DISCUSSION
First of all, we would like to evaluate whether our analysis was
consistent and reliable. In this point, lab parameters that are known as
“mortality/severity indicators” such as WBC, PLT, CRP, PCT, SEDIM,
D-dimer, LDH, Fibrinogen, Troponin, ALT, AST, and Ferritin were compared
between the patient and control group
(12)
(13). The comparison
analysis revealed no significant difference regarding neither of these
parameters and we consider that this result is a reliable indicator for
the comparability of DEX between these groups. Besides, since no
significant difference was found with respect to these lab parameters
between the groups, our result revealing no significant difference
regarding mortality would also be expected and is compatible with other
analyses. As for the effects of applied treatments upon mortality rates,
most of the patients received standard therapies that were recommended
by the guidelines of the Ministry of Health in our country at that time.
The recommended therapies for the patients with severe COVID-19 were
favipiravir, steroids (dexamethasone ≥ 8mg of methylprednisolone ≥ 40
mg), and LMWH at the time at which the study group was treated in the
ICUs. As you can see from Table 3 more than 90% of the patients
received these standard therapies (percentage of the patients receiving
dexamethasone + pulse steroid was between 85-90) revealing that there
was no significant difference regarding the applied treatments between
the groups. There was also no significant difference in terms of median
ages, gender distribution, place of treatment (all patients were treated
in the ICUs), and intubation rates between the groups. Therefore,
without the effect of these parameters and applied treatments except
DEX, the comparison of DEX treatment and its effects on the outcomes in
our study group is reliable.
Nowadays, it is very well know that advanced age, male gender, and
comorbidities such as DM, HT, and CAD are risk factors for advanced
disease in COVID-19 (14).
Concurrently, in our study group which consists of patients with severe
COVID-19, median age was 69.5. While the median age was higher in the
control group (70) than in the patient group (67), this difference did
not reach a significant level (p=0.094, p>0.05). Male
predominance was seen in both groups as expected. In a prospective
observational study in which 63 of 89 patients with severe COVID-19 were
treated with DEX, HFNC and long periods of PP, mean age was 67 ± 12 and
74% of the treatment group consisted of male patients
(15). These results are very
similar to our study. We would also like to point out that PP up to 16
hours a day was also applied to all patients in our study who were able
to tolerate as a part of standart therapy.
When we made a literature search regarding to the articles studying
theurapeutic value of DEX in patients with COVID-19, we could not find
any randomised controlled trials conducted with large patient
populations. Except one study which we mentioned above
(15), a few case reports,
case series, and letters to editor constitute all studies about this
issue (15)
(16)
(17)
(18)
(19)
(20)
(21). Among these, the
study conducted by Taboada et al. was the most appropriate candidate to
compare our results with. In that study, clinical characteristics of 63
patients treated with long PP, DEX, and HFNC, 20 of whom with failed
therapy and 43 of whom with successful therapy were compared. 20.6% of
the patients either died or remained in the ICU while 30.2% of the
patients required endotracheal intubation. In a case series in which 11
patients were treated with helmet CPAP in the prone position with DEX
infusion, 2 of these patients died and 3 of them required invasive
ventilatory support (18% and 27%
respectively)(17). However,
in our study, the intubation rate was 72.4% and the mortality rate was
74.6% for all patients. This huge difference might have been caused by
a few factors. Firstly, COVID-19 daily cases were very high in our
country at that time at which our study was conducted
(22). Therefore, even some
patients with SpO2<90% and/or respiratory rate
(RR)>20/min had to be treated in the ward since the ICUs
were full of patients with severe COVID-19. This situation might have
caused a delay in the transfer of the patients from emergency rooms or
wards to the ICUs. And this delayed start of ventilatory support and DEX
infusion might have caused these high mortality and intubation rates in
our study group. However, in the beforementioned studies, Paternoster et
al. and Taboada et al. reported that they dedicated special beds called
high dependency units (HDU) for the patients requiring helmet CPAP and
as soon as the SpO2 of the patients dropped to below 90% or PaO2/FiO2
dropped to below 200 mmHg they transferred them to ICUs. This rapid
transfer process and easy access to intensive care resources might have
been the reason for their lower mortality and intubation rates.
Secondly, the known side effects of DEX infusion are mostly cardiac such
as bradycardia and hypotension
(23). Although we could not
reach the data regarding the discontinuation rate of DEX during the
treatment from the medical files of the patients, as ICU doctors we had
to decide discontinuation of DEX infusion on several occasions
especially due to bradycardia (HR<50 beat/min). If the
intolerance rate would have been higher in our study group, this could
have caused shorter durations of DEX infusion and NIMV therapies and
thus, higher mortality and intubation rates.
None of the studies mentioned above compared the parameters of the
patients who received DEX therapy versus patients who received standard
therapy in patients with COVID-19. From this point of view, our study is
unique and can contribute to the literature. Although mortality and
intubation rates were lower numerically in our study group, the
difference was not statistically significant. Although there was no
significant difference regarding the duration of intubation between the
groups, the time between ICU admission and intubation was found to be
longer in the patient group (Table 1). This might be the most important
result of our analyses in this study since treatments to avoid
intubation or prolong the time before intubation are of vital importance
and potentially life-saving due to high mortality rates reported for
intubated patients with severe COVID-19
(12)
(13). With this result, we
think that DEX proved its therapeutic value even if not as a mortality
and intubation rate reducer, but as a time prolonger before intubation
in our study. The median time between ICU admission and intubation was
found as 3 days in a similar study in which all 63 patients received
long PP periods and HFNC treatment
(15). Maybe this time
prolongation effect before intubation would rebound on future trials
with large sample sizes as decreased intubation and mortality rates.
Comparison of lab parameters revealed no significant difference between
the groups which was considered as a healthy indicator for comparability
of DEX between the groups as we mentioned before. In the study conducted
by Taboada et al., lab parameters such as lymphocyte count, LDH,
D-dimer, CRP, PCT, and Ferritin were compared between the group with
response to DEX, HFNC, and PP therapy and the group with no response to
therapy. Neither of these comparisons revealed a significant difference
between the groups (15).
Our control group who were treated without DEX contained significantly
more patients with DM, and CHF than the patient group (Table 2). In the
similar study, no significant difference was found regarding co-existing
conditions between the groups
(15). HT-hyperlipidemia
(15) and HT-COPD
(17) were the two most
common comorbidities in similar studies whereas HT and DM were the two
most common co-existing condition in our study group. Predominance of
the patients with DM and CHF in our control group might be caused by
their fulminant course since these two co-existing conditions are known
as risk factors for higher mortality
(24)
(25). Our hypothesis is that
their more rapid progression to endotracheal intubation and death as
soon as they were transferred to ICUs might prevent them from receiving
DEX treatment. Congruently, significantly less requirement of the
patients under regular insulin therapy for DEX infusion may also be
explained by this hypothesis. Our second hypothesis for the patients
under insulin treatment is that they might be more familiar to ICU
setting and thus less agitated/anxious since these patients might be
frequently admitted to ICUs because of diabetic ketoacidosis. In the
similar study, no significant difference was found between successful
and failed therapy groups regarding home treatments, however, they
included only ACEIs, anticoagulants, corticosteroids, and statins in the
analysis (15).
Among all the treatments applied to the patients with severe COVID-19,
only IVIG and CPAP were significantly associated with DEX infusion
(Table 3). 4 of 5 patients (80%) were treated with DEX infusion.
Although IVIG group has a small number of patients the percentage is
high. When we searched for the possible etiology of this situation we
found out that headache, flushing, malaise, and pyretic reactions are
common side effects of this therapy
(26)
(27). This side effects may
easily cause delirium, anxiety, and agitation when occured. Our second
hypothesis for these patients is that since IVIG is a very expensive
treatment option, clinicians might have applied this valuable option to
younger patients with less risk factors. Therefore these patients could
have remained in NIMV support for longer and received DEX infusion.
Since one of the most important indications of DEX infusion is
maintaining cooperation with NIMV techniques, it was not surprising for
us to see more patients receiving CPAP in the patient group. However,
what is surprising was that not seeing more patients receiving HFNC in
the patient group. Because the standard treatment algorithm for patients
with severe respiratory failure was PP + HFNC with or without sedatives,
if not responsive PP + CPAP, if not responsive endotracheal intubation
respectively. Possible reasons for this condition might include the lack
of equipment, presentation of the patient to the ICUs at the end stages
of ARDS and thus directly applying CPAP or intubation by skipping the
first step (HFNC), and the choice of clinicians as a result of their
experience (found ineffective?). In a similar study in which all the
patients received HFNC support, there was not any significant difference
regarding hospital medical treatments between the successful and failed
therapy groups (15). What
should not be overlooked at this point is that patients receiving NIMV
support constituted only 26 of the 45 patients treated with DEX which
means 19 of the patients received DEX with the indication of either PP
without NIMV support and/or delirium. This number was more than what we
expected before the analysis.
Generally, the studies we mentioned above report that DEX can be a
beneficial option in patients with severe COVID-19 especially to
increase the patients’ tolerance to NIMV support and long periods of PP.
However, one letter to the editor drew attention to DEX-associated
hyperpyrexia as a side effect and dosage of infusion as a concern for
the withdrawal phenomenon
(20). The author recommends
using DEX with caution because of this potential side effect and narrow
therapeutic index. In our study, no apparent beneficial effect of DEX
has been shown on mortality and intubation rates, however, there are
limitations of our study. Performing in a single center, the missing
data regarding withdrawal rates and causes of DEX infusion, being
retrospective, and having a small sample size were the limitations of
our study.