Simonson, Tatum S. Altitude adaptation: A glimpse through various lenses. High Alt Med Biol 16:125–137, 2015.—Recent availability of genome-wide data from highland populations has enabled the identification of adaptive genomic signals. Some of the genomic signals reported thus far among Tibetans, Andeans, and Ethiopians are the same, while others appear unique to each population. These genomic findings parallel observations conveyed by decades of physiological research: different continental populations, resident at high altitude for hundreds of generations, exhibit a distinct composite of traits at altitude. The most commonly reported signatures of selection emanate from genomic segments containing hypoxia-inducible factor (HIF) pathway genes. Corroborative evidence for adaptive significance stems from associations between putatively adaptive gene copies and sea-level ranges of hemoglobin concentration in Tibetans and Amhara Ethiopians, birth weights and metabolic factors in Andeans and Tibetans, maternal uterine artery diameter in Andeans, and protection from chronic mountain sickness in Andean males at altitude. While limited reports provide mechanistic insights thus far, efforts to identify and link precise genetic variants to molecular, physiological, and developmental functions are underway, and progress on the genomics front continues to provide unprecedented movement towards these goals. This combination of multiple perspectives is necessary to maximize our understanding of orchestrated biological and evolutionary processes in native highland populations, which will advance our understanding of both adaptive and non-adaptive responses to hypoxia.
Xiaodan Yan. Cognitive impairments at high altitudes and adaptation. High Alt Med Biol. 15:141–145, 2014.—High altitude hypoxia has been shown to have significant impact on cognitive performance. This article reviews the aspects in which, and the conditions under which, decreased cognitive performance has been observed at high altitudes. Neural changes related to high altitude hypoxia are also reviewed with respect to their possible contributions to cognitive impairments. In addition, potential adaptation mechanisms are reviewed among indigenous high altitude residents and long-term immigrant residents, with discussions about methodological concerns related to these studies.
Roach, Robert C., Peter H. Hackett, Oswald Oelz, Peter Bärtsch, Andrew M. Luks, Martin J. MacInnis, J. Kenneth Baillie, and The Lake Louise AMS Score Consensus Committee. The 2018 Lake Louise Acute Mountain Sickness Score. High Alt Med Biol 19:1–4, 2018.— The Lake Louise Acute Mountain Sickness (AMS) scoring system has been a useful research tool since first published in 1991. Recent studies have shown that disturbed sleep at altitude, one of the five symptoms scored for AMS, is more likely due to altitude hypoxia per se, and is not closely related to AMS. To address this issue, and also to evaluate the Lake Louise AMS score in light of decades of experience, experts in high altitude research undertook to revise the score. We here present an international consensus statement resulting from online discussions and meetings at the International Society of Mountain Medicine World Congress in Bolzano, Italy, in May 2014 and at the International Hypoxia Symposium in Lake Louise, Canada, in February 2015. The consensus group has revised the score to eliminate disturbed sleep as a questionnaire item, and has updated instructions for use of the score.
Aldenderfer, Mark. Peopling the Tibetan plateau: insights from archaeology. High Alt. Med. Biol. 12:141–147, 2011.—Recent studies of the genome of modern Tibetans have revealed the existence of genes thought to provide an adaptive advantage for life at high elevation. Extrapolating from this discovery, some researchers now argue that a Tibetan–Han split occurred no more than 2750 yr ago. This date is implausible, and in this paper I review the archaeological data from the Tibetan plateau as one means by which to examine the veracity of this assertion. Following a review of the general state of knowledge of Tibetan prehistory, which is unfortunately only at its beginnings, I first examine the data that speak to the initial peopling of the plateau and assess the evidence that traces of their presence can be seen in modern Tibetans today. Although the data are sparse, both archaeology and genetics suggest that the plateau was occupied in the Late Pleistocene, perhaps as early as 30,000 yr ago, and that these early peoples have left a genetic signature in modern Tibetans. I then turn to the evidence for later migrations and focus on the question of the timing of the establishment of permanent settled villages on the plateau. Three areas of the plateau—northeastern Qinghai, extreme eastern Tibet, and the Yarlung Tsangpo valley—have evidence of permanent settlements dating from ca. 6500, 5900, and 3750 yr ago, respectively. These data are not consonant with the 2750 yr ago date for the split and suggest at a minimum that the plateau has been occupied substantially longer and, further, that multiple migrations at different times and from different places have created a complex mosaic of population history.
Swenson, Erik R. Hypoxic pulmonary vasoconstriction. High Alt Med Biol 14:101–110, 2013.—Hypoxic pulmonary vasoconstriction (HPV) continues to fascinate cardiopulmonary physiologists and clinicians since its definitive description in 1946. Hypoxic vasoconstriction exists in all vertebrate gas exchanging organs. This fundamental response of the pulmonary vasculature in air breathing animals has relevance to successful fetal transition to air breathing at birth and as a mechanism of ventilation-perfusion matching in health and disease. It is a complex process intrinsic to the vascular smooth muscle, but with in vivo modulation by a host of factors including the vascular endothelium, erythrocytes, pulmonary innervation, circulating hormones and acid-base status to name only a few. This review will provide a broad overview of HPV and its mechansms and discuss the advantages and disadvantages of HPV in normal physiology, disease and high altitude.
Ainslie, Philip N., and Andrew W. Subudhi. Invited Review: Cerebral blood flow at high altitude. High Alt Med Biol. 15:133–140, 2014.—This brief review traces the last 50 years of research related to cerebral blood flow (CBF) in humans exposed to high altitude. The increase in CBF within the first 12 hours at high altitude and its return to near sea level values after 3–5 days of acclimatization was first documented with use of the Kety-Schmidt technique in 1964. The degree of change in CBF at high altitude is influenced by many variables, including arterial oxygen and carbon dioxide tensions, oxygen content, cerebral spinal fluid pH, and hematocrit, but can be collectively summarized in terms of the relative strengths of four key integrated reflexes: 1) hypoxic cerebral vasodilatation; 2) hypocapnic cerebral vasoconstriction; 3) hypoxic ventilatory response; and 4) hypercapnic ventilatory response. Understanding the mechanisms underlying these reflexes and their interactions with one another is critical to advance our understanding of global and regional CBF regulation. Whether high altitude populations exhibit cerebrovascular adaptations to chronic levels of hypoxia or if changes in CBF are related to the development of acute mountain sickness are currently unknown; yet overall, the integrated CBF response to high altitude appears to be sufficient to meet the brain's large and consistent demand for oxygen. This short review is organized as follows: An historical overview of the earliest CBF measurements collected at high altitude introduces a summary of reported CBF changes at altitude over the last 50 years in both lowlanders and high-altitude natives. The most tenable candidate mechanism(s) regulating CBF at altitude are summarized with a focus on available data in humans, and a role for these mechanisms in the pathophysiology of AMS is considered. Finally, suggestions for future directions are provided.
Karl, J. Philip, Renee E. Cole, Claire E. Berryman, Graham Finlayson, Patrick N. Radcliffe, Matthew T. Kominsky, Nancy E. Murphy, John W. Carbone, Jennifer C. Rood, Andrew J. Young, and Stefan M. Pasiakos. Appetite suppression and altered food preferences coincide with changes in appetite-mediating hormones during energy deficit at high altitude, but are not affected by protein intake. High Alt Med Biol. 19:156–169, 2018.—Anorexia and unintentional body weight loss are common during high altitude (HA) sojourn, but underlying mechanisms are not fully characterized, and the impact of dietary macronutrient composition on appetite regulation at HA is unknown. This study aimed to determine the effects of a hypocaloric higher protein diet on perceived appetite and food preferences during HA sojourn and to examine longitudinal changes in perceived appetite, appetite mediating hormones, and food preferences during acclimatization and weight loss at HA. Following a 21-day level (SL) period, 17 unacclimatized males ascended to and resided at HA (4300 m) for 22 days. At HA, participants were randomized to consume measured standard-protein (1.0 g protein/kg/d) or higher protein (2.0 g/kg/d) hypocaloric diets (45% carbohydrate, 30% energy restriction) and engaged in prescribed physical activity to induce an estimated 40% energy deficit. Appetite, food preferences, and appetite-mediating hormones were measured at SL and at the beginning and end of HA. Diet composition had no effect on any outcome. Relative to SL, appetite was lower during acute HA (days 0 and 1), but not different after acclimatization and weight loss (HA day 18), and food preferences indicated an increased preference for sweet- and low-protein foods during acute HA, but for high-fat foods after acclimatization and weight loss. Insulin, leptin, and cholecystokinin concentrations were elevated during acute HA, but not after acclimatization and weight loss, whereas acylated ghrelin concentrations were suppressed throughout HA. Findings suggest that appetite suppression and altered food preferences coincide with changes in appetite-mediating hormones during energy deficit at HA. Although dietary protein intake did not impact appetite, the possible incongruence with food preferences at HA warrants consideration when developing nutritional strategies for HA sojourn.
Villafuerte, Francisco C., and Noemí Corante. Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High Alt Med Biol. 17:61–69, 2016.—Millions of people worldwide live at a high altitude, and a significant number are at risk of developing Chronic Mountain Sickness (CMS), a progressive incapacitating syndrome caused by lifelong exposure to hypoxia. CMS is characterized by severe symptomatic excessive erythrocytosis (EE; Hb ≥19 g/dL for women and Hb ≥21 g/dL for men) and accentuated hypoxemia, which are frequently associated with pulmonary hypertension. In advanced cases, the condition may evolve to cor pulmonale and congestive heart failure. Current knowledge indicates a genetic predisposition to develop CMS. However, there are important risk factors and comorbidities that may trigger and aggravate the condition. Thus, appropriate medical information on CMS is necessary to provide adequate diagnosis and healthcare to high-altitude inhabitants. After reviewing basic clinical aspects of CMS, including its definition, diagnosis, and common clinical findings, we discuss aspects of its etiology, and address its epidemiology, risk factors, and treatment.
Sutherland, Angus, Joseph Freer, Laura Evans, Alberto Dolci, Matteo Crotti, and Jamie Hugo Macdonald. MEDEX 2015: Heart rate variability predicts development of acute mountain sickness. High Alt Med Biol. 18: 199-208, 2017. Aims: Acute mountain sickness (AMS) develops when the body fails to acclimatize to atmospheric changes at altitude. Preascent prediction of susceptibility to AMS would be a useful tool to prevent subsequent harm. Changes to peripheral oxygen saturation (SpO2) on hypoxic exposure have previously been shown to be of poor predictive value. Heart rate variability (HRV) has shown promise in the early prediction of AMS, but its use pre-expedition has not previously been investigated. We aimed to determine whether pre-and intraexpedition HRV assessment could predict susceptibility to AMS at high altitude with better diagnostic accuracy than SpO2. Methods: Forty-four healthy volunteers undertook an expedition in the Nepali Himalaya to > 5000 m. SpO2 and HRV parameters were recorded at rest in normoxia and in a normobaric hypoxic chamber before the expedition. On the expedition HRV parameters and SpO2 were collected again at 3841 m. A daily Lake Louise Score was obtained to assess AMS symptomology. Results: Low frequency/high frequency (LF/HF) ratio in normoxia (cutpoint ae 2.28 a. u.) and LF following 15 minutes of exposure to normobaric hypoxia had moderate (area under the curve 0.8) diagnostic accuracy. LF/HF ratio in normoxia had the highest sensitivity (85%) and specificity (88%) for predicting AMS on subsequent ascent to altitude. In contrast, pre-expedition SpO2 measurements had poor (area under the curve < 0.7) diagnostic accuracy and inferior sensitivity and specificity. Conclusions: Pre-ascent measurement of HRV in normoxia was found to be of better diagnostic accuracy for AMS prediction than all measures of HRV in hypoxia, and better than peripheral oxygen saturation monitoring.
Lundeberg, Jenny, John R. Feiner, Andrew Schober, Jeffrey W. Sall, Helge Eilers, and Philip E. Bickler. Increased cytokines at high altitude: lack of effect of ibuprofen on acute mountain sickness, physiological variables or cytokine levels. High Alt Med Biol. 19:249–258, 2018. Introduction: There is no consensus on the role of inflammation in high-altitude acclimatization. Aims: To determine the effects of a nonsteroidal anti-inflammatory drug (ibuprofen 400 mg every 8 hours) on blood cytokines, acclimatization, acute mountain sickness (AMS, Lake Louise Score), and noninvasive oxygenation in brain and muscle in healthy volunteers. Materials and Methods: In this double-blind study, 20 volunteers were randomized to receive ibuprofen or placebo at sea level and for 48 hours at 3800 m altitude. Arterial, brain, and leg muscle saturation with near infrared spectroscopy, pulse oximetry, and heart rate were measured. Blood samples were collected for cytokine levels and cytokine gene expression. Results: All of the placebo subjects and 8 of 11 ibuprofen subjects developed AMS at altitude ( p = 0.22, comparing placebo and ibuprofen). On arrival at altitude, the oxygen saturation as measured by pulse oximetry (S p O 2 ) was 84.5% ± 5.4% (mean ± standard deviation). Increase in blood interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels occurred comparably in the placebo and ibuprofen groups (all not significant, univariate test by Wilcoxon rank sum). Increased IL-6 was associated with higher AMS scores ( p = 0.002 by Spearman rank correlation). However, we found no difference or association in AMS score and blood or tissue oxygenation between the ibuprofen and placebo groups. Conclusions: We found that ibuprofen, at the package-recommended adult dose, did not have a significant effect on altitude-related increases in cytokines, AMS scores, blood, or tissue oxygenation in a population of healthy subjects with a high incidence of AMS.
Clemente-Suárez, Vicente Javier, José Juan Robles-Pérez, Ketty Herrera-Mendoza, Beliña Herrera-Tapias, and Jesús Fernández-Lucas. Psychophysiological response and fine motor skills in high-altitude parachute jumps. High Alt Med Biol 18:392–399, 2017.—We analyzed the psychophysiological response and specific fine motor skill of an experienced jumper in HALO (high altitude low opening) and HAHO (high altitude high opening) parachute jumps. Eight HALO and eight HAHO jumpers were analyzed. They jumped at 5500 m, HALO jumpers opened the parachute at 500 m and HAHO jumpers at 4300 m of altitude. Before and after the jumps, parameters of muscle strength, cortical arousal, blood creatine kinase (CK) and glucose, blood oxygen saturation, rate of perceived exertion (RPE), and specific fine motor skills of an experienced jumper were assessed; during the jump, heart rate (HR), HR variability, and speed were evaluated. HALO and HAHO jumps produced a significant increase in CK, lactate, and RPE, and a decrease in glucose. HAHO decreased cortical arousal, presented a higher sympathetic modulation, and a higher HR during the jump than HALO. HALO and HAHO produced an increase in the physiological, sympathetic modulation and muscle destruction, and a decrease in cortical arousal and a higher blood lactate concentration only in the HAHO jump. Also, somatic and cognitive anxiety correlated with higher strength manifestation and muscle destruction. This novel research could be used to improve actual training systems in both civil and military parachute jumpers.
Miele, Catherine H., Alan R. Schwartz, Robert H. Gilman, Luu Pham, Robert A. Wise, Victor G. Davila-Roman, Jonathan C. Jun, Vsevolod Y. Polotsky, J. Jaime Miranda, Fabiola Leon-Velarde, and William Checkley. Increased cardiometabolic risk and worsening hypoxemia at high altitude. High Alt Med Biol. 17:93–100, 2016.—Metabolic syndrome, insulin resistance, diabetes, and dyslipidemia are associated with an increased risk of cardiovascular disease. While excessive erythrocytosis is associated with cardiovascular complications, it is unclear how worsening hypoxemia of any degree affects cardiometabolic risk factors in high-altitude populations. We studied the relationship between daytime resting oxyhemoglobin saturation and cardiometabolic risk factors in adult participants living in Puno, Peru (3825 m above sea level). We used multivariable logistic regression models to study the relationship between having a lower oxyhemoglobin saturation and markers of cardiometabolic risk. Nine hundred and fifty-four participants (mean age 55 years, 52% male) had information available on pulse oximetry and markers of cardiometabolic risk. Average oxyhemoglobin saturation was 90% (interquartile range 88%–92%) and 43 (4.5%) had excessive erythrocytosis. Older age, decreased height-adjusted lung function, and higher body mass index (BMI) were associated with having an oxyhemoglobin saturation ≤85%. When adjusting for age, sex, socioeconomic status, having excessive erythrocytosis, and site, we found that each 5% decrease in oxyhemoglobin saturation was associated with a higher adjusted odds of metabolic syndrome (OR = 1.35, 95% CI: 1.07–1.72, p 2 mass units (OR = 1.29, 95% CI: 1.00–1.67, p < 0.05), hemoglobin A1c ≥6.5% (OR = 1.66, 95% CI: 1.09–2.51, p < 0.04), and high sensitivity C-reactive protein (hs-CRP) ≥3 mg/L (OR = 1.46, 95% CI: 1.09–1.96, p < 0.01). In high-altitude populations in Puno, Peru, a higher BMI and lower pulmonary function were associated with lower resting daytime oxyhemoglobin saturation. Lower resting oxyhemoglobin saturation, in turn, was associated with higher odds of having multiple unfavorable cardiometabolic factors. Worsening hypoxia of any degree in high-altitude dwellers may be an independent risk factor for cardiovascular disease.
Introduction: Educational projects in mountain rescue in Nepal have a long tradition. They are usually led by Western experts who train their Nepalese colleagues using teams of people with diverse cultural background. To better understand the challenges of these encounters, we conducted a prospective cohort study during the first mountain rescue instructor course in Nepal. Methods: Western instructors (WIs) and Nepalese instructor candidates (NICs) were asked to self-assess their intercultural competence with the help of questionnaires. The responses were compared and analyzed for differences between WIs and NICs and differences in a pre–post assessment of the WIs. In addition, semistructured interviews were conducted with randomly selected NICs. Results: We found significant differences in communication styles between NICs and WIs: NICs showed a preference to establish relationships before discussing business and not to speak openly in conflict situations. WIs were much more direct and preferred dispassionate exchanges. In an assessment after the course, WIs had changed their attitude toward the host culture. Conclusions: We found differences in communication styles between WIs and NICs that are relevant to globalized medical education. Faculty members should be prepared before implementing medical training abroad and should have time to experience the host culture.
Introduction: Hypothermia and frostbite occur when there is a significant decrease in central and peripheral body temperature in individuals exposed to cold windy conditions, often at high altitude or in a mountain environment. Portable hyperbaric chambers increase the barometric pressure and thereby the partial pressure of oxygen inside the chamber, and their use is a well-known treatment for altitude illness. This study aims to show that a portable hyperbaric chamber could also be used to treat hypothermia and frostbite in the field, when rescue or descent is impossible or delayed. Methods: During a European research program (SOS-MAM, Flow Pulse study) measurements were taken from 27 healthy nonacclimatized voluntary subjects (21 men, 6 women, mean age 41 ± 17) at an altitude of 3800 m (Chamonix Mountain Lab, Aiguille du Midi, France) right before and immediately after spending 1 hour in a portable hyperbaric chamber at 300 mbar. We measured digital cutaneous temperature (Tcut), digital cutaneous blood flow (Fcut), digital tissue oxygenation (T c PO 2 ), blood oxygen saturation (S p O 2 ), heart rate, and core temperature. Air temperature inside the chamber (Tchamb) was measured throughout the whole session. Results: We observed significant increases in Tchamb: 9.3°C compared with the outside temperature, Tcut: +7.5°C (±6.2°C 71%), Fcut: +58 PU (±89) (+379%), T c PO 2 : +18 mmHg (±11.9) (304%), and S p O 2 : 13%. Conclusion: This study shows that a portable hyperbaric chamber can be used to treat frostbite and/or hypothermia in the field at altitude when descent or rescue is impossible or even simply delayed.
Exposure to high altitude activates several complex and adaptive mechanisms aiming to protect human homeostasis from extreme environmental conditions, such as hypoxia and low temperatures. Short-term exposure is followed by transient hyperglycemia, mainly triggered by the activation of the sympathetic system, whereas long-term exposure results in lower plasma glucose concentrations, mediated by improved insulin sensitivity and augmented peripheral glucose disposal. An inverse relationship between altitude, diabetes, and obesity has been well documented. This is the result of genetic and physiological adaptations principally to hypoxia that favorably affect glucose metabolism; however, the contribution of financial, dietary, and other life-style parameters may also be important. According to existing evidence, people with diabetes are capable of undertaking demanding physical challenges even at extreme altitudes. Still, a number of issues should be taken into account, including the increased physical activity leading to changes in insulin demands and resistance, the performance of measurement systems under extreme weather conditions and the potential deterioration of metabolic control during climbing expeditions. The aim of this review is to present available evidence in the field in a comprehensive way, beginning from the physiology of glucose homeostasis adaptation mechanisms to high altitudes and ending to what real life experience has taught us.
Locomotion during ascent requires higher energy consumption than on flat terrain. Locomotion efficiency decreases in snowy terrain, with changes in the biomechanical pattern of walking. This study aims to evaluate differences in both cardiorespiratory responses and energy expenditure between locomotion over snowy terrain with an established footstep pathway (FP) and fresh snow (FS) that has not previously been compacted. Fifteen volunteers with experience in mountain activities at a competition level and a regular training schedule of up to 10 hours a week participated in the study. Estimated maximal theoretical oxygen consumption showed a mild increase (2.6%, 95% confidence interval: 0.9%–4.5%, t = 3.2, p = 0.005) when subjects followed the FP compared with FS. More time was necessary to complete locomotion in FS (256 ± 30 seconds) than FP (225 ± 29 seconds; p = 0.01). Uphill walking velocity increased by 0.43 ± 0.11 km/h ( t = 4.2, p = 0.01) in FP compared with FS; and the FS respiratory rate was higher (by 2.3 ± 2.4 beats/min, t = 4.0, p = 0.001). For a same itinerary, locomotion in snow that has not been compacted before requires more time and represents a higher energetic cost, either at maximal or submaximal intensities. This should be considered in scheduling mountain ascents as part of the safety strategies. Climbing on virgin snow impedes developing maximal aerobic power, so athletes must regard the value of strength work of lower limbs to improve performance. Indirect calculation of maximal oxygen consumption based on time to complete locomotion in FP can have practical application as a field test.
High altitude-induced gastrointestinal (GI) problems are potentially life-threatening. GI tract bleeding and inflammation are the major problems induced by hypobaric hypoxia (HH). In this study, effects of acute exposure to HH up to 14 days at 7620 m on GI immune function have been studied. To fulfill these objectives, Sprague-Dawley (SD) rats were divided into five groups namely Control and HH exposed (1, 3, 7, and 14 days). All groups except control were exposed to 7620 m of HH in an animal decompression chamber for the respective time intervals. Different degrees of intestinal mucosal damage in terms of increased mucosal permeability and disruption of intestinal villi were observed for different time intervals. HH exposure also upregulated secretory immunoglobulin A (sIgA) and proinflammatory cytokines in GI lavage along with proinflammatory markers such as toll-like receptor 4 (TLR4) and inducible nitric oxide synthase (iNOS). HH exposure of rats for 7 days significantly increased interleukin-17 (IL-17) and natural killer (NK) cell and dendritic cell populations compared with unexposed control rats. However, the number of naive T cells was significantly decreased in Peyer's patches. Our results connect HH to GI immune axis and highlight Th17 cells and proinflammatory molecules as potential therapeutic targets to counteract HH-induced GI dysfunction.
Understanding the process of successful adaptation to high altitude provides valuable insight into the pathogenesis of conditions associated with impaired oxygen uptake and utilization. Prepubertal children residing at low altitude show a reduced cerebrovascular response to exercise in comparison to adults, and a transient uncoupling of cerebral blood flow to changes in the partial pressure of end-tidal CO 2 (P ET CO 2 ); however, little is known about the cerebrovascular response to exercise in high-altitude native children. We sought to compare the cerebral hemodynamic response to acute exercise between prepubertal children residing at high and low altitude. Prepubertal children ( n = 32; 17 female) of Sherpa descent (Sherpa children [SC]) at high altitude (3800 m, Nepal) and maturational-matched ( n = 32; 20 female) children (lowland children [LLC]) residing at low altitude (342 m, Canada). Ventilation, peripheral oxygen saturation (S p O 2 ), P ET CO 2, and blood velocity in the middle and posterior cerebral arteries (MCA v and PCA v ) were continuously measured during a graded cycling exercise test to exhaustion. At baseline (BL), P ET CO 2 (−19 ± 4 mmHg, p 0.001), but not in LLC ( R 2 = 0.03, p = 0.10). Our findings demonstrate a similar increase in intra-cranial perfusion during exercise in prepubertal SC, despite differential BL values and changes in P ET CO 2 and S p O 2 .