Right ventricular performance during acute hypoxic exercise.

Acute hypoxia increases pulmonary arterial (PA) pressures, though its effect on right ventricular (RV) function is controversial. The objective of this study was to characterize exertional RV performance during acute hypoxia. Ten healthy participants (34 ± 10 years, 7 males) completed three visits: visits 1 and 2 included non-invasive normoxic (fraction of inspired oxygen ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) = 0.21) and isobaric hypoxic ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12) cardiopulmonary exercise testing (CPET) to determine normoxic/hypoxic maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ). Visit 3 involved invasive haemodynamic assessments where participants were randomized 1:1 to either Swan-Ganz or conductance catheterization to quantify RV performance via pressure-volume analysis. Arterial oxygen saturation was determined by blood gas analysis from radial arterial catheterization. During visit 3, participants completed invasive submaximal CPET testing at 50% normoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ and again at 50% hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12). Median (interquartile range) values for non-invasive V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ values during normoxic and hypoxic testing were 2.98 (2.43, 3.66) l/min and 1.84 (1.62, 2.25) l/min, respectively (P < 0.0001). Mean PA pressure increased significantly when transitioning from rest to submaximal exercise during normoxic and hypoxic conditions (P = 0.0014). Metrics of RV contractility including preload recruitable stroke work, dP/dtmax , and end-systolic pressure increased significantly during the transition from rest to exercise under normoxic and hypoxic conditions. Ventricular-arterial coupling was maintained during normoxic exercise at 50% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . During submaximal exercise at 50% of hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ , ventricular-arterial coupling declined but remained within normal limits. In conclusion, resting and exertional RV functions are preserved in response to acute exposure to hypoxia at an F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12 and the associated increase in PA pressures. KEY POINTS: The healthy right ventricle augments contractility, lusitropy and energetics during periods of increased metabolic demand (e.g. exercise) in acute hypoxic conditions. During submaximal exercise, ventricular-arterial coupling decreases but remains within normal limits, ensuring that cardiac output and systemic perfusion are maintained. These data describe right ventricular physiological responses during submaximal exercise under conditions of acute hypoxia, such as occurs during exposure to high altitude and/or acute hypoxic respiratory failure.

No effect of patent foramen ovale on acute mountain sickness and pulmonary pressure in normobaric hypoxia.

NEW FINDINGS: What is the central question to this study? Is there a relationship between a patent foramen ovale and the development of acute mountain sickness and an exaggerated increase in pulmonary pressure in response to 7-10 h of normobaric hypoxia? What is the main finding and its importance? Patent foramen ovale presence did not increase susceptibility to acute mountain sickness or result in an exaggerated increase in pulmonary artery systolic pressure with normobaric hypoxia. This suggests hypobaric hypoxia is integral to the increased susceptibility to acute mountain sickness previously reported in those with patent foramen ovale, and patent foramen ovale presence alone does not contribute to the hypoxic pulmonary pressor response. ABSTRACT: Acute mountain sickness (AMS) develops following rapid ascent to altitude, but its exact causes remain unknown. A patent foramen ovale (PFO) is a right-to-left intracardiac shunt present in ∼30% of the population that has been shown to increase AMS susceptibility with high altitude hypoxia. Additionally, high altitude pulmonary oedema (HAPE) is a severe type of altitude illness characterized by an exaggerated pulmonary pressure response, and there is a greater prevalence of PFO in those with a history of HAPE. However, whether hypoxia per se is causing the increased incidence of AMS in those with a PFO and whether a PFO is associated with an exaggerated increase in pulmonary pressure in those without a history of HAPE is unknown. Participants (n = 36) matched for biological sex (18 female) and the presence or absence of a PFO (18 PFO+) were exposed to 7-10 h of normobaric hypoxia equivalent to 4755 m. Presence and severity of AMS was determined using the Lake Louise AMS scoring system. Pulmonary artery systolic pressure, cardiac output and total pulmonary resistance were measured using ultrasound. We found no significant association of PFO with incidence or severity of AMS and no association of PFO with arterial oxygen saturation. Additionally, there was no effect of a PFO on pulmonary pressure, cardiac output or total pulmonary resistance. These data suggest that hypobaric hypoxia is necessary for those with a PFO to have increased incidence of AMS and that presence of PFO is not associated with an exaggerated pulmonary pressor response.

Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia.

NEW FINDINGS: What is the central question of this study? Does the combination of methazolamide and theophylline reduce symptoms of acute mountain sickness (AMS) and improve aerobic performance in acute hypobaric hypoxia? What is the main finding and its importance? The oral combination of methazolamide (100 BID) and theophylline (300 BID) improved arterial oxygen saturation but did not reduce symptoms of AMS and impaired aerobic performance. We do not recommend this combination of drugs for prophylaxis against the acute negative effects of hypobaric hypoxia. ABSTRACT: A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry ( SpO2 ) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (PB  = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (α = 0.05). The drugs improved resting SpO2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance.

Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics.

Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity in vivo Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.

Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage.

Hypoxanthine catabolism in vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. Leukoreduced red blood cells from glucose-6-phosphate dehydrogenase-normal or -deficient human volunteers were stored in AS-3 under normoxic, hyperoxic, or hypoxic conditions (with oxygen saturation ranging from <3% to >95%). Red blood cells from healthy human volunteers were also collected at sea level or after 1-7 days at high altitude (>5000 m). Finally, C57BL/6J mouse red blood cells were incubated in vitro with 13C1-aspartate or 13C5-adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. Hypoxia in vitro and in vivo decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. In addition, hypoxanthine levels negatively correlated with post-transfusion red blood cell recovery in mice and - preliminarily albeit significantly - in humans. In conclusion, hypoxanthine is an in vitro metabolic marker of the red blood cell storage lesion that negatively correlates with post-transfusion recovery in vivo Storage-dependent hypoxanthine accumulation is ameliorated by hypoxia-induced decreases in purine deamination reaction rates.

Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia.

BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. RESULTS: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. CONCLUSIONS: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.

Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260 m) for 1, 7, and 16 days, and following reascent after 7 days at 1525 m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000 m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide, and sulfur/H2S metabolism. Metabolic adaptations were preserved 1 week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.

Cerebral autoregulation index at high altitude assessed by thigh-cuff and transfer function analysis techniques.

NEW FINDINGS: What is the central question of this study? Whether cerebral autoregulation (CA) is impaired at high altitude and associated with acute mountain sickness remains controversial. We sought to compare two of the most common methods to assess dynamic CA in subjects who ascended to 3424 m and acclimatized. What is the main finding and its importance? We found that CA was reduced at 3424 m when assessed by the classic thigh-cuff inflation-deflation technique, but not when evaluated by transfer function analysis. These findings suggest that the cerebral vasculature of healthy individuals may become less able to buffer a large, abrupt drop in arterial blood pressure, while still maintaining the ability to regulate slow rhythmical oscillations, during periods of moderate hypoxaemia. ABSTRACT: The occurrence and implications of changes in cerebral autoregulation (CA) at high altitude are controversial and confounded by differences in methods used to assess CA. To compare two of the most common methods of dynamic CA assessment, we studied 11 young, healthy sea-level residents (six females and five males; 20.5 ± 2.3 years old) as they ascended to 3424 m and acclimatized over 13 days. A common autoregulation index (ARI) was calculated from the following: (i) transfer function analysis (TFA ARI) of resting oscillations in arterial blood pressure (ABP; finger plethysmography) and middle cerebral artery blood velocity (MCAv; transcranial Doppler); and (ii) MCAv responses following large, abrupt reductions in ABP using the classic thigh-cuff technique (Cuff ARI). Symptoms of acute mountain sickness (AMS) were monitored using the Lake Louise AMS Questionnaire. Cuff ARI scores decreased (P = 0.021) as subjects ascended from low (4.7 ± 1.5) to high altitude (3.2 ± 1.6) and did not change after 13 days of acclimatization (2.9 ± 1.3). The TFA ARI scores were not affected by ascent or acclimatization to 3424 m. Neither Cuff nor TFA ARI scores were correlated with AMS symptoms. These findings suggest that the cerebral vasculature of healthy individuals may become less able to buffer large step changes in ABP, while still maintaining the ability to regulate slow rhythmical oscillations, during periods of moderate hypoxaemia. Given the inherent differences in the autoregulatory stimulus between methods, multiple assessment techniques may be needed to clarify the implications of changes in cerebrovascular regulation at high altitude.

AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery.

Cerebral hypoxaemia associated with rapid ascent to high altitude can be life threatening; yet, with proper acclimatization, cerebral function can be maintained well enough for humans to thrive. We investigated adjustments in global and regional cerebral oxygen delivery (DO2) as 21 healthy volunteers rapidly ascended and acclimatized to 5260 m. Ultrasound indices of cerebral blood flow in internal carotid and vertebral arteries were measured at sea level, upon arrival at 5260 m (ALT1; atmospheric pressure 409 mmHg) and after 16 days of acclimatization (ALT16). Cerebral DO2 was calculated as the product of arterial oxygen content and flow in each respective artery and summed to estimate global cerebral blood flow. Vascular resistances were calculated as the quotient of mean arterial pressure and respective flows. Global cerebral blood flow increased by ∼70% upon arrival at ALT1 (P < 0.001) and returned to sea-level values at ALT16 as a result of changes in cerebral vascular resistance. A reciprocal pattern in arterial oxygen content maintained global cerebral DO2 throughout acclimatization, although DO2 to the posterior cerebral circulation was increased by ∼25% at ALT1 (P = 0.032). We conclude that cerebral DO2 is well maintained upon acute exposure and acclimatization to hypoxia, particularly in the posterior and inferior regions of the brain associated with vital homeostatic functions. This tight regulation of cerebral DO2 was achieved through integrated adjustments in local vascular resistances to alter cerebral perfusion during both acute and chronic exposure to hypoxia.

AltitudeOmics: effects of 16 days acclimatization to hypobaric hypoxia on muscle oxygen extraction during incremental exercise.

Acute altitude exposure lowers arterial oxygen content ([Formula: see text]) and cardiac output ([Formula: see text]) at peak exercise, whereas O2 extraction from blood to working muscles remains similar. Acclimatization normalizes [Formula: see text] but not peak [Formula: see text] nor peak oxygen consumption (V̇o2peak). To what extent acclimatization impacts muscle O2 extraction remains unresolved. Twenty-one sea-level residents performed an incremental cycling exercise to exhaustion near sea level (SL), in acute (ALT1) and chronic (ALT16) hypoxia (5,260 m). Arterial blood gases, gas exchange at the mouth and oxy- (O2Hb) and deoxyhemoglobin (HHb) of the vastus lateralis were recorded to assess arterial O2 content ([Formula: see text]), [Formula: see text], and V̇o2. The HHb-V̇o2 slope was taken as a surrogate for muscle O2 extraction. During moderate-intensity exercise, HHb-V̇o2 slope increased to a comparable extent at ALT1 (2.13 ± 0.94) and ALT16 (2.03 ± 0.88) compared with SL (1.27 ± 0.12), indicating increased O2 extraction. However, the HHb/[Formula: see text] ratio increased from SL to ALT1 and then tended to go back to SL values at ALT16. During high-intensity exercise, HHb-V̇o2 slope reached a break point beyond which it decreased at SL and ALT1, but not at ALT16. Increased muscle O2 extraction during submaximal exercise was associated with decreased [Formula: see text] in acute hypoxia. The significantly greater muscle O2 extraction during maximal exercise in chronic hypoxia is suggestive of an O2 reserve.NEW & NOTEWORTHY During incremental exercise muscle deoxyhemoglobin (HHb) and oxygen consumption (V̇o2) both increase linearly, and the slope of their relationship is an indirect index of local muscle O2 extraction. The latter was assessed at sea level, in acute and during chronic exposure to 5,260 m. The demonstrated presence of a muscle O2 extraction reserve during chronic exposure is coherent with previous studies indicating both limited muscle oxidative capacity and decrease in motor drive.

A simple method to clamp end-tidal carbon dioxide during rest and exercise.

Carbon dioxide regulates ventilation and cerebral blood flow during exercise. There are significant limitations in breathing systems designed to control end-tidal gas concentrations when used during high-intensity exercise. We designed a simple, inexpensive breathing system which controls end-tidal carbon dioxide (PET CO2) during exercise from rest to peak work capacity (W(max)). The system is operated by an investigator who, in response to breath-by-breath PET CO2, titrates flow of a 10 % CO(2), 21 % O(2) mixture into an open-ended 5-L inspiratory reservoir. To demonstrate system efficacy, nine fit male subjects performed two maximal, incremental exercise tests (25 W min(-1) ramp) on a cycle ergometer: a poikilocapnic control trial in which PET CO2 varied with work intensity, and an experimental trial, in which we planned to clamp PET CO2 at 50 mmHg. With our breathing system, we maintained PET CO2 at 51 ± 2 mmHg throughout exercise (rest, 50 ± 2; W(max), 52 ± 5 mmHg; mean ± SD) despite large changes in ventilation (range 27-65 at rest, 134-185 L min(-1) BTPS at W (max)) and carbon dioxide production (range 0.3-0.7 at rest, 4.5-5.5 L min(-1) at W (max)). This simple, inexpensive system achieves PET CO2 control at rest and throughout exercise.

Erythrocyte transglutaminase-2 combats hypoxia and chronic kidney disease by promoting oxygen delivery and carnitine homeostasis.

Due to lack of nuclei and de novo protein synthesis, post-translational modification (PTM) is imperative for erythrocytes to regulate oxygen (O2) delivery and combat tissue hypoxia. Here, we report that erythrocyte transglutminase-2 (eTG2)-mediated PTM is essential to trigger O2 delivery by promoting bisphosphoglycerate mutase proteostasis and the Rapoport-Luebering glycolytic shunt for adaptation to hypoxia, in healthy humans ascending to high altitude and in two distinct murine models of hypoxia. In a pathological hypoxia model with chronic kidney disease (CKD), eTG2 is critical to combat renal hypoxia-induced reduction of Slc22a5 transcription and OCNT2 protein levels via HIF-1α-PPARα signaling to maintain carnitine homeostasis. Carnitine supplementation is an effective and safe therapeutic approach to counteract hypertension and progression of CKD by enhancing erythrocyte O2 delivery. Altogether, we reveal eTG2 as an erythrocyte protein stabilizer orchestrating O2 delivery and tissue adaptive metabolic reprogramming and identify carnitine-based therapy to mitigate hypoxia and CKD progression.

High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude.

The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (Q(UA)). This cross-sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600-4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ~0.62 cm in all groups, but indices of end-arteriolar vascular resistance were higher in PE or GH than in NORM. Q(UA) was lower in early-onset (≤34 wk) PE or GH than in NORM, but was normal in late-onset (>34 wk) illness. Left Q(UA) was consistently greater than right in NORM, but the pattern reversed in PE. Although Q(CI) and Q(EI) were higher in PE and GH than NORM, the fraction of Q(CI) distributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced Q(UA) (R(2) = 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited Q(UA) and restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of Q(UA) and pelvic blood flow in early- vs. late-onset PE in high-altitude residents.

Effects of hypobaric hypoxia on cerebral autoregulation.

BACKGROUND AND PURPOSE: Acute hypoxia is associated with impairment of cerebral autoregulation (CA), but it is unclear if altered CA during prolonged hypoxia is pivotal to the development of cerebral pathology, such as that seen in acute mountain sickness (AMS). This investigation evaluated relationship between CA and AMS over 9 hours of hypobaric hypoxia. METHODS: Fifty-five subjects (41 males, 14 females) were studied in normoxia (PB=625 mm Hg) and after 4 and 9 hours of hypobaric hypoxia (PB=425 mm Hg; approximately 4875 m). Resting, beat-by-beat changes in arterial blood pressure, and middle cerebral artery blood flow velocity were recorded at each time point while breathing room air. Transfer function analyses were used to estimate autoregulation indices (ARI). In 29 subjects, ARI during isocapnic hyperoxia and cerebral vasomotor reactivity during modified rebreathing were also determined to isolate effects of hypoxia and CO2 reactivity on CA. RESULTS: Self-reported Lake Louise AMS Questionnaire scores > or = 3 with headache were used to differentiate between AMS-positive (n=27) and AMS-negative (n=28) subjects (P<0.01). ARI decreased and CO2 reactivity increased in both groups at 4 hours (P<0.01) and did not progress at 9 hours, despite increased incidence and severity of AMS (P<0.01). Impairments in ARI were alleviated with isocapnic hyperoxia at 4 and 9 hours (P<0.01) and were not related to CO2 reactivity. CONCLUSIONS: These results indicate that hypoxia directly impairs CA but that impaired CA does not play a pivotal role in the development of AMS.

Food Insecurity Predicts Urban Gun Violence.

INTRODUCTION: Food insecurity (FI), defined as inadequate access to affordable and quality nutrition, has negative health consequences. FI and violence share similar root causes. The aim of this study was to determine the association of FI with gunshot injury (GSI) incidence. METHODS: We performed a retrospective review of all patients from 2012 to 2018 who sustained a GSI. Food access data was abstracted from the US Department of Agriculture. We analyzed the impact of FI, low food access (LA), and low food access with no vehicle (LANV) on the incidence of GSI using Poisson regression. We also compared high-risk zip codes for GSI, FI, LA, and LANV using geospatial analysis. RESULTS: There were 1700 patients in our cohort from 33 different zip codes. The median incidence of GSI per zip code was 142 (85-164); 5 zip codes comprised 50% of all GSI events. FI (incidence rate ratio [IRR] 4.05, 95% CI 3.98-4.13, P < .0001), LA (IRR 2.97, 95% CI 2.92-3.03. P < .0001), and LANV (IRR 2.58, 95% CI 2.55-2.62, P < .0001) were significant predictors of GSI incidence. The FI model was superior to the LA and LANV models. Geospatial analysis demonstrated that both FI (P < .0001) and LANV (P < .0001) were significantly associated with GSI, while LA was not (P > .05). CONCLUSION: FI is an independent risk factor for GSI incidence. Additionally, a majority of GSI events occur in a minority of communities. These data provide a novel opportunity for social services to guide future violence prevention strategies.

Implementation of a Prophylactic Anticoagulation Guideline for Patients with Traumatic Brain Injury.

BACKGROUND: Patients with traumatic brain injury (TBI) are at an increased risk of developing complications from venous thromboembolisms (VTEs [blood clots]). Benchmarking by the American College of Surgeons Trauma Quality Improvement Program identified suboptimal use of prophylactic anticoagulation in patients with TBI. We hypothesized that institutional implementation of an anticoagulation protocol would improve clinical outcomes in such patients. METHODS: A new prophylactic anticoagulation protocol that incorporated education, weekly audits, and real-time adherence feedback was implemented in July 2015. The trauma registry identified patients with TBI before (PRE) and after (POST) implementation. Multivariable regression analysis with risk adjustment was used to compare use of prophylactic anticoagulation, VTE events, and mortality. RESULTS: A total of 681 patients with TBI (368 PRE, 313 POST) were identified. After implementation of the VTE protocol, more patients received anticoagulation (PRE: 39.4%, POST: 80.5%, p < 0.001), time to initiation was shorter (PRE: 140 hours, POST: 59 hours, p < 0.001), and there were fewer VTE events (PRE: 19 [5.2%], POST: 7 [2.2%], p = 0.047). Multivariable analysis showed that POST patients were more likely to receive anticoagulation (odds ratio [OR] = 10.8, 95% confidence interval [CI] = 6.9-16.7, p < 0.001) and less likely to develop VTE (OR = 0.33, 95% CI = 0.1-1.0, p = 0.05). CONCLUSION: Benchmarking can assist institutions to identity potential clinically relevant areas for quality improvement in real time. Combining education and multifaceted protocol implementation can help organizations to better focus limited quality resources and counteract barriers that have hindered adoption of best practices.

Frontal and motor cortex oxygenation during maximal exercise in normoxia and hypoxia.

Reductions in prefrontal oxygenation near maximal exertion may limit exercise performance by impairing executive functions that influence the decision to stop exercising; however, whether deoxygenation also occurs in motor regions that more directly affect central motor drive is unknown. Multichannel near-infrared spectroscopy was used to compare changes in prefrontal, premotor, and motor cortices during exhaustive exercise. Twenty-three subjects performed two sequential, incremental cycle tests (25 W/min ramp) during acute hypoxia [79 Torr inspired Po(2) (Pi(O(2)))] and normoxia (117 Torr Pi(O(2))) in an environmental chamber. Test order was balanced, and subjects were blinded to chamber pressure. In normoxia, bilateral prefrontal oxygenation was maintained during low- and moderate-intensity exercise but dropped 9.0 +/- 10.7% (mean +/- SD, P < 0.05) before exhaustion (maximal power = 305 +/- 52 W). The pattern and magnitude of deoxygenation were similar in prefrontal, premotor, and motor regions (R(2) > 0.94). In hypoxia, prefrontal oxygenation was reduced 11.1 +/- 14.3% at rest (P < 0.01) and fell another 26.5 +/- 19.5% (P < 0.01) at exhaustion (maximal power = 256 +/- 38 W, P < 0.01). Correlations between regions were high (R(2) > 0.61), but deoxygenation was greater in prefrontal than premotor and motor regions (P < 0.05). Prefrontal, premotor, and motor cortex deoxygenation during high-intensity exercise may contribute to an integrative decision to stop exercise. The accelerated rate of cortical deoxygenation in hypoxia may hasten this effect.

Effect of ventilation on cerebral oxygenation during exercise: insights from canonical correlation.

We tested hypothesis that cerebral deoxygenation near maximal exercise intensity is mediated by hyperventilation, via hypocapnia-induced reductions in cerebral blood flow, by utilizing canonical correlation analysis (CCA) to determine the relative influence of cardiopulmonary changes on cerebral oxygenation, as assessed by near infrared spectroscopy (NIRS). Twenty-three subjects performed incremental exercise tests under normoxic and hypoxic conditions. Changes in ventilation (V (E)) were strongly correlated with end-tidal CO(2) (P(ET)(CO)(2)) and NIRS after the respiratory compensation point (RCP) (r(2)>0.97). However, in contrast to our expectations, CBF velocity (CBFv) shared the least amount of variance with NIRS measurements (r(2)<0.56) and the reduction in CBFv was not accompanied by a reduction in cerebral blood volume. These results demonstrate that while cerebral deoxygenation was associated with hyperventilation, it was not solely explained by hypocapnia-induced reductions in CBFv. CCA revealed that a relative increase in the venous contribution to NIRS explained a larger amount of variation in cerebral oxygenation than reductions CBFv.

Acute and critical care management of a pediatric patient with medullo-cerebellar impaling.

The authors present a child with an accidental cervical medullo-cerebellar impaling by an aluminum rod. Careful planning for safe removal of the rod as well as vigilant attention to early cardiac instability and flash neurogenic pulmonary edema were paramount to her successful recovery. This patient illustrates that it is possible to survive impaling of the brainstem but it requires both innovation and collaboration by multiple specialists across different departments. The value of well coordinated and collaborative neuro surgical intensive care is demonstrated in this young girl's nearly complete recovery from the accident.