Arterial O2 Tension Research Articles

The effect of targeted hyperoxemia in a randomized controlled trial employing a long-term resuscitated, model of combined acute subdural hematoma and hemorrhagic shock in swine with coronary artery disease: An exploratory, hypothesis-generating study.

Controversial evidence is available regarding suitable targets for the arterial O2 tension (PaO2) after traumatic brain injury and/or hemorrhagic shock (HS). We previously demonstrated that hyperoxia during resuscitation from hemorrhagic shock attenuated cardiac injury and renal dysfunction in swine with coronary artery disease. Therefore, this study investigated the impact of targeted hyperoxemia in a long-term, resuscitated model of combined acute subdural hematoma (ASDH)-induced brain injury and HS. The prospective randomized, controlled, resuscitated animal investigation consisted of 15 adult pigs. Combined ASDH plus HS was induced by injection of 0.1 ml/kg autologous blood into the subdural space followed by controlled passive removal of blood. Two hours later, resuscitation was initiated comprising re-transfusion of shed blood, fluids, continuous i.v. noradrenaline, and either hyperoxemia (target PaO2 200 – 250 mmHg) or normoxemia (target PaO2 80 – 120 mmHg) during the first 24 h of the total of 54 h of intensive care. Systemic hemodynamics, intracranial and cerebral perfusion pressures, parameters of brain microdialysis and blood biomarkers of brain injury did not significantly differ between the two groups. According to the experimental protocol, PaO2 was significantly higher in the hyperoxemia group at the end of the intervention period, i.e., at 24 h of resuscitation, which coincided with a higher brain tissue PO2. The latter persisted until the end of observation period. While neurological function as assessed using the veterinary Modified Glasgow Coma Score progressively deteriorated in the control group, it remained unaffected in the hyperoxemia animals, however, without significant intergroup difference. Survival times did not significantly differ in the hyperoxemia and control groups either. Despite being associated with higher brain tissue PO2 levels, which were sustained beyond the intervention period, targeted hyperoxemia exerted neither significantly beneficial nor deleterious effects after combined ASDH and HS in swine with pre-existing coronary artery disease. The unavailability of a power calculation and, thus, the limited number of animals included, are the limitations of the study.

Too much tolerance for hyperoxemia in mechanically ventilated patients with SARS-CoV-2 pneumonia? Report from an Italian intensive care unit.

BackgroundIn COVID-19 patients requiring mechanical ventilation, the administration of high oxygen (O2) doses for prolonged time periods may be necessary. Although life-saving in most cases, O2 may exert deleterious effects if administered in excessive concentrations. We aimed to describe the prevalence of hyperoxemia and excessive O2 administration in mechanically ventilated patients with SARS-CoV-2 pneumonia and determine whether hyperoxemia is associated with mortality in the Intensive Care Unit (ICU) or the onset of ventilator-associated pneumonia (VAP).Materials and methodsRetrospective single-center study on adult patients with SARS-CoV-2 pneumonia requiring invasive mechanical ventilation for ≥48 h. Patients undergoing extracorporeal respiratory support were excluded. We calculated the excess O2 administered based on the ideal arterial O2 tension (PaO2) target of 55–80 mmHg. We defined hyperoxemia as PaO2 > 100 mmHg and hyperoxia + hyperoxemia as an inspired O2 fraction (FiO2) > 60% + PaO2 > 100 mmHg. Risk factors for ICU-mortality and VAP were assessed through multivariate analyses.ResultsOne hundred thirty-four patients were included. For each day of mechanical ventilation, each patient received a median excess O2 of 1,121 [829–1,449] L. Hyperoxemia was found in 38 [27–55]% of arterial blood gases, hyperoxia + hyperoxemia in 11 [5–18]% of cases. The FiO2 was not reduced in 69 [62–76]% of cases of hyperoxemia. Adjustments were made more frequently with higher PaO2 or initial FiO2 levels. ICU-mortality was 32%. VAP was diagnosed in 48.5% of patients. Hyperoxemia (OR 1.300 95% CI [1.097–1.542]), time of exposure to hyperoxemia (OR 2.758 [1.406–5.411]), hyperoxia + hyperoxemia (OR 1.144 [1.008–1.298]), and daily excess O2 (OR 1.003 [1.001–1.005]) were associated with higher risk for ICU-mortality, independently of age, Sequential Organ failure Assessment score at ICU-admission and mean PaO2/FiO2. Hyperoxemia (OR 1.033 [1.006–1.061]), time of exposure to hyperoxemia (OR 1.108 [1.018–1.206]), hyperoxia + hyperoxemia (OR 1.038 [1.003–1.075]), and daily excess O2 (OR 1.001 [1.000–1.001]) were identified as risk factors for VAP, independently of body mass index, blood transfusions, days of neuromuscular blocking agents (before VAP), prolonged prone positioning and mean PaO2/FiO2 before VAP.ConclusionExcess O2 administration and hyperoxemia were common in mechanically ventilated patients with SARS-CoV-2 pneumonia. The exposure to hyperoxemia may be associated with ICU-mortality and greater risk for VAP.

Pulmonary vascular disease in pulmonary hypertension due to left heart disease: pathophysiologic implications.

Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in left heart disease (LHD). This study sought to characterize the pathophysiology of PVD across the spectrum of PH in LHD. Patients with PH-LHD [mean pulmonary artery (PA) pressure >20 mmHg and PA wedge pressure (PAWP) ≥15 mmHg] and controls free of PH or LHD underwent invasive haemodynamic exercise testing with simultaneous echocardiography, expired air and blood gas analysis, and lung ultrasound in a prospective study. Patients with PH-LHD were divided into isolated post-capillary PH (IpcPH) and PVD [combined post- and pre-capillary PH (CpcPH)] based upon pulmonary vascular resistance (PVR <3.0 or ≥3.0 WU). As compared with controls (n = 69) and IpcPH-LHD (n = 55), participants with CpcPH-LHD (n = 40) displayed poorer left atrial function and more severe right ventricular (RV) dysfunction at rest. With exercise, patients with CpcPH-LHD displayed similar PAWP to IpcPH-LHD, but more severe RV-PA uncoupling, greater ventricular interaction, and more severe impairments in cardiac output, O2 delivery, and peak O2 consumption. Despite higher PVR, participants with CpcPH developed more severe lung congestion compared with both IpcPH-LHD and controls, which was associated lower arterial O2 tension, reduced alveolar ventilation, decreased pulmonary O2 diffusion, and greater ventilation-perfusion mismatch. Pulmonary vascular disease in LHD is associated with a distinct pathophysiologic signature marked by greater exercise-induced lung congestion, arterial hypoxaemia, RV-PA uncoupling, ventricular interdependence, and impairment in O2 delivery, impairing aerobic capacity. Further study is required to identify novel treatments targeting the pulmonary vasculature in PH-LHD.

Impact of Arterial Carbon Dioxide and Oxygen Content on Cerebral Autoregulation Monitoring Among Children Supported by ECMO.

Cerebral autoregulation (CA) impairment is associated with neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Severe variations of arterial CO2 (PaCO2) and O2 (PaO2) tension after ECMO onset are common and associate with mortality and poor neurological outcome. The impact of gas exchange on CA among critically ill patients is poorly studied. Retrospective analysis of data collected prospectively from 30 children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France. A correlation coefficient between the variations of regional cerebral oxygen saturation (rSO2) and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). Cox-MAP plots were investigated allowing determining lower limit of autoregulation (LLA) and upper limit of autoregulation (ULA) limits of autoregulation. Age-based normal blood pressure was used to adjust the MAP, LLA, and ULA data from each patient and then reported as percentage (nMAP, nLLA, and nULA, respectively). RSO2, COx, nMAP, nLLA, and nULA values were averaged over one hour before each arterial blood gas (ABG) sample during ECMO run. Thirty children (median age 4.8months [Interquartile range (IQR) 0.7-39.1], median weight 5kg [IQR 4-15]) experiencing 31 ECMO runs were included in the study. Three hundred and ninety ABGs were analyzed. The highest values of COx were observed on day 1 (D1) of ECMO. The relationship between COx and PaCO2 was nonlinear, but COx values tended to be lower in case of hypercapnia compared to normocapnia. During the whole ECMO run, a weak but significant correlation between PaCO2 and nULA was observed (R = 0.432, p = 0.02). On D1 of ECMO, this correlation was stronger (R = 0.85, p = 0.03) and a positive correlation between nLLA and PaCO2 was also found (R = 0.726, p < 0.001). A very weak negative correlation between PaO2 and nULA was observed within the whole ECMO run and on D1 of ECMO (R = -0.07 p = 0.04 and R = -0.135 p = <0.001, respectively). The difference between nULA and nLLA representing the span of the autoregulation plateau was positively correlated with PaCO2 and negatively correlated with PaO2 (R = 0.224, p = 0.01 and R = -0.051, p = 0.004, respectively). We observed a complex relationship between PaCO2 and CA, influenced by the level of blood pressure. Hypercapnia seems to be globally protective in normotensive or hypertensive condition, while, in case of very low MAP, hypercapnia may disturb CA as it increases LLA. These data add additional arguments for very cautiously lower PaCO2, especially after ECMO start.

The impact of damage-associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body.

What is the central question of this study? Are carotid bodies (CBs) modulated by the damage-associated molecular patterns (DAMPs) and humoral factors of aseptic tissue injury? What are the main findings and their importance? DAMPs (HMGB1, S100 A8/A9) and blood plasma from rats subjected to tibia surgery, a model of aseptic injury, stimulate the release of neurotransmitters (ATP, dopamine) and TNF-α from ex vivo rat CBs. All-thiol HMGB1 mediates upregulation of immune-related biological pathways. These data suggest regulation of CB function by endogenous mediators of innate immunity. The glomus cells of carotid bodies (CBs) are the primary sensors of arterial partial O2 and CO2 tensions and moreover serve as multimodal receptors responding also to other stimuli, such as pathogen-associated molecular patterns (PAMPs) produced by acute infection. Modulation of CB function by excessive amounts of these immunomodulators is suggested to be associated with a detrimental hyperinflammatory state. We have hypothesized that yet another class of immunomodulators, endogenous danger-associated molecular patterns (DAMPs), released upon aseptic tissue injury and recognized by the same pathogen recognition receptors as PAMPs, might modulate the CB activity in a fashion similar to PAMPs. We have tested this hypothesis by exposing rat CBs to various DAMPs, such as HMGB1 (all-thiol and disulfide forms) and S100 A8/A9 in a series of ex vivo experiments that demonstrated the release of dopamine and ATP, neurotransmitters known to mediate CB homeostatic responses. We observed a similar response after incubating CBs with conditioned blood plasma obtained from the rats subjected to tibia surgery, a model of aseptic injury. In addition, we have investigated global gene expression in the rat CB using an RNA sequencing approach. Differential gene expression analysis showed all-thiol HMGB1-driven upregulation of a number of prominent pro-inflammatory markers including Il1α and Il1β. Interestingly, conditioned plasma had a more profound effect on the CB transcriptome resulting in inhibition rather than activation of the immune-related pathways. These data are the first to suggest potential modulation of CB function by endogenous mediators of innate immunity.

Optimal ventilator settings after return of spontaneous circulation.

To describe current practice, recent advances in knowledge and future directions for research related to the post return of spontaneous circulation (ROSC) ventilatory management of cardiac arrest patients. Out-of-hospital cardiac arrest (OHCA) is a major public health problem with an estimated incidence of approximately one per 1000 persons per year. A priority of intensive care management of resuscitated OHCA patients is to reduce secondary reperfusion injury. Most OHCA patients are mechanically ventilated. Most of these require mechanical ventilation as they are unconscious and for oxygen (O2) management and carbon dioxide (CO2) control. Low levels of O2 and CO2 following OHCA is associated with poor outcome. Recently, very high fraction of inspired oxygen has been associated with poor outcomes and elevated CO2 levels have been associated with improved neurological outcomes. Moreover, it is increasingly being appreciated that the ventilator may be a tool to adjust physiological parameters to enhance the chances of favourable outcomes. Finally, ventilator settings themselves and the adoption of protective ventilation strategies may affect lung-brain interactions and are being explored as other avenues for therapeutic benefit. Current evidence supports the targeting of normal arterial O2 and CO2 tensions during mechanical ventilation following ROSC after cardiac arrest. Use of protective lung strategies during mechanical ventilation in resuscitated cardiac arrest patients is advocated. The potential therapeutic benefits of conservative O2 therapy, mild hypercapnia and the optimal ventilator settings to use post-ROSC period will be confirmed or refuted in clinical trials.

Abstract 246: Development of a Reflex Work of Breathing Scale for Easy Implementation Outside Intensive Care Environments

Introduction: A common misconception is that increased work of breathing (WOB) in hospitalized patients can be ruled-out when arterial O 2 tension (or saturation) is adequate and arterial PCO 2 is not elevated. Unrecognized WOB increase leads to respiratory muscle fatigue, cessation of respiratory function, and cardiac arrest. We previously developed a WOB Scale for bedside use adding points (maximum 7) based on respiratory rate (1 to 20 bpm = 1 point; 21 to 25 bpm = 2 points; 26 to 30 bpm = 3 points; and &gt; 30 bpm = 4 points), nasal flaring (No = 0 points; Yes = 1 point), activation of the sternocleidomastoid muscle (No = 0 points; Yes = 1 point), and activation of abdominal muscles (No = 0 points; Yes = 1 point). A WOB Scale &gt; 3 points typical identifies a patient in need of intervention to reduce or support WOB increase. However, widespread application of our WOB Scale - especially outside intensive care environments - would likely benefit from a simplified approach. Thus, we investigated developing a “reflex” approach whereby measurement of all four components would be contingent on the respiratory rate level. Methods: We analyzed 110 WOB Scale measurements in a mixed population of ICU and General Ward patients and assessed WOB Scale levels hypothesizing that a respiratory rate of 1 point (1 to 20 bpm) would be predictive of a low WOB Scale (i.e., not exceeding 3 points); thus, obviating the need to perform a complete WOB Scale evaluation. Results: The WOB Scale distribution showed that most patients had normal WOB with only 14 patients (12.7%) having a WOB Scale &gt; 3 points (i.e., 1 point = 60; 2 points = 24; 3 points = 12; 4 points = 6; 5 points = 7; 6 points = 1; 7 points = 0). A respiratory rate level of 1 point (i.e., 1 to 20 bpm), occurred in 68 patients and only 3 (1.5%) had a WOB Scale &gt; 3 points. Yet, when the respiratory rate level was 2 points (i.e., 21 to 25 bpm), which occurred in 28 patients, 3 (10.7%) had a WOB Scale &gt; 3 points. Respiratory rate levels of 3 or 4 points (&gt; 26 bpm) were associated with activation of at least one accessory respiratory muscle examined in 64% of the patients. Conclusions: A respiratory rate of 20 bpm or less predicted low WOB in most patients supporting a Reflex WOB Scale whereby respiratory accessory muscle activation is assessed only when the respiratory rate exceeds 20 bpm.

Cerebral oxidative metabolism is decreased with extreme apnoea in humans; impact of hypercapnia.

The present study describes the cerebral oxidative and non-oxidative metabolism in man during a prolonged apnoea (ranging from 3min36s to 7min26s) that generates extremely low levels of blood oxygen and high levels of carbon dioxide. The cerebral oxidative metabolism, measured from the product of cerebral blood flow and the radial artery-jugular venous oxygen content difference, was reduced by ∼29% at the termination of apnoea, although there was no change in the non-oxidative metabolism. A subset study with mild and severe hypercapnic breathing at the same level of hypoxia suggests that hypercapnia can partly explain the cerebral metabolic reduction near the apnoea breakpoint. A hypercapnia-induced oxygen-conserving response may protect the brain against severe oxygen deprivation associated with prolonged apnoea. Prolonged apnoea in humans is reflected in progressive hypoxaemia and hypercapnia. In the present study, we explore the cerebral metabolic responses under extreme hypoxia and hypercapnia associated with prolonged apnoea. We hypothesized that the cerebral metabolic rate for oxygen (CMRO2 ) will be reduced near the termination of apnoea, attributed in part to the hypercapnia. Fourteen elite apnoea-divers performed a maximal apnoea (range 3min 36s to 7min 26s) under dry laboratory conditions. In a subset study with the same divers, the impact of hypercapnia on cerebral metabolism was determined using varying levels of hypercapnic breathing, against the background of similar hypoxia. In both studies, the CMRO2 was calculated from the product of cerebral blood flow (ultrasound) and the radial artery-internal jugular venous oxygen content difference. Non-oxidative cerebral metabolism was calculated from the ratio of oxygen and carbohydrate (lactate and glucose) metabolism. The CMRO2 was reduced by ∼29% (P<0.01, Cohen's d=1.18) near the termination of apnoea compared to baseline, although non-oxidative metabolism remained unaltered. In the subset study, in similar backgrounds of hypoxia (arterial O2 tension: ∼38.4mmHg), severe hypercapnia (arterial CO2 tension: ∼58.7mmHg), but not mild-hypercapnia (arterial CO2 tension: ∼46.3mmHg), depressed the CMRO2 (∼17%, P=0.04, Cohen's d=0.87). Similarly to the apnoea, there was no change in the non-oxidative metabolism. These data indicate that hypercapnia can partly explain the reduction in CMRO2 near the apnoea breakpoint. This hypercapnic-induced oxygen conservation may protect the brain against severe hypoxaemia associated with prolonged apnoea.

Focal cerebral ischemic tolerance and change in blood-brain barrier permeability after repetitive pure oxygen exposure preconditioning in a rodent model.

OBJECTIVE The goal of this study was to demonstrate that repetitive pure oxygen exposure preconditioning (O2PC) for 8 hours per day for 3 or 7 days, a practicable preconditioning for clinical use, is able to induce cerebral ischemic tolerance (IT) and further clarify the accompanying changes in the blood-brain barrier (BBB) that may be involved. METHODS A total of 68 adult male Sprague-Dawley rats and eight 1-day-old rat pups were used in this study. The adult rats were exposed to pure O2 (38 rats) 8 hours a day for 3 or 7 days or to room air (in an identical setup) for 8 hours a day for 7 days as controls (30 rats). Arterial O2 tension (PaO2) was measured in 6 rats exposed to O2 and 3 controls. Focal cerebral ischemia was elicited by middle cerebral artery occlusion (MCAO) in 37 rats, of which 21 had been exposed to pure O2 for 3 or 7 days and 16 to room air for 7 days as controls. Neurological behavior was scored with the Garcia score in 15 MCAO rats, of which 10 had been exposed to pure O2 for 3 or 7 days and 5 to room air for 7 days as controls, and cerebral infarct volumes were assessed with TTC (2,3,5-triphenyltetrazolium chloride) staining in 10 rats (5 from each group) after 7 days of exposure. Formamide-extraction method was used to detect leakage of Evans blue (EB) dye in 7 rats exposed to pure O2 for 7 days and 7 exposed to room air for 7 days. Fluorescence microscopy was used to analyze the leaked EB in the nonischemic areas of 4 rats exposed to pure O2 for 7 days and 4 exposed to room air for 7 days before MCAO and the brain of the rats that had not been subjected to MCAO. Astrocyte changes associated with O2PC were evaluated by means of fluorescence microscopy and electron microscopy in 14 rats that were exposed to the same O2 or control conditions as the MCAO rats but without MCAO. Astrocytes were also obtained from 8 rat pups and cultured; levels of AQP4 and VEGF were detected by Western blot and ELISA in cells with and without O2 treatment. RESULTS A significant increase in PaO2 was seen after O2PC. The neurological score was significantly increased in the O2PC groups (10.6 ± 0.6 in the 3-day O2PC group, p < 0.05; 12 ± 0.84 in the 7-day O2PC group, p < 0.05) compared with the control group (7 ± 0.55). The ratio of cerebral infarct volume to contralateral cerebral hemisphere volume was significantly lower in the O2PC group than in the control group (0.204 ± 0.03 vs 0.48 ± 0.05, p < 0.05). The amount of leaked EB in the ischemic cerebral hemisphere was also lower in the O2-treated rats than in controls (7.53 ± 1.4 vs 11.79 ± 3.3 μg EB/g brain weight, p < 0.05). However, fluorescence microscopy showed significantly greater BBB permeability in the nonischemic areas in the O2PC group than in controls (p < 0.05). More red fluorescence could be observed in the nonischemic areas in both the ipsilateral and contralateral sides of the ischemic brain in the O2PC animals than in the nonischemic areas in the corresponding sides of the controls. Further investigation of the effect of the O2PC itself on the BBB of rats that were not subjected to MCAO showed that there was no EB leakage in the brain parenchyma in the rats exposed to room air, but some red fluorescence patches were noticed in the normal brain from the rats in the O2PC group. Astrocytes, including those from areas around the BBB, were activated in the O2PC group. Levels of both aquaporin 4 (AQP4) and vascular endothelial growth factor (VEGF) were significantly increased in cultured astrocytes after O2PC. CONCLUSIONS These findings suggest that O2PC is able to induce IT, which makes it a strong candidate for clinical use. Moreover, O2PC can also promote BBB opening, which may contribute to the induction of IT as well as representing a possible strategy for promoting drug transportation into the CNS. Activated astrocytes are likely to be involved in these processes through astrocyte-derived factors, such as AQP4 and VEGF.

Hypoxemia, oxygen content, and the regulation of cerebral blood flow.

This review highlights the influence of oxygen (O2) availability on cerebral blood flow (CBF). Evidence for reductions in O2 content (CaO2 ) rather than arterial O2 tension (PaO2 ) as the chief regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O2 sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in CaO2 . We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in CaO2 and thus maintain cerebral O2 delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that CaO2 has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower CaO2 during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regulation during changes in O2 content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP, deoxyhemoglobin nitrite reductase activity, and the downstream interplay of several vasoactive factors including adenosine and epoxyeicosatrienoic acids. The emerging picture supports the role of deoxyhemoglobin (associated with changes in CaO2 ) as the primary biological regulator of CBF. The mechanisms for vasodilation therefore appear more robust during hypoxemic hypoxia than during changes in CaO2 via hemodilution. Clinical implications (e.g., disorders associated with anemia and polycythemia) and future study directions are considered.

Peripheral chemoreflex inhibition with low-dose dopamine: new insight into mechanisms of extreme apnea.

The purpose of this study was to determine the impact of peripheral chemoreflex inhibition with low-dose dopamine on maximal apnea time, and the related hemodynamic and cerebrovascular responses in elite apnea divers. In a randomized order, participants performed a maximal apnea while receiving either intravenous 2 μg·kg(-1)·min(-1) dopamine or volume-matched saline (placebo). The chemoreflex and hemodynamic response to dopamine was also assessed during hypoxia [arterial O2 tension, (PaO2 ) ∼35 mmHg] and mild hypercapnia [arterial CO2 tension (PaCO2 ) ∼46 mmHg] that mimicked the latter parts of apnea. Outcome measures included apnea duration, arterial blood gases (radial), heart rate (HR, ECG), mean arterial pressure (MAP, intra-arterial), middle (MCAv) and posterior (PCAv) cerebral artery blood velocity (transcranial ultrasound), internal carotid (ICA) and vertebral (VA) artery blood flow (ultrasound), and the chemoreflex responses. Although dopamine depressed the ventilatory response by 27 ± 41% (vs. placebo; P = 0.01), the maximal apnea duration was increased by only 5 ± 8% (P = 0.02). The PaCO2 and PaO2 at apnea breakpoint were similar (P > 0.05). When compared with placebo, dopamine increased HR and decreased MAP during both apnea and chemoreflex test (P all <0.05). At rest, dopamine compared with placebo dilated the ICA (3.0 ± 4.1%, P = 0.05) and VA (6.6 ± 5.0%, P < 0.01). During apnea and chemoreflex test, conductance of the cerebral vessels (ICA, VA, MCAv, PCAv) was increased with dopamine; however, flow (ICA and VA) was similar. At least in elite apnea divers, the small increase in apnea time and similar PaO2 at breakpoint (∼31 mmHg) suggest the apnea breakpoint is more related to PaO2 , rather than peripheral chemoreflex drive to breathe.

Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis.

IntroductionThe safety of arterial hyperoxia is under increasing scrutiny. We performed a systematic review of the literature to determine whether any association exists between arterial hyperoxia and mortality in critically ill patient subsets.MethodsMedline, Thomson Reuters Web of Science and Scopus databases were searched from inception to June 2014. Observational or interventional studies evaluating the relationship between hyperoxia (defined as a supranormal arterial O2 tension) and mortality in adult intensive care unit (ICU) patients were included. Studies primarily involving patients with exacerbations of chronic pulmonary disease, acute lung injury and perioperative administration were excluded. Adjusted odds ratio (OR) of patients exposed versus those not exposed to hyperoxia were extracted, if available. Alternatively, unadjusted outcome data were recorded. Data on patients, study characteristics and the criteria used for defining hyperoxia exposure were also extracted. Random-effects models were used for quantitative synthesis of the data, with a primary outcome of hospital mortality.ResultsIn total 17 studies (16 observational, 1 prospective before-after) were identified in different patient categories: mechanically ventilated ICU (number of studies (k) = 4, number of participants (n) = 189,143), post-cardiac arrest (k = 6, n = 19,144), stroke (k = 2, n = 5,537), and traumatic brain injury (k = 5, n = 7,488). Different criteria were used to define hyperoxia in terms of PaO2 value (first, highest, worst, mean), time of assessment and predetermined cutoffs. Data from studies on ICU patients were not pooled because of extreme heterogeneity (inconsistency (I2) 96.73%). Hyperoxia was associated with increased mortality in post-cardiac arrest patients (OR = 1.42 (1.04 to 1.92) I2 67.73%) stroke (OR = 1.23 (1.06 to 1.43) I2 0%) and traumatic brain injury (OR = 1.41 (1.03 to 1.94) I2 64.54%). However, these results are limited by significant heterogeneity between studies.ConclusionsHyperoxia may be associated with increased mortality in patients with stroke, traumatic brain injury and those resuscitated from cardiac arrest. However, these results are limited by the high heterogeneity of the included studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0711-x) contains supplementary material, which is available to authorized users.

Acclimatization to long-term hypoxia: gene expression in ovine carotid arteries.

Exposure to acute high-altitude hypoxia is associated with an increase in cerebral blood flow (CBF) as a consequence of low arterial O2 tension. However, in response to high altitude acclimatization, CBF returns to levels similar to those at sea level, and tissue blood flow is maintained by an increase in angiogenesis. Of consequence, dysregulation of the acclimatization responses and CBF can result in acute mountain sickness, acute cerebral and/or pulmonary edema. To elucidate the signal transduction pathways involved in successful acclimatization to high altitude, in ovine carotid arteries, we tested the hypothesis that high altitude-associated long-term hypoxia results in changes in gene expression of critical signaling pathways. We acclimatized nonpregnant adult sheep to 3,801 m altitude for ∼110 days and conducted oligonucleotide microarray experiments on carotid arteries. Of a total of 116 regulated genes, 58 genes were significantly upregulated and 58 genes were significantly downregulated (each >2-fold, P < 0.05). Major upregulated genes included suprabasin and myelin basic protein, whereas downregulated genes included BAG2. Several of these genes are known to activate the ERK canonical signal transduction pathway and the process of angiogenesis. We conclude that among other changes, the altered signal transduction molecules involved in high-altitude acclimatization are associated ERK activation and angiogenesis.

Cardiopulmonary Function in Thoroughbred Horses Running Uphill and Downhill on an Inclined Treadmill

IntroductionEccentric muscle contractions (“negative” work, e.g., downhill running) affect human skeletal muscle differently than concentric contractions, increasing muscle size and strength more than concentric exercise training with reduced oxygen consumption (VO2). Better understanding of skeletal muscle and cardiopulmonary responses to downhill training may indicate a role for this in Thoroughbred training. We hypothesised that Thoroughbreds would reduce metabolic energy cost and cardiopulmonary function when they ran at equivalent speed on a declined treadmill compared with running horizontally or uphill.MethodsFive well‐trained Thoroughbreds ran for 2‐min incremental exercise intervals on a treadmill at 1.7, 3.5, 6.0, 8.0 and 10.0 m/s on a +4% incline, 0% incline (horizontal) and −4% decline in random order on different days. Cardiopulmonary and O2‐transport variables were measured and analysed with two‐way repeated‐measures ANOVA and Holm‐Šidák pairwise‐comparisons.ResultsHorses ran at all inclines with identical stride frequency and length. At identical uphill speeds they had significantly higher (vs. horizontal) mass‐specific VO2 (43% mean increase) and CO2 production (VCO2/Mb), cardiac output (Q/Mb), heart rate, arterial CO2 tension (PaCO2), and reduced arterial O2 tension and saturation; tidal volume tended to be higher (P = 0.060). Downhill running reduced (vs. horizontal) VO2/Mb (19% mean decrease), VCO2/Mb, Q/Mb and PaCO2. Fractional energy cost increase (incline) and reduction (decline) decreased linearly with increasing speed.ConclusionsThoroughbreds run downhill with lower energy cost than on the level or uphill and the cost changes with speed. It remains to be determined if eccentric training induces skeletal muscle changes in horses.Ethical Animal ResearchThe study was approved by the Animal Welfare and Ethics Committee of the Equine Research Institute, Japan Racing Association. Sources of funding: none. Competing interests: none.

Oxygen management in mechanically ventilated patients: A prospective observational cohort study

Purpose: Oxygen (O2) is the most common therapy in mechanically ventilated patients, but targets and dose are poorly understood. We aimed to describe current O2 administration and titration in such patients in an academic intensive care unit. Materials and Methods: In consecutive ventilated (N48 hours) patients we prospectively obtained fraction of inspired O2 (FIO2), pulse oximetry O2 saturation (SpO2) and arterial O2 tension (PaO2) every 6 hours. We calculated the amount of excess O2 delivery and the intensivists’ response to hyperoxemia (SpO2 N98%). Results: During 358 mechanical ventilation days in 51 critically ill patients, median calculated excess O2 delivery was 3472 L per patient. Patients spent most of their time with their SpO2 N98% (59% [2983]) and PaO2 between 80 and 120 mm Hg (59% [38–72]). In addition, 50% of all observations showed hyperoxemia and 4% severe hyperoxemia (PaO2 N202.5 mm Hg). Moreover, 71% of the calculated total excess 263,841 L of O2 was delivered when the FIO2 was 0.3 to 0.5. When hyperoxemia occurred with an FIO2 between 0.3 and 0.4, for 88% of episodes, no FIO2 adjustments were made. Conclusions: Excess O2 delivery and liberal O2 therapy were common in mechanically ventilated patients. Current O2 therapy practice may be suboptimal and further investigations are warranted.

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Introduction: Hyperoxia with excessive supplemental oxygen (O2) may be injurious. While several studies have provided epidemiological data for oxygen administration in critically ill patients, evidence is inadequate for deciding the best target values for arterial O2 tension (PaO2). Methods: We retrospectively reviewed medical records of patients admitted to the ICU from January 2010 to May 2013. We included patients who were older than 15 years and had received mechanical ventilation (MV) for more than 48 hours. Patients at risk of imminent death on admission or treated by non-invasive positive pressure ventilation were excluded. We collected patient demographics, reasons for MV, arterial blood gas analyses and ventilator settings at 48 hours or later after beginning of MV. Performing multivariable logistic regression analysis to clarify independent factors related to hyperoxemia, we compared the hyperoxemia and non-hyperoxemia groups. Results: During the study period, 328 out of 1,664 patients were enrolled. Hyperoxemia occurred in 83 (25.3%) patients. Comparable values for each group were (hyperoxemia vs. non-hyperoxemia): PaO2, 133 (124–145) vs. 98 (84–108) mmHg; inspired O2 fraction, 0.3 (0.3–0.4) vs. 0.3 (0.3–0.4); positive end-expiratory pressure, 6 (6–8) vs. 8 (6–8) cmH2O; and duration of MV 144 (72–387) vs. 170 (105–325) hours. Hyperoxemia correlated with younger age (p = 0.027), lower serum lactate level (p = 0.029) and decompensated heart failure (p = 0.042). Multivariable logistic regression analysis revealed hyperoxemia to be independently associated with age ≤ 39 (odds ratio[OR], 2.6, 95% confidence interval [CI], 1.1 to 6.0) and decompensated heart failure (OR, 1.9, CI, 1.1 to 3.5). APACHE II score ≥ 30 was associated with lower incidence of hyperoxyemia (OR, 0.53, CI, 0.3 to 1.0). Conclusions: Hyperoxemia was common in younger and APACHE II score

Role of Central and Peripheral Chemoreceptors in Vasopressin Secretion Control

In this review, we analyzed the role played by central and peripheral chemoreceptors (CHRs) in vasopressin (AVP) secretion control. Central neural pathways subserving osmotic and non-osmotic control of AVP secretion are strictly correlated to brain areas participating in chemoreception mechanisms. Among the different brain areas involved in central chemoreception, the most important site has been localized in the retrotrapezoid nucleus of the rostral ventrolateral medulla. These central CHRs are able to detect very small pH/CO2 fluctuations, participating in brain blood flow regulation, acid-base balance and blood pressure control. Decreases in arterial pH and increases in arterial pCO2 stimulate AVP release by the Supraoptic and Paraventricular Nuclei. Carotid CHRs transduce low arterial O2 tension into increased action potential activity, leading to bradycardia and coronary vasodilatation via vagal stimulation, and systemic vasoconstriction via catecholaminergic stimulation. Stimulation of carotid CHRs by hypoxia increases neurohypophyseal blood flow and AVP release, an effect inhibited by CHRs denervation. Two renal CHRs have been identified: Type R1 CHRs do not have a resting discharge but are activated by renal ischemia and hypotension; Type R2 CHRs have a resting discharge and respond to backflow of urine into the renal pelvis. Signals arising from renal CHRs modulate the activity of hypothalamic AVPergic neurons: activation of R1 and R2 CHRs, following increased intrapelvic pressure with solutions of mannitol, NaCl and KCl, produces a significant increase of AVP secretion and the same effect has been obtained by the intrarenal infusion of bradykinin, which excites afferent renal nerves, as well as by the electrical stimulation of these nerves.

Influences of pleural effusion on respiratory mechanics, gas exchange, hemodynamics, and recruitment effects in acute respiratory distress syndrome

BackgroundAcute lung injury and acute respiratory distress syndrome (ALI/ARDS) cause substantial morbidity and mortality despite improvements in the understanding of lung injury and advances in treatment. Recruitment maneuver (RM) with high sustained airway pressures is proposed as an adjunct to mechanical ventilation to maintain alveolar patency. In addition, RM has been advocated to improve pulmonary gas exchange. However, many factors may influence responses to RM and the effect of pleural effusion (PLE) is unknown. MethodThere were four groups in this study (n = 6 in each group). Group A was the control group, group B was the PLE group, group C was ARDS with RM, and group D was ARDS with PLE and RM. RM was performed in groups C and D, consisting of a peak pressure of 45 cm H2O with positive end-expiratory pressure of 35 cm H2O sustained for 1 min. Arterial blood gas, systemic and pulmonary hemodynamics, lung water, and respiratory mechanics were measured throughout. ResultAfter the induction of ALI/ARDS, there were significant decreases in partial pressure of oxygen in arterial blood, mean arterial pressure, systemic vascular resistance, and lung compliance. There were also significant increases in the alveolar–arterial O2 tension difference, partial pressure of arterial carbon dioxide, mean pulmonary arterial pressure, pulmonary vascular resistance, and lung water. The RM improved oxygenation, which was attenuated by PLE. ConclusionsALI/ARDS leads to poor oxygenation and hemodynamics. RM results in improved oxygenation, but this improvement is attenuated by PLE.

Current oxygen management in mechanically ventilated patients: A prospective observational cohort study

PurposeOxygen (O2) is the most common therapy in mechanically ventilated patients, but targets and dose are poorly understood. We aimed to describe current O2 administration and titration in such patients in an academic intensive care unit. Materials and MethodsIn consecutive ventilated (>48 hours) patients we prospectively obtained fraction of inspired O2 (Fio2), pulse oximetry O2 saturation (Spo2) and arterial O2 tension (Pao2) every 6 hours. We calculated the amount of excess O2 delivery and the intensivists’ response to hyperoxemia (Spo2 >98%). ResultsDuring 358 mechanical ventilation days in 51 critically ill patients, median calculated excess O2 delivery was 3472 L per patient. Patients spent most of their time with their Spo2 >98% (59% [29-83]) and Pao2 between 80 and 120 mm Hg (59% [38–72]). In addition, 50% of all observations showed hyperoxemia and 4% severe hyperoxemia (Pao2 >202.5 mm Hg). Moreover, 71% of the calculated total excess 263,841 L of O2 was delivered when the Fio2 was 0.3 to 0.5. When hyperoxemia occurred with an Fio2 between 0.3 and 0.4, for 88% of episodes, no Fio2 adjustments were made. ConclusionsExcess O2 delivery and liberal O2 therapy were common in mechanically ventilated patients. Current O2 therapy practice may be suboptimal and further investigations are warranted.

Fish in hot water: Hypoxaemia does not trigger catecholamine mobilization during heat shock in rainbow trout (Oncorhynchus mykiss)

Rainbow trout (Oncorhynchus mykiss) exposed to an acute heat shock (1h at 25°C after raising water temperature from 13°C to 25°C over 4h) mount a significant catecholamine response. The present study investigated the proximate mechanisms underlying catecholamine mobilization. Trout exposed to heat shock in vivo exhibited a significant reduction in arterial O2 tension, but arterial O2 concentration was not affected by heat shock, nor was catecholamine release during heat shock prevented by prior and concomitant exposure to hyperoxia (to prevent the fall in arterial O2 tension). Thus, catecholamine mobilization probably was not triggered by impaired blood O2 transport. Heat-shocked trout also exhibited an elevation of arterial CO2 tension coupled with a fall in arterial pH, but these factors are not expected to trigger catecholamine release. The changes in blood O2 and CO2 tension occurred despite a significant hyperventilatory response to heat shock. Future studies should investigate whether catecholamine mobilization during heat shock in rainbow trout is triggered by a specific effect of high temperature activating the sympathetic nervous system via a thermosensitive transient receptor potential channel.