Dexamethasone infusion in community-acquired pneumonia

Community-acquired pneumonia (CAP) is common and approximately 20 percent of
all episodes of pneumonia result in hospitalization. It is the leading cause of
community-acquired infection requiring ICU admission. Especially elderly
patients may have a severe illness with a high morbidity and mortality rate. In
pulmonary infections, the release of cytokines and other inflammatory mediators
from alveolar macrophages serves as a useful mechanism in the elimination of
invading pathogens. However, this natural reaction can be potentially harmful
when excessive release of circulating inflammatory cytokines causes damage to
the patient, particularly the lung.
Interest in the role of corticosteroids in the pathophysiology of critical
illness has existed since the early part of the 20th century. On ICU, early
treatment with corticosteroids to attenuate systemic inflammation is
widespread. At the same time, outside the ICU little evidence is available on
the effect of treatment with corticosteroids in patients diagnosed with CAP.
Hypothetically, early initiated administration of corticosteroids in the course
of a CAP can lower systemic and pulmonary inflammation. This may lead to
earlier resolution of pneumonia and a reduction of complications (sepsis,
mortality).

In 2004 Confalonieri et al. evaluated 24 patients with a severe CAP who
received hydrocortisone 10 mg/hour for 7 days compared to 24 patients who
received placebo. The hydrocortisone group had a significant reduction in CRP
levels over time, a significant improvement in PaO2:FiO2 and reduction of
incidence of delayed septic shock. This is the only study evaluating infusion
of hydrocortisone in patients with a CAP outside the ICU. Monton et al.
evaluated the role of glucocorticoids on the ICU in mechanically ventilated
patients with a severe pneumonia. Eleven of the 20 patients received
methylprednisolone for 9±7 days. In this study there was a consistent trend for
an attenuated inflammatory respons, however the clinical efficacy was not
assessed. Meduri et al. found improvement in lung injury and multiple organ
dysfunction syndrome in 16 ICU patients with unresolving acute respiratory
distress syndrome (ARDS). These patients received methylprednisolone 2 mg/kg
per day for 32 days. In addition, no increase of infections was found in the
intervention group.

Unfortunately, some adverse side effects have been attributed to
corticosteroids, like hyperglycaemia or opportunistic infections. However, in
severe COPD exacerbation, short-term administration of systemic corticosteroids
has proved to be safe, with no clinically important side effects. Niewoenher et
al. found a moderate improvement in clinical outcomes among patients
hospitalized for exacerbations of COPD treated with systemic glucocorticoids.
Hyperglycaemia of sufficient severity to warrant treatment was the most
frequent complication. Other adverse effects, for example secondary infection,
did not differ significantly among the groups.

Inflammation and coagulation are closely related. Inflammation activates the
coagulation system, while several components of the coagulation cascade have
proinflammatory effects.37 This results in ongoing inflammation and deposition
of fibrin in intravascular and extravascular spaces. Several studies have
demonstrated the interaction between inflammation and coagulation activation in
lung diseases. It is known that coagulation is both activated in the
intravascular compartment, as in the pulmonary compartment in animals with CAP,
in patients with ventilator associated pneumoniae, in patients with sepsis and
in healthy humans pulmonary challenged with bacterial products.38-40 The
relevance of the activation of the coagulation system has recently become more
obvious. A randomized clinical trial in sepsis patients treated with placebo or
recombinant activated protein C (APC), a coagulation inhibitor, demonstrated a
statistically significant 6.1% absolute reduction in all-cause mortality at 28
days for patients receiving APC.41 A retrospective analysis of this trial
showed a relative risk reduction in 28 days mortality of 28% in patients with
severe CAP.42

There is little information about the coagulation system in patients with CAP.
This study gives us a unique opportunity to investigate the possible
intravascular and pulmonary activation of the coagulation system in these
patients. It also gives us, due to the existing study design and protocol, the
opportunity to investigate the interaction between inflammation and coagulation
and to investigate the effect of dexamethasone on both systems.

Primary objective:
1. Reduction of hospitality duration in patients with CAP treated with
intravenous dexamethasone.

Secondary objective:
1. Reduction of the use of intravenous antibiotics in patients with CAP treated
with intravenous dexamethasone.
2. What is the effect of intravenous dexamethasone in patients with a CAP on
admission to ICU, inflammation markers and health performance?
3. Toxicity of dexamethasone in patients with CAP.
4. What is the effect of intravenous dexamethasone in patients with a CAP on
lung function?
5. Mortality in patients with CAP treated with or without dexamethasone.
6. Prognostic value of serum ACE activity on pneumonia outcome
7.· Analysis of cost savings and effectiveness of the use of intravenous
dexamethasone in patients with a CAP.·
8 Is the coagulation cascade activated in the intravascular
compartment in patients with CAP?
9 Is the local pulmonary coagulation cascade activated in patients with CAP?
10 Relation between causative micro-organism and coagulation activation.
11 Evaluation of the effect of administered dexamethasone on the coagulation
activation

randomized placebo controlled trial

intervention:
On ER: bolus 5 mg (1 ml) dexamethasondisodiumphosphate
5 mg (1 ml) dexamethasonedisodiumphosphate once a day for three days

control:
On ER 1 ml sterile water
1 ml sterile water once a day for three days.

risks of the use of dexamethasone:
Hypokalemia
Fluid volume shift
Skin thinning and purpura
Cushingoid appearance
Alopecia
AcneHirsutism
Posterior subcapsular cataract
Elevated intraocular pressure/glaucoma
Hypertension
Arrhythmias with pulse infusions
Gastritis
Peptic ulcer disease
Pancreatitis
Amenorrhea/infertility
Osteoporosis
Avascular necrosis
Myopathy
Euphoria
Dysphoria/depression
Psychosis
Diabetes mellitus
Hypothalamic-pituitary-adrenal insufficiency
Heightened risk of typical infections
Opportunistic infections
Herpes zoster

Benefits:
reduction in time of hospital stay