DISCUSSION
In this study, we found that critically ill patients who received LC at
a dose of 3 gr/day for 7-day had significantly reduced levels of
inflammation markers and 28-day mortality in the intervention group
compared with the control group. Lee et al reported that daily
consumption of 1 g LC for 12 weeks significantly reduced levels of IL-6,
CRP, and Tumor necrosis factor-α (TNF-α) in patients with cardiovascular
diseases (13). Recent evidence has demonstrated that LC supplementation
prevents oxidative stress in patients with coronary artery disease (CAD)
by regulating and reducing lipid peroxidation and increasing antioxidant
enzymes for scavenging free radicals and reactive oxygen species (ROS)
(14-16). Furthermore, ROS and other radicals, can increase inflammation
and up-regulate nuclear factor kappa-light-chain-enhancer of activated B
cells )NF-Kβ( pathway (17-19), which is a transcription factor and
regulator of multiple gene expression in immune-inflammatory responses
and reduces gene expression of proinflammatory cytokines including IL-6,
IL-1, CRP, and enhances gene expression of anti-inflammatory cytokines
IL-10 (20-22). Consequently, LC could decrease inflammatory markers in
patients with chronic inflammation including critically ill patients
with the same mechanism. In their study, Shakeri et al. reported that
consumption of 1 gr/day of oral LC resulted in a 29% decrease in
baseline CRP and 61% decrease in IL-6 levels in hemodialysis patients
(23). Dastan et.al supplemented cardiovascular patients with 3 g/day of
LC for 5 days and reported a significant reduction in CRP levels (12).
In recent years, two clinical studies have shown that supplementation
with 20 mg/kg/day LC may decrease CRP levels in hemodialysis patients
(11, 24). However, two other clinical studies, it has been shown that LC
supplementation had no effect on the inflammatory markers, including CRP
and IL-6, in obese healthy subjects (25, 26). This lack of effect in
healthy people may be due to the fact that healthy subjects do not have
high levels of inflammation, while in our study, all subjects had high
levels of inflammation with CRP levels higher than 1 mg/dl and IL-6
levels higher than 1.5 pg.ml. In the present study, supplementation with
LC resulted in a significant reduction in IL-6 and CRP levels in
critically ill patients. Results of the previous meta-analysis showed a
significant reduction in CRP due to LC supplementation in comparison to
the control group . Recently, Haghighatdoost et al. conducted another
systematic review and meta-analysis, which included 13 clinical trials
to assess the effect of LC supplementation on inflammation and
inflammatory markers (IL-6, CRP). Findings of this study showed that
supplementation with LC led to a significant reduction in CRP and IL-6
levels compared with the control group (P = 0.001 and p=0.002
respectively) (28). The mentioned study showed that LC reduced
inflammation in patients, especially in studies that supplementation
continued for more than two weeks at a dose higher than 2 g/day.
Although in our study, LC was used for one week, intervention among
critically ill patients with high levels of inflammatory markers and
using mega-dose of 3 gr/day might be the main reason causes similar
findings of our study with the recent meta-analysis findings.
Pharmacological studies have reported that the bioavailability of oral
dose of LC is low and it is absorbed only by 5 to 16%, so it has been
suggested that doses higher than 2 g/day might have a greater effect
(29, 30). Therefore, the additional effect of LC on the level of
inflammatory markers can be dose and time-dependent. Besides, LC is able
to regulate the Peroxisome proliferator-activated receptor gamma is a
type of nuclear receptor (PPAR γ) pathway, which is a key factor in the
regulation of oxidative stress pathways and liver inflammation (31).
Another study showed that LC may be able to improve the inflammatory
response of the liver by regulating the PPAR γ signaling pathway, which
is a transcription factor for lipolytic genes including carnitine
palmitoyltransferase 1 (CPT1) (32, 33). They also reported that SOFA
score was significantly associated with LC deficiency in these patients,
and no significant difference was observed in clinical outcomes, length
of hospital stay between LC deficient patients and non-deficient
patients. They did not mention any mechanism for the increase in SOFA
score but one explanation could be due to the important role of LC in
transporting long-chain fatty acyl CoA into the mitochondrial matrix for
beta-oxidation by carnitine palmitoyltransferase 1 (CPT1) (10). LC
deficiency disrupts B-oxidation of fatty acid in critically ill
patients. Since most of the acyl-CoA in the body is used to bond with
fatty acid, in case of depleted CoA pool, due to metabolic dysfunction
in mitochondrial function, the multi-organ failure and mortality is
increased (34). Jones et al. assessed the effect of high-dose LC
supplementation in 250 sepsis patients. LC was administered three doses
of 6 g, 12 g, and 18 g during the first 24 hours of admission. They
reported that the SOFA score reduced in the first 48 hours and also
treatment with carnitine was significantly decreased 28 days mortality.
The effect of LC was dose dependent but the difference in LC did not
statistically significant. The proposed mechanism for this finding could
be that LC may decrease the metabolic effects of sepsis by promoting and
increasing the fatty acids transportation into the mitochondria, and
thereby reducing the inhibitory effects of acetyl-CoA on pyruvate
dehydrogenase (35). Puskarich et al reported that supplementation with
12 gr LC led to a greater reduction in SOFA score and mortality compared
to the control group in 31 sepsis patients. The mortality was reported
50% (8 of 16) in the LC group in the mentioned study while mortality
occurred in 80% (12 of 15) of patients in the control group (36)(38).
Chung et al. measured plasma levels of acylcarnitine in sepsis patients
and evaluated its association with multi-organ dysfunction and
mortality. They reported that plasma levels of acylcarnitine may reflect
the severity of multi-organ dysfunction, inflammation, infection, and
sepsis and may serve as a predictive biomarker for mortality. These
findings suggested that carnitine deficiency and disorder in B-Oxidation
of fatty acids lead to defects in lipid utilization by vital organs,
especially the liver and kidney, which may lead to mitochondrial
dysfunction in patients who died of sepsis (33). In the present study
study, critically ill patients who were supplemented with LC reduced the
duration of ventilation compared to the control group, and 37.5% of
patients in the LC group were discharged from the ICU. Goetzmen et al,
studied long-chain acyl-CoA dehydrogenase deficiency in relation to
pulmonary surfactant dysfunction. They showed that fatty acid oxidation
was increased in the lungs similar to the liver, and that the inhibition
of fatty acid oxidation by acyl-CoA can lead to abnormal synthesis of
surfactants (37). The main function of LC is the esterification and
transfer of long-chain fatty acids into the mitochondrial membrane and
production of energy, therefore, LC supplementation may improve clinical
outcomes by decreasing inflammatory mediators in critically ill
patients.
Although this is the first study investigating the effects of a mega
dose of oral LC supplementation for seven days among critically ill
patients, some limitations could be acknowledged. First, the present
study was conducted in the general ICUs with the heterogenic patients.
The second limitation was the duration of LC supplementation (7-day). We
suggest that larger and longer intervention studies are required to
document the effects of L-Carnitine on inflammatory markers and clinical
status in ICU patients.