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\begin{document}

\title{Early amiodarone pneumonitis: a case report}



\author[1]{Abbas  Soleimani}%
\author[1]{Houshang Bavandpour karvane}%
\author[1]{Masoud Mortezazadeh}%
\author[2]{abbas mofidi}%
\author[3]{seyyed taher seyyed mahmoudi}%
\author[1]{mehdi kashani}%
\affil[1]{Tehran University of Medical Sciences}%
\affil[2]{Iran University of Medical Sciences}%
\affil[3]{Tabriz Medical University}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Consider amiodarone pneumonitis as an important differential diagnosis
of ARDS , especially In clinically ill patients with renal failure who
recently received Intravenous amiodarone .%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION:}

Amiodarone, a class III antiarrhythmic drug is an iodinated benzofuran
derivate used as a potent agent for the prevention and treatment of
life-threatening ventricular and supraventricular arrhythmias.{[}1{]}

Its iodine-containing compound gives amiodarone the tendency to build up
in various organs, such as the lungs. Although many adverse reactions
and side effects of amiodarone have been reported, pulmonary toxicity
and pneumonitis could perhaps be one of the critical adverse
effects.{[}2{]}

Amiodarone is metabolized in the liver by cytochrome P-450 enzyme and is
then excreted through the biliary system and is not dialyzable in case
of overdose. Risk factors for amiodarone pulmonary toxicity consist of
the male gender, age, preexisting pulmonary diseases, high oxygen demand
conditions, thoracic surgery, and pulmonary angiography.

The most common forms of amiodarone pulmonary toxicity are interstitial
pneumonitis and organizing pneumonia but it can also present itself as a
lung mass or a consolidation.

Amiodarone Pneumonitis usually manifests itself with non-specific
respiratory symptoms such as cough, shortness of breath, myalgia, and
fever.{[}3{]}

Due to these indefinite presentations, Amiodarone Pneumonitis is mostly
diagnosed after excluding other differential diagnoses.

Amiodarone pulmonary toxicity is mostly delayed and occurs in higher
accumulative dosages, in this case despite most reported cases, we
report challenging early amiodarone-associated pneumonitis.{[}4{]}

Case presentation :

A 50-year-old heavy ex-smoker man with a past medical history of
hyperlipidemia and hypertension was brought to the emergency department
because of recent complaints of chest pain, sweating, nausea, and
progressive dyspnea.

The initial physical examination showed a body temperature of 37.5\selectlanguage{ngerman}°C,
blood pressure of 96/70\selectlanguage{english} mm\selectlanguage{english} Hg, pulse rate of 95 beats/minute,
respiratory rate of 26 breaths/minute, and oxygen saturation of 90\%
while the patient was breathing without supplemental oxygen.

He also had bilateral crackles in auscultation, especially in the right
lung, Other physical exam findings were unremarkable.

Immediately ECG and portable Chest x-ray were obtained which demonstrate
ST segment elevation in precordial leads and bat wing pattern in CXR in
favor of pulmonary edema. (figure1)

In less than 15 minutes the patient was sent to a catheterization
laboratory and angiographic imaging revealed total occlusion of the left
main artery.

Primary percutaneous catheter intervention and stenting on LAD and plain
old balloon angioplasty (POBA) on the ramus intermedius artery were
performed.

During the intervention he received, 150 mg amiodarone IV bolus in 10
minutes, 200 mg bolus of furosemide, heparin 12500 U, ondansetron 4 mg,
epinephrine infusion 2 mcg /kg/min,

After the patient was sent to the critical care unit he experienced
recurrent ventricular tachycardia episodes which 360 mg amiodarone over
the next 6 hours, then 540 mg over the remaining 18 hours administered.

Other medications such as IV furosemide 40 mg twice a day, Dobutamine
infusion ( 5 mg/hr and 5 mcg/kg/min respectively ) and oral
spironolactone ( 25 mg twice a day), aspirin( 80 mg daily) Clopidogrel
(75 mg daily ) and ivabradine (5 mg daily) were administered.

The next day patient's dyspnea gradually improved and amiodarone(200mg
BID) and furosemide(40 mg BID) changed to the oral form.

An Echocardiography was performed and an Ejection fraction of 20 \%,
Pulmonary artery pressure:45 mm Hg, severe left ventricular hypertrophy,
diastolic dysfunction of grade 3, normal right ventricle size,
antro-septal and apex akinesia, without significant valvular abnormality
,and pericardial effusion were reported.

Patient's general condition was improving however on the seventh day of
admission the patient developed worsening dyspnea, fever, and
nonproductive cough.

Routine biochemistry, CBC diff, CKMb, blood culture, procalcitonin,
autoimmune profiles, ESR, CRP, COVID-19 PCR, and Sputum culture samples
were obtained and empirical antibiotics ( levofloxacin 750 mg daily,
ceftriaxone 1 gr BID) administered and furosemide dosage was increased.

The ECG did not reveal any new changes.

Follow-up chest radiography was requested which demonstrated bilateral
interstitial infiltrations. (figure 2)

Laboratory results showed: WBC 14.8\selectlanguage{english} K/\selectlanguage{greek}μ\selectlanguage{english}L, Hgb 11 g/dL, PLT count 250 000
cell/mm\textsuperscript{3}, MCV 90.6 fL, neutrophil 70.9\%, lymphocyte
27.2\%,Eosinophil :1\% , CRP:42.7 mg/L, Urea 46 mg/dL, Cr 1.4 mg/dL,
blood and sputum culture:negative, procalcitonin: negative , CKMb:
negative , COVID-19 PCR (two times with the interval of 48 hours)
:negative, ANA: negative , Complements: normal

Spiral chest computed tomography was requested which showed bilateral
diffuse consolidations and ground glass opacities. (Figure 3)

First of all with the diagnosis of pulmonary edema and diuretic
resistance high dose of furosemide in combination with Indapamide,
hydrochlorothiazide, and metolazone was subsequently administered but no
improvement was seen.

The echocardiography after the worsening of the symptoms demonstrated no
change in Left Ventricle dysfunction and ejection fraction but an
increase in pulmonary arterial pressure (PAP) to 60 mm Hg which after
ruling out the pulmonary emboli the PAP increase was compatible with
lung parenchymal involvement.

Due to the worsening of symptoms despite high dose diuretic,
broad-spectrum antibiotic treatment and negative laboratory results for
both viral and bacterial pneumonia and the CT scan consistent with
interstitial pneumonitis, amiodarone-related interstitial pneumonitis
was highly suspected and the patient candidate for bronchoalveolar
lavage (BAL) and dexamethasone 8 mg IV daily started.

Despite the withdrawal of amiodarone his condition rapidly deteriorated
within three days and suffered respiratory and kidney failure and
cardiac arrest during hemodialysis. He underwent cardiorespiratory
resuscitation for over 45 min, but could not be resuscitated and
unfortunately died.

\textbf{Discussion :}

Amiodarone is one of the most commonly prescribed medications for the
treatment of life-threatening ventricular arrhythmia.

Treatment with amiodarone has various known neurologic, ophthalmic, bone
marrow

cutaneous, thyroid, hepatic, and pulmonary side effects.

Pulmonary toxicity is among the most serious adverse effects of
amiodarone.

Interstitial pneumonitis, eosinophilic pneumonia, organizing pneumonia,
acute respiratory distress syndrome, diffuse alveolar hemorrhage, lung
mass or consolidation, and rarely pleural effusion can occur in
amiodarone toxicity. {[}5{]}

Among these various types of pulmonary adverse effects, interstitial
pneumonitis is the most common presentation after two or more months of
treatment, particularly in individuals over 60 years old with
preexisting lung disease and whose daily amiodarone dosage exceeds 400
mg could occur.

Most of these effects occur due to the accumulation of amiodarone
metabolite so it rarely manifests in the early stage of administration
like in our case.

Interstitial pneumonitis due to amiodarone toxicity is characterized by
the sudden onset of nonproductive cough, dyspnea, and less likely
malaise and fever could be seen. Our case also presented with abrupt
onset of mentioned symptoms which could not be explained by pneumonia or
pulmonary edema.

Other rare microorganisms such as fungal infection in immune-competent
individuals were also unexpected.

A negative autoimmune panel was also more compatible with amiodarone
pneumonitis diagnosis.

When the clinical diagnosis of amiodarone-induced interstitial
pneumonitis is questionable, flexible bronchoscopy with (BAL) is done.
This procedure is more beneficial in excluding other differential
diagnoses.

Despite chronic amiodarone pneumonitis which lipoid cells are more
likely to be seen in pathology in acute amiodarone pneumonitis BAL
investigation, alveolar hemorrhage is more probable to be detected.
{[}6{]}

So we can conclude that the absence of lipoid macrophages in BAL is not
supported by excluding the diagnosis of amiodarone pneumonitis and
clinical and radiologic features such as abrupt worsening dyspnea and
cough, administering a high dosage of amiodarone, Exclusion of lung
infection and hypersensitivity pneumonitis, and New ground glass on
chest radiography are key features for diagnosis of early amiodarone
pneumonitis.

Even if our patient had the chance for the BAL it is not the gold
standard for diagnosing amiodarone pneumonitis and as mentioned in
previous studies only 50 \% of patients with amiodarone lung injury
manifest with lipoid macrophages in BAL, on the other hand these lipoid
cells could be seen in non-toxic patients who are taking amiodarone.
{[}7{]}

Previous studies also mentioned that the route of administration might
be another factor contributing to acute amiodarone pneumonitis like our
reported case, patients who received amiodarone 150mg IV in less than an
hour, followed by exceeding dose of 1000mg IV in a day, Amiodarone
metabolites can accumulate more rapidly in lungs. {[}8{]}

On the other hand, some studies believe that acute oxidant lung injury
also plays a major role in amiodarone lung injury in the acute
phase.{[}9{]}

Treatment of amiodarone pneumonitis consists primarily of cessation of
amiodarone and, in severe cases, initiating systemic glucocorticoids
(prednisone 40 to 60 mg per day or methylprednisolone 500 to 1000 mg/day
intravenously in severe cases) is recommended. {[}10{]}

It is reasonable not to administer antiarrhythmic with similar structure
in amiodarone lung injuries such as Dronedarone and a personalized
approach for each patient is recommended especially in the elderly
patient with underlying lung diseases such as previous severe COVID-19
which lead to permanent lung injury. {[}11-15{]}

Acute amiodarone-related interstitial pneumonitis is a rare and more
aggressive form of the disease, most often occurring in critically ill
and post-surgery patients. Acute respiratory distress syndrome (ARDS )
and alveolar hemorrhage are the most common pattern of amiodarone
pneumonitis, our case also encountered ARDS despite corticosteroid
treatment. {[}16 17{]}

Conclusion :

In brief, our challenging case illustrates the difficulties in the
diagnosis of acute amiodarone pneumonitis which should be considered as
a differential diagnosis of ARDS causes especially in patients whose
other related diagnoses are excluded and who had a history of receiving
a high dosage of intravenous amiodarone.

\textbf{Declarations:}

1. Funding: Not applicable

2. Conflicts of interest/Competing interests: The authors declare that
there is no conflict of interest to declare.

3. Ethics approval: In this study, no additional costs and procedures
were imposed on the patient' family members. We reported the retrograde
standard treatment process of the patient. We maintained the patient's
privacy

4. Consent to participate: The patient's family has consented to the
participation of this case report.

5. Consent for publication: The patient's next of kin(according to our
hospital policy, the eldest male child ) has consented to the
publication of this case report.

has consented to the publication of this case report.

6. Availability of data and material: The data that support the findings
of this study are available from the corresponding author, {[}MM{]},
upon reasonable request.

7. Code availability (Not applicable)

8. Authors' contributions: A.S and M.M. contributed to data collection,
writing, drafting of the manuscript, and critical appraisal of the
manuscript. M.K, SS ,AM and H.B contributed to scientific writing and
final revision

\textbf{ACKNOWLEDGEMENTS :}

The authors would like to thank Arya Golestan jozani for his generous
cooperation from internal medicine department

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Epub Date{]}\textbar{}.\selectlanguage{english}
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Figure 1: the CXR demonstrate the appearance of peri-hilar consolidation
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Figure 2: diffuse bilateral alveolar infitrates and right pleural
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Figure 3: bilateral diffuse consolidations and ground glass opacities\selectlanguage{english}
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