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Inhalational Ciclesonide found beneficial in

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DOI: 10.1007/s00068-016-0633-1

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Inhalational Ciclesonide found beneficial in
prevention of fat embolism syndrome and
improvement of hypoxia in isolated skeletal
trauma victims

R.K.Sen, S.Prakash, S.K.Tripathy,

A.Agarwal & I.M.Sen

European Journal of Trauma and

Emergency Surgery
Official Publication of the European
Society for Trauma and Emergency
Surgery Incorporating the International
Journal of Disaster Medicine

ISSN 1863-9933

Eur J Trauma Emerg Surg

DOI 10.1007/s00068-016-0633-1

1 23
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 Author's personal copy
Eur J Trauma Emerg Surg
DOI 10.1007/s00068-016-0633-1

ORIGINAL ARTICLE

Inhalational Ciclesonide found beneficial inprevention offat

embolism syndrome andimprovement ofhypoxia inisolated
skeletal trauma victims
R.K.Sen1 S.Prakash2 S.K.Tripathy1,4 A.Agarwal1 I.M.Sen3

Received: 17 August 2015 / Accepted: 4 January 2016

Springer-Verlag Berlin Heidelberg 2016

Abstract for 72h. The complications related to CIC administration

Background Many studies have established intravenous
corticosteroid as an effective prophylactic therapy in fat
embolism syndrome (FES). However, its use is limited
among surgeons because of systemic side effects. Inhala-
tional steroids have least systemic effects and are widely
used for several chest conditions (i.e., asthma), but their
effectiveness in FES has not been established.
Question/purpose This study was sought to evaluate
the (1) efficacy and (2) safety of inhalational Ciclesonide
(CIC) in prevention of FES and treatment of hypoxemia in
isolated skeletal trauma victims.
MethodsA nonrandomized prospective control trial was
designed in which all patients between 18 and 40years
with isolated skeletal injury who presented within 8h of
injury were allocated to either Trial group or control group.
Trial group patients received 640mcg of inhalational CIC
with a metered-dose inhaler at the time of admission, and
at 24h. Control group patients did not receive any prophy-
lactic therapy. Both groups were evaluated for development
of FES (Gurds criteria) and hypoxemia (PaO2 <70mmHg)
were evaluated in trial group patients during their hospital
stay.
Results Of 35 patients in each group, two patients in Trial
group and nine patients in control group developed FES
(P=0.022). Eight patients in Trial group had hypoxemia at
the time of admission, six of them improved and one addi-
tional patient developed hypoxemia after inhalational CIC
administration. In control group, ten patients had hypoxia
at the time of admission, only one of them improved and
remaining nine patients had persistent hypoxemia even
after 72h. Additionally, three patients developed hypox-
emia. A significant improvement in hypoxemia and a sig-
nificant decrease in the incidence of FES were observed in
Trial group (P<0.05) compared to control group. None of
the patients presented with any complications or adverse
effects of steroid in Trial group.
Conclusion Inhalational CIC is a safe and effective ther-
apy for prevention of FES and also an effective drug for
treatment of hypoxemia in orthopedic trauma victims.
Level of evidence Level III, therapeutic study.

Keywords Fat embolism syndrome Corticosteroid

* S. K. Tripathy
sujitortho@yahoo.co.in Inhalational steroid Gurd`s criteria Ciclesonide
1
Department ofOrthopaedics, Postgraduate Institute
ofMedical Education andResearch, Sector12,
Chandigarh160012, India
Introduction
2
Department ofOrthopaedics, Ex-resident Postgraduate
Fat embolism syndrome (FES) is a serious and a potentially
Institute ofMedical Education andResearch,
Chandigarh, India life threatening complication of long bone fractures. The
3 incidence of FES has been reported in different studies that
Department ofAnesthesia andCritical Care, Postgraduate
Institute ofMedical Education andResearch, varies from 2 to 22% [14] with mortality rates ranging
Chandigarh, India from 10 to 36% [58].
4
Department ofOrthopaedics, AIIMS, Bhubaneswar751019, The pathogenesis of FES involves a cascade of bio-
India chemical events that ultimately results in an inflammatory

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R. K. Sen etal.

reaction in the lung parenchyma leading to respiratory fail-

ure. There is no definite treatment of FES, so prevention,
early diagnosis, and adequate symptomatic treatment are
of paramount importance. Despite controversies about the
role of corticosteroids in FES, majority of the studies have
agreed with the consensus that parenteral corticosteroids in
low or high doses are effective therapy in preventing FES
[2, 912]. The proposed mechanism of action is largely
as an anti-inflammatory agent, reducing the perivascular
hemorrhage and edema [2]. Despite the proven efficacy in
reducing arterial hypoxemia and FES, corticosteroids have
not been uniformly used by surgeons as prophylactic ther-
apy in FES. The main reason behind this reluctance is the
apprehension of the steroid-related systemic complications,
infection and nonunion or delayed union of the fractures
after intravenous administration of steroid [2].
Corticosteroid is a miracle drug that has been used in
myriads of chest conditions in various forms with vari-
ous routes of administration. Inhaled corticosteroids (i.e.,
Budesonide, Fluticasone Propionate, CIC) have revolu-
tionized the treatment of asthma and have now become the
mainstay of therapy for patients with chronic disease [13
Fig.1Flow chart demonstrating patient recruitment in this study
15]. It has been proven that inhalational steroids have mini-
mal systemic complications with better efficacy [15]. There
have been tremendous improvements in the drug delivery
system for the inhalational steroid. The aerosol therapy is and abdominal injury), open femoral fractures, pathologi-
a modality of drug administration where the main advan- cal fractures or those with pre-existing cardiac or pulmo-
tage is that for a given therapeutic response, the drug dose nary disease or chronic smokers were excluded. After
is several-fold lower, and the systemic absorption is negli- obtaining an informed consent, a total of 70 patients of
gible [16]. There have been developments in aerosol prepa- both sexes were included in this study (Fig.1). Institutional
rations of steroids also and now these are having better pul- ethical committee approval was obtained before recruit-
monary deposition efficiency, low oral bioavailability, high ing patients. In all these patients, after initial resuscitation
systemic clearance and have selective binding capacity to and necessary splintage, appropriate imaging for all skel-
the glucocorticoid receptor [9]. etal injuries was done. Injury severity score was assessed
Our first study on inhalational Ciclesonide had shown a using New Injury severity score (NISS). A detailed history
good response (though statistically insignificant) in preven- including pre-hospital care (if the patient has received) was
tion of clinical and subclinical FES in orthopedic trauma mentioned in a predesigned proforma.
victims [17]. Admission shock was defined if systolic blood pressure
Accordingly, this nonrandomized prospective study at the time of admission was below 90mmHg. The inves-
was designed to observe the (1) efficacy and (2) safety of tigations at time of admission included (1) posteroanterior
inhaled CIC in prevention of FES and treatment of hypox- view of chest roentgenogram (CXR), (2) complete hemo-
emia in trauma victims. gram, (3) serum biochemistry for renal function param-
eters, blood glucose levels, serum lactate, etc., (4) Coagula-
tion profile, i.e., prothrombin time (PT), prothrombin index
Patients andmethods (PTI) and activatedpartial thromboplastin time (APTT),
and (5) arterial blood gas analysis (ABG).
The study was conducted over a period of 2years, i.e., We categorized the patients into two treatment groups.
from July 2010 to 2012. The selection of patients for the Every alternate patient was given inhalational CIC form-
study was made from those attending the surgical emer- ing the Trial group. The other group of patients who did
gency of our hospital. All patients of 1640 years old with not receive any prophylactic treatment formed the con-
isolated femoral shaft fracture or associated skeletal inju- trol group. Immediately after the admission, the Trial
ries presenting within 8h of injury were considered for group patients received 640 mcg of inhalational CIC with
inclusion. Patients with multi system trauma (head, chest a metered-dose inhaler; the drug was repeated once again

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Inhalational Ciclesonide found beneficial in prevention of fat embolism syndrome and

after 24h. All patients irrespective of the study groups Table1Comparative evaluation of two study groups
were taken up for surgical stabilization of fractures as Parameters Trial Groups control P value
per the conventional management protocol and moni-
tored for 3days for development of FES or hypoxemia Age
(PaO2 <70mmHg). In Trial group, nine patients were 1630 years 28 23 0.179
operated between 24 and 48h, and remaining 26 patients 3140 years 7 12
were operated between 48 and 72h. In control group, 12 Sex
patients were operated between 24 and 48h, and remaining Male 35 34 0.314
23 patients were operated between 48 and 72h. Reamed Female 0 1
intramedullary nailing was performed for femur shaft frac- Pre-hospital care
ture. Open or closed reduction with internal fixation using No 6 10 0.255
appropriate implants was performed for other long bone Yes 29 25
and pelvic/acetabulum fractures. Complete records were NISS
maintained for clinical evaluation including 4-hourly vitals 18 15 11 0.062
(pulse rate, respiratory rate, blood pressures and tempera- >18 20 24
ture). Patients were monitored with 12 hourly arterial blood Admission shock
gas analysis (ABG) for 72h. In these 3days, once daily N 31 31 1.000
CXR, hemogram and coagulation profile were taken. The Y 4 4
assessment was made for FES using Gurds Criteria [18]. Admission Hb (gm/dl)
The analysis was done by comparing the incidence of 10 6 5 0.743
FES and hypoxemia in both groups to evaluate the effect >10 29 30
of prophylactic role of inhalational steroid. Patients were Admission BD (meq/L)
discharged from the hospital once they were hemodynami- 5 10 11 0.794
cally stable, fractures were stabilized, patients were mobi- >5 25 24
lized and wounds were healthy. A note was made of any Admission PaO2 (mmHg)
side effects of inhalational steroids observed during the 70 7 10 0.255
hospital admission period, e.g., oropharyngeal candidiasis, <70 28 25
any alteration in serum electrolytes or blood parameters or
wound complication. NISS New Injury Severity Score, Hb hemoglobin, BD base deficit

Statistical analysis developed FES after surgical intervention (femur nailing

The statistical evaluation was accomplished using SPSS
software version 17. A p value less than 0.05 was consid-
ered to denote the presence of a statistically significant
difference.
MannWhitney test was used to analyze the quantita-
tive data, whereas Chi-square test was used to compare the
qualitative data.
Results
There were no significant differences between the groups
in regards to age, sex, pre-hospital care, admission shock,
injury severity (New Injury Severity Score, NISS), admis-
sion hemoglobin, base deficit and PaO2 (Table1). Of 35
patients in each group, two patients (5.71%) in Trial group
and nine patients (25.71%) in control group developed
FES (Table2). Both patients in Trial group developed FES
within 24h. In control group, seven patients (20%) devel-
oped FES within 24h and two patients (5.71%) between
24 and 48h. Only one patient (2.85%) in control group
for femur shaft fracture). There was a significant decrease
in the incidence of FES in Trial group compared to control
group (Chi-square test, P=0.022).
In Trial group, eight patients (22.85%) had hypoxemia
at the time of admission, six of them (75% of hypoxemic
patients) improved after inhalational steroid. One of the
remaining two patients developed full blown FES. One
patient who did not present with hypoxemia at the time of
admission developed hypoxemia after CIC administration
(following femur and tibia fracture fixations using intramed-
ullary nail). Thus, a total of three patients (9%) in CIC
receiving group had hypoxia. In control group, ten patients
(28.57%) had hypoxia at the time of admission, only one
of them improved and remaining nine patients had persistent
hypoxemia even after 72h. Additionally, three patients devel-
oped hypoxemia (two of them developed hypoxemia after
surgical intervention). Thus, a total of 12 patients (34.28%)
had hypoxemia in control group. A significant improvement
in hypoxemia and a significant decrease in the incidence of
FES were observed in Trial group (P<0.05) compared to
Control group. None of the patients presented with any drug
reaction or adverse effects of steroid in Trial group.

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R. K. Sen etal.

Table2Evaluation of FES in the trauma patients based on their clin- [22]. The major morbidity in FES is hypoxia which is
ical signs and symptoms (Gurds criteria because of an inflammatory response to the embolized fat
FES globules in the lung parenchyma. Our first study on inha-
Absent Present
lational Ciclesonide revealed the possible efficacy of this
drug in FES [17]. It was hypothesized that inhalational
Major criteria steroid will suppress the inflammatory response in the lung
Hypoxia parenchyma and would prevent development of FES in
Yes 5 10 trauma victims.
No 54 1 There are few limitations in this study. The Gurds
CNS depression clinical criterion used for diagnosis of FES has never been
Yes 2 9 proved as the gold standard diagnostic criteria of FES.
No 57 2 Many researchers believe that diagnosis of FES by Gurds
Petechie criteria [18] may underdiagnose the condition. But, in fact
Yes 0 8 there is no gold standard diagnostic criterion of FES and
No 59 3 Gurds criteria are still the most frequently used diagnostic
Minor criteria criterion [7, 8, 22]. Close observation of patients for subtle
Pyrexia signs of FES can accurately diagnose the syndrome. With
Yes 15 11 the prospective study design and evaluation by a dedicated
No 44 0 trauma team, a group of susceptible trauma victims were
Tachycardia strictly screened for FES development. Randomization of
Yes 18 11 the patients could have improved the quality of this study.
No 41 0 The other limitations are the bias of the observer physi-
Anemia cians (who are the same who treated the patients), the lack
Yes 20 7 of blinding, the lack of short- and long-term follow-up,
No 39 4 the lack of outcomes specific to the fracture healing (how
Decreased platelet did steroids influence this) and the lack of any measurable
Yes 5 3 response to inhaled steroids in terms of appropriate serum
No 54 8 markers. Despite these limitations, the nonrandomized pro-
High ESR spective study design and comparison with a control group
Yes 2 3
are strength of this study. There were no difference between
No 57 8
both the groups in terms of age, sex, NISS, pre-hospi-
Fat macroglobulinaemia
tal care, admission hemoglobin, PaO2 and BD. In these
two comparable groups, the incidence of FES was found
Yes 54 11
to be 26% in patients not receiving any prophylaxis and
No 5 0
6% in patients receiving CIC as a prophylactic treatment.
This difference was statistically significant indicating the
effectiveness of CIC in prevention of FES. Many trauma
Discussion victims do not develop full blown FES and merely present
with hypoxemia (subclinical FES). In this study, we have
Numerous studies have established the efficacy of intrave- evaluated the effectiveness of CIC in both full blown FES
nous corticosteroid (Methyl-Prednisolone) as prophylac- and hypoxemic conditions. There was significant improve-
tic drug for FES in susceptible trauma victims [2, 1012, ment of hypoxemia in patients receiving inhalational CIC;
19]. However, it is still being inconsistently used because 6 of 8 (75%) patients improved within 72h, but one of ten
of several reported complications, i.e., hypothalamic-pitui- patients (10%) only improved in the control group.
tary-adrenal suppression, hyperglycemia, peptic ulcer, poor CIC is a novel, newly marketed corticosteroid adminis-
wound healing, delayed union, wound infection, etc. [2]. tered by Hydrofluoroalkane (HFA) containing metered-dose
Steroid in any other form or route has never been tried in inhaler (MDI) [15, 22]. This drug is converted to an active
trauma victims. Inhaled steroid has shown promising result metabolite, desisobutyryl-CIC (des-CIC) in the lungs and has
in many inflammatory chest conditions such as asthma, minimal effect on endogenous cortisol. The other important
ARDS and acute lung injury after chlorine gas inhalation feature in CIC preparation is that it can reach the lung paren-
[15, 20, 21]. The main advantage of the aerosol therapy is chyma unlike most of the previous steroid inhalers which
that for a given therapeutic response, the drug dose is sev- were unable to go beyond the bronchial tree. The mean
eral-fold lower, and the systemic absorption is negligible lung deposition of CIC from HFA-containing MDI is 52%

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Inhalational Ciclesonide found beneficial in prevention of fat embolism syndrome and
[12, 19]. The efficacy of CIC has already been clinically
proved in asthma, perennial rhinitis, chlorine gas-induced
lung injury and acute respiratory distress syndrome due to
sepsis [21, 22]. The internal diameter of the smallest air-
ways in adults is typically 2m, thus, it can be inferred that
smaller inhaled steroid particles lead to greater pulmonary
deposition and more even distribution throughout the lungs.
Accordingly, the HFA-MDI formulation of CIC contains a
majority of inhaled steroid particles which range between
1.1 and 2.1m. This particle size is likely related to the high
observed pulmonary deposition of CIC. Furthermore, uptake
of CIC, Budesonide, and Fluticasone propionate in human
alveolar type II epithelial cells (A549) was measured, and at
all incubation time points, intracellular concentration of CIC
was higher than that of Budesonide and Fluticasone [1315,
22]. This indicates a more rapid uptake of CIC molecules
into target tissue, and at a higher concentration. Additionally,
separate invitro data indicate intracellular concentration of
des-CIC in A549 cells to be maintained for >20h [15]. FES
usually develops in first 24h of injury. In our previous study
also we observed peak value of inflammatory marker (i.e.,
IL-6) at 12h of injury in FES victims [23].
Thus, administration of CIC at the time of admission
and 24h effectively suppressed the inflammatory response
in the lung parenchyma preventing development of FES
and hypoxemia.
Chronic use of inhalational steroids (i.e., Fluticasone,
Budesonide) in asthmatic patients has shown develop-
ment of few serious complications such as oral candidi-
asis, HPA-axis (hypothalamic-pituitary axis) suppression,
growth velocity alteration, and wound infection [15]. CIC
is relatively inactive and it is activated to its active form
des-CIC mainly in the lung parenchyma with minimal
deposition in the oropharynx (57% of Fluticasone deposi-
tion and 43% of Budesonide deposition) and oral cavity
(<10% of Fluticasone and Budesonide) posing least risk of
oral candidiasis [13, 14, 22]. High protein binding capac-
ity and high systemic clearance of CIC explains its adre-
nal safety with minimal effects on HPA-axis suppression.
Even higher doses of CIC have not shown to cause HPA
suppression [15, 24, 25]. The growth velocity retardation
in children as observed with other inhalational steroids is
least noted with CIC [15]; however, this effect of the drug
was not evaluated in this study as all patients recruited were
adults of more than 16years. Although only two doses of
CIC (unlike asthma where this drug is used for continuous
use) were used for prevention of FES in this study, the drug
dose was relatively higher. We did not find any evidence of
oral candidiasis, electrolyte abnormalities, wound infection
or allergic reaction to the drug in our patients. Two doses
of CIC of 640 mcg in trauma victim patients effectively
prevented development of FES and hypoxemia without any
side effects.
To conclude, Inhalational CIC is a safe and effective
prophylactic therapy in post traumatic FES. It reduces inci-
dence of FES and improves hypoxemia in skeletally injured
patients.
Compliance with ethical standards
The institutional ethics Committee permission was obtained before
initiating the study.
Conflict of interest Ramesh Kumar Sen, Shiva Prakash, Sujit Kumar
Tripathy, Amit Agrawal and Indu Mohini Sen declare that they have no
conflict of interest.
Source of support/funding This project was supported by the
AADO Research Fund.
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