Blood Flow and Respiratory Gas Exchange in the Human Placenta at Term: A Data Update.

Reliable measurements using modern techniques and consensus in experimental design have enabled the assessment of novel data sets for normal maternal and foetal respiratory physiology at term. These data sets include (a) principal factors affecting placental gas transfer, e.g., maternal blood flow through the intervillous space (IVS) (500 mL/min) and foeto-placental blood flow (480 mL/min), and (b) O2, CO2 and pH levels in the materno-placental and foeto-placental circulation. According to these data, the foetus is adapted to hypoxaemic hypoxia. Despite flat oxygen partial pressure (pO2) gradients between the blood of the IVS and the umbilical arteries of the foetus, adequate O2 delivery to the foetus is maintained by the higher O2 affinity of the foetal blood, high foetal haemoglobin (HbF) concentrations, the Bohr effect, the double-Bohr effect, and high foeto-placental (=umbilical) blood flow. Again, despite flat gradients, adequate CO2 removal from the foetus is maintained by a high diffusion capacity, high foeto-placental blood flow, the Haldane effect, and the double-Haldane effect. Placental respiratory gas exchange is perfusion-limited, rather than diffusion-limited, i.e., O2 uptake depends on O2 delivery.

Cardiac autonomic activity during sleep in high-altitude resident children compared with lowland residents.

Study Objectives: We aimed to characterize heart-rate variability (HRV) during sleep in Andean children native to high altitude (HA) compared with age, gender, and genetic ancestry-similar low-altitude (LA) children. We hypothesized that the hypoxic burden of sleep at HA could induce variation in HRV. As children have otherwise healthy cardiovascular systems, such alterations could provide early markers of later cardiovascular disease. Methods: Twenty-six LA (14F) and 18 HA (8F) children underwent a single night of attended polysomnography. Sleep parameters and HRV indices were measured. Linear mixed models were used to assess HRV differences across sleep stage and altitude group. Results: All children showed marked fluctuations in HRV parameters across sleep stages, with higher vagal activity during nonrapid eye movement sleep and greater variability of the heart rate during rapid eye movement (REM). Moreover, HA children showed higher very low-frequency HRV in REM sleep and, after adjusting for heart rate, higher low-to-high frequency ratio in REM sleep compared with children living at lower altitude. Conclusions: We confirmed previous findings of a stage-dependent modulation of HRV in Andean children living at both HA and LA. Moreover, we showed subtle alteration of HRV in sleep in HA children, with intriguing differences in the very low-frequency domain during REM sleep. Whether these differences are the results of an adaptation to high-altitude living, or an indirect effect of differences in oxyhemoglobin saturation remains unclear, and further research is required to address these questions.

Predictive factors for the outcome of high flow nasal cannula therapy in a pediatric intensive care unit: Is the SpO2/FiO2 ratio useful?

OBJECTIVES: To determine the predictive factors for the outcome of high-flow nasal cannula (HFNC) therapy in a pediatric intensive care unit (PICU). MATERIALS AND METHODS: We prospectively included all patients with acute respiratory distress/failure aged 1month to 18years who were admitted to the PICU between January 2015 and May 2016 and treated with HFNC as a primary support and for postextubation according to our pre-established protocol. HFNC failure was defined as the need for escalation to non-invasive ventilation (NIV) or invasive mechanical ventilation (MV). HFNC responders and nonresponders were compared based on clinical data obtained just before HFNC and at 30, 60, and 120min, 12, 24, and 48h, and at the end of therapy. RESULTS: A total of 204 patients (median age: 16.5months) participated in the study. Twenty-six (12.7%) patients required escalation (4 to NIV and 22 to MV). Age >120months, higher PRISM-III and respiratory scores, and a lower SpO2/FiO2 (S/F) ratio at admission were predictors of HFNC failure. Achievement of the S/F>200 goal at 60min significantly predicted successful HFNC. CONCLUSION: Monitoring the S/F ratio might be useful and practical to avoid delaying escalation to another ventilation support. Failure to achieve S/F>200 at 60min should be a warning for the escalation of respiratory support.

Cerebral haemodynamic response to somatosensory stimulation in neonatal lambs.

KEY POINTS: Cerebral haemodynamic response to neural stimulation has been extensively studied in adults, but little is known about cerebral haemodynamic response in the fetal and neonatal brain. The present study describes the cerebral haemodynamic response measured by near infrared spectroscopy to somatosensory stimulation in newborn lambs, in comparison to recent findings in fetal sheep. The cerebral haemodynamic responses in the newborn lamb brain can involve an increase in oxyhaemoglobin (oxyHb), or a decrease of oxyHb suggestive of reduced perfusion and oxygenation. Positive correlations between changes in oxyHb and mean arterial blood pressure were found in newborn but not fetal sheep, which suggests the result is unlikely to be due to immature autoregulation alone. In contrast to adult studies, hypercapnia increased the changes in cerebral blood flow and oxyHb in most of the lambs in response to somatosensory stimulation. ABSTRACT: The neurovascular coupling response has been defined for the adult brain, but in the neonate non-invasive measurement of local cerebral perfusion using near infrared spectroscopy or blood oxygen level-dependent functional magnetic resonance imaging have yielded variable and inconsistent results, including negative responses suggesting decreased perfusion and localized tissue tissue hypoxia. Also, the impact of permissive hypercapnia (P aC O2 > 50 mmHg) in the management of neonates on cerebrovascular responses to somatosensory input is unknown. Using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb) in eight anaesthetized newborn lambs, we studied the cerebral haemodynamic functional response to left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8 s. Stimulation always produced a somatosensory evoked response, and superficial cortical perfusion measured by laser Doppler flowmetry predominantly increased following median nerve stimulation. However, with 1.8 s stimulation, oxyHb responses in the contralateral hemisphere were either positive (i.e. increased oxyHb), negative, or absent; and with 4.8 and 7.8 s stimulations, both positive and negative responses were observed. Hypercapnia increased baseline oxyHb and total Hb consistent with cerebral vasodilatation, and six of seven lambs tested showed increased Δtotal Hb responses after the 7.8 s stimulation, among which four lambs also showed increased ΔoxyHb responses. In two of three lambs, the negative ΔoxyHb response became a positive pattern during hypercapnia. These results show that instead of functional hyperaemia, somatosensory stimulation can evoke negative (decreased oxyHb, total Hb) functional responses in the neonatal brain suggestive of decreased local perfusion and vasoconstriction, and that hypercapnia produces both baseline hyperperfusion and increased functional hyperaemia.

Anemia and Oxygen Delivery.

Clinical assessment of tissue oxygenation is challenging. Anemia reflects a decreased oxygen carrying capacity of the blood and its significance in the perioperative setting relates largely to the associated risk of insufficient oxygen delivery and cellular hypoxia. Until meaningful clinical measures of tissue oxygenation are available in veterinary practice, clinicians must rely on evaluation of a patient's hemodynamic and ventilatory performance, along with biochemical and hemogasometric measurements. Blood transfusion is used commonly for treatment of perioperative anemia, and may improve tissue oxygenation by normalizing the rheologic properties of blood and enhancing perfusion, independent of increases in oxygen carrying capacity.

Low frequency oscillations in cephalic vessels assessed by near infrared spectroscopy.

BACKGROUND AND METHODS: Low frequency oscillations (LFO) of cerebral vessels are believed to reflect cerebral autoregulation. We investigated day-to-day and hemispheric variations in 0.1 Hz LFO with near infrared spectroscopy (NIRS) and transcranial Doppler (TCD) to determine phase shift and gain of oxygenated haemoglobin (oxyHb) and the velocity of the middle cerebral artery (Vmca) to the arterial blood pressure (ABP). The direct left-right phase shifts of oxyHb and Vmca were also assessed. We examined 44 healthy volunteers by simultaneous recordings of ABP, oxyHb and Vmca during spontaneous and paced breathing at 6 breaths per minute on two separate days. RESULTS: The variation between hemispheres had a prediction interval (PI) of ± 39° for ABP-oxyHb phase shift and ± 69% for gain. ABP-Vmca showed ± 57° PI phase shift and ± 158% PI for gain. The variation from day to day showed ± 61° PI for ABP-oxyHb phase shift and ± 297% PI for gain. ABP-Vmca showed ± 45° PI phase shift and ± 166% PI for gain. We found a linear relation between phase shift of oxyHb and Vmca at paced breathing (P=0.0005), but not at rest (P=0.235). CONCLUSION: Our results show that LFO phase shift ABP-oxyHb may be used as a robust measurement of differences in autoregulation between hemispheres and over time. In addition, we found a strong relation between oxyHb and Vmca during paced breathing. Gain showed too large variation for clinical use, as the SD was up to 100-fold of mean values.

Cerebrovascular responses of the rat brain to noxious stimuli as examined by functional near-infrared whole brain imaging.

While near-infrared (NIR) spectroscopy has been increasingly used to detect stimulated brain activities with an advantage of dissociating regional oxy- and deoxyhemoglobin concentrations simultaneously, it has not been utilized much in pain research. Here, we investigated and demonstrated the feasibility of using this technique to obtain whole brain hemodynamics in rats and speculated on the functional relevance of the NIR-based hemodynamic signals during pain processing. NIR signals were emitted and collected using a 26-optodes array on rat's dorsal skull surface after the removal of skin. Following the subcutaneous injection of formalin (50 µl, 3%) into a hindpaw, several isolable brain regions showed hemodynamic changes, including the anterior cingulate cortex, primary/secondary somatosensory cortexes, thalamus, and periaqueductal gray (n = 6). Time courses of hemodynamic changes in respective regions matched with the well-documented biphasic excitatory response. Surprisingly, an atypical pattern (i.e., a decrease in oxyhemoglobin concentration with a concomitant increase in deoxyhemoglobin concentration) was seen in phase II. In a separate group of rats with innocuous brush and noxious pinch of the same area (n = 11), results confirmed that the atypical pattern occurred more likely in the presence of nociception than nonpainful stimulation, suggesting it as a physiological substrate when the brain processes pain. In conclusion, the NIR whole brain imaging provides a useful alternative to study pain in vivo using small-animal models. Our results support the notion that neurovascular response patterns depend on stimuli, bringing attention to the interpretation of vascular-based neuroimaging data in studies of pain.

Should oxyhaemoglobin saturation be monitored continuously during the 6-minute walk test?

Guidelines for conducting the 6-minute walk test (6MWT) indicate that oxyhaemoglobin saturation (SpO( 2)) should not be monitored constantly during the test. The aim of this study was to determine whether the nadir SpO(2) differs from the end-6MWT SpO(2) in patients with chronic respiratory disease. A total of 86 subjects underwent the 6MWT according to a standardized protocol with continuous monitoring of SpO(2) by pulse oximeter. Comparison of nadir SpO(2) and end SpO(2) was made and the proportion of subjects with important desaturation according to each measure was determined. The effect of resting during the 6MWT on the likelihood of a significant difference between nadir and end SpO(2) was evaluated. A total of 29 subjects with chronic obstructive pulmonary disease (COPD; mean [SD] forced expiratory volume in 1 second [FEV(1)] 51[21] % predicted) and 57 with interstitial lung disease (ILD; TLCO 49[18] % predicted) were studied. Nadir SpO(2) was slightly lower than end-test SpO(2) (median 87% vs. 88%, p < 0.001) with differences ranging from 1% to 10%. Those who rested during the test (n = 14) were more likely to have a significant difference between nadir SpO(2) and end SpO(2) (p = 0.04). End SpO(2) did not accurately identify desaturation in 21% of subjects. No differences between COPD and ILD were observed. For most patients with chronic respiratory disease, the end SpO(2) and the nadir SpO( 2) are similar during the 6MWT. However, the end SpO(2) does not give an accurate estimate of nadir SpO(2) in patients who rest. Consideration should be given to the constant monitoring of SpO(2) during the 6MWT.

About the stability of phase shifts between slow oscillations around 0.1 Hz in cardiovascular and cerebral systems.

One important feature of the baroreflex loop is its strong preference for oscillations around 0.1 Hz. In this study, we investigated heart rate intervals, arterial blood pressure (BP), and prefrontal oxyhemoglobin changes during 5 min rest and during brisk finger movements in 19 healthy subjects. We analyzed the phase coupling around 0.1 Hz between cardiovascular and (de)oxyhemoglobin oscillations, using the cross-spectral method. The analyses revealed phase shifts for slow oscillations in BP and heart rate intervals between -10° and -118° (BP always leading). These phase shifts increased significantly (p<0.01) in the movement session. The coupling between cardiovascular and oxyhemoglobin oscillations was less clear. Only 12 subjects demonstrated a phase coupling (COH(2) ≥ 0.5) between oxyhemoglobin and BP oscillations. This may be explained by an overwhelming proportion of nonlinearity in cardiovascular and hemodynamic systems. The phase shifts between slow cardiovascular and hemodynamic oscillations are relatively stable subject-specific biometric features and could be of interest for person identification in addition to other biometric data. Slow BP-coupled oscillations in prefrontal oxyhemoglobin changes can seriously impair the detection of mentally induced hemodynamic changes in an optical brain-computer interface, a novel nonmuscular communication system.

Impairment of 3000-m run time at altitude is influenced by arterial oxyhemoglobin saturation.

UNLABELLED: The decline in maximal oxygen uptake (ΔVO(2)max) with acute exposure to moderate altitude is dependent on the ability to maintain arterial oxyhemoglobin saturation (SaO2). PURPOSE: This study examined if factors related to ΔVO(2)max at altitude are also related to the decline in race performance of elite athletes at altitude. METHODS: Twenty-seven elite distance runners (18 men and 9 women, VO(2)max = 71.8 ± 7.2 mL·kg(-1)·min(-1)) performed a treadmill exercise at a constant speed that simulated their 3000-m race pace, both in normoxia and in 16.3% O2 (∼2100 m). Separate 3000-m time trials were completed at sea level (18 h before altitude exposure) and at 2100 m (48 h after arrival at altitude). Statistical significance was set at P ≤ 0.05. RESULTS: Group 3000-m performance was significantly slower at altitude versus sea level (48.5 ± 12.7 s), and the declines were significant in men (48.4 ± 14.6 s) and women (48.6 ± 8.9 s). Athletes grouped by low SaO2 during race pace in normoxia (SaO2 < 91%, n = 7) had a significantly larger ΔVO(2) in hypoxia (-9.2 ± 2.1 mL·kg(-1)·min(-1)) and Δ3000-m time at altitude (54.0 ± 13.7 s) compared with athletes with high SaO2 in normoxia (SaO2 > 93%, n = 7, ΔVO(2) = -3.5 ± 2.0 mL·kg(-1)·min(-1), Δ3000-m time = 38.9 ± 9.7 s). For all athletes, SaO2 during normoxic race pace running was significantly correlated with both ΔVO(2) (r = -0.68) and Δ3000-m time (r = -0.38). CONCLUSIONS: These results indicate that the degree of arterial oxyhemoglobin desaturation, already known to influence ΔVO(2)max at altitude, also contributes to the magnitude of decline in race performance at altitude.

Lower extremity edema and pulmonary hypertension in morbidly obese patients with obstructive sleep apnea.

INTRODUCTION: In 70 consecutive male patients with obstructive sleep apnea (OSA) diagnosed at the Northport VA Medical Center Sleep Disorders Center, we have characterized the association between obesity, OSA, and pulmonary hypertension (PH). MATERIALS AND METHODS: By including anthropometric, pulmonary function, and sleep study parameters in a multivariate logistic regression model, we found that a BMI of >40 kg/m(2) and the minimum oxygen saturation in non-rapid eye movement (NREM) sleep predicted the presence of pretibial edema in this sleep apnea population. We then characterized the hemodynamics of those OSA patients that had lower extremity edema. Twenty-nine of the 70 consecutive patients with sleep apnea (41%) had pretibial edema, and right heart catheterization data was obtained for 28 (97%) of these patients. RESULTS AND DISCUSSION: Ninety-three percent (26/28) of the patients had right heart failure (mean RAP > 5 mm Hg; RAP range = 0-32 mmHg) and PH (PA mean >or= 20 mm Hg) was present in 86% (24/28.) The OSA patients with lower extremity edema had an increased cardiac output (7.0 + 1.4 l/min) with a normal cardiac index (2.9 + 0.5 l/min/m(2)) in the setting of an elevated pulmonary capillary wedge pressure (PCWP 17 +/- 7 mmHg) and a normal pulmonary vascular resistance (122 + 70 dynes s cm(-5)). While PCWP, FEV(1)% predicted, and the minimum oxygen saturation in NREM sleep all independently predicted PH, PCWP was the most important predictor of PH. CONCLUSION: We conclude that pulmonary hypertension is commonly seen in patients with OSA with pretibial edema and that pretibial edema is a highly specific sign of PH in OSA patients. Pulmonary hypertension appears to result from an elevated back pressure and diastolic dysfunction with contributions from lung function and nocturnal oxygen saturation.

Ligand reactivity and allosteric regulation of hemoglobin-based oxygen carriers.

Historically, exogenous administration of hemoglobin solutions to implement the oxygen transport capacity for clinical applications suffered from dramatic drawbacks, resulting in the failure of many attempts. In the last decades, the biochemical and physiological basis responsible for the therapeutic failures has been extensively investigated. It is now widely accepted that they mostly arise because, out of the confined and controlled environment of the red blood cell, hemoglobin exhibits tetramer instability, increased auto-oxidation rate, higher oxygen affinity, altered cooperativity and nitric oxide reactivity. Moreover, it became evident that the design of a hemoglobin-based oxygen carrier that exactly reproduces the "physiological" oxygen-binding curve is not only an overly ambitious task, but may also represent a wrong approach for many potential clinical applications. Under these premises, and given the complex chemical nature of blood, it is obvious that any strategy undertaken to modify the stability and function of the hemoglobin tetramer for clinical use should be driven by a detailed knowledge of its structure, dynamics and mechanism of allosteric regulation. We briefly review the most recent theories and experiments that increased our understanding of the mechanism of homo- and heterotropic effects in human hemoglobin, trying to interpret, on a biophysical basis, how diverse approaches like polymerization, cross-linking, site-directed mutagenesis, surface decoration and encapsulation may affect ligand affinity and allosteric regulation.

Respiratory system determinants of peripheral fatigue and endurance performance.

We briefly summarize recent evidence pertaining to how mechanisms primarily under the control of the respiratory system-namely, arterial oxyhemoglobin desaturation, respiratory muscle work and fatigue, and cyclical fluctuations in intrathoracic pressure-may contribute to exercise limitation. Respiratory influences on cardiac output and on sympathetic vasoconstrictor activity and blood flow distribution are shown to be important determinants of performance. We also address how a compromised O2 transport exacerbates the rate of development of peripheral muscle fatigue and, in turn, precipitates central fatigue and exercise limitation.

Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas.

RATIONALE: Epidemiologic studies on the consequences of sleep-disordered breathing invariably use the apnea-hypopnea index as the primary measure of disease severity. Although hypopneas constitute a majority of disordered breathing events, significant controversy remains about the best criteria used to define these events. OBJECTIVES: The current investigation sought to assess the most appropriate definition for hypopneas that would be best correlated with cardiovascular disease. METHODS: A community sample of middle-aged and older adults was recruited as part of the Sleep Heart Health Study. Full-montage polysomnography was conducted and hypopneas were defined using different thresholds of oxyhemoglobin desaturation with and without arousals. Prevalent cardiovascular disease was assessed based on self-report. Logistic regression analysis was used to characterize the independent association between the hypopnea index and prevalent cardiovascular disease. MEASUREMENTS AND MAIN RESULTS: Using a sample of 6,106 adults with complete data on cardiovascular disease status and polysomnography, the current study found that hypopneas associated with an oxyhemoglobin desaturation of 4% or more were associated with prevalent cardiovascular disease independent of confounding covariates. The adjusted prevalent odds ratios for quartiles of the hypopnea index using a 4% desaturation criterion were as follows: 1.00 (<1.10 events/h), 1.10 (1.01-3.20 events/h), 1.33 (3.21-7.69 events/h), and 1.41 (>7.69 events/h). Hypopnea measures based on less than 4% oxyhemoglobin desaturation or presence of arousals showed no association with cardiovascular disease. CONCLUSIONS: Hypopneas comprise a significant component of sleep-disordered breathing in the general community. By varying the criteria for defining hypopneas, this study demonstrates that hypopneas with a desaturation of at least 4% are independently associated with cardiovascular disease. In contrast, no association was observed between cardiovascular disease and hypopneas associated with milder desaturations or arousals.

Cheyne stokes breathing at high altitude: a helpful response or a troublemaker?

Sleep disorders at high altitude are common and well-known for centuries. One symptom of the complex is periodic breathing (PB). PB occurs from a disbalance of the negative feedback loop of ventilation control, and at high altitude, it is increased by a phase shift of 180 degrees between hyperventilation and hypoxia. This paper explains the mechanisms that trigger the problem and discusses whether PB may be of advantage or disadvantage for the person going to high altitude. Up to about 3,000-3,500 m, PB may be of advantage because it stabilizes oxygen saturation at a relatively high level. At higher altitudes, disadvantages predominate because frequent arousals cause total sleep deprivation and mental and physical impairment of the victim. Correct acclimatization and "defensive" altitude profiles are gold standard, which minimize PB and optimizes recreative sleep, although they cannot mask PB completely, especially at extreme altitude.

Allogeneic red blood cell transfusion: physiology of oxygen transport.

Allogeneic red blood cell (RBC) transfusions have been shown to be associated with considerable risks. While their efficiency in many clinical situations has not been proven, the number of studies finding adverse outcomes in terms of morbidity (e.g. postoperative infections) and mortality continues to rise. In view of these facts, physicians involved in transfusion medicine have to be as restrictive as possible with RBC transfusions. Only a thorough knowledge of the physiology and pathophysiology of oxygen transport can be a solid base for meaningful transfusion decisions. Therefore, the goal of this article is to review the basics of oxygen transport and normovolaemic anaemia.

Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes.

Oxyhemoglobin (OxyHb) can suppress voltage-dependent K(+) channel (K(V)) currents through protein tyrosine kinase activation, which may contribute to cerebral vasospasm following subarachnoid hemorrhage. Here we have tested the hypothesis that shedding of heparin-binding EGF-like growth factor (HB-EGF) and the resulting activation of the tyrosine kinase EGF receptor (EGFR) underlie OxyHb-induced K(V) channel suppression in the cerebral vasculature. With the use of the conventional whole cell patch-clamp technique, two EGFR ligands, EGF and HB-EGF, were found to mimic OxyHb-induced K(V) suppression in rabbit cerebral artery myocytes. K(V) current suppression by OxyHb or EGF ligands was eliminated by a specific EGFR inhibitor, AG-1478, but was unaffected by PKC inhibition. Compounds (heparin and CRM-197) that specifically interfere with HB-EGF signaling eliminated OxyHb-induced K(V) suppression, suggesting that HB-EGF is the EGFR ligand involved in this pathway. HB-EGF exists as a precursor protein that, when cleaved by matrix metalloproteases (MMPs), causes EGFR activation. MMP activation was detected in OxyHb-treated arteries by gelatin zymography. Furthermore, the MMP inhibitor (GM-6001) abolished OxyHb-induced K(V) current suppression. We also observed K(V) current suppression due to EGFR activation in human cerebral artery myocytes. In conclusion, these data demonstrate that OxyHb induces MMP activation, causing HB-EGF shedding and enhanced EGFR activity, ultimately leading to K(V) channel suppression. We propose that EGFR-mediated K(V) suppression contributes to vascular pathologies, such as cerebral vasospasm, and may play a more widespread role in the regulation of regional blood flow and peripheral resistance.