Oedema risk of endotracheal intubation
in rabbits with cessation of steroid
therapy
Hüseyin FİDAN1, Önder ŞAHİN2, Fatma FİDAN3, Yüksel ELA1, Ahmet SONGUR4, Murat YAĞMURCA5
1
Afyon Kocatepe Üniversitesi Tıp Fakültesi, Anesteziyoloji Anabilim Dalı,
Afyon Kocatepe Üniversitesi Tıp Fakültesi, Patoloji Anabilim Dalı,
3 Afyon Kocatepe Üniversitesi Tıp Fakültesi, Göğüs Hastalıkları Anabilim Dalı,
4 Afyon Kocatepe Üniversitesi Tıp Fakültesi, Anatomi Anabilim Dalı,
5
Afyon Kocatepe Üniversitesi Tıp Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı, Afyon.
2
ÖZET
Steroid tedavisi kesilen tavşanlarda endotrakeal entübasyonun ödem riski
Dokulardaki rebound ödem, steroid tedavisinin kesilmesinin iyi tanımlanmış bir komplikasyonudur. Kronik obstrüktif akciğer hastalığı akut alevlenmesinde, kısa süreli steroid tedavisinde sistemik steroidin kademeli olarak azaltılması çoğu durumlarda gereksiz görülür, bu durumda larengeal rebound ödemin varlığı araştırılmamıştır. Biz steroid tedavisinin kesilmesinden sonra entübasyon uygulandığında entübasyonun larengeal ödemi arttırıp arttırmadığını araştırdık. Randomize olarak 36 tavşan altı gruba bölündü. Steroid uygulanan dört gruba 10 gün boyunca intraperitoneal 1 mg/kg metilprednizolon verildi. Bir gruba 10 gün boyunca serum fizyolojik verildi ve son kontrol grubu sadece entübe edildi. Steroid tedavisi
verilen tavşanlar steroid tedavisinin kesilmesinden sonra birinci gün, birinci hafta, ikinci hafta ve birinci ayda entübe edilerek gruplara ayrıldı. Hava yolu alanı ve larenks lümeninin tiroid kartilaj ve özefagus ile çevrili larenks dokularına kesitsel yüzdesi stereolojik yöntemle çalışıldı. Birinci hafta steroid grubunun kontrol grubuna göre larenks lümen alanları anlamlı olarak daha dardı ve larenks lümeninin tiroid kartilaj ve özefagus ile çevrili larenks dokularına kesitsel yüzdesi anlamlı olarak daha büyüktü. Tavşanlarda steroid tedavisinin ani kesilmesinden bir hafta sonra larenkste rebound ödem oluşur. Steroid tedavisinin kesilmesinden sonra entübasyon için klinik olarak güvenli zaman çalışmamızla tanımlanmıştır. Bu
sonuçlar steroid tedavisinin kesilmesinden sonraki bir haftalık sürecin entübasyon için riskli bir zaman olabileceğini düşündürmektedir.
Anahtar Kelimeler: Larenks ödemi, steroid, rebound ödem, entübasyon.
Yazışma Adresi (Address for Correspondence):
Dr. Fatma FİDAN, Hattat Karahisar Mahallesi 4. Sokak Kaya Apartmanı Daire: 7 03200 AFYON - TURKEY
e-mail: [email protected]
Tüberküloz ve Toraks Dergisi 2008; 56(4): 414-421
414
Fidan H, Şahin Ö, Fidan F, Ela Y, Songur A, Yağmurca M.
SUMMARY
Oedema risk of endotracheal intubation in rabbits with cessation of steroid therapy
Hüseyin FİDAN1, Önder ŞAHİN2, Fatma FİDAN3, Yüksel ELA1, Ahmet SONGUR4, Murat YAĞMURCA5
1
Department of Anesthesiology, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey,
Department of Pathology, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey,
3 Department of Chest Diseases, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey,
4 Department of Anatomy, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey,
5
Department of Histology and Embriology, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey.
2
Rebound oedema of tissues is a well defined complication of cessation of steroid therapy. Tapering of systemic corticosteroid regimens in short course steroid therapy is considered unnecessary in most circumstances in acut exacerbation of chronic obstructive pulmonary diseases, presence of laryngeal rebound edema is obscure in this situtation. We studied whether or not laryngeal oedema increases after intubation when intubation is established after cessation of steroid therapy.
Thirty-six rabbits were randomly divided into six groups. We administered 1 mg/kg methyl prednisolone intraperitoneally
to four steroid groups for ten days. Another group received serum physiologic for ten days and last group was sham control that was intubated only. Rabbits that received steroid therapy were intubated and separated into groups one day, one
week, two weeks, and a month after the cessation of steroid therapy. Airway area and percentage of cross sectional area
of larynx lumen to their own larynx tissues surrounded by thyroid cartilage and oesophagus were studied by stereological methods. Larynx lumen area of one week steroid group was significantly narrower and percentage of cross sectional
area of larynx lumen to their own larynx tissues surrounded by thyroid cartilage and oesophagus was significantly larger
than sham control. Rebound oedema forms in larynx with abrupt cessation of steroid therapy in rabbits. Clinical safe time
for intubation after abrupt cessation of steroid therapy is also defined with our study. These results suggest that one week
after the cessation of steroid therapy may be a hazardous time for tracheal intubation.
Key Words: Larynx oedema, steroid, rebound oedema, intubation.
increases airway resistance and, consequently,
the respiratory work (6).
Endotracheal intubation is one of the most frequently used methods to ventilate patients in
critical care units and operating rooms. Although life saving, this invasive method may cause
laryngeal damage (1,2). Inflammatory response
can be seen as early as an hour following extubation and characterized with glottic or subglottic oedema, ulceration, and stenosis (3). After
short intubation periods, inflammatory cell accumulation was shown at submucosal vessels
resembling ischemia-reperfusion injury in other
organs (4).
Corticosteroids are potent anti-inflammatory
agents. The mode of action, however, is not
completely understood. It has been shown that
steroids restore ground substance and basement
membranes of connective tissue, probably restoring normal function. Besides, steroids have
also an unpleasant effect. Rebound oedema
forms with abrupt cessation of steroid therapy.
Rebound oedema has been shown to form in
cornea, macula, unstable asthma and dermal
flaps (8-10). However, tapering of systemic corticosteroid regimens in short course steroid therapy is considered unnecessary in most circumstances, evidence of laryngeal rebound
edema is uncertain (11). Global Initiative for
Chronic Obstructive Lung Disease (GOLD) suggests to apply 30 to 40 mg of oral prednisolone
Laryngeal oedema manifests itself by respiratory distress and inspiratory whistling called
“stridor”. Such oedema formation can develop
as early as 6 hour following intubation, so that
prolonged intubation is not a prerequisite to its
development (5-7). By decreasing the upper
respiratory tract diameter, laryngeal oedema
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Tüberküloz ve Toraks Dergisi 2008; 56(4): 414-421
Oedema risk of endotracheal intubation in rabbits with cessation of steroid therapy
to Chronic Obstructive Pulmonary Disease
(COPD) patients as a short course steroid therapy for 10 to 14 days when COPD exacerbates
(12). 0.5-1.0 mg/kg prednisolone is administered as the treatment of acute asthma excacerbation (13).
(IP) to the rabbits in this group for ten days. One
day after the final injection of ten injections, rabbits were intubated and went through above procedures.
3rd group (st 1d group): We have administered
methyl prednisolone (1 mg/kg) in 2 mL of SP IP
to the rabbits in this group for ten days. One day
after the final injection of ten injections, rabbits
were intubated and went through above procedures.
We studied whether or not laryngeal oedema
increases after intubation when intubation is established after cessation of steroid therapy.
MATERIALS and METHODS
4th group (st 1w group): We have administered
methyl prednisolone (1 mg/kg) in 2 mL of SP IP
to the rabbits in this group for ten days. Rabbits
were fed for one week after the final injection.
One week after the final injection, rabbits were
intubated and went through above procedures.
This study was approved by Animal Committee
of Ethics of our institution. Thirty six female New
Zealand rabbits were enrolled into the study.
Rabbits were divided into six groups.
Surgical Procedures
Anesthesia was induced by Xylazin HCl (15
mg/kg) and ketamine (25 mg/kg) intramuscularly (IM). We have placed an arterial line from
one ear and venous line from the other. We intubated rabbits with uncuffed polivinylchloride endotracheal tube (I.D. 2.5, Kendall) by the help of
laryngoscope that has Millar blade. Anesthesia
was maintained by 1-2% sevoflurane and rabbits
were ventilated with volume-controlled ventilator (CWE Inc. SAR 830/AP, Ardmore, USA) for
an hour. During anesthesia, invasive arterial tension, heart rate and peripheral oxygen saturation were monitored (Datex Ohmeda Type FCU8, Helsinki, Finland).
5th group (st 2w group): We have administered
methyl prednisolone (1 mg/kg) in 2 mL of SP IP
to the rabbits in this group for ten days. Rabbits
were fed for two weeks after the final injection.
Two weeks after the final injection, rabbits were
intubated and went through above procedures.
All rabbits were extubated and kept on spontaneous respiration for two hours with oxygen support. Finally, all rabbits were sacrificed with 50
mg/kg pentothal Na intravenously (IV). Immediately their necks were dissected to reach larynx.
Larynx was harvested from the level of hyoid
cartilage above and fifth to sixth tracheal cartilages below. Harvested tissue was put into formalin for further histological examination.
We have harvested the larynx 0.5 cm proximally
and distally to cricoid’s process which was our
reference point.
6th group (st 1m group): We have administered
methyl prednisolone (1 mg/kg) in 2 mL of SP IP
to the rabbits in this group for ten days. Rabbits
were fed for one month after the final injection.
One month after the final injection, rabbits were
intubated and went through above procedures.
Histopathologic Examinations
Anatomical examination of rabbit larynx showed
us that the level of vocal cords was its narrowest
place and its width was about 1.0 mm horizontally (Figure 1). We sectioned whole larynx
transversely every 150 µm. We obtained 25 to
35 sections with 10 µm width from every larynx.
We chose two sections as target sections not to
miss a target section if a technical accident happens.
Groups
1st group (sham control group): Anesthesia was
induced. We intubated rabbits and kept them on
mechanical ventilation for an hour. Rabbits were
extubated and went through above procedures.
All obtained transverse sections were processed
with haematoxylin and eosin. The sections that
resemble human vocal cords transverse sections were chosen (14). We have chosen the sec-
2nd group (SP control group): We have administered 2 mL of 0.9% NaCl (SP) intraperitoneally
Tüberküloz ve Toraks Dergisi 2008; 56(4): 414-421
416
Fidan H, Şahin Ö, Fidan F, Ela Y, Songur A, Yağmurca M.
Figure 1. Inferior view of vocal cords in rabbit larynx.
tion that had the most anterior protruding arytenoid cartilage, while arytenoid cartilage was
protruding anteriorly and drawing back in sections that follow one after the other. We suggest
that maximum level difference that one can
make with our targeting method between different rabbits is about 75 to 85 µm according to
the choice of the first or the second target section at the target level.
Figure 2. View of target cross section of larynx with
microfilm (wall thickness of every square is 100 µm)
placed on the preparation.
tio) while tissue becomes swollen and airway
narrows when laryngeal oedema forms. The a/b
ratio was arbitrarily graded to reflect varying
degrees of airway narrowing with higher grades
indicating more extreme airway narrowing.
Two different measurements were performed on
target sections. Firstly we measured the airway
area because airway gets narrower when laryngeal oedema forms. We put a microfilm consisting of squares with 100 µm wall thickness on
histological target sections. We photographed
them and magnified (Figure 2). We counted the
squares that matched the airway. The half squares that match the right side of the larynx were
counted but the squares on the other side were
not counted. This measurement was done for all
target sections. The counted number for target
section was divided by 100 to give the airway
area in mm2 because 100 squares form an area
of 1 mm2.
Target sections were magnified 100 times and
printed. We counted a/b ratios by the help of independent counting measures stereologically.
Independing counting measures have points on
the measure, and points are equally distant to
each other. “a” was defined as the counts that
matched airway when independent counting
measure was placed over the target section. “b”
was defined as the counts that matched larynx
tissues surrounded by thyroid cartilage and oesophagus when independent counting measure
was placed over the target section (Figure 3). In
other words; “a” is the cross-sectional area of
the airway and “b” is the cross-sectional area of
the laryngeal tissues surrounding the airway lumen and internal to the cartilaginous skeleton of
the airway. The “a/b ratio” measures airway lumen relative to the surrounding soft tissues; a
decrease in the ratio is hypothesized to result
from airway edema.
The above measurement gave us the quantitative airway area. Furthermore, we examined the
airway narrowing in each individual rabbit. This
meauserement was done to rule out faulty
analysis because rabbits may have different airway area although they may have the same weight. We graded the proportion of airway to larynx tissue surrounded by the cartilages (a/b ra-
We have graded a/b ratios from zero to five to
measure them statistically. We have graded a/b
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Tüberküloz ve Toraks Dergisi 2008; 56(4): 414-421
Oedema risk of endotracheal intubation in rabbits with cessation of steroid therapy
Figure 3. “a” was defined as the counts that matched airway (encircled with dots in Figure 3.1 above) when independent counting measure was placed over the target section (Figure 3.2). “b” was defined as the counts that
matched larynx tissues surrounded by thyroid cartilage and oesophagus (area between two dotted circles above)
when independent counting measure was placed over the target section.
were expressed as mean ± standard deviation. p<
0.05 is considered as statistically significant.
ratios from the lowest ratio to the highest ratio.
The highest ratio was 0.5035 and the lowest ratio was 0.2485. The difference between the highest and lowest ratios were divided into six grades; grade 0 (range: 0.5035-0.4610), grade 1
(range: 0.4610-0.4185), grade 2 (range:
0.4185-0.3760), grade 3 (range: 0.37600.3335), grade 4 (range: 0.3335-0.2910) and
grade 5 (range: 0.2910-0.2485). When airway
narrows and tissue is swollen, a/b ratio decreases, and consequently gets a higher grade.
RESULTS
Mean weight of rabbits between groups were not
significantly different (Table 1). Larynx airway
areas and a/b ratios are also presented in Table
1. Airway areas were not statistically different
between sham control group and SP control group. Airway areas in st 1d group and st 2w group
were not significantly different than any other
groups. Airway areas in st 1w group were significantly narrower than airway areas of control
group, and st 1m groups but not than SP control
group. Airway areas in st 1w group were not significantly different than airway areas of st 1d
group and st 2w group.
Statistical Analysis
Statistical analysis was carried out using the Statistical Package for Social Sciences SPSS 10.0.
Comparison between groups was performed using
one-way ANOVA and posthoc Tukey test. Data
Table 1. Weight, larynx area and a/b ratioes of rabbits.
Weight (grams)
Larynx area (mm2)
(mean ± SD)
a/b ratio (grade)
(mean ± SD)
Sham control
2126.67 ± 317.17
12.5 ± 0.5
0.83 ± 0.41
SP control
2132.50 ± 267.32
11.9 ± 0.7
1.50 ± 1.05
St 1d group
2223.33 ± 404.85
10.8 ± 0.7
3.33 ± 1.63c
St 1w group
2225.83 ± 319.49
10.5 ± 1.2a
3.67 ± 1.21d,e
St 2w group
2214.17 ± 262.00
11.6 ± 1.0
2.17 ± 1.47
St 1m group
2186.67 ± 283.45
12.6 ± 1.8b
1.83 ± 0.98
Groups
a
d
Compared to sham control group, p= 0.038, b Compared to St 1w group, p= 0.030, c Compared to sham control group, p= 0.012,
Compared to sham control group, p= 0.003, e Compared to SP control group, p= 0.039.
Tüberküloz ve Toraks Dergisi 2008; 56(4): 414-421
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Fidan H, Şahin Ö, Fidan F, Ela Y, Songur A, Yağmurca M.
a/b ratios were not statistically different between
sham control and SP control groups. a/b ratios
in st 1d group had significantly higher grades
than a/b ratios of control group but not SP control groups. a/b ratios in st 1d group were not significantly different than a/b ratios of st 1w group, st 2w group and st 1m group. However, a/b
ratios in st 1w group had significantly higher
grades than a/b ratios of control group and SP
control group. a/b ratios in st 1w group were not
significantly different than a/b ratios of st 1d
group, st 2w group and st 1m group. a/b ratios
in st 2w group and st 1m group were not significantly different than a/b ratios of sham control
group and SP control group.
ent is not able to sustain the increase in respiratory work (15). The development of laryngeal
oedema requires close monitoring, and sometimes the application of non-invasive respiratory
assistance, aerosolized epinephrine and perhaps
corticosteroids, although the latter are controversial (6,16,17). If not rapidly recognized and adequately treated, laryngeal oedema can be fatal.
Laryngeal oedema can also be formed by endotracheal intubation and this injury is influenced by
many reasons. Serious laryngeal injuries like haematoma, laceration of mucous membrane and
muscles and subluxation of arytenoid cartilage
are reported in 6.2% of patients in a study by
Kambic et al. (1). Endotracheal intubation may
generate local complications, including mechanical lesions like friction, compressions between
the tube and the anatomic structures, and also
biochemical reactions between the plastic or silicone tube material and the upper airway mucosa (18). It is shown that the pressure of the endotracheal tube balloon should be lower than 20
mmHg to allow tracheal mucosa blood flow (19).
Even though their incidence has decreased with
the use of far more flexible polyvinyl chloride tubes generating less pressure on the anatomical
structures and high volume low pressure cuffs inducing fewer mucosal lesions, these complications remain frequent (20,21).
DISCUSSION
This study shows that rebound oedema forms in
larynx with abrupt cessation of steroid therapy
in rabbits. Although rebound oedema formation
was shown in many tissues before, this is the
first study to show rebound oedema in larynx
tissue after intubation. Clinical safe time for intubation after abrupt cessation of steroid therapy
is also defined with our study.
Tapering of systemic corticosteroid regimens
are used in long course steroid therapy, however, tapering of corticosteroids in short course
steroid therpy is considered unnecessary in
most circumtances in treating exacerbation of
COPD (12). Laryngeal rebound oedema secondary to cessation of steroid therapy wasn’t studied before. We wanted to study rebound oedema in a clinical scenario by applying the steroid
therapy model that is suggested for exacerbation of COPD is used as steroid therapy because
we suggest that patients with this model, are one
of the most frequent ones that anaesthesiologists may meet (13). Although elective surgeries may be postponed during exacerbation period, emergent surgeries and elective surgeries after acute exacerbation period may be met by
anaesthesiologists. Again, COPD patients may
need intubation during acute exacerbation period in intensive care units.
Oedema in the airway can have disastrous consequences if airway compromise occurs. Treatment of airway oedema with steroids has been
shown to be effective (22). They have also been
shown to decrease migration of inflammatory
cells, decrease vascular permeability, and reduce exudation (23). Intravascular and perivascular leukocyte aggregation is diminished with corticosteroid therapy, improving microvascular
flow (23,24). The production of phospholipase
A2 is inhibited, which leads to inhibition of the
arachidonic acid cascade and platelet activating
factor synthesis. However, it was demonstrated
that dexamethasone significantly impaired the
healing of tracheal anastomoses in rats (25).
It is not easy to monitorize laryngeal oedema
and perform a randomized study with equal steroid therapy and cessation times in humans so
we decided to perform the study in rabbits. The
When oedema is present in airways, re-intubation or tracheostomy may be required if the pati-
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Tüberküloz ve Toraks Dergisi 2008; 56(4): 414-421
Oedema risk of endotracheal intubation in rabbits with cessation of steroid therapy
than the results of SP control group. These results may suggest that laryngeal oedema was
not formed in st 1d group and may be the result
of continuation of steroid effect. However, result
of a/b ratio of st 1w group was significantly higher than both sham control and SP control groups. Larynx area was significantly narrower than
sham control group. These results suggest that
laryngeal oedema occurred in st 1w group.
rabbit vocal folds are similar to human in structure although the lamina propria is less well developed (26). We used rabbit larynx in our experimental model because rabbit was used by other researchers for human larynx airway area
models (27,28).
Quantification of oedema in tissues may be argued. Rebound graft oedema was quantified by Odland et al. with weighing grafts previously (11).
We suggested that this was not an appropriate
way to show laryngeal oedema because it would
not be possible to determine the exact tissue definitely. Also oedema may not be in the same extend with the previous study because we have
used 1 mg/kg instead of 100 mg/kg. Tissue oedema may be restricted to muscular area or submucosal area so all tissue with the oedematous
tissue should be weighed so this would have decreased the sensitivity of measurement. We used
histopathology to identify oedema.
Although we have used a clinical scenario, we
haven’t traumatized the larynx during tracheal
intubation in rabbits. Because we have used uncuffed endotracheal tubes to limit traumatization. Traumatization during tracheal intubation
may lead to further oedema to cause respiratory
distress. A study should also be performed in
humans to show whether rebound oedema that
will form secondary to either traumatized or non
traumatized tracheal intubation in a week after
cessation of steroid therapy lead to stridor and
respiratory distress. It is difficult to state laryngeal oedema with ethical issues and without invasive measurements in humans. Therefore, incidence of stridor and respiratory distress secondary to traumatic or non-traumatic tracheal
intubation with the history of cessation of steroid therapy should be sought.
We studied the oedema risk of tracheal intubation that can form laryngeal oedema itself. Rebound oedema that form secondary to steroid therapy cessation, may exaggerate due to tracheal
intubation and lead to respiratory distress. Sham
control and SP control groups were planned to
rule out the effect of just intubation and intubation for one hour.
We suggest that one week after cessation of steroid therapy may be a risky time for endotracheal intubation. Since we are not often experiencing
such problems in COPD patients in the clinical
practice, to translate these results to human being may not be suitable. However, the results of
this study showed that abrupt cessation of systemic steroid treatment following 10 day course
causes rebound oedema in the upper airways of
rabbits and this may increase the risk for postextubation upper airway oedema if intubation necessities one week following steroid cessation.
Although study times of larynxes can be argued,
we let rabbits to breathe spontaneously for two
hours after one hour of intubation because Kil et
al. reported that subglottic pressures declined
gradually after two hours following extubation
(29). We wanted to sacrifice rabbits when laryngeal oedema was excessive.
Although present study confirms that a week after cessation steroid therapy is an risky time for
endotracheal intubation, we haven’t experienced
stridor or peripheral oxygen desaturation in none of the rabbits. We consider that laryngeal oedema that is formed in a week after cessation of
steroid therapy, does not cause stridor and respiratory distress but these results should also be
revealed for humans as well. However, the results of st 1d group were not as worse as the results of st 1w group and results of larynx area
and a/b ratio of st 1d group were not different
Tüberküloz ve Toraks Dergisi 2008; 56(4): 414-421
ACKNOWLEDGEMENT
Our study was presented in Annual meeting of
European Society of Anaesthesiology, Vienna,
Austria, 2005.
This study has been supported by The Commission of Scientific Research Projects of Afyon Kocatepe University, Turkey.
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Fidan H, Şahin Ö, Fidan F, Ela Y, Songur A, Yağmurca M.
15. Mishra S, Bhatnagar S, Jha RR, Singhal AK. Airway management of patients undergoing oral cancer surgery: A
retrospective study. Eur J Anaesthesiol 2005; 22: 510-4.
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