Changes in renal metabolite profile and ammoniagenesis during acute and chronic metabolic acidosis in dog and rat

Acute metabolic acidosis was induced by an i.v. administration of hydrochloric acid to dogs and rats to decrease the plasma bicarbonate concentration from 22 to 12 mM in dogs and from 26 to 10 mM in rats. Chronic metabolic acidosis was also induced in dogs by ammonium chloride feeding for 5 days. Rats also were given ammonium chloride for 24 hours. The renal metabolite profile was determined on the freeze-clamped renal tissue before and after 100 min (dogs) or 30 to 240 min (rats) of acsute acidosis. Measurements on chronically acidotic dogs and rats with 24-hour acidosis were obtained also for comparison with acute acidosis. In both species, kidney glutamine, glutamate, and alpha-ketokglutarate concentrations decreased drastically following induction of acute or chronic acidosis, In the dog, or in the rat during the first 2 hours of acidosis, malate concentration was unchanged. Malate concentration fell significantly in the rat kidney only after 2 hours of acidosis without change in phosphoenolpyruvate (PEP) concentration. In chronically acidotic dogs, malate and oxaloacetate rose fivefold with no change in PEP concentration. Phosphoenolpyruvate carboxykinase (PEPCK) activity was not stimulated by chronic metabolic acidosis in the dog in contrast to the rat. Acute acidosis by hydrochloric acid increased net renal glutamine extraction in the rat but not in the dog. These data suggest that an increased metabolic flux occurs between alpha-ketoglutarate and malate in both rat and dog kidney during acute metabolic acidosis. In the rat, however, after 2 hours, PEPCK activation modifies the kidney metabolite profile. Intrarenal glutamine transport seems to be a rate-limiting factor for adaptation to acute acidosis in the dog but not in the rat kidney.     

Effects of chronic renal insufficiency and metabolic acidosis on glutamine metabolism in man

1. Arterial concentration and arterial-venous differences of glutamine across the kidney, forearm, hepato-splanchnic bed and brain were measured in patients with chronic renal insufficiency and in patients with normally functioning kidneys before and during chronic ammonium chloride acidosis. 2. In chronic renal insufficiency and in chronic metabolic acidosis there is a rise in glutamine release from the muscles and a suppression of glutamine uptake by the hepato-splanchnic bed and the brain. 3. In chronic renal insufficiency arterial glutamine concentrations is significantly increased in comparison with subjects with normal renal function and either normal acid-base balance or chronic metabolic acidosis. 4. In patients with chronic renal insufficiency the kidney extracts negligible amounts of glutamine, which cannot account for the renal ammonia production measured in the same patients.     

Effects of methionine sulphoximine treatment on renal amino acid and ammonia metabolism in rats

Renal glutamine metabolism in relation to ammoniagenesis has been extensively studied during chronic metabolic acidosis, when arterial glutamine levels are reduced. However, little is known about the effects of reduced glutamine delivery on renal glutamine and ammonia metabolism at physiological systemic pH values. Therefore, a model of decreased arterial glutamine concentrations at normal pH values was developed using methionine sulphoximine (MSO). Renal glutamine and ammonia metabolism was measured by determining fluxes and intracellular concentrations after an overnight fast in ether anaesthetized normal rats, MSO-treated rats and their pair-fed controls. Moreover, fluxes and intracellular concentrations of several other amino acids were determined concomitantly. After 2 and 4 days of MSO treatment, arterial glutamine concentrations were reduced to 55%, while arterial ammonia concentrations increased by 70%. Kidney glutamine uptake reduced, but systemic pH was unchanged. Fractional extraction of glutamine remained unchanged, suggesting that also in vivo net uptake of glutamine by the kidney at subnormal levels is related to arterial glutamine concentrations. As a result, at day 2 but not at day 4, the kidney reduced the net release of ammonia into the renal vein and thus reduced net renal ammonia addition to body ammonia pools. Therefore at day 2, the kidney seems to play an important role in adaptation to both hyperammonaemia and hypoglutaminaemia.     

Stimulation of ammonia production and excretion in the rabbit by inorganic phosphate. Study of control mechanisms

The purpose of this study was to clarify the mechanism (s) responsible for regulation of ammonia production and excretion in the rabbit. The normally low ammonia excretion rate during acute metabolic acidosis was stimulated acutely and increased approximately ninefold after infusion of sodium phosphate, but remained low if sodium sulphate or Tris was substituted for phosphate. Ammonia production was increased significantly by phosphate in rabbit renal cortex slices and in isolated renal cortex mitochondria. In isolated mitochondria, mersalyl, an inhibitor of both the phosphate/hydroxyl and phosphate/dicarboxylate mitochondrial carriers, inhibited the phosphate-induced stimulation, indicating that phosphate must enter the mitochondrion for stimulation. A malate/phosphate exchange seemed to be involved since N-ethylmaleimide, an inhibitor of the phosphate/hydroxyl exchange, did not inhibit phosphate-stimulated ammonia production, whereas there was inhibition by 2-n-butylmalonate, a competitive inhibitor of the dicarboxylate carrier. Phosphate itself was not essential since malonate stimulated ammoniagenesis in the absence of added phosphate. Similarly, citrate stimulated ammoniagenesis in isolated mitochondria in the absence of inorganic phosphate provided that it induced L-malate exit on the citrate transporter associated with inhibition of citrate oxidation by fluoroacetate. Similar results were also seen in mitochondria from rat renal cortex. A fall in mitochondrial alpha-ketoglutarate level resulted in an increase in ammonia production. This could be achieved directly with malonate or indirectly via L-malate exit. Simultaneous measurements of glutamate showed that the rate of ammonia production was reciprocally related to the glutamate content. We conclude that phosphate-induced stimulation of ammoniagenesis in the rabbit kidney is mediated by removal of glutamate, the feedback inhibitor of phosphate-dependent glutaminase. Glutamate removal is linked to phosphate-induced dicarboxylate exit across the mitochondrial membrane.     

Acute abdomen masking pyelonephritis (author's transl)

Analysis of 10 case histories shows that the picture of the acute abdomen may predominate in acutely exacerbated pyelonephritis. Viscero-dermal reflexes with hyperalgesia and muscular defense, visero-visceral organ reflexes with shock, vomiting, meteorism and disturbances of intestinal motility and metabolic acidosis are temptations to laparotomy. Fever in particular, pathological urinalysis, renal acidosis and occasionally hyperchloremia suggest the diagnosis of "abdominal type of acutely exacerbated pyelonephritis".     

Endomyocardial biopsies for early detection of mitochondrial disorders in hypertrophic cardiomyopathies

An early response to metabolic acidosis is an increase in the degradation of muscle protein to provide the nitrogen needed to increase glutamine production so the kidney can excrete acid. In patients with renal insufficiency, this process may represent an example of a trade-off adaptation to uremia. It requires a hormone (glucocorticoids) and the metabolic response is maladaptive because the inability of the damaged kidney to maintain acid-base balance results in loss of muscle protein. Studies of cultured cells and rats and humans with normal kidneys demonstrate that acidosis stimulates the degradation of both amino acids and protein, which would block the normal adaptive responses to a low-protein diet (ie, to reduce the degradation of essential amino acids and protein). Evidence from studies in rats and humans with chronic uremia show that acidosis is a major stimulus for catabolism. The mechanism includes stimulation of specific pathways for the degradation of protein and amino acids. Since other catabolic conditions (eg, starvation) appear to stimulate the same pathways, understanding the mechanism in acidosis could be applicable to other conditions. Thus, the loss of lean body mass in uremia appears to be a consequence of a normal metabolic response that persists until acidosis is corrected.     

Adenosine triphosphate citrate lyase mediates hypocitraturia in rats

Chronic metabolic acidosis increases proximal tubular citrate uptake and metabolism. The present study addressed the effect of chronic metabolic acidosis on a cytosolic enzyme of citrate metabolism, ATP citrate lyase. Chronic metabolic acidosis caused hypocitraturia in rats and increased renal cortical ATP citrate lyase activity by 67% after 7 d. Renal cortical ATP citrate lyase protein abundance increased by 29% after 3 d and by 141% after 7 d of acid diet. No significant change in mRNA abundance could be detected. Hypokalemia, which causes only intracellular acidosis, caused hypocitraturia and increased renal cortical ATP citrate lyase activity by 28%. Conversely, the hypercitraturia of chronic alkali feeding was associated with no change in ATP citrate lyase activity. Inhibition of ATP citrate lyase with the competitive inhibitor, 4S-hydroxycitrate, significantly abated hypocitraturia and increased urinary citrate excretion fourfold in chronic metabolic acidosis and threefold in K+-depletion. In summary, the hypocitraturia of chronic metabolic acidosis is associated with an increase in ATP citrate lyase activity and protein abundance, and is partly reversed by inhibition of this enzyme. These results suggest an important role for ATP citrate lyase in proximal tubular citrate metabolism.     

Induction of the c-fos gene in the chick brain during visual imprinting

We describe a patient with combined meningococcal septicemia and meningitis, cerebral edema and acute respiratory distress syndrome, in whom we balanced the conflicting carbon dioxide strategies for optimal pulmonary and neurological management using jugular oxygen saturation (SjvO2) monitoring to identify the upper limit of "tolerable" hypercapnia. Our observations suggest that significant acidosis was not well tolerated; however, cautious induction of pH down to 7.32 and an arterial carbon dioxide tension (PaCO2) < 5.9 kPa was tolerated acutely without significant cerebral hyperemia. Moreover, with the development of metabolic compensation and normal pH, higher levels of PaCO2 could be permitted. In similar cerebro-pulmonary circumstances we suggest that these findings warrant consideration. Alternatively, invasive monitoring of SjvO2 could be undertaken so that patient-specific criteria for permissive hypercapnia can be determined.     

Influence of metabolic acidosis on serum 1,25(OH)2D3 levels in chronic renal failure

Metabolic acidosis has been shown to alter vitamin D metabolism. There is also evidence that calcium may modulate 1,25(OH)2D3 by a parathyroid hormone (PTH)-independent mechanism. To investigate the effect of rapid correction of chronic metabolic acidosis on serum 1,25(OH)2D3 levels by free calcium clamp in chronic renal failure, 20 patients with mild to moderate metabolic acidosis (mean pH 7.31 +/- 0.04) and secondary hyperparathyroidism (mean intact PTH 156.47 +/- 84.20 ng/l) were enrolled in this study. None had yet received any dialysis therapy. Metabolic acidosis was corrected by continuous bicarbonate infusion for 3-4 h until plasma pH was around 7.4, while plasma ionized calcium was held at the preinfusion level by calcium solution infusion during the entire procedure. The plasma pH, bicarbonate, total CO2, sodium, and serum total calcium levels were significantly increased while serum concentrations of alkaline phosphatase and albumin were significantly decreased after bicarbonate infusion. The plasma ionized calcium, potassium, serum magnesium, inorganic phosphorus, and 25(OH)D levels showed no significant change before and after bicarbonate infusion. The serum 1,25(OH)2D3 levels were significantly increased (38.66 +/- 11.77 vs. 47.04 +/- 16.56 pmol/l, p < 0.05) after correction of metabolic acidosis. These results demonstrate that rapid correction of metabolic acidosis raises serum 1,25(OH)2D3 levels in vitamin D-deficient chronic renal failure patients, and may underline the importance of maintaining normal acid-base homeostasis in the presence of secondary hyperparathyroidism in chronic renal failure.     

Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism

Because it is well known that excess branched-chain amino acids (BCAAs) have a profound influence on neurological function, studies were conducted to determine the impact of BCAAs on neuronal and astrocytic metabolism and on trafficking between neurons and astrocytes. The first step in the metabolism of BCAAs is transamination with alpha-ketoglutarate to form the branched-chain alpha-keto acids (BCKAs). The brain is unique in that it expresses two separate branched-chain aminotransferase (BCAT) isoenzymes. One is the common peripheral form [mitochondrial (BCATm)], and the other [cytosolic (BCATc)] is unique to cerebral tissue, placenta, and ovaries. Therefore, attempts were made to define the isoenzymes' spatial distribution and whether they might play separate metabolic roles. Studies were conducted on primary rat brain cell cultures enriched in either astroglia or neurons. The data show that over time BCATm becomes the predominant isoenzyme in astrocyte cultures and that BCATc is prominent in early neuronal cultures. The data also show that gabapentin, a structural analogue of leucine with anticonvulsant properties, is a competitive inhibitor of BCATc but that it does not inhibit BCATm. Metabolic studies indicated that BCAAs promote the efflux of glutamine from astrocytes and that gabapentin can replace leucine as an exchange substrate. Studying astrocyte-enriched cultures in the presence of [U-14C]glutamate we found that BCKAs, but not BCAAs, stimulate glutamate transamination to alpha-ketoglutarate and thus irreversible decarboxylation of glutamate to pyruvate and lactate, thereby promoting glutamate oxidative breakdown. Oxidation of glutamate appeared to be largely dependent on the presence of an alpha-keto acid acceptor for transamination in astrocyte cultures and independent of astrocytic glutamate dehydrogenase activity. The data are discussed in terms of a putative BCAA/BCKA shuttle, where BCATs and BCAAs provide the amino group for glutamate synthesis from alpha-ketoglutarate via BCATm in astrocytes and thereby promote glutamine transfer to neurons, whereas BCATc reaminates the amino acids in neurons for another cycle.     

Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum--a clinicopathologic and immunohistochemical study of 64 cases

Substrate fluxes in response to growth hormone administration depend on both the calorie as well as acid-base balance. Growth hormone's acidogenic action as a consequence of promoting fatty acid utilization yields protons required for driving hepatic glutamate efflux; effective uncoupling of nitrogenous precursors from ureagenesis and recycling as glutamate bound for the periphery appears dependent upon this mechanism. Subsequent peripheral retrieval of the salvaged glutamate requires insulin-like growth factor-1 (IGF-1) activated uptake and acid-base homoeostasis. In addition to this nitrogen sparing acidogenic effect, growth hormone is also basogenic in combination with IGF-1 and acting on the kidney as a target organ. Therefore acid-base and nitrogen homoeostasis are normally attuned to one another through the co-ordinated action of growth hormone/IGF-1 on substrate fluxes. However during starvation ketoacid production as the consequence of incomplete fatty acid oxidation and ketone excretion swamps the basogenic limb and full-blown metabolic acidosis prevails; under this condition growth hormone's effectiveness in sparing nitrogen for anabolic processes is curtailed as glutamate (emanating from the liver) and glutamine (derived from muscle proteolysis) are directed to the kidneys, supporting ammoniogenesis: nitrogen balance is now sacrificed for acid-base homoeostasis. Underlying this state is an intracellular acidosis that may contribute to insulin resistance and developing hyperglycaemia in response to growth hormone. In acute injury, an additional acid load contributed from muscle proteolysis and cytokines reinforces an intracellular acidosis that further blunts growth hormone responsiveness and suppresses coupled IGF-1 production. From this perspective growth hormone's acidogenic and basogenic actions should balance for an effective anabolic response during hypermetabolic catabolic illnesses.     

Hemodynamic pulmonary edema in dogs with acute and chronic lymphatic ligation

The effect of lymphatic ligation on relative lung water (g H2O/g dry lung) was studied in dogs. Raising left atrial pressure to 20 mmHg for 2 h in chronically lymphatic-ligated dogs (4 days) caused a significantly greater increase in relative lung water than the same hemodynamic challenge did in sham-operated and acutely lymphatic-ligated dogs. There was no significant difference in relative lung water between the acutely lymphatic-ligated and sham-operated dogs. At normal left atrial pressures, there was no significant difference in relative lung water between the sham-operated and chronically lymphatic-ligated dogs. Since the combined effects of chronic lymphatic ligation and left atrial hypertension is greater than the sum of the individual effects, it appears that chronic lymphatic ligation increases the susceptibility of the lung to hemodynamic edema, we suggest that chronic lymphatic ligation may have produced increases in the interstitial volume and protein mass that are undetectable by our technique. These increases, in turn, could lead to a reduction in tissue safety factors against hemodynamic pulmonary edema.     

Simultaneous determination of nerisopam, a novel anxiolytic agent showing polymorphic metabolism, and its N-acetyl metabolite from human plasma by a validated high performance liquid chromatographic method

OBJECTIVE: Our goal was to determine the effect of chronic and acute umbilical-placental embolization on placental hemodynamic and fetal heart rate patterns in relation to fetal oxygenation in the near-term ovine fetus. STUDY DESIGN: Daily fetal placental embolization was performed during 10 days in 9 sheep fetuses until fetal arterial oxygen content decreased by approximately 30%. Nine control fetuses received saline solution. Mean and pulsatile umbilical blood flow, perfusion pressure, placental vascular resistance, fundamental impedance, pressure pulsatility index, and umbilical artery resistance index corrected to a fetal heart rate of 160 beats/min were measured. On day 10 both groups were acutely embolized until fetal arterial pH decreased to approximately 7.00. Fetal heart rate was measured with the Sonicaid System 8000 (Oxford Sonicaid, Oxford, United Kingdom). RESULTS: Chronic fetal placental embolization was associated with a progressive reduction in umbilical blood flow (p < 0.00001) and fetal arterial oxygen content (p < 0.001) whereas fetal heart rate patterns remained unaltered. A chronic increase in umbilical artery resistance index corrected to a fetal heart rate of 160 beats/min could be entirely explained only if the changes in umbilical artery pressure pulsatility index and the fundamental impedance were taken into account, in addition to the changes observed in placental vascular resistance. During acute embolization leading to a 50% reduction in umbilical blood flow (p < 0.0002) and a three times increase in placental vascular resistance (p < 0.0001), the most consistent change in fetal heart rate patterns related to progressive metabolic acidosis was an 84% decrease in absolute acceleration frequency (p < 0.0001) whereas short-term fetal heart rate variability remained unaltered. CONCLUSION: Changes in umbilical artery resistance index induced by chronic umbilical-placental embolization resulting in fetal hypoxemia occurred before any changes in fetal heart rate patterns were detectable. A decrease in the absolute acceleration frequency was the only component of fetal heart rate patterns related to progressive metabolic acidosis in the near-term ovine fetus.     

Acidosis and neuroprotection in two types of acidosis model rats under isoflurane anesthesia: evaluation of blood flow, pH and amino acid levels in the cortex

In order to evaluate the effect of brain acidosis on neuronal functions as assessed by the in vivo studies, changes of cerebral blood flow (CBF), brain pH ([pH]o) and brain amino acid levels in the same brain region of the two different acidosis model rats were measured under isoflurane anesthesia. Three micro probes to measure CBF, [pH]o and amino acids, respectively, were implanted into the frontal cortex, and these parameters were recorded simultaneously. In the metabolic acidosis rats, the sustained decrease of [pH]o and amino acid levels, particularly Glu, were detected after the treatment with 10 min-i.v. infusion of 1 N HCl, although the significant changes of CBF did not appear because of the respiratory management. In the respiratory acidosis model, however, transient and significant increase of CBF and decrease of Glu and [pH]o were recorded after 10 min-exposure to about 30% CO2 (N2O:O2:CO2 = 2:5:3). The levels of Gly and Gln were reduced after acute exposure to hypercapnia, but these levels recovered to the control level in 20-30 min after hypercapnia exposure. In both animals, the amounts of Tau was gradually reduced after the treatment with 1 N HCl and hypercapnia, and these levels did not return to the control level when other amino acid levels had recovered. These differences of brain amino acid levels in the two different types of acidosis model rats may be related to the brain amino acid metabolic pathway. Thus, during brain acidosis induced by 1 N HCl and hypercapnia, the amount of extracellular Glu in the brain was reduced, and this reduction may contribute to the neuroprotective effects.     

Evidence that 3-aminopicolinate stimulates glutamine metabolism by rat renal cortical tissue in vitro

The hyperglycemic agent 3-aminopicolinate used at concentrations of 0.05 and 0.1 mM stimulates the removal of 5 mM glutamine. It also stimulates the accumulation of glutamate and the formation of ammonia, glucose and aspartate by isolated rat kidney-cortex tubules. These effects are consistent with a stimulation of glutaminase and an inhibition of phosphoenolpyruvate carboxy-kinase by this compound. Higher concentrations (0.5 and 1 mM) of 3-aminopicolinate fail to affect the removal of 5 mM glutamine, but greatly alter the fate of both glutamine carbon and amino nitrogen. Similar effects of 3-aminopicolinate are observed when glutamine is used at a near-physiological concentration.     

Multinuclear NMR spectroscopy studies on NH4Cl-induced metabolic alterations and detoxification processes in primary astrocytes and glioma cells

Glutamine synthesis, the major pathway of ammonia detoxification, and the intracellular concentration of organic osmolytes in primary astrocytes and F98 glioma cells were investigated with multinuclear magnetic resonance spectroscopy. Acute exposure to ammonia (3 h incubation with NH4Cl) raised the concentration of glutamine and other amino acids, such as glutamate and aspartate, and decreased myo-inositol, hypotaurine, and taurine concentrations. The loss of these osmolytes was partially reversed by co-treatment with the glutamine synthetase inhibitor, methionine sulphoximine. Glutamate, the precursor of glutamine, is provided by stimulated anaplerotic flux via pyruvate carboxylase and glutamate dehydrogenase activity. Thus, the glutamine increase and myo-inositol decrease observed by in vivo magnetic resonance spectroscopy on patients with hepatic encephalopathy may be due to the disturbed osmoregulation in astrocytes caused by accumulation of glutamine and the subsequent loss of organic osmolytes.     

Hemodynamics in sleep-induced apnea. Studies during wakefulness and sleep

Twelve patients with predominantly obstructive type sleep apnea underwent cardiac catheterization, hemodynamic monitoring, and arterial blood gas analysis during wakefulness and sleep. Abnormalities during wakefulness included systemic hypertension in four of 12, exercise-induced mild pulmonary hypertension in five of 12, and alveolar hypoventilation in one. During sleep nine patients had cyclic elevations of arterial pressure with each apneic episode, exceeding 200 mm Hg systolic in three of 12. Pulmonary artery pressures increased in 10 of 12, exceeding 60 mm Hg systolic in five. Marked degrees of hypoxemia (arterial P02, less than 50 mm Hg in eight of 12) and moderate hypercapnia with respiratory acidosis were associated with these hemodynamic changes. Cyclic upper airway obstruction during sleep may result in hypercapnia, acidosis, and pronounced hypoxemia, which can lead to hemodynamic abnormalities during sleep. Sustained pulmonary hypertension and possibly systemic hypertension may follow. Tracheostomy is an effective therapy and is recommended to symptomatic patients who have predominantly obstructive apnea but no relievable anatomic cause of upper airway obstruction.     

Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes

The metabolic fate of glutamate in astrocytes has been controversial since several studies reported > 80% of glutamate was metabolized to glutamine; however, other studies have shown that half of the glutamate was metabolized via the tricarboxylic acid (TCA) cycle and half converted to glutamine. Studies were initiated to determine the metabolic fate of increasing concentrations of [U-13C] glutamate in primary cultures of cerebral cortical astrocytes from rat brain. When astrocytes from rat brain were incubated with 0.1 mM [U-13C] glutamate 85% of the 13C metabolized was converted to glutamine. The formation of [1,2,3-13C3] glutamate demonstrated metabolism of the labeled glutamate via the TCA cycle. When astrocytes were incubated with 0.2-0.5 mM glutamate, 13C from glutamate was also incorporated into intracellular aspartate and into lactate that was released into the media. The amount of [13C] lactate was essentially unchanged within the range of 0.2-0.5 mM glutamate, whereas the amount of [13C] aspartate continued to increase in parallel with the increase in glutamate concentration. The amount of glutamate metabolized via the TCA cycle progressively increased from 15.3 to 42.7% as the extracellular glutamate concentration increased from 0.1 to 0.5 mM, suggesting that the concentration of glutamate is a major factor determining the metabolic fate of glutamate in astrocytes. Previous studies using glutamate concentrations from 0.01 to 0.5 mM and astrocytes from both rat and mouse brain are consistent with these findings.     

Respiratory failure based on pulmonary tuberculosis sequelae and its management

According to the complexity of pathological change of pulmonary tuberculosis sequelae (TB seq), on which respiratory failure based shows the higher incidence of marked degree of hypoxemia and hypercapnia than that based on chronic pulmonary emphysema (CPE). In TB seq, pulmonary artery mean pressure is higher, nocturnal oxyhemoglobin desaturation is much lower than in CPE. Also hypoxemia on exercise is lower, and oxygen inhalation for this hypoxemia is more effective than in CPE. The most effective therapy is continuous oxygen therapy. Home oxygen therapy has improved the prognosis and quality of life (QOL) of patients with respiratory failure based on TB seq. Artificial positive pressure ventilation (TIPPV) with intubation or tracheotomy is carried out for patients with severe hypercapnia and respiratory acidosis. Recently, early application of nasal mask ventilation (NPPV) on patients with TB seq has prohibited acute exacerbation of chronic respiratory failure. And also for patients with severe hypercapnia, NPPV with BIPAP method is effective for their QOL. Comprehensive respiratory rehabilitation is also successfully applied for their management.