The effects of enoximone in acute exacerbation COPD: a pilot study

A severe acute exacerbation of chronic obstructive pulmonary disease (AE-COPD)
is a frequent occurring disorder in patients with COPD and may lead to
respiratory failure despite treatment, consisting of corticosteroids,
nebulized bronchodilators, magnesiumsulphate and non-invasive ventilation. If
treatment fails, invasive mechanical ventilation may be necessary. Further
treatment options in this situation are (es)ketamine, sevoflurane and
enoximone. However, limited data is available to support all these treatment
options. Since no other treatment options are available for these patients,
research is necessary for this specific patient group.
Sevoflurane is an inhalation anaesthetic agent, which needs a special method
for delivery in an ICU, thus limiting the availability. (es)Ketamine has the
disadvantage of being an anaesthetic agent, for which intubation is necessary.
Therefore, a patient is likely to have an increased duration of ventilation.
The level of evidence for these agents in AE-COPD is low. A third agent is
enoximone, which has no sedative effects and is administered intravenously.
Enoximone is a phosphodiesterase-3 inhibitor (PDE-3). Phosphodiesterase
hydrolyses cyclic adenosine monophosphate (cAMP) and cyclic guanosine
monophosphate (cGMP) in the cell. Inhibitors of PDE results in the elevation of
cAMP and cGMP which will lead to a number of various cell effects including the
relaxation of smooth airway muscle cells. This pathway is believed to be
beneficial in patients with an AECOPD.

Enoximone is commonly used in a ICU for patients with cardiac failure. A usual
loading dose is 0.5 mg/kg after which further titration or a continuous
infusion is started. However, in a study for bronchodilatory effects in
AE-COPD, a dose of 3.0 mg/kg was administered, which led to ventricular
tachycardia and limited the use of enoximone.
Recently, the use of low dose enoximone in acute asthma showed an remarkable
bronchodilatory effect. Furthermore, other PDE-3 and PDE-4-inhibitors are
developed for bronchodilatory therapy in COPD. Since extensive clinical
experience with enoximone is available in ICU*s, low-dose enoximone may be an
attractive treatment option.

A low-dose of enoximone is not yet studied for bronchodilatory properties.
Furthermore, a dose-dependent effect has not been investigated previously. This
pilot study aims to answer these questions and may lead to a randomised
controlled trial if proven beneficial.

Primary Objective: a reduction in bronchoconstriction, measured by auto-PEEP,
in patients with AE-COPD.

Secondary Objective(s):
* To test for a dose-dependency.
* Decrease in pulmonary artery pressures
* Enhance cardiac output
* Measure occurrence of side effects by enoximone administration

The study design is a prospective interventional randomized clinical study.

Three doses of intravenous 0,5 mg/kg enoximone, leading to a total dose of 1.5
mg/kg enoximone

The participants will already be intubated and sedated when eligible for
participation. Scientifically proven therapy, consisting of nebulized
salbutamol/ipratropium, corticosteroids, magnesiumsulphate and neuromuscular
blocking agents, will be continued throughout the study period. All outcome
measures are non-invasively measured (e.g. echocardiography, ventilator
measurements and arterial bloodgas analysis, obtained through a catheter
already placed for clinical guidance). Therefore, the burden can be regarded as
minimal.
The risks of enoximone are supraventricular arrhythmias, ventricular
tachycardia and hypotension. These risks are minimally encountered in common
practice. Furthermore, all patients will be treated in an ICU, where these
side-effects can be treated and supported.
The benefit for a patient may be a reduction in time of ventilator-support and
increased cardiac output, which may lead to less renal dysfunction.