Acute and Critical Care

Original Articles

Infection
The Effects of Flecainide Acetate on Inflammatory-Immune Response in Lipopolysaccharide-Stimulated Neutrophils and on Mortality in Septic Rats: Shi Young Chung, Jinyoung Kim, Hong Bum Bae, Tran Duc Tin, Wan Ju, Sang Hyun Kwak; Acute Crit Care. 2018;33(1):34-41. Published online February 28, 2018; DOI: https://doi.org/10.4266/acc.2017.00577

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Background
Flecainide acetate is a drug used primarily for cardiac arrhythmia. Some studies also imply that flecainide acetate has the potential to regulate inflammatory-immune responses; however, its mechanism of action is contended. We determined the effects of flecainide acetate on lipopolysaccharide (LPS)-stimulated human neutrophils in vitro and on mortality in a septic rat model.
Methods
Neutrophils from human blood were cultured with varying concentrations of flecainide acetate (1 μM, 10 μM, or 100 μM) with or without LPS (100 ng/ml). To assess neutrophil activation, the protein levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and IL-8 were measured after a 4-hour culture period. To assess the intracellular signaling pathways, the levels of phosphorylation of p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) were measured after a 30-minute culture period, and the nuclear translocation of nuclear factor (NF)-κB was measured after a 1-hour culture period. Additionally, the survival rate was investigated in a rat sepsis model.
Results
Flecainide acetate down-regulated the activation of proinflammatory cytokines, including TNF-α and IL-6 and IL-8, and intracellular signaling pathways including ERK 1/2 and NF-κB. Flecainide acetate also improved the survival rate in the rat sepsis model.
Conclusions
Collectively, these findings indicate that flecainide acetate can improve survival in a rat sepsis model by attenuating LPS-induced neutrophil responses. We therefore suggest that flecainide acetate plays an important role in modulating inflammatoryimmune responses.

Citations

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Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis
Andy Y. An, Arjun Baghela, Peter Zhang, Reza Falsafi, Amy H. Lee, Uriel Trahtemberg, Andrew J. Baker, Claudia C. dos Santos, Robert E. W. Hancock
Frontiers in Immunology.2023;[Epub] CrossRef

The Effects of Moderate Hypothermia on the Formation of Apoptosis in Transient F degrees Cal Cerebral Ischemia Model in Rats: Tae Jung Woo, Seong Wan Baik, Kyoo Sub Chung, Inn Se Kim, Hae Kyu Kim, Jae Young Kwon; Korean J Crit Care Med. 2002;17(1):12-18.

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Abstract PDF: BACKGROUND
Delayed neuronal injury after cerebral ischemia came major neurologic complication after stroke or cardiac arrest. Apoptosis formation after ischemia may be one of a mechanism of delayed neuronal injury. This study was conducted to evaluate the effect of moderate hypothermia on apoptosis formation after one hour of middle cerebral artery degrees Cclusion in rats.
METHODS
Ten Sprague-Dawley rats (300 g) were freely fed till just before operation. Anesthesia was induced with 4 vol% isoflurane in oxygen and then maintained with 2 vol% isoflurane in oxygen. Middle cerebral artery degrees Cclusion (MCAO) was induced by intraluminal monofilament nylon with blunted tip. All rats were divided randomly into two groups. In group 1 (n=5), rectal temperature was maintained at 38 degrees C. In group 2 (n=5), rectal temperature was maintained at 32 degrees C. Rectal temperature was monitored during experiment. After 60 minutes of MCAO, intraluminal monofilament was removed and all rats were returned to cages. Brain were quickly removed and cerebral hemispheres were separated after 23 hours reperfusion. Apoptosis formation were counted with TUNEL stain.
RESULTS
In group 1, after 60 minutes of MCAO and 23 hours reperfusion, 51 3.6% of hipp degrees Campal neurons were TUNEL-positive stained apoptotic cells. In group 2, TUNEL-positve neurons were 26.1 6.5% and significantly less than those of group 1 (p<0.05).
CONCLUSIONS
Sixty minutes of MCAO and 23 hours reperfusion induce hipp degrees Campal neuronal apoptosis. Moderate hypothermia of 32 degrees C reduces apoptosis of hipp degrees Campal neurons after 60 minutes of MCAO and 23 hours reperfusion.

Effects of Blood-Brain Barrier Disruption on Cerebral Oxygen Balance: Doo Ik Lee, Young Kyu Choi, Dong Ok Kim, Keon Sik Kim, Ok Young Shin, Moo Il Kwon; Korean J Crit Care Med. 1999;14(2):126-130.

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Abstract PDF: BACKGOUND: Disruption of the blood-brain barrier (BBB) can alter the internal milieu and may increase the release of excitatory amino acid neurotransmitters or catecholamines, which may affect metabolic rate or coupling. This study was performed to evaluate whether disruption of BBB by unilateral intracarotid injection of hyperosmolar mannitol would alter oxygen supply/consumption balance in the ipsilateral cortex.
METHODS
Rats were anesthetized with 1.4% isoflurane using mechanical ventilation via tracheostomy. 25% mannitol was administered at a rate of 0.25 mlxkg-1s-1 for 30 s through unilateral internal carotid artery. The BBB transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid was measured in one group (N=7) after administering mannitol. Regional cerebral blood flow (rCBF), regional arterial and venous O2 saturation and O2 consumption were measured in another group using a 14C-iodoantipyrine and microspectrophotometry (N=7).
RESULTS
Vital signs were similar before and after administering mannitol. Ki was significantly higher in the ipsilateral cortex (IC) than in the contralateral cortex (CC), (22.3+/-8.4 vs 4.4+/-1.1 microliterxg-1min-1). rCBF was similar between IC (105+/-21 mlxg-1min-1) and the CC (93+/-20). Venous O2 saturation was lower in the IC (43+/-7%) than in the CC (55+/-4). O2 consumption was higher in the IC (9.6+/-3.0 mlx100 g-1min-1) than in the CC (6.7+/-1.5).
CONCLUSIONS
Our data suggested that increasing permeability of the BBB increased cerebral O2 consumption and deteriorated cerebral oxygen balance.

The Effects of Nitric Oxide on Oxygen Balance in Cerebral Ischemia: Doo Ik Lee, Young Kyu Choi, Oak Za Chi; Korean J Crit Care Med. 1998;13(2):179-185.

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Abstract PDF: Bockground: Nitric oxide (NO) is an important regulator of blood flow and also works as a neuronal messenger via cyclic GMP. Recent studies regarding the therapeutic utility of nitric oxide synthase (NOS) inhibitors in reducing ischemia-induced neuronal damage are very controversial. The possible neuroprotective effect of NO or NOS inhibitors in ischemic neuronal damage could occur at the vascular and or neuronal level. This study investigated whether the NOS inhibitor, NG-nitro-L-arginine-methyl ester (L-NAME) would alter oxygen balance in ischemic cerebrocortex of isoflurane-anesthetized rats.
METHODS
Fifteen minutes after middle cerebral artery occlusion, L-NAME (1.5 mgxmin-1kg-1) was infused intravenously to the L-NAME group (n=14), and normal saline was given to the control group (n=14) for 45 minutes. Regional cerebral blood flow was determined with [14C]iodoantipyrine, and arterial and venous oxygen saturations were determined by microspectrophotometry.
RESULTS
Regional cerebral blood flow of the ischemic cortex was significantly lower than that of the contralateral cortex in both groups. In the control group, ischemic cortex; 55+/-13, contralateral cortex; 110+/-29 mlxmin-1100 g-1, and in the L-NAME group, ischemic cortex; 35+/-13, contralateral cortex; 90+/-24 mlxmin-1100 g-1. Compared with the blood flow in the ischemic cortex of the control group, L-NAME significantly reduced ischemic blood flow by 36%. Venous oxygen saturation was significantly increased in the ischemic cortex (41+/-1% in control, 44+/-3% in L-NAME) but decreased in the contralateral cortex (65+/-3% in control, 61+/-3% in L-NAME) by L-NAME. Ischemic cortical oxygen consumption in the L-NAME group was 39% lower than that in the corresponding control group, whereas the difference was only 11% in the contralateral sides between groups. The ratio of oxygen supply to consumption was lower in the ischemic than in the nonischemic regions in both groups. In the ischemic cortex, this ratio was significantly lower in the control group (1.7+/-0.1) than in the L-NAME group (1.9+/-0.1). In contrast, the ratio tended to be decreased by L-NAME in nonischemic regions.
CONCLUSIONS
These observations suggest that despite a decrease in cerebral blood flow, inhibition of nitric oxide synthesis mildly improves the oxygen supply and consumption balance in the ischemic cortex.

The Effects of Lipopolysaccharide on the Reactivity of Isolated Rat Trachea with or without Epithelium: Hyo Chul Shin, Yoon Hee Kim, Dong Sik Hur, Seok Hwa Yoon, Yong Sup Shin, Sae Jin Choi; Korean J Crit Care Med. 1998;13(1):25-32.

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Abstract PDF: BACKGOUND: Gram negative bacterial lipopolysaccharide (LPS) induces increase in the production of nitric oxide (NO), or a related substance derived from L-arginine in the animal tissue. Recent evidence indicates that airway epithelium may secrete NO or a related compound. It has multiple regulatory roles in the airways. In vitro, the effects of lipopolysaccharide (LPS) on the reactivity of rat' tracheal wall with or without epithelium were examined.
METHODS
Tracheas were removed from Sprague Dawley rats. Preparations were mounted for isometric recording in 20ml organ baths at 37degrees C containing Tis-buffered Tyrode solution continuously gassed with 100% O2. Tensions were measured with force displacement transducers and responses were recorded on a polygraph. Cummulative concentration-response curves were constructed for acetylcholine (Ach) in the tracheal strips with or without preincubation of Escherichia coli LPS (100 mcg/ml, 5hrs). And then effects of NO synthase inhibitors and removal of epithelium were examined.
RESULTS
In isolated perfused tracheas preincubated by LPS, both removed epithelium and intact epithelium of rat tracheal rings showed decreased Ach-induced contraction. In intact epithelium group, 10 (-5)M L-NAME (N-nitro-L-arginine methyl ester), 10 (-5)M L-arginine or dexamethasone pretreatment was restored in Ach-induced contraction response. But in the removed epithelium group, Ach-induced contraction was potentiated by L-arginine pretreatment and was not restored by the pretreatment of L-NAME and dexamethasone.
CONCLUSIONS
The results suggest that nitric oxide synthase is induced by endotoxin in the tracheal epithelium, resulting in inhibition of the contractile response.

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