N-Acetylcysteine to Combat COVID-19: An Evidence Review.

The novel coronavirus disease (COVID-19) is caused by a virus (SARS-Cov-2) and is known for inducing multisystem organ dysfunction associated with significant morbidity and mortality. Current therapeutic strategies for COVID-19 have failed to effectively reduce mortality rate, especially for elderly patients. A newly developed vaccine against SARS-Cov-2 has been reported to induce the production of neutralizing antibodies in young volunteers. However, the vaccine has shown limited benefit in the elderly, suggesting an age-dependent immune response. As a result, exploring new applications of existing medications could potentially provide valuable treatments for COVID-19. N-acetylcysteine (NAC) has been used in clinical practice to treat critically ill septic patients, and more recently for COVID-19 patients. NAC has antioxidant, anti-inflammatory and immune-modulating characteristics that may prove beneficial in the treatment and prevention of SARS-Cov-2. This review offers a thorough analysis of NAC and discusses its potential use for treatment of COVID-19.

Endotracheal intubation results in acute tracheal damage induced by mtDNA/TLR9/NF-κB activity.

Tracheitis secondary to placement of an endotracheal tube (ETT) is characterized by neutrophil accumulation in the tracheal lumen, which is generally associated with epithelial damage. Mitochondrial DNA (mtDNA), has been implicated in systemic inflammation and organ dysfunction following trauma; however, less is known about the effects of a foreign body on local trauma and tissue damage. We hypothesized that tracheal damage secondary to the ETT will result in local release of mtDNA at sufficient levels to induce TLR9 and NF-κB activation. In a swine model we compared the differences between uncoated, and chloroquine (CQ) and N-acetylcysteine (NAC) coated ETTs as measured by tracheal lavage fluids (TLF) over a period of 6 h. The swine model allowed us to recreate human conditions. ETT presence was characterized by neutrophil activation, necrosis, and release of proinflammatory cytokines mediated by TLR9/NF-κB induction. Amelioration of the tracheal damage was observed in the CQ and NAC coated ETT group as shown in tracheal tissue specimens and TLF. The role of TLR9/NF-κB dependent activity was confirmed by HEK-Blue hTLR9 reporter cell line analysis after coincubation with TLF specimens with predetermined concentrations of NAC or CQ alone or TLR9 inhibitory oligodeoxynucleotide (iODN). These findings indicate that therapeutic interventions aimed at preventing mtDNA/TLR9/NF-κB activity may have benefits in prevention of acute tracheal damage.

Mitochondrial DNA induces Foley catheter related bladder inflammation via Toll-like receptor 9 activation.

Bladder instrumentation engages the innate immune system via neutrophil activation, promoting inflammation and pain. Elevated levels of mitochondrial DNA (mtDNA) have been associated with tissue damage and organ dysfunction. We hypothesized that local bladder trauma induced by a Foley catheter (FC) will result in mtDNA release, migration of neutrophils into the bladder lumen, and activation of the Toll-like receptor 9 (TLR9) and nuclear factor kappa B (NF-κB) pathway leading to bladder tissue damage. We randomized 10 swine into two groups receiving uncoated, or chloroquine/N-Acetylcysteine (CQ/NAC)-coated FCs. Urine samples were analyzed for mtDNA activation of TLR9/NF-κB as demonstrated by indicators of neutrophil adhesion, migration, and activation. We found that uncoated FCs resulted in a unique active neutrophil phenotype that correlated with bladder epithelial injury, neutrophilia, necrosis, mtDNA release, TLR9/NF-κB activation, transcription and secretion of pro-inflammatory cytokines, and enhanced respiratory burst. In our study we observed that the high levels of mtDNA and elevated TLR9/NF-κB activity were ameliorated in the CQ/NAC-coated FC group. These findings suggest that post-migrated bladder luminal neutrophils are involved in local tissue damage and amelioration of the mtDNA/TLR9/NF-κB inflammatory axis may represent a therapeutic target to prevent inflammation, and bladder tissue injury.

Endotracheal tube-induced sore throat pain and inflammation is coupled to the release of mitochondrial DNA.

In the absence of infection, the pathophysiology of endotracheal tube-induced sore throat pain is unclear. Activated neutrophils release elastase, reactive oxygen species, and inflammatory cytokines known to contribute to neuropathic pain. Sterile tissue injury can cause the release of damage-associated molecular patterns such as mitochondrial DNA that promote neutrophil activation. We hypothesized that endotracheal tube-induced sore throat pain is linked to mitochondrial DNA-mediated neutrophil inflammation. A nonrandomized prospective survey for sore throat pain was conducted in 31 patients who required short-term intubation and had no evidence of upper airway infection. Patterns of neutrophil abundance, activation, and mitochondrial DNA levels were analyzed in tracheal lavage fluid following intubation and prior to extubation. Thirteen of 31 patients reported sore throat pain. Sore throat patients had high neutrophilia with elevated adhesion molecule and TLR9 expression and constitutive reactive oxygen species generation. Tracheal lavage fluid from sore throat patients accumulated mitochondrial DNA and stimulated neutrophils to release mediators associated with pain in a TLR9- and DNAse-dependent fashion. Endotracheal tube-induced sore throat is linked to the release of mitochondrial DNA and can drive TLR9-mediated inflammatory responses by neutrophils reported to cause pain. Mitigating the effects of cell-free mitochondrial DNA may prove beneficial for the prevention of endotracheal tube-mediated sore throat pain.

Does a Multimodal No-Compression Suture Technique of the Intercostal Space Reduce Chronic Postthoracotomy Pain? A Prospective Randomized Study.

INTRODUCTION: Chronic postthoracotomy pain is a significant adverse outcome of thoracic surgery. We evaluated with a prospective randomized trial the effect of a multimodal no-compression suture technique of the intercostal space on postoperative pain occurrence in patients undergoing minithoracotomy. METHODS: Patients undergoing a muscle-sparing lateral minithoracotomy for different thoracic diseases were randomly divided into two groups: 146 patients received intercostal muscle flap harvesting and pericostal no-compression "edge" suture (the IMF group), and 151 patients received a standard suture technique associated with an intrapleural intercostal nerve block (the IINB group). Pain scores and interference of pain with daily activities were assessed by using the Italian version of the Brief Pain Inventory on day 1, and at 1 to 6 months postoperatively. The results of pulmonary function tests (spirometry and the 6-minute walking test ) were evaluated preoperatively and at 1 and 6 months postoperatively. RESULTS: Postthoracotomy pain scores throughout the first postoperative day were significantly lower in the IMF group. After 1 and 6 months, patients in the IMF group had a significantly lower average pain score (p = 0.001). There were no significant differences in pain interference scores at each evaluation time point in either group. However, differences were shown in lung function test results at 1 and 6 months postoperatively (the forced expiratory volume in 1 second in the IINB group averaged 68.8 ± 17.4% of predicted value and 72.8 ± 10.5%, respectively, and in the IMF group it averaged 83.1 ± 7.4% and 86.4 ± 12.8%, respectively [p = 0.023 and 0.013, respectively]; the 6-minute walking test results in the IINB group averaged 311.1 ± 51.0 and 329.9 ± 54.8 m, respectively, and those in the IMF group averaged 371.2 ± 54.8 and 395.7 ± 56.4 m, respectively [p = 0.0001]). CONCLUSIONS: The multimodal no-compression suture technique is a rapid and feasible procedure that reduces the intensity of early and chronic postthoracotomy pain.

Human recombinant apyrase therapy protects against canine pulmonary ischemia-reperfusion injury.

BACKGROUND: There is accumulating evidence that extracellular adenosine triphosphate (eATP) promotes many of the underlying mechanisms that exacerbate acute lung injury. However, much of these data are from inbred rodent models, indicating the need for further investigation in higher vertebrates to better establish clinical relevance. To this end we evaluated a human recombinant apyrase therapy in a canine warm pulmonary ischemia-reperfusion injury (IRI) model and measured eATP levels in human lung recipients with or without primary lung graft dysfunction (PGD). METHODS: Warm ischemia was induced for 90 minutes in the left lung of 14 mongrel dogs. Seven minutes after reperfusion, the apyrase APT102 (1 mg/kg, n = 7) or saline vehicle (n = 7) was injected into the pulmonary artery. Arterial blood gases were obtained every 30 minutes up to 180 minutes after reperfusion. Bronchioalveolar lavage fluid (BALF) was analyzed for eATP concentration, cellularity, and inflammatory mediator accumulation. Thirty bilateral human lung transplant recipients were graded for immediate early PGD and assessed for BALF eATP levels. RESULTS: APT102-treated dogs had progressively better lung function and less pulmonary edema during the 3-hour reperfusion period compared with vehicle-treated controls. Protection from IRI was observed, with lower BALF eATP levels, fewer airway leukocytes, and blunted inflammatory mediator expression. Human lung recipients with moderate to severe PGD had significantly higher eATP levels compared with recipients without this injury. CONCLUSIONS: Extracellular ATP accumulates in acutely injured canine and human lungs. Strategies that target eATP reduction may help protect lung recipients from IRI.

Innate immunity mediating inflammation secondary to endotracheal intubation.

OBJECTIVE: To investigate the inflammatory markers associated with short-term endotracheal intubation in healthy surgical patients. DESIGN: An observational and prospective study of subjects scheduled for same-day surgery procedures. SETTING: Level I trauma center. PATIENTS: Fourteen healthy patients intubated for same-day surgery procedures. The median duration of surgery was 3 hours. INTERVENTIONS: Serial lavages above the tracheal cuff were obtained at the beginning of surgery, at 1 hour, and at the end of surgery; samples were assayed for cellular counts and levels of cytokines and complement 5a (C5a). RESULTS: The total number of polymorphonuclear cells (PMNs) increased almost 10-fold from intubation to extubation (P < .01). The levels of 3 of the cytokines measured in tracheal lavage supernatants were significantly elevated over the time of intubation: tumor necrosis factor (TNF) (P < .01), interleukin 6 (IL-6) (P < .01), and IL-1ß (P < .025). Levels of IL-8 showed an upward trend over time but were not significantly increased; C5a levels were significantly elevated over time (P < .05). CONCLUSIONS: Short-term intubation in healthy patients resulted in significant tracheal inflammation. Involvement of the innate immune system as documented in the present study provides information that may help to better understand the pathophysiologic characteristics of subglottic stenosis and other endotracheal injuries secondary to endotracheal intubation.

Early biochemical markers of inflammation in a swine model of endotracheal intubation.

BACKGROUND: A common complaint after endotracheal tube use is sore throat, which may be due to abrasion, ischemia-reperfusion injury, or an inflammatory reaction. Few studies have evaluated localized tracheal inflammation as part of the response to intubation. METHODS: Inflammation of the trachea due to intubation was assessed in a swine model by following indicators of inflammation over time in the tracheal lumen. Repeated tracheal lavages proximal to the endotracheal tube cuff were performed, and recovered lavage was analyzed for cells, protein, lactate dehydrogenase, and cytokines. RESULTS: The baseline tracheal lavage samples contained 18% polymorphonuclear cells. These cells increased rapidly to 43% by 1 h. The polymorphonuclear cell increase from baseline was significant at 1, 2, and 4 h (P < 0.01) after intubation. Tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and interleukin 8 increased over time, but only interleukin 6 increased significantly (P < 0.01). Interleukin 6 was not detected at baseline or 1 h, but was detected at 2 h and increased significantly by 4 h. Neither lavage protein concentration nor lactate dehydrogenase activity increased over time. CONCLUSIONS: These results demonstrate that inflammation does occur during tracheal intubation, even when markers suggest minimal tracheal damage. The dramatic elevation in polymorphonuclear cells, along with the increase in interleukin 6, suggests an inflammatory response to the endotracheal tube itself or to some aspect of the intubation process. A more complete understanding of the response of the tracheal tissues is important in improving the treatment of intubated patients.

Acute respiratory distress syndrome update.

Respiratory failure and eventual ventilator dependence are hallmarks of the acute respiratory distress syndrome (ARDS). ARDS carries a significant mortality in all patient populations and the treatment strategies are largely supportive in nature. Despite years of clinical experience, ARDS continues to pose a substantial threat and no definitive therapy has yet to be described. We will present an overview of management options.

Cifosis lumbar congénita en pacientes con mielomeningocele / Congenital lumbar kyphosis in patients with myelomeningocele

Se propone el tratamiento quirúrgico precoz en la cifosis lumbar congénita de pacientes con mielomeningocele por medio de la técnica de Hall, sugiriendo el tercer o cuarto año de vida como la edad ideal para la cirugía. Se presenta la evolución alejada de 3 pacientes tratados con dicha técnica

Cifosis lumbar congénita en pacientes con mielomeningocele / Congenital lumbar kyphosis in patients with myelomeningocele

Se propone el tratamiento quirúrgico precoz en la cifosis lumbar congénita de pacientes con mielomeningocele por medio de la técnica de Hall, sugiriendo el tercer o cuarto año de vida como la edad ideal para la cirugía. Se presenta la evolución alejada de 3 pacientes tratados con dicha técnica