A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure.

Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors' biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.

Central deficiency of norepinephrine synthesis and norepinephrinergic neurotransmission contributes to seizure-induced respiratory arrest.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with intractable epilepsy. However, the pathogenesis of SUDEP seems to be poorly understood. Our previous findings showed that the incidence of seizure-induced respiratory arrest (S-IRA) was markedly reduced by atomoxetine in a murine SUDEP model. Because the central norepinephrine α-1 receptor (NEα-1R) plays a vital role in regulating respiratory function, we hypothesized that the suppression of S-IRA by atomoxetine was mediated by NE/NEα-1R interactions that can be reversed by NEα-1R antagonism. We examined whether atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 mice can be reversed by intraperitoneal (IP) and intracerebroventricular (ICV) administration of prazosin, a selective antagonist of NEα-1R. The content and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, in the lower brainstem was measured by ELISA. Electroencephalograms (EEG) were obtained from using the PTZ-evoked SUDEP model. In our models, atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or PTZ was significantly reversed by low doses of IP and ICV prazosin. Neither repetitive acoustic stimulation nor S-IRA reduced TH levels in lower brainstem. However, the enzyme activity of TH levels in lower brainstem was significantly increased by mechanical ventilation with DBA/1 mice, which makes the dying DBA/1 mice suffering from S-IRA and SUDEP recover. EEG data showed that although the protective effect of atomoxetine was reversed by prazosin, neither drug suppressed EEG activity. These data suggest that deficient synthesis of NE and norepinephrinergic neurotransmission contributed to S-IRA and that the NEα-1R is a potential therapeutic target for the prevention of SUDEP.

Influence of Herbal Medicines on HMGB1 Release, SARS-CoV-2 Viral Attachment, Acute Respiratory Failure, and Sepsis. A Literature Review.

By attaching to the angiotensin converting enzyme 2 (ACE2) protein on lung and intestinal cells, Sudden Acute Respiratory Syndrome (SARS-CoV-2) can cause respiratory and homeostatic difficulties leading to sepsis. The progression from acute respiratory failure to sepsis has been correlated with the release of high-mobility group box 1 protein (HMGB1). Lack of effective conventional treatment of this septic state has spiked an interest in alternative medicine. This review of herbal extracts has identified multiple candidates which can target the release of HMGB1 and potentially reduce mortality by preventing progression from respiratory distress to sepsis. Some of the identified mixtures have also been shown to interfere with viral attachment. Due to the wide variability in chemical superstructure of the components of assorted herbal extracts, common motifs have been identified. Looking at the most active compounds in each extract it becomes evident that as a group, phenolic compounds have a broad enzyme inhibiting function. They have been shown to act against the priming of SARS-CoV-2 attachment proteins by host and viral enzymes, and the release of HMGB1 by host immune cells. An argument for the value in a nonspecific inhibitory action has been drawn. Hopefully these findings can drive future drug development and clinical procedures.

[Role of Notch-Jagged/Delta signaling pathway in arthritis rats of reduced lung function induced by adjuvant].

OBJECTIVE: To observe the changes of pulmonary function and Notch signaling pathway of lung tissues in adjuvant-induced arthritis rats, and to investigate the mechanism of reduced lung function. METHODS: A total of 30 rats were randomly divided into a normal group and a model group. Rats in the model group were induced to establish the adjuvant arthritis AA model by intradermally injecting 0.1 mL Freund's complete adjuvant into the right paw. After 30 days, we observed the paw edema volume, arthritis index, pulmonary function, histomorphology, and Notch receptor/ligand of the lung tissue. RESULTS: Compared with the normal group, the paw edema volume, arthritis index, average expiratory flow within 0.3 s (FEV0.3/FVC), and the level of Notch3, Notch4 and Jagged2 of the lung tissue in the model group was significantly increased, while maximum expiratory flow at 50% of vital capacity (FEF50), maximum expiratory flow at 75% of vital capacity (FEF75), forced expiratory flow (PEF) and the expression of Notch1 of Jagged1 and Delta1 in the lung were significantly decreased (P<0.05, P<0.01). There were significant positive correlations between FEV0.3/FVC and Notch4. FEV0.3/FVC, FEF25, FEF50 and Notch3, Delta1 were negatively correlated, respectively (P<0.05, P<0.01). CONCLUSION: While arthritis occurs in AA rats, pulmonary function declines and significantly correlates with the expression of Notch receptor/ligand. The deposition of immune complex in the lung after the injection of CFA activates the Notch signaling pathway, and results in further decline of pulmonary function by signaling cascades.

Vitamin D deficiency in patients with neuromuscular diseases with chronic respiratory failure.

BACKGROUND: The prevalence and clinical implications of vitamin D deficiency have never been studied in patients with underlying neuromuscular diseases complicated with chronic respiratory failure. The aim of this study is to demonstrate the prevalence of vitamin D deficiency, its relationship with other bone markers, and mode of nutrition. MATERIALS AND METHODS: Serum 25-hydroxyvitamin D (25[OH]D) levels along with calcium, serum albumin, and phosphorus levels were obtained from 57 patients with chronic respiratory failure due to underlying neuromuscular diseases. These levels were obtained during their first visit to a chronic respiratory diseases clinic. Data with regard to nutrition, respiratory muscle function, and level of mobility were also obtained at the same time. RESULTS: Seventy-five percent of patients had serum 25(OH)D levels ≤ 30 ng/mL. There is a negative correlation between parathyroid hormone and 25(OH)D levels (P = .006) and corrected calcium levels (P = .066). Serum 25(OH)D levels varied with the mode of nutrition. Patients on enteral nutrition had the highest serum levels of 25(OH)D, whereas combined oral and tube feeds had the lowest 25(OH)D levels (P = .006). CONCLUSION: Low serum 25(OH)D levels are highly prevalent in patients with neuromuscular disease and chronic respiratory failure. The route of nutrition has an impact on these levels.

Effects of high-dose mucosolvin on lung functions in infant patients with cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass may cause serious impairment of lung function. It has been reported that administration of mucosolvin can prevent acute respiratory insufficiency through the improvement of pulmonary surfactant. OBJECTIVES: This study aimed to explore the effects of high-dose mucosolvin on infant lungs following cardiopulmonary bypass. METHODS: One hundred infants were randomly divided into 2 groups. In Group 1, patients did not receive any respiratory drug perioperatively and underwent conventional mechanical ventilation postoperatively. In Group 2, patients were administered mucosolvin (15 mg/kg per day) perioperatively, and doxofylline (15 mg/kg per day) and ipratropium bromide solution (200 µg) were administrated postoperatively. Mechanical ventilation parameters, pulmonary surfactant-related protein (SP-B), and cytokines were evaluated after induction of anesthesia and 30 minutes, 24 hours, and 48 hours after CPB. RESULTS: At the end of CPB, all PaO2/FiO2 values in Group 2 were higher than those in Group 1. Postoperative SP-B levels in Group 1 decreased significantly compared to the baseline value (P < .05). There was no significant difference in hospitalization time between both groups, but both mechanical ventilation time and intensive care unit time of infants in Group 2 were significantly shorter than those in group 1 (P < .05). CONCLUSIONS: These findings indicate that high-dose mucosolvin has certain protective effects on respiratory functions in infants undergoing heart operations with CPB and that it that has no adverse effects.

Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy.

Adult-onset acid maltase deficiency is an inherited lysosomal skeletal-muscle disease characterized by progressive myopathy and respiratory failure, for which there is no known therapy. In an uncontrolled, prospective study, we evaluated whether adherence to high-protein and low-carbohydrate nutrition and exercise therapy (NET) can slow the progressive deterioration of muscle function in this disease. Thirty-four patients have been treated with NET for periods of 2-10 years (mean 4.5 +/- 2.5). Pre-NET rate of muscle function deterioration, as measured by the Walton scale, was compared to post-NET rate. Twenty-six patients were deemed to be consistently compliant with NET. Difference between pre-NET slope of muscle function deterioration to that of post-NET slope in compliant patients was -0.29 (95% CI -0.19, 0.39) (P < 0.0001). We conclude that compliance with NET can slow deterioration of muscle function and improve the natural history of adult-onset acid maltase deficiency. Muscle Nerve, 2006.

Functional magnetic ventilation in dogs.

OBJECTIVE: To investigate the efficacy of the magnetic stimulation of inspiratory muscles as an alternative to mechanical ventilation and functional electric stimulation. DESIGN: A prospective before-after trial. SETTING: Functional magnetic stimulation laboratory in a Veterans Administration health care system. ANIMALS: Six male mongrel dogs, each weighing between 25 and 35 kg. INTERVENTIONS: Commercially available magnetic stimulators with a round magnetic coil were used. The center of the magnetic coil was placed posteriorly over the C5-7 vertebrae of the spinal cord transected dogs. Magnetic stimulation parameters were set at 80% intensity, 20 Hz, and a 1.2-second on and 3.8-second off pulse train. MAIN OUTCOME MEASURES: The major outcomes were changes in tidal volume (VT), tracheal pressure (Ptr), and arterial partial pressure of carbon dioxide (PaCO2) and oxygen sustained by magnetic stimulation over time. RESULTS: The average Vt and Ptr produced during functional magnetic ventilation (FMV) were.47+/-.07 L and -4.7+/-.51 cmH2O, respectively. Blood gas data showed that PaCO2 increased from a baseline of 33 to 75 mmHg, whereas pH decreased from 7.33 to 6.99 at the end of the 1-hour FMV period. CONCLUSIONS: FMV was achieved for 2 hours in dogs with C2 spinal cord transection. Additional refinements in magnetic stimulation are needed to improve ventilation in animals.

The effect of hypoxaemia on drug disposition in chronic respiratory failure.

OBJECTIVE: The influence of hypoxaemia on the disposition of two common drugs has been examined in ten adults with stable chronic respiratory failure. METHODS: There were two experimental periods in this cross-over study: during these periods supplemental oxygen was either withheld or administered to impose clinical hypoxaemia or maintain normoxaemia, respectively. Each participant received either oral (40 mg) or intravenous (20 mg) frusemide combined with oral paracetamol (500 mg) on consecutive days of the two experimental periods. RESULTS: The total (bound plus unbound) plasma clearance of frusemide during hypoxaemia (arterial oxygen tension, PaO2 < or = 50 Torr) was not significantly different from the value during normoxaemia (PaO2 > or = 60 Torr) [76.9 and 62.4 ml.min-1]. The volume of distribution was not affected by acute hypoxaemia (121 ml.kg-1 without and 109 ml.kg-1 with oxygen; P > 0.05). Renal and non-renal clearances of frusemide were similar during the period of hypoxaemia (31 and 38 ml.min-1, respectively) compared to respective values during supplemental oxygen delivery (29 and 32 ml.min-1). The absolute bioavailability of frusemide during hypoxaemia (0.62) was not different to that obtained during normoxaemia (0.56). The combined sodium and potassium excretion rate (expressed as a function of the frusemide excretion rate) was not altered by changing the oxygen tension. The pharmacokinetics of paracetamol were unaffected by hypoxaemia.

[Effect of postoperative complications on nutritional status: therapeutic consequences]. / Retentissement des complications postopératoires sur l'état nutritionnel: conséquences thérapeutiques.

The occurrence of a postoperative complication represents an additional stress factor for patients and leads in many cases rapidly to a malnutrition status. Thus a nutritional support is required as soon as the foreseeable duration of starvation has a longer duration than one week. Considering its lower risk of septic complications and lower cost, enteral feeding should be initiated as soon as possible. Appraisal of caloric needs with standard formulas often leads to inappropriate nutritional management. Therefore the requirements should be assessed by indirect calorimetry if available. Nutritional support is a part of the management of a postoperative septic patient. It must be initiated when initial phase of haemodynamic instability is amended. Branched chain amino acids, medium chain triglycerides and other specific nutrients have failed to demonstrate a real clinical beneficial effect. In case of acute respiratory failure, nutritional support must be cautious with regard to caloric load, as carbohydrates may increase CO2 production and lipids may worsen hypoxaemia. In case of postoperative acute renal failure, nutritional management is facilitated by continuous haemofiltration techniques allowing an unlimited nutrient intake. Solutions containing only essential amino acids are not recommended. During severe acute pancreatitis, enteral feeding is indicated when ileus does not permit the use of the intestinal tract. Jejunal access must be preferred to stomach or duodenum. Lipid emulsions can be used safely if serum triglyceride concentrations remain below 4 g.L-1 during infusion and below 2 g.L-1 between infusions.

Hypophosphatemia and phosphorus depletion in respiratory and peripheral muscles of patients with respiratory failure due to COPD.

In 22 patients (19 men, 3 women; mean [+/- SD] age, 63 +/- 6 years) with chronic obstructive pulmonary disease (COPD), phosphorus content was measured by spectrophotometric methods on muscle fragments of both peripheral (quadriceps femoris needle biopsy in 22 patients) and respiratory muscles (external intercostal muscle surgical biopsy in 14 patients). Thirty age- and sex-matched subjects were used as controls (19 for quadriceps femoris muscle biopsy and 11 for intercostal muscle biopsy). Serum phosphorus levels, as well as the main determinants of overall phosphorus metabolism (dietary intake of phosphorus and renal phosphate handling), were also obtained in all patients and control subjects. Muscle phosphorus content of both respiratory and peripheral muscles was significantly reduced in the COPD patient group, no matter what reference index was used (fat-free dry muscle weight or muscle fragment DNA content); muscle phosphorus depletion was present in about 50 percent of patients with COPD. In the same patient group, a significant relationship between muscle and serum phosphorus levels was demonstrable in the case of peripheral muscles only. No relationship was found between phosphorus content of both types of skeletal muscles and dietary phosphorus intake levels or with nutritional status, even though patients with COPD had significantly reduced anthropometric, biochemical, and immunologic indices as compared with controls. Renal phosphorus handling indices of the COPD patient group were compatible with a condition of inadequacy of the renal compensatory mechanism to hypophosphatemia and phosphorus depletion (low percent tubular reabsorption of phosphorus, low renal threshold concentration values). Our study suggests that phosphorus depletion occurs frequently in COPD, but in this clinical condition serum phosphorus levels are not representative of cellular phosphorus levels. Phosphorus depletion, which is equally severe in respiratory and peripheral muscles, could depend, at least in part, on malnutrition and a condition of renal phosphorus wasting possibly linked to some drugs commonly used in patients with COPD (xanthine derivatives, diuretics, etc).

Skeletal muscle metabolism during exercise and recovery in patients with respiratory failure.

BACKGROUND: Patients with respiratory failure have early fatiguability which may be due to limitation of oxygen supply for oxidative (mitochondrial) ATP synthesis. Skeletal muscle in exercise and recovery was studied to examine the effect of chronic hypoxia on mitochondrial activity in vivo. METHODS: The skeletal muscle of five patients with respiratory failure (PaO2 < 9 kPa) was studied by phosphorus-31 magnetic resonance spectroscopy and compared with 10 age and sex matched controls. Patients lay in a 1.9 Tesla superconducting magnet with the gastrocnemius muscle overlying a six cm surface coil. Spectra were acquired at rest, during plantar flexion exercise, and during recovery from exercise. Relative concentrations of inorganic phosphate (Pi), phosphocreatine (PCr) and ATP were measured from peak areas, and pH and free ADP concentration were calculated. For the start of exercise, the rates of PCr depletion and estimated lactic acid production were calculated. For the post exercise recovery period, the initial rate of PCr recovery (a quantitative measure of mitochondrial ATP synthesis), the apparent Vmax for mitochondrial ATP synthesis (calculated from initial PCr resynthesis and the end exercise ADP concentration which drives this process), and the recovery half times of PCr, Pi, and ADP (also measures of mitochondrial function) were determined. RESULTS: Considerably greater and faster PCr depletion and intracellular acidosis were found during exercise. This is consistent with limitation of oxygen supply to the muscle and might explain the early fatiguability of these patients. There was no abnormality in recovery from exercise, however, suggesting that mitochondria function normally after exercise. CONCLUSIONS: These results are consistent with one or more of the following: (a) decreased level of activity of these patients; (b) changes in the fibre type of the muscle; (c) decreased oxygen supply to the muscle during exercise but not during recovery. They are not consistent with an intrinsic defect of mitochondrial ATP synthesis in skeletal muscle in respiratory failure.

[Calcium and phosphorus levels in serum and urine of patients with chronic cor pulmonale complicated with respiratory insufficiency].

The levels of Ca and P in serum and urine, and the renal functions: Ccr. TRCa and TRP were determined in 43 patients with chronic Cor Pulmonale complicated with respiratory insufficiency. The results showed that the level of SCa decreased in 72.1% (31/43) and after correction by serum protein 58.1% (25/43). The SP was normal in 60.5%, (26/43). UCa and UP reduced in 62.8% (27/43) and 88.4% (38/43) respectively.

Regional distribution of neuropeptide Y-like immunoreactivity in human hypothalamus measured by immunoradiometric assay: possible influence of chronic respiratory failure on tissue levels.

The regional distribution of neuropeptide Y-like immunoreactivity (NPY-IR) in the human hypothalamus has been determined using a highly specific immunoradiometric assay. Hypothalami were removed during postmortem examination from 19 subjects. The pituitary stalk and 11 anatomically defined nuclei and areas were microdissected from one or both sides of each hypothalamus. NPY-IR was detectable in the acid extracts of tissue samples prepared from all the hypothalamic regions studied, with the highest concentrations being found in the infundibular nucleus (325 +/- 53 fmol/mg wet weight of tissue) and the ventromedial nucleus (217 +/- 22 fmol/mg). For the 11 subjects where both sides of the hypothalamus were dissected, values obtained for the areas in one half showed a good degree of symmetry with the corresponding areas on the contralateral side. The infundibular nucleus exhibited the greatest range of values (72-1,137 fmol/mg). Interestingly, variations in other parts of the hypothalamus were observed to parallel those of this nucleus. Expressed as correlation coefficients (r), levels in the infundibular nucleus appeared to be most closely related to those of the ventromedial nucleus (VM; r = 0.89) and paraventricular nucleus (PV; r = 0.84). In addition, retrospective analysis of the clinical histories showed that all patients with very high NPY levels in the infundibular nucleus (621.0 +/- 107.7 fmol/mg; n = 8) had suffered from respiratory failure or severe dyspnea of at least 10 days duration prior to death. The remaining patients (166.7 +/- 17.1 fmol/mg; n = 11) had either died 48 h from the onset of cardiorespiratory difficulties or of unrelated causes.(ABSTRACT TRUNCATED AT 250 WORDS)

Central nervous system glucose utilization rate during oxygen-induced respiratory changes at 2 atmospheres oxygen in the rat.

Hyperbaric oxygenation (HBO) at pressures higher than 3 atmospheres absolute (ATA) primarily affects the CNS, while at lower pressures, the respiratory functions are predominantly changed. Due to the outstanding respiratory manifestations of HBO at pressures lower than 3 ATA O2, the possible overlapping neurological effects of oxygen toxicity may not be easily identified. However, rats exposed for 1 and 4 h to 2 ATA O2 have shown increases in the regional cerebral metabolic rate for glucose (rCMRgl) when neither visible signs of respiratory nor nervous distress were observed. The purpose of the present study was to differentiate between the CNS and the respiratory effects of HBO at 2 ATA during development of the early signs of the respiratory distress. Changes in the rCMRgl measured by [14C]-2-deoxyglucose (2-DG) autoradiographic technique and respiratory frequency (Rf) were used as criteria for determination of CNS and respiratory effects of HBO, respectively. The results demonstrate no differences in the rCMRgl (28 major structures examined) among 3 groups of conscious rats exposed to 2 ATA O2 and normoxia at 1 and 2 ATA. At the same time a significant reduction was found in the Rf of the oxygen-exposed rats. In conclusion the respiratory system at 2 ATA O2 is apparently affected earlier than, and independent from the CNS. However, due to limited resolution power of the [14C]2-DG technique, the effect of HBO on certain undetected central respiratory control centers cannot yet be ruled out.

In vivo time-resolved brain phosphorus nuclear magnetic resonance.

Methods used to obtain and quantify high-quality time-resolved dog brain phosphorus nuclear magnetic resonance (31P NMR) spectra are described. In eight animals the normoxic dog brain spectra showed 10% of total phosphorus in ATP, 14% in phosphocreatine (PCr), and 38% in brain phospholipids containing phosphodiesters. The chemical shift between PCr and inorganic phosphate, 5.09, corresponded to an intracellular brain pH of 7.2. During hypoxia, PCr declined to 0.5 +/- 0.3 (n = 8) of starting levels, prior to any changes in brain ATP. Simultaneous recording of the EEG was obtained in two animals. During hypoxia, progressive PCr depletion was associated with progressive slowing of the EEG, which was essentially silent before significant changes occurred in brain ATP. Finally, the brain 31P NMR spectrum and pH were measured at 90-s intervals, and the sequential changes that followed respiratory arrest were monitored in one dog until high-energy phosphate depletion was complete.