Japi 07.2015 PDF

Journal of The Association of Physicians of India Vol.
63 July 2015
11
editorial
First the ESBLs, now the Carbapenemases:

Where will it End?
Rajeev Soman1, Anjali Shetty2, Camilla Rodrigues2
h e s e e - s a w b a t t l e b e t we e n
humans and microbes
con t i nues. Ex t ended Spectrum
Beta-lactamases (ESBLs) in Gramnegative Bacteria (GNB) emerged
in the past two decades as a major
public health challenge. They
spelt disaster for 3 rd generation
Cephalosporins and Aztreonam.
Organisms harbouring them
were frequently co-resistant to
Fluoroquinolones (FQN) and
Aminoglycosides further curtailing
treatment choices. Although
ESBL producing organisms were
susceptible to Carbapenems and
Beta-lactam plus Beta-lactamase
inhibitor combinations (BL-BLI)
it was recommended to use
Carbapenems in preference to
BL-BLI due to the perceived
inferiority of the BL-BLI. This was
attributed to the inoculum effect,
co-existence of other resistance
mechanisms that are not inhibited
by inhibitors, animal data and
some human observational studies
showing poor outcomes.1 The
preferential use of Carbapenems
would have been reasonable
w h e n E S B L o r g a n i s m s we r e a
rarity and confined to the hospital.
H o we ve r t h e y r a p i d l y s p r e a d
through the networks of bacterial
populations so that a large
proportion of even communityacquired infections were due to
ESBL producing organisms.
out and the kinetics of the drugs

ensured penetration at the site
of infection. We had suggested
that Carbapenems should be
restricted both for reasons of cost
and selection of Carbapenemresistant organisms. 3 This was
subsequently borne out by studies
across the globe,4 although
there are conflicting studies5
and opinions. 6 In the absence of
randomized controlled trials, an
appraisal of treatment schemes
has to be, necessarily, based on
retrospective, observational case
series. The question, as always, is
maximizing the outcome for the
individual patient and minimizing
the selection of further resistance.
Keeping this in mind, we had

explored the role of BL-BLI in these
infections with a view to spare
Carbapenem use. 2 We found that
it was possible to treat successfully
at least the less serious infections,
where source control was carried
The dangers of overuse of

Carbapenems, and indeed of any
antimicrobial, are obvious. The
There has been a recent lowering

of break points to identify the
truly susceptible organisms
that can be treated with BL-BLI.
Besides, there is a trend of
optimizing Pharmacokinetic and
Pharmacodynamic (PK PD) indices
with high-doses and prolonged
infusions of Beta-lactams. These
factors will undoubtedly help
to achieve success with BL-BLI.
Thus inhibitors may still protect
Beta-lactams, patients and the
environment. Should we be
using such Carbapenem sparing
strategies both for initial treatment
and for de-escalation or are we too
late and have the Carbapenems
already met their doom? 7
study results by Shah et al 8 is an

indication of what is to come in
future. They needed only 4 months
to collect 42 Carbapenem-resistant
Enterobacteriaceae (CRE) isolates
from blood culture. Prior antibiotic
use was present in the vast majority
of these patients. It is not clear
h o we ve r , w h e t h e r t h e i s o l a t e s
were also obtained from peripheral
venepuncture with a differential
time to positivity (DTP) of more
than 2 hours. This is an important
clinical parameter indicating a
b lood-st ream infect i o n . Gra mnegative bacilli otherwise are often
colonizers of the central venous
catheter. The clinician must make
an effort to rule out colonization
by the resistant organism. Not
treating a colonizer and saving
antimicrobial use is an important
component of good stewardship.
Whilst patients in this study 8
were treated with Colistin and
Colistin combinations, as is the
case elsewhere, these last resort
strategies may not hold out much
longer. Colistin, Tigecycline,
Fosfomycin, Aminoglycosides need
active companion drugs due to their
own individual limitations. The
best combinations and dosaging
strategies to treat such infections
have yet to be unravelled. The
scientific world is looking to the
areas of high endemicity such as
the Indian subcontinent to produce
good quality evidence to advise on
these issues.
We certainly need new antibiotics
Consultant Internal Medicine and Infectious Diseases, 2Consultant Microbiologist, PD Hinduja Hospital and
Medical Research Centre, Mumbai, Maharashtra
12
Journal of The Association of Physicians of India Vol. 63 July 2015
with novel mechanisms of action.

However we submit that merely
having new antibiotics will not
solve the problem. We need to
introspect why some of the highest
rates of resistance are found here.
Poor sanitation, overcrowding,
sparse diagnostic facilities,
growing healthcare expectations
with scant attention to infection
control practices, easy availability
of antibiotics, lack of awareness
of antimicrobial resistance issues
have all to be addressed at various
levels.
References
1.
Harris PNA, Tambyah PA, Paterson DL.

Beta lactam and beta lactamase inhibitor
combinations in the treatment of extended
spectrum beta lactamse producing
Enterobactereiaceae: time for a reappraisal
in the era of few antibiotic options? Lancet
Infect Dis 2015; 475-85.

2.
Patel V, Soman R, Rodrigues C, Singhal T,

Mehta A, Dastur FD. Outcome of Treating
Infections due to ESBL Producing Organisms
with Non-Carbapenem Antimicrobials A
Prospective Observational Study. Poster
1100. Program and Abstracts of the 45th
Annual Meeting of the Infectious Diseases
Society of America. San Diego, California.
Oct 3-7, 2007
3.
Trivedi M, Patel V, Soman R, Rodrigues C,

Singhal T. The outcome of treating ESBL
infections with Carbapenems vs Non
Carbapenem Antimicrobials. J Assoc Phy
Ind 2012; 60:28-30
4.
Rodriguez-Bano J, Maria DN, Pilar R,

Encarnacion P, lvaro P and the ExtendedSpectrum Beta-LactamasesRed Espanola
de Investigacion en Patologa Infecciosa/
Grupo de Estudio de Infeccion Hospitalaria
Groupa. Beta-Lac tam/Beta-Lac tam
Inhibitor Combination for the Treatment
of Bacteremia Due to Extended-Spectrum
b-LactamaseProducing Escherichia coli: A
Post Hoc Analysis of Prospective Cohorts.
Clin Infect Dis 2012; 54:16774.

5.
Tamma PD, Han JH, Rock C, Harris AD,

Lautenbach E, Hsu AJ, Avdic E, Cosgrove SE.
For the antibacterial resistance leadership
group. Carbapenem therapy is associated
with improved survival compared with
piperacillin-tazobactam for patients
with extended-spectrum -lactamase
bacteremia. Clin Infect Dis 2015; 60:1319-25.
6.
Perez F, Bonomo RA Can We Really Use

-Lactam/- Lactam Inhibitor Combinations
for the Treatment of Infections Caused
by Extended-Spectrum -Lactamase
Producing Bacteria? Clin Infect Dis 2015;
60:1326-9.
7.
Deshpande P, Shetty A, Kapadia F, Hedge A,

Soman R, Rodrigues C. New Delhi Metallo
1: Have Carbapenems Met Their Doom?
Letter. Clin Infect Dis 2010; 51:12221222.
8.
Shah PG, Shah SR. Treatment and Outcome

of Carbapenem-Resistant Gram-Negative
Bacilli Blood-Stream Infections in a
Tertiary Care Hospital. J Assoc Phy Ind 2015;
63:14-18.
14
Original Article
Treatment and Outcome of CarbapenemResistant Gram-Negative Bacilli Blood-Stream

Infections in a Tertiary Care Hospital
Pooja G Shah1, Sweta R Shah2
Abstract
Editorial Viewpoint
Context: Infections caused by carbapenem-resistant bacteria constitute

a major challenge for current medical practice.
G r a m - n e g a t i v e b a c i l l i
(GNBs) are adding to
the menace by causing
carbapenem resistance as
supported by this study.
Objective: To describe treatment and outcome of carbapenem-resistant

Gram-negative bacilli (GNB) blood-stream infection (BSI) caused by these
organisms at a tertiary care hospital in Mumbai.
Methods: Carbapenem-resistant isolates from blood cultures were
collected from January 2013 to April 2013. Identification and antimicrobial
susceptibility testing were performed using Vitek 2 analyzer (Biomerieux
Ltd.). Carbapenemase production was detected by modified Hodges test
(MHT). Patients medical history, treatment and co-morbid conditions
were noted. Outcomes of BSIs were evaluated.
Results: Forty-two isolates of carbapenem-resistant GNB isolated from
BSIs were Enterobacteriaceae spp. (19), Acinetobacter baumannii (15),
and Pseudomonas aeruginosa (8). Colistin had maximum in vitro activity
with 97% against Enterobacteriaceae, 100% against Acinetobacter, and
100% activity against Pseudomonas aeruginosa isolates. Positivity of MHT
was 92.9%. Outcome of colistin mono and combination therapy was
comparable with 83% and 79%, respectively. Outcome of colistin and
carbapenem combination therapy was found to be 100 percent.
Conclusions: High incidences of bacteremia by carbapenem-resistant
GNB including Enterobacteriaceae is a worrisome trend. Treatment options
are compromised and only available option is colistin which has its
own limitation. Colistin monotherapy may be non-inferior compared to
combination therapy for treating BSIs caused by isolates with minimum
inhibitory concentration (MIC) for colistin as 0.5 mg/l. Combined use
of the colistin and carbapenem may provide good therapeutic options
for BSI caused by carbapenem-resistant GNB and warrants further
investigations.
Introduction
arbapenem such as imipenem

and meropenem are
recommended as first-line therapy
for severe infections caused
by multidrug-resistant (MDR)
Gram-negative bacilli. 1 Resistance
to carbapenem is commonly
seen in non-fermenting Gramnegative bacilli (GNB); emergence
of carbapenem resistance in
A d d i t i o n o f c o l i s t i n
or tigecycline with
carbapenem are the
current treatment options
for curbing infections
caused by GNBs.
The study needs further
validation by the
multicentric reporting.
Enterobacteriaceae has also been
observed. The later raises an added
risk of its dissemination in the
community.2-4 Very few therapeutic
options are available for treatment
of carbapenem-resistant GNB
blood stream infection (BSI), and
are basically limited to colistin
and tigecycline. 1 However, the
low plasma concentrations of
tigecycline and the toxicity
associated with colistin make
these less appealing options for
use in BSI. In addition to these
concerns, there is limited literature
on the clinical consequences of
such infections. 5 This study aims
to describe the epidemiology
and clinical outcome of bloodstream infections associated with
Sr. Technical Officer, 2Consultant, Microbiology Department, Kokilaben Dhirubhai Ambani Hospital and Medical
Research Institute, Mumbai, Maharashtra
Received: 01.04.2015; Accepted: 20.04.2015
carbapenem-resistant Gramnegative bacilli.
according to the manufacturers

guidelines (BioMerieux Ltd).
Subjects and Methods
Phenotypic method
Study location
The study was conducted in a

750 bedded tertiary care hospital
in Mumbai from January 2013 to
April 2013 (4 months). This study
was approved by the Institutional
Scientific and Ethics Board (ISEB)
of the hospital.
Clinical isolate
All isolates obtained from blood

cultures received in Microbiology
Laboratory during the study
period, that exhibited an imipenem
or meropenem minimal inhibitory
concentration (MIC) of >1 mg/l,
according to CLSI (Clinical and
Laboratory Standard Institute)
guidelines, were considered. 6 All
samples were processed as per
standard microbiology protocol.
Antibiotic susceptibility testing
Automated systems were used

to process blood cultures (BacT
Alert) and for identification (Vitek
2). Antimicrobial susceptibility
testing was performed using the
automated broth microdilution
system (Vitek 2). For isolates of
Acinetobacter baumannii sensitivity
testing against amikacin and
meropenem was done using Kirby
Baur disk diffusion method as
per CLSI guidelines, due to the
limitation of sensitivity testing
card used in Vitek 2 analyzer.
Carbapenem resistance in all
isolates was rechecked by Kirby
Baur disk diffusion method and
interpreted as per CLSI standards. 6
For tigecycline interpretive criteria
approved by the US Food and Drug
A d m i n i s t r a t i o n ( U S - F D A) 7 f o r
Enterobacteriaceae were used for both
Enterobacteriaceae and Acinetobacter
baumannii. For colistin, break points
proposed by European Committee
on Antimicrobial Susceptibility
Te s t i n g ( E U C A S T ) 8 we r e u s e d
b e c a u s e r e l e va n t b r e a k - p o i n t s
were not available from CLSI.
MIC of colistin-resistant isolate
was rechecked by E-test method
A Modified Hodges test (MHT)

wa s p e r f o r m e d o n a l l i s o l a t e s
to determine carbapenemase
production, as described. 9
Patients and data collection
Data, including patient

demographics, co-morbid
conditions, source of infection,
and treatment were collected from
the electronic medical records,
laboratory data and medication
administration records from the
date of admission till discharge.
Only first episode of BSI from the
patient was included. Outcome at
the end of treatment was defined
as successful (partial or complete
improvement of signs/symptoms
of infection or positive microbial
response in terms of sterile
culture results post or during
the treatment), and failure (no
improvement or deterioration of
signs/symptoms of infection or
negative microbial response in
terms of persistent positive culture
results with the same organism 3
days after initiation of antibiotic
therapy). Final disposition was
defined as death, discharged
during illness or transferred to
ward or discharged.
Results
A total of 42 clinically significant
carbapenem-resistant Gramnegative bacilli were isolated from
blood cultures during the study
period of 4 months. Epidemiology
Table 1: Epidemiology of
carbapenem-resistant Gramnegative bacilli from bloodstream infection
Carbapenem-resistant isolates
from BSI
Acinetobacter baumannii
Enterobacteraiceae spp.
Klebsiella pneumoniae
Escherichia coli
Enterobacter cloacae
Citrobacter freundii
Pseudomonas aeruginosa
Total
Total
15
15
1
2
1
8
42
15
of carbapenem-resistant isolates
in BSI is depicted in (Table 1).
Antimicrobial susceptibility of
all isolates is shown in (Table
2). Kirby Baur disk diffusion
method confirmed the carbapenem
resistance amongst all the isolates
and did not show any discrepancy
in results of susceptibility for
imipenem and meropenem. Except
three isolates of Pseudomonas
aeruginosa all other (92.9%) isolates
were positive for carbapenemase
production by MHT.
The medical records of patients
included in study cohort were
reviewed. Their characteristics are
given in (Table 3).
The source of bacteremia
included central venous catheter
(71.5%), respiratory tract infection
(7.1%), urinary tract infection
(2.4%), and uncertain in eight cases
(19%). In these eight cases patients
were diagnosed with bacteremia
from the blood culture collected on
the first day of admission and were
known to have previous history
of hospitalisation. Eleven (26%)
patients died within 48 hours from
the day of initial blood culture,
of which four did not receive any
effective antimicrobial therapy
and seven received effective
clinical therapy for less than 24
hours. These were not included in
further analysis. In one of the cases
patient suffered from secondary
bacteremia caused by colistinresistant Klebsiella pneumonia (MIC
of colistin 8 mg/l) while the patient
wa s o n c o l i s t i n m o n o t h e r a p y .
Patient died within 24 hours from
the time of collection of blood
culture. Antimicrobial regimen
received by 31 patients having BSI
and their clinical outcome is given
in (Table 4).
Discussion
Carbapenem-resistant Gramnegative bacilli pose a serious
threat to current medical practices.
Carbapenem has been the treatment
of choice for serious infections
(MDR infections) caused by
16
Table 2: Antimicrobial susceptibility

Susceptibility of 19 isolates of Enterobacteriaceae spp.
Antimicrobial agent
MIC range
MIC50
Imipenem
1 to 16
4
Meropenem
1 to 16
8
Amikacin
4 to 64
32
Tobramycin
2 to 16
16
Gentamycin
1 to 16
16
Colistin
0.5 to 8
0.5
Tigecycline
0.5 to 8
8
Ciprofloxacin
4
4
MIC90
16
16
64
16
16
0.5
8
4
% Sensitivity
5.3
5.3
47.4
5.3
15.8
94.7
36.8
0
Susceptibility of 15 isolates of Acinetobacter baumannii

Antimicrobial agent
MIC range
MIC50
Imipenem
8 to 16
16
Meropenem
ND
Amikacin
ND
Tobramycin
4 to 16
16
Gentamycin
8 to 16
16
Colistin
0.5
0.5
Tigecycline
0.5 to 8
4
Ciprofloxacin
4
4
Ampicillin sulbactam
8 to 32
32
Cefoperazone sulbactam
16 to 64
64
MIC90
16
16
16
0.5
8
4
32
64
% Sensitivity
0
0
0
6.7
0
100
46.7
0
6.7
13.3
Susceptibility of 8 isolates of Pseudomonas aeruginosa

Antimicrobial agent
MIC range
MIC50
MIC90
% Sensitivity
Imipenem
1 to 16
16
12.5
Meropenem
1 to 16
16
16
12.5
Amikacin
64
64
64
Tobramycin
16
16
16
Gentamycin
16
16
16
Colistin
0.5
0.5
0.5
100
Tigecycline
NA
1 to 4
12.5
Ciprofloxacin
Note: MIC, Minimum inhibitory concentration in mg/l; MIC50, MIC required to inhibit the growth
of 50% isolates of this study; MIC90, MIC required to inhibit 90% isolates of this study; MICs were
determined by broth dilution method; ND Not Done; NA Not Applicable.
MDR Gram-negative bacilli but

unfortunately the resistance to
carbapenem compromises the
treatment options. Carbapenemase
production is one mechanism
of resistance; other carbapenem
resistance mechanisms also exist
like porin loss, efflux of drug and
target alteration. However, it is well
known that multiple mechanisms of
resistance and enzyme production
can coexist in a single organism. 10
Carbapenem resistance is most
commonly seen in non-fermenter
Gram-negative organisms (nonEnterobacteriaceae) i.e., Pseudomonas
and Acinetobacter. 3 Recent surveys
have identified extended spectrum-lactamase (ESBLs) in 70-90%
of Enterobacteriaceae in India,
making widespread use of reserved
antibiotics such as carbapenems

necessary. 10 Consequently, there is
selection pressure for carbapenem
resistance in Enterobacteriaceae.
This results in an increasing
incidence of carbapenem resistance
in Enterobacteriaceae family as
well. The treatment options are
limited especially for BSI hence
the current study aims to add to
the limited literature available on
the optimum treatment options for
treating blood stream infections
by carbapenem-resistant Gram
negative bacilli.
Of the 42 isolates obtained
from BSI, 19 (45%) isolates
were carbapenem-resistant
Enterobacteriaceae. This is an
increasingly important threat due
Table 3: Characteristics of patients

having bacteremia with
carbapenem-resistant strain
Variable
n (%)
Demographics
Age [median
54 yrs
(range)]
(1 month 89 yrs)
Sex (male)
21 (50.0)
Comorbidity
Heart dysfunction
12 (28.6)
Malignancy
3 (7.1)
Diabetes mellitus
12 (28.6)
Hypertension
18 (42.9)
Chronic renal failure
6 (14.3)
Admission to ICU
37 (88.1)
Prior surgery
3 (7.1)
Prior antibiotic use
40 (95.2)
BL/BLI
26 (61.9)
Carbapenem
24 (57.1)
Aminoglycosides
6 (14.3)
Colistin
5 (11.9)
Fluoroquinolones
4 (9.5)
Tigecycline
2 (4.8)
Prior hospitalization
17 (40.5)
12.83 13.13
Time to develop
(0 to 62)
infection with CR-GNB*
38.12 31.12
Duration of
(1 to 111)
hospitalization*
Note: BL/BLI - -lactam/-lactamase inhibitor,
ICU - intensive care unit. *mean standard
deviation (range) in days
to its ability to disseminate in the

community. The susceptibility
profile of isolates recovered during
the present study underscores
the extremely limited therapeutic
choices available for treatment of
patients infected with carbapenemresistant strains. Colistin had
maximum in vitro activity, with
94.7% against Enterobacteriaceae,
100% against Acinetobacter
baumannii, and 100% activity
against Pseudomonas aeruginosa.
A total of 92.9% isolates were
positive for carbapenemases by
MHT indicating carbapenemase
production as one of the important
mechanism of resistance. In other
isolates resistant mechanisms other
than carbapenemase production
may be responsible for resistance
to carbapenem.
Presence of severe underlying
conditions and previous exposure
to multiple antibiotics in the
present study cohort indicate the
patient to be critically ill. In 71.5%
Table 4: Antibiotic treatment and

outcome of patient having
bacteremia with carbapenemresistant strain
Antibiotic regimen Outcome of treatment
Total
Successful
Colistin therapy
(mono and
25
20 (80)
combination)
Colistin
6
monotherapy
5 (83)
Colistin
combination
therapy
19
15 (79)
Colistin +
carbapenem
12
12 (100)
Colistin
+noncarbapenem
7
3 (43)
Colistin +
Tigecycline
5
1 (20)
Colistin +
Amikacin
1
1 (100)
Colistin +
Sulbactam
1
1 (100)
4
4 (100)
Carbapenem*
1
1 (100)
Tigecycline*
Tigecycline +
carbapenem
1
0 (0)
Total
31
25 (81)
Note: *Catheter removal associated with
antimicrobial regimen
of cases the source of bacteremia

was found to be central venous
catheter, thus severe underlying
illness, susceptibility to infection
and antibiotic selection pressure
may lead to increasing risk of
infection with multidrug-resistant
organisms. Smaller studies have
reported similar risk factors. 11
Colistin-containing
c o m b i n a t i o n s we r e m o s t o f t e n
used in our study (81% i.e. 25
out of 31) either as monotherapy
(24%) or combination therapy
(76%). 160 to 240 mg (2 to 3 MIU)
of colistimethate sodium (CMS)
per 8 or 12 hours was administered
and doses were adjusted according
to the renal functions. Among
colistin combination therapy,
colistin and carbapenem was the
most commonly used combination
(63% i.e. 12 out of 19). Colistin
monotherapy showed success
rate of 83% whereas colistin and
carbapenem combination therapy
s h o we d 1 0 0 % s u c c e s s r a t e . O f
the 12 BSI successfully treated
with colistin and carbapenem

combination therapy, six were
caused by Enterobacteriaceae spp.,
four by Acinetobacter baumannii,
and two by Pseudomonas aeruginosa,
indicating its effectiveness against
all strains. This may be due to
the synergistic or additive effect
of colistin and carbapenem
combination as reported by many
in vitro studies. 12-14 This study
supports the data from the small
number of relevant human studies
suggesting non-inferiority of
colistin monotherapy compared
w i t h c o m b i n a t i o n t h e r a p y . 14
However, one patient developed
secondary BSI with colistinresistant Klebsiella pneumoniae while
on colistin monotherapy. This
raises concern regarding potential
problem of heteroresistance among
Gram-negative bacterial population
exposed to colistin alone. In that
case combination therapy may be
helpful in improving outcomes
and preventing bacterial resistance,
as there has been reported
development of resistance to
colistin during monotherapy. 15
A special attention needs to be
given to the relationship between
pharmacokinetics (PK) and
pharmacodynamics of colistin. In
2008, Markou et al 16 published PK
data of the colistin in critically ill
patients using a chromatographic
assay. In this study, CMS dosage
regimens administered to those
critically ill adult patients were
associated with suboptimal
C max/MIC ratios for many strains of
Gram-negative bacilli. Markou et
al 16 and Imberti et al 17 reported
plasma colistin C max at a steady
state of 1.155.14 mg/l (Dosage of
CMS 3 MIU per 8 or 12 hours) and
0.684.65 mg/l (Dosage of CMS 2
MIU per 8 hours), respectively,
in critically ill patients with
moderate-to-good renal function.
Very recently, Garonzik et al 18
described the effects of CMS and
formed colistin in 105 critically
ill patients. This population PK
analysis suggests the traditional
CMS doses are often suboptimal
17
considering the breakpoint for

colistin susceptibility of 2 mg/l.
Thus the success of colistin
monotherapy obtained in present
study may be attributed to MIC 90
for colistin being 0.5 mg/l for
clinical isolate and for infections
caused by isolates with MICs of
>1.0 mg/l colistin may best be
used as part of a highly active
combinations as recommended by
Garonzik et al. 18
Clinical success with
carbapenem monotherapy and
tigecycline monotherapy was noted
in the present study cohort, but
the degree to which it contributed
to the successful outcome was
difficult to ascertain as all cases
were associated with removal of
foci of infection (catheter removal)
which may have a role to play. 11
Clinical isolates obtained from
bacteremia treated with colistin
and tigecycline combination
t h e r a p y s h o w e d M I C 50 o f
2 mg/l for tigecycline. Clinical
success was achieved in 20% (1/5)
cases treated with colistin and
tigecycline combination therapy.
Thus present study supports
reports on raised concern about
the use of tigecycline to treat
bloodstream infections caused by
organisms with MIC value 1 mg/l
given the low mean peak serum
concentrations of tigecycline. 19
Limitation of our study is
that its a small study which was
conducted over a short period
of 4 months. Characterization of
carbapenemases produced by these
isolates was performed but it is not
a part of this study.
Carbapenemase production
is currently associated with
nosocomial isolates; one of the most
worrisome concerns is the spread
of these carbapenemase producing
isolates in the community. This
represents a signicant threat to
public health, warranting increased
e f f o r t s t o wa r d s d e t e c t i o n a n d
infection control strategies.1
Severe underlying condition,
use of invasive procedures and
antibiotic selection pressure in
18
critically ill patient may predispose

them to acquiring infection with
carbapenem-resistant Gramnegative bacilli. For strains with
colistin MIC of 0.5 mg/l, colistin
monotherapy may be non-inferior
compared to colistin combination
t h erapy . Colist in-carbap enem
combination may be a promising
regimen to treat BSI caused by
carbapenem-resistant GNB and it
need to be further evaluated.
Performance standard for antimicrobial

susceptibility testing: Twenty-second
informational supplement. M100-S23 CLSI,
2013. Wayne P.A.
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(FDA), Highlights of prescribing information
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ucm132714.htm (Accessed 19 February
2014).
14. Petrosillo N, Ionnidou E, Falagas E. Colistin

monotherapy vs. combination therapy:
evidence from microbiological, animal
and clinical studies. European Soc of Clin
Microbiol and Infect Dis 2008; 14:816-27.
8.
EUCAST. Available at: http://www.eucast.

org/fileadmin/src/media/PDFs/EUCAST_
files/Disk_test_documents/EUCAST_
breakpoints_v_2.0_111130.pdf. Accessed
January 3, 2012.
15. Lee J, Patel G, Huprikar S, Calfee DP, Jenkins

SG. Decreased Susceptibility to Polymyxin
B during Treatment for CarbapenemResistant Klebsiella pneumoniae Infection.
J Clin Microbiol 2009; 47:1611-2.
Noyal MJC, Menezes GA, Harish BN, Sujatha

S, Parija SC. Simple screening tests for
detection of carbapenemases in clinical
isolates of nonfermentive Gram-negative
bacteria. Indian J Med Res 2009;129:707-12.
16. Markou N, Markantonis SL, Dimitrakis E,

et al. Colistin serum concentrations after
intravenous administration in critically
ill patients with serious multidrugresistant, Gram-negative bacilli infections:
a prospective, open-label, uncontrolled
study. Clin Ther 2008; 30:14351.
References
1.
Kosmidis C, Poulakou G, Markogiannakis A,

Daikos GL. Treatment options for infections
caused by carbapenem-resistant Gramnegative bacteria. European Infect Dis 2012;
6:28-34.
9.
2.
Nordmann P, Naas T, Poirel L. Global

spread of Carbapenemase-producing
Enterobacteriaceae. Emerg Infect Dis 2011;
17:1791-8.
10. Kumarasamy KK, Toleman MA, Walsh

TR, et al. Emergence of a new antibiotic
resistance mechanism in India, Pakistan,
and the UK: a molecular, biological, and
epidemiological study. Lancet Infect 2010;
10:597 602.
3.
Gupta E, Mohanty S, Sood S , Dhawan B,

Das BK, Kapil A. Emerging resistance to
carbapenems in a tertiary care hospital in
north India. Indian J Med Res 2006; 124:95-8.
4. Nagaraj S, Chandran SP, Shamanna P,

Macaden R. Carbapenem resistance
among Escherichia coli and Klebsiella
pneumoniae in a tertiary care hospital in
south India. Indian J Med Microbiol 2012;
30:93-5.
5.
Neuner EA, Pharm D, Yeh JY, et al. Treatment

and outcomes in carbapenem-resistant
Klebsiella pneumoniae bloodstream
infections. Diagn Microbiol Infect Dis
2011;69:35762.
6.
Clinical and Laboratory Standard Institute.
combination of colistin and doripenem is

synergistic against Klebsiella pneumoniae
at multiple inocula and suppresses colistin
resistance in an in vitro pharmacokinetic/
pharmacodynamic model. Antimicrob
Agents Chemother 2012; 56:510312.
11. Patel G, Huprikar S, Factor SH, Jenkins

SG, Calfee DP. Outcomes of carbapenemresistant Klebsiella pneumoniae infection
and the impact of antimicrobial and
adjunctive therapies. Infect control and
hospital epidemiology 2008; 29:1099-106.
12. Lee CH, Tang YF, Su LH, Chien CC, Liu
JW. Antimicrobial effects of varied
combinations of meropenem, sulbactam,
and colistin on a multidrug-resistant
Acinetobacter baumannii isolate that
caused meningitis and bacteremia. Microb
Drug Resist 2008; 14:233-37.
13.
Deris ZZ, Yu HH, Davis K, et al. The
17. Imberti R, Cusato M, Villani P, et al.

Steady-state pharmacokinetics and BAL
concentration of colistin in critically ill
patients after IV colistin methanesulfonate
administration. Chest 2010; 138:13339.
18. Garonzik SM, Li J, Thamlikitkul V, et al.
Population pharmacokinetics of colistin
methanesulfonate and formed colistin in
critically ill patients from a multicenter
study provide dosing suggestions for
various categories of patients. Antimicrob
Agents Chemother 2011; 55:328494.
19. Peleg AY, Potoski BA, Rea R, et al.
Acinetobacter baumannii bloodstream
infection while receiving tigecycline: a
cautionary report. J Antimicrob Chemother
2007; 59:12831.
20
Original Article
Left Ventricular Diastolic Dysfunction in

Primary Hypertension and its Relation with
Leisure Time Physical Activity
Vikas Ratnaparkhe1, Amit Bhangale2
Abstract
Editorial Viewpoint
Objective: Left ventricular diastolic dysfunction with preserved ejection

fraction is associated with an increased risk of morbidity and mortality.
Population-based survey studied the associations between diastolic
dysfunction in primary hypertension and its association with lifestyleas one of risk factors. Exercise prevents and prolongs the degenerative
changes but whether leisure time physical activity (LTPA) is associated
with similar effects is being studied here.
L e i s u r e t i m e p h y s i c a l
activity has an association
with progress of
diastolic dysfunction in
hypertension.
Methods: Total 301 patients of age 30-60 year old with essential
hypertension were included in prospective observational study. Patients
were classified according to their leisure time physical activity and
subjected for echocardiography and color Doppler.
Results: Out of 301 patients, 149 (49.66%) were sedentary during leisure
time, out of which 114 (76.5%) were having diastolic dysfunction and
35 (23.5%) were normal, while 104 (34.66%) were having moderate
physical activity in which 66 (63%) were normal. Twenty-nine (60%) of
48 vigorously active were found to be normal. By using Fishers exact
test p-value was < 0.05.
Conclusion: In this study, a sedentary lifestyle is found to be associated
with a rapid decline of ventricular compliance.
Physical activity in any form has definite protective role in prevention of
degenerative changes occurring inside the body.
Introduction
n the natural habitat of our

ancestors, physical activity was
not a preventive intervention but
a matter of survival. In that hostile
environment with scarce food
and ubiquitous dangers, human
genes were selected to optimize
aerobic metabolic pathways and
c o n s e r ve e n e r g y f o r p o t e n t i a l
future famines. 1
Cardiac and vascular functions
were continuously challenged by
intermittent bouts of high-intensity
physical activity and adapted to
meet the metabolic demands of

the working skeletal muscle under
these conditions. 2
The scenario has completely
changed from physically active to
almost inactive lifestyle. Average
physical activity in our society is
much below the levels normal for
our genetic background. 3
The sedentary lifestyle in
combination with excess food
intake has surpassed all other
S e d e n t a r y l i f e s t y l e
is associated with
deterioration in diastolic
dysfunction.
More prospective studies
with long-term follow-up
required to strengthen
this association.
preventable causes of death in all
over the world. 4
Physical activity i.e. exercise has
been shown to have beneficial effects
on glucose metabolism, skeletal
muscle function, ventilator muscle
strength, bone stability, locomotor
coordination, psychological wellbeing, and other organ functions. 5
The hypertension and
cardiovascular disease burden is
ever increasing globally. The World
Health Organization attributes
hypertension, as the third leading
cause of cardiovascular morbidity
and mortality. 6 As estimated 17.3
million people i.e. 30% of all
global deaths are attributed to
cardiovascular disease in 2008. 7
In Indian scenario it is 29 % of all
deaths.
Nearly one billion people
are affected by hypertension
Senior Consultant, 2Resident, Dr. Hedgewar Hospital, Aurangabad, Maharashtra

Received; 21.01.2013; Accepted: 24.06.2014
worldwide; and this figure is

predicted to increase to 1.5 billion
by 2025.
The epidemiological studies
show that hypertension is present
in 25% urban and 10% rural subjects
in India. 8
Uncontrolled hypertension leads
to a number of structural changes
i n t h e h e a r t w h i c h e ve n t u a l l y
cumulates into interstitial fibrosis,
myocardial wall thickness and
functional alteration such as
diastolic dysfunction.
We in our study focused our
attention on diastolic heart failure
w h i c h d e ve l o p s i n t w o - t h i r d s
of patients of hypertension and
its correlation with leisure time
physical activity which indirectly
indicates the relation of diastolic
dysfunction and exercise.
Leisure time physical activity
(LTPA) is a form of slow exercise,
and it is nothing but the lifestyle
of the person. The importance of
this preventive role of LTPA can be
conveyed to the persons so that they
may change their lifestyle and that
will in turn help them to decrease
the burden of hypertensive heart
disease.
Material and Methods

A Prospective observational
study, in which patients from age
group 30 to 60 years were included
in study. Detected or newly
diagnosed essential hypertensive
patients presenting to OPD/IPD
were included in the study.
Patients were considered eligible
for entry to the study if they
fulfilled the following clinical
criteria.
Inclusion criteria was patients
with primary hypertension.
Exclusion criteria were renal
disease, diabetes mellitus, ischemic
heart disease, acute myocardial
ischemia, chronic coronary
heart disease, cardiomyopathy
(hypertrophic, infiltrative,
restrictive), valvular heart
disease (acute aortic or mitral
regurgitation, mitral stenosis,

aortic stenosis), pericardial disease,
tamponade, circulatory congestive
states, rapid fluid administration,
a r t e r i o - ve n o u s f i s t u l a , s e ve r e
anemia, thyrotoxicosis, patients
with congenital heart disease and
patients with LVEF < 40%.
All cases with secondary
hypertension and pregnancyinduced hypertension were
excluded.
All patients on drugs and toxins
that cause hypertension were also
excluded.
The study was approved by the
ethical committee of the institution.
Methodology
A written informed consent was
taken from all patients, complete
history and clinical examination
was done according to a proforma.
Blood pressure was measured as
a mean of two readings recorded
on the right arm, measured under
standardized conditions with the
participant seated (after 5 min rest).
In all the patients of essential
hypertension information
regarding the leisure time physical
activity was gathered.
Then patients were subjected
to detailed clinical examination
routine hematological and
biochemical examination and ECG
to rule out secondary hypertension
and IHD.
Patients who were detected or
diagnosed as essential hypertension
as per JNC VII criteria were
included.
Definitions
Essential Hypertension
Essential hypertension is the

form of hypertension that has no
identifiable cause.
SBP/DBP
<120/80
120 139/80 - 89
140 149/90 - 99
>160/100
JNC 7
Normal
Prehypertension
Hypertension
Stage 1
Stage 2
21
Diastole9
Diastole is the time period

during which the myocardium
loses its ability to generate force
and shortens and returns to an
unstressed length and force.
Diastolic Dysfunction
Diastolic dysfunction occurs

when these processes are prolonged,
slowed, or incomplete.
It depends on the onset, rate,
and extent of ventricular pressure
decline and filling and the
relationship between pressure and
volume or stress and strain during
diastole.
Leisure Time Physical Activity10
Leisure is: free time, i.e.:

non-work, non-obligated or nonconstrained.
The amount of time people
spend away from work whatever
they do.
This data was computed based
on three questions 11
Does your [recreation, sport
or leisure time] involve mostly
sitting, reclining, or standing,
with no physical activity lasting
more than 10 minutes at a time?
[if yes, the person was graded
as sedentary during leisure].
In your leisure time do you
do any moderate intensity
activities like brisk walking
(cycling or swimming) for at
least 10 minutes at a time?
[if yes, the person was coded
as moderately active during
leisure].
In your leisure time do you
do any vigorous activities like
(running or strenuous sports,
weight lifting) for at least 10
minutes at a time? [if yes, the
person was graded vigorously
active during leisure].
If an individual said yes for all
the three, he / she was graded
as vigorously active during
leisure.
If an individual said yes for both
moderate and sedentary, he /
she was graded as moderately
22
Table 1: Leisure time physical activity and diastolic dysfunction

LTPA
Diastolic dysfunction
Present
Sedentary
114(76.5%)
Moderate
38(37%)
Vigorous
19(40%)
Fig. 1: Age group and diastolic

dysfunction
Diastolic dysfunction
Absent
35(23.5%)
66(63%)
29(60%)
pump with a late diastolic filling

of LV was noted. (Contributes to
almost 20 % of LV filling in normal
subjects).
Tissue Doppler imaging (TDI) is
not dependent on imaging quality
and tracings are easily obtainable.
It is taken at mitral annulus either
medial or lateral. The contraction
and relaxation produces a wave
form or that is recorded.
Fig. 2: Gender and diastolic

dysfunction
active during leisure.

If the individual did not do any
physical activity he was labeled as
sedentary.
E a r l y d i a s t o l i c wa ve E i . e .
E p r i m e o r E m wa ve a n d l a t e
diastolic wave A at the time of atrial
contraction we recorded and E/A
and E/E ratio were calculated.
Results
If an individual said yes for all

the three, he / she was graded as
vigorously active at work.
Out of 301 hypertensive patients

171 (55.70%) were having diastolic
dysfunction and 130 (44.30%) were
normal.
If an individual said yes for both

moderate and sedentary, he / she
were graded as moderately active
at work.
Distribution of patients
with respect to age (years) and
occurrence of diastolic dysfunction
is shown in Figure 1.
All those included for study were

subjected for echocardiography
and colour Doppler.
By using chi-square test

p-value <0.05 showing association
between the occurrence of diastolic
dysfunction and age (years).
A n a l y s i s wa s p e r f o r m e d b y
using PHILIPS HD 7 and following
parameters were measured.
Assessment of Diastolic Function Using
Doppler12
Fundamental information viz.

c h a m b e r s i z e , wa l l t h i c k n e s s
and motion, systolic function,
the valves, and the pericardium
was noted on two dimensional
echocardiography)
The diastolic filling wave known
as E wave which is due to rapid
filling of LV due to atrio-ventricular
g r a d i en t i n e a r l y d ias tole was
noted. (Almost 80 % of the LV
filling occurs during this phase.)
A wave. During the late diastolic
phase the LA acts as a booster
Majority i.e. 137 (74%) of the

patients of diastolic dysfunction
were from the age group of 5160
years.
Distribution of patients with
respect to gender and occurrence
of diastolic dysfunction is shown
in Figure 2.
Among 171 males 98 (57.3 %) were
having diastolic dysfunction, out of
136 females 73 (53.6 %) were found
to have diastolic dysfunction. There
was no association between the
occurrence of diastolic dysfunction
and gender (p>0.05).
Majority of patients, 177 (59.8%)
were from urban areas where 118
( 6 6 . 6 % ) we r e h a v i n g d i a s t o l i c
Total
p-value
149
104
48
< 0.001
dysfunction. One hundred twentysix (41.85%) were from rural areas

where 73 (58.01%) were found to
be normal. There was association
between the diastolic dysfunction
and area of population (P<0.05).
Distribution of patients with
respect to leisure time physical
activity and occurrence of diastolic
dysfunction is shown in Table 1.
Majority of patients 149 (48.5%)
were having sedentary lifestyle
114 (76.5%) having diastolic
dysfunction. There was association
between the occurrence of diastolic
dysfunction and leisure time
physical activity (P<0.05).
Discussion
The study included 301 cases
fulfilling inclusion criteria, found
171 (55.70%) were having abnormal
diastolic function.
Slama et al 14 demonstrated that
diastolic dysfunction preceded
the left ventricular hypertrophy.
Also Ike et al in a study found that
prevalence of diastolic dysfunction
in the hypertensive group to be
82.86%. 15
In our study the majority i.e. 137
(74%) patients out of 301, were from
the age group of 51 60 years. As
the age advances the leisure time
activity decreases. 16
Similar to this Redfield et al
in cross-sectional survey found
diastolic dysfunction common
above 65 years. 17
Among 167 males 98 (58.68%)
were having diastolic dysfunction,
out of 134 females 73 (54.47 %)
were found to having diastolic
dysfunction. It seems that females
have more sedentary lifestyle than
males. 16 Similar to this Masoudi, et
al in a cross-sectional study using
data from retrospective medical
chart abstraction of a national
sample of Medicare beneficiaries

found preserved LVSF was present
in 35%, out of which 79% were
women. 18 Contradictory results
were found by Wachter et al in
2007 in their study of hypertensive
patients, Sex-specific analysis
revealed that diastolic function
was mainly limited to the male
subgroup. 19
In our study out of 134 female
patients 72% post menopausal
patients. Out of which 62% patients
were found to have diastolic
dysfunction. Similar to our study
Kangro et al found that Left
ventricular diastolic function seems
to be affected in the postmenopausal
state; postmenopausal women
have greater left ventricular
wall thickness and lower peak
E velocities and E/A ratios on
Doppler echocardiography than
premenopausal women. 20
Majority of patients, 177 (59.8%)
were from urban areas where 118
( 6 6 . 6 % ) we r e h a v i n g d i a s t o l i c
dysfunction, whereas 73 (58.01%)
out of 126 rural patients were found
to be normal.
These may be because of
d i f f e r e n c e i n l i f e s t yl e i n r u r a l
and urban population. Because of
mechanization and its application
in urban area, the population has
become sedentary. Rural population
has less sedentary lifestyle than
urban population. Though, this
needs further evaluation. 21
Regular exercise and endurance
training has been shown to
reduce arterial pressure, improve
endothelial function. Increased
body mass index is associated
with worsening diastolic function
in patients with normal systolic
function. Majority of patients 149
(48.5%) were having sedentary
lifestyle of which 114 (76.5%) were
having diastolic dysfunction.
A study done by Bennete et
al on men and women of 30 75
years of age showed that sedentary
leisure time physical activity is
independently associated with
diastolic dysfunction in females.
Identification of a sedentary
lifestyle in females increases the
probability of diagnosing diastolic
dysfunction. 22
Similarly, Arbab-Zadeh et al in
twelve healthy sedentary seniors
and 12 masters athlete found that
sedentary lifestyle during healthy
aging is associated with decreased
left ventricular compliance,
leading to diminished diastolic
performance. 23
Prolonged, sustained endurance
t r a i n i n g p r e s e r ve s ve n t r i c u l a r
compliance with aging and may
help to prevent heart failure in the
elderly.
Kitzman et al reported the first
single-center, single-blind RCT on
exercise training in older patients
with diastolic dysfunction. The
benefits of exercise training in
patients with heart failure include
an improvement in exercise
tolerance as assessed not only
by exercise duration but more
importantly by peak VO 2. 24
Leisure-time physical activity
is associated with longer lifeexpectancy, even at relatively low
levels of activity and regardless of
body weight, according to a study
by a team of researchers led by the
National Cancer Institute (NCI),
part of the National Institutes of
Health. The study, which found
that people who engaged in leisuretime physical activity had lifeexpectancy gains of as much as 4.5
years. 25
In conclusions, our study
suggests that urban population
is more susceptible for diastolic
dysfunction as compared to rural
population. This is definitely linked
with leisure time physical activity.
It is shown that there is definite
cardioprotection with a leisure time
physical activity which is feasible,
safe, and effective in patients with
diastolic dysfunction.
delays the development of
ventricular diastolic dysfunction.
A sedentary lifestyle is definitely
23
associated with a decline of

ventricular compliance.
may therefore be considered as
having potential role in preventing
diastolic dysfunction in addition to
regular exercise.
References
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Booth F, Laye M, Lees S, Rector R, Thyfault

J. Reduced physical activity and risk of
chronic disease: the biology behind the
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2.
Gielen S, Schuler G, Adams V. Cardiovascular

effects of exercise training: molecular
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Fahey, Insel, Roth. Introduction to Wellness,

Fitness, and Lifestyle Management.
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Lopez AD, Mathers CD, Ezzati M, Jamison

DT, Murray CJ. Global and regional burden
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Chaitman, Duscha BD, Fletcher BJ, et al,

Committee on Exercise, Rehabilitation,
and Prevention Exercise and Heart Failure
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6.
Chockalingam A. World Hypertension Day

and global awareness. Can J Cardiol 2008;
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Cardiovascular diseases (CVDs), Fact sheet

N317, September 2011.
8.
G u p t a R . Tre n d s i n hy p e r te n s i o n
epidemiology in India. J Human Hypertens
2004; 18:7378.
9.
Hall JE, Guyton AC. Textbook of medical

Physiology. St. Louis, Mo: Elsevier Saunders.
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10. Parrv J, Long J. Immaculate concepts?

Paper to the 2nd International Conference
of the Leisure Studies Association, University
of Sussex,Brighton, England, 29 June - 3
July 1988 (Authors: Leeds Univ. and Leeds
Polytechnic).
11. WHO India-ICMR, NCD RF surveillance
2003-04.
12. Shah S: Heart failure with preserved ejection
fraction. Michael Cramford in current
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edition. McGraw Hill 2011.
13. Algeria-Ezquerra E, Gonzalez-Juanatey JR,
Gonzlez-Maqueda. Hypertensive heart
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24
14. Slama M, Susic D, Varagic J, Frohlich ED et

al. Diastolic dysfunction in hypertension.
Curr Opin Cardiol 2002; 17:368-73.
al. Gender, age, and heart failure with

preserved left ventricular systolic function.
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15. Ike SO, Ikeh VO. The prevalence of diastolic

dysfunction in Adult Hyper tensive
Nigerian. Ghana Med J 2006; 40:55-60.
19. Wachter R, Lers C, Kleta S, et al. Impact

of diabetes on left ventricular diastolic
func tion in patients with ar terial
hypertension. European J Heart Fail 2007;
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16. Charlotte A. Schoenborn, M.P.H., and

Patricia M. Barnes, M.A., Division of Health
Interview Statistic CDC Leisure-Time
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States, 199798 s.
17. Redfield MM, Jacobsen SJ, Burnett JC
Jr, et al. Burden of Systolic and Diastolic
Ventricular Dysfunction in the Community:
Appreciating the Scope of The Heart Failure
Epidemic. JAMA 2003; 289:194-202.
18. Masoudi FA, Havranek EP, Smith G, et
20. Kangro T, Henriksen E, Jonason T, et al.

Effects of menopause on left ventricular
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21. Eberhardt MS, Pamuk ER. The Importance
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22. Bennet L, Larsson C, Marrieme SO, et al.
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sedentary leisure time physical activity
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Thomas Relationship among diastolic
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6,2012
27
Original Article
An Open Label, Prospective, Single Centre Study

to Evaluate the Efficacy and Safety of Fixed Dose
Combination of Rabeprazole (Enteric-Coated,
EC) 20 mg + Domperidone (Sustained Release,
SR) 30 mg Capsule in Treatment of Patients
with Laryngopharyngeal Reflux Disease
K Semmanaselvan1, Qayum I Mukaddam2, Manoj Naik3
Abstract
Objective: To evaluate the efficacy, safety and tolerability of fixed dose combination of Rabeprazole (enteric-coated,
EC) 20mg + Domperidone (sustained release, SR) 30 mg for treatment of laryngopharyngeal reflux disease (LPRD).
Design: A prospective, single centre, open-label, non-comparative, observational study
Setting: The study was conducted at an otolaryngology clinic in India between May2012 and November2012.
Patients: Patients (>18 yrs) with suspicious LPR-related symptoms, reflux symptom index (RSI) score >13 and reflux
finding score (RFS) >7, willing to undergo rigid laryngoscopy and requiring fixed dose combination of Rabeprazole
(enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment according to the
investigators discretion were eligible for enrolment in the study.
Methods: Fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release,
SR) 30 mg capsule treatment was given for a total duration of 90days and efficacy was assessed by the change
in RFS and RSI score at Day90. The safety and tolerability of the study drug was assessed by monitoring adverse
events, vital signs and physical examination.
Results: Overall, 50 patients were enrolled and completed the study. After 12 weeks of fixed dose combination
of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment there
was a significant change in mean RSI scores [mean (SD) RSI: 19.18 (3.24) at baseline to 2.52 (2.31) at end of study;
(p<0.0001)] as well as mean RFS score [mean (SD) RFS: 12.62 (1.48) at baseline to 0.30 (0.51) at end of study;
(p<0.0001)]. No adverse event was reported by any patient during the study period.
Conclusion: Twelve weeks of treatment with combination of fixed dose combination of Rabeprazole (entericcoated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule significantly improved reflux symptoms
in patients with LPR. The combination was found to be safe and well tolerated.
Editorial Viewpoint
Laryngopharyngeal reflux disease (LPRD) is diagnosed in 10% of ENT OPD patients.
Combination of gastroesophageal reflux disease (GERD) and LPRD seems to be common.
Combination of rabeprazole and domperidone for 12 weeks effectively reduced LPRD symptoms.
1
Director, Selvam ENT Clinic, Chennai, Tamil Nadu; 2Medical Director, 3Chief Manager, Medical Services Division, Abbott Healthcare Private Limited, Mumbai, Maharashtra
Received: 03.07.2014; Revised: 29.10.2014; Re-revised: 25.11.2014; Accepted: 29.11.2014
28
Introduction
he Montreal definition and

classification of gastroesophageal reflux disease (GERD)
was developed by an International
Consensus Group and is valuable for
physicians, patients and regulatory
agencies. GERD was dened as a
condition that develops when the
reux of stomach contents causes
troublesome symptoms and/or
complications. The manifestations
of GERD were sub-classied into
oesophageal and extra-oesophageal
syndromes, with extra-oesophageal
syndromes further divided
into established and proposed
associations. Laryngo-pharyngeal
reflux (LPR) or reux laryngitis was
considered as one of the constitute
syndromes of the established extraoesophageal syndromes. 1 LPR is
due to backflow of gastric contents
into the laryngopharynx, which
may result in posterior laryngitis
with a group of laryngeal signs and
symptoms. 2 Laryngopharyngeal
reflux disease (LPRD) is diagnosed
in approximately 10% of patients
presenting to the outpatient
otolaryngology clinic and more
than 50% of patients presenting
with voice complaints. 3 In Western
populations, GERD symptoms
occur at least once a month in 44%,
once a week in 20% and daily in
7% of the adult US population. 4
A multi-center prospective
questionnaire-based study of 3,224
patients reported a weekly GERD
prevalence of 7.6% in the Indian
population. 5
Specific and consistent
guidelines for the diagnosis of
LPRD are lacking and diagnosis
is usually based on clinical signs
and symptoms rather than by use
of specific diagnostic methods. 6
The typical signs and symptoms
of LPR include excessive throat
clearing, cough, hoarseness, and
globus pharyngeus (a sensation
of a lump in the throat). These
symptoms are not specific and can
be produced by a wide variety of
other conditions, including; voice
abuse, postnasal drip, infectious

agents, smoking, or allergy.
Hallmark physical findings such
as posterior laryngeal cobblestone
appearance, arytenoid erythema,
and subglottic edema can also be
found in the healthy population.
A frequent occurrence of laryngeal
symptoms such as hoarseness,
cough, globus sensation, throat
clearing, laryngitis and pharyngitis
is observed in patients with GERD.7
Ambulatory 24-hour doubleprobe pH monitoring in the proximal
and distal esophageal regions is
considered as the diagnostic gold
standard for LPR. However, this
procedure is not widely used
by many otolaryngologists as a
diagnostic modality because of
patient resistance, expense, and
its challenging interpretation. 8
Multichannel intraluminal
impedance monitoring is a
r e c e n t l y d e ve l o p e d t e c h n i q u e
which involves arranging
multiple electrode pairs on a pHprobe-type catheter that allows
detection of virtually all reflux
episodes, liquid, gas or mixed. 9-11
Investigative modalities such as
pH monitoring and impedance
studies are generally reserved for
treatment failures. 12
Laryngoscopic findings and
symptom scales like reflux findings
score (RFS) and reflux symptom
index (RSI) have been used for
interpretation of normal and
abnormal pH levels in patients 13,14
and were introduced to overcome
diagnostic limitations and to
permit convenient disease status
follow-up. These scales are
widely used to analyse patients
perception of suspicious LPRD.
Failure to diagnose LPRD can
lead to prolonged symptoms
and delayed healing. Inflammed
laryngeal tissues have a greater
risk of progressing to contact
ulcers and granulomas, evolve to
symptomatic subglottic stenosis
and lower airway disease, and
are more easily damaged from
intubation. 9
Main treatment possibilities for
LPR are lifestyle modifications,

pharmacological and surgical
options. There are four categories of
drugs used in treating LPR: Proton
pump inhibitors (PPIs), H2-receptor
antagonists, prokinetic agents,
and mucosal cytoprotectants. 15
PPIs have been recognized as the
foundation to pharmacological
treatment of LPR. 16,17 These class
of drugs work by blocking the final
step in the H + ion secretion by the
parietal cell and are known to be
safe for long-term administration.
A 3-month empirical trial of PPI
is reg arded as a cost -effect ive
approach to initial assessment
and management of LPR. Several
placebo-controlled studies have
produced results that support the
potential benefits with long-term
P P I u s e . 7,15,18,19 H o w e v e r , P P I
monotherapy cannot completely
resolve symptoms in all cases of
LPRD, and combination therapy
with prokinetic is known to
help in further improvement of
symptoms. 20 The combination of
PPI and prokinetic is synergistic by
decreasing acid production as well
as increasing lower oesophageal
tone and oesophageal clearance
thus producing a better therapeutic
response. Several placebo
controlled studies have proved
that adding prokinetics to PPIs
in the treatment of LPR improves
the outcome, shortens the need for
oral medication helps in speeding
up relief of reflux symptoms and
reduces the rates of recurrence of
symptoms. 21,22
A l t h o u g h f e w s t u d i e s h a ve
been reported on administration
of PPI and prokinetic combination
in Indian patients suffering from
GERD, there is a lacunae of studies
reported on administration of
t he comb inat ion for t r ea t men t
of LPR in Indian population.
The present study is one of the
first reported on Fixed dose
combination of Rabeprazole
(enteric-coated, EC) 20 mg +
Domperidone (sustained release,
SR) 30 mg capsule in the treatment
of Indian patients with LPRD.
This was an investigator initiated

observational study conducted to
evaluate the efficacy and safety
of (F ix ed dose combination of
Rabeprazole (enteric-coated, EC)
20 mg + Domperidone (sustained
release, SR) 30 mg in treatment of
patients with LPRD.
Methods
This was a prospective,
single centre, open-label, noncomparative, observational study
conducted between May2012 and
November2012 at an ENT clinic in
India. The primary objective of the
study was to evaluate the efficacy,
safety and tolerability of fixed
dose combination of Rabeprazole
SR) 30 mg for treatment of LPRD.
The study was approved by an
independent ethics committee and
was conducted in compliance with
the guidelines of the World Medical
Association declaration of Helsinki
in its revised edition (Seoul, 2008),
the guidelines of GCP (CPMP/
ICH/135/95) as well as the Schedule
Y (2005). All patients were given a
detailed description of the study
and their written informed consent
was obtained prior to study.
The patients who visited the
ENT clinic with suspicious LPR
symptoms and requiring Fixed
SR) 30 mg treatment according to
the investigators judgement were
eligible for enrolment for the study.
Rigid laryngoscopy was performed
to document the laryngeal findings
and determine the RFS scores.
Specific inclusion criteria for
LPR patients in the present study
included the following: patients
with more than 18 years of age,
LPR-related symptoms (hoarseness
of voice, dry throat, throat itchiness,
sudden onset of coughing with loss
of breath), having RSI score greater
than 13 and RFS score greater than
7 and those willing to undergo rigid
laryngoscopy. Patients who had
received antacids or PPI treatment

in last 3 months, had history of
receiving radiotherapy or surgery
in the head and neck area, history
o f s e ve r e h e p a t i c i m p a i r m e n t ,
chronic obstructive pulmonary
disease or asthma, lactating and
pregnant women and known
hypersensitivity to any of the
study drugs were excluded from
the study.
The patients were enrolled in
the study on Day 2 (baseline)
and were administered fixed
SR) 30 mg one tablet daily for 90
days on investigators judgement
and fulfilment of the inclusion
and exclusion criteria. Further
study visits were scheduled at 30,
60 and 90 days of treatment. The
efficacy of the study medication
was assessed by the change in RFS
score and RSI score from baseline to
Day 90. The safety and tolerability
of the study drug was assessed by
monitoring adverse events, vital
signs and physical examination.
Reflux Finding Scores (RFS) and Reflux
Symptom Index (RSI)
The RFS serves as a scoring tool

that grades eight specific physical
examination findings which may
be attributed to LPR. Some of the
components are scored as present
or absent while others are graded
with respect to severity. The RFS
score can range from 0 to 26, and
a score greater than 7 suggests
a 95% statistical likelihood of a
positive dual-probe pH study. 13
To supplement the diagnostic
va l u e o f t h e R F S , t h e R S I wa s
created with the intention to serve
as a validated self-administered
9-question survey administered
to patients who graded specific
symptoms on a scale from 0 to 5.
A RSI score greater than 13 was
found to recommend a positive
dual-probe pH study. 14
At t h e e n d o f t h e s t u d y ( 9 0
days), global assessment for
efficacy was done on a 5-point scale
(1=Excellent, 2=Very Good, 3=Good,
29
4=Satisfactory, 5=Poor ) and global

assessment for tolerability was
done on a 3-point scale (1=Good,
2=Moderate, 3=Poor ) by both
investigator and patient.
Statistical Analysis
Statistical analysis was

performed with the SPSS statistics
program (version. 21; SPSS Inc.,
Chicago, IL). The intention-to-treat
(ITT) population was considered
for efficacy and safety analysis
and included all patients who
had taken at least one dose of
study medication. Data describing
categories or nominal data were
expressed as numbers with
percentages. Measurement data
wa s e x p r e s s e d a s m e a n s w i t h
standard deviation.
Paired t-test was performed to
analyse the statistical significance
o f t h e d i f f e r e n c e b e t we e n t h e
baseline and follow-up visits for
total scores for RSI and RSF. For
individual symptom / signs the
comparison of baseline (Day 2)
d a t a w i t h f o l l o w u p d a t a wa s
performed using Friedman test
( n o n - p a r a m e t r i c A N O VA) . A
p va l u e < 0 . 0 5 wa s c o n s i d e r e d
statistically significant.
Results
A t o t a l o f 6 5 p a t i e n t s we r e
screened to enrol 50 in the
study. All the enrolled patients
successfully completed the study.
The demographic details of the
enrolled patients are presented in
Table 1. The mean age was found
to be 45.3 years old and 56% of the
patient population in the study
were females.
The pre-treatment RSI score was
19.18 3.24 (mean SD) which
significantly decreased to 10.20
3.22 and 2.52 2.31 at Day 30 and
Day 90 of Fixed dose combination
of Rabeprazole (enteric-coated, EC)
release, SR) 30 mg treatment,
respectively (p<0.0001). There was
a 46.82% reduction in RSI score at
Day 30 and 86.86% reduction at Day
90 (Table 2). The nine individual
30
Table 1: Demographic details of the

patients (n=50)
No.
Gender
Male
22
Table 2: Change in of reflux symptom index (RSI) and reflux finding score (RFS) scale
from baseline (n=50)
%
Scores
44.00
Female
28
56.00
Mean SD
Age (yrs.)
45.30 9.90
Height (cm) 163.16 5.54
Weight (kg) 65.50 9.38
BMI
24.62 3.34
Min.
24
151
48
18.59
Max.
66
175
85
31.25
BMI: Body mass index; SD: Standard

deviation; Min.: Minimum; Max: Maximum
items of RSI also showed significant

changes (p<0.0001) after 90 days
of treatment (Table 3). Similar
to changes in the RSI score, the
changes in RFS score assessed
at Day 30 and Day 90 were also
significant. The pre-treatment RFS
score was 12.62 1.48 (mean
SD) which significantly decreased
to 1.74 1.24 and 0.30 0.51
at Day 30 and Day 90 of fixed
SR) 30 mg treatment respectively
(p<0.0001) (Table 2). The percentage
reduction in RFS was 86.21% at
Day 30 and 97.62% at Day 90. The
eight individual items of RFS also
showed significant improvement
(p<0.0001) after 12 weeks (90
days) of fixed dose combination of
release, SR) 30 mg treatment (Table
4).
Global assessment of
efficacy at the end of therapy
wa s r a t e d a s e x c e l l e n t ( 1 0 %
by both investigators and
patients),very good (80% by
investigator and 82% by patients)
and good (10% by investigator
and 8% by patients) (Table 5). Both
investigator and patient rated the
product to have good (98%)
tolerability at the end of the study
(Table 6).
Discussion
The importance of diagnosis of
LPRD is developing progressively
in the otolaryngological practice.
RSI
RFS
Screening
Day 30
Day 90
Screening
Day 30
Day 90
Mean
SD
19.18
10.20
2.52
12.62
1.74
0.30
3.24
3.22
2.31
1.48
1.24
0.51
Change from
baseline
Mean
%
change change
-8.98
-46.82
-16.66
-86.86
-10.88
-86.21
-12.62
-97.62
95% CI for
change
Paired t test
Lower
Upper
-9.02
-17.15
-8.94
-16.17
449.00 <0.0001
68.91 <0.0001
-11.29
-12.72
-10.47
-11.92
53.51
61.33
<0.0001
<0.0001
RSI: Reflux Symptom Index; RFS: Reflux Finding Score; SD: Standard Deviation; CI: Confidence
Interval
Table 3: Changes of reflux symptom index (RSI) before and after 30 and 90 days
of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg +
Domperidone (sustained release, SR) 30 mg treatment
Reflux symptom index (RSI)
RSI components
Screening
Day 30
Day 90
Hoarseness of voice
Throat clearing
Excess throat mucus / post-nasal drip
Difficult swallowing
Coughing after eating or lying down
Breathing difficulties or choking episodes
Troublesome or annoying cough
Sticky/lump sensation in throat
Heartburn /chest pain / indigestion /reflux
2.120.87
2.060.65
2.040.57
1.840.62
2.000.61
2.180.69
2.480.54
2.300.54
2.160.74
1.120.87
1.060.65
1.040.57
0.860.57
1.000.61
1.180.69
1.480.54
1.300.54
1.160.74
0.360.63
0.220.42
0.180.39
0.100.30
0.200.45
0.300.46
0.500.51
0.340.48
0.320.55
Friedman test
p
2
95.15 <0.0001
96.14 <0.0001
96.50 <0.0001
93.48 <0.0001
92.98 <0.0001
96.88 <0.0001
99.51 <0.0001
99.03 <0.0001
96.50 <0.0001
Table 4: Changes of reflux finding score (RFS) before and after 30 and 90 days
of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg +
Domperidone (sustained release, SR) 30 mg treatment
Reflux finding score (RFS)
Friedman test
P
Screening
Day 30
Day 90
2
Infraglottic edema (pseudosulcus vocalis) 2.000.00
0.000.00 0.000.00 100.00 <0.0001
Ventricular obliteration
2.000.00
0.000.00 0.000.00 100.00 <0.0001
Erythema / hyperemia
2.080.57
0.120.48 0.000.00 96.16 <0.0001
Vocal fold edema
1.260.49
0.260.49 0.020.14 94.37 <0.0001
Diffuse laryngeal edema
1.180.39
0.200.40 0.000.00 93.89 <0.0001
Posterior commissure hypertrophy
2.220.58
1.160.62 0.280.45 97.28 <0.0001
Granuloma / granulation
0.520.89
0.020.14 0.000.00 25.40 <0.0001
Thick endolaryngeal mucus
1.360.94
0.000.00 0.000.00 68.00 <0.0001
RFS components
It has been recognised as a

different entity from GERD and
otolaryngologists are evaluating
and treating LPRD in their
practice. In GERD, patients mostly
present with oesophagitis and
heartburn. But in LPRD, only 12%
of the patients have heartburn
or oesophagitis. The anatomical
abnormality in LPR is believed
to be at the upper oesophageal
sphincter.23 LPR has been attributed
as a cause of a number of laryngeal
pathologies.
There is great variability in
Table 5: Global assessment for efficacy

on day 90 (n=50)
By investigator By patient
No. of patients No. of patients
(%)
(%)
Excellent
5 (10)
5 (10)
Very good
40 (80)
41 (82)
Good
5 (10)
4 (8)
Satisfactory
0
0
Poor
0
0
the methods of both diagnosis

and treatment of LPR amongst
otolaryngologists. PPIs continue
to be the backbone of therapy for
acid suppression, providing relief
Table 6: Global assessment for

tolerability on day 90 (n=50)
By investigator
By patient
No. of patients No. of patients
(%)
(%)
Good
49 (98)
49 (98)
Moderate
1 (2)
1 (2)
Poor
0
0
of symptoms and healing of erosive

oesophagitis. Recommendations of
treatment with PPIs in suspected
LPR are based on the results
of number of open-label trials,
placebo-controlled trials, and
various meta-analysis studies. 18,20
Combination of PPIs and prokinetic
agents is universally prescribed by
medical practitioners for severe
and resistant GERD and have found
to achieve significant symptomatic
improvement in a number
studies. 22,26 Combinations of these
two agents leads to a significant
increase of pharmacokinetic
parameters like mean Cmax and
mean AUC of PPI which results in
having a synergistic effect on PPI
therapy. 27 Shahani et al conducted
an open label, prospective, noncomparative study to assess
the efficacy and tolerability of
rabeprazole and domperidone in
the treatment of patients suffering
from GERD. The combination was
efficacious in providing significant
symptomatic improvement and
was found to be safe and well
tolerated by patients. 28
The present study was an open
label, single centre, prospective,
observational study to evaluate
the efficacy and safety of fixed
SR) 30 mg in treatment of patients
with LPRD. Often, poor compliance
to therapy is seen in patients
with LPR which leads to poor
symptomatic improvement. 27 In
o u r r e p o r t e d s t u d y ; h o we ve r ,
all the 50 enrolled patients were
followed up over a period of 90
days with fixed dose combination
of Rabeprazole (enteric-coated, EC)
release, SR) 30 mg treatment.
A l l p a t i e n t s we r e f o u n d t o b e
compliant to the study medication,
i.e. took more than 80% of study
medication during the therapy
period. The high percentage of
compliance could be attributed to
the fixed dose combination (FDC)
of PPI and prokinetic drug. It is
a well-known fact that there is
an inverse correlation between
the complexity of a drug regimen
and medication adherence. FDC
therapies are hypothesised to
enhance compliance by decreasing
the number of required pills and
simplify dosing which could result
in better patient adherence to
therapy.28
RSI and RSF scores have been
used for many years in centres
worldwide and are believed
to be valid and reliable in the
documentation of patient treatment
outcomes. 13,14 Patients identified by
positive results of these tests have
a high probability of responding
to 8-12 weeks of PPI treatment. By
implementation of RFS and RSI,
most patients may not require costintensive diagnostic examinations
in the first-line assessment of
LPR and these examinations can
be reserved for non-responders
o f P P I t r e a t m e n t . 29 I n t h i s
study, the RSI and RFS scores
wa s f o u n d t o b e s i g n i f i c a n t l y
reduced after 30 (46.82% and
86.21%) and 90 days (86.86% and
97.62%) respectively. In addition
to significant improvement in total
RSI and RFS scores, individual
components of both the scores
showed significant improvement
after 90 days of therapy (p<0.0001).
This is consistent with the findings
of similar studies conducted by
other authors. 30,31 The investigators
rated global assessment of efficacy
of the combination at the end of
the study as very good in 80%
of patients and global assessment
f o r t o l e r a b i l i t y o f t h e p r o du c t
as good in 98% of patients.
Approximately, 82% patients rated
global assessment of efficacy as
very good and 98% patients rated
global assessment for tolerability
31
as good.
The results of two previous
meta-analysis based on Western
literature failed to show any
significant clinical benefit for PPI
over placebo. 7 However most of
the studies included in the metaanalysis had limitations of either
having a small sample size or of
using a non-standardised rating
for documentation of LPR-related
symptoms and laryngeal findings.
Most of the studies did not use RSI
score in the documentation of LPRrelated symptoms. 31
The stringent inclusion criteria
followed for enrolling the patients
in this study could be one of
the main reasons for obtaining
encouraging results. Patients with
a RSI score less than 13 and RFS
less than 7 were excluded from
our study population. A study
reported by Reichel et al showed
significant improvement in RSI
and RFS with esomeprazole 20 mg
twice daily for 12 weeks duration
c o m p a r e d w i t h p l a c e b o . 32 T h e
authors recruited 62 patients
with RFS greater than 7 and RSI
greater than 13 in the study. Similar
results observed in our study thus
might underline the importance
of stringent inclusion criteria for
enrolment of participants in further
randomized controlled trials for
different treatments of LPRD.
The combination of Rabeprazole
(EC) 20 mg + Domperidone (SR)
30mg studied on Indian population
was found to be safe and well
tolerated. No adverse events were
reported by any of the patients
and no concomitant drugs were
reported to be consumed by the
patients during the study period.
These findings were comparable
to studies conducted with similar
combinations on patients with
GERD. 20,21,24,26
This observational study was
marked by limitations of being
open-label and non-comparative
in design. Despite the constraints
of this study, this is one of the first
study conducted on evaluating
32
the efficacy and safety of fixed

SR) 30 mg in treatment of patients
with LPRD in Indian scenario.
However, the results needs to be
validated by a randomized, double
blind, placebo or comparator
controlled clinical trials.
In conclusion, twelve weeks
treatment with fixed dose
combination of Rabeprazole
SR) 30 mg significantly improved
reflux symptoms in patients with
LPR. The combination was found
to be safe and well tolerated.
Acknowledgements
This was an investigatorinitiated study. The author would

like to thank and acknowledge the
contributions of Abbott Healthcare
Pvt Ltd for providing samples
of fixed dose combination of
release, SR) 30 mg.
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Foster M, Fisher M, et al. Impact of pH
monitoring on laryngopharyngeal reflux
treatment: improved compliance and
symptom resolution. Otolaryngol Head
Neck Surg 2011; 144:558-62.
28. Pan F, Chernew ME, Fendrick AM. Impact
of fixed-dose combination drugs on
adherence to prescription medications. J
Gen Intern Med 2008; 23:611-4.
29. Habermann W, Schmid C, Neumann
K , Devaney T, Hammer HF. Reflux
symptom index and reflux finding score
in otolaryngologic practice. J Voice 2012;
26:e123-7.
30. Lee YS, Choi SH, Son YI, Park YH, Kim SY,
Nam SY. Prospective, observational study
using rabeprazole in 455 patients with
laryngopharyngeal reflux disease. Eur Arch
Otorhinolaryngol 2011; 268:863-9.
31. Lam PK, Ng ML, Cheung TK, Wong BY, Tan
VP, Fong DY, et al. Rabeprazole is effective
in treating laryngopharyngeal reflux in a
randomized placebo-controlled trial.Clin
Gastroenterol Hepatol 2010; 8:770-6.
32. Reichel O, Dressel H, Wiedernders K, Issing
WJ. Double-blind, placebo-controlled trial
with esomeprazole for symptoms and signs
associated with laryngopharyngeal reflux.
Otolaryngol Head Neck Surg 2008; 139:41420.
33
Original Article
Psychological Insulin Resistance in Patients with

Type 2 Diabetes
Sujeet Jha1, Manju Panda2, Surya Kumar3, Rekha Gupta4, Archana Neemani5,
Jenu Jacob 6, Nisha M Thomas7, Archana James7, Swati Waghdhare3, Gunjan Agarwal8
Abstract
Editorial Viewpoint
Aims/hypothesis: To identify risk factors associated with psychological

insulin resistance (PIR) in Indian type 2 diabetes (T2DM) population.
F e a r o f i n j e c t i o n a n d
hypoglycemia, social
stigma and lack of
education are major
factors for psychological
insulin resistance (PIR).
Methods: Patients with T2DM, aged 18 years, undergoing treatment

with oral hypoglycaemic agents and providing written informed consent
were considered eligible for the study. Patients data was collected by
face-to-face interaction using 5 validated diabetes questionnairesDiabetes Attitude Scale, Diabetes Knowledge Test, Diabetes Self-Efficacy
Scale, Interpersonal Processes of Care Survey-29, and Barriers to Insulin
Treatment scale. Demographic variables, categories of patients based
on their annual family income, education, glycosylated haemoglobin
(HbA1c), occupation and type of healthcare setup were correlated with
overall scores of validated questionnaires. Statistical analyses were
performed using Pearson correlation coefficients, analysis of variance,
two-group t-test and hierarchical multiple regression.
Results: One hundred ninty-eight patients with T2DM were enrolled
where 63% were males, 52% had HbA1c <7 % (<53 mmol/mol), 32% were
in service, 35% had the annual family income between Rs 100000-500000,
50% were graduates and 81% were enrolled from private healthcare set
ups. Significant high opposition to use insulin was observed in females,
patients based at home, patients with insufficient education, and patients
visiting government set-ups compared to males, service-class patients,
graduates, and patients approaching private set-ups, respectively.
Conclusions: In India, major factors contributing to PIR were fear of
injection or fear of pain during injection, fear of hypoglycemia, social
stigma and lack of education. Effective interpersonal interactions with
healthcare providers could help to counteract PIR, especially in patients
who are not sufficiently literate highlighting the need of skilled healthcare
staffs in Indian public hospitals.
Introduction
ccording to the International

Diabetes Federation (IDF),
Indias growing economy,
urbanization and the mix of eastern
and western lifestyle has led to
an increased incidence of obesity
and diabetes reaching epidemic
proportion. In 2010, India had
50.8 million people with type 2
diabetes (T2DM) which rose to 62.4

million by 2011. The IDF predicts
that by 2030, India would have
High opposition to insulin

use is observed in females
and home-based and lesseducated patients.
PIR can be countered by
effect ive int erperso n el
interactions with healthcare providers.
approximately 100 million people
with diabetes. 1,2 Strict glycemic
control in T2DM has considerably
reduced the risk of microvascular
disease but not the macrovascular
diseases. 3 The total direct cost for
diabetes treatment in India has
doubled from 1998 to 2005. In 2007,
Ramachandran et al reported an
increase in the cost of treatment with
the duration of diabetes, presence
of complications, hospitalization,
surgery, insulin therapy and urban
setting. 4
There is a positive relationship
b e t we e n g l y c e m i c c o n t r o l a n d
amelioration of diabetes
complications. 5 Both the American
Diabetes Association guidelines
and the European Association
Director, 2Sr. Diabetes Educator, 3Associate Consultant, 7Diabetes Nurse Educator, Institute of Endocrinology
Diabetes and Metabolism, Max Healthcare Inst. Ltd., New Delhi; 4Diabetes Educator, RG Diabetes and Healthcare
Centre, Varanasi, Uttar Pradesh; 5Diabetes Nurse Educator, Kalazar Research Center, Muzaffarpur, Bihar; 6Diabetes
Nurse Educator, Institute of Endocrinology, Max Healthcare, Gurgaon, Haryana; 8Sr. Medical Writer, Medical
and Scientific Writing Dept., Max Neeman International, New Delhi
Received: 14.05.2013; Revised: 22.01.2014; Accepted: 29.01.2014
1
34
guidelines for the Study of

D i a b e t e s r e c o m m e n d s t o h a ve
a rapid addition of medications
and transition to new regimens
to achieve target glycemic goals
and to use insulin in patients
who do not meet goals with two
or three oral agents. 6 Given the
progressive nature of T2DM and
the declining beta-cell function,
insulin is considered as a choice
of initial therapy in most of the
patients with T2DM. 7 However,
considerable resistance both on
part of patients and clinicians
to initiate insulin therapy has
been reported. 9 This psychological
opposition or reluctance to use
insulin is termed as psychological
insulin resistance (PIR). 10,11 Various
clinical trials have been conducted
to study the factors associated with
PIR worldwide. An international
survey of over 3600 nurses and
doctors in 13 countries reported
that clinicians and healthcare
workers who delayed in initiating
insulin therapy also delayed in
initiating oral medication. On
the other hand, specialists and
opinion leaders were less likely
to delay insulin initiation. Several
factors like self-blame, concern
about life-restriction, fear of social
rejection, fear of weight gain, fear of
hypoglycemia, wrong attitude and
behaviour of healthcare team and
the perception that insulin therapy
worsens diabetes have been some
of the most unwarranted fears and
misperceptions in patients about
insulin treatment. 12,13
Though several global studies
h a ve i n ve s t i g a t e d r i s k f a c t o r s
l e a d i n g t o P I R , 9-11 t h e r e h a v e
been only few Indian studies
b a s e d o n P I R . 14-16 O n e o f t h e
Indian study, Chennai Urban
Rural Epidemiological Study
(CURES), identified various
patient and physician-associated
f a c t o r s l e a d i n g t o P I R . 14 S o m e
of the patient-associated factors
were lack of knowledge about
diabetes and its associated
complications, poor adherence
to treatment regimens and poor
health literacy; and the suboptimal

knowledge of guidelines, time and
facility constraints and attitudinal
issues were few of the physician
as s oc iat ed fact ors. Two recent
Indian studies reported patients
of lower socioeconomic groups to
have poor self-care activities with
regard to diet and exercise and
emphasized on adequate targeted
health education to improve their
self-care behavior. 15,16
The present study was conducted
to explore different psychological
risk factors associated with PIR in
Indian T2DM population using 5
validated questionnaires. These
psychological risk factors would
help healthcare professionals
in identifying problem areas so
that education can be targeted
to those groups and areas so as
to increase insulin acceptability
among patients with T2DM.
Methods
T h i s wa s a c r o s s - s e c t i o n a l ,
retrospective, non-interventional
survey of 206 patients with T2DM.
Of these, data of 198 patients
were analyzed and the incomplete
data of remaining 8 patients was
excluded.
The study protocol was
approved by the ethics committee
of Max Healthcare. To gather
data from varying socioeconomic
groups, patients were recruited
from different healthcare set upsgovernment organizations, tertiarycare private hospitals and private
c l i n i c s . T h e s t u d y d e s i g n wa s
based on the previous literature. 11
T h e s t u d y wa s c a r r i e d o u t i n
accordance with the principles
of the Declaration of Helsinki as
revised in 2000.
Patients who met all the inclusion
criteria and none of the exclusion
criteria were enrolled in the study.
The inclusion criteria were age
18 years, diag nosis of t y pe 2
diabetes, treatment with the oral
hypoglycemic agents, ability to
communicate in English/Hindi, and
ability to provide written informed
c o n s e n t . Pa t i e n t s w i t h t y p e 1
diabetes, severe psychiatric disease
(e.g., active schizophrenia and
drug dependency) or on current/
previous insulin treatment were
excluded from the study. The study
was conducted in co-ordination
with the local physicians. Besides
medical and socioeconomic history,
the patients data was obtained
by mostly face-to-face interaction
and incomplete information was
collected telephonically using 5
different validated questionnairesDiabetes Attitude Scale (DAS-3
which assessed patients diabetes
attitude), Diabetes Knowledge
Test (DKT which assessed patients
diabetes knowledge), Diabetes
Self-Efficacy Scale (DSES which
assessed patients self-efficacy
and how confident a patient feels
while doing certain activity/ies),
Interpersonal Processes of Care
Survey- 29 (IPC-29 which assessed
an understanding of how a patient
feels while talking to doctors
and their staff ) and Barriers to
Insulin Treatment (BIT which
assessed patients barriers to
insulin treatment). 17-21 BIT score
was considered as a direct measure
of PIR and other 4 scores (DKT,
D S E S , I P C - 2 9 a n d D A S ) we r e
compared against BIT; serving as
an indirect measure of PIR.
To identify potential risk
factors leading to PIR, different
demographic variables viz. age,
height, weight, body mass index
(BMI), blood pressure; different
categories of patients based on
their annual family income,
level of education, glycosylated
haemoglobin (HbA1c) level,
occupation and the type of
healthcare setup were compared
with overall scores of validated
questionnaires. Four categories of
patients were constructed based
on their annual family income:
> Rs1000000 (18,260.00 USD),
Rs1000000-Rs500000 (9,130.00
USD),Rs500000-Rs100000 (1,826.00
USD),and< Rs100000 (1833.52
USD); 3 categories were based on
the education level- graduates
Table 1: Patient characteristics

(Total Patients = 198)
Parameters
Value
Type of hospitals, n (%)

Private
161 (81%)
Government
37 (19%)
Gender, n (%)
Female
68 (34.3)
Male
125 (63.1)
Age (years), mean (SD)
51.6 (10.8)
Height (cm), mean (SD)
163.1 (11.0)
Weight (kg),a,b mean (SD) 71.8 (13.1)
BMI (Kg/m2),b,c mean (SD) 27.2 (6.1)
HbA1c, mean (SD)
9.2 (3.5)
Blood pressure
Systolic (mmHg)
126.08 (15.6)
Diastolic (mmHg)
81.1 (11.1)
Annual family income, n (%)
<100000
21 (10.6)
100000-500000
70 (35.4)
500000-1000000
65 (32.8)
>1000000
23 (11.6)
Level of education, n (%)
Graduate
98 (49.5)
No formal education 19 (9.6)
Schooling
57 (28.8)
Other
2 (1.0)
Occupation, n (%)
At home
61 (30.8)
Business
35 (17.7)
Service
63 (31.8)
HbA1c, n (%)
<7
104 (52.5)
7-9
49 (24.7)
>9
42 (21.2)
Average BIT, mean (SD)
5.4 (1.6)
Fear of injection
4.3 (3.1)
Fear of hypoglycemia 6.7 (2.6)
Stigmatization
5.8 (2.5)
Expected hardship
4.9 (2.6)
Expectation regarding
6.0 (2.4)
positive outcome
Average DAS,d mean (SD) 3.5 (0.5)
Average DKT, mean (SD) 16.7 (3.3)
Average IPC-29, mean (SD) 2.8 (0.5)
Average DSES, mean (SD) 7.0 (1.8)
Negative correlation with average BIT;
Positive correlation with average DSES;
c
Negative correlation with average IPC-29;
d
Positive correlation with average DSES
and IPC-29
a
(holding postgraduate/ doctorate

degree), schooling (either schooling
education or undergraduate
degree), and no formal education;
3 categories were based on the
H b A 1 c l e ve l ( < 7 % [ 5 3 m m o l /
mol], 7-9% [53-75 mmol/mol], >
9% [75 mmol/mol]); 3 categories

we r e b a s e d o n t h e o c c u p a t i o n
level: service, business, and no
occupation (included housewives
and retired patients); and 2
categories were based on the type
of healthcare set up (private and
government hospitals).
All the medical records were
collected by healthcare workers
from the physicians office and
Max Neeman International (a
clinical research organization)
used SAS 9.1.3 to perform the
statistical analyses of the data.
Descriptive statistics was presented
for PIR and the level of significance
a m o n g d e m o g r a p h i c va r i a b l e s
wa s c o m p a r e d b y a n a l y s i s o f
variance (ANOVA) and two group
t-test. Correlation analyses were
done to analyze the relationship
between different demographic
variables and DAS, DKT, IPC-29,
DSES, and BIT (and its subscales)
scores. A hierarchical multiple
regression model was constructed
to investigate the effect of the
demographic variables (selected
from significant correlation [P
0.05] with PIR), the five subscales
for DAS, and possible interaction,
i.e., the DAS subscales and DSES
on PIR. All the statistical tests were
two sided and type I error was
controlled at 0.05 level.
Results
Of 198 patients, 63% (n=125)
were males, 52% (n=104) had
HbA1c <7 % (<53 mmol/mol),
32% (n=63) were in service, 35%
(n=70) had the annual family
income between Rs 100000-500000
and 50% (n=98) were graduates.
Approximately 81% (n=161) of the
patient population were enrolled
from private healthcare set ups
(Table 1).
Following factors were
considered as obstacles in the use of
insulin treatment: fear of injections,
fear of pain while injecting insulin,
fear of pain during regular blood
checks, low expectations regarding
positive outcome of the treatment
35
(like insulin works better than pills,

patients using insulin feels better,
i n s u l i n c a n p r e ve n t l o n g - t e r m
complications due to diabetes),
higher expected hardships (a feeling
that more time would be required
for regular insulin dosing, could
not pay as close attention to the
diet as insulin treatment requires
or could not organize the day as
carefully as required for insulin
treatment), higher stigmatization (a
feeling of embarrassment of using
injections in public and found pills
to be more discreet, had a feeling
of dependency in case of regular
insulin treatment), and the fear of
hypoglycaemia.
Patients who had higher fear
of injection or of pain during
injection or of pain during regular
blood checks had higher fear
o f h y p o g l y c a e m i a , we r e m o r e
embarrassed to take injections in
public, and had higher apprehension
in using insulin. None of the
DAS subscale was statistically
significantly correlated with
overall BIT score (Table 2). Patients
believed that apprehensions to
use insulin will be allayed by the
trained persons. No correlation
was observed between BIT and
other scores. However, a positive
correlation was observed between
DAS and DSES and DSES and IPC
(Table 3).
Different categories of patients
based on their gender, annual
family income, level of education,
occupation, HbA1c level, and type
of healthcare setup were compared
with different PIR questionnaires
(Table 4). Gender-wise, females
had statistically significantly
higher fear of injection, higher
apprehension in using insulin and
feel more embarrassed to take
insulin injections in public leading
to significant higher BIT score than
males. Patients who were based at
home had a higher fear of injection
and stigmatization than service
class patients and businessmen.
Patients with no formal education
had statistically significantly
higher BIT score than graduates.
36
Table 2: Correlation of DAS subscales with BIT, DKT, DSES and IPC score
DAS subscales
Mean
Need for special Seriousness of
Value of
Psychosocial
Patient
BIT
training
NIDDM
tight control impact of DM
autonomy
*
*
*
*
0.40
0.53
0.81
-0.09
Need for special
1.0
0.39
training
Seriousness of
1.0
0.59*
0.43*
0.30*
-0.003
NIDDM
0.20*
-0.08
Value of tight
1.0
0.35*
control
-0.08
Psychosocial
1.0
0.46*
impact of DM
Patient
1.0
-0.08
autonomy
Parameters
BIT subscales
Mean
BIT
Fear of injection
Expectation
Expected Stigmatization
Fear of
positive outcome hardship
hypoglycemia
Fear of injection
1.0
0.001
0.18*
0.22*
0.17*
0.65*
Expectation
1.0
0.04
-0.004
0.09
0.40*
positive outcome
Expected
1.0
0.3*
0.04
0.6*
hardship
Stigmatization
1.0
0.23
0.64*
Fear of
1.0
0.47*
hypoglycemia
Parameters
Mean
DAS
Mean
DSES
Mean
IPC
DKT
total
score
0.75*
0.14
0.21*
-0.3*
0.06
0.12
0.02
0.02
-0.08
-0.04
-0.1
0.05
0.16*
-0.02
0.07
-0.06
0.67*
0.15
0.18*
-0.34*
Mean
DAS
Mean
DSES
Mean
IPC
DKT
total
score
-0.1
-0.01
-0.16
0.24*
0.19*
-0.16
0.07
0.01
-0.01
-0.23*
0.003
0.09
-0.08
0.04
-0.03
0.11
0.06
0.22*
0.08
0.14
*Statistical significant correlation; negative sign denotes a negative correlation between PIR scale
Table 3: Correlation of PIR parameters

Parameters
Mean BIT
Mean DAS
Mean DSES
IPC Average
DKT total score
Mean
BIT
1.0
Mean
DAS
-0.09
1.0
PIR scales
Mean
DSES
-0.07
0.23*
1.0
Mean
IPC
0.1
0.04
0.28*
1.0
DKT total
score
0.07
-0.09
-0.05
0.02
1.0
*
Statistical significant correlation; negative sign denotes a negative correlation between PIR
scale
Annual family income did not serve

as a potential factor of PIR. Patients
v i s i t i n g g o ve r n m e n t h o s p i t a l s
had not only a higher BIT score
than patients at private hospitals
but had statistically significantly
lower DAS, DSES and IPC scores.
Patients with HbA1c <7% (53 mmol/
mol) reported lower IPC score than
patients with HbA1c between 7-9 %
(53-75 mmol/mol).
Discussion
This was a first major
observational, non-interventional,
a n d c r o s s - s e c t i o n a l s u r ve y i n
Northern India determining
factors for psychologically induced
barriers in initiating and complying
with insulin treatment based on
5 validated questionnaires. The

benefits of insulin therapy in
achieving glycemic control and
reducing risk of long-term diabetes
complications are well documented.
However, it remains underutilized
reflecting numerous barriers to
initiation of treatment with insulin
and obstacles hindering patients
adherence to insulin treatment. 22
The landmark study on diabetes,
t h e D i a b e t e s At t i t u d e Wi s h e s
and Needs (DAWN) highlighted
that resistance to insulin use
was a major problem in patients
and healthcare providers alike,
and are often psychologically
induced and founded on myths
and false believes.9 In India,
majority of the population are
not sufficiently literate with low
awareness on diabetes-care leading

t o c o n s i d e r a b l y h i g h P I R . 23,24
Education programs have been
reported to play a key role in
removing myths and false beliefs in
people. Several studies emphasized
that training programmes on the
use of insulin if provided at the
ve r y o u t s e t o f d i a b e t e s c o u l d
help t o overcome unnec essa ry
p s y c h o l o g i c a l b a r r i e r s . 25-27 I n
India, public sector hospitals are
comparatively less in number than
European counterparts, as a result
these setups are over-burdened
to cater a large population. The
government funded superspeciality
hospitals dealing with specialized
diseases such as diabetes are even
less. Therefore, Indian healthcare
is mostly dependant on the private
healthcare providers. In 2004,
Skinner reports that diabetes
patients with PIR need more
support system as they have
insufficient knowledge about
diabetes; 28 requiring more support
from diabetes educators who
through their in-depth knowledge
and skills in biological and social
sciences, communication, and
counseling could help people with
37
Table 4: Determination of psychological insulin resistance

Parameters
Fear of
injection
BIT variables
Expectations
Expected
Fear of
positive
Stigmatization
hardship
hypoglycemia
outcome
Gender, mean (SD)a

Females
5.6 (3.2)
5.9 (2.3)
Males
3.6 (2.9)
6.0 (2.4)
Occupation, mean (SD)b
At home
5.0 (3.2)
6.2 (2.3)
Business
4.3 (3.0)
5.5 (2.5)
Service
3.3 (2.7)
6.2 (2.4)
Level of education, mean (SD)b
No formal
6.4 (2.6)
5.6 (2.0)
education
Highschool
4.3 (3.0)
6.4 (2.3)
Graduate
4.1 (3.0)
6.0 (2.4)
Annual family incomeb
<100000
3.4 (3.1)
6.1 (2.0)
1000004.0 (3.1)
5.8 (2.2)
500000
5000004.7 (2.9)
6.4 (2.6)
1000000
>1000000
5.1 (3.7)
5.6 (2.3)
Types of Hospital
Private
4.04 (3.1)
5.94 (2.5)
6.49 (1.7)
Government 5.49 (2.9)
HbA1C, mean [SD] (mol/mol)
<7% (53)
3.9 (2.9)
6.2 (2.3)
7-9% (53-75)
4.6 (3.1)
6.3 (2.2)
>9% (75)
4.7 (3)
5.6 (2.7)
Average
BIT
DKT
DAS
DSES
IPC
5.7 (2.9)
4.6 (2.4)
6.5 (2.4)
5.5 (2.6)
6.7 (2.5)
6.8 (2.7)
6.0 (1.5)
5.1 (1.6)
16.6 (3.7)
16.7 (3.2)
3.5 (0.4)
3.5 (0.5)
6.8 (1.9)
7.0 (1.8)
2.6 (0.5)
2.8 (0.5)
5.5 (2.9)
4.7 (2.5)
4.8 (2.4)
6.3 (2.5)#
4.9 (2.5)
5.9 (2.5)
6.9 (2.5)
6.4 (3.0)
6.6 (2.5)
5.8 (1.4)#
5.0 (1.8)
5.3 (1.5)
16.2 (3.9)
16.1 (2.8)
17.8 (3.6)
3.5 (0.5)
3.7 (0.4)*
3.4 (0.6)
6.8 (1.9)
7.0 (1.9)
6.6 (1.7)
2.8 (0.5)
2.7 (0.5)
2.8 (0.5)
6.3 (2.2)
7.0 (1.5)
7.6 (1.2)
6.5 (0.7) $
14.3 (2.3)
3.3 (0.4)
6.0 (1.8)
2.8 (0.5)
5.0 (2.9)
4.6 (2.5)
6.5 (2.0)
5.4 (2.9)
6.4 (3.0)
7.0 (2.5)
5.6 (1.5)
5.2 (1.7)
16.5 (3.2)
17.0 (3.4)
3.5 (0.5)
3.5 (0.41)
5.6 (2.6)
7.0 (1.8)
2.9 (0.5)
2.7 (0.5)
4.7 (2.5)
7.1 (1.7)
7.6 (2.0)
5.6 (1.2)
15.4 (4.5)
3.3 (0.6)
5.9 (2.0)
2.7 (0.5)
5.6 (2.9)
6.1 (2.4)
6.4 (2.5)
5.5 (1.6)
16.0 (3.2)
3.5 (0.4)
6.7 (1.9)
2.8 (0.5)
4.6 (2.5)
5.1 (2.4)
6.9 (2.6)
5.3 (1.5)
17.5 (3.1)
3.6 (0.4)
7.1 (1.8)
2.7 (0.5)
4.9 (2.3)
7.0 (2.8)
7.4 (3.1)
5.9 (1.9)
17.8 (3.6)
0.7 (0.7)
7.8 (1.4)
2.8 (0.6)
4.66 (2.6)
6.46 (2.0)
5.77 (2.6)
6.22 (2.1)
6.67 (2.8)
7.02 (1.7)
5.23 (1.6)
6.46 (1.2)
7.24 (1.8)
5.82 (1.5)
2.84 (0.5)
2.56 (0.5)
5.1 (2.6)
4.9 (2.7)
4.6 (2.4)
5.8 (2.5)
5.7 (2.6)
6.1 (2.5)
6.8 (2.6)
7.0 (2.4)
6.3 (2.8)
5.4 (1.4)
5.6 (1.5)
5.3 (1.9)
6.9 (1.9)
7.1 (1.7)
6.9 (1.9)
2.7 (0.5)
3.0 (0.4)
2.9 (0.4)
16.83 (3.3) 3.52 (0.5)

15.13 (4.2) 3.18 (0.3)
16.6 (2.6)
16.2 (4.1)
17.4 (4.1)
3.6 (0.4)
3.4 (0.5)
3.4 (0.6)
a
P-value calculated using independent T-test; bP-value calculated by Tukeys studentized range test; Statistically significant higher in: female versus
male; at home versus service; #at home versus business; *business versus service; high school versus graduate; $no formal education versus graduates;
no formal education versus high school; 500000-1000000 and >1000000 versus <100000 and private versus government; <7 versus 7-9
and at risk for diabetes and related

conditions. Nowadays, the services
of diabetes educators are available
in large private hospitals in India.
However, most public hospitals
do not have the services of trained
diabetes educators despite their
increasing need as public hospitals
mostly cater to people from poor
and low socioeconomic strata. In
our study, patients attached with
private hospitals showed low PIR
than public hospital, highlighting
t h e i m p o r t a n t r o l e p l a ye d b y
diabetes educators or nurses with
specialized diabetes certification.
Unfortunately, Certified Diabetes
Educator (CDE) credentials and/
or Board Certified in Advanced
Diabetes Management (BC-ADM) 22
are not recognized in India unlike
United Kingdom, United States
and most European countries.
Hence, the present study indicates
the need of diabetes educators/

skilled diabetes educator nurses
f o r g o ve r n m e n t h o s p i t a l s t h a t
mostly cater to people who are not
sufficiently literate and belong to
low socioeconomic class. Given
the importance of diabetes nurse
educator in diabetes care and
support, government should take
i n i t i a t i ve s t o e n s u r e d i a b e t e s
educators in every government
primary and tertiary hospitals and
introduce courses specializing in
diabetes education. In 2007, project
HOPE was initiated with an aim
to train and educate healthcare
professionals in India about
diabetes. In 2009, Venkataraman et
al reported that patient-education
a n d s e l f - c a r e wa s a n e c e s s i t y ,
especially in developing countries
like India where trained healthcare
professionals (physicians and
nurses) and modern medical care
remained out of reach for poor and

destitute. 29
Clinicians remain the first
point of contact for patients and
play a pivotal role in promoting
psychological support to diabetes
patients and educate them the
need for strict adherence to insulin
therapy. Recently, Hasan et al
noted that there was considerable
improvement in self-monitoring
and self-care after patient
education by means of educational
programs (like continuing medical
education and trainings), and
hence, highlighted the need of
t a r g e t e d e d u c a t i o n . 3 0 , 3 1 I t wa s
observed that education to diabetic
patients would be effective if the
level of knowledge and attitude
towards diabetes could be known
beforehand. Therefore, we used
DAS-3 score to measure diabetesrelated attitudes towards diabetes.32
38
In our study as well,

more educated service-class
(professional) patients with good
salaries showed lower reluctance to
use insulin, had positive attitudes
and improved self-care on diabetes
as was evident from their higher
DAS and DSES scores than patients
with either no formal education
or low income. It was observed
that educated patients were
understandable, had increased
comprehension of talk with
physician and receptive to their
suggestions provided leading to
less reluctance to use insulin.
Self-efficacy is an indicator
of future behaviour, and serves
as the inducer or inhibitor of
appropriate actions. Increased selfefficacy could enhance adherence
to recommended treatment
regimens in a chronic disease such
as diabetes.
In our study, fear of injection
and fear of hypoglycemia were
major determining factors for PIR.
Besides, females, less educated
and non-working patients reported
higher fear of injections than males,
higher educated and working
class patients. Our findings were
in concordance with the past
literature where females showed
more unwillingness to initiate
insulin treatment than males. 4,11,33
The fear of weight gain with the
use of insulin, especially in females,
further aggravates their reluctance
to use insulin. 34,35
Cleary indicated that satisfaction
with healthcare and clinicians was
the key indicator of the qualityof-care (QoC). 36 In 1999, Stewart
et al reported that interpersonal
processes of care were the key
components of quality and defined
a s p s y c h o so c i a l a s p ec ts of th e
patient-physician interaction, such
as communication, friendliness,
and sensitivity. 37 In comparison
to the overburdened government
hospitals, higher QoC has been
reported at most of the private
hospitals. In our study as well,
patients visiting private hospitals
were more satisfied with the
healthcare services, had higher

attitude towards diabetes and had
low opposition toward insulin use.
Our study had few limitations.
Firstly, the parameters used
to assess PIR were based on
patients self-reported beliefs and
expectations which did not mimic
the actual patient behavior. Hence,
the data obtained does not give the
true picture of patient reluctance to
use insulin. Secondly, attitudinal
items were necessarily limited, and
thirdly, the study involved only a
limited pool of patient population.
Hence, large studies with huge
patient database would help to
provide conclusive remarks on
factor contributing PIR in Indian
diabetes patients. However, the
present study presented large
heterogeneity in patient population
by including them from both private
and government hospitals; data
from this study would definitely
help to improve healthcare system
at government-run hospitals.
Conclusion
In conclusion, in India, the
major contributing factors to PIR
are fear of injection or fear of pain
during injection including fear of
hypoglycemia. Social stigma and
lack of education are other major
factors presenting PIR to Indian
diabetic patients. However, PIR
in Indian diabetes patients could
be lowered by good and effective
interpersonal interactions with
healthcare providers.
References
1.
Shetty P. Public health: Indias diabetes time

bomb. Nature 2012; 485(7398):S14-6.
2.
Sicree R, Shaw J, Zimmet P. Diabetes

and impaired glucose tolerance in India.
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Diabetes Federation: 2006; 15-103.
3.
Ramachandran A, Shobhana R, Snehalatha

C, et al. Increasing expenditure on health
care incurred by diabetic patients subjects
in a developing country. Diabetes Care
2007; 30:252-256.
4.
King P, Peacock I, Donnelly R. The UK

prospective diabetes study (UKPDS):
clinical and therapeutic implications for
type 2 diabetes. Br J Clin Pharmacol 1999;

48:643-8.
5.
Effects of Glycemic Control on Diabetes

Complications and on the Prevention of
Diabetes. Clinical Diabetes 2004; 22:162166.
6.
Nathan DM, Buse JB, Davidson MB, et al.

Medical management of hyperglycemia in
type 2 diabetes: a consensus algorithm for
the initiation and adjustment of therapy:
a consensus statement of the American
Diabetes Association and the European
Association for the Study of Diabetes.
Diabetes Care 2009; 32:193
7.
Davis SN, Renda SM. Psychological insulin

resistance: overcoming barriers to starting
insulin therapy. Diabetes Educ 2006;
32(Suppl4):146S-152S.
8.
Rosenstock J, Riddle MC. Insulin therapy in

type 2 diabetes. In The CADRE Handbook of
Diabetes Management. Cefalu WT, Gerich
JE, LeRoith D, Eds. New York, Medical
Information Press: 2004; 145168.
9.
Peyrot M, Rubin RR, Lauritzen T, et al.

Resistance to insulin therapy among
patients and providers: results of the crossnational Diabetes Attitudes, Wishes, and
Needs (DAWN) study. Diabetes Care 2005;
28:2673-9.
10. Polonsky WH, Villa-Caballero L, Fisher L,

et al. Psychological insulin resistance in
patient with type 2 diabetes- the scope of
the problem. Diabetes Care 2005; 28:25432545.
11. Nam S, Chesla C, Stotts NA, et al. Factors
associated with psychological insulin
resistance in individuals with type 2
diabetes. Diabetes Care 2010; 33:1747-9.
12. Stehouwer M. Glimepride and insulin
multicentre in NIDDM: hypoglycaemic
events and perceived barriers to good
glycaemic control. Diabetologia 1998;
42(Suppl1):A250.
13. Bogatean MP, Hancu N People with
type 2 diabetes facing the reality of
starting insulin therapy: Factors involved
in psychological insulin resistance. Practical
Diabetes International 2004; 21:247252.
14. Deepa M, Deepa R, Shanthirani CS, et al.
Awareness and Knowledge of diabetes
in Chennai-the Chennai Urban Rural
Epidemilogy Study (CURES-9). J Assoc
Physicians India 2005; 53:283-7.
15. Shobhana R, Begum R, Snehalatha C, et al.
Patients adherence to diabetes treatment.
J Assoc Physicians India 1994; 47:1173-5.
16. Gopichandran V, Lyndon S, Angel MK, et al.
Diabetes self-care activities: A community
based survey in urban southern India. Natl
Med J India 2012; 25:14-17.
17. Anderson RM, Fitzgerald JT, Funnell MM, et
al. The third version of the Diabetes Attitude
Scale. Diabetes Care 1998; 21:14031407.
18. Fitzgerald JT, Funnell MM, Hess GE, Barr

et al. The reliability and validity of a brief
diabetes knowledge test. Diabetes Care
1998; 21:706-710.
et al. Awareness, about diabetes and its

complications in the general and diabetic
patients population in a city in southern
India. Diabetes Res Clin Pract 2007; 77:433-7.
19. Rapley P, Passmore A, Phillips M. Review

of the psychometric properties of the
Diabetes Self-Efficacy Scale: Australian
longitudinal study. Nurs Health Sci 2003;
5:289297.
25. Azmiah ZN, Zulkarnain AK, Tahir A.

Psychological Insulin Resistance (PIR)
Among Type 2 Diabetes Patients at Public
Health Clinics in Federal Territory of
Malaysia. Int Medic J Malay 2011; 10:7-12.
20. Stewart AL, Napoles-Springer A, PerezStable EJ. Interpersonal processes of care

in diverse populations. Milbank Q 1999;
77:305339
26. Meece J. Dispelling myths and removing

barriers about insulin in type 2
diabetes.Diabetes Educ2006; 32(Suppl):9S
18S.
21. Petrak F, Stridde E, Leverkus F, et al.

Development and validation of a new
measure to evaluate psychological
resistance to insulin treatment. Diabetes
Care 2007; 30:21992204
27. Aljasem LI, Peyrot M, Wissow L et al. The

impact of barriers and self-efficacy on
self-care behaviors in type 2 diabetes.
Diabetes Educ 2001; 27:393-404.
22. http://www.diabeteseducator.org/export/
sites/aade/_resources/pdf/Definition_
Diabetes_Educator.pdf
23. Rema M, Premkumar S, Anitha B, et
al. Prevalence of Diabetic patients
Retinopathy in Urban India: The Chennai
Urban Rural Epidemiology Study (CURES)
Eye Study-1. Invest Ophthalmol Vis Sci 2005;
46:2328-33.
24. Murugesan N, Snehalatha C, Shobhana R,
28. Skinner TC. Psychological barriers. Eur J

Endocrinol 2004; 151(Suppl2): T13-7
29. Venkataraman K, Kannan AT, Mohan V.
Challenges in diabetes management with
particular reference to India. Int J Diab Dev
Ctries 2009; 29:103-9.
30. Hasan H, Zodpey S, Abhay S. Diabetes care
in India: Assessing the need for evidencebased education. South-East Asian J Medic
Educ 2011; 5:15-18.
39
31. Herman WH. Evidence-based diabetes care.

Clin Diabetes 2002; 20:22-23.
32. Van Zyl DG, Reeder P. Survey on knowledge
and attitudes regarding diabetic patients
inpatient management by medical and
nursing staff at Kalafong Hospital. JEMDSA
2008; 13:90-97.
33. Rosenstock J, Wyne K. Insulin treatment
in type 2 diabetes. In: Goldstein B, MllerWieland D, eds. Textbook of Type 2
Diabetes. London: Martin Dunitz 2003;
131154.
34. Larkin ME. Overcoming psychological
barriers to insulin use. US Endocrinolgy
2008; 46-48.
35. Brod M , Kongs JH, Lessard S, et al.
Psychological insulin resistance: patient
beliefs and implication for diabetes
management. Qual Life Res 2009; 18;23-32.
36. Cleary PD, McNeil BJ. Patient satisfaction as
an indicator of quality care. Inquiry 1988;
25:25-36.
37. Stewart AL, Npoles-Springer A, PrezStable EJ. Interpersonal processes of care
in diverse populations. Milbank Q 1999;
77:305-39.
41
Review Article
Echocardiography in a Patient on Mechanical

Ventilation
Ankush Sachdeva1
Abstract
Cardiopulmonary interactions or effects of spontaneous and mechanical
ventilation (MV ) were first documented in the year 1733. Stephen
Hales showed that the blood pressure of healthy individual fell during
spontaneous inspiration and he later went on to discover the ventilator.
A year later Kussmaul described pulsus paradoxus (inspiratory absence
of radial pulse) in patients with tubercular pericarditis. Echocardiography
can help to diagnose a wide variety of cardiovascular diseases and can
guide therapeutic decisions in patients on mechanical ventilation.
Introduction
pontaneous and mechanical

ve n t i l a t i o n i n d u c e c h a n g e s
in intrapleural or intrathoracic
pressure or lung volume. These
changes can independently affect
the cardiovascular performance
i.e. atrial filling or preload,
the impedance to ventricular
emptying or afterload, heart
rate or myocardial contractility.
Echocardiographic examination
i s wa r r a n t e d i n h e m o d y n a m i c
instability either due to ventricular
failure, pulmonary embolism,
hypovolemia, valvular dysfunction,
cardiac tamponade or in patients on
MV after cardiothoracic surgery.
Other issues which need a good
e c h o c a r d i o g r a p h i c e va l u a t i o n
in such clinical setting include
infective endocarditis, aortic
dissection or rupture, cardioembolism and hypoxemia.
Influence of Ventilation on
Cardiac Function
Changes in intrathoracic
pressures are transmitted to the
heart and pericardium, the great
arteries and viens. Spontaneous
inspiration produces a negative

pleural pressure, the reduction
in intrathoracic pressure is
transmitted to right atrium. In
c o n t r a s t , i n t e r m i t t e n t p o s i t i ve
pressure ventilation (IPPV)
produces inspiratory increase in
intrathoracic pressures thereby
increasing the right atrial (RA)
pressures and if posit ive endexpiratory pressure (PEEP) is
added, these pressures will remain
greater than atmospheric pressure
throughout the respiratory cycle.
Major compromise in cardiac
output by impeding venous return
may be seen in cases of septic shock
and hypovolemia. 1
Hemodynamic Changes
During Weaning
Cardiac-related weaning
failure can be assessed by
echocardiography. High risk
weaning failure can be detected
by low ejection fraction (LVEF),
diastolic dysfunction and elevated
LV filling pressures. LV filling
pressures and progression of

diastolic failure can be followed
by transthoracic echocardiography
(TTE). In patients with weaning
failure, significantly lower heart
rate and E/E ratio and higher
LV E F a r e o b s e r v e d b e f o r e
spontaneous breathing test (SBT).
During SBT, significant increase
in cardiac output, systolic arterial
pressure, E/A ratio relation and
non-significant increase in E/E
a r e o b s e r ve d w i t h s i g n i f i c a n t
shortening of deceleration time
( D T E ) . Pe r c e n t a g e o f we a n i n g
failure goes on increasing as LVEF
declines. In simple terms, the
patients with weaning failure are
t a c h y c a r d i c , h a ve a d e p r e s s e d
systolic and diastolic function
(shorter DTE) with elevated LV
filling pressures (higher E/E
ratio) before SBT and during SBT
a further increase in LV filling
pressure (increase E/A and
E/E ratio) and deterioration of
diastolic dysfunction is observed.
Transthoracic echocardiography
(TTE) is able to identify patients
who are at risk of cardiac related
we a n i n g f a i l u r e b y m e a s u r i n g
LVEF, E/E and DTE before SBT. 2
During SBT, hemodynamic changes
i.e. increase in pulmonary capillary
wedge pressure (PCWP) and
changes in stroke volume can be
followed up by TTE (Figure 1)
Limitations include poor window,
patients in atrial fibrillation and
paced rhythm. Practical approach is
to do a TTE before SBT, second SBT
in cardiac-related weaning failure
Junior Consultant Cardiologist, Fortis Escorts Heart Institute, Okhla, New Delhi
42
(TEE) accurately predicts increase

in CO with volume expansion in
septic ventilated patients. 3
D i s t e n s i b i l i t y i n d e x o f ivc
(Divc) is calculated by measuring
the IVC at end-expiration (Dmin)
and at end inspiration (Dmax) in
subcostal view.
Divc is ratio of Dmax-Dmin/
Dmin expressed in percentage.
Fig. 1: Representative image of mitral inflow pattern (MIP) showing E and A
wave; E and A wave on tissue Doppler imaging (tdi)
Va r i a b i l i t y i n d e x i s r a t i o o f
Dmax-Dmin /Dmean expressed in
percentage.
Assessment of Right
Ventricle in Mechanically
Ventilated Patients
Fig. 2: Dilatation and absent collapse in Inferior vena cava (IVC) in subcostal
view (arrows) in a patient on mechanical ventilation.
Echocardiographic
Assessment of Fluid
Responsiveness During
Mechanical Ventilation
Fig. 3: Showing assessment

of cardiac output by
echocardiography in a
patient with severe left
ventricular dysfunction on
mechanical ventilation
should be closely monitored by

pulmonary artery catheterization
(PAC). Along with brain natriuretic
l e ve l s ( B N P ) , T T E c a n h e l p t o
monitor and treat pulmonary
edema induced by weaning.
A smaller LV cavity, systolic

obliteration of LV cavity (kissing
ventricles) signifies underfilling
of heart and hypovolemia, and
predicts augmentation of cardiac
output (CO) in response to fluid
challenge. LV end-diastolic area
(LVEDA) in short axis at level of
papillary muscle can be traced
and can be followed up to trend
the changes in response to fluid
boluses where one is uncertain
about the central venous pressure
(CVP). Increase in the inferior
vena cava (IVC) (Figure 2)
diameter by 12-18% (variability
and distensibility index) predicts
positive response to fluid challenge
and 36% distensibility of superior
vena cava (SVC) with respiratory
cycle on transesophageal echo
Direct measurement of right

ventricle (RV) is not recommended.
The RV should be smaller than
LV. The RV:LV end-diastolic area
ratio >0.6 indicates dilatation
consistent with volume or pressure
o ve r l o a d . 4 RV d i l a t a t i o n w i t h
increase in tricuspid regurgitation
from baseline echo and pulmonary
arterial hypertension (PAH) may
be seen in patients on positive
pressure ventilation and should
be considered as a differential
diagnosis while evaluation for
other causes like pulmonary
embolism etc. RV function can be
depressed in pulmonary embolism
and acute respiratory distress
syndrome (ARDS). Increased RV
afterload may be seen in positive
end-expiratory pressure (PEEP)
or increased pulmonary vascular
resistance from vascular, cardiac,
metabolic or pulmonary causes.
I n f e r i o r w i t h RV m y o c a r d i a l
infarction, acute sickle cell crisis,
fat or air embolism, myocardial
contusion and sepsis can lead to
acute RV dysfunction.
Cardiac Output
Cardiac output varies by 50%
with respiration in mechanically
ventilated patients. Therefore, endexpiratory phase measurements
should be taken into account.
Maintaining a high CO has not
shown to improve any outcomes but
Table 1: Showing comparison of echocardiography VS pulmonary artery catheter

(PAC) monitoring. ED-emergency department.
Potential advantages and disadvantages of echocardiography versus invasive monitoring6
Echocardiography
Invasive haemodynamic
monitoring
PAC invasive arterial waveform
analysis semi-invasive
Generally not portable
No
Yes
Yes
Less user dependent, some
methods require calibration
TTE noninvasive TEE semiinvasive

Portability
Scanners easily moved to patient
Use in acute care
Yes, also documented for ED
Diagnostic value
Yes
Monitoring capability Yes
User dependent
Very user dependent
Invasiveness
a CO <5 L/min and cardiac index

(CI) <2 L/min/m 2 significantly
increase the mortality and suggest
a poor prognosis 5 (Figure 3).
Cardiac output (CO) = Stroke
volume x Heart rate.
Stroke volume= End-diastolic
volume (EDV) End-systolic
volume (ESV).
Transthorcic vs.
Transesophageal Echo in
MV Patients
T r a n s e s o p h a g e a l
echocardiography (TEE) is
performed when TTE does not
solve clinical problems and when
TTE has shown some unsuspected
fin di n g s wh i ch req uir ed t o b e
confirmed and therapeutic decision
needs to be taken. TEE is well
tolerated imaging technique in
MV patients for assessment of LV
function and pericardial effusion,
h o we ve r T T E c o n t i n u e s t o b e
excellent diagnostic tool even when
PEEP is present.
Advantages vs
Disadvantages: Echo vs
Invasive Monitoring
The advantages and
disadvantages of echocardiography
comparing invasive monitoring are
discussed in Table 1.
Echo Protocols in ICU

RACE (rapid assessment by
cardiac echo)
43
some amount of ST-T changes and

cardiac ischemia occurs during
weaning which also contributes to
weaning failure.
Conclusion
Hemodynamics in patient
on MV are much different
from physiological state.
Echocardiography can help in both
prognosis and follow up of patients
on MV. Fluid responsiveness, CO,
LV systolic and diastolic parameters
with patients on positive pressure
ventilation can well be followed
up by a non-invasive method using
echocardiography.
I. What is LV function?
II. What is RV function?
III. Is there any evidence of

pulmonary embolism or
cardiac tamponade?
References
IV. What is fluid status?
1.
Jardin F, Valtier B, Beauchet A, et al.

Invasive monitoring combined with twodimensional echocardiographic study in
septic shock. Ann Intern Med 1984; 100:48390.
2.
Caille V, Amiel JB, Charron C, et al.

Echocardiography : a help in the weaning
process. Crit Care 2010; 14:R120.
3.
Vieillard-Baron A, Chergui K, Rabiller A, et

al. Superior Vena Caval collapsibility as a
gauge of volume status in ventilated septic
patients. Intensive Care Med 2004; 30:17349.
4.
Ueti OM, Camargo EE, Veti AA, et al.

Assessment of right ventricular function
with Doppler echocardiographic indices
derived from tricuspid annular motion
: Comparison with radionucleotide
angiography. Heart 2002; 88:244-48.
5.
Salem R, Vallee F, Rusca M, et al.

Hemodynamic monitoring by
echocardiography in the ICU: the role of
the new echo techniques. Curr Op Crit Care
2008; 14:561-568.
6.
Handian M, Pinsky MR. Evidence based

review of the use of the pulmonary artery
catheter: impact data and complications.
Crit Care 2006; 10(suppl 3):S8.
7.
Ferrada P, Murthi S, Anand RJ, Bochicchio

GV, Scalea T. Transthoracic focused rapid
echocardiographic examination : real
time evaluation of fluid status in critically
ill trauma patients. J Trauma 2011; 70:56-62.
F A T E
( f o c u s e d
assessed transthoracic
echocardiography)

I.
Rapid and systemic protocol

for cardiopulmonary
screening and monitoring.
The above two echocardiography

protocols are widely accepted in
high volume centers in ICU setting
including mechanically ventilated
patients. 7 The RACE protocol will
only answer the above questions
while the FATE protocol is used
when only a particular question
by the intensivist needs to be
answered and it need not look into
the other aspects.
Observations
A larger left atria (LA) size has
been observed in patients with
repeated weaning failures. Patients
w i t h s u c c e s s f u l we a n i n g h a ve
smaller sized cardiac chambers. Not
much difference has been observed
in echocardiographic parameters
in patients with pressure support
ve n t i l a t i o n ( P S V ) a n d T - p i e c e
breathing. Unlike spontaneous
breathing patient, IVC diameter
an d response t o respirat ion is
unvalidated in MV patients and
44
Art of Writing
Writing Introduction:
Laying the Foundations of a Research Paper
Sandeep B Bavdekar
Abstract
The Introduction section explains the rationale for undertaking the study
and clearly describes the main purpose of conducting it. It should be
focused, succinct and crisp. Providing an extensive and detailed literature
review, not stating the hypothesis of the objectives with clarity and not
providing focused information are some of the common mistakes that
the authors should steer clear of.
research study is not

completed until one writes
it up for a scientific journal. Once
the authors choose the journal they
intend to submit their manuscript
to, it is time to sit down to write
the manuscript itself. 1 There is no
unanimity regarding the section
that should be written first. Some
think that it is easier to write the
section on Methodology first,
as one has to only edit what has
been written in the protocol. Some
advise writing the Conclusions
first, as they think that authors will
then find it easier to align the rest
of the article, as per the conclusions
drawn. There are still others, who
prefer penning the Abstract first, as
they then have to just expand the
summary that has been finalized. 2
However, we will start the series
regarding writing research article
with the description of various
sections of the IMRaD format
(Introduction, Methodology, Result
and Discussion) in the order that
they appear in a manuscript.
The first section of a research
article is the Introduction. Almost
a l l j o u r n a l s p r e f e r t o h a ve a n
introduction section for the original
research articles. Some journals
publish a few research articles as
Brief Reports, which may not
have a designated Introduction

section. The basic purpose of
having an Introduction section is
to sell the study to the editors
a n d r e v i e we r s a n d t o c a p t u r e
t h e a t t e n t i o n o f t h e r e a d e r s . 3,4
This section gradually introduces
readers to the core parts and hard
facts that are presented later. 4
Annesely5 aptly describes it as being
similar to the process of setting the
scene in theatrical productions,
in which a situation, scene or
circumstance is described so that
the audience clearly comprehends
what is happening. A wellwritten introduction describes the
background and the context, goes
on to state deficiencies that exist in
knowledge and understanding and
then defines what is being planned
thereby providing a glimpse of
what to expect in the remainder of
the article. 5
Planning the Introduction

An introduction generally
consists of three components. The
first part provides background
information, the second part
justifies the need to explore the area

that is not known while the third
component states the hypothesis
or describes the purpose and
objectives of the study. 3,6
Background Information: This
component informs the reader
about the topic that is being
investigated or discussed. It consists
of information about what is known
about the issue and provides a gist
of work already carried out and
reported in the literature. This can
be done by providing the salient
findings and conclusions of the
previously published studies. Then
the authors describe the unexplored
areas, unanswered questions and
unresolved issues of the topic. This
is generally stated by referring to
the paucity of literature on the
issue, by providing information
about conflicting research findings
from various studies, limitations of
the previously conducted research 5
or by mentioning the differences
of opinions among experts in the
field.
Description of the rationale of
the study: After having described
the current situation of what is
known and what is not known,
the authors then proceed to
convince the reader why it is
import ant t o find solu t i on s t o
the unanswered questions and
issues. The importance of filling
these knowledge gaps is usually
justified on the basis of possibility
of determining a mechanism
that could open the doors for
Professor and Head, Department of Pediatrics, TN Medical College and BYL Nair Charitable Hospital, Mumbai,
Maharashtra
While preparing for and

actually conducting the study,
investigators read a lot on the
topic 4 and while writing the
manuscript, they have an inner
urge to transfer and transmit
all the knowledge that they
have gained, to their readers.
Falling for that temptation,
they tend to write a long essay
on the subject and incorporate
it in the Introduction section. In
fact, the authors should avoid
including what an average
reader would already know
and then proceed to include
that information related to
the problem being addressed.
They should remember that the
Background information should
be focused and should not aim
to provide all that is known on
the broad subject. For example,
while describing a study that
attempted to determine the
comparative efficacy and
safety of two regimens in HIVinfected children, information
r e l a t e d t o t h e p r e va l e n c e ,
clinical manifestations and
complications of HIV-infection
would not be quite relevant.
The Introduction, in this case,
should begin with the known
advantages and limitations of
the currently used therapy.
the discovery of novel therapies

a n d i n t e r ve n t i ons , d es c rip tion
of new associations that may aid
design new preventive strategies or
determining the efficacy and safety
of interventions that may reduce
morbidity and mortality or improve
quality of life. The authors also use
this opportunity to emphasize the
new and special aspects of their
research. 7 This component of the
Introduction attempts to convince
the reader that it was important
to conduct the study that is being
described and that novel outcomes
can be expected.
Stating the hypothesis and
Purpose: After having convinced the
reader about the need to undertake
the study, the authors then state
the hypothesis or the purpose or
objectives of the study. This enables
the reader to know about the exact
nature of the research question that
is being asked and which questions
answers to expect by the time the
whole article is read.
The Language, the Length

and the Depth
The purpose of introduction
is merely to introduce the reader
to the definition of the problem,
justify need for conducting the
study and to describe the main
theme of the study. Hence, it needs
to be focused, brief (a one- to
two- paragraph introduction good
enough for most topics) and crisp.
It should not be written to provide
a broad review of the information
available. 5,8,9 It is written in the
present tense.
Pitfalls that Authors

Stumble into and Ways of
Avoiding them
Although writing Introduction
seems straightforward, it is one of
the most difficult sections to write
in a manuscript. The authors should
steer clear of certain commonly
encountered pitfalls:

Stuffing the Introduction with

too much of general information:
Providing details of the previously

conducted research: While
describing the current state of
knowledge, the authors will
need to refer to previously
conducted research. This
should be done by stating the
conclusions drawn by these
studies without going into
the details such as the study
sites, number of participants
enrolled, follow-up rates,
etc. If some readers wish to
confirm the statements made
or to find out more about these
studies, they can easily do so
on the basis of reference details
provided by the authors.
Packing the Introduction with too
many references: Introduction
is not the section to have an
45
extensive literature review.

Hence, only the absolutely
required material should
be cited. Other reference
material can be used while
discussing the study findings
in Discussion. Authors would
do well to cite original research
articles (rather than review
articles), while providing
information about current state
of knowledge in Introduction.

Providing extensive critique of the

previous studies: Authors may
have decided to conduct the
study because of the limitations
or methodological flaws in the
previously reported evidence.
While, they may refer to this
fact while providing rationale
for conducting the study;
they should avoid extensive
criticism of the earlier studies in
Introduction. 7 They can touch
upon the better methodology
employed in the study while
discussing the strengths of the
study under Discussion.
Describing conclusions of the

study: The authors should
remember that Introduction
is not the same as Abstract of
the article. It should include
information about what
question is being answered,
but the actual answer needs
to be provided through the
sections titled Results and
Discussion. Providing answers
in the Introduction would be
akin to a novelist describing the
climax of a suspense thriller, in
the first few paragraphs of the
novel. The readers, then would
have no inclination to read the
complete story, whether in the
novel or in the manuscript!
Inconsistencies among various

sections: Most authors
ch eck t h ei r ma nu sc r i p t f or
inconsistencies before
submitting the manuscript
to a Journal. However, many
a times, they amend certain
portions of the manuscript in
response to reviewers and
editors suggestions. At times,
46
changes made in one section,

requires alterations in other
sections, as well. For example, if
a reviewer requests for a change
in the way research question
is framed; it may require
corresponding changes in the
Discussion. The authors should,
therefore, diligently check if
there are any inconsistencies
or contradictory statements,
every time any portion of the
manuscript is revised. 5

Overlapping information under

Introduction and Discussion:
As both these sections refer
to published literature on the
subject, there is danger of
duplication of statements.
It must be kept in mind that
Introduction is a section
wherein the authors use
published studies to explain
the current state of knowledge;
while in Discussion, they
describe the overall evidence
available and compare it with
evidence generated by the
study. 2 Although, the articles
referred to in the two sections
could overlap, to a certain
extent; the perspective with

which they would be referred
to should differ. Repeating
ideas, words and phrases
makes the reader think that
the author does not have much
to discuss. 5

Not reporting relevant information

in the Introduction: Sometimes,
it is noticed that authors do not
cite an important study that has
already answered the research
question in the Introduction
section to bestow a status
of originality to their study.
However, a diligent reader
spots that the findings from
the earlier study are discussed
subsequently in the manuscript.
The reader is likely to feel
cheated when he understands
that the present manuscript is
merely reiterating previously
reported results. 10
To summarize, the Introduction

section of the manuscript should
be brief and yet informative. It
should convince the reader about
the need to conduct the study and
the importance of research work
done. It should make the reader

inquisitive about how the mystery
was unraveled and motivate him to
read further.
References
1.
Bavdekar SB, Save S. Choosing the Right

Journal for a Research Paper. J Assoc
Physicians India 2015; 63:56-59.
2.
Neill US. How to write a scientific

masterpiece. J Clin Invest 2007; 117:3599602.
3.
Jha KN. How to Write Articles That Get

Published. J Clin Diagn Res 2014; 8:XG01-03.
4.
Masic I, How to Search, Write, Prepare

and Publish the Scientific Papers in the
Biomedical Journals. AIM 2011; 19:68-9.
5.
Annesley TM. It was a cold and rainy night:

Set the Scene with a Good Introduction.
Clin Chem 2010; 56:705-13.
6.
Boyd JC, Rifai N, Annesley TM. Preparation

of Manuscripts for Publication: Improving
Your Chances for Success. Clin Chem 2009;
55:1259-64.
7.
Peh WCG, Ng KH. Writing the Introduction.

Singapore Med J 2008; 49:756-7.
8.
Branson RD. Anatomy of a Research Paper.

Respiratory Care 2004; 49:1222-8.
9.
Alexandrov AV. How to write a Research

Paper. Cerebrovasc Dis 2004; 18:135-8.
10. Wells WA. Unpleasant surprises: how

the Introduction has wandered into the
Discussion. J Cell Biol 2006; 174:741.
52
Pictorial CME
Herpes Zoster of Mandibular Division of

Trigeminal Nerve (V3)
Rakhi Malhotra, Awanish Karan
Fig. 1: Vesicular eruptions on right

half of face
Fig. 4: Blisters on right tympanic

membrane
2 ye a r s o l d l a d y p r e s e n t e d
with complaints of painful
blisters on the right lower face,
ulcers in the mouth and severe
right otalgia of 24 hours duration.
She had burning sensation in the
skin near the lower lip two days
prior to the appearance of the
blisters. Examination revealed
vesicular eruptions with clear fluid
on right half of face involving the
cheek, chin and lower lip (Figure
1 ) . o r a l e x a m i n a t i o n r e ve a l e d
multiple shallow mucosal ulcers
Fig. 2: Shallow ulcers with whitish

slough on lower gingiva on
right side
Fig. 3: Multiple shallow ulcers on

buccal mucosa and retromolar
area right side
on lower lip, cheek and lower

gum. Ulcers were irregular in shape
with erythematous margins and
floor covered with yellowish white
slough (Figures 2, 3). The ulcers
were tender on palpation. Otoscopy
revealed blisters on right tympanic
membrane and external auditory
canal corresponding to the supply
area of auriculotemporal nerve, a
branch of the posterior division of
mandibular nerve (Figure 4). The
lesions were unilateral and did
not cross the midline. Audiometry
was normal and no facial palsy was
observed. She was diagnosed as a
case of trigeminal zoster involving
the mandibular branch (V3). She
was managed with oral Acyclovir
and analgesics for seven days with
good response and no residual
complications.
ganglia. 1 The incidence of Herpes

zoster increases with age and
immunosuppression. 2 The most
commonly affected cranial nerves
are trigeminal and facial nerve
due to reactivation of HZV latent
in the gasserian and geniculate
ganglia. The ophthalmic branch of
trigeminal nerve is affected several
times more frequently than the
second or third divisions. 3 Early
diagnosis and prompt treatment
with antiviral drugs is the mainstay
of management.
Herpes zoster is an infection

caused by reactivation of the latent
va r i c e l l a v i r u s i n t h e s e n s o r y
3.
References
1.
Fristad I, Bardsen A, Knudsh GC, Molven

O. Prodromal herpes zoster A diagnostic
challenge in endodontics. International
Endodontic Journal 2002; 35:1012-16.
2. Arvin AM. Varicella-zoster virus. Clin

Microbiol Rev 1996; 9:361-381.
Military Hospital Wellington, Tamil Nadu

Pattni N, Hudson P, Yates JM. Herpes zoster,

odontalgia and nephropathy. A case report
and review. Oral Surgery 2011; 4:35-38.
54
CASE OF THE MONTH
An Interesting Case of Bilateral Lung

Consolidation
Satyajit Pawar1, Animesh Sharma2, R Ragesh1, Neeraj Nischal1, Saket Jha1,
Chandan J Das 3, MC Sharma4, SK Sharma1
Abstract
Organising pneumonia is a histopathological entity characterised by
intra-alveolar buds of granulation tissue, intermixed myofibroblasts
and connective tissue. Cryptogenic organising pneumonia (COP) is
characterised by this particular histopathological pattern, along with
typical clinical and imaging features, when no other underlying aetiology
is found. COP (previously known as bronchiolitis obliterans organising
pneumonia [BOOP]) is one of the rare variants of interstitial pneumonias.
This condition is characterised by a rapid clinical and radiological
improvement with steroid treatment. Here we are reporting a case of COP
in adult female with discussion on approach and basic pathophysiology
of this type of pneumonia.
Introduction
rganising pneumonias (OP)

usually present with nonspecific symptoms, radiographic
and pulmonary function test (PFT)
findings. The cause can be primary
(cryptogenic organising pneumonia
[COP]) or secondary (secondary
OP). Cryptogenic organising
pneumonia is classified under
idiopathic interstitial pneumonia.
Secondary causes of OP include
infections, connective tissue
di se a s e s, dr u g s, malign ancies,
organ transplantation, aspiration
and radiation injury. It is important
to make such distinction as
the management of secondary
organising pneumonia involves
treatment of the underlying
disease or potential avoidance of
the offending agent. It is often
associated with poor prognosis and
is less responsive to treatment as
compared to COP.
Case and Discussion

A 5 5 - ye a r - o l d h o u s e w i f e , a
known diabetic, presented to
the outpatient department of All
India Institute of Medical Sciences
(AIIMS) hospital, New Delhi
with 4 month history of cough
and high grade fever. The cough
was dry in nature, no diurnal or
postural variation and without any
significant aggravating or relieving
factors. Patient had complaints
o f we i g h t l o s s o f a b o u t 4 k g s
over last one month. She also had
progressive shortness of breath for
last 1 month, which had progressed
from mMRC (modified medical
research council) grade 1 to grade
4 over 1 month. She was a known
diabetic since last 7 years and was
on oral hypoglycemic agents. She
had history of exposure to passive
smoking and exposure to chulha

for 20 years in the past. There was
no history suggestive of connective
tissue disease, exposure to fumes,
dust or working in the farm. At
the same time her husband was
diagnosed to have extra-pulmonary
TB (tubercular pleural effusion).
At admission, she was febrile
with temperature of 100F. Blood
pressure was 110/70 mmHg with
pulse rate of 110/min. Respiratory
rate was 30/min with use of
accessory respiratory muscles and
visible intercostal recession. The
SpO 2 was 80% on room air and
96% on oxygen (O 2 ) at 6 litres/
m i n u t e v i a f a c e m a s k . Pa t i e n t
wa s p a l e , h o we ve r , t h e r e wa s
no icterus, clubbing, cyanosis,
lymphadenopathy, skin rash or
pedal edema. The ocular and
fundus examination was normal.
Examination of upper respiratory
tract, oral cavity, tonsils and
posterior pharyngeal wall was
normal. Examination of respiratory
system reveled bilateral coarse
mid-inspiratory crepitation were
heard in infra-axillary and infrascapular area. Examination of
cardiovascular, abdominal and
central nervous system revealed no
abnormality.
Laboratory investigations
revealed haemoglobin 12.6 g/dl,
total leucocyte count 14.6 x 10 3/
mm 3, platelet count 490 x 10 3/mm 3
and erythrocyte sedimentation rate
Departments of 1Internal Medicine, 3Radio-diagnosis, 4Pathology, All India Institute of Medical Sciences,
New Delhi; 2Intern, Sir Ganga Ram Hospital, New Delhi
Fig. 1: Chest radiograph showing

air space consolidation in
bilateral mid and lower
zone. Note a round opacity
with central lucency in left
mid zone (arrow)
102 mm at the end of 1 st hour.

C h e s t X - r a y r e ve a l e d b i l a t e r a l
l o we r a n d m i d z o n e a i r - s p a c e
opacities (Figure 1). Differential
diagnosis considered were
pulmonary tuberculosis, bacterial/
fungal pneumonia, lung carcinoma
(bronchoalveolar variant),
hypersensitivity pneumonitis and
sarcoidosis were considered.
Liver and renal functions were
in normal range with exception
of reversal of albumin:globulin
ratio. Electrocardiogram (ECG)
and 2D-echocardiography (ECHO)
were within normal limits. Arterial
blood gas (ABG) analysis revealed
pH 7.40, PaCO 2 30.8 mmHg,
PaO 2 - 55.6 mmHg, HCO 3 20.3
mmol/L with FiO 2 0.4. Alveolar
(A) to arterial (a) oxygen gradient
was 196 mmHg (normal value - 5
20 mmHg) suggestive of pulmonary
Fig. 2: HRCT axial image showing

symmetrical bronchocentric
consolidation in both lungs.
Note consolidation in left
lung with central lucency
(arrow) ---reversed halo or
Atoll sign suggesting COP
parenchymal pathology. Normal

(A-a) gradient adjusted for age
can be calculated as estimated
(A-a) gradient which is (4 + age
in years/4). 1 (A-a) gradient helps
in differentiating the extrapulmonary causes of respiratory
failure from those involving
parenchymal lung disease. In
extra-pulmonary failure, the (A-a)
gradient remains normal. In cases
of shunt, diffusion impairment
or vent ilat ion-perfusion (V -Q)
mismatch, the gradient is usually
elevated. Hypoxemia due to V-Q
mismatch or diffusion impairment
can be corrected with supplemental
oxygen while that due to right-left
shunt cannot. (A-a) gradient is also
a measure of the severity of gas
exchange impairment and is used
as guide for steroid therapy in cases
of Pneumocystis carinii pneumonia.
Fig. 3: CT-guided lung biopsy specimen under haematoxylin-eosin stain

(original magnification x 100). (A) Biopsy shows thickening of interalveolar septae along with chronic inflammatory cell infiltrate. (B) Type
II pneumocytes proliferation with intra-alveolar smooth muscle bundle
proliferation forming a ball-like structure (Masson body) (arrow)
55
HIV ELISA was negative.

Au t o i m m u n e w o r k - u p i n t h e
form of rheumatoid factor (RF),
p-ANCA and c-ANCA and double
stranded (ds) -DNA was negative.
Anti-nuclear antibody (ANA) was
positive in 1:40 titer with speckled
pattern. Positive titres of less than
1:160 can be present in up to 20%
of the healthy elderly population.
Titres more than 1:160 are seen in up
to 5% of normal adult individuals.
Serology for Aspergillus and
Histoplasma was negative. Serum
lactate dehydrogenase (LDH) and
angiotensin converting enzyme
(ACE) levels were within normal
limits. Serum C - reactive protein
(CRP) was elevated. Sputum smear
examination with Gram stain
and acid-fast bacilli (AFB) stain
wa s n e g a t i ve . H i g h r e s o l u t i o n
computed tomography (HRCT) of
the chest (Figure 2) revealed areas of
bilateral lower zone consolidation
mainly involving peri-hilar areas,
without any surrounding groundglassing with presence of reversehalo sign suggesting organizing
pneumonia. Reverse halo sign is
characterized by presence of central
ground-glass opacity surrounded
by area of consolidation. It was
first described as a specific sign
f o r C O P , h o we ve r i t h a s b e e n
reported in a variety of pulmonary
diseases including invasive
fungal pneumonias, tuberculosis,
granulomatous polyangiitis,
lymphomatoid granulomatosis
and sarcoidosis. 2 Based on this
revised differentials of pulmonary
tuberculosis (spouse diagnosed as
TB, systemic symptoms, elevated
ESR, imaging compatible), bacterial
pneumonia (sick, elevated total
peripheral blood counts, imaging
compatible), sarcoidosis (though
serum ACE was normal and HRCT
was not typical, alveolar sarcoid still
a possibility), limited Wegeners
( A N C A c a n b e n e g a t i ve ) , a n d
cryptogenic organizing pneumonia
(age group compatible, subacute
presentation, imaging compatible)
were kept.
C T - g u i d e d l u n g b i o p s y wa s
56
Table 1: Various aetiologies for

organizing pneumonia
Infections
1. Bacterial

Chlamydia pneumoniae
Coxiella burnetii
Legionella pneumophila
Mycoplasma pneumoniae
Nocardia asteroides
Pseudomonas aeruginosa
Serratia marcescens
Staphylococcus aureus
Streptococcus
2. Viral

Herpes virus
Human immunodeficiency virus
Influenza virus
Parainfluenza virus
3. Fungal

Cryptococcus neoformans
Pneumocystis carinii
Drugs
Amiodarone
Bleomycin
Carbamazepine
Cocaine
Interferon alpha
Minocycline
Phenytoin
Sulfasalazine
Tacrolimus
Sotalol
Systemic inflammatory diseases
Rheumatoid arthritis
Polymyositis/dermatomyositis
Polymyalgia rheumatic
Solid organ malignancies
Colon
Breast
Haematological malignancies
Non- Hodgkin lymphoma
Renal transplant
Post-radiation
Aspiration pneumonia
done. Biopsy revealed thickening

o f i n t e r - a l ve o l a r s e p t a e a l o n g
with chronic inflammatory cell
infiltrate (Figure 3A) and type II
pneumocytes proliferation with
intra-alveolar smooth muscle
bundles proliferation forming a
ball-like structure (Masson body)
(Figure 3B) which is a characteristic
finding of organizing pneumonia.
A final diagnosis of COP was made
in view of characteristic clinical,
Table 2 : Comparison of pre-treatment

and post-treatment lab
parameters and arterial blood
gas values
COP should be included in the

differential diagnosis in any patient
with bilateral airspace disease that
is unresponsive to antibiotics.
Parameter
The typical imaging

characteristic of COP is of
multiple patchy alveolar opacities
with a peripheral and bilateral
distribution. These opacities may
migrate spontaneously. Their size
is often variable and can range from
a few centimetres to a whole lobe.
Two other patterns include solitary
opacity (focal COP), and infiltrative
opacities (infiltrative COP). This
imaging pattern, although highly
suggestive of COP, is not specific
and the differential diagnosis on
imaging include conditions such as
the primary-low grade pulmonary
lymphomas, chronic eosinophilic
pneumonias (which can occur
with COP), and bronchioloalveolar
carcinoma. Pulmonary functions
reveal mild to moderate restrictive
defect, with minimal or no airflow
obstruction and reduced carbon
monoxide diffusion capacity. No
specific lab findings are observed in
COP. Patients usually have raised
ESR and CRP with neutrophilic
leucocytosis more so in secondary
OP. The gold standard for diagnosis
is video-assisted thoracoscopic
lung biopsy, as it provides large
lung specimens allowing diagnosis
to be made with confidence and
other pathological features can also
be searched. Trans-bronchial lung
biopsy specimens are inadequate
for excluding secondary causes.
pH
Pretreatment
7.40
Posttreatment
7.42
PaO2 (mmHg)
55.6
66.5
PaCO2 (mmHg)
30.8
32.5
FiO2
ESR (mm/hr)
D(A-a)O2 (mmHg)
0.4
102
194
0.21
40
44
D (A-a) O2 Alveolar to arterial oxygen

gradient
radiological and histopathological

features with no other secondary
cause.
The term cryptogenic organizing
pneumonia (COP) was introduced
by Davison et al in 1983. 3 It was
later supplanted in the American
literature by the term BOOP.
In 2002, the American Thoracic
Society/European Respiratory
Society International Consensus
Pa n e l f or t h e C l a ssi f i ca t i on of
Idiopathic Interstitial Pneumonia
( AT S / E R S ) r e c o m m e n d e d t h e
term COP be used as preferred
clinical term for idiopathic cases,
emphasising the cryptogenic
nature of the process. 4 COP is
characterised by insidious onset,
non-specific physiologic findings,
and variable radiographic patterns,
but with typical histopathologic
findings that are sine qua non
for diagnosis. It is important to
remember that COP is a diagnosis
of exclusion and secondary causes
(Table 1) should be ruled out before
making final diagnosis. Patients
usually experience a 210 week
prodrome prior to seeking medical
attention. The disease has no sex
predilection and occurs usually
in 6 th decade, although paediatric
c a s e s h a ve b e e n r e p o r t e d . N o
predisposing factors have been
identified and, in particular,
organising pneumonia is not related
to smoking in comparison to other
ILDs like respiratory bronchiolitisassociated interstitial lung
disease, desquamative interstitial
pneumonia, and pulmonary
Langerhans cell histiocytosis.
Treatment decisions are based on

clinical experience and observations
from case series because of lack of
randomized trials. The decision
to initiate treatment and choice
of initial therapy depends on
severity of symptoms, extent of
disease on imaging and rapidity
of progression. In patients with
minimal symptoms and mild
radiographic involvement it is
reasonable to monitor abnormalities
at 8 to 12 weeks interval. In patients
with mild to moderate symptoms
treatment with macrolides is an
option, particularly for those
Fig. 4: Chest radiograph (A) and HRCT thorax (B) showing marked clearing of
bilateral lung consolidation after treatment
who chose to avoid steroids.5

Clarithromycin 250 to 500 mg twice
a day has been used in few cases.
Corticosteroids is the treatment of
choice in patients with persistent
or progressive disease. The ideal
dose and duration of steroids in
COP is not well-defined. Clinical
improvement is seen within 48 hrs,
while radiological resolution takes
several months. The recommended
daily dose of steroids is 0.75 1 mg/
kg of prednisone and usual duration
is six to twelve weeks. 6 COP is
associated with frequent relapses
involving initial or different
sites and some patients require
prolonged treatment with steroids.
In such cases steroid-sparing
agents in from of azathioprine and
cyclophosphamide can be used.
The prognosis of typical COP with
patchy alveolar involvement is
usually good.
was tapered over next 3 months.

Subsequently, she was shifted to
steroid-sparing agent in the form of
azathioprine due to development of
side effects of steroids. At the end
of 6 months, she was doing well
with remarkable relief in fever,
weight loss, shortness of breath
and cough. Her diabetic status is
also well controlled. Investigations
showed normalizat ion of ESR,
CRP and albumin:globulin ratio.
Arterial blood gas (ABG) analysis
on room air revealed pH 7.42,
PaCO 2 32.5 mmHg, PaO 2 - 66.5
mmHg. D (A-a) O 2 was 44 mmHg
compared to 194 mmHg at the time
of presentation (Table 2). Both chest
X-ray and HRCT (Figure 4) showed
significant resolution. The patient
is currently on follow-up in the
outpatient department.
Our patient was started on 60 mg

(1 mg/kg) prednisone initially which
COP is one of the rare idiopathic

interstitial pneumonias and
Conclusion
57
remains as diagnosis of exclusion.

Patient is labelled to have a COP
based on clinical, radiological
and characteristic histological
findings only after excluding
secondary causes. A careful history
of occupation, exposure to dusts,
fumes, therapeutic radiation and
history suggestive of connective
tissue diseases should be elicited as
other pulmonary pathologies such
as chronic eosinophilic pneumonia,
hypersensitivity pneumonitis
or diffuse alveolar damage can
h a ve s i m i l a r r a d i o l o g i c a l a n d
histopathological findings.
References
1.
Harris EA, Kenyon AM, Nisbet HD, et al. The

normal alveolar-arterial oxygen tension
gradient in man. Clin Sci Mol Med 1974;
46:89-104.
2.
Godoy MCB, Viswanathan C, Marchiori E,

et al. The reversed halo sign: update and
differential diagnosis. Brit J Radiol 2012;
85:1226-1235.
3.
Davison AG, Heard BE, McAllister WA, et al.

Cryptogenic organizing pneumonitis. QJ
Med 1983; 52:382394.
4.
Travis WD, Colby T, Bateman ED, et al.

ATS/ERS international multidisciplinary
consensus classification of idiopathic
interstitial pneumonia. Am J Respir Crit Care
Med 2002; 165:277-304.
5.
Stover DE, Mangino D et al. Macrolides:

a treatment alternative for bronchiolitis
obliterans organizing pneumonia?
Chest2005; 128:3611-7.
6.
Bradley B, Branley HM, Egan JJ, Greaves

MS, Hansell DM, Harrison NK, Hirani N et al.
Interstitial lung disease guidelines. Thorax
2008; 63:1029.
58
Case Reports
A Novel Variant of Bartters Syndrome

Sachin B Punatar1, Divyashree S2, Vishal M Jogi1
Abstract
Bartters syndrome, a rare disorder affecting the renal tubular potassium
handling, is characterized by metabolic alkalosis, hypokalemia and
renal salt wasting. Here we describe a patient with Bartters syndrome
with hitherto undescribed clinical features and also discuss the various
possibilities leading to such variant of Bartters syndrome.
Introduction
artters syndrome is a rare

genetic disorder characterized
by renal salt wasting, hypokalemia
and metabolic alkalosis. Before
the identification of the causal
gene defects, the syndrome was
classified into distinct phenotypes,
based on the age of onset and the
severity of symptoms. 1 However,
now the syndrome is classified
i n t o f i ve d i f f e r e n t t y p e s ( t y p e
1 to type 5) based on genetic
mutations. The affected proteins
include the apical loop-diuretic
sensitive sodium-potassiumchloride transporter NKCC-2 (type
1), the apical potassium channel
ROMK (type 2), the basolateral
chloride channel CIC-Kb (type 3),
barttin (type 4) and CASR (type
5). Although these five types of
Bartters syndrome differ with
regards to some clinical features
like severity and age of onset, all
of them share the basic features of
renal salt wasting, hypokalemia
and metabolic alkalosis. All clinical
features of Bartters syndrome are
explained by renal abnormalities
and their consequences. Extrarenal features are found in type
4 Bartters syndrome in form of
sensori-neural deafness. 2 Here we
describe a patient who had absence
o f s a l i va t i o n , l a c r i m a t i o n a n d
sweating since birth in addition to
biochemical features of Bartters

syndrome.
Case Report
A 2 2 ye a r o l d m a l e M u s l i m
patient presented with history of
an episode of fever 2 days prior.
He had a single episode of vomiting
on the day before presentation
following which he had developed
generalized muscle weakness. He
had been previously apparently
well, except that he did not have
salivation, sweating or lacrimation

since birth. He complained of
difficulty in swallowing dry
foods and chronic redness and
dryness of eyes. Such a history
of absence of salivation, sweating
and lacrimation was present in 11
family members (including this
patient); 7 of them had expired and
4 were alive. All these 7 deaths had
occurred in the 3rd decade of life and
all had similar pre-terminal events.
According to available history,
none of these deaths were due to
unrelated illness. Specific details
or documentation regarding these
deaths were not available. Among
other three alive, are 15 years,
4 years and 6 months of age, all
females. A history of consanguinity
was present in the patients family.
The pedigree chart of the patient is
as shown in Figure 1.
II
III
This patient
IV
15 years
4 years 6 months
Fig. 1: Pedigree chart of the patients family
Ex-Asst. Professor, 2Ex-Senior Resident, Dept. of Medicine, MP Shah Medical College and GG Hospital, Jamnagar,
Gujarat
Table 1: Investigations during first

hospital admission
Table 2: Investigations during second

hospital admission
Investigation
Admission Discharge
Hb (g%)
12.4
RBC Count
4.53
PCV (%)
37.7
83.4
MCV (m3)
MCH (pg/cell)
27.4
MCHC (g/dL)
32.9
RDW (%)
12.9
WBC Count
8100
DC N/L/E/M/B
70/27/2/1/0
PS for MP
- ve
RBS (mg/dL)
122
Blood urea
78
Serum creatinine
1.77
Serum sodium
123
120
Serum potassium
1.3
1.6
Serum chloride
92.6
Arterial pH
7.399
7.502
Urine R/M
NAD
Urine Na+ (mEq/L)
58
random
+
Urine K (mEq/L)
16.6
random
Investigation
Admission Discharge
Serum creatinine
2.7
Serum sodium
105
124
Serum potassium
0.9
2.8
Serum chloride
91
Serum bicarbonate
23
Serum calcium
8.8
Serum magnesium
1.96
Arterial pH
7.500
Venous pH
7.324
Urine sodium
124.23
(mEq/day)
Urine potassium
56.52
(mEq/day)
Urine chloride
357.96
(mEq/day)
Urine bicarbonate
66.64
(mEq/day)
Urine calcium
122.4
(mg/day)
For his acute complaints, he had

consulted a general practitioner,
who treated him with intravenous
fluids (1 liter of normal saline) and
intravenous ranitidine.
In view of severe muscle
weakness, he was referred and
presented to us the next day. At
admission, he was afebrile, pulse 80/
min regular, blood pressure 90/50
mmHg and respiratory rate 15/
min. General examination showed
no significant finding and except
for generalized muscle weakness,
t h e s y s t e m i c e x a m i n a t i o n wa s
also normal. The muscle weakness
was severe with grade 2 power
in various muscle groups of the
body. His blood investigations are
tabulated in Table 1.
He was treated with potassium
chloride infusion, oral rehydration
salt solution, intravenous fluids
and antibiotics. Potassium chloride
infusion was stopped on day 3
and antibiotics were stopped on
d a y 6 . O n t h e 7 t h d a y , h e wa s
started on spironolactone (50 mg/
day) and oral potassium chloride
(20 mEq 3 times a day). He was
symptomatically better and was
discharged on the same day.
T h e p a t i e n t f o l l o we d u p o n
8 th day after discharge. He had
no acute symptoms at follow
up. Arterial blood gas analysis
at the time of follow up showed
metabolic alkalosis, hypokalemia
and hyponatremia (pH 7.537,
serum sodium 117 mEq/L, serum
potassium 1.2 mEq/L and serum
bicarbonate 29.4 mEq/L). He was
continued on the same medications
and was asked to follow up a week
later. 56 days after his 1 st follow
up, he stopped all his medications.
Further 56 days later, he had
a few episodes of vomiting and
was readmitted. At the time of 2 nd
admission, he had hypotension (BP
70/60 mmHg). This was quickly
restored to normal by 1 liter of
normal saline. At this admission,
drugs which affect the renal
sodium and potassium handling
we r e a v o i d e d . H e wa s t r e a t e d
with potassium chloride (infusion
and oral) till all other work-up
was completed. His investigations
during 2 nd admission are tabulated
in Table 2.
These investigations confirmed
that the patient was having
hypokalemia, metabolic alkalosis,
renal sodium and potassium
wasting and normal to low blood
pressure without hypomagnesemia
and without hypocalciuria. Urinary
59
chloride excretion was increased

when compared to serum chloride.
Based on these findings, he was
d i a g n o s e d a s h a v i n g B a r t t e r s
syndrome. Additional work-up was
carried out for his clinical features
of absence of salivation, sweating
and lacrimation.
Ultrasound of Kidneys, ureter
and bladder showed increased
echogenecity of kidneys and
prominent pyramids with normal
size of both kidneys (suggestive
of bilateral renal parenchymal
disease). X-ray KUB was
normal. Ultrasound of salivary
glands showed normal parotid
and submandibular glands.
Unstimulated salivary flow test
revealed a salivary flow of 0 ml in
15 minutes (Normal 1.5 ml in 15
minutes).
An ophthalmological assessment
revealed positive Schirmers test (<
5 mm in 5 min) in both eyes.
The starch iodide test (a
qualitative test for sweating in
which iodine is applied on skin
followed by application of starch.
In presence of moisture, there
is bluish discoloration whereas
in absence of moisture no color
change is seen) was performed
on both palms and both axillae of
the patient. It revealed complete
absence of sweating (Figure 2).
S e r u m H I V a n t i b o d i e s we r e
absent (by ELISA).
T h e p a t i e n t wa s s t a r t e d o n
spironolactone 50 mg/day and oral
potassium chloride (20 mEq TDS)
on the 3 rd day. Ibuprofen 400 mg 3
times a day was added from the 6 th
day and was discharged on the 7 th
day. In addition to these drugs he
also takes ranitidine (150 mg BD) or
famotidine (20 mg BD) as he is on
chronic ibuprofen therapy.
The patient remains in regular
follow up. His general health is good
although his salivation, lacrimation
a n d s we a t i n g a r e s t i l l a b s e n t .
Serum antinuclear antibody (by
indirect immunofluorescence) and
antinuclear antibody profile testing
(including anti SS-A and SS-B) done
60
Fig. 2: Starch iodide test showing complete absence of sweating. (Upper row: Testing on palms. Lower row: Testing on axilla.)
Images in each row from left to right Before application of iodine, after application of iodine, after application of
starch and after application of moisture
on follow up were negative. No

lymphocyte infiltration was seen
on minor salivary gland biopsy. A
punch biopsy of the skin revealed
hyperplastic keratinized stratified
squamous epithelial lining with
normal sweat glands and other skin
appendages.
was alkaline. Although this random

sample was taken when the patient
was on his regular medications
(including ibuprofen, potassium
chloride and ranitidine), it still
suggested that, if he would have
vomiting he would lose alkaline
fluid.
Over the months, his sodium and

potassium have normalized and
his creatinine has decreased. These
investigations are shown in Table 3.
Discussion
An additional observation in this

patient is that arterial pH of the
patient shows metabolic alkalosis.
However, the first blood pH testing
after admission revealed that this
p H wa s l e ss t h a n th e bas elin e
alkaline pH. On the basis of this
observation we speculated that the
patient might be having alkaline
vomit. To test this, we evaluated
the patient with a random gastric
fluid pH. This pH value was 7.067
suggesting that the gastric fluid
The differential diagnosis

of hypochloremic metabolic
alkalosis with hypokalemia
without hypertension includes
Bartters syndrome, Gitelmans
syndrome, surreptitious vomiting
and diuretic abuse. 2 Gitelmans
syndrome was excluded by the
absence of hypomagnesemia
and hypocalciuria. 2 There was
no history of diuretic abuse.
Furthermore, during the hospital
stay, the biochemical abnormalities
of hypokalemia and alkalosis
persisted till the 6th day inspite of no
Table 3: Follow up investigations of the patient

S. creatinine (mg/dL)
S. sodium (mEq/L)
S. potassium (mEq/L)
Arterial pH
2 months
1.7
135
4.1
3 months
1.6
135.7
3.7
7.500
5 months
1.5
137.5
4.28
19 months
1.4
133
3.23
7.460
diuretics being taken by the patient.

T h e p a t i e n t a l s o d i d n o t h a ve
any episode of vomiting during
both the hospital admissions.
Persistence of abnormalities in
spite of absence of vomiting till the
6 th day during 1 st admission and 3 rd
day during 2 nd admission indicate
that surreptitious vomiting was not
a cause of patients abnormalities.
Acquired Bartters and Gitelmans
like syndromes have been
described with autoimmune
disorders, sarcoidosis and various
drugs. 3-4 These were excluded by
history, clinical picture, negative
autoantibody profile and minor
salivary gland biopsy.
We speculate that this patient
represents a new variant of Bartters
syndrome. Features other than
usual features of Bartters syndrome
i n c l u d e a b s e n c e o f s a l i va t i o n ,
s we a t i n g a n d l a c r i m a t i o n a n d
alkaline gastric fluid pH. These
extrarenal features have not yet
been described in association with
Bartters syndrome. This patient
could have a yet undetected or
unknown mutation of a protein
which has a structural or a functional
role in renal tubular cells (of Loop

of Henle), ocular glands, salivary
glands, sweat gland and gastric
glands (or gastric acid secreting
c e l l s ) . A l t e r n a t i ve l y , h e c o u l d
have two different mutations, one
explaining his Bartters syndrome
and other explaining the exocrine
gland abnormalities.
Bartters syndrome is not available

in India.
References
1.
Davison AM, Cameron JS, Grnfeld JP,

et al, editors. Oxford textbook of clinical
nephrology. 3rd ed. New York: Oxford
University Press; 2005. p. 995-1000.
2.
Salant DJ, Patel PS. Polycystic kidney

disease and other inherited tubular
disorders. In: Fauci AS, Braunwald E, Kasper
DL, Hauser SL, Longo DL, Jameson JL, et
al, editors. Harrisons principles of internal
medicine. 17th ed. New York: McGraw Hill
Medical; 2008. p. 1797-1806.
However, our hypothesis about

the possibility of a yet unknown
new mutation or co-existence of
two different mutations could not
be confirmed as genetic testing for
61
3.
Tung-Miny,Shih-Hua L,Chuang Y, et al. A

syndrome resembling Bartters syndrome
in sarcoidosis. Nephrol Dial Transplant 2009;
24:667-9.
4.
Schwarz C, Barisani T, Bauer E, Druml W. A

woman with red eyes and hypokalemia: A
case of acquired Gitelman syndrome. Wien
Klin Wochenschr 2006; 118:239-42.
5.
Moutsopoulos HM. Sjgrens syndrome. In:

Fauci AS, Braunwald E, Kasper DL, Hauser
SL, Longo DL, Jameson JL, et al, editors.
Harrisons principles of internal medicine.
17th ed. New York: McGraw Hill Medical;
2008. p. 2107-9.
Pulmonary Hypoplasia Wrongly Diagnosed and

Treated as Pulmonary Tuberculosis
VK Tiwari1, Amit Kumar2, Ankit Khurana
from pulmonary tuberculosis is
presented.
Abstract
Pulmonary hypoplasia (PH), a rare congenital anomaly is observed
with incomplete development of the lung, and may be associated with
anomalies in other body systems. The clinical presentation varies with the
extent of hypoplasia and the patient may be asymptomatic or may present
with severe respiratory distress in the neonatal, infancy or childhood
period. A six year old girl suffering from right sided hypoplasia was
hospitalized with common presenting chest symptoms. She had taken
antituberculosis treatment for past three years and was thought to be
an MDR suspect. The child was thoroughly investigated was diagnosed
to be a case of PH and is under followup.
Introduction
ulmonary hypoplasia (PH), a rare

congenital anomaly is observed
with incomplete development of
the lung, may be associated with
anomalies in other body systems
s u c h a s c a r d i o va s c u l a r , r e n a l ,
musculoskeletal, central nervous
system and GI. The lung fails
to attain the maturity, which is
due to the decrease in number of
lung cells, airways, vessels, and
alveoli resulting in decrease in
the size and weight. 1 However
the gross morphology of the lung
is essentially unremarkable. 2 The
delay in alveolar tissue development

causes underdeveloped lung
which becomes small, fibrotic
and non-functioning. The clinical
presentation varies with the extent
of hypoplasia, and the patient may
be either asymptomatic or may
present with severe respiratory
distress in the neonatal, infancy
or childhood period. 2 A case of PH
wrongly diagnosed as suffering
Case Report
A six years old girl was treated
by private medical practitioners/
h o s p i t a l s a n d wa s r e f e r r e d t o
the department of Pulmonary
Medicine, Rohilkhand Medical
College and Hospital, Bareilly (UP)
as a case of suspected MDR-TB
for establishing the diagnosis and
management with the complaints
of breathlessness increased on
exertion, cough with expectoration,
mild chest pain, cold, fever off
and on and loss of appetite for
t h r e e ye a r s . T h e r e wa s n o h / o
haemoptysis. The h/o recurrent
infection (LRTI) since 6 months
of age was noticed. There was no
h/o jaundice, seizure etc. The child
had not been fully immunized
except oral Polio vaccine. The
child was given antituberculosis
treatment for past three years. The
family history was unremarkable.
Professor, 2Assistant Professor, 3Resident, Department of Pulmonary Medicine, Rohilkhand Medical College
and Hospital, Bareilly, Uttar Pradesh
61
Pulmonary Hypoplasia Wrongly Diagnosed and

Treated as Pulmonary Tuberculosis
VK Tiwari1, Amit Kumar2, Ankit Khurana
Abstract
Pulmonary hypoplasia (PH), a rare congenital anomaly is observed
with incomplete development of the lung, and may be associated with
anomalies in other body systems. The clinical presentation varies with the
extent of hypoplasia and the patient may be asymptomatic or may present
with severe respiratory distress in the neonatal, infancy or childhood
period. A six year old girl suffering from right sided hypoplasia was
hospitalized with common presenting chest symptoms. She had taken
antituberculosis treatment for past three years and was thought to be
an MDR suspect. The child was thoroughly investigated was diagnosed
to be a case of PH and is under followup.
Introduction
ulmonary hypoplasia (PH), a rare

congenital anomaly is observed
with incomplete development of
the lung, may be associated with
anomalies in other body systems
s u c h a s c a r d i o va s c u l a r , r e n a l ,
musculoskeletal, central nervous
system and GI. The lung fails
to attain the maturity, which is
due to the decrease in number of
lung cells, airways, vessels, and
alveoli resulting in decrease in
the size and weight. 1 However
the gross morphology of the lung
is essentially unremarkable. 2 The
delay in alveolar tissue development
causes underdeveloped lung
which becomes small, fibrotic
and non-functioning. The clinical
presentation varies with the extent
of hypoplasia, and the patient may
be either asymptomatic or may
present with severe respiratory
distress in the neonatal, infancy
or childhood period. 2 A case of PH
wrongly diagnosed as suffering
from pulmonary tuberculosis is
presented.
Case Report
A six years old girl was treated
by private medical practitioners/

h o s p i t a l s a n d wa s r e f e r r e d t o
the department of Pulmonary
Medicine, Rohilkhand Medical
College and Hospital, Bareilly (UP)
as a case of suspected MDR-TB
for establishing the diagnosis and
management with the complaints
of breathlessness increased on
exertion, cough with expectoration,
mild chest pain, cold, fever off
and on and loss of appetite for
t h r e e ye a r s . T h e r e wa s n o h / o
haemoptysis. The h/o recurrent
infection (LRTI) since 6 months
of age was noticed. There was no
h/o jaundice, seizure etc. The child
had not been fully immunized
except oral Polio vaccine. The
child was given antituberculosis
treatment for past three years. The
family history was unremarkable.
General physical examination
was non-contributory except
kyphoscoliosis. The respiratory
system examination revealed
impairment on right side. Air
entry and movements of the chest
were diminished on right side with
restricted expansion of the chest.

Trachea and heart were shifted to
right side. The percussion note was
dull and diffuse crepitations were
present on right side. There was no
remarkable finding in other body
systems.
Direct smear microscopy of
sputum specimen and culture
was negative for acid-fast bacilli.
The routine haematological
examination such as blood counts,
l i ve r a n d r e n a l f u n c t i o n t e s t s ,
blood sugar examination were
within normal limits. Chest
r o e n t g e n o g r a m r e ve a l e d r i g h t
sided massive homogenous opacity,
shifting of mediastinum, and chest
retraction. The intercostal spaces
o n r i g h t s i d e we r e n a r r o we d .
Left lung showed compensatory
emphysema (Figure 1). X-ray whole
spine revealed kyphoscoliosis and
hemivertebra (at the level of T3)
(Figure 2). CECT thorax showed
right sided markedly reduced
lung volume associated with
hypoplastic right pulmonary artery
with kyphoscoliosis. There was no
evidence of any fibrocavitatory
lesion (Figure 3). Bronchoscopy
showed underdevelopment of right
upper lobe bronchus and only two
openings could be seen, middle
lobe bronchus could not be seen and
lower lobe bronchus was normally
v i s u a l i z e d . T h e r e wa s n o r m a l
development of tracheobronchial
tree on left side.
The child was discharged on
symptomatic treatment. In the last
two visits, she was observed to be
doing well. She showed relief in
Professor, 2Assistant Professor, 3Resident, Department of Pulmonary Medicine, Rohilkhand Medical College
and Hospital, Bareilly, Uttar Pradesh
62
Fig. 1: Chest x-ray revealed right

sided massive homogenous
opacity, shifting of
mediastinum, and chest
retraction. The Intercostal
spaces on right side were
narrowed. Left lung showed
compensatory emphysema
symptoms and is still under follow

up.
Fig. 2: X-ray whole spine revealed kyphoscoliosis and hemivertebra (at the level
of T3)
Discussion
Pulmonary hypoplasia is the
failure of the development of the
lung in the utero, which is often
u n i l a t e r al a n d can range from
hypoplasia to aplasia resulting
in an abnormally low number
and size of bronchopulmonary
segments or alveoli. The lungs
are abnormally small and the
hypoplastic lung doesnt have
enough tissue and blood flow to
allow the individual to breathe on
his/her own. This condition can be
grave and sometimes fatal. 1,2
Monaldi categorizes
developmental disorders of the lung
in four groups . 4 l. No bifurcation
of trachea; ll. Rudimentary main
bronchus only; lll. Uncompleted
development after bifurcation of
main bronchus; lV. Incomplete
development of small segment
and subsegmental bronchi of
corresponding lobe. According
to Boyden, 5 the developmental
disorders are seen in three different
extents: (1) agenesis: complete
absence of lung tissue, (2) aplasia:
no lung tissue but rudimentary
bronchus, (3) hypoplasia:
all lung tissues exist but are
underdeveloped. The present case
belongs to fourth group of Monaldi
Fig. 3: CECT thorax showed right sided markedly reduced lung volume
associated with hypoplastic right pulmonary artery
classification.
The causes of PH are multiple
and include (a) Thoracic:
Congenital diaphragmatic hernia,
extra lobar sequestration, agenesis
of diaphragm, mediastinal
mass(es), teratoma, decreased
p u l m o n a r y va s c u l a r ( a r t e r i a l )
perfusion from a congenital
cardiovascular anomaly e.g. Fallots
tetralogy or unilateral absence of
pulmonary artery (b) Extrathoracic:
oligohydramnios, Potter sequence,
renal abnormalities, preterm
premature rupture of membrane
(PPROM); skeletal dysplasias
causing narrow fetal thorax,
Jeune syndrome asphyxiating
thoracic dystrophy, thanatophoric
dysplasia, achondrogenesis,
osteogenesis imperfecta, short rib
polydactyly syndrome, campomelic
dysplasia, Klippel Feil syndrome,
Down syndrome; large intraabdominal mass compressing

thorax; neuromuscular disorders
interfering fetal breathing; CNS
- anencephaly, hydroencephaly;
urogenital and GI . 1-3
The diagnosis of PH is made on
the basis of clinical presentation.
The pathological diagnosis
requires formalin inflated routinely
processed lung. The important tests
are (1) lung weight (2) lung volume
( 3 ) l u n g v o l u m e : b i r t h we i g h t
ratio of 1.2%. (The ratio 0.9%
indicates PH) (4) Radial alveolar
count (RAC), (5) Biometric indices
eg. thoracic circumference to head
or abdominal circumference ratio,
thoracic area (TA) minus heart area
(HA), HA/ TA ratio (6) Estimation
of tissue maturity. 1,3
Imaging eg. Chest X Ray, 3 D
ultrasound, Doppler ultrasound
63
velocimetry, CT thorax, MRI, CT/

MRI angiography, bronchography
are beneficial in the diagnosis of
PH. The other tests are required
to exclude tuberculosis and other
cardiopulmonary diseases.
supplemental oxygen to mechanical

v e n t i l a t i o n . 2,3 I n p r o p h y l a c t i c
measures, the immunization
against influenza, pneumococcus,
and respiratory syncytial virus has
been recommended. 1-3,6
The management of PH includes

medical and surgical care. In
prenatal medical intervention, the
patient is treated medically when
repeated amnioinfusions with
or without the use of tocolytics,
antimicrobials, steroids and use
of fibrin glue are advised.6 In
postnatal period, the respiratory
support is given ranging from
The prognosis depends on the

size of the lungs and the underlying
cause. The survivors will have
chronic lung problems, decrease
in lung capacity, recurrent chest
infections and impaired growth.
4. M o n a l d i V . M a l f o r m a t i v e
bronchopulmonary diseases caused by
anatomical defects. Minerva Medica 1960;
51:3474 3478.
5.
References
Boyden EA. Developmental anomalies of

the lungs. Am J Surg 1955; 89:7989.
6.
Knox WF, Barson AJ. Pulmonary hypoplasia

in a regional perinatal unit. Early Hum Dev
1986; 14:3342.
1.
Laudy JAM, Wladimiroff JW. The fetal lung

1and 2: development aspect. Ultrasound
Obst Gynecol 2000; 16:284 290 and 482

494.
2.
Kant S. Unilateral Pulmonary Hypoplasia

A case report. Lung India 2007; 24:6971.
3.
Hsu JS, Lee YS, Lin CH, et al. Primary

congenital pulmonary hypoplasia of a
neonate Case Report. J Chinese Med Ass
2012; 75:8790.
63
Herpes Zoster Infection Presenting with Urinary

Retention and Constipation
VM Bhalerao1, BS Gedam2, AK Mukharjee2
Abstract
antibiotics, and bladder training

exercises.
Herpes zoster is a sporadic disease that results from the reactivation of

latent Varicella zoster virus infection (VZV) from the dorsal root ganglion.
We report a case of herpes zoster of lumbosacral region presenting as
acute retention of urine and constipation, an uncommon presentation.
The patient improved after 10

days. His catheter was removed
and he started passing urine and
anal sphincter tone became normal.
Introduction
aricella zoster virus (VZV)

causes two distinct entities
i.e. chicken pox and herpes zoster,
chickenpox is usually a benign
illness during the childhood while
herpes zoster present as dermatome
rash associated with severe pain
and burning sensation. The virus
remain dormant in the dorsal root
ganglion for many years and may
get reactivated. The commonest
dermatome affected are thoracic
(42.4%), cranial (28.2%), lumbar
(7.8%) and sacral (4.8%).1 The
common clinical presentation is
severe pain followed by vesicular
rash in the affected dermatome.
I t l a s t f o r 7 t o 1 0 d a y s . We
report a case of herpes zoster of
lumbosacral nerves (L1-L2) and
(S2-S4) presenting as acute urinary
retention and constipation.
Case Report
A 75 year old man non-diabetic,
non-hypertensive was admitted
with the complaints of urinary
retention and constipation since
last 24 hours. There was no history
of urinary complaints in the past.
There was history of rash and
burning sensation on his lower
back and lower abdomen on
the right side, 8 days prior to
admission. He was diagnosed as
a case of herpes zoster infection at
government medical college and
was put on symptomatic treatment.
Otherwise there was no significant
past medical history. There was no

history of chickenpox.
On examination he was afebrile,
BP 120/80 mm Hg. There was no
edema feet. There was vesicular
rash over the lumbar and sacral
dermatomes (L1-L2 and S2-S4)
on right side (Figure 1). His
n e u r o l o g i c a l e x a m i n a t i o n wa s
normal, there was no weakness
i n t h e l o we r l i m b s , n o n u c h a l
rigidity and reflexes were normal.
His bladder was palpable up to
umbilicus. Other systems were
normal.
H i s i n ve s t i g a t i o n s r e ve a l e d
Hb-10.2 gm%, TLC- 8600/cmm,
DLC- normal, blood sugar- 86 mg/
dl. His kidney function tests and
liver function tests were normal.
His HIV and AA were non-reactive.
His MRI of lumbosacral spine was
normal, USG abdomen showed no
evidence of obstructive uropathy
and CT brain was normal. CSF
examination done to rule out aseptic
m e n i n g i t i s wa s a c e l l u l a r w i t h
normal proteins. His cystoscopy
was normal.
Considering his typical rash
over the lumbosacral dermatome
he was diagnosed as case of VZV
infection causing urinary retention
and constipation. He underwent
Foleys catheterization. He was also
treated with acyclovir for 10 days,
Discussion
The most common presentations
were paresthesias, pain and
itching. 2 In a study conducted
on 205 patients of herpes Abdul
et al found that only 4.8% had
sacral involvement while 42% had
thoracic involvement. 1
There are three syndromes
of zoster associated bladder
dysfunction. They are zoster
cystitis, zoster retention of urine
and zoster myelitis. Retention is
caused by spread of infection from
dorsal root ganglion into the sacral
motor neurons, roots or peripheral
nerves causing interruption of
bilateral detrusor reflex to manifest
as atonic bladder. 2
Involvement of the sacral nerve
roots (S2-S4) in herpes zoster is
uncommon. The virus involves
not only the ipsilateral nerve root
ganglion but also the meninges
and contralateral root involvement
partially. Thus herpes zoster may
cause bilateral pelvic nerve root
involvement eventhough the skin
eruption is unilateral. 3
Symptoms of sacral and lumbar
radiculopathy in herpes cause
dull or tingling pain in the lower
back, buttocks or anogenital area,
sciatica-like pain down the thighs,
weakness of the lower limb and
inability to walk on tip toes. In
Associate Professor, 2Lecturer, Department of Medicine, S.D.K.S.D.C. and Hospital, Nagpur, Maharashtra
64
constipation which fully recovered

after 3 weeks. Urodynamic
investigations should be considered
if symptoms fail to improve within
6-8 weeks of onset.
In conclusion patients
presenting with lumbosacral
herpes zoster should be warned
about possible urinary and bowel
symptoms and monitored carefully.
References
Fig. 1: Rash over lumbosacral dermatomes
rare cases urinary retention (5%),

constipation and transient paralysis
occur. 4
Urinary retention in herpes
zoster can also occur due to aseptic
meningitis, but in our patient there
was no evidence of fever, nuchal
rigidity, headache, weakness in the
lower limbs. His CSF examination
was normal.
We demonstrated a rare case

of acute urinary retention and
constipation secondary to herpes
zoster infection of the lumbosacral
nerve roots It is speculated that
n e u r o p a t h i c b l a d d e r d e ve l o p s
because of involvement of
detrusor reflex. VZV infection
in our case also resulted in anal
sphincter dysfunction resulting in
1.
Abdul EN, Pavithranm K. Herpes zoster

A clinical study of 205 patients. Indian J
Dermatol 2011; 56:529-32.
2.
Biddlestone J, Suraparaju L, Shah N. Herpes

zoster induced acute urinary retention in
the immunocompetant female. BMJ Case
Rep 2009 bcr-07, 2008, 0452.
3.
Sakakibara R, Yamanishi T, Uchiyama T,

Hattori T. Acute urinary retention due to
benign inflammatory nervous diseases. J
Neurol 2006; 253:1103-1110.
4.
Oates JK, Green House PR. Retention of

urine in anogenital herpatic infection.
Lancet 1978; 1:691-692.
65
Classical Cardiovascular Manifestations of

Marfan Syndrome
Girish R Sabnis1, Devendra V Patil1, Milind S Phadke2, Charan P Lanjewar3,
Ashish A Nabar 3, Prafulla G Kerkar4
Abstract
Presence of multiple cardiovascular manifestations of the Marfan
syndrome in the same patient is not commonly encountered. We present a
49 year-old lady with this syndrome who presented with decompensated
heart failure. Evaluation revealed presence of extensive Stanford type
A aortic dissection alongwith severe aortic and mitral incompetence.
However, the patient declined surgery and was discharged on medical
management. At a years follow-up, she had dyspnea of NYHA class II
with persistent cardiovascular findings.
Case Report
49 year-old lady presented

with acute severe retrosternal
pain and progressive dyspnea over
three days. Morphologic features
o f t h e M a r f a n s y n d r o m e we r e
observed: a height of 166 cm, arm
span of 176 cm, thin built, scoliosis,
arachnodactyly, high-arched palate
and positive thumb and wrist signs
(Figure 1). Left upper limb pulses
were weaker than the right; all
peripheral pulses were palpable
with no bruit. Blood pressures were
100/45 mm Hg and 90/50 in the right
and left upper limbs and 120/60 and
134/70 in the right and left lower
limbs respectively. A short grade
3 early diastolic murmur in the
2 nd right intercostal space and a
grade 4 pansystolic murmur at the
apex were auscultable. Routine
hemogram, renal and liver function
tests were within normal limits.
Echocardiography demonstrated
a dilated aortic root (54 mm),
with a dissection flap extending
from the non-coronary cusp to the
visualized descending thoracic
aorta with associated severe aortic
incompetence. Presence of posterior
mitral leaflet prolapse causing an
anteriorly directed eccentric jet
of severe mitral regurgitation was

also noted (Figure 2). There was
evidence of chamber dilatation
with left atrial diameter of 43 mm
and left ventricular (LV) systolic
and diastolic dimensions of 44 mm
and 60 mm, respectively. There was
mild tricuspid regurgitation (TR)
with severe pulmonary arterial
(PA) hypertension (estimated PA
systolic pressure by TR jet of 67mm
Hg). Biventricular function was
normal with LV ejection fraction

of 60%. A 64-slice multi-detector
CT aortogram confirmed extensive
dissection of the aorta extending
from the aortic root to the abdominal
aorta with involvement of the right
brachiocephalic, bilateral common
carotid and left renal arteries
without frank luminal occlusion
(Figures 3 and 4).
Urgent surgical aortic root
r e p l a c e m e n t w i t h a o r t i c va l ve
replacement (Bentall procedure)
along with mitral valve repair
wa s r e c o m m e n d e d . H o w e v e r ,
the patient declined surgery and
was discharged on a conservative
anti-failure regimen. At a years
follow-up, the patient was doing
well, with exertional dyspnoea of
NYHA class II. Echocardiography
s h o we d s i m i l a r f i n d i n g s w i t h
marginally worsened LV dilatation
and function. She opted to continue
Fig. 1: Morphologic features of MFS- arm span as compared to height, wrist

sign, arachnodactyly and thumb sign
1
Resident, 2Assistant Professor, 3Associate Professor, 4Professor and Head, Department of Cardiology, Seth GS
Medical College and The King Edward VII Memorial Hospital, Mumbai, Maharashtra
66
Fig. 3: 3D reconstructed image

of entire aorta and both
kidneys showing dissection
extending from aortic root
to upto the renal arteries
Fig. 2: Echocardiographic images in parasternal long (A) and short (B) axes
image showing dilated aortic root, dissection flap (arrow), severe aortic
incompetence (C) and associated mitral valve prolapse causing severe
directed eccentric mitral incompetence (D)
with medical management.
Discussion
The Marfan syndrome is
a disorder of connective tissue
caused by mutations in the fibrillin1 gene, a major component of
extracellular microfibrils, with
multi-organ involvement. 1 Our

patient was diagnosed with
the Marfan syndrome based on
m a j o r i n v o l ve m e n t o f s k e l e t a l
and cardiovascular systems
in accordance with the Ghent
nosology. Cardiovascular
manifestation of this syndrome
include mitral valve prolapse,

aortic root and pulmonary
artery dilation, mitral and aortic
incompetence, aortic aneurysm
and aortic dissection.3 Anomalies of
the cardiovascular system account
for a significant proportion of the
shortened life-span of patients
with this disorder. The prevalence
of aortic root dilation and mitral
Fig. 4: CT Aortogram- views showing aortic dissection extending from the root and involving right brachiocephalic trunk,
extending down to the abdominal aorta, involving renal arteries)
valve prolapse is around 80% and

that for aortic and mitral valvular
incompetence is 2440%.3 Our
patient had involvement of the
aortic root as well as the mitral
valve. Acute aortic dissection can be
life-threatening and hence should
be the primary focus of evaluation
of these patients. Marfan syndrome
is one of the adverse predictors of
mortality in patients with type A
aortic dissection and accounts for
upto 5% of all aortic dissections. 6
The risk of dissection in Marfan
syndrome is greatest in presence
of aortic root dilation, reaching
10% in high-risk patients (aortic
root diameter >40 mm or rapid
dilation). Surgical correction is
recommended for all patients
with acute type A dissection. Root
replacement with or without aortic
valve replacement is the preferred
c h o i c e . 5 At p r e s e n t t h e r e i s n o
role of endovascular therapy for
type A dissection. The one year
mortality in patients with type A

aortic dissection can be as high as
58% in patients on medical therapy
and upto 27% in the surgically
treated group. 6 The 3 year survival
of patients with type A dissection
who are managed medically and
survive the initial hospital stay is
50-70%. 6 In a recent series from the
Johns Hopkins Medical Institutions
on Bentall repair in patients with
the Marfan syndrome, concomitant
mitral valve repair/replacement
wa s r e q u i r e d i n u p t o 2 0 % o f
patients. 7 This case was remarkable
for the multiple, severe prototype
cardiovascular manifestations of
this syndrome and survival without
surgical intervention.
References
1.
Tsai TT, Nienaber CA, Eagle KA. Acute Aortic

Syndromes. Circulation 2005; 112:38023813.
2.
De PaepeA,Devereux RB, Dietz HC, et al.

Revise diagnostic criteria for the Marfan
67
syndrome. Am J Med Genet 1996; 62:417426.

3.
van Karnebeeka CDM, Naeffa MJ, Mulderb

BJM, Hennekama RCM, Offringaa M. Natural
history of cardiovascular manifestations in
Marfan syndrome. Arch Dis Child 2001;
84:129-137.
4.
Stevens LM, Madsen JC, Isselbacher EM, et

al. Surgical management and long-term
outcomes of acute ascending aortic
dissection. J Thorac Cardiovasc Surg 2009;
138:1349.
5.
Vijaykumar AR, Menon S, S Kumar, Prasad

S. Acute aortic dissection-De Bakey Type
1 and Stanford Type A. J Assoc Physicaians
India 2004; 52:154-155.
6.
Tsai TT, Evangelista A, Nienaber CA, et al.

Long-term survival in patients presenting
with type A acute aortic dissection.
Insights from the International Registry of
Acute Aortic Dissection. Circulation 2006;
114(Suppl I):350.
7.
Patel ND, Weiss ES, Alejo DE, et al. Aortic

root operations for Marfan syndrome:
a comparison of the Bentall and valvesparing procedures. Ann Thorac Surg 2008;
85:2003-10.
67
Dengue Fever and Takotsubo Cardiomyopathy

Suhas V Badve1, Sachin Patil2, Niranjan M Rathod1, Chetanprakash K Jumrani1
Abstract
A young male admitted for dengue fever and systemic involvement developed ECG abnormalities on third day,
in the form of prolonged QT interval and deep and symmetrical inversion of T wave. Echocardiography revealed
akinesia of mid and apical segments and well contracting basal segments, typical of Takotsubo cardiomyopathy
or stress cardiomyopathy. These changes were transient and echocardiography findings reverted to normal kinesis
of left ventricle without any treatment or without any residual left ventricle dysfunction.
Introduction
Takotsubo cardiomyopathy or
stress cardiomyopathy, also called
transient left ventricular apical
ballooning syndrome or broken
heart syndrome was first described
in Japan in 1991 and named
a s Ta k a t s u b o a s i t r e s e m b l e s
a n o c t o p u s t r a p . Pa t h o g e n e s i s
postulated are catecholamine
excess, coronary artery spasm
o r m i c r o va s c u l a r s p a s m , f o c a l
myocytolysis and myocarditis.
It is usually seen in elderly and
postmenopausal women and seen
after acute emotional stress. It is also
mentioned after an acute medical
conditions such as septicaemia,
lactic acidosis, acute abdominal
surgery, hypoglycemia, pneumonia
and adult respiratory distress
syndrome. Electrocardiogram
may reveal ST segment elevation
or depression, T wave changes,
prolonged QT interval and abnormal
Q waves. Cardiac enzymes may be
mildly elevated. Transthoracic
echocardiogram typically shows
akinesis of apical and distal
anterior wall, left ventricular apical
ballooning and hypercontractile
basal walls giving typical shape
of Takatsubo. Coronary arteries
are normal on angiography. These
echocardiographic changes show
complete resolution of apical
wall motion abnormality and also
resolution of impaired systolic
function.
Case Report
An 11 years old boy was admitted
with history of fever, headache,

vomiting of 4 days duration. There
was history of reddish urine once
prior to admission.
On admission, his temperature
was normal, pulse 70/min, BP 80 mm
Hg systolic, no lymphadenopathy,
no icterus, hydration normal and
normal systemic examination.
H e did not have any b leeding
manifestations. No petechiae, gum
bleeding, hematuria or malena
were seen.
L a b o r a t o r y r e p o r t s we r e a s
follows:
Hemoglobin 16.5 gm%, WBC
6200/cmm, platelet count 10,000/
cmm, peripheral smear for malarial
parasite negative.
Test for dengue fever NS 1 was
positive.
Blood urea 22 mg%, serum
creatinine 0.9 mg%, liver function
tests were normal. His chest x-ray
was normal.
Abdominal sonography showed
n o n s p e c i f i c t h i c k - wa l l e d g a l l
bladder, mild ascites and minimal
left-sided plural effusion.
CT scan of head performed
because of persistent headache and
vomiting revealed mild cerebral
edema.
He was treated with IV fluids,
noradrenaline for hypotension and
one unit of platelet transfusion
was given for thrombocytopenia
and supportive treatment. As his

test was positive for dengue, he
was not given any antibacterials,
antimalarials, antivirals or
antifungal agents.
Gradually, his fever and
headache subsided, vomiting
stopped, appetite improved. Blood
pressure 100/80 mm Hg. Platelet
count improved to 34,000/cmm on
day 2 and to 45,000/cmm on day 3.
On day 3, electrocardiogram
showed prolonged QT interval
and deep and symmetrical T wave
inversion in all leads (Figure 1).
His serum sodium was 134 mEq/L
and potassium 3.9 mEq/L. His
Trop-T was negative. Patient was
asymptomatic at this stage.
Transthoracic echocardiogram
showed akinesia of mid and
apical segments, akinesia of left
ventricular apex and normally
contracting basal segments (Figure
2). These signs were interpreted
as stress cardiomyopathy or of
myocarditis. The shape of left
ventricle was typical of Takotsubo.
He remained symptom-free; no
headache or vomiting and appetite
and oral intake improved. Platelet
count on day 5 was 143,000/cmm
and on day 8 was 203,000/cmm.
Repeat electrocardiogram
on day 8 showed normal QT
interval, but T wave inversion
was persistent (Figure 3). Repeat
echocardiography on day 8 done,
Consultant Physician, 2Visiting Cardiologist, Apex Hospital, Kolhapur, Maharashtra

Received: 07.11.2013; Revised: 09.04.2014; Re-revised: 03.07.2014; Accepted: 08.07.2014
68
Fig. 2: Day 3 : Akinetic and

ballooned mid and apical
segments of left ventricle
Fig. 1: Electrocardiogram on day 3
Fig. 4: Day 8 : Normal sized and

normokinetic left ventricle
in dengue hemorrhagic fever are

reported.
Fig. 3: Electrocardiogram on Day 8
which showed normally contracting

all segments, with normal systolic
and diastolic functions (Figure 4).
Discussion
T h i s wa s a c a s e o f d e n g u e
f e ve r w i t h t h r o m b o c y t o p e n i a ,
hypotension, mild cerebral
edema and transient regional
left ventricular wall motion
abnormality that normalized
without any specific treatment as
the patient improved.
The literature search showed
va r i e d c a r d i a c i n v o l ve m e n t i n
severe dengue fever. Many case
reports are of severe myocarditis
and cardiogenic shock. There are
reports of elevation of cardiac

enzymes, myocarditis, segmental
wall motion abnormalities,
pericardial effusion and tamponade,
systolic and diastolic function
impairment with predominant
involvement of septal and right
ventricular wall. Wali et al from
India reported series of 17 cases
of dengue fever with low ejection
fraction, global hypokinesia and
ECG changes, that reverted back
to normal after recovery. There are
reports of fulminant myocarditis
with ECG changes mimicking
acute myocardial infarction. Also
cardiac involvement in the form of
noncompaction myocarditis and
transient ventricular arrhythmias
The patient under discussion had

acute changes of left ventricular
wall motion abnormality typical of
Takotsubo cardiomyopathy, which
reverted to normal contractility
without any specific treatment. The
condition occurred after dengue
fever with systemic involvement.
In the literature, association of
dengue fever is mentioned with
myocarditis and cardiomyopathy,
but not with stress cardiomyopathy.
This patient showed QT interval
prolongation and T wave changes
on electrocardiogram without
e l e va t i o n o f c a r d i a c e n z y m e s .
His echocardiogram revealed
akinesia of apical segments that
resolved completely without
any treatment. In dengue fever,
cardiac involvement in the
form of myocarditis indicates
bad prognosis. But stress
cardiomyopathy should be kept in
mind, which has good prognosis
a n d c h a n g e s r e ve r t t o n o r m a l
without any specific measures as

in this patient.
References
1.
Virani S, Khan AN, Mendoza CE. Takotsubo

Cardiomyopathy, or Broken-Heart Syndrom
Tex Heart Inst J 2007; 34:7679.
2.
Iga K, Hori K, Kitaguchi K. Transient

Segmental Asynergy of left ventricle
of patients with var ious clinical
manifestations possibly unrelated to
coronary artery disease. Jpn Circ J 1991;
55:1061-7.
3.
4.
Seth PS, Aurigemma GP, Krasnow JM, Tighe

DA. A syndrome of transient left ventricular
apical wall motion abnormality in the
absence of coronary artery disease : A
perspective from United State. Cardiology
2003; 100:61-6.
Mori H, Ishikawa S, Kojima S, Watanabe
Y. Increased responsiveness of left
ventricular myocardium to adrenergic
stimuli. Cardiovasc Res 1993; 27:192-8.
69
5.
Obeyesekere I, Hermon Y. Myocarditis and

cardiomyopathy after arbovirus infection
(Dengue and chickungunya fever). Br Heart
J 1972; 34:821827.
10. Wali JP, Biswas A, Chandra S, Malhotra A,

Aggarwal P, Handa R. Cardiac involvement
in dengue haemorrhagic fever. Int J Cardiol
1998; 64:31-6.
6.
Miranda CH, Borges Mde C, Schmidt A,

Pazin-Filho A, Rossi MA. A case presentation
of a fatal dengue myocarditis showing
evidence for dengue virus-induced lesion.
Eur Heart J Acute Cardiovasc Care 2013;
2:127-30.
11. Majumdar R, Jana CK, Ghosh S, Biswas

U. Clinical spectrum of dengue fever
in a tertiary care centre with particular
reference to atypical presentation in the
2012 outbreak in Kolkata. J Indian Med
Assoc 2012; 110:904-6.
7.
Miranda CH, Borges Mde C, Matsuno AK,

Vilar FC, Gali LG, Volpe GJ. Evaluation of
cardiac involvement during dengue viral
infection. Clin Infect Dis 2013; 57:812-9.
12. Lee CH, Teo C, Low AF. Fulminant dengue

myocarditis masquerading as acute
myocardial infarction. Int J Cardiol 2009;
136:e69e71.
8.
Yacoub S, Griffiths A, Chau TT, et al. Cardiac

function in Vietnamese patients with
different dengue severity grades. Crit Care
Med 2012; 40:477-83.
9.
Wichmann D, Kularatne S, Ehrhardt

S, Wijesinghe S, Brattig NW. Cardiac
involvement in dengue virus infections
during the 2004/2005 dengue fever season
in Sri Lanka. Southeast Asian J Trop Med
Public Health 2009; 40:727-30.
13. Neo HY, Wong RC, Seto KY, Yip JW, Yang H,
Ling LH. Noncompaction cardiomyopathy
presenting with congestive heart failure
during intercurrent dengue viral illness :
importance of phenotypic recognition. Int
J Cardiol 2006; 107:123-5.
14. Chuah SK. Transient ventricular arrhythmia
as a cardiac manifestation in dengue
haemorrhagic fever a case report.
Singapore Med J 1987; 28:569-72.
70
Foreign Body in Left Main Bronchus

Shubhangi V Dhadke1, Amit L Chaudhari2, Neelima S Deshpande1, Vithal N Dhadke1,
Shashikala A Sangle 3
Abstract
Tracheobronchial foreign body (TFB) aspiration is rare in adults, although
incidence rates increases with advancing age. We report a case of foreign
body in left main bronchus in an adult female who had no risk factor. She
was successfully treated with removal of betel nuts by bronchoscopy.
Unusual presentation and high index of suspicion can help in proper
management.
Introduction
ymptoms associated with

tracheobronchial foreign body
(TFB) aspiration may range from
acute asphyxiation with or without
complete airway obstruction, to
cough, dyspnoea, choking or fever.
In adults, many other medical
conditions mimic breathing
abnormalities similar to those
associated with TFB aspiration. If
the history is not suggestive, then
only a high index of suspicion
can ensure proper diagnosis and
t i m e l y r e m o va l o f t h e f o r e i g n
body. Bronchoscopic removal of
the foreign body is necessary to
avoid long-term sequel. Flexible
bronchoscopy is effective in both
the diagnosis and foreign body
removal.
back, where she was diagnosed as

interstitial lung disease and started
on bosentan, azathioprine and
sildenafil. She didnt get relief. She
was known case diabetes mellitus
on metformin 500 mg BD taking
regularly. At the time of admission,
she was tachypneic, and febrile. On
respiratory examination, coarse
crepitations were present in right
interscapular and infrascapular
area and wheeze in left
infrascapular area. Other systemic
examination was normal. Her chest
X-ray on admission was normal
(Figure 1). Routine investigations
including WBC count, BSL, KFT
and LFT were normal. We started
her on intravenous antibiotics

and bronchodilators, insulin
therapy and nebulisations. On 3 rd
day , pat ient underwent H R C T
thorax which revealed tree in bud
appearance in right mid and lower
zone suggestive of endobronchial
tuberculosis (Figure 2). Her sputum
f o r A F B wa s n e g a t i ve . Pa t i e n t
was started on anti-tubercular
(DOTS CAT I) treatment. She didnt
improve. So we planned flexible
bronchoscopy. On bronchoscopy
it revealed 1 cm brownish
mass, 4 cm distal to carina in
left main bronchus suggestive of
?granulation tissue, ?foreign body.
Two days later, 2 small pieces of
betel-nuts were removed by rigid
bronchoscopy (Figure 3). Next
day, she had shown improvements
in form of relief of dyspnoea and
disappearance of rhonchi. After
10 days of symptom-free interval,
we repeated HRCT thorax it was
within normal limits (Figure 4)
and we stopped anti-tubercular
treatment and discharged her on
oral antibiotics and anti-diabetics.
Case Report
A 45 year old female presented
with complaints of breathlessness
and cough since 2 months,
fever since 5 days. She started
developing breathlessness which
was progressive and more in lying
down position associated with
dry cough. She also gave history
o f 4 - 5 e pi so de s o f fever along
with above symptoms. She took
treatment in form of oral antibiotics
from local practitioners. She was
admitted in private hospital for
the same complaints 15 days
Fig. 1: Chest X-ray of patient on

day of admission
Fig. 2: HRCT thorax showing tree

in bud appearance in Right
mid and lower zone
Associate Professor, 2Senior Resident, 3Professor and Head, Dept. of Medicine, Dr. V.M. Govt. Medical College,
Solapur, Maharashtra
Received; 24.01.2013; Revised: 26.12.2013; Accepted; 02.07.2014
endoscopic instruments are unable

to gain a firm and wide grasp
of solid objects such as a knife
blade, and the attempt is more
locally traumatic than therapeutic.
Hence, early involvement of a
thoracic surgeon is of paramount
importance in the management
of large aspirated foreign bodies
because expertise in both rigid and
flexible bronchoscopy, as well as in
airway surgery, is necessary.
Fig. 3: Two pieces of betel

nuts removed during
bronchoscopy
Discussion
Unlike foreign-body aspiration
in young children and in the elderly,
this occurrence is uncommon in
adults. In the adult population,
such aspiration is most commonly
secondary to unconscious
accidental ingestion during general
anaesthesia, sedation, intoxication,
seizures or neurologic disorders
affecting the oropharynx. 1 The
foreign bodies can be dietary or
non-dietary but are associated with
similar sequelae. 2 The symptoms
of foreign-body aspiration range
from coughing, wheezing and
dyspnoea to haemoptysis and
choking. 1 Computed tomography
of the chest may be valuable in
identifying small aspirated objects
or when associated chest disease
is suspected. Bronchoscopy is
frequently both diagnostic and
therapeutic. 1,2 The availability of
both rigid and flexible bronchoscopy
should be emphasized since larger
71
References
Fig. 4: Normal HRCT thorax after
removal of foreign bodies
aspirates may not be retrievable

with a flexible bronchoscope. 2
Surgery constitutes the final,
definitive option and is generally
well tolerated, particularly when
the lung parenchyma is spared. 2,3
What makes this case unusual is
the rather delayed and innocuous
presentation after aspiration of such
a large foreign object. It emphasizes
the fact that healthy adults may
tolerate aspiration of foreign bodies
for a long time without acute lifethreatening consequences. As seen
in this case, betel nuts were found
in left bronchus though anatomical
factor favours it in right side. 4
However, the incidence of foreign
bodies were found almost equal
for both right and left bronchi. 5,6
Bronchoscopic removal of large
aspirated objects in general is
an arduous t ask b ecause most
1.
Baharloo F, Veyckemans F, Francis C, Biettlot

MP, Rodenstein DO. Tracheobronchial
fo re i gn bo d i e s : pre sentati on and
management in children and adults.Chest
1999; 115:1357-62.
2.
Moura e S J1, Oliveira A, Caiado A, et al.

Tracheobronchial foreign bodies in adultsexperience of the Bronchology Unit of
Centro Hospitalar de Vila Nova de Gaia.Rev
Port Pneumol2006; 12:31-43.
3.
Hasdiraz L, Bicer C, Bilgin M, Oguzkaya F.

Turban pin aspiration: non-asphyxiating
tracheobronchial foreign body in young
Islamic women Thorac Cardiovasc Surg
2006; 54:273-5.
4.
Baharloo F, Veyckemans F, Francis C.

Tra c h e o b ro n c h i a l fo re i gn b o d i e s :
Presentation and management in children
and adults. Chest 1999; 115:1357-62.
5.
Merchant SN, Kirtane MV, Shah KL, Karnik

PP. Foreign bodies in the bronchi (a 10 year
review of 132 cases). J Postgrad Med 1984;
30:219.
6.
Enzan K, Mitsuhata H, Sato W, Suzuki M

Statistical analysis of tracheo-bronchial
foreign bodies. Masui 1991; 40:1417-22.
72
Idiopathic Pyoderma Gangrenosum as a

Novel Manifestation of the HIV Immune
Reconstitution Inflammatory Syndrome:
A Report of Three Cases
Vinod E Nambudiri1,2, Romona Kersellius3, Joanna Harp4, JK Maniar5, Toby A Maurer6
Abstract
The initiation of antiretroviral treatment for individuals with HIV may be
accompanied by a paradoxical flare of underlying inflammatory diseases,
the recurrence of dormant infections, or worsening of prior treated
opportunistic infections, termed the immune reconstitution inflammatory
syndrome (IRIS). Cutaneous manifestations of IRIS are common. Pyoderma
gangrenosum is a neutrophilic dermatosis postulated to reflect disrupted
innate immune regulation causing altered neutrophil chemotaxis. It is
uncommonly reported in association with HIV. In this case series, we
present three cases of IRIS manifesting with pyoderma gangrenosum in
individuals with HIV from India and the United States to raise awareness
of this previously undescribed presentation and discuss the treatment
challenges in the management of these patients.
Introduction
IV continues to account
for a significant burden
of worldwide disease. While
much work remains to be done
in earlier disease diagnosis and
enhancing access to treatment,
the introduction of increasingly
sophisticated antiretroviral
therapies over the last two
decades has saved countless lives.
Antiretroviral treatment allows for
the reestablishment of the immune
system, resulting in enhanced
ability to fight off organisms
responsible for opportunistic
infections in immunocompromised
individuals.
By the end of 2011, an estimated

8 million individuals around the
world out of 34 million living
with HIV were on some form
of antiretroviral treatment. 1 The
initiation of antiretroviral therapy
in patients with HIV may be
accompanied by a paradoxical
flare of underlying inflammatory
diseases, recurrence of dormant
infections, or worsening of prior
treated opportunistic infections;
this constellation of occurrences,
in association with rising CD4
counts or decreasing HIV viral
R N A l e ve l s , h a s b e e n t e r m e d
the immune reconstitution
inflammatory syndrome (IRIS). A
postulated molecular mechanism of
IRIS invokes a treatment-induced
dysregulation of effector and
regulatory T-cells in the process
of immune recovery, leading to an
imbalance of cells for particular
pathogen-related antigens. 2 The
resulting inflammation that
is observed is thought to be a
manifestation of specific immune
response targeted at a given
pathogen. 2
Systematic reviews indicate
IRIS is more likely to present in
individuals with lower CD4 counts
at the time of initiation and may
affect up to 22% of individuals
started on antiretroviral treatment.3
Other potential risk factors for
the development of IRIS include
male sex and higher HIV viral
load level at time of antiretroviral
initiation. 4 While any organ system
may be affected by IRIS, cutaneous
manifestations are seen in more
than half of individuals with
IRIS. 5-8 Frequently encountered
skin findings in IRIS include
infectious (e.g., primary herpes
simplex, herpes zoster, genital
warts, molluscum contagiosum,
cutaneous mycobacterial
infections), inflammatory (e.g. acne
vulgaris, eosinophilic folliculitis),
and malignant etiologies (e.g.
Kaposis sarcoma, non-Hodgkins
lymphoma). 9 IRIS can occur de
novo or unmask or exacerbate
underlying condition in individuals
with HIV.
Pyoderma gangrenosum
is an inflammatory dermatosis
characterized by sterile neutrophilic
ulceration with an increased
Department of Medicine, Brigham and Womens Hospital, Boston, MA USA; 2Harvard Combined Dermatology
Residency Program, Boston, MA, USA; 3Department of Medicine, Weill Cornell Medical College, New York, NY
USA; 4Department of Dermatology, Weill Cornell Medical College, New York, NY USA; 5Department of HIV
Medicine, Jaslok Hospital, Mumbai, Maharashtra, India; 6Department of Dermatology, University of California
at San Francisco, San Francisco, CA USA
1
Table 1: IRIS-associated pyoderma gangrenosum (PG)

Clinical cases
Age
Gender
Ethnic origin
Country of residence
Baseline CD4 /L
HIV-1 RNA copies
Combination ART
regimen
Onset of IRIS PG
Follow up CD4 /L
HIV-1 RNA copies
Morphology of PG
Treatments tried
Co-morbidities
Case 1
40 Years
Male
Asian
India
14
1,28,000
TDF + FTC + EFV
Case 2
46 Years
Male
Asian
India
171
1,67,500
ZDV + 3TC + NVP
Case 3
39 Years
Female
African American
USA
33
46,434
ENF (T20) + 3TC + DRV/r
After 12 wks of ART

CD4 213
< 20
Vegetative
Clofazimine,
Minocycline,
Thalidomide,
Clindamycin
Diabetes mellitus,
Dyslipidemia,
After 33 mths of ART

CD4 384
< 53
Superficial erosive
Dapsone,
Clofazimine,
Topical Tacrolimus
After 3.5 wks of HAART

CD4 217
62
Ulcerative
Cyclosporine,
Dapsone,
Minocycline
Alcoholic,
Frailty syndrome
Diabetes mellitus,
Eczema
p r e va l e n c e a m o n g i n d i v i d u a l s
with underlying inflammatory
conditions such as autoimmune
arthritis and inflammatory bowel
disease, as well as in association
with hematologic malignancies.
Etiopathologically, pyoderma
gangrenosum is postulated to reflect
disrupted innate immune regulation
causing altered neutrophil
chemotaxis. 10,11 It is uncommonly
reported in association with HIV.
In this case series, we present
three cases of IRIS-associated
development and worsening of
pyoderma gangrenosum in patients
with HIV. None of the patients
had any of the characteristic risk
factors for pyoderma gangrenosum
such as autoimmune arthritis,
inflammatory bowel disease or

hematologic malignancies, raising
the possibility of IRIS-associated
idiopathic pyoderma gangrenosum
as a distinct entity.
(a)
(b)
Case Reports
Summary information regarding
the three patients with pyoderma
gangrenosum is presented in Table
1.
Case 1
The first patient was a 40-yearold male from India with HIV
presenting with a CD4 count of
14. His comorbidities included
diabetes mellitus and dyslipidemia.
He was initiated with triple
antiretroviral treatment with a
73
regimen consisting of tenofovir,

emtricitabine, and efavirenz.
Twe l ve we e k s a f t e r i n i t i a t i n g
antiretrovirals, he developed
extensive vegetative, ulcerating
lesions over the penis (Figure 1
A, B). The ulcers were refractory
to treatment with systemic
antibiotics including clofazimine
and minocycline. Biopsies of the
ulceration demonstrated dense
mixed infiltration of the epidermis
and follicular structures with
neutrophils and eosinophils (Figure
1C). The dermis also demonstrated
dense mixed infiltrate comprising
neutrophils, eosinophils,
lymphocytes, and plasma cells
(Figure 1D). There was no histologic
or microbiologic evidence for
vegetative herpes simplex. No
evidence of microorganisms
was detected, and a diagnosis of
vegetative pyoderma gangrenosum
was made. Additional treatments
tried for the ulceration included
thalidomide and clindamycin.
The ulcer demonstrated 90%
healing with this regimen after 6
weeks. At follow-up, after sudden
discontinuation of treatment one
year after presentation, the lesions
recurred and were again responsive
to treatment re-initiation.
Case 2
The second patient was a 46year-old Indian male with HIV

with a CD4 count of 171 at the
time of diagnosis. His medical
(c)
(d)
Fig. 1: Vegetative pyoderma gangrenosum in a 40 year old Indian male after initiation of antiretroviral treatment for AIDS. (a,
b) Vegetative lesions on the dorsal and lateral aspects of the penis. (c) Dense mixed inflammation of neutrophils and
eosinophils in the epidermis and perifollicularly; hematoxylin and eosin stain. (d) Dense dermal inflammation with a
neutrophil predominance; hematoxylin and eosin stain
74
(a)
(b)
(c)
(d)
Fig. 2: Superficial erosive pyoderma gangrenosum in a 46 year old Indian male after initiation of antiretroviral treatment
for AIDS. (a) Superficial ulcerative lesions on the buttocks. (b) Improvement in the buttock lesion after treatment with
dapsone, clofazimine, and topical tacrolimus. (c,d) Multiple recurrences of superficial erosive pyoderma gangrenosum
on the back and scalp
comorbidities included chronic

alcoholism. He was started on
an antiretroviral regimen of
zidovudine, lamivudine, and
nevirapine. Thirty-three months
after starting antiretrovirals,
he developed a non-infected
superficial ulcer of the buttocks
(Figure 2A). The ulcer did not
respond to treatment with topical
antibiotics and new ulcerations
developed. A trial of systemic
s t e r o i d s wa s a l s o i n e f f e c t i v e .
Biopsy demonstrated ulcerated
squamous epithelium with a dermal
p e r i va s c u l a r m i x e d i n f i l t r a t e ,
predominantly neutrophilic. GMS
and PAS stains did not reveal any
fungal or parasitic organisms. The
patient was started on treatment
with dapsone, clofazimine, and
topical tacroliums with some initial
benefit to the perianal lesion (Figure

2 B ) . H o we ve r , t h e p a t i e n t h a s
had multiple recurrences at other
body sites in spite of treatment
continuation (Figure 2 C, D).
Patient 3
The third patient was a 40-yearold HIV+ African American female

who had been initially diagnosed
with AIDS several years ago but
had discontinued antiretroviral
treatment. She re-presented for
medical attention with CD4 count
of 30. She was initiated on an
antiretroviral regimen consisting
of ritonavir, darunavir, enfuvirtide,
and lamivudine. Within weeks
o f i n i t i a t i o n , s h e d e ve l o p e d a
5-cm ulceration with violaceous
undermined borders on her right
breast (Figure 3 A). Initial wound
swabs grew Streptococcus viridans,
and she was placed on systemic

antistreptococcal antibiotics
without improvement. Skin
biopsies performed of the ulcer
we r e s u g g e s t i ve o f p y o d e r m a
g a n g r e n o s u m . Tw o s e p a r a t e
tissue cultures were negative for
bacterial, fungal, and atypical
mycobacterial organisms. She was
started on systemic cyclosporine
to which she responded with
some healing of the ulcer, but
also experienced the development
of several subcutaneous nodules
which were also ruled out for
infectious etiologies. She developed
nephrotoxicity secondary to the
cyclosporine and was switched
to treatment with dapsone and
minocycline in concert with her
antiretrovirals which resulted in
stabilization of her ulcer (Figure
3B).
Discussion
(a)
(b)
Fig. 3: Ulcerative pyoderma gangrenosum in a 40 year old African American

female started on antiretroviral treatment for AIDS. (a) Undermined
ulceration of the right breast with violaceous borders characteristic
of ulcerative pyoderma gangrenosum. (b) Clinical improvement after
treatment with dapsone and minocycline
This case series highlights the

rare occurrence of pyoderma
gangrenosum as a manifestation
of IRIS in three patients with
H I V. P y o d e r m a g a n g r e n o s u m
is an inflammatory dermatosis
marked by dense infiltration of
neutrophils (hence, pyoderma) in
the absence of infectious organisms.
Pyoderma gangrenosum has
been seen in frequent association
with underlying systemic
illness, including inflammatory
bowel diseases and hematologic
malignancies. 12 Clinical variants
of pyoderma gangrenosum include
ulcerative, pustular, bullous, and

ve g e t a t i ve t y p e s , a l l o f w h i c h
demonstrate neutrophilic infiltrates
on histopathology. 13
An important differential
diagnosis for pyoderma
gangrenosum, given its clinical
appearance, is frank infection.
Biopsy for both histopathology and
tissue cultures must be performed
to exclude an infectious etiology
when pyoderma gangrenosum
is suspected. Other differential
diagnoses may include cutaneous
vasculitis, vasculopathy, or
skin neoplasms, depending
on the clinical presentation. In
individuals with HIV initiated
on antiretrovirals who develop
suppurative ulceration, infection
must be excluded given the
individuals immunocompromised
s t a t u s a s we l l a s t h e c o m m o n
infectious etiologies that may
present as components of IRIS
reactions. Pyoderma gangrenosum
has been previously reported
in association with HIV, but the
specific etiopathogenic role that
the reconstitution of the immune
system which occurs during
IRIS plays in the development of
pyoderma gangrenosum is an area
for further investigation. There
are currently no reliable molecular
markers for the diagnosis of
pyoderma gangrenosum.
The management of pyoderma
gangrenosum should first involve
the treatment of any underlying
systemic comorbidity, followed by
treatment directed at the cutaneous
manifestations with either
topical, intralesional, or systemic
medications. Local treatments,
including appropriate wound care,
are a cornerstone of pyoderma
gangrenosum management and
crucial to prevent secondary
infectious colonization and
infection. Topical or intralesional
immunosuppressive medications,
including corticosteroids,
calcineurin inhibitors, and
antibiotics have been used with
varying success in the treatment
of pyoderma gangrenosum.
Systemic immunosuppression
w i t h c o r t i c o s t e r o i d s, d a p so n e ,
azathioprine, and several biologic
agents has been tried with varying
success in patients refractory
to local treatments. Treatment
of pyoderma gangrenosum in
the context of HIV presents a
special therapeutic challenge,
given the balance between immune
reconstitution and medical
immunosuppression. In all three
patients, clinical improvement
wa s n o t e d w i t h s o m e f o r m o f
immunomodulatory therapy in
contrast to immunosuppression,
raising consideration for a
protective inflammatory role in
keeping pyoderma gangrenosum
controlled.
While mild or superficial
pyoderma gangrenosum will
often respond to treatment
with corticosteroids alone, the
deep ulcerations as seen in our
patients often require a multiagent immunosuppressive or
immunomodulatory approach. 11
The slow healing of deep ulcerations
in response to immunosuppressive
or immunomodulatory treatment,
as seen in Case 3, are in keeping with
the clinical history of pyoderma
gangrenosum. The chronic
relapsing course with development
of new lesions, as seen in Case 2,
is not uncommon for patients with
pyoderma gangrenosum as well.
I n o u r p a t i e n t s w i t h H I V,
treatment of their underlying
immunocompromised condition
with antiretrovirals and the resulting
IRIS may have paradoxically led to
the development or worsening of
pyoderma gangrenosum. Other
inflammatory conditions such as
sarcoidosis have been noted to
flare in association with IRIS, at
times even greater than 1 year after
antiviral initiation. 14 As one of our
patients presented here developed
pyoderma gangrenosum more
than two years after antiretroviral
initiation, the timeline is still
in keeping with other reported
IRIS-associated worsening of
inflammatory disease. Pyoderma
75
gangrenosum is a diagnosis of
exclusion which may be seen in
the setting of other underlying
systemic diseases such as
hematologic malignancies or
inflammatory bowel disease. None
of the patients presented in this
report demonstrated any history
or physical findings suggestive
of these conditions, and as such
invasive diagnostic procedures
such as bone marrow biopsies or
endoscopies were not performed in
the absence of such findings.
Initiation of antiretrovirals
targeting the HIV virus results
i n s e ve r a l c h a n g e s w i t h i n t h e
immune system; most notable is the
restoration of CD4+ T-lymphocyte
counts and function. However,
antiretroviral therapy has also been
noted to impact neutrophil numbers
and function as well. The incidence
of neutropenia in individuals with
HIV is estimated to be as high as
44% based on large population
studies. 13 Neutrophil function is
also markedly reduced in advanced
HIV. 15 The start of antiretroviral
therapy has been demonstrated to
increase neutrophil counts, as well
as result in enhanced neutrophil
chemotaxis and antimicrobial
activity. 13,16 The exact mechanism
of such neutrophil enhancement
by antiretrovirals remains to be
fully elucidated. In our patients,
this neutrophil activation may have
served to catalyze the development
of pyoderma gangrenosum as a
manifestation of IRIS.
These cases raise several
important lessons for
dermatologists and other clinicians
caring for patients with HIV who
d e ve l o p c u t a n e o u s u l c e r a t i o n .
First and foremost, in addition
t o r a i s i n g a wa r e n e s s o f I R I S associated idiopathic pyoderma
gangrenosum, we hope to stress the
importance of ruling out infectious
etiologies in patients with HIV. As
pyoderma gangrenosum does have
the potential to exhibit pathergy,
we would caution against vigorous
surgical debridement, as this has
the potential to worsen the disease.
76
Immunosuppressive medications
in patients with HIV may present
particular challenges, both from
the basic immune physiology as
well as in the form of drug-drug
interactions or side effects (such
as the impact of cyclosporine on
renal failure in individuals on
antiretroviral medications, seen
in Case 3). Antibiotic agents used
for their inflammatory properties,
such as minocycline, may have a
useful therapeutic role here, as seen
in our series of patients. Finally,
immunomodulatory drugs that
have been explored for the treatment
of pyoderma gangrenosum such
as anti-TNF biologic agents may
n o t b e a s r e a d i l y a va i l a b l e o r
easily dispensed globally in areas
w i t h h i g h p r e va l e n c e o f H I V
(such as in India and sub-Saharan
A f r i c a ) a n d t h e p r e va l e n c e o f
significant infectious diseases
such as tuberculosis and hepatitis
B may limit their utility in such
settings. Future work dedicated
to better understanding the
molecular mechanisms underlying
o u r o b s e r va t i o n i s n e c e s s a r y
to fully characterize this rare
occurrence and shed light on future
diagnostic and therapeutic options
for pyoderma gangrenosum
presenting as a manifestation of
HIV associated IRIS.
References
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Available online at: http://www.unaids.
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Erin H, Veronica P, Toby M, Margot W.

Cutaneous manifestations of immune
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10. Adachi Y, Kindzelskii AL, Cookingham G,

et al. Aberrant neutrophil trafficking and
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78
VIEWPOINT
Rethinking the Postgraduate Teaching Program

and Examinations in Todays India
Georgi Abraham1, Tarun K George2
of doctors that pass through these
portals.
Abstract
Postgraduate medical education has undergone drastic changes in
the developed and developing countries on par with advancements in
technology.
The Indian examination system which we imbibed from the British
requires a rethinking and restructuring to keep pace with the changing
trends shown by the Federation of the Royal Colleges of UK. In this
manuscript we look at the strengths and weaknesses of different
examination systems. We suggest changes in the theory examination
which should be objectively based rather than the outdated essay and
short notes.
We discuss positive and proactive changes to reform our clinical
examination system to enable a just and fair assessment of the candidate
in a strictly time bound fashion.
The Current Scenario in

India
ndia is a land of burgeoning

numbers. We are a population
bordering over 1.2 billion. 1 We
have a GDP amounting to $ 1.87
trillion. The rural to urban ratio of
our population is 69:31. 2 In todays
India health care needs are also
rising. TheThe doctor to patient
ratio is 1:1800 in comparison to
the national goal of 1:1000. 2,3 This
is further skewed with the rural
to urban distribution. Illness is
the single most significant cause
that pushes a family into poverty.
There is so much that we as health
professionals have to contribute
towards this chaos of numbers
and we need to concentrate on
something fundamental about the
health system - our education.
In order to face the complexities
of presentations, illnesses and
individual patients, we need to
ensure that the doctor of todays

India undergoes the right training.
The MD Training Program

The postgraduate training
system falls under two different
bodies - The Medical Council
of India and the National Board
of Examinations. These bodies
regulate the entry, monitor the
training and finally certify the
exit of postgraduate doctors. As
we noted that the doctor patient
ratio is low, over the last few years
India has begun to increase the
number of doctors being trained at
the under and postgraduate level.
There are many public and private
institutions that are springing up.
However this also means it is our
responsibility to ensure the quality
As Physicians we know that

competence in clinical expertise is
a process that involves experience,
the right attitude to learning,
clinical reasoning, exposure to a
diverse array of cases and building
the fund of knowledge. 4 Although
universities and colleges have
va r i o u s d e p a r t m e n t s a n d s u b specialties, it is vital that training
doctors are adequately exposed to
a variety of cases, instructed on the
clinical approach, demonstrated
critical thinking, guided through
procedures and areassessedfor
their knowledge in these areas. The
process of learning is a continuous
one and hence so should be
the process ofassessment. We
should alsorealizethat there are
o t h e r d o m a i n s o f t h e d o c t o r s
personality that we should
train - ethics, communication
andempathizingwith patients
and their relatives. As teachers to
doctors in training we should take
on the responsibility of guiding
our trainees,assessingtheir
performance and motivating them
to do better. One aspect to stress
is t he process of learn i n g a n d
thinking.
As a physician proceeds through
his years of apprenticeship he
aims to gradually improve his
skills. The progression involves
mastering history taking and
physical examination, picking up
Prof. of Medicine, Pondicherry Institute of Medical Sciences, Puducherry; 2Jr. Consultant in Medicine, Christian
Medical College and Hospital, Vellore, Tamil Nadu
the nuances of each patients illness

and appreciating the detailed
approach and challenges that is
unique within each subspecialty.
Then comesacquiring technical
and procedural skill - some of
wh i c h a r e di a gnos tic an d als o
lifesaving. Later on one obtains
the ability to come to the most
likely diagnosis and a sensible
list of probable differentials. One
learns the management involving
a cost-effective investigation plan,
aware of the attributes of each
test and the implication of the
result. One should be able to
explainthe diagnosis to the patient
and relatives in a lucid manner,
give a realistic prognosis, possible
complications and finally chalk
out a follow up plan. These are
essential skills that we as teachers
must strive to impart.
Our roles also involve mentoring
in locally relevant research. Are our
students adept in asking the right
clinical or basic science question?
Can they structure a sound
methodology to find that answer?
Are they honest and sincere about
seeking the truth? And can they
criticallyanalyzesuch information
in context to their individual
patient. The skills involved in
growing into aholisticphysician
are numerous and the task of
guiding that process is even more
arduous, yet gratifying. A journey
t o wa r d s p r o f e s s i o n a l i s m a n d
humanism.
The Requirements for

Assessment in the Exam Introspecting the Current
Scenario5
So after thisgruelingperiod
ofregistrarshipthe final exams are
always a trying test. Any method
of examination has its strengths
and limitations. Most exams in
our Indian context have openended long and short questions
for the theory exam and systemspecific long and short cases for the
practical exams. The theory exam
asseses the fund of knowledge
that the student hasacquired

however since it is not approached
in a context-specific manner such
as a clinical scenarionecessitating
a diagnosis or treatment, one
cannot asses how the student is
able to apply this knowledge in a
real world scenario. The practical
exams usually have one long case
andthree short cases. The students
work them up in a stipulated time
and then are cross-examined by
the examiners. However there are
many limitations in this system:
Most of the time no one knows what
is going on during this working
up period. Very often the cases
may be known to the candidates
beforehand and this can bias his
approach. Are we calibrating the
cases appropriately prior to the
exam and do we detect the signs
expected of the candidate? Is the
candidates technique accurate,
smooth, meticulous and systematic?
Does the candidate handle the
patient appropriately? Does he pick
up the expected findings and not
create signs that are not present?
Also during the cross
examination we find that although
there are guidelines on different
aspects of the case that are to
be focused on many a times we
note that examiners concentrate
a prominent part to miniscule
details in history andoutdated
clinical signs in percussion and
auscultation which dont always
have a bearing on the diagnosis
or management. As examiners we
should try and be more clinically
relevant in our expectation of the
case andrealizethat a major part
involves the clinical diagnosis and
appropriate management plan
that the candidate can outline. In
the changing trend of healthcare,
emphasis on the relevant
investigations in a cost-efficient
manner is paramount. Often we
als o f in d e x ami ne rs amon g us
who int imidat e t he candidat e,
expecting them to know forgotten
named syndromes of yesteryears
and throwing them off-guard by
diverting and admonishing them.
79
There are also cases where the time

limit is not adhered to. A thirty
minute long case evaluation ends up
going for hours by the end of which
the candidate is again expected
to move onto the next round of
short case discussions. When we
expect to certify professionals
of tomorrow we should conduct
ourselves professionally - being on
time; being courteous, considerate,
encouraging the candidate, and
politely avoiding cell phones.
As examiners we need to be
honest to our system and truly
assess the candidate individually
and independently. Basically what
we need to look for is - has this
candidate elicited the relevant
history and findings, can he
structure a good list of differentials
and can he plan a management
safely and effectively.
What can we Learn from

Exams in the Other
Nations?
Analyzing the exams in other
countries, the United Kingdom
for example, The Membership of
the Royal College of Physicians
(MRCP) UK has a very compact
and focused examination. The
candidate is closely monitored for
a smooth and effective technique
and focused questions are asked
to assess his understanding of
the problem. The time allotted is
fixed and the team moves onto
the next station immediately. This
exam also focused on an observed
history taking and breaking bad
news stations. The examiner can
asses if the candidate is systematic,
thorough and is ruling out problems
one by one. The knowledge of
clinical case, sensitiveness of the
candidate and explanation to
patients is alsoassessed. Here
they determine importance of
appropriate communication
techniques with patients in difficult
times and varying trying scenarios.
Another interesting station is
a b r i e f c l i n i c a l s c e n a r i o , ve r y
similar to our everyday outpatient
80
system. Here the examiner creates

almost a real world situation of a
patient presenting with common
everyday problems and observing
the candidate in this station is
very informative on how he has
integrated all his skills in the brief
period of time.
How we as an Academic
Community should Rise Up
S o we b e l i e ve t h a t i t i s o u r
role as teachers of tomorrows
physicians to structure a more
robust post graduate education
system - from start to finish, that
we are made aware of our role
in their mentoring, that we guide
them in the different domains of
competence, continually gauge,
motivate improvement, that we
finally asses with standards and
that this cycle continues on and
improves.
This is our individual

contribution to the numbers of
tomorrow.
role of the examiners should

only be to assess the candidate
and not intimidate them.
We p r o p o s e t h e f o l l o w i n g
recommendations for restructuring
the examination:
5. The sanctity of the clinical

examination should be strictly
adhered to.
1. Objective type questions in

theory examination relevant
to Indian clinical medicine in
a multiple choice format.
References
2. The prospective examiners for

clinical examinations should be
trained and accredited before
they can be appointed for
conducting the examinations.
3. All examiners should be briefed
the day before the beginning of
the examination of how the
practical should be conducted.
4. The examiners should strictly
follow the time schedule as
advised by the university while
examining the candidates. The
1.
http://www.census2011.co.in/.
2. Rural Health Statistics in India 2011.

Available from:http:// nrhm-mis.nic.in/
UI/RHS/RHS%202011/RHS%202011%20
Webpage.htm.
3. High Level Expert Group Report on
Universal Health Coverage for India
Planning Commission of India New Delhi,
November, 2011. Available from: http://
planningcommission. nic.in/reports/
genrep/rep_uhc0812.pdf.
4.
Stern DT, Papadakis M. The Developing

Physician Becoming a Professional. N
Engl J Med 2006; 355:17949.
5. Epstein RM. Assessment in Medical

Education. N Engl J Med 2007; 356:38796.
83
drug corner
Fondaparinux in Acute Coronary Syndromes

Abhijit Trailokya1, Anil Dhall2, DK Kumbla3
Abstract
Anticoagulant therapy is a major component in the management of acute
coronary syndromes (ACS). Anticoagulant-associated adverse events
like heparin-induced thrombocytopenia, bleeding complications and
need of close monitoring of anticoagulation led to focus on developing
agents causing anticoagulation without affecting primary haemostasis.
Fondaparinux, a new-age synthetic anticoagulant, acts by inhibiting
factor Xa. It is simple to administer and has low inter and intra-subject
variability. Moreover, there is no risk of significant drug interactions
and no need for monitoring the platelet count. Efficacy of fondaparinux
has been studied in various disorders including prevention of venous
thromboembolism in major orthopaedic surgery, abdominal surgery
and acutely ill medical patients, treatment of venous thromboembolism,
non-ST-elevation acute coronary syndromes and ST-elevation acute
myocardial infarction. This article covers the review of fondaparinux and
its practical advantages mainly in the management of ACS including
non-ST-elevation acute coronary syndromes and ST-elevation acute
myocardial infarction.
Introduction
isk of venous thromboembolism

is well recognized as a
postoperative complications
in major orthopaedic surgery
involving lower limbs like hip
replacement or knee replacement.
In such cases, prophylactic use
of anticoagulants significantly
reduces the risk of venous
thromboembolism.1 Similarly,
anticoagulant therapy is a major
component in the management of
acute coronary syndromes (ACS). 2
The anticoagulants may impose
many limitations for their usage in
clinical practice including chances
of adverse events like heparininduced thrombocytopenia,
bleeding complications and need of
close monitoring of anticoagulation.
These concerns led to focus on the
development of agents which can
cause anticoagulation and at the
same time do not affect the primary

haemostasis. 1
As factor Xa is the major target for
developing anticoagulant agents. 2
A synthetic pentasaccharides
which can specifically inhibit
factor Xa activity and produce
an antithrombotic effect without
causing inhibition of factor IIa
or antiplatelet activity has been
discovered. 1
Fondaparinux
Fondaparinux is a synthetic,
factor Xa inhibitor which is
structurally similar to the
antithrombin binding site of
heparin and low-molecular-weight
heparin (LMWH). 3 The inhibition
of factor Xa is mediated by plasma
antithrombin. 2 Through its unique

mechanism of action, fondaparinux
attaches to the antithrombin and
changes its structure leading to
inhibition of factor Xa. The affinity
of fondaparinux for antithrombin
is 15 times higher as compared to
unfractionated heparin.4 Compared
to heparins, fondaparinux offers
advantages due to its selective
binding to antithrombin and rapid
and predictable inhibition of factor
Xa. It shows low interindividual and
intraindividual variability. There is
no need of laboratory monitoring
with the use of fondaparinux. 3
Major Pharmacokinetic
and Pharmacodynamic
Properties
Fondaparinux can be
administered by intravenous
or subcutaneous route.2
Subcutaneously administered
fondaparinux sodium 2.5 mg
has been shown to be rapidly
and completely absorbed in
healthy volunteers 1 with 100%
bioavailability.5 The mean
maximum plasma concentration
i s a c h i e ve d i n a m e a n t i m e o f
1.7 hours.1 With intravenous
dosage, the maximum plasma
concentration of fondaparinux is
achieved even faster as compared
to subcutaneous administration,
without any effect on the half-life. 6
The mean elimination half-life of
fondaparinux is 17.2 hours, which
allows once daily administration 1
and also result in maintenance
of significant, 2 predictable and
1
Chief Medical Manager, Abbott Healthcare Pvt. Ltd., Mumbai, Maharashtra; 2Director, Delhi Heart and Lung
Institute, Delhi; 3Consultant Clinical and Interventional Cardiologist, Jupiter Hospital, Thane, Maharashtra
84
5.8%
16.00%
5.7%
14.00%
6.0%
11.20%
12.00%
5.0%
8.90%
10.00%
4.0%
8.00%
3.0%
6.00%
2.0%
4.00%
1.0%
2.00%
0.0%
14.80%
13.40%
0.00%
Fondaparinux
Enoxaparin
Fig. 1: Incidence of death, myocardial infarction, or

refractory ischemia in OASIS-5 trial
sustained7 anticoagulant activity for

24 hours. 2 There is no need for any
dose adjustment or dose monitoring
in most of the patients in routine
practice, 8 providing significant
benefit for the clinician using it.
However, in special populations, if
required, fondaparinux monitoring
should be done quickly with a
validated commercially available
anti-Xa assay using fondaparinux
calibrators. 9
Kidney is the main elimination
route of fondaparinux sodium
through which it is mainly
excreted unchanged. 1 Studies in
healthy volunteer have shown that
fondaparinux sodium does not
have pharmacokinetic interaction
with warfarin 10 and aspirin. 1 Thus,
the pharmacokinetic properties,
pharmacodynamic effects and route
of administration offer remarkable
advantages and simplify the
treatment making administration
more convenient. 7
Dose of Fondaparinux
The recommended dose of
fondaparinux for the treatment
of ACS is 2.5 mg. 8 The dose of
fondaparinux 2.5 mg once daily
subcutaneously is selected based
on the dose-ranging study. In the
Pentasaccharide in Unstable Angina
(PENTUA) study, fondaparinux
was administered subcutaneously
in four different dosages 2.5, 4, 8,
or 12 mg once daily and efficacy
of different dosages was compared
with enoxaparin 1 mg/kg twice
9.70%
7.40%
Fondaparinux
Control group
Day 9
Day 30
End of study
(3-6 month)
Fig. 2: Incidence of death or reinfarction in OASIS-6 trial
d a i l y g i ve n f o r t h r e e t o s e ve n
days, in ACS without persistent
ST-segment elevation. The results
o f t h i s s t u d y s h o we d n o d o s e
response. 11
Efficacy of Fondaparinux
The efficacy and safety of
fondaparinux has been evaluated
in many clinical studies. It has
been found to be effective and well
tolerated in prevention of various
thromboembolic conditions.
Efficacy in Acute Coronary

Syndrome
Tw o p i v o t a l s t u d i e s w e r e
conducted to evaluate the efficacy of
fondaparinux in ACS management.
The OASIS-5 trial was conducted in
patients with non-ST-elevation ACS
(NSTE-ACS) while the OASIS-6
trial was performed in ST-elevation
myocardial infarction (MI).
The OASIS-5 Trial

Selecting a right anticoagulant
in patients with NSTE-ACS is
critical. The Fifth Organization to
Assess Strategies in Acute Ischemic
S y n d r o m e s ( O A S I S - 5 ) s t u d y 12
evaluated the comparative efficacy
and safety of fondaparinux versus
enoxaparin in this condition. The
primary efficacy outcome in the
s t u d y wa s d e a t h , m y o c a r d i a l
infarction, or refractory ischemia.
The study proved its objective
of showing non-inferiority of
fondaparinux versus enoxaparin
by demonstrating similar primary

outcome events in both group at nine
days (Figure 1). Thus, in patients
with acute coronary syndrome,
the efficacy of fondaparinux was
found to be similar to enoxaparin in
reducing the risk of ischemic events
at nine days. It also improves long
term mortality and morbidity.
The combined use of
anticoagulant and antiplatelet
agents with invasive procedure
reduces ischemic events in high-risk
patients with acute coronary
syndromes. However, there are
concerns of increased bleeding
and higher risk of complications
like myocardial infarction, stroke
and even death. In light of this
the results of this trial make
fondaparinux an attractive option
for the patients with acute coronary
syndrome. 12
Place of Fondaparinux in
the Management of ACS
In the European Society of
C a r d i o l o g y ( E S C ) 1 3 a s we l l a s
American College of Cardiology/
American Heart Association (ACC/
AHA) Practice Guidelines 14 on
the management of patients with
NSTE-ACS, use of an anticoagulant
drugs has class IA recommendation.
Thus, fondaparinux has class
I recommendation in both the
ESC and ACC/AHA NSTE-ACS
guidelines. As per ESC guidelines,
in case of pending decision between
e a r l y i n va s i ve o r c o n s e r va t i ve
strategy, fondaparinux was
preferred based on its better

efficacy/safety profile. 13
The OASIS-6 Trial

The OASIS-6 was a randomized
double-blind comparative trial
of fondaparinux 2.5 mg once
daily versus control group for up
to 8 days in ST-elevation acute
myocardial infarction (STEMI).
A total of 12,092 patients were
enrolled in the study. 15 In STEMI,
especially patients not undergoing
primary percutaneous coronary
intervention, fondaparinux
significantly reduces mortality and
reinfarction. The results of OASIS-6
trial showed significantly less
incidence of death or reinfarction
at 9 days, 30 days and at the end
of study compared to the control
group (day 9, P=.003; day 30,
P=.008; and at study end P=.008;
(Figure 2).
Significant benefits i.e. reduction
in death and reinfarction were seen
in patients receiving thrombolytic
therapy and patients not receiving
any reperfusion therapy.
A French registry of NSTEMI
patients, predominantly managed
invasively, has not shown
superiority of fondaparinux versus
enoxaparin in terms of bleeding
events or 1-year mortality. 16 An
open label, study compared the
safety and efficacy of enoxaparin
andfondaparinux in patients with
unstable coronary artery disease. 17
Similar recovery was seen with
both drugs. Numerically high,
but statistically non-significant
recurrent MI or angina was seen in
patients receiving enoxaparin. At
30 days, there was higher incidence
of haemorrhage in enoxaparin
group. Patients with fondaparinux
had no haemorrhage at day 30.
Efficacy in Patients
Undergoing Percutaneous
Coronary Intervention
(PCI)
Factor Xa is a target for treatment
of arterial thrombosis because of its
important role in the formation

of thrombin. In the ASPIRE trial 18
involving 350 patients undergoing
contemporary PCI, fondaparinux
2.5 and 5.0 mg was found to be
comparable to UFH in terms of
safety and efficacy outcomes. The
incidence of total bleeding was
7.7% in the UFH group and 6.4%
in the combined fondaparinux
groups, with less incidence seen
in 2.5 mg fondaparinux group
compared to 5 mg fondaparinux
group (3.4% versus 9.6%). There
wa s n o s i g n i f i c a n t d i f f e r e n c e
in efficacy of fondaparinux as
compared with UFH. 18
Thus, fondaparinux has
particular advantages for use in
acute coronary syndromes, and
its efficacy and safety have been
clearly demonstrated in two large
randomized clinical trials in ACS.
A recent study in Chinese patients
e va l u a t e d e f f i c a c y a n d s a f e t y
offondaparinuxin combination
with tirofiban in high-risk unstable
angina patients undergoing
complex PCI. The patients received
eitherfondaparinuxplus tirofiban
or enoxaparin plus tirofiban. In
both groups, there was no severe
bleeding during hospitalization.
However, patients in fondaparinux
g r o u p h a s s i g n i f i c a n t l y l o we r
incidence of mild and minor
bleeding. The results of this
study demonstrated good efficacy
and safety of fondaparinuxplus
tirofiban combination in high-risk
unstable angina patients
undergoing complex PCI. 19
Catheter-induced thrombosis
in fondaparinux-treated patients
undergoing PCI may be prevented
by giving heparin as practiced in
FUTURA/OASIS-8 trial. 20
Fondaparinux in Other
Conditions
The efficacy and safety of
fondaparinux in preventing venous
thromboembolism (VTE) during
orthopedic surgery has been proved.
Fondaparinux is at least as effective
and safe as body-weight-adjusted
85
enoxaparin in the initial treatment

of symptomatic deep venous
thrombosis (DVT). Fondaparinux
offers a simple dosage regimen of
once-daily subcutaneous dosage
as compared to twice-daily dosage
with enoxaparin. 21 Fondaparinux
is found to be superior to standard
treatment in the prevention of
v e n o u s t h r o m b o s i s . 18 I n a
retrospective review, fondaparinux
has been shown comparable efficacy
and safety to that of enoxaparin in
preventing DVT and pulmonary
embolism (PE) in patients with
stroke. The demonstrated efficacy
and safety of fondaparinux, makes
it a potentially important option for
the prevention of VTE in stroke. 22
With daily monitoring of anti-Xa
activity,fondaparinux may be
u s e d a s a n a l t e r n a t i ve f o r t h e
management of heparin-induced
thrombocytopenia in postoperative
cardiac surgery patients as shown in
a recently published retrospective
study. 23
Fondaparinux in
Pregnancy
Heparin is considered as the
drug of choice for the treatment
or prevention of thromboembolic
e v e n t s d u r i n g p r e g n a n c y . 24
Fondaparinux does not cross the
placenta. It belongs to pregnancy
class B. It can be used in outpatients
without need for monitoring. 25
Though fondaparinux has been
shown to be successfully used in
case of severe allergic reactions
to heparin, its use in pregnancy,
should be limited to the patients
with severe allergic reactions to
heparin or those with heparininduced thrombocytopenia, till
larger studies are available. 24
Safety
As fondaparinux does not
cross-react with heparin-induced
antibodies, the monitoring of
platelet count may not be
required. 7 Similarly, it has been
used successfully in cases with
hypersensitivity to unfractioned
86
4.1%
4.5%
4.0%
3.5%
3.0%
2.2%
2.5%
2.0%
1.5%
1.0%
0.5%
0.0%
Fondaparinux
Enoxaparin
Bleeding complications
a r e t h e m o s t c o m m o n a d ve r s e
events associated with the use
of fondaparinux. Mild local
adverse events may occur after
the injection. Other reported
adverse events include anaemia,
insomnia, increased wound
drainage, hypokalemia, dizziness,
hypotension, confusion, hematoma,
purpura etc. Fondaparinux is
contraindicated in patients with
serious hypersensitivity to the
product, creatinine clearance
<30 mL/min in prophylaxis/
treatment of VTE, active major
bleeding, bacterial endocarditis,
thrombocytopenia (associated
with a positive anti-platelet
antibody in vitro test in presence
o f f o n da p a r i n u x ) a n d p at i en t s
with body weight <50 kg (VTE
References
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Keam SJ, Goa KL. Fondaparinux sodium.

Drugs 2002; 62:1673-1685.
2.
Turpie AGG. Selective factor Xa inhibition

with fondaparinux: from concept to clinical
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2008; 10;Supplement C:C1-C7.
3.
Bauer KA. Fondaparinux sodium: a selective

inhibitor of factor Xa. Am J Health Syst
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Approval Status
Schiele F. Fondaparinux and acute coronary

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5.
US FDA approval for

f o n d a p a r i n u x wa s r e c e i ve d i n
2001. 27 It is approved for use in
prophylaxis of DVT, treatment of
acute DVT and treatment of acute
PE.27 Fondaparinux is not approved
for use in ACS by the US Food and
Drug Administration 4
Bassand JP. The place of fondaparinux

in the ESC and ACC/AHA guidelines for
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Donat F, Duret JP, Santoni A, Cariou

R, Necciari J, Magnani H, et al. The
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regulatory authority in India. 29
In 2008, fondaparinux sodium
injection is approved for the
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7.
Amiral J, Lormeau JC, Marfaing-Koka A,

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Nagler M, Haslauer M, Wuillemin WA.

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Johnson PN, Benefield EC, Phi-Yen N,

Gausman JN, Marlar RA, Gessouroun MR.
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Fig. 3: Incidence of major bleeding with fondaparinux
heparin (UFH) or low molecular

weight heparin (LMWH). Hence,
it can be a good alternative to
patients with UFH or LMWH
hypersensitivity. 26 The OASIS-5
trial, proved its primary safety
objective of showing fondaparinuxs
superiority over enoxaparin in
preventing major bleeding. The
results demonstrated significantly
less incidence of major bleeding
with fondaparinux compared to
enoxaparin at nine days (Figure 3;
p<0.0001). 12 Similarly, in OASIS-6,
no increase in major bleeding or
intracranial hemorrhage was seen
with fondaparinux. 15
deep-vein thrombosis and

pulmonary embolism, and in
patients with non-ST and STelevation acute coronary syndromes.
It can be used as an alternative to
UFH or LMWH in the presence
of hypersensitivity. This new-age
anticoagulant provides various
advantages including low inter and
intra-subject variability, no risk of
significant drug interactions, no
need to monitor platelet count and
simple administration.
prophylaxis only). 27
Extreme caution is required
while using fondaparinux during
spinal or epidural anesthesia to
avoid possibility of spinal and
epidural hematoma. Indwelling
catheters should not be used when
patient is on fondaparinux. 28
Fondaparinux has a positive

benefit-risk ratio in the prophylaxis
of venous thromboembolism in
high-risk surgical and acutely ill
medical patients. Its efficacy and
safety is well demonstrated in
various conditions that include
initial treatment of symptomatic
10. Fa a i j R A , B u rg g r a a f J, Co h e n A F.
Lack of pharmacok inetic (PK ) and
pharmacodynamic (PD) interaction
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12. Yusuf S, Mehta SR, Chrolavicius S, Afzal R,
Pogue J, Granger CB, et al. Comparison
of fondaparinux and enoxaparin in
acute coronary syndromes. The Fifth
Organization to Assess Strategies in Acute
Ischemic Syndromes Investigators. N Engl
J Med 2006; 354:1464-76.
13. Bassand JP, Hamm CW, Ardissino D,
Boersma E, Budaj A, Fernandez-Aviles F,
et al. Guidelines for the diagnosis and
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Bridges CR, Califf RM, Casey DE Jr, et al ACC/
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15. Yusuf S, Mehta SR, Chrolavicius S, Afzal
R, Pogue J, Granger CB, et al. Effects
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295:1519-30.
16. Puymirat E, Schiele F, Ennezat PV,
Coste P, Collet JP, Bonnefoy-Cudraz E,
et al. Impact of fondaparinux versus
enoxaparin on in-hospital bleeding and
1-year death in non-ST-segment elevation
myocardial infarction. FAST-MI (French
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Lal M. Comparative evaluation of efficacy,
safety and haemostatic parameters of
enoxaparin andfondaparinuxin unstable
coronary artery disease. J Clin Diagn Res
2014; 8:31-4.
18. Mehta SR, Steg PG, Granger CB, Bassand
JP, Faxon DP, Weitz JI, et al. Randomized,
blinded trial comparing fondaparinux
with unfractionated heparin in patients
undergoing contemporary percutaneous
coronary intervention Arixtra Study in
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19. Li MW, Zhao XM, Rao LX, Chen Y, Zhu
ZY, et al. The clinical efficacy and safety
offondaparinuxcombined with tirofiban
hydrochloride in patients with acute
coronary syndrome undergoing complex
percutaneous coronary intervention.
Zhonghua Nei Ke Za Zhi 2013; 52:1037-40.
20. Steg PG, Jolly SS, Mehta SR, Afzal R,
Xavier D, Rupprecht HJ et al. Low-dose
vs standard-dose unfractionated heparin
for percutaneous coronary intervention
in acute coronary syndromes treated
with fondaparinux: the FUTURA/OASIS-8
randomized trial. JAMA 2010; 304:1339-49.
21. Buller HR, Davidson BL, Decousus H, Gallus
A, Gent M, Piovella F, et al. Fondaparinux
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symptomatic deep venous thrombosis A
Randomized Trial. Ann Intern Med 2004;
140:867-873.
22. M u k a n d J A , M u k a n d N H . A p i l o t
retrospective comparison of fondaparinux
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23. Cegarra-Sanmartin V, Gonzalez-Rodriguez
R, Paniagua-Iglesias P, SantamariaOrtiz A, Cueva LF, Galan-Serrano J, et
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Vasc Anesth 2014; 28:1020-4.
24. Mazzolai L, Hohlfeld P, Spertini F, Hayoz D,
Schapira M, Duchosal MA. Fondaparinux
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26. Parody R, Oliver A, Souto JC, Fontcuberta
J. Fondaparinux (arixtra), as an alternative
antithrombotic prophylaxis when there
is hypersensitivity to low molecular
weight and unfractionated heparins.
Haematologica. Hematol J 2003; 88:147148.
27. Arixtra Prescribing Information. September
2013; available at https://www.gsksource.
com/gskprm/htdocs/documents/
ARIXTRA-PI-PIL.PDF Accessed on 11th
November 2014.
28. Claer hout A J, Johnson M, R adtke
JD, Zaglaniczny KL. AANA Journal
course update for nurse anesthetists.
Anticoagulation and spinal and epidural
anesthesia. AANA Journal 2004; 72:225-31.
29. Kataria BC, Bhavsar VH, Donga BN.
Contemplation on approved drugs in India
from 1999 through 2011. Asian J Pharm Clin
Res 2012; 5;3:25-29.
30. Fondaparinux EU-RMP (Adherence)
available at http://clinicaltrials.gov/show/
NCT01406301 Accessed on 11th November
2014.
89
Pioneers in Infectious Diseases
Introduction to the Series

Rajeev Soman1, Anjali Shetty2, Camilla Rodrigues3
nfectious diseases often

manifest in a dramatic manner
affecting individuals and whole
communities. It is not surprising
therefore that historically, they
we r e c o n s i d e r e d t o b e d u e t o
the wrath of gods, evil spirits
or black magic. The ideas of the
early pioneers were against the
prevailing notions of religious
leaders and society. Hence some of
the early pioneers were persecuted
and ran great personal risks while
propagating their ideas. These
factors made their times and
lives colourful and interesting.
Factors such as serendipity, acting
on chance remarks and lateral
thinking led to turning points
and landmark discoveries. They
described infections, distinguished

one from another and surmised
about the cause and mode of
spread. Concepts in this field were
evolved on which depended all later
developments such as diagnostic
t e s t s , t r e a t m e n t , va c c i n e s a n d
preventive public health measures.
This has developed into the practice
of infectious diseases as we know
it today.
We h a ve c h o s e n s o m e e a r l y
pioneers for this series in view
of their revolutionary ideas.
Contemporary research also has
special challenges and pioneering
scientists. However the drama

behind them is less easily
understood by all. This compilation
is by no means complete and there
are many others whose work is
equally important. As Rene and
Jean Dubos wrote in 1952 In
science, credit goes to the man who
convinces the world, not to the man
to whom the idea first occurs.
We do hope that the series will
be of interest to the busy physician
of today. He will realize that his
craft is born out of the efforts of all
the early pioneers.
Consultant Physician and infectious Diseases Specialist, 2Consultant Microbiologist, 3Consultant Microbiologist
and Chairperson Infection Control, PD Hinduja National Hospital and MRC, Mumbai
89
Pioneers in Infectious Diseases
Pioneers in Conventional and Molecular Diagnosis

Kinjal Patel1, Mehul Panchal2, Camilla Rodrigues3, Rajeev Soman4
he milestones of progress
in microbiology from
conventional to molecular diagnosis
involved contributions of many
scientists who devoted their lives
to revolutionize microbiology.
he learned to grind lenses, making

simple microscopes, which he used
to make simple observations.
Leeuwenhoek made more than
500 optical lenses. He also created
Antonie Philips Van

Leeunwenhoek
(1632 1723)1
Leeuwenhoek was the son of a
Dutch basket maker and worked
as a draper in his youth. He was
an unlikely scientist, since he came
from a family of tradesmen, had
no fortune and received no higher
education or university degrees.
While running his drapers shop,
at least 25 microscopes, of differing

types. It is said that Leeuwenhoek
possessed some microscopes that
could magnify up to 500 times. He
maintained throughout his life that
there are aspects of microscope
construction which I only keep
for myself, in particular his most
critical secret of how he created
lenses. For many years no-one was
able to reconstruct Leeuwenhoeks
design techniques.
He used to observe almost
anything that could be placed
under his lenses, and described
Clinical Assistant in Microbiology, 3Consultant Microbiologist and Chairperson Infection Control, 4Consultant
Physician and Infectious Diseases Specialist, PD Hinduja National Hospital and MRC, 2Associate Consultant
Microbiologist, Sir HN Reliance Foundation Hospital, Mumbai, Maharashtra
1
90
what he saw. Although he himself

could not draw well, he hired an
illustrator to prepare drawings of
the things he saw, to accompany
his written descriptions. Using his
handcrafted microscopes, he was
the first to observe and describe
single-celled organisms, which he
originally referred to as animalcules,
and which are now referred to
as microorganisms. He was also
the first to record microscopic
o b s e r va t i o n s o f m u s c l e f i b e r s ,
bacteria, spermatozoa, and blood
flow in capillaries.
from a Dutch neighbour emigrated

from the island of Java, Indonesia.
Agar turned out to be an ideal
gelling agent that stayed firm even
in the incubator and could not be
digested by any bacterial enzymes.
Walter Hesse notified Koch of this
new technique, who immediately
added agar to his nutrient broths.
Hans Christian Joachim

Gram (1853 1938)3
Walther Hesse
(1846 1911)2
Hesse studied medicine at the

University of Leipzig from 1866
till 1870, when he received his
doctorate in pathology and began
his career as a country doctor.
Hesse joined Robert Kochs
laboratory in 1881 to study air
quality. He was convinced that
m i c r o o r g a n i s m s we r e p r e s e n t
everywhere, even in water and in the
air. He used a series of filters, made
mainly from wadding, to capture
and observe microorganisms. He
used a gelatin-containing medium
for culturing the organisms trapped
with his filter. Frustratingly, the
medium always melted during
the summer months, thus ruining
the experiments. Additionally,
many of the organisms he cultured
degraded the gelatin medium, also
ruining his experiments.
One day, Hesse went on a picnic
with his wife Angelina Fannie
and noticed that the jellies and
puddings that she had brought
along did not melt in the hot
summer weather. When asked, his
wife replied that they contained
agar and that she had borrowed it
Gram was a Danish bacteriologist

studied botany at the University of
Copenhagen. His study of plants
introduced him to the fundamentals
of pharmacology and the use of the
microscope.
Gram entered medical school
in 1878 and graduated in 1883. In
Berlin, in 1884, while examining
lung tissue from patients who
had died of pneumonia, he
d i s c o ve r e d t h a t c e r t a i n s t a i n s
were preferentially taken up and
retained by bacterial cells. Within
a few years, Gram developed a
staining procedure which divided
almost all bacteria into two large
groups - the Positive and Negative
- Purple and Pink. This technique,
the Gram stain, continues to be
a standard procedure in medical
microbiology. In his initial
publication he remarked, I have
therefore published the method,
although I am aware that as yet
it is very defective and imperfect,
but it is hoped that in the hands of
other investigators it will turn out
to be useful.
James Watson (1928-)

and Francis Crick
(1916-2004)4
J a m e s Wa t s o n wa s b o r n o n
April 6, 1928 in Chicago, Illinois.

He was a very intelligent child.
James loved birds and initially
studied ornithology. He later
changed his specialty to genetics.
Francis Crick was born in Weston
Favell, England. His father was a
shoemaker, but Francis soon found
a love for learning and science.
In 1951, When Crick and Watson
met at Cambridge they quickly
learned that they had the same
passion for solving the DNA
structure. They both had similar
ideas as well on how the problem
could be solved. Using stick-andball models, Watson and Crick
tested their ideas of how the DNA
molecule might fit together. Their
first attempt in 1951 failed, but they
kept at it. They generated flawed
models with the chains inside and
the bases pointing outwards. Later,
Rosaline Franklin who was an X ray
crystallographer presented some
of her experimental findings for
DNA at a public seminar to which
Watson and crick were invited. By
studying X-ray diffraction images
taken by Franklin and her colleague
Williams, the solution became
apparent to Watson and Crick and
they prepared DNA model. In 1953,
they immediately published there
results in the journal Nature.
References
1.
Ford B J. From Dilettante to Diligent

E x p e r i m e n t e r, a R e a p p r a i s a l o f
Leeuwenhoek as microscopist and
investigator, Biology History 1992;5.
2.
Hesse W. Walther and Angelina Hesse-Early

contributors to bacteriology. ASM News
1992; 58:425-428.
3.
Casanova JM. Bacteria and their dyes:

Hans Christian Joachim Gram. Historia de
la inmunologia 1992; 11.
4.
Pollock MR. The discovery of DNA: An ironic

tale of chance, prejudice and insight. J Gen
Microbiol 1970; 62:1-20.
92
Medical Philately
Norman Bethune: Gifted Surgeon and a Strange

Idealist
JV Pai-Dhungat
Norman Bethune, Stamp-Canada, 1980
orman Bethune (1890-1939),

a Canadian physician is best
known for his services in wartime
medical units during the Spanish
Civil War, and as a hero in Peoples
Republic of China and his impact
on Sino-Canadian relations.
A gifted surgeon, an inventor,
a political activist, and an early
proponent of Universal healthcare
system, he was virtually unknown
in his homeland during his
lifetime. He received international
recognition when Chairman Mao
Z e d o n g o f Pe o p l e s R e p u b l i c
of China published his essay
entitled Memory of Norman Bethune
documenting the final months of
his life in China. It was a part of
reading curriculum in Chinas
elementary schools, during its
cultural revolution.
Bethune was born in Ontario in
1890 and completed his medical
degree from University of Torontos
faculty of medicine in 1916. The
famous Frederick Banting was
his classmate. In a flourish of
patriotism, Bethune joined the Field
Ambulance to serve as a stretcher
bearer in France during WW-I. He
was wounded by shrapnel and
spent three months recovering in
a hospital in England.
Bethune China, 1979
With the war still raging, he

felt compelled to return to service,
so he joined the Royal Navy as
Lieutenant-Surgeon. At wars end
he took on a six month internship
at the prestigious Hospital for Sick
Children in London. After earning
his FRCS qualification in 1923,
he married the beautiful Frances
Penny. However, the marriage
failed largely due to his lavish
spending and flamboyant lifestyle.
Bethune felt the crisis in his life
when he contracted tuberculosis
in 1926 due to overwork and close
contact with the sick. He insisted
t hat h is wife divorce him and
returns to Scotland. He then sought
treatment at the Trudeu Sanatorium
at Saranac Lake, America. This
was a turning point in his life. It
was tuberculosis which gave him
direction. He had been disabled
by it and took the, cure with
artificial pneumothorax introduced
by Forlarni. He became interested
in and insistent on the use of
new compression treatment of
tuberculosis, either by artificial
pnuemothorax or thoracoplasty,
in either case resting it. He went
to Montreal to learn and practice
Dwarkanath Kotnis- China, 1982
chest surgery under the pioneer

Dr. Edward Archibald, of the Royal
Victoria Hospital. He perfected
his skills in thoracic surgery and
d e ve l o p e d n e w s u r g i c a l t o o l s .
Bethune Rib Shear is still used
today.
Bethune was strange and
idealistic. He was a ruthless man,
in having his own merciful way,
as one who devoted to left wing
causes and to a radical cure of
the incurable, letting his politics
imitate his practice. When Spanish
Civil War broke out in 1936, he left
for Spain to head the Canadian
Medical Unit in Madrid. There he
conceived the idea of administering
blood transfusion on the spot on
the battlefield and developed the
worlds first mobile transfusion
unit (1936), saving countless lives.
He emerged from that Civil war as
a convinced Communist.
In 1938, Bethune joined the
guerrilla communist armies in
China, in their struggle against
Japanese invaders. He established
their medical service and set an
example that communist and noncommunist armies followed. He
performed emergency battlefield
Professor of Medicine (Retd.), T.N. Medical College, Hon. Physician, Bhatia Hospital, Mumbai, Maharashtra
surgical operations on war

causalities and started training
for doctors and nurses. He did not
distinguish between casualties,
treating Japanese prisoners as well
as Chinese.
Stationed with Chinas Eight
Route Army in the midst of Second
Sino-Japanese War, Bethune cut
his finger while operating on a
soldier. Due to his weakened state,
he contracted septicemia and died
in November 1939.
Bethune is one of the few
foreigner to whom china has
dedicated statues, of which many
in his honour have been erected

throughout the country. He is
buried in Revolutionary Martyrs
Cemetery, in Shijiazhuang City,
where lies his tomb and memorial.
In Canada, Bethune College at
Yo r k U n i ve r s i t y , a n d B e t h u n e
Collegiate Institute in Scarborough,
are named after him.
Opposite the tomb of Bethune is
the tomb of our doctor Dwarkanath
Kotnis, who is also honoured for
his humanitarian contribution
t o C h i n a . D wa r k a n a t h K o t n i s
succeeded Bethune in the same
Eight Route Army. It is unlikely
93
that the two heroes of modern

China met each other in person.
Biographers refer to his anxiously
waiting for the arrival of Kotnis,
which was inordinately delayed
due to Japanese blockade.
This article was first
published in its full form in
American Journal of Medical
Philately- Scalpel & Tongs-JulySeptember 2011 issue- in the series
Tu b e r c u l o s i s a n d p r o m i n e n t
people. It is reprinted here with
the kind permission of the Editor
Dr. Frederick C Skvara, MD.
94
Correspondences
Splenic Infarction in
Polycythemia Vera:
Can the Spleen be
Saved?
VD Charan1
Clinical Hematologist, Pune, Maharashtra
Sir,
I read the above article ( JAPI
Mar 2014, Vol 62, pg 64-66) with the
great intrest. Patient was detected
to be hypertensive 10 years back,
that is at the age of 35 yrs, in all
probability it was manifestation of
polycythemia vera (PV), as is almost
50% of PV present with sencondary
hypertension.Hypertension is
caused by rise in hematocrit and
resultant hyperviscosity leading to
increase in intraarterial pressure.
Since the patient had no fever,
tachycardia, leucocytosis or tender
spleen on admission thereby
suggesting that most likley he had
infarction 2 months back when he
developed left hypochondriac pain.

The natural history of infarction
is progression to fibrosis as it
is a bland infarction. Clinical
examination in this case recorded
spleen size 16 cm below left coastal
margin while USG abdomen and
CT abdomen reported splenic span
of 18 cm and 20 cm, respectivley,
i m p l y i n g s i z e c o u l d n o t h a ve
been 16 cm below coastal margin.
Splenomegaly in active PV is
mostly due to increased red cell
mass and not due to medullary
hematopoiesis which occurs in case
of spent burnt out PV.
Patient underwent five
phlebotomies for 4 weeks and as
expected and as reflected in Table
1 his Hb serially diminished but
surprisingly the hematocrit (Hct)
kept on rising from 64.2 to 69.3%,
so also the MCH from 21.7 to 23.5
pg, despite frequent phlebotomies
draining 500 ml blood each time.
The goal of phlebotomy is to bring
Hct to less than 45% in male and

less than 42% in female cases.
Initially it can be done weekly or
twice weekly till Hct normalises
and later once in a 3-6 months.
With the advent of efffective
cytoreductive agents such as
hydroxyurea, interferron alfa,
anagrelide and pipobroman,
splenectomy is hardly performed in
PV except few select patients who
are intolerant of or unresponsive to
cytoreductive agents. 1 The safety
and benefits of low dose aspirin
in PV has been proved in ECLAP
study 2 and thus low dose apsirin
could have been added in this case.
References
1.
Skeensma DP, Richard RE. Myloproliferative

disorders - in Am Soc Hemat, Self Assesment
Programme, 3rd Edn,2007,172-184.
2.
Landofi R, Marchioli R, Kutti J, et al.

Efficacy and saftey of low dose aspirin
in Polycythemia Vera. N Eng J Med 2004;
350:114-124.
94
Correspondences
Successful
Management of
Highly Drug-Resistant
Tuberculosis with
Individualized Drug
Susceptibility Testing
Bharat Purandare1
Consultant in Infectious Diseases, Deenanath
Mangeshkar Hospital and Medical Research Institute,
Pune, Maharashtra
Sir,
I read with interest the original
article Successful management of
highly drug-resistant tuberculosis
with individualized drugsusceptibility testing by Soman
et al in July 2014 issue of JAPI. I
have following comments to make.
Multi-drug resistant tuberculosis
(MDR-TB) cases are on the rise 1
and our tertiary care hospitals are
reporting up to 20-25% of TB isolates
as MDR (personal communication).
The article puts forth real-life
scenario that a physician faces
while managing such complex
cases. Large number of regimens
used to treat the patients in this
case-series reflects the differences
in drug-susceptibility of MDR-TB
strains as well as patient tolerance
to various drugs. Single regime
(like in DOTS PLUS program) is less
likely to work in this heterogeneous
population. Rapid molecular tests
like Gene Xpert MTB/RIF or Line
probe assay can provide quick

results and usually correlate
well with the traditional drugsusceptibility tests 2 and should be
used wherever available.
careful selection of drugs based on

individualized drug susceptibility
test and drug-exposure history and
good patient compliance seem to be
critical for success.
Injectable aminoglycosides
given for several months (minimum
6 months or sometimes even
longer ) appear to be the key
to successful treatment. Short
duration courses run the risk of
TB relapse. Injection site pain and
fibrosis, hearing loss, tinnitus,
and renal function abnormalities
are common adverse effects which
limit patient compliance. Use of
fluoroquinolones (FQ), wherever
possible, increase the chances of
t h e r a p e u t i c su c c e s s . H o we ve r ,
rates of FQ resistance found in this
study are >40%, way beyond PETTS
study which reported around 13%
resistance to FQ,3 indicating serious
situation that we face in India.
PAS, cycloserine, ethionamide,
linezolid, high-dose isoniazid and
clofazimine are useful agents but
have their own range of side effects
on long-term use. Newer and safer
anti-MDRTB drugs are therefore
urgently required.
The cost of treating a patient

with MDR-TB infection can be
prohibitive 4 and availability of
second-line agents across medical
s t o r e s i s a l wa y s a p r o b l e m . I f
clinicians, counselors and social
workers, pharmacists and even
pharmaceutical companies come
together to establish TB-care
centers with facilities such as
patient consultation, counseling,
laboratory services, social support
services and uninterrupted secondline drug supply; high cure rates
can be expected.
In extrapulmonary TB cases,
judging the response to antiMDR-TB treatment is difficult
as follow-up cultures are not
easily possible. Good outcome
was reported in 49/52 patients in
this study, which is encouraging.
Competent microbiology support,
References
1.
WHO update on MDRTB (2013).
2.
Boehme CC, Nicol MP, Nabeta P, et al.

Feasibility, diagnostic accuracy, and
effectiveness of decentralised use of
the Xpert MTB/RIF test for diagnosis of
tuberculosis and multidrug resistance: a
multicentre implementation study. Lancet
2011; 377:1495-1505.
3.
Dalton, T, Cegielski, P, Akkslip, S et al.

Prevalence of and risk factors for resistance
to second-line drugs in people with
multidrug-resistant tuberculosis in eight
countries: a prospective cohort study.
Lancet 2012; 380:1406-1417.
4.
Pooran A, Pieterson E, Davids M, Theron

G, Dheda K. What is the Cost of Diagnosis
and Management of Drug Resistant
Tuberculosis in South Africa? PLoS ONE
2013; 8: e54587.

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Journal of The Association of Physicians of India Vol.

First the ESBLs, now the Carbapenemases:

out and the kinetics of the drugs

Keeping this in mind, we had

The dangers of overuse of

There has been a recent lowering

study results by Shah et al 8 is an

Journal of The Association of Physicians of India Vol. 63 July 2015

with novel mechanisms of action.

Harris PNA, Tambyah PA, Paterson DL.

Infect Dis 2015; 475-85.

Patel V, Soman R, Rodrigues C, Singhal T,

Trivedi M, Patel V, Soman R, Rodrigues C,

Rodriguez-Bano J, Maria DN, Pilar R,

Clin Infect Dis 2012; 54:16774.

Tamma PD, Han JH, Rock C, Harris AD,

Perez F, Bonomo RA Can We Really Use

Deshpande P, Shetty A, Kapadia F, Hedge A,

Shah PG, Shah SR. Treatment and Outcome

Journal of The Association of Physicians of India Vol. 63 July 2015

Treatment and Outcome of CarbapenemResistant Gram-Negative Bacilli Blood-Stream

Context: Infections caused by carbapenem-resistant bacteria constitute

Objective: To describe treatment and outcome of carbapenem-resistant

arbapenem such as imipenem

Journal of The Association of Physicians of India Vol. 63 July 2015

carbapenem-resistant Gramnegative bacilli.

according to the manufacturers

Subjects and Methods

The study was conducted in a

All isolates obtained from blood

Automated systems were used

A Modified Hodges test (MHT)

Data, including patient

Journal of The Association of Physicians of India Vol. 63 July 2015

Table 2: Antimicrobial susceptibility

Susceptibility of 15 isolates of Acinetobacter baumannii

Susceptibility of 8 isolates of Pseudomonas aeruginosa

MDR Gram-negative bacilli but

antibiotics such as carbapenems

Table 3: Characteristics of patients

to its ability to disseminate in the

Journal of The Association of Physicians of India Vol. 63 July 2015

Table 4: Antibiotic treatment and

of cases the source of bacteremia

with colistin and carbapenem

considering the breakpoint for

Journal of The Association of Physicians of India Vol. 63 July 2015

critically ill patient may predispose

Performance standard for antimicrobial

United States Food and Drug Administration

14. Petrosillo N, Ionnidou E, Falagas E. Colistin

EUCAST. Available at: http://www.eucast.

15. Lee J, Patel G, Huprikar S, Calfee DP, Jenkins

Noyal MJC, Menezes GA, Harish BN, Sujatha

16. Markou N, Markantonis SL, Dimitrakis E,

Kosmidis C, Poulakou G, Markogiannakis A,

Nordmann P, Naas T, Poirel L. Global

10. Kumarasamy KK, Toleman MA, Walsh

Gupta E, Mohanty S, Sood S , Dhawan B,

4. Nagaraj S, Chandran SP, Shamanna P,

Neuner EA, Pharm D, Yeh JY, et al. Treatment

Clinical and Laboratory Standard Institute.