg positivity, HBeAg positivity
more than 6 months, active viral replication
(HBV DNA >105 copies/ml) and elevated
serum alanine aminotransferase (ALT) more
than twice the normal value in patients older
than 2 years. It has been demonstrated in
multiple trials that better response is
achieved when there is low viral replication
(low HBV DNA level), severe histologic
activity with high baseline serum ALT levels,
ideally more than twice the normal value.
Many times the biochemistry consisting of
serum AST/ALT levels might be within
INTERNATIONAL PEDIATRIC UPDATE 2004
normal limits and a liver biopsy is imperative
to determine the histologic activity. A liver
biopsy before treatment, although being an
invasive procedure, is a relatively benign
and low risk procedure, which provides an
objective status of the liver for further
management.
While treatment with standard interferon
alpha requires daily subcutaneous injections
and shows immediate peaks followed by
zero-levels, pegylated interferon has a
constant serum concentration level and
seems to provide better viral clearance than
interferon alpha. Pediatric data on treatment
with pegylated interferon in hepatitis B
however, is not available. Lamivudine is a
nucleoside analogue, which can be
administered orally and is tolerated well. The
initial hope for a better treatment option has
been overshadowed by the increasing risk
of YMDD mutation with duration of
treatment. The ideal treatment time to attain
viral clearance compromises with the risk
of mutation. Due to fear of exacerbation of
hepatitis after stopping treatment, the
emergence of YMDD mutation and
emergence of resistant mutant viruses, there
has been an interest in opting for
combination therapy consisting of interferon
alpha or pegylated interferon with
lamivudine. Not only does one hope to
decrease the risk of lamivudine induced
mutation, but also to gain from additional
antiviral effects. Very few studies exist on
combination therapy in children with no
significant benefit in terms of viral response.
No consensus on the most appropriate
combination regimen exists till date. Follow
up requires monitoring the virological
response and should include serum
transaminases, HBV DNA, HBeAg/ anti-Hbe
every 1-3 months after cessation of therapy
for the first year and annual determination
of HBsAg.
Hepatitis C
The first dilemma is labeling a child as a case
of chronic hepatitis C since the natural
history and immunological response is very
variable. While treatment goals are to
eradicate hepatitis C virus by complete loss
of HCV RNA from liver and serum, to
decrease progression of liver disease as well
as reduce frequency of hepatocellular
carcinoma and improve survival, the time
of initiating therapy poses a challenge.
Patients with evidence of ongoing infection
(HCV RNA postive), elevated transaminases
more than twice the normal value and
evidence of histological liver disease should
be started on therapy. Direct correlation
between HCV seropositivity and extent of
liver disease is not always present and
serum AST/ALT levels may in fact be normal
in spite of histological evidence of
inflammation.
Although there is limited data on treatment
of chronic hepatitis C in children, interferon
alpha remains an important part of therapy.
Combination therapy with interferon alpha
and ribavarin are promising and pegylated
interferon may increase further efficacy with
clinical trials eagerly awaited.
Given the limited treatment options and risks
involved, treating children appropriately
remains a challenge.
References:
1. Chongsrisawat V, Poovorawan Y.
Management of chronic hepatitis B and C
virus infections. Indian J Pediatr 2002 Feb;
69(2): 149-54
2. Jara P, Bortolotti F. Interferon-alpha
treatment of chronic hepatitis B in childhood:
a consensus advice based on experience
on European children. J Pediatr
Gastroenterol Nutr 1999 Aug; 29(2): 163-70
3. EASL
International
Consensus
Conference on Hepatitis B (13-14
Sept.2002). J Hepatol 38(2003): 533-540
4. Craxi A, Cooksley WG. Pegylated
interferons for chronic hepatitis B. Antiviral
Res 2003 Oct; 60(2): 87-9.
5. Liaw YF. Management of YMDD mutations
during lamivudine therapy in patients with
chronic hepatitis B. J Gastroenterol Hepatol.
2002 Dec;17 Suppl 3:S333-S337
6. Schwarz KB. Pediatric issues in new
therapies for hepatitis B and C. Curr
Gastroenterol Rep. 2003 Jun;5(3): 233-9
59
Proceedings & Abstract Book
A Novel Diagnostic Aid (ISABEL):
Development and Preliminary Evaluation
of Clinical Performance
Padmanabhan Ramnarayana, Amanda Tomlinsona, Gautam Kulkarnia, Anupama
Raob, Joseph Brittoa
a
Department of Paediatric Intensive Care, St Mary’s Hospital, London, UK
b
Department of Haematology, Watford General Hospital, Watford, UK
Abstract
Clinical diagnostic aids are relatively scarce,
and are seldom used in routine clinical
practice, even though the burden of
diagnostic error may have serious adverse
consequences. This may be due to
difficulties in creating, maintaining and even
using such expert systems. The current
article describes a novel approach to the
problem, where established textbook matter
is used as the knowledge base for a
pediatric diagnostic tool called ISABEL. The
inference engine (Autonomy™) utilizes
advanced textual pattern-recognition
algorithms to extract key concepts from
textbook description of diagnoses, and
generates a list of diagnostic suggestions
in response to clinical features entered in
free text. The system was developed over
the course of months without significant
manpower requirement. Development was
an iterative process, relying on sequential
evaluation of clinical performance to provide
the basis for improvement. The usage of the
system over the past 2 years, as well as
results of preliminary clinical performance
evaluation are presented. These results are
encouraging. The ISABEL model may be
extended to cover other domains, including
adult medicine.
Keywords: Decision support; diagnosis;
evaluation studies; pattern recognition;
diagnostic error
Introduction:
Biomedical knowledge has grown
exponentially in the past few years, resulting
in severe information overload for clinicians
[1]; it is estimated that this problem will
double every 20 years [2]. However, rapid
growth has not affected all domains of
60
medical knowledge equally, information
related to newer medical tests and treatment
is constantly evolving, whereas traditional
knowledge pertaining to clinical diagnosis
has changed relatively little. Recent
techniques that attempt to summarize latest
treatment recommendations in line with
changing medical evidence are now
available, and are popular with clinicians
[3][4], whereas systems that might assist in
routine clinical diagnosis remain scarce.
We know, however, that medical information
relevant to making clinical diagnoses is
constantly needed [5], and that this
information need is fulfilled mainly by
consulting textbooks [6]. We also know that
errors related to misdiagnoses, or missed
diagnoses, constitute a significant
proportion of the preventable burden of
medical error [7]. Some diagnostic errors
may be due to ‘errors of omission’ (failure
to consider all clinically relevant diagnoses
during initial workup). In addition, incorrect
formulation of the clinical problem, as well
as difficulty in extracting relevant information
from textbooks quickly, whether paperbased or electronic, may contribute to
diagnostic error.
One reason why computerized diagnostic
aids are scarce may be related to the
difficulty of converting traditional medical
knowledge into computer-readable form.
Existing aids for internal medicine, such as
DXplain, QMR and ILIAD [8][9][10], were
developed over many years, involving the
input of multiple experts to provide semiprobabilistic relationships between
thousands of clinical features and hundreds
of diseases. These tools were also
developed to assist the clinician primarily
during the rare entity of a diagnostic
INTERNATIONAL PEDIATRIC UPDATE 2004
dilemma (clinical dead-end), by acting as
‘oracles’. As a result of this design, they often
required the user to expend a considerable
amount of time interrogating the system
[11]. In order to regularly use such a standalone system in practice, a clinician had to
be highly motivated, one reason why
diagnostic decision support as a concept
may not have captured clinicians’ interest.
This paper aims to describe the
development of a novel diagnostic aid called
ISABEL (http://www.isabelhealthcare.com)
[12][13][14], which utilizes unstructured
information from standard textbooks to
provide a set of diagnostic reminders for any
clinical scenario, in response to clinical
features entered in free text. In stand-alone
format, it is intended to be used by clinicians
in routine practice, in a negligible amount
of time. An analysis of the system’s
performance is also described.
Materials and Methods:
Underlying knowledge base:
Electronic text from 4 standard pediatric
textbooks, provided by Elsevier Health
Sciences, was used to populate a predesigned diagnostic tree comprising around
3500 diagnoses. This tree was based on the
table of contents derived from one standard
textbook (Nelson’s Textbook of Pediatrics,
16th Edition). Figure 1 depicts part of this
diagnostic tree.
paediatric view
Categories
Allergic Disorders
Bone and Joint Disorders
Cardiovascular System
Endocardium Diseases
Acquired Heart Disease
Cardiac Arrhythmias
Congenital Heart Disease
Diseases of the Myocardium
Diseases of the Pericardium
Diseases of the Peripheral Vascular System
Heart Failure / Congestive Heart Failure
Tumors of the Heart
Children with Special Health Needs
Digestive System
Diseases of the Blood
Figure 1- View of part of the ISABEL
diagnostic tree
61
Electronic text pertaining to each diagnosis
within the tree was copied from each of the
textbooks into the ISABEL database, without
any modifications, by one research nurse.
Thus, unformatted text relating to the same
disease, from different sources, was collated
under one disease label. Where new disease
labels were necessary to accommodate text
from a new textbook, they were created
within the same overall diagnostic tree
model. Since there was no modification of
the text involved, this entire process took
less than 4 months for one researcher, for
all 4 textbooks.
Inference engine:
Commercially available software was used
as the inference engine (Autonomy™,
Autonomy Corporation, Cambridge, UK,
www.autonomy.com). This software
employs advanced pattern-recognition
techniques on unstructured text to extract a
document’s digital essence, identifies and
encodes the unique signature of key
concepts within a document, and creates
concept agents to match document profiles
with similar ideas as the input text. The
software utilizes Bayesian Inference and
Shannon’s principles of information theory
to generate its pattern-matching algorithms
to enable sophisticated concept extraction
from documents.
By aggregating text related to one specific
diagnosis under a single diagnostic label
within the diagnostic tree, it was possible
for the software to generate a unique
signature of key concepts for each
diagnosis, by using its concept extraction
techniques. This signature was constantly
modified with the addition of text from each
additional textbook used to populate the
ISABEL database.
Search methodology:
In response to a set of key clinical features
for a patient (concepts), ISABEL utilized
Autonomy™ to search the underlying
database of text, and return all documents
(diagnostic labels) whose concept signature
matched that generated from the clinical
features. Clinical features could be altered
(by entering additional findings or deleting
findings) to reflect a different concept
signature, and thus alter the results of the
search. Due to the nature of the search
mechanism, only clinical features described
in textual language were used to generate
Proceedings & Abstract Book
a concept signature (i.e numerical values,
such as the age of the child, were not used).
System architecture and delivery
platform:
In order to maximize the use of the system,
and eliminate inequalities of regional
distribution, ISABEL was delivered on the
World Wide Web to all medical practitioners,
after a short registration process. To this end,
a website was created by DynamicWeb, UK
using Javascript. The Autonomy Dynamic
Reasoning Engine™ (DRE) was hosted on
a dedicated ISABEL server, as was the
database comprising the diagnostic tree,
which could be construed as being the
equivalent of multiple documents of text in
html.
At the front end, a free text box, into which
the user could enter the clinical features of
a patient, was created on a dedicated
diagnostic tool webpage on the ISABEL
website. On searching the database with
these features, a list of all matching
diagnostic labels (diseases) was returned.
The maximum and minimum number of the
diagnoses displayed on the results page
could be varied by the developers of the
system.
Remodeling the search mechanism:
Preliminary examination of the system’s raw
results by the medical team (consisting of
three pediatricians) suggested four
problems, which led to a remodeling of the
underlying architecture of the ISABEL
database.
• Since numerical values were not used in
the generation of the concept signature,
it became obvious that users had to
specify the patient’s age group separate
from the clinical features to avoid ageinappropriate diagnoses being displayed
(such as neonatal meningitis for a 3 year
old child)
• Due to the global audience, it was
essential to take into account where the
patient originated from, and to tailor
diagnostic suggestions accordingly.
• Due to the free text (variable) nature of
input, it was necessary to create an
intermediate filter between the input and
the DRE, whose main function was to
convert non-medical terminology into
medical terms.
• Since the primary function of the system
62
was to provide diagnostic reminders,
each holding equal clinical value, it was
felt that the degree of concept matching,
as expressed by Autonomy™, should not
be used as the basis for the ordering of
the diagnostic suggestions.
These changes were achieved by tagging
each of the diagnostic labels in the tree to
specific age groups (newborn, infant, child
and adolescent), and to specific regions of
the world (e.g. North America, Western
Europe etc., as per World Health
Organization guidelines). This was done by
the development team in 4 weeks. In
addition, the intermediate filter to convert
common non-medical terms into
appropriate medical terms was developed
specifically for ISABEL by the medical team
in 4 weeks. Table 1 shows some common
terms included in this filter.
Table 1 – Examples of terms included in the
filter
Lay terms &
abbreviations
Nad
Hot, high temperature
WBC
Shut down,
peripheries
Medical
translation
Normal
Fever, pyrexia
White cell
Shock, cold
vasoconstriction
Additional drop-down boxes were provided
for the user to specify the age-group and
the region, in addition to the existing free
text box for clinical features. Diagnostic
results were arranged into body systems to
which they pertained (Asthma - Respiratory
disorder), rather than in rank order of the
degree of concept match. This facilitated a
patho-physiological approach to the
diagnostic process. Further information
regarding each diagnosis in the suggestion
list could be obtained by clicking on it – text
from Nelson’s textbook was provided for
reference.
Figures 2 & 3 show how a set of clinical
features entered in free text into the search
box produce a set of diagnostic labels (with
the preceding text: have you considered?)
for the user’s attention.
Measuring usage of the system on the
Web:
The complete system as described above
was available on the Internet from June
2001. Usage statistics were used as
indicators of the popularity of the system,
INTERNATIONAL PEDIATRIC UPDATE 2004
Figure 3 – Diagnostic suggestions arranged to reflect
patho-physiological process involved
Figure 2 – Clinical features entered into free text box
and were measured using analog 5.22. Data
from July 2001 to date are provided in the
results section.
Preliminary estimates of the system’s
performance:
Since the primary role of the system was to
offer relevant significant diagnostic
reminders for a variety of clinical scenarios
in pediatrics in a negligible amount of time,
preliminary testing of the performance of the
system was based on examining if important
diagnostic suggestions were offered, and
how long it took to obtain results from the
system. This testing was done by the
developers of the system, rather than users,
in a laboratory setting removed from clinical
practice.
Clinical data from 100 real patients, drawn
from an unselected consecutive sample of
children attending 4 emergency
departments in the UK was used. These data
consisted of age-group, initial clinical
features (including results of available ‘firstpass’ tests) and final discharge diagnoses.
They were collected by clinicians working
in these departments for the study, and were
not modified by the developers in any way
during testing. Cases were examined by a
panel of two pediatricians, working together,
who produced a bare minimum list of
‘significant’ diagnoses that ought to have
formed part of the examining physician’s
diagnostic work-up list to ensure clinical
safety (gold standard). These clinical data
were also entered into ISABEL by one
research nurse, and the resultant diagnostic
suggestion list was compared to the gold
63
standard list. The maximum number of
suggestions was fixed at 15 for this study.
Outcomes:
Comprehensiveness ratio: mean value of
match between the gold standard list and
ISABEL’s list (expressed as a proportion).
Relevance ratio: Ratio of matching gold
standard diagnoses in the ISABEL list to the
total number of diagnostic suggestions
offered by ISABEL.
Interrogation time: Time taken to enter
clinical data into the system and generate a
diagnostic suggestion list (on a 56 KBps
modem connection)
Results:
Usage statistics:
25 GB of data was transferred in the period
from July 2001-August 2003 (average/day:
32 MB). There were 9,168,147 successful
page requests (average/day: 11,641); over
12,000 users registered to use the site in
the specified period. Over a fifth of users
accessed the system >5 times since
registration. The entire National Health
Service (NHS), UK was provided log-in free
access via IP address recognition in mid2002; it then proved difficult to estimate the
true number of users. This facility was also
extended to cover many teaching hospitals
in the US (over 10% of the registered users
are currently US-based).
Performance of the system:
The panel provided gold standard
diagnoses for all 100 cases. The median
number of such diagnoses per case was 2
Proceedings & Abstract Book
(range 1-4). ISABEL provided a maximum
number of 15 diagnoses (minimum 10,
mode 15). In 73/100 cases, ISABEL
displayed all gold standard diagnoses
(comprehensiveness ratio 1.0). In an
additional 15/100 cases, at least half of the
gold standard was present in the ISABEL
suggestions (comprehensiveness ratio
0.50). The mean comprehensiveness ratio
across all 100 cases was 0.81.
Since the best raw relevance ratio in this
study could only have been 0.27 (all 4 gold
standard diagnoses matched in a set of 15
ISABEL diagnoses), a final relevance ratio
was calculated (expressed as a proportion
of 0.27). In this study, the mean final
relevance ratio was 0.45 (95% CI 0.39-0.51).
Over a 56KBps modem connection, ISABEL
results took less than 1 sec to display in all
cases. Time taken to enter clinical data into
the system (interrogation time) was variable
depending on the level of detail entered
(range: 30 sec – 2 min).
Discussion:
This paper describes the development and
preliminary analysis of the performance of
a diagnostic tool for pediatric medicine. We
have shown that, using a novel technique
to search an established medical knowledge
base (textbooks), it is possible to deliver
relevant diagnostic suggestions in a suitable
format for physicians’ consideration. The
system does not aim to provide
probabilistically ranked diagnoses like other
similar systems. We feel that organizing
diagnostic suggestions in terms of pathophysiological causes is useful for the
clinician. Further information on each
diagnosis can be sought in the form of text
from established medical textbooks. This
approach empowers the user, and leaves
the final decision making capacity in their
hands (treating them as ‘learned
intermediaries’) [15].
Other diagnostic systems have attempted
to closely replicate the human processes
involved in diagnostic decision making.
They were intended to be expert systems,
functioning at a level akin to a diagnostic
consultant. Human efforts at making
medical diagnoses involve, among others,
some implicit method of assigning
probabilities (a priori, as well as posterior)
associated with clinical features, and
reconciling patterns learnt or observed from
clinical experience. However, this approach
64
has limitations – low base-rate events, which
have enormous clinical significance if
missed, may be assigned lower probability
estimates (‘common things are common’)
during clinical encounters leading to
diagnostic ‘errors of omission’ [16].
Furthermore, such errors may not result
always from not knowing, but may be a
result of the loss of a checklist function when
busy or fatigued during clinical work [17]. It
has been demonstrated that using
checklists to process many medical tasks
leads to improvement in clinical care [18].
In that sense, ISABEL was intended only as
a reminder system, to prompt consideration
of alternative diagnoses that may have been
pushed down by clinicians in their rank
order, either because they were uncommon
or due to simple omissions.
The development time involved to reach a
working prototype of the system was only
in the order of months, rather than years.
The manpower required to achieve this level
was also minimal (one research nurse, and
a medical team to ensure quality control).
Utilizing established and recognized
knowledge bases and applying advanced
textual pattern-recognition techniques to the
matter contained within them is a novel
approach, which ensures minimal
manipulation of data by non-experts
developing the system. It was apparent
during the development of this system that
this alone did not satisfy clinical
requirements and expectations, and that
further input by medical experts to fine-tune
the raw output of the system was necessary.
Previous attempts at developing diagnostic
systems have taken many years and
involved input from many medical experts.
This point is clear from studying the Internist
system, that later developed into the QMR
system [19]. Textbooks also have
established mechanisms to be kept up to
date (although sometimes they may lag
behind by roughly 2-3 years). Updates to
the ISABEL system are easy: new text simply
replaces the old text in the diagnostic tree.
Keeping previously mentioned expert
systems up to date was an arduous task that
involved searching through the literature for
new updates, and consulting with many
medical experts.
We used previously researched outcome
measures to characterize the clinical
performance of the ISABEL system. In
comparison to four expert diagnostic
INTERNATIONAL PEDIATRIC UPDATE 2004
systems tested previously by Berner et al in
1994, ISABEL performs well, with a
comprehensiveness ratio of 0.81[20].
Testing the relevance ratio was also quite
important: it reflects how focused the
diagnostic suggestion list was. This is
important, because users may reject a
system that displays important diagnoses
but also provides many other trivial
possibilities, detracting from the value of the
relevant suggestions. However, since our
gold standard consisted of only a few
diagnoses that were considered so clinically
important that they could not be omitted, as
opposed to all possible relevant diagnoses,
our relevance ratios were small. For this
reason, we also tested the performance of
the system with varying numbers of
maximum ISABEL diagnostic suggestions.
A maximum of 10 diagnostic suggestions
retained the comprehensiveness ratio
>0.75, and improved the relevance ratio to
0.40. We have also shown that these
encouraging results were obtained in a
clinically negligible amount of time (<2 min),
during which the system was interrogated.
This is in contrast to other expert systems
that may take an average of 22 min to
interrogate [21].
Limitations:
Limitations of system design include the fact
that negative findings cannot be used to
influence the diagnostic suggestions
produced, and that diagnosis are not ranked
in order of probability. Results from the
usage statistics suggest that the system is
popular, perhaps indicating that they find its
advice useful [22], but a more
comprehensive user survey is needed to
determine usability issues. The clinical
performance evaluation described is a
preliminary study, and the case mix in the
validation sample may not have been fully
representative. In addition, results from an
isolated examination of the system cannot
be extrapolated to suggest the impact of the
system on clinicians. It is important that this
is assessed by means of different studies
that focus on the impact of the system on
diagnostic decision-making.
Conclusions
The ISABEL system promises a novel
method of delivering clinically relevant
diagnostic suggestions for a variety of
clinical scenarios in pediatrics in a negligible
amount of time. This model can be
extrapolated to develop similar systems for
adult medicine.
Acknowledgments
The authors would like to acknowledge the
useful comments provided by Dr Jeremy
Wyatt and Dr Paul Taylor during the
development of the ISABEL system. We also
remain thankful to Jason and Charlotte
Maude, who were instrumental in setting up
the ISABEL Medical Charity to support the
development of the ISABEL system.
References
[1]
Wyatt JC. Clinical Knowledge and Practice in the
Information Age: a handbook for health
professionals. London: The Royal Society of
Medicine Press:2001.
[2]
Wyatt J. Uses and sources of medical
knowledge. Lancet 1991:338:1368-72.
[3]
Brassey J, Elwyn G, Price C, Kinnersley P. Just
in time information for clinicians: a questionnaire
evaluation of the ATTRACT project. BMJ. 2001
Mar 3:322(7285):529-30.
[4]
Godlee F, Smith R, Goldmann D. Clinical
evidence. BMJ. 1999 Jun 12:318(7198):1570-1.
[5]
Smith R. What clinical information do doctors
need? BMJ 1996:313:1062-1068.
[6]
Ely JW, Osheroff JA, Ebell MH, Bergus GR, Levy
BT, Chambliss ML, Evans ER. Analysis of
questions asked by family doctors regarding
patient care. BMJ. 1999 Aug 7:319(7206):35861.
[7]
Leape LL, Brennan TA, Laird N, Lawthers AG,
Localio AR, Barnes BA, Hebert L, Newhouse JP,
Weiler PC, Hiatt H. The nature of adverse events
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Miller R, Masarie FE, Myers JD. Quick medical
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[10] Warner HR Jr. Iliad: moving medical decisionmaking into new frontiers. Methods Inf Med.
1989 Nov:28(4):370-2.
[11] Graber MA, VanScoy D. How well does decision
support software perform in the emergency
department? Emerg Med J. 2003 Sep:20(5):426-8.
[12] Greenough A. Help from ISABEL for paediatric
diagnoses.
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Oct
19:360(9341):1259.
[13] Thomas NJ. ISABEL. Critical Care 2002; 7(1):99100.
[14] Ramnarayan P, Britto J. Paediatric clinical
decision support systems. Arch Dis Child. 2002
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Nov:87(5):361-2.
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Lancet 1989;2:632-4.
[16] Bornstein BH, Emler AC. Rationality in medical
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doctors’ decision-making biases. J Eval Clin
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[17] Graber M, Gordon R, Franklin N. Reducing
diagnostic errors in medicine: what’s the goal?
Acad Med. 2002 Oct;77(10):981-92.
[18] Balas EA, Weingarten S, Garb CT, Blumenthal
D, Boren SA, Brown GD. Improving preventive
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2000 Feb 14:160(3):301-8.
[19] Miller RA, Pople HE Jr, Myers JD. Internist-1, an
experimental computer-based diagnostic
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J Med. 1982 Aug 19:307(8):468-76.
[20] Berner ES, Webster GD, Shugerman AA,
Jackson JR, Algina J, Baker AL, Ball EV, Cobbs
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[21] Friedman CP, Elstein AS, Wolf FM, Murphy GC,
Franz TM, Heckerling PS, Fine PL, Miller TM,
Abraham V. Enhancement of clinicians’
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[22] Berner ES. Diagnostic decision support
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J Am Med Inform Assoc. 2003 NovDec:10(6):608-10.
Stressed School Child
Dr. V.K. Mundra, Dr Anupama Shah
Children are making news for the last few
months – Children who hang themselves or others
– Children who rape
– Children who fail exams and jump
– Others who master skills much beyond
their age
– Children who answer quiz masters on TV
– And children who give up hope
And as a chorus, conducted by the media,
the stricken conscience of the thinking class
cries out how society is tressing out the child
Is it reality ? who is “stressing” which child
? who is hurting, who is doing the hurting?
From children who protest not being allowed
to wear mehendi, to children who are
interviewed at the age of 3 yrs, is there a
common thread?
If the system is so cruel, how is todays Indian
youth conquering the world? Arent these
boys and girls who have stormed the
superpowers also a product of this system?
As America goes to elections it debates the
loss of livelihood because of our keyboard
invaders; whom India budgets for its
economy, it counts the billions of dollars
66
repatriated by them for its foreign exchange
reserves.
Suddenly within a generation, the gates
have opened , and horizons have changed.
Shall we plan for the average or cater to the
best?
Doctors see those who fall by the wayside;
those who succumbed to the infection, not
those who have resisted it, those who wilted
under the onslaught, not those who
overcame it.
We see the ill not the healthy.
Is there a middle path?
Can there BE a middle path?
Atleast for children who attending tuition’s
in class II , for children at the receiving end
of the highly touted “ quality time “ sparingly
dispensed by the working mothers, for
children getting their personalities
“rounded” by the never ending chain of
karate class, dance class , elocution class,
for children living out the unfulfilled dreams
of ambitious parents, for these children, do
doctors offer hope?
Can we as a group stand up and say “STOP
IT”
INTERNATIONAL PEDIATRIC UPDATE 2004
Growth Hormone Beyond
Growth Hormone Deficiency
Dr. Archana D. Arya, Consultant Pediatric Endocrinologist and Diabetologist,
Centre for Child Health, Sir Ganga Ram Hospital, New Delhi.
Human Growth hormone (hGH) was first
used in 1950’s to stimulate growth in
children with hypopituitarism (1). It was
obtained by purifying cadaveric pituitary
extract, and hence the availability was
limited. In 1985 the first case of CreutzfeldJacob disease was reported in a patient who
had received growth hormone and
subsequently more cases were reported.
The preparation was banned and in the
same year (2), the 192 amino-acid
biosynthetic GH was approved by the FDA,
USA.
Since then there has been abundant supply
of the recombinant hGH. Its growth
promoting effect in children who do not have
classical GH deficiency has been
investigated in a large number of children.
Now it is also being studied for its metabolic
effects besides the effect on linear growth.
The paradigm has shifted from GH
replacement to GH augmentation therapy.
The number of FDA approved indications
has more than doubled in the last 5 years.
This has made the decision about GH use
for short stature, more complex.
Data to support that improvement in height
would improve psychological health is
scarce, except in severe GH deficiency (3).
Growth Hormone Physiology:
Human growth hormone is secreted by the
anterior pituitary gland under the influence
of Growth Hormone Releasing Hormone
(GHRH) and inhibitory somatostatin that are
released by the hypothalamus. The
secretion of GH is cyclical and pulsatile, and
it is released in response to sleep, exercise
and hypoglycemia. It is bound to GH binding
protein in the circulation and has a short half
life of less than 20 minutes. Hence to identify
peaks, frequent sampling would be
required. Due to the pulsatile secretion and
short half life, GH response to
pharmacological stimuli is used for judging
adequacy of secretion.
67
GH mediates its effects through Insulin like
Growth factor I (IGFI), which is a peptide
secreted by the liver in response to
stimulation by GH. It is bound in the
circulation to IGF binding proteins (IGFBP)
the most important one being IGFBP-3.
IGF 1 levels correlate with the clinical state
of GH deficiency, sufficiency or excess but
do not exclusively reflect GH production
because levels of IGF1 vary with age. IGF1
correlates better with bone age and puberty
rather than chronological age. Poor nutrition
and chronic disease may decrease the IGF1
levels.
Effects Of Growth Hormone:
The most apparent effect of GH is to
stimulate linear growth in children before
epiphyseal fusion occurs. Besides this it has
a number of other metabolic effects:
• Anabolic (Cell proliferation & protein
synthesis)
• Lipolytic (Decreases adipose tissue)
• Increases lean tissue
• Increases bone density
• Bolsters cardiac contractility
• Improves mood & motivation
• Increases exercise capacity
• Alters the carbohydrate metabolism
INDICATIONS OF GROWTH HORMONE
THERAPY:
The FDA, USA, has approved the
following indications of GH therapy:
1. Growth Hormone Deficiency:
Growth Hormone has been used for GH
deficiency (GHD) for almost 50 years now.
The diagnostic criteria for GH deficiency
have changed over the years as more and
more children were tested. The gold
standard for diagnosing GHD was to
demonstrate inadequate GH stimulation with
2 pharmacological agents. GH level of <
10 ng/dl on provocative stimulation is
Proceedings & Abstract Book
suggestive of GH inadequacy.
The Growth Hormone Research Society
recently recommended measurement of
IGF-1 and IGFBP3 in addition to provocative
GH testing to identify children with
abnormalities in the GH/IGF axis not
detected by standard tests. Children with
GH levels in the high subnormal range and
with normal stimulated levels but low
spontaneous secretion or low IGF-1 and
IGFBP3 are now considered to have partial
GH deficiency.
Early initiation of treatment with GH, in cases
with Growth Hormone deficiency results in
normal adult height. (4)
2. Turner Syndrome:
The longest trials of GH therapy, after GHD
have been on girls with Turner syndrome.
Turner syndrome (TS) occurs because of the
complete deletion of an X chromosome or
a part of one of the arms. Mosaicism may
occur in this condition. 95-100% of these
girls have growth retardation and untreated
their height is about 143cms as reported
from the western literature, which is about
20 cms less that their average height.
Special growth charts are available for girls
with Turner syndrome. These girls are
usually not GH deficient. They gain about
4.4 cms/year, do not have a pubertal growth
spurt because of hypogonadism and have
some degree of GH resistance.
GH therapy with or without anabolic steroids
like oxandrolone accelerates growth in girls
with TS (5). Studies have shown that the
mean final height of girls with TS treated with
GH was 150.4cms, which was about 8.4cms
more than the expected average height and
those treated with GH and oxandrolone was
152.1cm, which was 10.4 cms more than
the predicted height without treatment.(6)
At this time initiation of therapy is
recommended as soon as females with TS
have dropped below the 5th percentile of the
normal female growth curve. This could be
as early as 2 years of age. The
recommended starting dose is 0.05mg/kg/
day. In older girls or those >8 years of age
if therapy is started when short stature is
extreme, concomitant administration of
oxandrolone should be considered.
3. Chronic Renal Failure:
Growth failure is often the presenting
symptom of Chronic Renal Failure (CRF).
The genetic height potential is usually not
68
attained in these children and the mean
adult height is 2 standard deviations below
the mean. Poor growth in children with CRF
is due to non-endocrine factors like
malnutrition, acidosis, and renal
osteodystrophy and endocrine factors such
as GH resistance suggested by exaggerated
response on provocative stimulation,
decreased levels of IGF1 and increased
levels of IGFBP1.Despite dialysis, growth
failure persists in these children and post
transplant, growth rate may normalize, but
no catch up growth is seen.
Pharmacological doses of GH correct height
deficit in most children with CRF before
transplant. In a study of 38 children with CRF,
GH treatment resulted in a final height that
was 1.4 SD above standardized height at
baseline and the mean final height of 50 non
treated matched control children with CRF
was 0.6 SD below standardized height at
baseline. (7) Current information suggests
no adverse effect of GH on the glomerular
filtration rate. GH therapy is approved for
treatment of children with growth failure
associated with CRF, up-to the time of renal
transplantation and it should be used in
conjunction with optimal management of
CRF.
4. Prader Willi Syndrome:
Prader-Willi Syndrome (PWS) occurs due to
deletion in chromosomal region 15q11-13.
The incidence is1:10,000 -25,000 live births.
This condition is typically characterized by
hypotonia, hyperphagia leading to gross
obesity, short stature that is often due to GH
deficiency,
hypogonadism
and
psychomotor retardation. GH therapy in
these children results in growth rate
increases similar to those seen in GH
deficient children. In addition it improves the
muscle tone, decreases the fat mass,
increases the lean body mass and bone
mineral density (8). Growth failure related
to PWS is an approved indication for GH
treatment.
5. Intrauterine Growth Retardation:
Intrauterine growth retardation (IUGR) is
defined as a birth weight or length, more
than 2 SD below the mean. 3% babies are
born with IUGR and 10% of these do not
show catch-up growth. Growth retardation
is assumed to be due to abnormality of the
GH - IGF1 axis. Puberty invariably starts
early in these children, compromising the
INTERNATIONAL PEDIATRIC UPDATE 2004
growth potential further and resulting in a
height that is below their genetic potential.
This group includes children with
dysmorphic features compatible with
Russell Silver Syndrome.
A number of studies indicate that
administration of GH can normalize stature
of short IUGR children who are not GH
deficient during childhood and early
puberty. (9) Effect of GH on final height still
remains to be seen and will finally determine
the efficacy and safety of use of GH in these
children.
6. Idiopathic Short Stature:
Idiopathic short stature (ISS) includes
children with short stature that is not due to
any known illness or GH deficiency. A recent
study of 80 non GHD children treated with
GH showed a mean increase in SD score
for height from -2.7 to -1.4. The mean
difference between the predicted adult
height before treatment and achieved adult
height among boys was 5.0 + 5.1 cm and
5.9 + 5.2 cm for girls. Only a few subjects
in this study reached their mid-parental
height (10). It seems that long term GH
treatment of non-GHD children can lead to
statistically significant increases in final
height in some children. The FDA recently
approved use of GH to treat children with
ISS.
Growth disorders, illnesses and
metabolic conditions for which GH
treatment has been investigated are:
Familial short stature, Constitutional growth
delay, Skeletal dysplasias, Syndromes
(Noonan’s, Down’s), Thalassemia Major, Xlinked hypophosphatemic rickets. Patient’s
on chronic glucocorticoid therapy (Juvenile
rheumatoid arthritis, Asthma), Cystic
fibrosis, AIDS wasting, Post operative wound
healing, Burns, Inflammatory bowel disease,
Adult GH deficiency, Aging
Dosage and Monitoring of GH Therapy:
The dose of growth hormone used varies
according to the condition being treated.
Pharmacological doses are 0.07-0.1 u/kg/
day. It is given as a daily subcutaneous
injection at night. Growth with daily dosing
is better than with thrice weekly doses which
were being used earlier. The preparation can
be given with a pen device by the parents
at home. Routine monitoring of thyroid
functions, blood glucose, IGF1 and IGFBP3
during therapy is recommended. Cost of GH
therapy is very high and is approximately
RS. 20,000 per month for a child weighing
20kgs. Treatment should be continued till
response to therapy is good or satisfactory
height is achieved or till epiphyses fusion
occurs.
Side Effects of GH Therapy:
Side effects of GH therapy are listed below.
They are not encountered very often but
monitoring for side effects must be done
regularly.
- Hypothyroidism
- Pseudotumor cerebri
- Slipped femoral capital epiphysis
- Possible salt and water retention
- Hyperinsulinemia
- Growth attenuation from antibody
formation
In the past there had been a concern about
recurrence of malignancy /occurrence of
new malignancies in GH treated patients.
Prolonged follow-up studies indicate that the
rates of new leukemia in-patients without
pre-existing factors who are treated with GH
is not greater than the general population.
There is also no risk of developing nonleukemic neoplasms or recurrence of
malignancy in GH treated patients. The
decision to treat or not to treat a patient with
GH should be made judiciously after careful
evaluation by an experienced pediatric
endocrinologist. What can be done with
Growth Hormone is not necessarily what
should be done.
References:
1. Raben MS. Treatment of a pituitary dwarf with
human growth hormone (letter). Journal Clin.
Endocrinol 1958: 18:901.
2. Underwood LE, Fisher DA, Frasier SD, et al.
Degenerative neurologic disease in patients
formerly treated with human growth hormoneReport of the Committee Growth Hormone Use of
69
the Lawson Wilkins Pediatric Endocrine Society,
May 1985. J Pediatr 1985: 107:10.
3. Sandberg DE, McGillviray MH. Growth Hormone
therapy in childhood-onset growth hormone
deficiency;
adult
anthropometric
and
psychological outcomes. Endocrine 2000: 12(2);
173-182.
Proceedings & Abstract Book
4. Allen DB. Childhood growth hormone deficiency:
statural and psychological effects of long-term GH
replacement. Endocrinologist 1998: 8:3S-7S.
5. Rosenfeld RG. Update on growth hormone therapy
for Turner’s syndrome. Acta Pediatr Scand 1989
(suppl.) 356:103-108.
6. Rosenfeld RG, Frane J, Attie KM, et al. Growth
Hormone therapy of Turner’s syndrome: beneficial
effects on final height. J Pediatr 1998:132:319-324.
7. Haffner D. Schaefer F, Nissel R, Wuhl E, Tonshoff
B, Mehls O. Effect of growth hormone treatment
on the adult height of children with chronic renal
failure. N Engl J Med 2000; 343(13):923-930.
8. Lindgren AC, Hagenas L, Muller J, Blichfeldt S,
Rosenborg M, Brismar M, Ritzen EM. Growth
hormone treatment of children with Prader-Willi
syndrome affects linear growth and body
composition favorably. Acta Pediatr Scand
1998:87:28-31.
9. Sas T, Waal W, Mulder P et al. Growth hormone
treatment in children with short stature born small
for gestational age; 5-year results of a randomized,
double blind, dose-response trial. J Clin Endocrinol
Metab . 1999: 84:3064-3070.
10.Hintz RL, Attie KM, Baptista J, Roche A. Effect of
growth hormone treatment on adult height of
children with idiopathic short stature. N Engl J Med
1999: 340:502-507.
The Skin as the External Marker
of Illness in Children
Assoc Prof Giam Yoke Chin, Senior Consultant, Pediatric Dermatologist,
National Skin Centre, Singapore
The skin presents with signs of diseases
which are easily seen and a doctor can
easily make a diagnosis.
For the last decade, there has been
advances in pediatric dermatology,
genodermatoses and discovery of the
genome and location of genes in diseases.
This lecture will present a spectrum of
pediatric dermatology, both common and
some rare diseases, with the clinical
approach and management, as far as
possible.
The following are presented:
Neonatology: physiological skin problems,
eg erythema toxicum neonatorum, nevus
sebaceous
70
Diseases at birth: congenital ichthyoses,
haemangiomas, the new classification,
PHACE syndrome
Common disorders: Atopic eczema, new
approach and new calcineurin inhibitors
Infections: eg molluscum contagiosum, use
of imiquimoid, new biological response
modifier.
Autoimmune diseases: neonatal lupus
erythematosus, dermatomyositis.
Life threatening diseases: Steven Johnson
disease
Hair disorders: hypotrichosis
Genodermatoses: erythrokeratodema,
Nethertons syndrome
INTERNATIONAL PEDIATRIC UPDATE 2004
Interpreting Laboratory Results for
Diagnosing Infectious Diseases
Dr. T. Jacob John
One cannot imagine diagnosing and treating
cardiac, renal or any other organ disorder
without careful laboratory testing for
diagnosis and follow up. But when it comes
to infectious diseases (IDs) there is a
tendency to treat without diagnosis, simply
because a wide variety of antimicrobials are
available. This is a vicious spiral – low
demand, low supply. Thus, when tests are
required, facilities may not be readily
available.
When Laboratory facilities are available,
some pediatricians rely too much on test
results. Too many tests may be a source of
additional income to the institution. A
balance is essential. Norms of diagnosis
with and without laboratory tests must be
available to the practicing pediatrician.
Laboratory diagnosis is essential both for
clinical diagnosis of individual children as
well as for public health needs of
determining the cause of outbreaks.
Sometimes we place undue reliance on
laboratory results, without knowing that the
quality of tests – reagents and procedures
may not be satisfactory. For these reasons,
laboratory results must be interpreted taking
into account all available pieces of
information on the sick child or in the
outbreak, as the case may be.
Even when quality assured, laboratory tests
have accuracy indices less than 100%. In
most instances we live with this problem and
occasionally even go wrong. On some
infections we simply cannot afford to be
wrong. HIV infection is one such. Here,
stringent criteria have been established to
make the laboratory results accurate. When
in doubt, the result is not announced.
The presentation will illustrate other
situations in which results must be
interpreted and also provide clues for the
same.
Kawasaki Disease
Dr Sujata Sawhney, Consultant Paediatric Rheumatologist Centre for Child Health,
Sir Ganga Ram Hospital, New Delhi.
Introduction:
Tomisaku Kawasaki saw his first case of an
unusual 4-year-old child with fever and a
rash in Tokyo in 1961. Over the next 6 years
he saw 50 similar patients and published the
first English report in 1974-a mere four
decades ago. This disease was
characterised by high fever, cervical
lymphadenopathy, conjunctival injection,
red tongue, fissured lips, erythema and
swelling of hands and feet followed by
periungual digital peeling. The association
of these clinical manifestations, initially
71
called Mucocutaneous Lymph Node
Syndrome is now recognised as Kawasaki
disease (KD), the most common systemic
vasculitis in childhood after HenochSchonlein purpura. Controversy raged in
Japan over whether or not KD had any longterm cardiac sequelae, and carried on till
1970, when it was established that KD did
cause coronary artery aneurysms.
In fact, KD is a systemic vasculitis
complicated by coronary and peripheral
arterial aneurysms in 20% to 35% of
untreated patients, and by myocardial
Proceedings & Abstract Book
infarction in a small proportion. In developed
countries it is the most common cause of
acquired heart disease in children and may
also be a risk for adult ischemic heart
disease. Prompt diagnosis is critical and the
early administration of IVIG dramatically
reduces the rate of coronary abnormalities
to less than 5% of patients. Despite efforts
over the last three decades, there is still no
diagnostic test available for KD, and the
diagnosis is based on clinical criteria after
the exclusion of other diseases presenting
with high persistent fever.
Epidemiology:
Although KD has been reported all over the
world, the disease is over expressed among
Asian populations, especially Japanese.
Nationwide epidemiological surveys indicate
that the number of KD patients has gradually
increased in Japan since the last 1960s. The
annual attack rates are 120 to 150 cases
per 100,000 children under 5 years, with
6000-8000 new cases annually. In US
Caucasians the attack rate is 4 to 15 cases
per 100,000. In Europe the annual reported
incidence ranges from 3 to 8 per 100,000
children under 5 years. A recent analysis of
hospital admission data in England shows
that the incidence of KD among English
children has increased between 1991 and
2000. It is possible that this reflects an
increase in recognition rather than
incidence.
Etiology:
The cause is unknown and a search for an
infectious agent has not been successful to
date. An infectious etiology has been long
suspected as the disease has seasonal
peaks, and many of the clinical features are
similar to those of an infectious disease. The
hypothesis that KD could be a super antigen
disease has been widely debated.
Immunopathogenesis:
Activation of the immune system is a central
feature
of
Kawasaki
syndrome.
Concentrations of many proinflammatory
cytokines and chemokines, including
tumour necrosis factor á (TNF á),
interleukins 1, 6, and 8, are higher than
normal during the acute phase of the
disease. Activated monocytes/macrophages
seem to have an important role in Kawasaki
syndrome. These cells have been found in
the vessel walls of patients who died and in
skin biopsy samples from patients in the
72
acute phase of the disease.
Clinical manifestations:
KD is a systemic vasculitis predominantly
affecting children less than 5 years of age.
KD is rare in neonates, but if it occurs, it
may follow a rapid and severe course.
Infants may often present as atypical cases
and commonly experience very severe
inflammatory changes, especially vasculitic
signs. In children older than 8 years of age,
KD mainly affects male and Caucasian
subjects; the diagnosis is frequently delayed
in the acute phase, and the incidence of
coronary artery abnormalities is higher than
in younger children. The fever lasts for at
least five days, but may persist for up to a
month. The sub acute phase lasts for about
a further month, with full recovery in most
patients by day 50.
The typical manifestations of KD are detailed
in table 1. The child must have high fever
lasting more than 5 days without reasonable
explanation and unresponsive to antibiotics
plus
i) Bilateral non-exudative conjunctivitis.
ii) Polymorphous exanthemata.
iii) Bilateral non-suppurative cervical
lymphadenopathy (at least one lymph
node larger than 1.5 cm).
iv) Changes of the extremities: peripheral
edema, peripheral erythema, and
periungual desquamation.
v) Mucous membrane changes (i.e.
injected or fissured lips, redness of
pharynx, strawberry-like tongue).
Fever of five days duration plus four of the
five remaining criteria or the presence of
fever and coronary artery aneurysms (CAA)
detected on 2D- echocardiogram with three
additional criteria are needed for the
diagnosis of complete KD.
Atypical KS is a term that has emerged in
recent years. It is used for those children
who have
1. Fever for at least five days
2. At least two of the diagnostic criteria for
KS
3. Lab finding consistent with significant
inflammation
It has been reported that infants can present
CAA without developing the classic
diagnostic criteria, supporting the evidence
that the disease is often under recognised
or misdiagnosed. Atypical cases of KD are
INTERNATIONAL PEDIATRIC UPDATE 2004
Kawasaki disease
Diagnostic Criteria
Fever
Duration of 5 days or more
plus 4 of the following
Conjunctivitis
Bulbar, non-suppurative, bilateral
Lymphadenopathy
Cervical >1.5cm
Rash
Polymorphous, non vesicles or crusts
Changes of lips
or oral mucosa
Red cracked lips; “strawberry tongue;
diffuse erythema of oropharynx
Changes of
extremities
Initial stage : erythema and edema of
palms and soles. Convalescent stage :
peeling of skin from fingertips
Table 1
common (up to 10% of the total) and the
diagnosis should be considered even
without the full complement of diagnostic
criteria.
Kawasaki syndrome is usually self-limited.
The signs and symptoms usually evolve
over ten days and gradually resolve in most
children even without any specific treatment.
In untreated patients, Coronary Artery
Aneurysms develop in 20%, and notably are
clinically silent in most cases. They are
recognized many years later, because of
myocardial infarction or sudden death.
The eye findings in KD could play a role in
the earlier diagnosis and treatment; the
presence of iridocyclitis and conjunctivitis
provide additional support to the diagnosis
in patients with incomplete KD. Ocular
evaluation is usually mild and bilateral,
sometimes associated with keratic
precipitates, and resolves within 2-8 weeks
without any sequelae. Slit-lamp examination
may be useful in helping to differentiate KD
from diseases that closely mimic the
condition, such as streptococcal and
staphylococcal toxin-mediated diseases
and drug reactions.
Digital peeling, a useful diagnostic hint,
usually occurs 10-15 days from the onset
of typical fever even in children who had
received IVIG. A long-term follow-up of
patients with KD has reported recurrent
episodes of skin peeling for several years
after the disease recovery. It has been
reported only in patients with complete KD
and its significance and mechanisms are still
unknown. It may also be observed in a
number of other conditions caused by
infectious agents and their toxins.
Since the clinical criteria of KD present
sequentially, and often the interval between
73
the appearance of fever and the
development of all clinical manifestations
may be longer than 1 to 2 weeks, it often is
a diagnostic dilemma for the clinician. Other
causes of the non-specific symptoms can
be difficult to exclude. In these patients KD
should be suspected in the presence of high
fever of unknown origin lasting more than 4
to 5 days, and IVIG should be administered
even before diagnostic criteria are satisfied.
Two signs that could help physicians in the
diagnosis, even though it is not included in
the diagnostic criteria are
1. Irritability present in the majority of
children with KD that can be related to
aseptic meningitis.
2. The appearance of erythema and
induration at sites of BCG immunizations
as a useful early diagnostic sign.
In many cases the clinical features of KD
are not all present on any given day. The
challenge for the clinician lies in the ability
to exclude diseases that closely resemble
KD, but need entirely different treatment (for
example disease caused by staph/strep
toxin)
Specific features of KD that confuse the
clinician are as follows:
1. Sterile pyuria misdiagnosed as urinarytract infection
2. Cerebrospinal-fluid
pleiocytosis
misdiagnosed as aseptic meningitis or
partially treated bacterial meningitis
3. Rash misdiagnosed as viral or drug
eruption
4. Cervical lymphadenopathy misdiagnosed
as bacterial adenitis.
Complications that occur in Kawasaki
disease are detailed in table 2
Differential diagnosis:
The differential diagnoses include the
following conditions; they are detailed below
along with the main features that help to
differentiate the illness from KD.
1. Streptococcal infections :
a. Scarlet fever: extensive
lymphadenopathy, no conjunctivitis
b. Toxic shock syndrome: Very sick
child, often with shock even at
presentation
2. Staphylococcal infections Initial erythema
of skin, in later stages there are bullae on
the skin, no mucosal involvement
Proceedings & Abstract Book
List of complications in Kawasaki disease
•
•
•
•
•
•
•
•
•
Irritability and aseptic meningitis
Gallbladder hydrops
Diarrhoea
Hepatitis
Otitis media
Pancreatitis
Myositis
Pericarditis
Aneurysm formation leading to peripheral gangrene,
cerebral infarction and cardiac aneurysm.
Table 2
3. Other viral infections:
a. Measles: Very similar in initial stages.
Usually generalized lymphadenopathy,
in KD more than half have a solitary
lymph gland. Desquamation in
measles does not affect the palms and
soles.
b. Rubella: Usually patients have
generalized lymphadenopathy, and
low grade fever
c. Epstein Barr infections: Older child,
sore throat, and lymphadenopathy.
d. Influenza A, and Influenza B: Fever
duration 3-5 days, upper respiratory
tract symptoms
4. Mycoplasma pneumoniae: Rarely is there
any conjunctival involvement, erythema
of the hands and feet, and oral
involvement.
5. Stevens Johnson syndrome: Erythema
multiforme, erosive mucosal lesions, rash
fades in ten days
6. Systemic onset juvenile idiopathic
arthritis: High fevers, evanescent rash,
serositis, organomegaly and arthritis.
Differential diagnoses for children who fail
to respond to IVIG are: Polyarteritis
nodosa, systemic onset JIA and
malignancies.
Laboratory findings
Recommended investigations in Kawasaki
disease are detailed in table 3
Laboratory findings in patients with
Kawasaki disease include raised white cell
count with neutrophilia, changing to
lymphocytosis by the end of the first week.
By day 14 there may be a hypochromic
anaemia and thrombocytosis.
A moderate-high increase of serum
74
concentration of liver enzymes may occur
in the early stage, unrelated to aspirin
administration. Urinalysis may show
leukocytes and erythrocytes but no bacteria.
CSF contains increased numbers of WBC,
mainly lymphocytes, as expression of
aseptic meningitis.
Lipid profile alterations occur in the early
phase including decreased levels of highdensity lipoprotein (HDL), and cholesterol,
and increased levels of triglycerides. Low
HDL levels may persist over months to years
after the acute phase, and may have a
correlation with Coronary artery aneurysms.
Cardiac investigations:
All children with typical or suspected KD
have to be closely monitored by
electrocardiogram (EKG) and twodimensional echocardiography (2D-echo).
The EKG may reveal arrhythmia, myocardial
dysfunction and ischemia. 2D-echo is useful
in detecting coronary artery dilation and
aneurysms. Ultrasound may reveal
aneurysms and other changes in peripheral
arteries.
The high-risk groups for coronary artery
disease are infants younger than 6 months
of age, and older children with very high
platelet count, high ESR and fever lasting
for more than 2 weeks.
Cardiac monitoring includes 2D-echo at
onset and six to eight weeks after onset of
the disease. However, in order to detect
possible coronary alteration not observed
at the first evaluation, a third 2D-echo study
at 14 days has also been suggested. In
patients with CAA, close follow-up by
echocardiography is mandatory in order to
evaluate the size of aneurysms and to detect
the formation of thrombus.
EKG and 2D-echo studies need to be
tailored to single patient depending on the
size of CAA. Children with giant aneurysms
(diameter greater than 8 mm) require stress
testing to define myocardial function.
Because of the risk of coronary stenosis in
these patients, coronary angiography is also
recommended. Cardiac monitoring reveals
that about 50% of mild CAA normalise within
two years, while 5-year follow-up shows a
complete regression of all CAA.
Unfortunately, giant aneurysms persist in
most patients over time and may evolve in
severe stenosis, myocardial infarction, and
even death. The mortality rate has
completely changed after the introduction
INTERNATIONAL PEDIATRIC UPDATE 2004
List of investigations to exclude Kawasaki disease
•
•
•
•
•
•
•
•
•
•
CBC, and film
ESR and CRP
Blood culture
ASOT
LFT, urea, creatinine
Clotting screen, auto antibody screen
Urine routine for hematuria, and proteinuria
Auto antibody screen
Viral titres: Adeno, Parvo, EBV, CMV.
ECG, ECHO, X-Ray Chest PA.
Table 3
of IVIG, and in Japan it is reported as low as
0.14 %.
Treatment:
It was only in1983 that Japanese
investigators reported that children with KD
treated with IVIG had quicker resolution of
fever, and had fewer coronary artery
abnormalities than historical controls. A
multi center, open-level, randomized trial in
the USA showed that children treated with
IVIG and high-dose aspirin had significantly
faster resolution of fever and other
inflammatory markers than children treated
with high-dose aspirin alone. In addition the
rate of coronary-artery abnormalities among
children with normal echocardiography at
study entry was significantly lower for those
assigned IVIG and aspirin than for those
assigned aspirin alone (3% vs. 15% 7 weeks
after treatment).
Thus a single dose of 2gm/kg IVIG infused
over 12 hours is now the standard therapy
for Kawasaki disease. An epidemiological
survey of more than 5000 patients in Japan
treated with 2 g/kg IVIG showed that patients
treated before day 6 of illness had fewer
cardiac complications at 1 month after onset
of the syndrome than those treated later in
the course of the illness. Any child with
Kawasaki disease, who has evidence of
persisting inflammation, including fever or
high concentrations of inflammatory makers
with or without coronary - artery
abnormalities, should be treated even if the
diagnosis is made after illness day 10.
Administration of live virus vaccines
(measles, mumps, and rubella, or varicella)
should be deferred for at least 11 months
after IVIG administration owing to reduced
immunogenicity of the vaccine related to
75
passive antibodies in the IVIG preparation.
Aspirin is used to reduce inflammation and
to inhibit platelet aggregation in children with
Kawasaki syndrome, although it has no
effect on development of coronary-artery
aneurysms. Currently, high doses of aspirin
(80-100 mg/kg daily divided into four doses)
are used in the acute inflammatory stage of
the disease. There is no consensus on the
dose of aspirin used early on in these
patients with recent recommendations
suggesting using 30-50mg/kg/day, and
others advocating no role at all. If aspirin is
used in the acute phase, the dose is reduced
once the patient has been afebrile for 3-7
days, to a single daily dose of 3-5 mg/kg.
This antiplatelet dose is continued for 4-6
weeks, until the concentrations of all
inflammatory markers have returned to
normal and no coronary-artery damage has
been noted by echocardiography.
Treated of persistent of recrudescent
fever:
10-15% of children diagnosed with Kawasaki
syndrome and treated with high-dose aspirin
and 2 g/kg IVIG will have persistent or
recrudescent fever. If fever persists after the
first dose of IVIG the following steps should
be taken:
1. Reconsider the diagnosis of the Kawasaki
syndrome
2. If it is the diagnosis give a second dose
of IVIG 2 g/kg
3. If after the second dose of the IVIG the
fever persist consider the following
options:
a. Pulsed intravenous methylprednisolone
b. Cyclophosphamide plus prednisone
c. Monoclonal antibodies to TNFα
Treatment of cardiovascular
complications:
The aims of therapy in-patients who have
coronary-artery aneurysms are to prevent
thrombosis and the myointimal proliferation
that lead to stenosis. The treatment
modalities available are:
1. Low-dose aspirin (3-5 mg/kg daily) for
small to medium aneurysms (<8 mm).
2. Antiplatelet agents (eg, clopidogrel )
3. Low-molecular-weight heparins, and
warfarin in the long-term management of
children with gaint aneurysms.
A dedicated pediatric cardiologist should
Proceedings & Abstract Book
carefully follow up all patients with
cardiovascular complications. It is important
for these children to be followed up well into
adult hood, for the blood pressure to be
monitored, stress testing undertaken, and
sport activities to be supervised on the
individual bases. The question remains
whether Kawasaki syndrome is a risk factor
for accelerated atherosclerosis in adulthood.
A registry and structured follow-up study
should be established in each country so
that investigators can to collect data to
address the unanswered questions about
long-term outcome for children, with
Kawasaki syndrome.
Conclusion:
Kawasaki syndrome may contribute to the
burden of adult cardiovascular disease. Until
a diagnostic test is devised, children may
continue to be misdiagnosed and suffer
preventable morbidity and mortality. Like in
many rheumatological conditions the best
cure for Kawasaki syndrome would come
with more research in to the
etiopathogenesis of this sometimes-fatal
childhood affliction.
References:
1. Kawasaki T, Kosaki F, Okawa S, Shigematsu I,
Yanagawa H. A new infantile acute febrile
mucocutaneous lymph node syndrome (MLNS)
prevailing in Japan. Pediatr 1974:54:271-6.
2. Han RK, Silverman ED, Newman A, McCrindle BW.
Management and outcome of persistent or
recurrent fever after initial intravenous gamma
globulin therapy in acute Kawasaki disease. Arch
Pediatr Adolesc Med 2000:154:694-9.
3. Maury CP, Salo E, Pelkonen P. Elevated circulating
tumor necrosis factor-? in patients with Kawasaki
disease. J Lab Clin Med 1989:113:651-4
4. Petty RE, Cassidy JT. Kawasaki Disease. In:
Cassidy JT, Petty RE editors. Textbook of pediatric
Rheumatology, 4th ed. Philadelphia: WB Saunders
Company, 2001: 580-94
5. Newburger JW. Kawasaki disease: who is at risk?
J Pediatr 2000: 137:149-52
6. Hsieh YC, Wu MH, Wang JK, Lee PI, Lee CY, Huang
LM. Clinical features of atypical Kawasaki disease.
J Microbiol Immunol Infect 2002; 35: 57-60
7. Stanley TV, Grimwood K. Classical Kawasaki
disease in a neonate. Arch Dis Child Fetal Neonatal
Ed 2002: 86 (2): F135-6
8. Stockheim JA, Innocentini N, Shulman ST.
Kawasaki disease in older children and
adolescents. J Pediatr 2000: 137: 250-2
9. Brogan PA, Bose A, Burgner D, Shingadia D, Tulloh
R, Michie C, Klein N, Booy R, Levin M, Dillon MJ.
Kawasaki: an evidence based approach to
diagnosis, treatment, and proposals for future
research, Ann Rheum Dis 2002; 86: 286-290
10.Wright DA, Newburger JW, Baker A, Sundel RP.
Treatment of immunoresistant Kawasaki disease
with pulsed doses of corticosteroids. J Pediatr
1996: 128:146-9.
Safer Antipyretics
Dr. C. P. Bansal
Is it really an issue?
Certainly a BIG YES!
Because, “Antipyretics” is The Most
Commonly Prescribed Group among
pediatricians. Nearly every prescription of
ours has one or the other antipyretic. Fever
is the presenting symptom in nearly 80% of
pediatric patient in every setup – OPD,
Indoor or in emergency room. Therefore we
must be concerned about the safety profile
of the members of this group.
Temperature Regulation is done by a
thermostat in the hypothalamus where
equilibrium between Heat Production and
Heat Loss is maintained.
76
Certain Normal Values of Temperature:
• Normal Oral Temp at –
6 A.M.
37.2o C (98.9o F )
4-6 P.M.
37.7 o C (99.9o F)
Variation
0.5 o C (0.9 o F) – 1 o C
• Rectal Temp. –
= 0.6 o C (1.0 o F) > Oral Temp.
I would like to discuss this topic in two heads
1] Antipyretics are safe or unsafe – riskbenefit analysis of the use of the group
as such.
2] Which member of the group is best suited
to infants and children – out of available
INTERNATIONAL PEDIATRIC UPDATE 2004
options?
The risk-benefit ratio of antipyretics:
The dictum that “antipyretics are uniformly
beneficial and safe in febrile illnesses” may
not be entirely true [1]. Some negative
impacts from using antipyretics for
common disease, viral shedding was
found to be prolonged a bit in rhinovirus
infected volunteers [2,3,4], duration of
parasitaemia was found to be increased
mildly [5] specially in Malaria [6]. Thus it
has been opined by some that antipyretic
therapy actually does more harm than
benefit. After several such studies now
enough evidence exists to warrant even
more research into this topic and to cause
clinicians to consider that the risk-tobenefit ratio of these medications may not
be as favorable as once thought. [1]. Few
studies have also concluded that
antipyretics suppress polymorphonuclear
activity.
HARMFUL EFFECTS OF FEVER
1. Fever poses a threat of convulsions.
2. Children are exposed to the risk of
Metabolic Acidosis & Heat stroke
3. Children feel discomfort (parents also
feel discomfort) in a febrile state as their
blood pressure and respiration rate both
are increased and this causes irritation.
4. During fever appetite is lost i.e. kids
become anorexic and due to excessive
evaporative loss of water also become
thirstier leading to dehydration.
5. Studies have proved that in febrile state
O2 Consumption is increased and by
an estimate the increase is 13% for every
degree rise of temperature.
6. Increased requirements of calories and
of fluid in fever can be well expected.
7. Finally a depression of Mental Activitydelirium/stupor can be dangerous
outcomes of high fever – Heat Stroke.
However a recently published study
concludes that the antipyretic drugs at
recommended doses do not suppress
polymorphonuclear function in vitro [7].
Thus treating Fever especially in children
becomes our responsibility and duty, at least
to bring comfort to the patient and parent.
The settling of the first part makes the
second part – “the Safety of Antipyretics”
all the more important.
77
Possible Options
1. Physical Methods
2. Antipyretic Agents ;
• Aspirin (Non selective cox inhibitor)
• Acetaminophen (Paracetamol)
• Ibuprofen (Propionic Acid)
• Nimesulide (Cox 2 inhibitor)
• Mefenamic Acid (Anthranalic Acid
Derivatives)
3. Alternating Antipyretics
4. Combination of Antipyretics
1. Physical Methods
Tepid sponging and fanning have been
effective in the earlier phase only. This
lowering of temperature is present only till
these are continuously done, as they neither
reset the thermostat nor they interfere with
the chemical mediators of fever. Further,
many studies have concluded that the main
aim of the antipyretic therapy is to bring
comfort to the patient and when temperature
is high or is rising, tepid sponging is always
an act of discomfort to the patient. Thus it is
not advisable. However some authors
recommend that a combination of physical
therapy such as tepid sponging and
Paracetamol [8] is best way of controlling
temperature, as till the effect of
PARACETAMOL comes tepid sponging
lowers the temperature. Others are cold
drinks, cold water or saline enema, more
fluid, comfortable, airy environment.
2. Antipyretics
A. ASPIRIN :
Aspirin is the most widely used and is
probably one of the oldest drug, with more
than 80 billion tablets consumed a year, in
the United States alone, as well as being
listed as the active ingredient for more than
50 other drugs. Records show it was in use
more than 2,000 years ago. Yet full
implications of the effects of this drug are
still to be realized. Aspirin is commonly
known as “The Wonder Drug”.
When we were students every prescription
of our worthy consultants used to contain
Aspirin. Its therapeutic effects were so good
that even today in clinical use the effect of
Paracetamol or any other antipyretic or
analgesic are judged as “effect equivalent
to aspirin”. But when it’s association with
the Reye’s Syndrome and other serious side
effects on blood and on gastric mucosa
Proceedings & Abstract Book
were confirmed, its use as antipyretic was
abandoned.
B. PARACETAMOL :
It has a clinical standing and a safety profile
of more then 50 years.
• It is today the most popular home
medicine.
• Its analgesic (pain relief) and antipyretic
(fever relief) effects are comparable to
those of aspirin.
• There are virtually no groups of people
who should not take it.
• Interactions with other treatments are not
a problem.
• At the recommended dosage there are
virtually no side effects.
• It is suitable for small children and the
elderly.
• It can be taken by those sensitive to
aspirin.
• It is well tolerated by patients with peptic
ulcers.
Dosage:
Previously it was 10mg/kg then came
recommendations of 15mg/kg (4 hrly)
Maximum 90mg/kg day, recently it has been
postulated that initial dose of 30mg/kg with
a maintenance dose of 15mg/kg brings
about better antipyresis [9].
Toxic dose is 150mg/kg – only possible –
by homicidal/suicidal intentions and that too
in elderly. However, there has never been a
problem of serious accidental overdose with
paracetamol in the under fives. [10, 11] The
Paracetamol toxicity is treated with - Nacetylcysteine (NAC) (Parvolex).
Mechanism of Action:
As with many medicines, the effectiveness
of Paracetamol was discovered without
knowing how it works. Over 100 years after
it was first discovered, we are now learning
its mechanism of action which makes
paracetamol such an effective and useful
medicine. Paracetamol has no significant
action on COX-1 and COX-2, this explains
its lack of anti-inflammatory action and also,
more importantly, its freedom from
gastrointestinal side effects typical of
NSAIDs.
Recent research (13) has shown the
presence of a new, previously unknown
cyclooxygenase enzyme COX-3, found in
78
the brain and spinal cord, which is
selectively inhibited by paracetamol, and is
distinct from the two already known
cyclooxygenase enzymes COX-1 and COX2. It is now believed that this selective
inhibition of the enzyme COX-3 in the brain
and spinal cord explains the effectiveness
of Paracetamol in relieving pain and
reducing fever without having unwanted
gastrointestinal side effects.
Paracetamol And Asthma
Paracetamol is not known to be linked with
asthma. Indeed, Paracetamol is the
preferred analgesic for asthma sufferers,
because NSAIDs are much more likely to
precipitate asthma attacks and are to be
avoided by asthma sufferers. [14]
C. IBUPROFEN :
Ibuprofen is a non-steroidal antiinflammatory drug with established
analgesic, anti-inflammatory and antipyretic
properties. Dose 7.5 Mg/Kg to 10 Mg/Kg6-8 Hrly, Max. 40 Mg /Kg /Day
Ibuprofen was first approved in the UK in
February 1969 and has been one of the most
heavily prescribed non-steroidal antiinflammatory drugs (NSAIDs) since then. It
was launched in the UK as an over-thecounter (OTC) medicine, in 1983 and is now
widely used in self-medication. A switch to
General Sales List (GSL) status in the UK
was obtained in January 1996. A large safety
study involving 84,000 children showed a
similar safety profile for ibuprofen and
paracetamol[12,15] .
As antipyretics it has not been preferred over
Paracetamol because –
1. It is thought to have less antipyretic
property
2. It’s association with asthma.
3. Renal side effects & complications.
Thus it was supposed to be relatively slightly
more toxic then Paracetamol.
However few recent (all dependable
Randomized Control Trials or Double Blind)
studies have proved it to be better than
Paracetamol. [16,17,18,19,20]. It is found to
be longer acting, yielding significantly better
antipyretic effect after four hrs of initial dose
than paracetamol. But it is a fact that its
antipyretic activity is, if not better, then at
least equal to paracetamol by all. Maximum
reduction of temperature occurs 3-4 hours
after administration, has a greater half life
INTERNATIONAL PEDIATRIC UPDATE 2004
then Paracetamol – so 8 hourly convenient
doses are possible. [21,22]
Ibuprofen has clear edge over Paracetamol
in conditions like – flu like syndrome, URIs,
Otitis Media, Pneumonias, Septic Arthritis
and all other inflammatory febrile conditions.
The next allegation on Ibuprofen about its
association with asthma & renal
complications (as other NSAIDs) has also
been negated by recent authenticated
studies [23,24]. Its safety in children below
two years of age has also been documented
[25]
D. NIMESULIDE :
Nimesulide was introduced in 1985 in Italy,
in India in the early nineties and soon
became the best selling anti-inflammatory
drug. There are over 150 Nimesulide brands
available in the market and are often
prescribed to bring down high fever in
children and as an anti-inflammatory drug
amongst elders. Ironically, Nimesulide
world over is only prescribed for
musculo-skeletal pains.
This could be the main reason why no
multinational drug firm has launched this
drug in India. The product has combined
sales in excess of Rs 270 crore annually.
The reasons for this tremendous take off by
the drug are its potent anti-inflammatory
effect, better compliance & wide range of
formulations.
Properties of the Nimesulide
- Nimesulide is a non-steroidal antiinflammatory drug (NSAID) with analgesic
and antipyretic properties and a specific
mode of action, similar to selective COX
2 inhibitor. It is weak inhibitor of
Prostaglandin synthesis and also inhibits
leukocyte function.
- Its dose is 2.5mg/kg and can be given
twice a day – Maximum dose is 5mg/kg.
- It is generally well tolerated by the
children
- Nimesulide is currently marketed in 50
countries. It is available as tablets,
suppositories and topical gel. In some
countries also oral drops and oral
suspension are/were on the market.
I would like to discuss the controversy about
Nimesulide in a bit detail.
Though Nimesulide is a preferential COX-2
inhibitor and therefore, assumed to be safer
79
in clinical use, its gastrointestinal tolerance
has not been proven to be superior to other
NSAIDs because “various epidemiological
studies give little weight to the hypothesis
that selective inhibition of COX-2 may have
a sparing effect on the GI Tract” [26,27].
Why the current controversy?
Nimesulide was aggressively promoted in
India and attained the top position as antipyretic in private practice. But recently the
status of Nimesulide has become
questionable following reports of fatal
adverse drug reactions (ADR). The National
Pharmacovigilance Centre (CNF, Portugal)
from 1993 to 99 [28] received 17 ADR
reports of Nimesulide, which included ;- skin
(five), hepatic (four), peripheral edema (two),
stomatitis (two), paraesthesia (one),
thrombocytopenic purpura (one), irritability
(one) and headache/reduced visual acuity
in (one).
From the hepatic ADRs, two, which occurred
in children, were compatible with Reye’s
syndrome and both resulted in fatality. Also
seen was one case of cholestasis and
another of liver enzyme elevation and
coagulopathy, the later being fatal. Another
report informed three cases of fixed drug
eruptions with Nimesulide [29].
Nimesulide induced liver injury usually
presents with hepatocellular necrosis or
cholestasis. Many cases of Nimesulide
induced hepatotoxicity (some even fatal)
have been reported [30 to 47]. Patients with
liver toxicity typically revealed features of
hypersensitivity i.e. an increase in blood and
tissue eosinophilia. This indicates that both
immunological and metabolic idiosyncratic
reactions can be involved as the
pathogenetic mechanism of Nimesulide
induced liver disease. Neonatal renal
failure following the use of nimesulide has
been reported [48].
Even if the risk of hepatotoxicity is small and
fatality rare, nimesulide use for fever
particularly in children cannot be justified
when safer alternatives like p
aracetamol and ibuprofen are available.
We all should be aware of the fact that due
to its toxicity, ADRs and suspected danger,
Nimesulide has never been licensed for use
in developed economies like US, Canada,
UK, Australia, New Zealand and
Scandinavian countries.
Small countries like Portugal, Israel and our
Proceedings & Abstract Book
neighbors Sri-Lanka and Bangladesh have
shown the guts and grit to withdraw the
drug. Nimesulide was withdrawn in 2002 by
the innovator, Boehringer from Spain and
Finland. The European Union has recently
issued a precautionary advice on the
marketing of this drug following serious
complications after its use.
Medical activists highlighted the rampant
misuse and overuse of Nimesulide, and its
ADRs leading to fatalities in children through
various media, including cable TV. Letters
appeared in press warning the Nimesulide
users of its toxicity [49].
It is a matter of great concern that while other
countries have banned the sale of this drug,
the Drug Controller-General of India (DCGI)
merely ordered a review of this drug. The
DCGI has gone on record to admit that due
to powerful commercial interests, it might
be difficult to get objective answers even
from doctors. True to the anticipated fears,
Delhi Medical Association has declared
Nimesulide safe [50] Criticizing this act of
DMA, leading pediatricians and
neonatologists of India have questioned the
validity of this survey from merely fifty
doctors of Delhi who gave clean chit to
Nimesulide.
Editor of Monthly Index of Medical
Specialties (MIMS) has rightly pointed that
ADR monitoring is not done by any
professional body of doctors in the world
[51]. Industrial interests surely prevail over
professional ethics and obligations.
Not surprisingly, to the tune of DCGI, Delhi
High Court has issued a clean chit to
nimesulide in response to the PIL filed by a
true medical activist. This judgment and the
decision of the DCGI were mainly based on
the IAP declaration “it is as safe or unsafe
as other…” which again is based on just one
study conducted in Delhi. This certainly has
earned a bad name for IAP [51] in the
leading news papers of the country.
However as against this judgment of Delhi
High Court; recently The European Medicine
Evaluation Agency (EMEA) has disallowed
the use of Nimesulide by children below the
age of 12 years in all its member-countries.
They have reached this conclusion only after
a 16-month long review of the controversial
drug by experts drawn from European Union
member states [52]. Following this decision,
India is the only country where nimesulide
is being marketed for use not only by
80
children, but also by infants below the age
of one year [52].
Result of this Controversy:
Despite the clearance from the DCGI and
High Court and despite the intense lobbying
from the drug manufacturers, the outcry of
media and activist doctors have made the
common practioner of India genuinely
worried and they are now gradually shifting
away from Nimesulide [52]. Hereunder are
some figures that will prove this statement• It had a growth rate of seven % in October
2002 and is now degrowing at minus 1%.
• Faster negative growth rates are
predicted in the coming months,
according to experts.
• In comparison to October 2002, the sale
of two most popular brands of pediatric
tablets declined by 52.4 % and 44 %
respectively.
• The pediatric suspensions of these two
brands witnessed a decline of 22 % and
29 % respectively.
• According to a survey by AC NielsenORG-MARG, annual turnover figure for
Nimesulide in Oct. 2002 was at Rs 200
crore. It declined by 20 % by March 2003;
further sales went down by around 17 %
in June 2003.
Birth Story of Nimesulide [53]
It is very important to know the origin and
background of this drug. Nimesulide has
been developed and licensed by Helsinn
Healthcare SA, Switzerland, which acquired
the exclusive worldwide rights for the drug
in 1976.
1. Nimesulide was discovered by 3M
Pharmaceuticals, an American
manufacturer at St. Paul, Minnesota,
United States. Therefore the origin of the
molecule is United States, where it is not
approved.
2. 3M Riker - the parent company of 3M
Pharmaceuticals - It sold the molecule to
a private company in Switzerland called
Helsinn. Helsinn, instead of launching
Nimesulide in Switzerland, licensed the
drug to Boehringer in Italy where it was
launched in 1985. In Italy, it is licensed
for use only in musculo-skeletal
inflammation and accompanying pain
(not as an anti-pyretic). Its use in children
below 6 years is prohibited.
3. Nimesulide was launched in Switzerland,
INTERNATIONAL PEDIATRIC UPDATE 2004
the home country of Helsinn, in 1995 i.e.
10 years after Italy.Based on the human
data from Italy, the Swiss Government
permitted its use in adults only. Its use in
children below 12 years is prohibited.
Some other Facts [54] :
4. Everyone connected with pharma
business around the world knows that
introducing new molecules in USA,
Britian, Australia, Denmark etc. is not very
easy while it is not very difficult in Italy
and Brazil.
5. Today Nimesulide is licensed for use in
fewer than 40 countries. In other words
its use is not permitted in over 150
countries.
6. India is the ONLY country on earth where
Nimesulide drops were marketed for use
in neonates and infants. The only two
countries where nimesulide is permitted
in children are Italy and Brazil and even
there its use is prohibited below 12 and
3 years of age respectively.
7. As per Rule 122 (E) of the Drugs &
Cosmetics Act read with Schedule Y, all
drugs require mandatory prior permission
from Drugs Controller, India (DCI). Fresh
permission is required if a new
formulation of approved drug is to be
launched such as sustained release etc.
In India only two formulations are
approved i.e. 100mg tablet and 50mg/5ml
suspension. The following formulations
are being marketed without the
permission from Drug Controller of India50mg tablets for kids, 25mg/ml drops,
200mg tablets, 400mg tablets, 100mg
EF tablets, 100mg MD tablets. Even
when one company obtains permission
for any formulation, another company
needs fresh DCI approval if introducing
the same drug within 4 years. Over 170
companies in India are marketing
nimesulide single ingredient formulations
without mandatory DCI approval.
8. ALL fixed-dose combinations of
Nimesulide with other agents such as
Paracetamol, Diclofenac, Tizanidine etc
are being marketed without mandatory
DCI approval. This fact has been admitted
by DCI in reply to a question in Loksabha
on 20-08-2000. India is the ONLY country
on earth where Nimesulide with other
agents is being marketed.
9. The retail price of Nimesulide for 10
tablets ranges between Rs. 14.50 to Rs.
81
29. It is not the cheapest “analgesic” or
“antipyretic.” It is about 200 to 400%
more expensive. Besides, the basic cost
price of 10 tablets of Nimesulide 100mg
is Rs. 1.80. As per ORG-MARG data,
no other NSAID has such a huge profit
margin.
10. Several laboratory, animal and human
studies in Canada and USA have shown
that Nimesulide is partially, but not fully,
COX-2 Selective. Besides, NIMESULIDE
INHIBITS COX-1 MUCH BEFORE AND
AT MUCH LESSER SERUM LEVELS.
Thus it is not gastro-protective. This was
one of the reasons for aborting an
attempt to get USFDA approval in 1998.
11. All studies submitted to DCI in India by
manufacturers of Nimesulide were
sponsored and financed by Helsinn many of them actually written by Helsinn
employees.
Equipotent single dose of Antipyretics
[55]
Paracetamol, 10 -15 mg/kg, 4-6 Hrly
Ibuprofen 8-10 mg/kg 6 -8 Hrly, and
Nimesulide is 2.5 mg/kg 12 Hrly
Therefore in practice, practically,
underdosing of Paracetamol and
overdosing of Nimesulide becomes
unavoidable and hence parents and
physicians feel that Paracetamol does not
work while Nimesulide never fails - This has
resulted in overuse of Nimesulide, which has
nearly replaced Paracetamol in clinical
practice. Strong and often unethical
marketing practices have contributed to
such a scenario. Considering practical
issues beyond Nimesulide as an antipyretic
is best avoided.
Alternating Antipyretics:
It has been a common practice to use two
different antipyretics with full therapeutic
dose alternating both of them in one patient
in a particular febrile episode – this is not
an ethical practice [56, 57, 58, and 59]. If
need arises then the same antipyretic should
be used again – this makes PARACETAMOL
a preferable Antipyretic as it can be repeated
after 4 hours while ibuprofen after 6 hrs
however it again keeps nimesulide as it can
only be repeated after 12 hours. This
practice can lead to confusion in parents
and chances of toxic overdose increases –
further chances of renal complications are
Proceedings & Abstract Book
increased especially if child is dehydrated.
4. Combination of Antipyretics
Combinations of antipyretics (fixed dose)
are totally irrational. They result in doubling
of the dose. Further no two Antipyretics have
similar frequency of administration thus their
administration together is unethical .The
practice of combining them with other
agents like metoclopromide with an idea to
potentiate their effect is also not evidence
based.
Conclusions
1. We should do not let “Fever Phobia” rule
our mind.
2. Treat Fever above 101F
3. Physical methods are of limited value and
are discomforting to child.
4. Ibuprofen is coming up as still better then
Paracetamol
5. Nimesulide as Antipyretic should better
be avoided.
6. Use one Antipyretic in proper
recommended
doses
and
in
recommended intervals if needed.
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34. Liver toxicity due to Nimesulide is well known, but
to our knowledge the occurrence of haemolytic
anaemia has not been related to this drug
previously. For these reasons, Nimesulide has
been restricted or removed from the market in
several countries in recent months.
35. Weiss P. Nimesulide-induced hepatitis and acute
liver failure. Isr Med Assoc J. 1999 Nov;1(3):221
36. Merlani G, Fox M, Oehen HP, Cathomas G, Renner
EL, Fattinger K, Schneemann M, Kullak-Ublick GA.
Fatal hepatoxicity secondary to Nimesulide. Eur
J Clin Pharmacol. 2001 Jul;57(4):321-6.
37. Ferreiro C, Vivas S, Jorquera F, Dominguez AB,
Espinel J, Munoz F, Herrera A, Fernandez MJ,
Olcoz JL, Ortiz de Urbina J. Toxic hepatitis caused
by Nimesulide, presentation of a new case and
review of the literature. [Article in Spanish]
Gastroenterol Hepatol. 2000 Nov;23 (9):428-30.
38. Schattner A, Sokolovskaya N, Cohen. Fatal
hepatitis and renal failure during treatment with
Nimesulide. J. Rehovot, Israel. J Intern Med. 2000
Jan; 247 (1):153-5.
39. Tejos S, Torrejon N, Reyes H, Meneses.Bleeding
gastric ulcers and acute hepatitis: 2 simultaneous
adverse reactions due to Nimesulide in a case
[Article in Spanish] M. Rev Med Chil. 2000
Dec;128 (12):1349-53.
40. Ozgur O, Hacihasanoglu A, Karti SS, Ovali E
Nimesulide-induced fulminant hepatitis. Turk J
Gastroenterol. 2003 Sep;14(3):208-10.
41. Traversa G, Bianchi C, Da Cas R, Abraha I, MennitiIppolito F, Venegoni M. Cohort study of
hepatotoxicity associated with Nimesulide and
other non-steroidal anti-inflammatory drugs. BMJ.
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A. Nimesulide-induced acute hepatitis. [Article in
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probably induced by Nimesulide [Article in
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592-3.
45. Gallego Rojo FJ, Fernandez Perez F, Fernandez
Perez R, Porcel A, Blas JM, Diez F. Nimesulideinduced hepatotoxicity. [Article in Spanish]. Rev
Esp Enferm Dig. 2002 Jan: 94(1): 41-2.
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E, Sinapidis D. Nimesulide-induced acute
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47. Perez-Moreno J, Llerena Guerrero RM, Puertas
Montenegro M, Jimenez Arjona MJ.Gastroenterol.
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EMEA,ban: Nimesulide market slips further
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Gulhati, Editor, MIMS
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Proceedings & Abstract Book
Long-Term Benefits of
Breastfeeding
Dr. Armida Fernandez, Retired Prof of Neonatology & Ex Dean, LTMG Hospital &
L.T.M.M College, Sion, Mumbai
Human milk is the ideal food for a baby and
provides all the nutrients necessary for
growth and development. Extensive
research has documented compelling
evidence that the benefits of breastfeeding
continue through infancy, childhood &
adulthood. This article will highlight the longterm benefits of breastfeeding for the baby
and the mother.
In addition to proteins, carbohydrate and
fats necessary for the growth of the baby,
breast milk is replete with protective factors
and bioactive substances, which enhance
the development of the gut and play an
important role in immuno-protection of the
baby. Besides the active role of breast milk,
alternatively early introduction of artificial
milks and foods increases the risk of chronic
disease in adulthood.
Evidence suggests that breastfeeding
reduces the risk of insulin dependent
diabetes mellitus, childhood cancer, obesity
& inflammatory bowel disease. There is also
evidence to suggest that breastfeeding
improves intelligence and cognitive
functions particularly in preterm babies. The
protective effect of breast milk on long term
diseases is probably related to the
abundance of bioactive factors including
secretory antibodies, leucocytes, lipids,
carbohydrates as well as other anti
inflammatory agents & compounds that
modulate the immune response such as
prostaglandin’s, hormones enzymes,
cytokines and growth factors (1) The
breastfed baby is also protected by the
absence of large foreign proteins before gut
closure, before the development of oral
tolerance and before immune system
maturation. Besides a breastfed baby is also
protected against infection & inflammation.
There may be critical window period for
exposure to certain proteins for children with
certain risk profiles that increases the risk
for autoimmune disease.
84
Insulin Dependent Diabetes Mellitus
(IDDM)
IDDM is an autoimmune disease determined
by a complex of factors both genetic and
environmental in origin. The risk of
developing IDDM in childhood may be
influenced by infant feeding practices. The
relationship of IDDM to breastfeeding was
first described by Borch-Johnson in 1984
when he reported an increased risk of IDDM
in children who were breastfed for less than
three months. (3) There is sufficient data
available today relating feeding practices to
IDDM (4) (5). Complex biochemical,
hormonal, anti-microbial and antiinflammatory substances present in human
milk influence the development of the gastro
intestinal tract and the developing immune
system, much of which is in the gut.
Introduction of artificial feeds in the first three
to six months increases the risk of IDDM in
genetically susceptible children by providing
early exposure to foreign proteins and
depriving the infants from the complex
immuno- activity of breast milk (6)
Factors associated with increase risk of
IDDM in genetically susceptible infants
include
a) Breastfeeding duration of less than three
months
b) Early introduction of cow’s milk
c) Early introduction of solids
A meta analysis of case – control studies
carried out by Gerstein demonstrated (4) the
relationship of breastfeeding for less than 3
months and the development of IDDM. (7).
There was a much stronger correlation in
children who developed IDDM before four
years of age.
Celiac Disease
Celiac disease is an auto immune
enteropathy resulting from a genetic
susceptibility and dietary exposure to gluten.
INTERNATIONAL PEDIATRIC UPDATE 2004
Studies indicate that the incidence of celiac
disease decreased in those babies who
were breastfed when gluten was introduced
(8)(9). There was a delayed onset of the
disease in those who were breastfed for a
longer duration and babies who were
exclusively breastfed.
Childhood Cancer
A number of case controlled studies have
found an association between artificial
feeding and increased risk of childhood
cancers i.e lymphoma and leukemia (10)
(11) (12)
There is also experimental evidence that has
shown apoptosis of cancer cells in human
milk. This is a result of selective activity of
multi meric ± lactalbumin which is
described as potent Ca++ at elevating and
apoptosis inducing agent with broad yet
selective cytotoxic activity. Normal cells are
not affected. This protein most abundant in
human milk is created in the acid
environment of the gastro-intestinal tract.
Inflammatory Bowel Disease & Ulcerative
colitis and Chrons disease
The causes of these diseases remain
unclear and are probably multi factorial.
Available case control studies suggest that
inflammatory bowel disease was less likely
in babies who were breastfed as compared
to controls (14) (15) Hypothesis relate
association to the protective action of
breastfeeding against gastro intestinal
infections and the early development and
maturation of the gut.
Obesity
There is increasing evidence relating early
infant feeding practices to obesity (16). Case
control studies in an adolescent clinic
showed a significantly high risk for obesity
in those infants who were not breastfed (17).
Bioactive substances in breast milk may
influence adi pocyte differentiation and
proliferation. The infant’s ability to regulate
intake differs between babies who are
breastfed and artificially fed which may alter
later regulation of food intake that may result
in obesity.
Breastfeeding and Neurodevelopment
Breastfed children have a better
neurodevelopment outcome (18, 19). A
number of factors could be responsible
which include biological, nutritional, genetic
85
or a combination of factors. There is some
evidence that supports a nutritional role.
Breast milk contains Docohexanoic &
arachnadoic acids, long chained polyunsaturated fatty acids. Large quantities of
these are used in the growing brain of the
fetus and the neonate. The placenta is a
source of fatty acids in the fetus. After birth,
baby is dependent on the LCFA present in
human milk. This is particularly relevant to
the preterm baby who has been born early.
Photo receptor membranes in the retina also
have highest concentration of DHA.
Maturation of visual system may be affected
in preterm babies who have not received
breast milk.
A meta analysis of various studies on
cognitive outcome in babies showed a
higher score in breastfed babies starting as
early as two months which continued
through childhood at 10-15 years of age
(20). Duration of breastfeeding correlated
with development and cognitive outcome.
Lucas’ long-term study of preterm babies
showed a significantly higher IQ in preterm
babies who had received breast milk (21)
Atopy & Asthma
Atopic disease is a common health problem.
Environmental exposure in early infancy
may be particularly important for
sensitization and later development of atopy
probably because of physiological
immaturity of the immune system. As in
other immune disorders breast milk has a
protective role in atopic disease. Studies
have shown that prolonged breastfeeding
is prophylactic against atopic disease
throughout childhood & adolescence (22).
Other long-term benefits for the baby
Breastfeeding also offers protection against
otitis media, attributed to the factors present
in breast milk itself or the harmful effects of
bottle-feeding. Studies have shown that this
protective effect is related to duration of
breastfeeding and lasts for a year after
breastfeeding has stopped. (24)
A systematic review of studies on the effects
of infant feeding on cholesterol in infancy
childhood, adolescence & adulthood
concluded that breastfeeding is associated
with increase in Total Cholesterol & Low
Density Lipoproteins in infancy but with
lower levels in adulthood. This suggests
long-term benefits of breastfeeding for
cardiovascular health (25)
Proceedings & Abstract Book
Long-term benefits of Breastfeeding for
the Mother
Hormones of breastfeeding aid in
adjustment to mothering, conservation of
energy and in subsequent nutrient recovery.
Long-term benefits include decreased risk
of pre-menopausal breast cancer epithelial
cancer of the ovary and reduced risk of
spinal and hip fractures after menopause.
The relative risk of pre-menopausal breast
cancer decreases with the duration of
breastfeeding (26,27). Initiation and
physiological completion of breastfeeding
during two to seven months postpartum is
associated with decrease in ovarian cancer.
(28)
Clinical studies show bone loss during
lactation and paradoxically positive effects
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of significantly longer periods of
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50
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(27) Nduati R, John G, Mbori-Ngacha D, et al: Effect of
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(29) John E.M, Whittemore AS, Harry R, Itnyre J.
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