Goal-directed therapy for severely hypoxic patients with acute respiratory distress syndrome: permissive hypoxemia

Permissive hypoxemia is a lung-protective strategy that aims to provide a patient with severe acute respiratory distress syndrome (ARDS) a level of oxygen delivery that is adequate to avoid tissue hypoxia while minimizing the detrimental effects of the often toxic ventilatory support required to maintain normal arterial oxygenation. However, in many patients with severe ARDS it can be difficult to achieve a balance between maintaining adequate tissue oxygenation and avoiding ventilator-induced lung injury (VILI). A potential strategy for the management of such patients involves goal-oriented manipulation of cardiac output and, if necessary, hemoglobin concentration, to compensate for hypoxemia and maintain a normal (but not supranormal) value of oxygen delivery. Although it has not yet been studied, this approach is theorized to improve clinical outcomes of critically ill patients with severe ARDS. We stress that the goal of this article is not to convince the reader that this approach is necessarily correct, as data are clearly lacking, but rather to provide a basis for continued thought, discussion, and potential research.     

Sleep apnea in patients with acute myocardial infarction

OBJECTIVE: To document sleep apnea in the acute phase of myocardial infarction. If apnea occurs in patients with myocardial infarction, hypoxemia induced by apnea might exaggerate insufficiency of oxygen supplied to the damaged myocardium. DESIGN: Prospective controlled study. SETTING: Critical care unit of a teaching hospital. PATIENTS: Forty-nine patients, average age 64 yrs (range 49 to 91). MEASUREMENTS AND MAIN RESULTS: Patient measurements were recorded on a polygraph using an apnea-monitor, pulse oximeter, pulmonary artery pressure monitor, and an ECG. All of the patients observed showed frequent apneic episodes. The apnea was especially frequent when the cardiac index was low. Capillary oxygen saturation of less than 90% (suggesting systemic hypoxia) was observed in 21 patients concomitantly with apnea. Occasionally, arrhythmias followed these episodes (premature supraventricular contractions [n = 10], premature ventricular contraction [n = 4], and ventricular tachycardia [n = 2]). CONCLUSIONS: This study suggests that sleep apnea is common in the setting of acute myocardial infarction. It may be a factor predisposing to, or even causing, sudden death in patients with acute phase of myocardial infarction.     

Diagnosis and management of hypoxemia.

The following steps are necessary in the successful management of hypoxia: 1. Establish the presence of hypoxemia with measurements of arterial blood gases. 2. Search for signs of tissue hypoxia. 3. Assign a physiologic cause for hypoxemia. 4. Begin oxygen therapy by a method appropriate to underlying pathophysiologic mechanism, as outlined in Table 2. 5. Repeat arterial blood gas measurements to assure adequate reversal of hypoxemia. 6. Treat any underlying disease(s).     

Pathophysiology and clinical effects of chronic hypoxia

Hypoxia exists when there is a reduced amount of oxygen in the tissues of the body. Hypoxemia refers to a reduction in PO2 below the normal range, regardless of whether gas exchange is impaired in the lung, CaO2 is adequate, or tissue hypoxia exists. There are several potential physiologic mechanisms for hypoxemia, but in patients with COPD the predominant one is V/Q mismatching, with or without alveolar hypoventilation, as indicated by PaCO2. Hypoxemia caused by V/Q mismatching as seen in COPD is relatively easy to correct, so that only comparatively small amounts of supplemental oxygen (less than 3 L/min for the majority of patients) are required for LTOT. Although hypoxemia normally stimulates ventilation and produces dyspnea, these phenomena and the other symptoms and signs of hypoxia are sufficiently variable in patients with COPD as to be of limited value in patient assessment. Chronic alveolar hypoxia is the main factor leading to development of cor pulmonale--right ventricular hypertrophy with or without overt right ventricular failure--in patients with COPD. Pulmonary hypertension adversely affects survival in COPD, to an extent that parallels the degree to which resting mean pulmonary artery pressure is elevated. Although the severity of airflow obstruction as measured by FEV1 is the best correlate with overall prognosis in patients with COPD, chronic hypoxemia increases mortality and morbidity for any severity of disease. Large-scale studies of LTOT in patients with COPD have demonstrated a dose-response relationship between daily hours of oxygen use and survival. There is reason to believe that continuous, 24-hours-per-day oxygen use in appropriately selected patients would produce a survival benefit even greater than that shown in the NOTT and MRC studies.     

重叠综合征临床分析

目的　研究重叠综合征的临床特点。方法　对 2 1例重叠综合征患者及 2 0例OSAS患者颈围、体重指数、肺功能及多导睡眠图进行研究。结果　重叠综合征患者觉醒次数增加 ,入睡潜伏期缩短 ,睡眠呼吸暂停时间长 ,夜间低氧血症明显。结论　重叠综合征引起睡眠呼吸障碍更为明显 ,夜间低氧血症明显 ,危害性大 ,须引起高度重视。     

Pulmonary hypertension

Repetitive pulmonary artery pressure(PAP) elevation during apnea is commonly reported in patients with obstructive sleep apnea syndrome(OSAS). Hypoxic pulmonary vasoconstriction(HPV) plays an important role in this PAP elevation. In addition to the HPV, augmentation of intrathoracic negative pressure which occurs concomitantly with apnea and activation of sympathetic nervous system during REM sleep, influences pulmonary blood flow, resulting in the PAP elevation. Many previous study have been declared that the daytime pulmonary hypertension(PH), which is observed in significant populations of OSAS, is related to chronic airflow limitation and/or daytime hypoxemia. Furthermore, it had been suggested that the daytime PH in OSAS can be elicited, at least in parts, by vascular remodeling together with both nocturnal and daytime hypoxemia. Such pulmonary vascular remodeling may induce greater vascular sensitivity to sympathetic stimulation and modify HPV in OSAS with daytime PH.     

New strategies of screening and treatment for sleep apnea syndrome.

The prevalence of sleep apnea syndrome (SAS) is approximately 7.5% in Japanese adults aged 18-68 years old. SAS is characterized by repeated episodes of apnea, especially obstructive apnea, during sleep. Severe SAS has life-threatening complications such as pulmonary hypertension, arrhythmias, right heart failure or brain damage, which could be caused by hypoxemia and/or hypercapnia. Upper airway relaxation is responsible for the obstruction during apnea, and an increase in the activities of the upper airway muscles dilates and stiffens the upper airway wall. Maintaining the activities of the upper airway muscles may contribute to keeping the airway patent. Submental electrical stimulation of the upper airway muscles would be a novel treatment method for obstructive apnea.     

预吸氧辅以鼻咽通气管预防肥胖患者行无痛宫腔镜术中低氧血症的价值

目的 探讨术前采用预吸氧辅以术中放置鼻咽通气管,对行无痛宫腔镜术肥胖患者低氧血症的预防作用.方法 选取2017年1~6月在该院行无痛宫腔镜检查的90例肥胖患者作为研究对象,按随机数字表法分为对照组和实验组各45例.对照组采用常规鼻导管吸氧方法,实验组采用术前3~5min面罩预吸氧,术中放置鼻咽通气管的方法,比较两组患者检查过程中不同时间点血氧饱和度(SpO2)变化、低氧血症及呼吸抑制情况.结果 实验组与对照组检查前、中、后SpO2差异均有统计学意义(均P<0.01);实验组和对照组术中舌后坠、低氧血症、呼吸暂停、苏醒延迟发生率差异均有统计学意义(均P<0.05).结论 肥胖患者行无痛宫腔镜术前采用面罩预吸氧3~5min,可有效提高机体氧储备能力,放置鼻咽通气管可维持呼吸道通畅,降低发生低氧血症的风险,具有较好的临床应用价值.     

Lipid peroxidation and osmotic fragility of red blood cells in sleep-apnea patients

BACKGROUND: Obstructive sleep apnea (OSA) refers to the occurrence of episodes of complete or partial pharyngeal obstruction with oxyhemoglobin desaturation during sleep. These hypoxia/reoxygenation episodes may cause generation of reactive oxygen species. Reactive oxygen species are toxic to biomembranes and may lead to the peroxidation of lipids. We tested the hypothesis that obstructive sleep apnea is linked to increased oxidative stress and lipid peroxidation. In order to identify target tissue/cell damage, we studied the osmotic fragility of red blood cells. METHODS: Six subjects polysomnographically diagnosed as obstructive sleep apnea syndrome and 10 controls were included. After all subjects gave written informed consent, blood samples were collected in the morning between 08:00 and 09:00 a.m. following polysomnography. Blood samples were immediately transferred to the laboratory. Glutathione, lipid peroxidation and osmotic fragility of red blood cells were measured manually. RESULTS: Mean glutathione and lipid peroxidation concentrations of patients were not different than those of control subjects (105.6+/-38.6 U/g Hb and 3.1+/-2.3 nmol MDA/l vs. 100.6+/-62.1 U/g Hb and 3.2+/-2.8 nmol MDA/l, respectively). In both groups, osmotic fragility of red blood cells was not changed. CONCLUSION: The present study failed to support the hypothesis that obstructive sleep apnea is linked with increased oxidative stress and lipid peroxidation.     

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.     

Concepts in hypoxia reborn

The human fetus develops in a profoundly hypoxic environment. Thus, the foundations of our physiology are built in the most hypoxic conditions that we are ever likely to experience: the womb. This magnitude of exposure to hypoxia in utero is rarely experienced in adult life, with few exceptions, including severe pathophysiology in critical illness and environmental hypobaric hypoxia at high altitude. Indeed, the lowest recorded levels of arterial oxygen in adult humans are similar to those of a fetus and were recorded just below the highest attainable elevation on the Earth's surface: the summit of Mount Everest. We propose that the hypoxic intrauterine environment exerts a profound effect on human tolerance to hypoxia. Cellular mechanisms that facilitate fetal well-being may be amenable to manipulation in adults to promote survival advantage in severe hypoxemic stress. Many of these mechanisms act to modify the process of oxygen consumption rather than oxygen delivery in order to maintain adequate tissue oxygenation. The successful activation of such processes may provide a new chapter in the clinical management of hypoxemia. Thus, strategies employed to endure the relative hypoxia in utero may provide insights for the management of severe hypoxemia in adult life and ventures to high altitude may yield clues to the means by which to investigate those strategies.     

Experimental models of pathologic oxygen supply dependency

Pathologic oxygen supply dependency is an abnormal situation in which oxygen uptake (Vo2) varies directly with oxygen delivery. Its presence in patients with adult respiratory distress syndrome and/or sepsis has been associated with particularly high mortality rates that may be the result of tissue hypoxia that causes multiple organ failure. The evidence for this association has been indirect because we cannot use invasive methods that would be necessary to verify or disprove the hypothesis. Because further progress will depend on the development of adequate animal models of pathologic oxygen supply dependency, we have attempted to evaluate some of the available information in this area as well as the likelihood that tissue hypoxia will prove to be the precipitating factor. In anesthetized dogs injected or infused with endotoxin, many of the features of pathologic oxygen supply dependency have been successfully produced. These features include defective peripheral oxygen extraction, increased oxygen demand, and increased lactate levels. Regional measurements have shown that gut Vo2 decreases before other areas, particularly skeletal muscle. Lactate measurements alone were shown not to be sufficient proof of tissue hypoxia. More direct measurements of actual energy states and tissue Po2 are indicated for future research efforts.     

Long-term oxygen therapy--state of the art.

Long-term oxygen therapy prolongs life in adults with chronic hypoxia caused by chronic bronchitis and emphysema who have cor pulmonale, pulmonary hypertension, and secondary polycythemia ('blue bloaters'). Good results require oxygen therapy for more than 15 hours and preferably 20-24 hours per day. The oxygen concentrator, delivering 1 to 3 l/min of oxygen by nasal prongs, is probably the most cost-effective method of providing this therapy. Dangers of the therapy include fires and burning of patients who smoke, and this is a contraindication to treatment. Excessive CO2 retention during sleep should not result from controlled low-dose oxygen therapy unless the patient also has an obstructive sleep apnea syndrome. Oxygen therapy during sleep may prevent hypoxemic episodes in blue bloaters, and it may thus reverse their pulmonary hypertension, which probably potentiates the risk of right-heart failure and cor pulmonale.     

Cardiac sympathovagal balance during sleep apnea episodes

Summary. The main acute cardiovascular effects of obstructive sleep apnea syndrome (OSAS) are elevation of blood pressure and reflectory bradycardia, which are followed by an abrupt tachycardia on resumption of breathing. This haemodynamic instability is related to hypoxemia and arousal, and may lead to increased risk from cardiac arrhythmias and sudden cardiac death, as well as to the development of chronic arterial hypertension, in these patients. The aim of this study was to apply frequency domain analysis of heart rate variability (HRV) measured from continuous electrocardiogram (ECG) recordings to evaluate how cardiac autonomic function, and especially cardiac sympathovagal tone, changes during sleep apnea episodes. We identified 41 apneas leading to more than 4%-unit arterial oxygen desaturation in 12 patients (11 men, 1 women, age range 27–67 years). Frequency domain analysis of HRV was performed from ECG recordings using 4 min epochs starting 20 min before apnea began and lasting 20 min after the beginning of apnea. The mean (± SEM) fall in oxygen saturation during the apnea was 6.8±0.6%-units. While high frequency band (HF, reflects cardiac vagal activity) remained unchanged, low frequency band (LF, mainly sympathetic activity) showed a constant increase, leading to significant change in the sympathovagal balance (LF/HF ratio). In conclusion, concordantly with previous peripheral sympathetic-nerve recordings, frequency domain analysis of HRV is able to detect sympathetic activation during sleep apnea episodes, leading to marked change in the sympathovagal balance.     

Acute lung injury. Assessment of tissue oxygenation

The physiologic factors governing oxygen delivery to the peripheral tissues are briefly reviewed to show how tissue PO2 is defended when acute lung injury causes arterial hypoxemia. A loss of recruitable capillary reserve in the tissues may be another serious consequence of the same events that cause lung injury in the adult respiratory distress syndrome, and may cause a defect in tissue oxygen extraction.     

Chronic obstructive pulmonary disease and sleep

The control of breathing in patients with chronic obstructive pulmonary disease (COPD) follows the same basic principles as in normal subjects, both awake and asleep, with an expected lower feedback response during sleep. This impacts nocturnal gas exchange and sleep quality most profoundly in patients with more severe COPD, as multiple factors come into play. Hypoventilation causes the most important gas-exchange alteration in COPD patients, leading to hypercapnia and hypoxemia, especially during rapid-eye-movement sleep, when marked respiratory muscle atonia occurs. The hypoxia leads to increased arousals, sleep disruption, pulmonary hypertension, and higher mortality. The primary mechanisms for this include decreased ventilatory responsiveness to hypercapnia, reduced respiratory muscle output, and marked increases in upper airway resistance. In the presence of more profound daytime hypercapnia, polysomnography should be considered (over nocturnal pulse oximetry) to rule out other co-existing sleep-related breathing disorders such as obstructive sleep apnea (overlap syndrome) and obesity hypoventilation syndrome. Present consensus guidelines provide insight into the proper use of oxygen, continuous positive airway pressure, and nocturnal noninvasive positive-pressure ventilation for those conditions, but several issues remain contentious. In order to provide optimal therapy to patients, the clinician must take into account certain reimbursement and implementation-process obstacles and the guidelines for treatment and coverage criteria.     

Acute hypoxemia in humans enhances the neutrophil inflammatory response

The neutrophil (PMN) is regarded as a key component in the hyperinflammatory response known as the systemic inflammatory response syndrome. Acute respiratory distress syndrome (ARDS) and subsequent multiple organ failure (MOF) are related to the severity of this hyperinflammation. ICU patients who are at highest risk of developing MOF may have acute hypoxic events that complicate their hospital course. This study was undertaken to evaluate the effects of acute hypoxia and subsequent hypoxemia on circulating PMNs in human volunteers. Healthy subjects were exposed to a changing O2/N2 mixture until their O2 saturation (SaO2) reached a level of 68% saturation. These subjects were then exposed to room air and then returned to their baseline SaO2. PMNs were isolated from pre- and post-hypoxemic arterial blood samples and were then either stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) or PMA alone, or they were primed with L-alpha-phosphatidylcholine, beta-acetyl-gamma-O-alkyl (PAF) followed by fMLP activation. Reactive oxygen species generation as measured by superoxide anion production was enhanced in primed PMNs after hypoxemia. Protease degranulation as measured by elastase release was enhanced in both quiescent PMNs and primed PMNs after fMLP activation following the hypoxemic event. Adhesion molecule upregulation as measured by CD11b/CD18, however, was not significantly changed after hypoxemia. Apoptosis of quiescent PMNs was delayed after the hypoxemic event. TNFalpha, IL-1, IL-6, and IL-8 cytokine levels were unchanged following hypoxemia. These results indicate that relevant acute hypoxemic events observed in the clinical setting enhance several PMN cytotoxic functions and suggest that a transient hypoxemic insult may promote hyperinflammation.     

Microcirculatory oxygenation and shunting in sepsis and shock.

OBJECTIVE: To review optical spectroscopic techniques for assessment of the determinants of tissue oxygenation and to evaluate the notion that the disturbances in oxygen pathways in sepsis can be accounted for by enhanced functional shunting of parts of the microcirculation. DATA RESOURCES: Experimental data from previous research and the literature were analyzed. STUDY SELECTION: The data selected pertained to a) whether cellular distress in sepsis is caused by tissue hypoxia or disturbed metabolic pathways, b) optical spectroscopic techniques used to study microcirculatory oxygenation, and c) possible mechanisms underlying shunting of the microcirculation in hypoxemia and sepsis. STUDY SYNTHESIS: Despite resuscitation of oxygen-derived variables, signs of regional tissue hypoxia persist in sepsis. The mechanisms underlying this condition are expected to be associated with oxygen pathways in the microcirculation. Optical spectroscopic techniques are providing new insights into these mechanisms. These include absorption spectroscopy for hemoglobin saturation of erythrocytes, reduced nicotinamide adenine dinucleotide fluorescence for tissue mitochondrial bioenergetics, and palladium-porphyrin phosphorescence for microvascular PO2. Reduced nicotinamide adenine dinucleotide videofluorescence studies have shown the heterogeneous nature of hypoxia. Measurement of gut microvascular PO2 in pigs has shown the development of a PO2 gap between microvascular PO2 and venous PO2 during hemorrhage and endotoxemia, with a larger gap occurring in sepsis than in hemorrhage. It is hypothesized that this difference is caused by the enhanced shunting of the microcirculation present in sepsis. CONCLUSIONS: Microcirculatory distress may form one of the earliest stages in the progress of sepsis to multiple organ failure, and shunting of the microcirculation may be an important contributing factor to this development. To evaluate the severity of microcirculatory distress and the effectiveness of resuscitation strategies, new clinical technologies aimed at the microcirculation will need to be developed. It is anticipated that optical spectroscopy will play a major role in the development of such tools.     

Effect of NaHCO3 on cardiac energy metabolism and contractile function during hypoxemia

OBJECTIVE: To examine the impact of administration of NaHCO3 on contractility and energy metabolism of the myocardium during hypoxemia. METHODS: Regional myocardial hypoxia was induced in the left anterior descending (LAD) artery myocardium in anesthetized, open-chest dogs, using a perfusion circuit between the right atrium and the LAD artery, and a membrane oxygenator. The rate of flow in LAD artery was maintained constant with the use of a roller pump. During hypoxia, eight dogs were administered isotonic NaHCO3 in the circuit and six other dogs received equimolar NaCl. Myocardial contractile function was assessed using sonomicrometry for measurement of percentage of systolic shortening and preload recruitable stroke work. Oxygen consumption and the rate of appearance of lactate were measured. Clamp-frozen tissue samples were obtained at the end of the experiment from the hypoxic LAD myocardium and the nonhypoxic circumflex myocardium for measurement of tissue lactate level. RESULTS: During hypoxia, there was a significant decrease in oxygen consumption by the LAD myocardium (35 +/- 7 micromol/min in the NaCl group and 40 +/- 7 micromol/min in the NaHCO3 group during hypoxia vs. 131 +/- 11 micromol/min during aerobic perfusion). There was also a significant decrease in myocardial contractility as measured by percentage of systolic shortening (14 +/- 3% to -8 +/- 3%); NaHCO3 infusion during hypoxia did not improve myocardial contractility (-7 +/- 2%). Similar results were obtained with measurements of preload recruitable stroke work. The rate of production of lactate during hypoxia was substantially lower than expected, based on the calculated oxygen deficit, and was not significantly increased by the administration of NaHCO3 (33 +/- 9 micromol/min in the NaCl group and 51 +/- 5 micromol/min in the NaHCO3 group). Tissue lactate was not statistically different in the hypoxic myocardium supplied by the LAD artery and the nonhypoxic myocardium supplied by the circumflex artery in either group. CONCLUSION: The response of the myocardium to hypoxia is to decrease its mechanical work and metabolic demand. The infusion of NaHCO3 did not enhance myocardial contractile function or flux in glycolysis during hypoxia. We speculate that this diminished mechanical work and metabolic demand may represent an adaptive response to preserve cellular integrity until oxygen delivery is restored.