Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Subjective and objective survival prediction in mechanically ventilated critically ill patients: a prospective cohort study.

BACKGROUND: ICU risk assessment tools, routinely used for predicting population outcomes, are not recommended for evaluating individual risk. The state of health of single patients is mostly subjectively assessed to inform relatives and presumably to decide on treatment decisions. However, little is known how subjective and objective survival estimates compare. METHODS: We performed a prospective cohort study in mechanically ventilated critically ill patients across five European centres, assessed 62 objective markers and asked the clinical staff to subjectively estimate the probability of surviving 28 days. RESULTS: Within the 961 included patients, we identified 27 single objective predictors for 28-day survival (73.8%) and pooled them into predictive groups. While patient characteristics and treatment models performed poorly, the disease and biomarker models had a moderate discriminative performance for predicting 28-day survival, which improved for predicting 1-year survival. Subjective estimates of nurses (c-statistic [95% CI] 0.74 [0.70-0.78]), junior physicians (0.78 [0.74-0.81]) and attending physicians (0.75 [0.72-0.79]) discriminated survivors from non-survivors at least as good as the combination of all objective predictors (c-statistic: 0.67-0.72). Unexpectedly, subjective estimates were insufficiently calibrated, overestimating death in high-risk patients by about 20% in absolute terms. Combining subjective and objective measures refined discrimination and reduced the overestimation of death. CONCLUSIONS: Subjective survival estimates are simple, cheap and similarly discriminative as objective models; however, they overestimate death risking that live-saving therapies are withheld. Therefore, subjective survival estimates of individual patients should be compared with objective tools and interpreted with caution if not agreeing. Trial registration ISRCTN ISRCTN59376582 , retrospectively registered October 31st 2013.

Increased Longevity of a Novel Gas Exchanger System for Low-Flow Veno-Venous Extracorporeal CO2 Removal in Acute Hypercapnic Respiratory Failure.

INTRODUCTION: Low-flow veno-venous extracorporeal CO2 removal (ECCO2R) is an adjunctive therapy to support lung protective ventilation or maintain spontaneous breathing in hypercapnic respiratory failure. Low-flow ECCO2R is less invasive compared to higher flow systems, while potentially compromising efficiency and membrane lifetime. To counteract this shortcoming, a high-longevity system has recently been developed. Our hypotheses were that the novel membrane system provides runtimes up to 120 h, and CO2 removal remains constant throughout membrane system lifetime. METHODS: Seventy patients with pH ≤ 7.25 and/or PaCO2 ≥9 kPa exceeding lung protective ventilation limits, or experiencing respiratory exhaustion during spontaneous breathing, were treated with the high-longevity ProLUNG system or in a control group using the original gas exchanger. Treatment parameters, gas exchanger runtime, and sweep-gas VCO2 were recorded across 9,806 treatment-hours and retrospectively analyzed. RESULTS: 25/33 and 23/37 patients were mechanically ventilated as opposed to awake spontaneously breathing in both groups. The high-longevity system increased gas exchanger runtime from 29 ± 16 to 48 ± 36 h in ventilated and from 22 ± 14 to 31 ± 31 h in awake patients (p < 0.0001), with longer runtime in the former (p < 0.01). VCO2 remained constant at 86 ± 34 mL/min (p = 0.11). Overall, PaCO2 decreased from 9.1 ± 2.0 to 7.9 ± 1.9 kPa within 1 h (p < 0.001). Tidal volume could be maintained at 5.4 ± 1.8 versus 5.7 ± 2.2 mL/kg at 120 h (p = 0.60), and peak airway pressure could be reduced from 31.1 ± 5.1 to 27.5 ± 6.8 mbar (p < 0.01). CONCLUSION: Using a high-longevity gas exchanger system, membrane lifetime in low-flow ECCO2R could be extended in comparison to previous systems but remained below 120 h, especially in spontaneously breathing patients. Extracorporeal VCO2 remained constant throughout gas exchanger system runtime and was consistent with removal of approximately 50% of expected CO2 production, enabling lung protective ventilation despite hypercapnic respiratory failure.

Evaluation of Acute Mountain Sickness by Unsedated Transnasal Esophagogastroduodenoscopy at High Altitude.

BACKGROUND & AIMS: It is not clear how rapid ascent to a high altitude causes the gastrointestinal symptoms of acute mountain sickness (AMS). We assessed the incidence of endoscopic lesions in the upper gastrointestinal tract in healthy mountaineers after a rapid ascent to high altitude, their association with symptoms, and their pathogenic mechanisms. METHODS: In a prospective study, 25 mountaineers (10 women; mean age, 43.8 ± 9.5 y) underwent unsedated, transnasal esophagogastroduodenoscopy in Zurich (490 m) and then on 2 test days (days 2 and 4) at a high altitude laboratory in the Alps (Capanna Regina Margherita, 4559 m). Symptoms were assessed using validated instruments for AMS (the acute mountain sickness score and the Lake Louise scoring system) and visual analogue scales (scale, 0-100). Levels of messenger RNAs (mRNAs) in duodenal biopsy specimens were measured by quantitative polymerase chain rection. RESULTS: The follow-up endoscopy at high altitude was performed in 19 of 25 patients on day 2 and in 23 of 25 patients on day 4. The frequency of endoscopic lesions increased from 12% at baseline to 26.3% on day 2 and to 60.9% on day 4 (P < .001). The incidence of ulcer disease increased from 0 at baseline to 10.5% on day 2 and to 21.7% on day 4 (P = .014). Mucosal lesions were associated with lower hunger scores (37.3 vs 67.4 in patients without lesions; P = .012). Subjects with peptic lesions had higher levels of HIF2A mRNA, which encodes a hypoxia-induced transcription factor, and ICAM1 mRNA, which encodes an adhesion molecule, compared with subjects without lesions (fold changes, 1.38 vs 0.63; P = .001; and 1.37 vs 0.66; P = .011, respectively). CONCLUSIONS: In a prospective study of 25 mountaineers, fast ascent to a high altitude resulted in rapid onset of clinically meaningful mucosal lesions and ulcer disease. Duodenal biopsy specimens from these subjects had increased levels of HIF2A mRNA and ICAM1 mRNA, which might contribute to the formation of hypoxia-induced peptic lesions. Further studies are needed of the mechanisms of this process.

Influenza-associated aspergillosis in critically-ill patients-a retrospective bicentric cohort study.

Influenza was recently reported as a risk factor for invasive aspergillosis (IA). We aimed to describe prognostic factors for influenza-associated IA (IAA) and poor outcome and mortality in critically ill patients in Switzerland. All adults with confirmed influenza admitted to the ICU at two Swiss tertiary care centres during the 2017/2018 influenza season were retrospectively evaluated. IAA was defined by clinical, mycological and radiological criteria: a positive galactomannan in bronchoalveolar lavage or histopathological or cultural evidence in respiratory specimens of Aspergillus spp., any radiological infiltrate and a compatible clinical presentation. Poor outcome was defined as a composite of in-hospital mortality, ICU length of stay (LOS), invasive ventilation for > 7 days or extracorporeal membrane oxygenation. Of 81 patients with influenza in the ICU, 9 (11%) were diagnosed with IAA. All patients with IAA had poor outcome compared to 26 (36%) patients without IAA (p < 0.001). Median ICU-LOS and mortality were 17 vs. 3 days (p < 0.01) and 3/9 (33%) vs. 13/72 (18%; p = 0.37) in patients with vs. without IAA, respectively. Patients with IAA had significantly longer durations of antibiotic therapy, vasoactive support and mechanical ventilation. Aspergillus was the most common respiratory co-pathogen (9/40, 22%) followed by classical bacterial co-pathogens. IAA was not associated with classical risk factors. Aspergillus is a common superinfection in critically ill influenza patients associated with poor outcome and longer duration of organ supportive therapies. Given the absence of classical risk factors for aspergillosis, greater awareness is necessary, particularly in those requiring organ supportive therapies.

Recruitment of non-perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m.

KEY POINTS: A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries. In the present study, we report that high altitude-induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance. Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude-related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis. The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success. ABSTRACT: A high altitude (HA) stay is associated with an increase in sublingual capillary total vessel density (TVD), suggesting microvascular recruitment. We hypothesized that microvascular recruitment occurs independent of cardiac output changes, that it relies on haemodynamic changes within the microcirculation as opposed to structural changes and that microcirculatory function is related to individual performance at HA. In 41 healthy subjects, sublingual handheld vital microscopy and echocardiography were performed at sea level (SL), as well as at 6022 m (C2) and 7042 m (C3), during ascent to 7126 m within 21 days. Sublingual topical nitroglycerin was applied to measure microvascular reactivity and maximum recruitable TVD (TVDNG ). HA exposure decreased resting cardiac output, whereas TVD (mean ± SD) increased from 18.81 ± 3.92 to 20.92 ± 3.66 and 21.25 ± 2.27 mm mm-2 (P < 0.01). The difference between TVD and TVDNG was 2.28 ± 4.59 mm mm-2 at SL (P < 0.01) but remained undetectable at HA. Maximal TVDNG was observed at C3. Those who reached the summit (n = 15) demonstrated higher TVD at SL (P < 0.01), comparable to TVDNG in non-summiters (n = 21) at SL and in both groups at C2. Recruitment of sublingual capillary TVD to increase microcirculatory oxygen extraction capacity at HA was found to be an intrinsic mechanism of the microcirculation independent of cardiac output changes. Microvascular reactivity to topical nitroglycerin demonstrated that HA-related capillary recruitment is a functional response as opposed to a structural change. The performance of the vascular microcirculation needed to reach the summit was found to be associated with a higher TVD at SL and the ability to further increase TVDNG upon ascent to extreme altitude.

Clinical recommendations for high altitude exposure of individuals with pre-existing cardiovascular conditions: A joint statement by the European Society of Cardiology, the Council on Hypertension of the European Society of Cardiology, the European Society of Hypertension, the International Society of Mountain Medicine, the Italian Society of Hypertension and the Italian Society of Mountain Medicine.

Take home figureAdapted from Bärtsch and Gibbs2 Physiological response to hypoxia. Life-sustaining oxygen delivery, in spite of a reduction in the partial pressure of inhaled oxygen between 25% and 60% (respectively at 2500 m and 8000 m), is ensured by an increase in pulmonary ventilation, an increase in cardiac output by increasing heart rate, changes in vascular tone, as well as an increase in haemoglobin concentration. BP, blood pressure; HR, heart rate; PaCO2, partial pressure of arterial carbon dioxide.

Effect of diagnosis related groups implementation on the intensive care unit of a Swiss tertiary hospital: a cohort study.

BACKGROUND: In 2013 the Swiss Diagnosis Related Groups ((Swiss)-DRG) was implemented in Intensive Care Units (ICU). Its impact on hospitalizations has not yet been examined. We compared the number of ICU admissions, according to clinical severity and referring institution, and screened whether implementation of Swiss-DRG affected admission policy, ICU length-of-stay (ICU-LOS) or ICU mortality. METHODS: Retrospective, single centre, cohort study conducted at the University Hospital Zurich, Switzerland between January 2009 and end of September 2013. Demographic and clinical data was retrieved from a quality assurance database. RESULTS: Admissions (n = 17,231) before the introduction of Swiss-DRG were used to model expected admissions after DRG, and then compared to the observed admissions. Forecasting matched observations in patients with a high clinical severity admitted from internal units and external hospitals (admitted / predicted: 709 / 703, [95% Confidence Interval (CI), 658-748] and 302 / 332, [95% CI, 269-365] respectively). In patients with low severity of disease, in-house admissions became more frequent than expected and external admission were less frequent (admitted / predicted: 1972 / 1910, [95% CI, 1898-1940] and 436 / 518, [95% CI, 482-554] respectively). Various mechanisms related to Swiss-DRG may have led to these changes. DRG could not be linked to significant changes in regard to ICU-LOS and ICU mortality. CONCLUSIONS: DRG introduction had not affected ICU admissions policy, except for an increase of in-house patients with a low clinical severity of disease. DRG had neither affected ICU mortality nor ICU-LOS.

Parasympathetic withdrawal increases heart rate after 2 weeks at 3454 m altitude.

KEY POINTS: Heart rate is increased in chronic hypoxia and we tested whether this is the result of increased sympathetic nervous activity, reduced parasympathetic nervous activity, or a non-autonomic mechanism. In seven lowlanders, heart rate was measured at sea level and after 2 weeks at high altitude after individual and combined pharmacological inhibition of sympathetic and/or parasympathetic control of the heart. Inhibition of parasympathetic control of the heart alone or in combination with inhibition of sympathetic control abolished the high altitude-induced increase in heart rate. Inhibition of sympathetic control of the heart alone did not prevent the high altitude-induced increase in heart rate. These results indicate that a reduced parasympathetic nervous activity is the main mechanism underlying the elevated heart rate in chronic hypoxia. ABSTRACT: Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic nervous systems, along with potential non-autonomic mechanisms, by individual and combined pharmacological inhibition of muscarinic and/or ß-adrenergic receptors. In seven healthy lowlanders, resting HR was determined at sea level (SL) and after 15-18 days of exposure to 3454 m high altitude (HA) without drug intervention (control, CONT) as well as after intravenous administration of either propranolol (PROP), or glycopyrrolate (GLYC), or PROP and GLYC in combination (PROP+GLYC). Circulating noradrenaline concentration increased from 0.9 ± 0.4 nmol l-1 at SL to 2.7 ± 1.5 nmol l-1 at HA (P = 0.03). The effect of HA on HR depended on the type of autonomic inhibition (P = 0.006). Specifically, HR was increased at HA from 64 ± 10 to 74 ± 12 beats min-1 during the CONT treatment (P = 0.007) and from 52 ± 4 to 59 ± 5 beats min-1 during the PROP treatment (P < 0.001). In contrast, HR was similar between SL and HA during the GLYC treatment (110 ± 7 and 112 ± 5 beats min-1 , P = 0.28) and PROP+GLYC treatment (83 ± 5 and 85 ± 5 beats min-1 , P = 0.25). Our results identify a reduction in cardiac parasympathetic activity as the primary mechanism underlying the elevated HR associated with 2 weeks of exposure to hypoxia. Unexpectedly, the sympathoactivation at HA that was evidenced by increased circulating noradrenaline concentration had little effect on HR, potentially reflecting down-regulation of cardiac ß-adrenergic receptor function in chronic hypoxia. These effects of chronic hypoxia on autonomic control of the heart may concern not only HA dwellers, but also patients with disorders that are associated with hypoxaemia.

Neurologic Injury With Severe Adult Respiratory Distress Syndrome in Patients Undergoing Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Analysis.

This retrospective single-center study investigated the incidence of neurologic injury as determined by autopsy or cerebral imaging in 74 patients undergoing extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome. Seventy-three percent of patients were treated with venovenous and 27% with venoarterial ECMO. ECMO-associated intracerebral hemorrhage was diagnosed in 10.8% of patients. There were no cases of ischemic stroke. Clinical characteristics did not differ between patients with and without neurologic injury. Six-month survival was 13% (Wilson confidence interval, 2%-47%) in patients with severe intracerebral hemorrhage compared to an overall survival rate of 57% (Wilson confidence interval, 45%-67%).

Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema.

Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR (1.9 ± 0.4 at SL versus 2.3 ± 0.5 at HA, p < 0.01), CRP (0.7 ± 0.5 at SL versus 3.6 ± 4.6 at HA, p < 0.01), and IL-6 (0.8 ± 0.4 at SL versus 3.3 ± 4.9 at HA, p < 0.01) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (r = 0.46, p < 0.001), but not suPAR (r = 0.27, p = 0.08); the increase in IL-6 was not correlated with suPAR (r = 0.16, p = 0.24). Baseline suPAR plasma concentration was higher in the HAPE-s group (2.0 ± 0.4 versus 1.8 ± 0.4, p = 0.04); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict HAPE susceptibility.

The effects of advanced monitoring on hemodynamic management in critically ill patients: a pre and post questionnaire study.

In critically ill patients, many decisions depend on accurate assessment of the hemodynamic status. We evaluated the accuracy of physicians' conventional hemodynamic assessment and the impact that additional advanced monitoring had on therapeutic decisions. Physicians from seven European countries filled in a questionnaire in patients in whom advanced hemodynamic monitoring using transpulmonary thermodilution (PiCCO system; Pulsion Medical Systems SE, Feldkirchen, Germany) was going to be initialized as part of routine care. The collected information included the currently proposed therapeutic intervention(s) and a prediction of the expected transpulmonary thermodilution-derived variables. After transpulmonary thermodilution measurements, physicians recorded any changes that were eventually made in the original therapeutic plan. A total of 315 questionnaires pertaining to 206 patients were completed. The mean difference (±standard deviation; 95 % limits of agreement) between estimated and measured hemodynamic variables was -1.54 (±2.16; -5.77 to 2.69) L/min for the cardiac output (CO), -74 (±235; -536 to 387) mL/m(2) for the global end-diastolic volume index (GEDVI), and -0.5 (±5.2; -10.6 to 9.7) mL/kg for the extravascular lung water index (EVLWI). The percentage error for the CO, GEDVI, and EVLWI was 66, 64, and 95 %, respectively. In 54 % of cases physicians underestimated the actual CO by more than 20 %. The information provided by the additional advanced monitoring led 33, 22, 22, and 13 % of physicians to change their decisions about fluids, inotropes, vasoconstrictors, and diuretics, respectively. The limited clinical ability of physicians to correctly assess the hemodynamic status, and the significant impact that more physiological information has on major therapeutic decisions, support the use of advanced hemodynamic monitoring in critically ill patients.

External validation of scores proposed for estimation of survival probability of patients with severe adult respiratory distress syndrome undergoing extracorporeal membrane oxygenation therapy: a retrospective study.

INTRODUCTION: This study was designed as an external validation of the recently proposed Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) score, The respiratory extracorporeal membrane oxygenation survival prediction (RESP) score and a scoring system developed for externally retrieved patients on extracorporeal membrane oxygenation (ECMO) at our institution. All scores are proposed for the estimation of survival probability after ECMO treatment for severe adult respiratory distress syndrome. METHODS: Data from 51 patients (2008 to 2013) were analyzed in this retrospective single-center study. A calculation of an adapted PRESERVE score, the RESP score as well as the score developed for externally retrieved ECMO patients was performed. RESULTS: Seventy one percent of patients received veno-venous (v-v) and 29% venous-arterial (v-a) ECMO support during the study period. Overall survival at 6 months was 55%, with a 61% survival rate for v-v cannulated patients and a 40% survival rate for v-a cannulated patients. The PRESERVE score discriminated survivors and non-survivors with an area under the curve of 0.67 (95% CI 0.52 to 0.82, P = 0.03). Analyzing survival prediction according to cannulation modus, the PRESERVE score and the RESP score significantly predicted survival for patients on v-v ECMO with an area under the curve of 0.75 (95% CI 0.57 to 0.92, P = 0.01) and 0.81 (95% CI 0.67 to 0.95, P = 0.035), respectively, while the scoring system developed for externally retrieved ECMO patients failed to predict survival in our study population. All scores failed to predict mortality for patients on v-a ECMO. CONCLUSION: Our single-center validation confirms that the proposed PRESERVE and RESP score predict survival for patients treated with v-v ECMO for severe adult respiratory distress syndrome.

Effects of exercise and vasodilators on cerebral tissue oxygenation in pulmonary hypertension.

BACKGROUND: Arterial and thromboembolic pulmonary hypertension (PH) lead to arterial hypoxaemia. OBJECTIVE: To investigate whether cerebral tissue oxygenation (CTO) in patients with PH is reduced and whether this is associated with reduced exercise tolerance. METHODS: 16 patients with PH (mean pulmonary arterial pressure ≥25 mmHg, 14 arterial, 2 chronic thromboembolic) and 15 controls underwent right heart catheterisation with monitoring of CTO at rest, during maximal bicycle exercise and during inhalation of oxygen and NO. The 6 min walk distance (6MWD) was measured. RESULTS: Median CTO in PH-patients at rest was 62 % (quartiles 53; 71), during exercise 60 % (53; 65); corresponding values in controls were 65 % (73; 73) (P = NS) and 68 % (66; 70) (p = .013 vs. PH). Inhalation of NO and oxygen improved CTO in PH. In multivariate regression analysis CTO at maximal exercise predicted the work load achieved when controlled for age, pulmonary vascular resistance and mixed venous oxygen saturation (R (2) = .419, p < .000); in addition, the 6MWD was predicted by CTO (adjusted R (2) = .511, p < .000). CONCLUSION: In PH-patients but not in controls CTO decreased during exercise. Since CTO was an independent predictor of the work load achieved and the 6MWD cerebral hypoxia may contribute to exercise limitation in PH. Clinicaltrials.gov: NCT01463514.

Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans.

Solute carrier (SLC) transporters mediate the uptake of biologically active compounds in the intestine. Reduced oxygenation (hypoxia) is an important factor influencing intestinal homeostasis. The aim of this study was to investigate the pathophysiological consequences of hypoxia on the expression and function of SLCs in human intestine. Hypoxia was induced in human intestinal epithelial cells (IECs) in vitro (0.2; 1% O2 or CoCl2). For human in vivo studies, duodenal biopsies and serum samples were obtained from individuals (n = 16) acutely exposed to 4,554 meters above sea levels. Expression of relevant targets was analyzed by quantitative PCR, Western blotting, or immunofluorescence. Serum levels of inflammatory mediators and nucleosides were determined by ELISA and LC/MS-MS, respectively. In the duodenum of volunteers exposed to high altitude we observed decreased mRNA levels of apical sodium-dependent bile acid transporter (ASBT), concentrative nucleoside transporters 1/2 (CNT1/2), organic anion transporting polypeptide 2B1 (OATP2B1), organic cation transporter 2 (OCTN2), peptide transporter 1 (PEPT1), serotonin transporter (SERT), and higher levels of IFN-γ, IL-6, and IL-17A. Serum levels of IL-10, IFN-γ, matrix metalloproteinase-2 (MMP-2), and serotonin were elevated, whereas the levels of uridine decreased upon exposure to hypoxia. Hypoxic IECs showed reduced levels of equilibrative nucleoside transporter 2 (ENT2), OCTN2, and SERT mRNAs in vitro, which was confirmed on the protein level and was accompanied by activation of ERK1/2, increase of hypoxia-inducible factor (HIF) proteins, and production of IL-8 mRNA. Costimulation with IFN-γ and IL-6 during hypoxia further decreased the expression of SERT, ENT2, and CNT2 in vitro. Reduced oxygen supply affects the expression pattern of duodenal SLCs that is accompanied by changes in serum levels of proinflammatory cytokines and biologically active compounds demonstrating that intestinal transport is affected during systemic exposure to hypoxia in humans.

Adaptation of iron transport and metabolism to acute high-altitude hypoxia in mountaineers.

UNLABELLED: Human iron homeostasis is regulated by intestinal iron transport, hepatic hepcidin release, and signals from pathways that consume or supply iron. The aim of this study was to characterize the adaptation of iron homeostasis under hypoxia in mountaineers at the levels of (1) hepatic hepcidin release, (2) intestinal iron transport, and (3) systemic inflammatory and erythropoietic responses. Twenty-five healthy mountaineers were studied. Blood samples and duodenal biopsies were taken at baseline of 446 m as well as on day 2 (MG2) and 4 (MG4) after rapid ascent to 4559 m. Divalent metal-ion transporter 1 (DMT-1), ferroportin 1 (FP-1) messenger RNA (mRNA), and protein expression were analyzed in biopsy specimens by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Serum hepcidin levels were analyzed by mass spectrometry. Serum iron, ferritin, transferrin, interleukin (IL)-6, and C-reactive protein (CRP) were quantified by standard techniques. Serum erythropoietin and growth differentiation factor 15 (GDF15) levels were measured by enzyme-linked immunosorbent assay (ELISA). Under hypoxia, erythropoietin peaked at MG2 (P < 0.001) paralleled by increased GDF15 on MG2 (P < 0.001). Serum iron and ferritin levels declined rapidly on MG2 and MG4 (P < 0.001). Duodenal DMT-1 and FP-1 mRNA expression increased up to 10-fold from baseline on MG2 and MG4 (P < 0.001). Plasma CRP increased on MG2 and MG4, while IL-6 only increased on MG2 (P < 0.001). Serum hepcidin levels decreased at high altitude on MG2 and MG4 (P < 0.001). CONCLUSION: This study in healthy volunteers showed that under hypoxemic conditions hepcidin is repressed and duodenal iron transport is rapidly up-regulated. These changes may increase dietary iron uptake and allow release of stored iron to ensure a sufficient iron supply for hypoxia-induced compensatory erythropoiesis.

Glucose control in intensive care: usability, efficacy and safety of Space GlucoseControl in two medical European intensive care units.

BACKGROUND: The Space GlucoseControl system (SGC) is a nurse-driven, computer-assisted device for glycemic control combining infusion pumps with the enhanced Model Predictive Control algorithm (B. Braun, Melsungen, Germany). We aimed to investigate the performance of the SGC in medical critically ill patients. METHODS: Two open clinical investigations in tertiary centers in Graz, Austria and Zurich, Switzerland were performed. Efficacy was assessed by percentage of time within the target range (4.4-8.3 mmol/L; primary end point), mean blood glucose, and sampling interval. Safety was assessed by the number of hypoglycemic episodes (≤2.2 mmol/L) and the percentage of time spent below this cutoff level. Usability was analyzed with a standardized questionnaire given to involved nursing staff after the trial. RESULTS: Forty medical critically ill patients (age, 62 ± 15 years; body mass index, 30.0 ± 8.9 kg/m2; APACHE II score, 24.8 ± 5.4; 27 males; 8 with diabetes) were included for a period of 6.5 ± 3.7 days (n = 20 in each center). The primary endpoint (time in target range 4.4 to 8.3 mmol/l) was reached in 88.3% ± 9.3 of the time and mean arterial blood glucose was 6.7 ± 0.4 mmol/l. The sampling interval was 2.2 ± 0.4 hours. The mean daily insulin dose was 87.2 ± 64.6 IU. The adherence to the given insulin dose advice was high (98.2%). While the percentage of time spent in a moderately hypoglycemic range (2.2 to 3.3 mmol/L) was low (0.07 ± 0.26% of the time), one severe hypoglycemic episode (<2.2 mmol/L) occurred (2.5% of patients or 0.03% of glucose readings). CONCLUSIONS: SGC is a safe and efficient method to control blood glucose in critically ill patients as assessed in two European medical intensive care units.

Mechanisms maintaining right ventricular contractility-to-pulmonary arterial elastance ratio in VA ECMO: a retrospective animal data analysis of RV-PA coupling.

BACKGROUND: To optimize right ventricular-pulmonary coupling during veno-arterial (VA) ECMO weaning, inotropes, vasopressors and/or vasodilators are used to change right ventricular (RV) function (contractility) and pulmonary artery (PA) elastance (afterload). RV-PA coupling is the ratio between right ventricular contractility and pulmonary vascular elastance and as such, is a measure of optimized crosstalk between ventricle and vasculature. Little is known about the physiology of RV-PA coupling during VA ECMO. This study describes adaptive mechanisms for maintaining RV-PA coupling resulting from changing pre- and afterload conditions in VA ECMO. METHODS: In 13 pigs, extracorporeal flow was reduced from 4 to 1 L/min at baseline and increased afterload (pulmonary embolism and hypoxic vasoconstriction). Pressure and flow signals estimated right ventricular end-systolic elastance and pulmonary arterial elastance. Linear mixed-effect models estimated the association between conditions and elastance. RESULTS: At no extracorporeal flow, end-systolic elastance increased from 0.83 [0.66 to 1.00] mmHg/mL at baseline by 0.44 [0.29 to 0.59] mmHg/mL with pulmonary embolism and by 1.36 [1.21 to 1.51] mmHg/mL with hypoxic pulmonary vasoconstriction (p < 0.001). Pulmonary arterial elastance increased from 0.39 [0.30 to 0.49] mmHg/mL at baseline by 0.36 [0.27 to 0.44] mmHg/mL with pulmonary embolism and by 0.75 [0.67 to 0.84] mmHg/mL with hypoxic pulmonary vasoconstriction (p < 0.001). Coupling remained unchanged (2.1 [1.8 to 2.3] mmHg/mL at baseline; - 0.1 [- 0.3 to 0.1] mmHg/mL increase with pulmonary embolism; - 0.2 [- 0.4 to 0.0] mmHg/mL with hypoxic pulmonary vasoconstriction, p > 0.05). Extracorporeal flow did not change coupling (0.0 [- 0.0 to 0.1] per change of 1 L/min, p > 0.05). End-diastolic volume increased with decreasing extracorporeal flow (7.2 [6.6 to 7.8] ml change per 1 L/min, p < 0.001). CONCLUSIONS: The right ventricle dilates with increased preload and increases its contractility in response to afterload changes to maintain ventricular-arterial coupling during VA extracorporeal membrane oxygenation.

Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

BACKGROUND: An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, beta-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans, propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). METHODS: In seven healthy male lowlanders, Ppa was invasively measured without medication, with PROP and PROP + GLYC, both at sea level (SL, 488 m) and after a 3-week sojourn at 3454 m altitude (HA). Bilateral thigh-cuff release manoeuvres were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. RESULTS: At SL, PROP increased Ppa and PVR from (mean ± SEM) 14 ± 1 to 17 ± 1 mmHg and from 69 ± 8 to 108 ± 11 dyn s cm-5 (21% and 57% increase, P = 0.01 and P < 0.0001). The PVR response to PROP was amplified at HA to 76% (P < 0.0001, P[interaction] = 0.05). At both altitudes, PROP + GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9 ± 0.5 to 1.7 ± 0.2 at HA (P < 0.0001) and to 1.2 ± 0.2 with PROP, and further decreased to 0.9 ± 0.2% mmHg-1 with PROP + GLYC (P = 0.01). CONCLUSIONS: Our data show that beta-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that beta-adrenergic blockade exaggerates HPV for the management of mountaineers using beta-blockers for prevention or treatment of cardiovascular conditions.