Effects of inorganic nitrate on ischaemia-reperfusion injury after coronary artery bypass surgery: a randomised controlled trial.

BACKGROUND: Nitric oxide (NO) is an important signalling molecule in the cardiovascular system with protective properties in ischaemia-reperfusion injury. Inorganic nitrate, an oxidation product of endogenous NO production and a constituent in our diet, can be recycled back to bioactive NO. We investigated if preoperative administration of inorganic nitrate could reduce troponin T release and other plasma markers of injury to the heart, liver, kidney, and brain in patients undergoing cardiac surgery. METHODS: This single-centre, randomised, double-blind, placebo-controlled trial included 82 patients undergoing coronary artery bypass surgery with cardiopulmonary bypass. Oral sodium nitrate (700 mg×2) or placebo (NaCl) were administered before surgery. Biomarkers of ischaemia-reperfusion injury and plasma nitrate and nitrite were collected before and up to 72 h after surgery. Troponin T release was our predefined primary endpoint and biomarkers of renal, liver, and brain injury were secondary endpoints. RESULTS: Plasma concentrations of nitrate and nitrite were elevated in nitrate-treated patients compared with placebo. The 72-h release of troponin T did not differ between groups. Other plasma biomarkers of organ injury were also similar between groups. Blood loss was not a predefined outcome parameter, but perioperative bleeding was 18% less in nitrate-treated patients compared with controls. CONCLUSION: Preoperative administration of inorganic nitrate did not influence troponin T release or other plasma biomarkers of organ injury in cardiac surgery. CLINICAL TRIAL REGISTRATION: NCT01348971.

Organ uptake and release of inorganic nitrate and nitrite in the pig.

Numerous studies have shown beneficial cardiovascular and metabolic effects of dietary nitrate but the release or uptake of these anions on an organ level is still poorly elucidated. Here we administered sodium nitrate in the pig and measured acute changes in release/uptake of nitrate and nitrite across several organs as well as cardiovascular and metabolic functions. In 17 anesthetized pigs multiple venous catheters and arterial ultrasonic blood flow probes were positioned. After pretreatment with the NO synthase (NOS) inhibitor l-NAME to minimize involvement of NOS-dependent nitrate/nitrite generation, the animals received bolus injections of either sodium nitrate or sodium chloride. Organ blood flows and release/uptake of nitrate and nitrite were measured in the pulmonary, splanchnic, hepatic and renal circulations for up to two hours. In addition, small intestinal luminal NO, gut secretion of nitrate, as well as hepatic and renal NADPH oxidase activity were measured. At baseline there was a significant uptake of nitrite in the liver and kidneys together with a release of nitrite from the lungs. In the control pigs, arterial plasma nitrite progressively declined during the observation period (-54%) but was stable in the nitrate group, indicating conversion of nitrate to nitrite. Sodium nitrate led to a marked accumulation of nitrate in the small intestinal lumen with a parallel increase in luminal nitrite. This was coupled with release of nitrite in the portal vein and a concomitant uptake of this anion in the liver. There was a trend towards reduced NADPH oxidase-dependent superoxide generation in the liver but an increase in the kidney. Nitrate had no acute effects on cardiovascular parameters or regional and systemic oxygen consumption. In conclusion, we found a notable difference in release and uptake of nitrate and nitrite between the organs investigated. Our findings indicate an acute conversion of nitrate to nitrite, most likely independent of oral bacteria but by a mammalian nitrate reductase and/or gut bacteria.

Continuous renal replacement therapy in intensive care patients with COVID-19; survival and renal recovery.

BACKGROUND: Outcome for critically ill patients with COVID-19 treated with continuous renal replacement therapy (CRRT) is largely unknown. We describe mortality and renal outcome in this group. METHODS: This observational study was conducted at a university hospital in Sweden. We studied critically ill adult COVID-19 patients with Acute Kidney injury (AKI) who received CRRT. RESULTS: In 451 patients, AKI incidence was 43.7%. 18.2% received CRRT. Median age of CRRT patients was 60 years (IQR 54-65), 90% were male, median BMI was 29 (IQR 25-32), 23.2% had Diabetes, 37.8% hypertension and 6.1% chronic kidney disease prior to admission. 100% required mechanical ventilation. 8.5% received Extra Corporeal Membrane Oxygenation. Median length of stay was 23 days (IQR 15-26). ICU mortality was 39% and 90-day mortality was 45.1%. Age, baseline creatinine values and body weight change were associated with 60 days mortality. Of the survivors, no patients required dialysis at hospital discharge, 73.8% recovered renal function and a median 10.5% of body weight was lost during admission. CONCLUSIONS: Critically ill COVID-19 patients with AKI who received CRRT had a 90-day mortality of 45.1%. At follow-up, three quarters of survivors had recovered renal function. This information is important in the clinical management of COVID-19.