Veno-venous extracorporeal blood phototherapy increases the rate of carbon monoxide (CO) elimination in CO-poisoned pigs.

BACKGROUND AND OBJECTIVES: Carbon monoxide (CO) inhalation is the leading cause of poison-related deaths in the United States. CO binds to hemoglobin (Hb), displaces oxygen, and reduces oxygen delivery to tissues. The optimal treatment for CO poisoning in patients with normal lung function is the administration of hyperbaric oxygen (HBO). However, hyperbaric chambers are only available in medical centers with specialized equipment, resulting in delayed therapy. Visible light dissociates CO from Hb with minimal effect on oxygen binding. In a previous study, we combined a membrane oxygenator with phototherapy at 623 nm to produce a "mini" photo-ECMO (extracorporeal membrane oxygenation) device, which improved CO elimination and survival in CO-poisoned rats. The objective of this study was to develop a larger photo-ECMO device ("maxi" photo-ECMO) and to test its ability to remove CO from a porcine model of CO poisoning. STUDY DESIGN/MATERIALS AND METHODS: The "maxi" photo-ECMO device and the photo-ECMO system (six maxi photo-ECMO devices assembled in parallel), were tested in an in vitro circuit of CO poisoning. To assess the ability of the photo-ECMO device and the photo-ECMO system to remove CO from CO-poisoned blood in vitro, the half-life of COHb (COHb-t1/2 ), as well as the percent COHb reduction in a single blood pass through the device, were assessed. In the in vivo studies, we assessed the COHb-t1/2 in a CO-poisoned pig under three conditions: (1) While the pig breathed 100% oxygen through the endotracheal tube; (2) while the pig was connected to the photo-ECMO system with no light exposure; and (3) while the pig was connected to the photo-ECMO system, which was exposed to red light. RESULTS: The photo-ECMO device was able to fully oxygenate the blood after a single pass through the device. Compared to ventilation with 100% oxygen alone, illumination with red light together with 100% oxygen was twice as efficient in removing CO from blood. Changes in gas flow rates did not alter CO elimination in one pass through the device. Increases in irradiance up to 214 mW/cm2 were associated with an increased rate of CO elimination. The photo-ECMO device was effective over a range of blood flow rates and with higher blood flow rates, more CO was eliminated. A photo-ECMO system composed of six photo-ECMO devices removed CO faster from CO-poisoned blood than a single photo-ECMO device. In a CO-poisoned pig, the photo-ECMO system increased the rate of CO elimination without significantly increasing the animal's body temperature or causing hemodynamic instability. CONCLUSION: In this study, we developed a photo-ECMO system and demonstrated its ability to remove CO from CO-poisoned 45-kg pigs. Technical modifications of the photo-ECMO system, including the development of a compact, portable device, will permit treatment of patients with CO poisoning at the scene of their poisoning, during transit to a local emergency room, and in hospitals that lack HBO facilities.

Real-time urinary electrolyte monitoring after furosemide administration in surgical ICU patients with normal renal function.

BACKGROUND: Although the loop-diuretic furosemide is widely employed in critically ill patients with known long-term effects on plasma electrolytes, accurate data describing its acute effects on renal electrolyte handling and the generation of plasma electrolyte alterations are lacking. We hypothesized that the long-term effects of furosemide on plasma electrolytes and acid-base depend on its immediate effects on electrolyte excretion rate and patient clinical baseline characteristics. By monitoring urinary electrolytes quasi-continuously, we aimed to verify this hypothesis in a cohort of surgical ICU patients with normal renal function. METHODS: We retrospectively enrolled 39 consecutive patients admitted to a postoperative ICU after major surgery, and receiving single low-dose intravenous administration of furosemide. Urinary output, pH, sodium [Na(+)], potassium [K(+)], chloride [Cl(-)] and ammonium [NH4 (+)] concentrations were measured every 10 min for three to 8 h. Urinary anion gap (AG), electrolyte excretion rate, fractional excretion (Fe) and time constant of urinary [Na(+)] variation (τNa(+)) were calculated. RESULTS: Ten minutes after furosemide administration (12 ± 5 mg), urinary [Na(+)] and [Cl(-)], and their excretion rates, increased to similar levels (P < 0.001). After the first hour, urinary [Cl(-)] decreased less rapidly than [Na(+)], leading to a reduction in urinary AG and pH and an increment in urinary [NH4 (+)] (P < 0.001). Median urinary [Cl(-)] over the first 3-h period was higher than baseline urinary and plasmatic [Cl(-)] (P < 0.001). During the first 2 h, difference between FeCl(-) and FeNa(+) increased (P < 0.05). Baseline higher values of central venous pressure and FeNa(+) were associated with greater increases in FeNa(+) after furosemide (P = 0.03 and P = 0.007), whereas higher values of mean arterial and central venous pressures were associated with a longer τNa(+) (P < 0.05). In patients receiving multiple administrations (n = 11), arterial pH, base excess and strong ion difference increased, due to a decrease in plasmatic [Cl(-)]. CONCLUSIONS: Low-dose furosemide administration immediately modifies urinary electrolyte excretion rates, likely in relation to the ongoing proximal tubular activity, unveiled by its inhibitory action on Henle's loop. Such effects, when cumulative, found the bases for the long-term alterations observed. Real-time urinary electrolyte monitoring may help in tailoring patient diuretic and hemodynamic therapies.

Hypoxia as a therapy for mitochondrial disease.

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.