Hypoxic apnea and gasping.

We have tested the hypothesis that severe lypoxia causes apnea, regardless of the arterial CO2 and pH, and that extreme hypoxia causes gasping. Acute experiments with airway occlusion and with low inspired oxygen (FIo2) were performed on anesthetized adult dogs and monkeys. Arterial oxygen saturation was recorded continuously with fiberoptic oximetry, and Pco2 by an electrode catheter. In addition, blood samples were obtained for Po2, Pco2, and pH. Apnea was induced regularly when the Pao2 fell below 10 torr, whether the Paco2 was high with asphyxia (63 torr) or low (26 torr) with low FIo2. Similarly, the Pao2 at apnea was the same whether the pH was 7.17 with asphyxic hypoxia or 7.46 with hypoxic hypoxia. Gasping occurred at even lower Pao2 (below 5 torr) after 1 or 2 min of apnea. Gasping promptly restored the Pao2 to levels of moderate hypoxia (over 30 torr) which permitted resumption of regular respiration, with gradual elimination of the gasping. Fetal monkeys at term were studied in a similar manner from the moment of cord clamping. Their blood gases with apnea were quite similar to adult values in the narrow range of Pao2 and the wide range of Paco2 and pH. In the fetus, gasping was less immediately effective in improving arterial oxygen, but more persistent than in the adult. Regular respirations would not develop in the absence of oxygen in either the fetus or adult animal.     

Hypoxemia and tissue hypoxia in sleep apnea syndrome

Hypoxemia is defined as abnormally reduced oxygenation of the blood, whereas tissue hypoxia indicates inadequate oxygen supply against oxygen demand in the integrity of cellular metabolic processes. Thus, the presence of tissue hypoxia may not be predicted by the level of hypoxemia alone. Obstructive sleep apnea syndrome is characterized by periodic apnea/hypopnea, which is often associated with severe hypoxemia. In this chapter, we discussed how tissue hypoxia should be assessed in this syndrome, and also what is the clinical usefulness and/or limitations of such assessment.     

Long-term oxygen therapy: physiologic and economic considerations.

Long-term oxygen therapy appears to be a safe means of treating hypoxemia. It can provide many physiologic improvements and prolongs life in persons with severe chronic arterial hypoxemia at rest. Recent studies suggest that arterial hypoxia is common during exercise and sleep, and it is likely that some patients with intermittent desaturation would benefit physiologically from supplemental oxygen. Oxygen is an expensive drug, and we do not know whether its benefits are greater than its costs in patients who are not hypoxic at rest. I believe that low-flow oxygen administered as continuously as possible should be strongly considered for all patients whose PaO2 is 55 mm Hg or less at rest, regardless of whether they have cor pulmonale, and for all patients with cor pulmonale, regardless of their PaO2.     

Increased left ventricular stiffness impairs filling in dogs with pulmonary emphysema in respiratory failure.

In a chronic canine model of pulmonary emphysema, we studied the interaction between left ventricular (LV) mechanics and pulmonary disease during severe hypoxemia. The hypoxemia was similar to that which may occur during a severe exacerbation of chronic obstructive lung disease. In six dogs with papain-induced emphysema and in seven dogs without emphysema, LV mechanics were examined when a hypoxic gas mixture was inspired to reduce PO2 to about 35 mmHg (hypoxic study) and during nonhypoxic conditions (room air study). In both groups, LV diastolic compliance was reduced during the hypoxic study by a similar amount. This finding could not be explained in terms of ventricular interdependence. Our analysis suggested that hypoxia decreased diastolic compliance (i.e., increased LV diastolic stiffness) by impairing LV relaxation. The primary effect of hypoxia was to decrease the extent to which LV relaxation occurred for a given end-diastolic pressure, while the rate of LV relaxation was decreased just slightly. This study indicates that severe hypoxemia because of respiratory failure may impair myocardial relaxation leading to a decrease in LV filling.     

慢性低氧环境下微血管增生的生理机制及病理生理学特征

长期慢性低氧可通过多种机制促进微血管增生，其目的是增强血液与组织液的有效交换，保证氧输送，这是机体适应低氧环境的一种生理机制。但当机体遭受严重创伤、感染、缺氧等各种应激时，这种微血管增生可能伴有不利的角色，在疾病早期机体可能易发生低血容量性休克，随着疾病发展和不恰当的医疗干预，易发生毛细血管渗漏，出现器官及组织水肿，加重病情，此时，机体可能具有特殊的病理生理。本文阐述慢性低氧环境下微血管增生的生理机制，探讨其可能的病理生理临床特征，利于临床治疗的准确实施。     

Hyperoxygenated solutions in clinical practice: preventing or reducing hypoxic injury

In cases of hypoxia, oxygen can be supplied via a number of methods including face masks, nasal cannulae, hyperoxygenated oxygen chambers and mechanical ventilation. Administering oxygen via the respiratory tract is, however, limited in respiratory diseases such as pulmonary fibrosis, pneumoconiosis and severe acute respiratory syndrome, or following the inhalation of asphyxiating poisons. This has led to research into new methods of supplying oxygen that bypass the lungs. Research has investigated the efficacy of intravenous hyperoxygenated solutions (HOS) as auxiliary oxygen supplies in several hypoxic states including cardiopulmonary resuscitation, respiratory failure, cerebrovascular disease, myocardial ischaemia, severe acute respiratory syndrome, poisoning, neonatal hypoxia, altitude sickness, large burns and traumatic haemorrhagic shock. Much of the research has taken place in China and more than 3.5 million hypoxic patients have received HOS, with good therapeutic effects. This review summarizes the literature supporting the use of this novel treatment.     

Paradoxical effects of mild hypoxia and moderate altitude on human visual perception.

1. Prolonged (> 10 h) exposure to hypoxia and high altitude (> 5000 m) invariably have detrimental effects on cognitive performance. Paradoxically, mild improvements in cognitive function in patients with chronic obstructive pulmonary disease after cessation of oxygen therapy have been reported. 2. We studied in each of 10 healthy subjects the effect of an acute altitude challenge [rapid helicopter transport to the Jungfraujoch (3450 m), experiment 1] and of an acute exposure to mild hypoxia (fractional inspiratory oxygen concentration 14.5% experiment 2) on a simple test of cognitive performance (the time needed to read briefly displayed letters). 3. Under both hypoxic conditions the time needed to read briefly presented letters decreased, from 12.1 +/- SD 3.8 ms to 8.3 +/- 1.5 ms (P < 0.01) in experiment 1, and from 11.9 +/- 1.9 ms to 8.1 +/- 1.1 ms (P < 0.01) in experiment 2. 4. A rapid and mild hypoxic challenge seems to improve a simple measure of cognitive performance above normal values. The common notion that exposure to hypoxia and altitude invariably impairs cognitive performance may have to be re-evaluated.     

Current advances in the novel functions of hypoxia‐inducible factor and prolyl hydroxylase in invertebrates

Oxygen is essential for aerobic life, and hypoxia has very severe consequences. Organisms need to overcome low oxygen levels to maintain biological functions during normal development and in disease states. The mechanism underlying the hypoxic response has been widely investigated in model animals such as Drosophila melanogaster and Caenorhabditis elegans. Hypoxia‐inducible factor (HIF), a key gene product in the response to oxygen deprivation, is primarily regulated by prolyl hydroxylase domain enzymes (PHDs). However, recent findings have uncovered novel HIF‐independent functions of PHDs. This review provides an overview of how invertebrates are able to sustain hypoxic damages, and highlights some recent discoveries in the regulation of cellular signalling by PHDs. Given that some core genes and major pathways are evolutionarily conserved, these research findings could provide insight into oxygen‐sensitive signalling in mammals, and have biomedical implications for human diseases.     

Severe exercise-induced hypoxemia

Exercise training is an essential component of pulmonary rehabilitation and is associated with improved function and other important outcomes in persons with chronic lung disease. A subset of pulmonary rehabilitation patients experience hypoxemia that may occur or worsen with exercise. For the purpose of this review, severe exercise-induced hypoxemia is defined as an S(pO(2)) of < 89% during exercise, despite use of supplemental oxygen delivered at up to 6 L/min. There is a paucity of evidence and clinical guidelines that address assessment and management of this important manifestation of chronic lung disease. This review presents background of this topic and suggests strategies for assessment, management, and safety measures for patients with severe exercise-induced hypoxemia.     

Monocytes and tissue factor promote thrombosis in a murine model of oxygen deprivation.

Clinical conditions associated with local or systemic hypoxemia can lead to prothrombotic diatheses. This study was undertaken to establish a model of whole-animal hypoxia wherein oxygen deprivation by itself would be sufficient to trigger tissue thrombosis. Furthermore, this model was used to test the hypothesis that hypoxia-induced mononuclear phagocyte (MP) recruitment and tissue factor (TF) expression may trigger the local deposition of fibrin which occurs in response to oxygen deprivation. Using an environmental chamber in which inhaled oxygen tension was lowered to 6%, hypoxic induction of thrombosis was demonstrated in murine pulmonary vasculature by 8 h based upon: (a) immunohistologic evidence of fibrin formation in hypoxic lung tissue using an antifibrin antibody, confirmed by 22.5-nm strand periodicity by electron microscopy; (b) immunoblots revealing fibrin gamma-gamma chain dimers in lungs from hypoxic but not normoxic mice or hypoxic mice treated with hirudin; (c) accelerated deposition of 125I-fibrin/fibrinogen and 111In-labeled platelets in the lung tissue of hypoxic compared with normoxic animals; (d) reduction of tissue 125I-fibrin/fibrinogen accumulation in animals which had either been treated with hirudin or depleted of platelets before hypoxic exposure. Because immunohistochemical analysis of hypoxic pulmonary tissue revealed strong MP staining for TF, confirmed by increased TF RNA in hypoxic lungs, and because 111In-labeled murine MPs accumulated in hypoxic pulmonary tissue, we evaluated whether recruited MPs might be responsible for initiation of hypoxia-induced thrombosis. This hypothesis was supported by several lines of evidence: (a) MP depletion before hypoxia reduced thrombosis, as measured by reduced 125I-fibrin/fibrinogen deposition and reduced accumulation of cross-linked fibrin by immunoblot; (b) isolated murine MPs demonstrated increased TF immunostaining when exposed to hypoxia; and (c) administration of an anti-rabbit TF antibody that cross-reacts with murine TF decreased 125I-fibrin/fibrinogen accumulation and cross-linked fibrin accumulation in response to hypoxia in vivo. In summary, these studies using a novel in vivo model suggest that MP accumulation and TF expression may promote hypoxia-induced thrombosis.     

Sympathoadrenal responses to acute and chronic hypoxia in the rat.

The sympathoadrenal responses to acute and chronic hypoxic exposure at 10.5 and 7.5% oxygen were determined in the rat. Cardiac norepinephrine (NE) turnover was used to assess sympathetic nervous system (SNS) activity, and urinary excretion of epinephrine (E) was measured as an index of adrenal medullary activity. The responses of the adrenal medulla and SNS were distinct and dependent upon the degree and duration of hypoxic exposure. Chronic hypoxia at 10.5% oxygen increased cardiac NE turnover by 130% after 3, 7, and 14 d of hypoxic exposure. Urinary excretion of NE was similarly increased over this time interval, while urinary E excretion was marginally elevated. In contrast, acute exposure to moderate hypoxia at 10.5% oxygen was not associated with an increase in SNS activity; in fact, decreased SNS activity was suggested by diminished cardiac NE turnover and urinary NE excretion over the first 12 h of hypoxic exposure, and by a rebound increase in NE turnover after reexposure to normal oxygen tension. Adrenal medullary activity, on the other hand, increased substantially during acute exposure to moderate hypoxia (2-fold increase in urinary E excretion) and severe hypoxia (greater than 10-fold). In distinction to the lack of effect of acute hypoxic exposure (10.5% oxygen), the SNS was markedly stimulated during the first day of hypoxia exposure at 7.5% oxygen, an increase that was sustained throughout at least 7 d at 7.5% oxygen. These results demonstrate that chronic exposure to moderate and severe hypoxia increases the activity of the SNS and adrenal medulla, the effect being greater in severe hypoxic exposure. The response to acute hypoxic exposure is more complicated; during the first 12 h of exposure at 10.5% oxygen, the SNS is not stimulated and appears to be restrained, while adrenal medullary activity is enhanced. Acute exposure to a more severe degree of hypoxia (7.5% oxygen), however, is associated with stimulation of both the SNS and adrenal medulla.     

高原低氧大鼠肺组织超微结构及其低氧诱导因子1α的表达(英文)

背景:低氧诱导因子1α可介导哺乳动物细胞适应低氧环境。目的:观察高原低氧对大鼠肺组织超微结构的影响及其低氧诱导因子1α表达变化。方法:将SD大鼠分别为进行高原低氧干预1,2,3和30d,并设置对照组。4个高原低氧组由海拔5m的西安地区途中耗时1d带到海拔2700m的青海格尔木地区、途中耗时2d带到海拔5000m的唐古拉地区,途中耗时3,30d分别带到海拔4500m的西藏那曲地区。结果与结论:光镜及电镜观察显示,急性高原低氧2d组肺组织出现明显的高原肺水肿,急性高原低氧30d组低氧诱导因子1αmRNA的表达明显增高(P<0.01),高原肺水肿现象则明显减轻。结果证实,低氧习服后肺组织低氧诱导因子1αmRNA表达的提高有利于减轻高原肺水肿。     

Changes in BOLD and ADC weighted imaging in acute hypoxia during sea-level and altitude adapted states

Acute normobaric hypoxia as well as longstanding hypobaric hypoxia induce pronounced physiological changes and may eventually lead to impairment of cerebral function. The aim of the present study is to investigate the effect of hypoxia on the cerebral activation response as well as to explore possible structural changes as measured by diffusion weighted imaging. Eleven healthy sea-level residents were studied after 5 weeks of adaptation to high altitude conditions at Chacaltaya, Bolivia (5260 m). The subjects were studied immediately after return to sea-level in hypoxic and normoxic conditions, and the examinations repeated 6 months later after re-adaptation to sea-level conditions. The BOLD response, measured at 1.5 T, was severely reduced during acute hypoxia both in the altitude and sea-level adapted states (50% reduction during an average S(a)O(2) of 75%). On average, the BOLD response magnitude was 23% lower in altitude than sea-level adaptation in the normoxic condition, but in the hypoxic condition, no significant differences were found. A small but statistically significant decrease in the apparent diffusion coefficient (ADC) was seen in some brain regions during acute hypoxia, whereas ADC was slightly elevated in high altitude as compared to sea-level adaptation. It is concluded that hypoxia significantly diminishes the BOLD response, and the mechanisms underlying this finding are discussed. Furthermore, altitude adaptation may influence both the magnitude of the activation-related response, as well as micro-structural features.     

Ascorbic acid enhances hypoxic ventilatory reactivity in elderly subjects

The reducing properties of ascorbic acid in the carotid body make it a likely modifier of hypoxia-sensing mechanisms. This open-label study aimed to determine the effect of ascorbic acid on the hypoxic ventilatory response (HVR) in a population of elderly women, in whom both hypoxic reactivity and ascorbic acid levels may be deficient. We examined the HVR to progressive eucapnic hypoxia in 18 healthy females aged 60-80 years, before and after 10 days' ascorbic acid supplementation, given as a sustained release preparation of 1 g twice daily. Respiratory variables were recorded breath by breath, and hypoxic sensitivity was assessed from the linear slopes of minute ventilation and mouth occlusion pressure plotted against oxygen saturation. We found that ascorbic acid increased the HVR by a mean of 44%, this effect being driven by a higher occlusion pressure. We conclude that augmentation of hypoxic reactivity by ascorbic acid may have therapeutic potential in pathologies associated with hypoxia, which frequently develop in old age.     

Mechanisms of hypoxemia and hypercapnia in the perioperative period

There are numerous mechanisms of hypoxemia and hypercapnia during the perioperative period. Mechanisms of hypoxemia include oxygen delivery problems, decreased FAC-CC relationship, hypoventilation, decreased cardiac output, increased oxygen consumption, decreased hypoxic pulmonary vasoconstriction, and increased nonalveolar right-to-left shunting. Mechanisms of hypocapnia include increased carbon dioxide production, increased alveolar dead space, and increased external dead spaces. Pulmonary diseases often involve multiple mechanisms to produce hypoxemia and hypercapnia.     

高原低氧大鼠肺组织超微结构及其低氧诱导因子1α的表达（英文）

背景：低氧诱导因子1α可介导哺乳动物细胞适应低氧环境。目的：观察高原低氧对大鼠肺组织超微结构的影响及其低氧诱导因子1α表达变化。方法：将SD大鼠分别为进行高原低氧干预1,2,3和30d,并设置对照组。4个高原低氧组由海拔5m的西安地区途中耗时1d带到海拔2700m的青海格尔木地区、途中耗时2d带到海拔5000m的唐古拉地区,途中耗时3,30d分别带到海拔4500m的西藏那曲地区。结果与结论：光镜及电镜观察显示,急性高原低氧2d组肺组织出现明显的高原肺水肿,急性高原低氧30d组低氧诱导因子1αmRNA的表达明显增高（P〈0.01）,高原肺水肿现象则明显减轻。结果证实,低氧习服后肺组织低氧诱导因子1αmRNA表达的提高有利于减轻高原肺水肿。     

Cardiovascular and respiratory agents during pregnancy: implications for fetal development

The management of common medical problems in pregnancy often requires adjustments in drug therapy to assure a healthy fetus. The management of steroid-dependent bronchial asthma in pregnancy requires oxygen supplementation as well as vigorous treatment of airway obstruction to protect the fetus from maternal hypoxemia. The hypertensive pregnant patient should discontinue dietary sodium restriction and diuretic therapy and should be managed with alphmethyldopa or beta-blocker therapy. Hydralazine may be added if hypertension is severe. Mitral valve prolapse appears to produce no difficulties during pregnancy and the use of prophylactic antibiotics is probably not necessary for routine vaginal delivery, unless complications occur. Digoxin and quinidine are safe to use in pregnancy, provided careful monitoring is maintained. Oral anticoagulants are contraindicated in pregnancy and should be replaced with heparin if pregnancy is desired.     

Coronary vasomotor disorders during hypoxia-reoxygenation: do calcium channel blockers play a protective role?

During heart surgery, myocardial dysfunction may occasionally appear when extracorporeal circulation is discontinued, causing serious haemodynamic disorders. Many mechanisms are involved in this hypoxia-reoxygenation syndrome. The aim of this experimental study was to characterize the vasomotor disorders that take place in the isolated porcine coronary artery during in vitro hypoxia-reoxygenation and to analyse the effect of nifedipine on them. Rings of porcine coronary artery were placed in an organ chamber connected to a system that recorded isometric forces. The vascular rings were divided into two groups: control group (no nifedipine) and study group (nifedipine, 10^-6 mol/l). The vascular rings were precontracted with 30 mmol/l KCl and then hypoxia-reoxygenation was induced. Control arterial rings showed important changes in coronary vasomotor tone: severe hypoxic contraction (from 14.48ǃ.16 g of stable contraction to 17.6ǂ.44 g after the imposition of hypoxia), and transient vasodilation during reoxygenation (69.9ᆞ.1% of the maximum contraction achieved). The nifedipine group experienced a slow, progressive, vasodilation throughout the whole experiment (73Dž.5% of the maximum contraction). Neither hypoxic vasospasm nor fluctuations of the coronary vascular tone occurred. Thus, at the end of the hypoxia, the control vessels presented a degree of contraction similar to the initial level. However, in the rings treated with nifedipine, the percentage of dilation was 73Dž.5% (P<0.05). In the isolated porcine coronary artery with intact endothelium undergoing a situation of hypoxia-reoxygenation, we have detected transient vasoconstriction during the first period of hypoxia, followed by vasodilation during reoxygenation. The intracoronary administration of nifedipine prior to the imposition of hypoxia prevents hypoxic contraction, achieving a greater and more stable degree of coronary vasorelaxation during the complete process of hypoxia-reoxygenation.     

Hypoxia Impairs Vasodilation in the Lung

Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin II-induced constriction as the lung oxygen tension fell progressively below 60 Torr. KCl, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCl-induced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCl, (b) hypoxia slows vasodilation following KCl-induced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.