Associations of Plasma Nitrite, l-Arginine and Asymmetric Dimethylarginine With Morbidity and Mortality in Patients With Necrotizing Soft Tissue Infections

Hansen, Marco Bo; Rasmussen, Lars S.; Garred, Peter; Pilely, Katrine; Wahl, Anna Mygind; Perner, Anders; Madsen, Martin Bruun; Hedegaard, Elise Røge; Simonsen, Ulf; Hyldegaard, Ole

doi:10.1097/shk.0000000000000975

Cited by 12 publications

(9 citation statements)

References 44 publications

(50 reference statements)

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“…Previous reports have demonstrated high baseline nitrite and nitrate levels in patients with NSTI. 61 A theoretical explanation for the absence of a nitrite+nitrate response in our cohort could be that nitric oxide synthase systems were already highly expressed at baseline.…”

Section: Original Researchmentioning

confidence: 88%

Hyperbaric oxygen treatment impacts oxidative stress markers in patients with necrotizing soft-tissue infection

Hedetoft

Jensen

Moser

et al. 2021

Journal of Investigative Medicine

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Necrotizing soft-tissue infection (NSTI) is a rare, severe, and fast-progressing bacterial infection associated with a high risk of developing sepsis or septic shock. Increasing evidence indicates that oxidative stress is crucial in the development and progression of sepsis, but its role in NSTI specifically has not been investigated. Some patients with NSTI receive hyperbaric oxygen (HBO2) treatment as the restoration of oxidative stress balance is considered an important mechanism of action, which HBO2 facilitates. However, a gap in knowledge exists regarding the effect of HBO2 treatment on oxidative stress in patients with NSTI. In the present observational study, we aimed to investigate HBO2 treatment effects on known markers of oxidative stress in patients with NSTI. We measured plasma myeloperoxidase (MPO), superoxide dismutase (SOD), heme oxygenase-1 (HO-1) and nitrite+nitrate in 80 patients with NSTI immediately before and after their first HBO2 treatment, and on the following day. We found that HBO2 treatment was associated with a significant increase in MPO and SOD by a median of 3.4 and 8.8 ng/mL, respectively. Moreover, we observed an HBO2 treatment-associated increase in HO-1 in patients presenting with septic shock (n=39) by a median of 301.3 pg/mL. All markers were significantly higher in patients presenting with septic shock compared to patients without shock, and all markers correlated with disease severity. High baseline SOD was associated with 90-day mortality. In conclusion, HBO2 treatment was associated with an increase in MPO and SOD in patients with NSTI, and oxidative stress was more pronounced in patients with septic shock.

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Section: Original Researchmentioning

confidence: 88%

Hyperbaric oxygen treatment impacts oxidative stress markers in patients with necrotizing soft-tissue infection

Hedetoft

Jensen

Moser

et al. 2021

Journal of Investigative Medicine

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“…The development of rapid diagnostic tools for NSTI, such as levels of disease-associated biomarkers, to support clinical decisions could increase the accuracy of early diagnosis, leading to swifter surgical exploration and treatment only when clinically indicated. However, to date, there are only a few studies of molecular biomarkers in NSTIs (22,(28)(29)(30)(31)(32), and these are limited to analyses of only a few markers. The comprehensive multiplex analysis of 36 analytes conducted here revealed, as expected, a greater systemic inflammatory response in NSTI patients than in noninfected patients (surgical controls).…”

Section: Discussionmentioning

confidence: 99%

Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections

Medina¹,

Rath²,

Jahagirdar³

et al. 2021

Journal of Clinical Investigation

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These infections are infrequent, but are associated with a significant health burden due to high mortality and risk of severe long-term disability as a consequence of extensive tissue loss or amputations (3)(4)(5). The progression of the disease is rapid, and early identification is therefore pivotal for improving the prognosis of affected patients. Currently, the initial diagnosis of NSTI is challenging due to the often vague symptoms during early stages, a heterogeneous patient group, and lack of specific diagnostic tools (6), which lead to misdiagnoses of NSTI in many cases (7). Still, doctors are advised that in case of NSTI suspicion, patients should be referred to surgical evaluation immediately (8). Previous efforts to improve the diagnosis of NSTIs led to the proposal of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) CONCLUSIONS. This study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01790698.

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“…The pathological activities of ADMA are particularly relevant to sepsis. Multiple studies have shown that high concentrations of ADMA are present in the blood of sepsis patients [26][27][28][29][30][31][32][33][34]. More importantly, ADMA levels in patients with sepsis correlate with disease severity (higher in septic shock) and mortality [26,30,33].…”

Section: Adma Levels and Sepsis Mortalitymentioning

confidence: 99%

A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach

2022

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The nitric oxide pathway plays a critical role in vascular homeostasis. Increased levels of systemic nitric oxide (NO) are observed in preclinical models of sepsis and endotoxemia. This has led to the postulation that vasodilation by inducible nitric oxide synthase (iNOS) generated NO may be a mechanism of hypotension in sepsis. However, contrary to the expected pharmacological action of a nitric oxide synthase (NOS) inhibitor, clinical studies with L-NAME produced adverse cardiac and pulmonary events, and higher mortality in sepsis patients. Thus, the potential adverse effects of NO in human sepsis and shock have not been fully established. In recent years, the emerging new understanding of the NO pathway has shown that an endogenously produced inhibitor of NOS, asymmetric dimethylarginine (ADMA), a host response to infection, may play an important role in the pathophysiology of sepsis as well as organ damage during ischemia–reperfusion. ADMA induces microvascular dysfunction, proinflammatory and prothrombotic state in endothelium, release of inflammatory cytokines, oxidative stress and mitochondrial dysfunction. High levels of ADMA exist in sepsis patients, which may produce adverse effects like those observed with L-NAME. Several studies have demonstrated the association of plasma ADMA levels with mortality in sepsis patients. Preclinical studies in sepsis and ischemia–reperfusion animal models have shown that lowering of ADMA reduced organ damage and improved survival. The clinical finding with L-NAME and the preclinical research on ADMA “bed to bench” suggest that ADMA lowering could be a potential therapeutic approach to attenuate progressive organ damage and mortality in sepsis. Testing of this approach is now feasible by using the pharmacological molecules that specifically lower ADMA.

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Associations of Plasma Nitrite, l-Arginine and Asymmetric Dimethylarginine With Morbidity and Mortality in Patients With Necrotizing Soft Tissue Infections

Cited by 12 publications

References 44 publications

Hyperbaric oxygen treatment impacts oxidative stress markers in patients with necrotizing soft-tissue infection

Hyperbaric oxygen treatment impacts oxidative stress markers in patients with necrotizing soft-tissue infection

Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections

A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach

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