The microcirculation in the first days of ICU admission in critically ill COVID-19 patients is influenced by severity of disease.

The objective of this study was to investigate the relationship between sublingual microcirculatory parameters and the severity of the disease in critically ill coronavirus disease 2019 (COVID-19) patients in the initial period of Intensive Care Unit (ICU) admission in a phase of the COVID-19 pandemic where patients were being treated with anti-inflammatory medication. In total, 35 critically ill COVID-19 patients were included. Twenty-one critically ill COVID-19 patients with a Sequential Organ Failure Assessment (SOFA) score below or equal to 7 were compared to 14 critically ill COVID-19 patients with a SOFA score exceeding 7. All patients received dexamethasone and tocilizumab at ICU admission. Microcirculatory measurements were performed within the first five days of ICU admission, preferably as soon as possible after admission. An increase in diffusive capacity of the microcirculation (total vessel density, functional capillary density, capillary hematocrit) and increased perfusion of the tissues by red blood cells was found in the critically ill COVID-19 patients with a SOFA score of 7-9 compared to the critically ill COVID-19 patients with a SOFA score ≤ 7. No such effects were found in the convective component of the microcirculation. These effects occurred in the presence of administration of anti-inflammatory medication.

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 while using antihypertensive medications such as betablockers. 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, ß-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, pulmonary artery pressure was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a three-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release maneuvers 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±1mmHg and from 69±8 to 108±11dyn*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 ß-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that ß-adrenergic blockade exaggerates HPV for the management of mountaineers using ß-blockers for prevention or treatment of cardiovascular conditions.

Effects of enhanced adsorption haemofiltration versus haemoadsorption in severe, refractory septic shock with high levels of endotoxemia: the ENDoX bicentric, randomized, controlled trial.

BACKGROUND: Endotoxin adsorption is a promising but controversial therapy in severe, refractory septic shock and conflicting results exist on the effective capacity of available devices to reduce circulating endotoxin and inflammatory cytokine levels. METHODS: Multiarm, randomized, controlled trial in two Swiss intensive care units, with a 1:1:1 randomization of patients suffering severe, refractory septic shock with high levels of endotoxemia, defined as an endotoxin activity ≥ 0.6, a vasopressor dependency index ≥ 3, volume resuscitation of at least 30 ml/kg/24 h and at least single organ failure, to a haemoadsorption (Toraymyxin), an enhanced adsorption haemofiltration (oXiris) or a control intervention. Primary endpoint was the difference in endotoxin activity at 72-h post-intervention to baseline. In addition, inflammatory cytokine, vasopressor dependency index and SOFA-Score dynamics over the initial 72 h were assessed inter alia. RESULTS: In the 30, out of 437 screened, randomized patients (10 Standard of care, 10 oXiris, 10 Toraymyxin), endotoxin reduction at 72-h post-intervention-start did not differ among interventions (Standard of Care: 12 [1-42]%, oXiris: 21 [10-51]%, Toraymyxin: 23 [10-36]%, p = 0.82). Furthermore, no difference between groups could be observed neither for reduction of inflammatory cytokine levels (p = 0.58), nor for vasopressor weaning (p = 0.95) or reversal of organ injury (p = 0.22). CONCLUSIONS: In a highly endotoxemic, severe, refractory septic shock population neither the Toraymyxin adsorber nor the oXiris membrane could show a reduction in circulating endotoxin or cytokine levels over standard of care. Trial registration ClinicalTrials.gov. NCT01948778. Registered August 30, 2013. https://clinicaltrials.gov/study/NCT01948778.

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.

Do cardiopulmonary exercise tests predict summit success and acute mountain sickness? A prospective observational field study at extreme altitude.

OBJECTIVE: During a high-altitude expedition, the association of cardiopulmonary exercise testing (CPET) parameters with the risk of developing acute mountain sickness (AMS) and the chance of reaching the summit were investigated. METHODS: Thirty-nine subjects underwent maximal CPET at lowlands and during ascent to Mount Himlung Himal (7126 m) at 4844 m, before and after 12 days of acclimatisation, and at 6022 m. Daily records of Lake-Louise-Score (LLS) determined AMS. Participants were categorised as AMS+ if moderate to severe AMS occurred. RESULTS: Maximal oxygen uptake (V̇O2max) decreased by 40.5%±13.7% at 6022 m and improved after acclimatisation (all p<0.001). Ventilation at maximal exercise (VEmax) was reduced at 6022 m, but higher VEmax was related to summit success (p=0.031). In the 23 AMS+ subjects (mean LLS 7.4±2.4), a pronounced exercise-induced oxygen desaturation (ΔSpO2exercise) was found after arrival at 4844 m (p=0.005). ΔSpO2exercise >-14.0% identified 74% of participants correctly with a sensitivity of 70% and specificity of 81% for predicting moderate to severe AMS. All 15 summiteers showed higher V̇O2max (p<0.001), and a higher risk of AMS in non-summiteers was suggested but did not reach statistical significance (OR: 3.64 (95% CI: 0.78 to 17.58), p=0.057). V̇O2max ≥49.0 mL/min/kg at lowlands and ≥35.0 mL/min/kg at 4844 m predicted summit success with a sensitivity of 46.7% and 53.3%, and specificity of 83.3% and 91.3%, respectively. CONCLUSION: Summiteers were able to sustain higher VEmax throughout the expedition. Baseline V̇O2max below 49.0 mL/min/kg was associated with a high chance of 83.3% for summit failure, when climbing without supplemental oxygen. A pronounced drop of SpO2exercise at 4844 m may identify climbers at higher risk of AMS.

Identifying a sublingual triangle as the ideal site for assessment of sublingual microcirculation.

The sublingual mucosa is a commonly used intraoral location for identifying microcirculatory alterations using handheld vital microscopes (HVMs). The anatomic description of the sublingual cave and its related training have not been adequately introduced. The aim of this study was to introduce anatomy guided sublingual microcirculatory assessment. Measurements were acquired from the floor of the mouth using incident dark-field (IDF) imaging before (T0) and after (T1) sublingual cave anatomy instructed training. Instructions consists of examining a specific region of interested identified through observable anatomical structures adjacent and bilaterally to the lingual frenulum which is next to the sublingual papilla. The anatomical location called the sublingual triangle, was identified as stationed between the lingual frenulum, the sublingual fold and ventrally to the tongue. Small, large, and total vessel density datasets (SVD, LVD and TVD respectively) obtained by non-instructed and instructed measurements (NIN (T0) and IM (T1) respectively) were compared. Microvascular structures were analyzed, and the presence of salivary duct-related microcirculation was identified. A total of 72 video clips were used for analysis in which TVD, but not LVD and SVD, was higher in IM compared to NIM (NIM vs. IM, 25 ± 2 vs. 27 ± 3 mm/mm2 (p = 0.044), LVD NIM vs. IM: 7 ± 1 vs. 8 ± 1mm/mm2 (p = 0.092), SVD NIM vs. IM: 18 ± 2 vs. 20 ± 3 mm/mm2 (p = 0.103)). IM resulted in microcirculatory assessments which included morphological properties such as capillaries, venules and arterioles, without salivary duct-associated microcirculation. The sublingual triangle identified in this study showed consistent network-based microcirculation, without interference from microcirculation associated with specialized anatomic structures. These findings suggest that the sublingual triangle, an anatomy guided location, yielded sublingual based measurements that conforms with international guidelines. IM showed higher TVD values, and future studies are needed with larger sample sizes to prove differences in microcirculatory parameters.

Microcirculatory alterations in critically ill COVID-19 patients analyzed using artificial intelligence.

BACKGROUND: The sublingual microcirculation presumably exhibits disease-specific changes in function and morphology. Algorithm-based quantification of functional microcirculatory hemodynamic variables in handheld vital microscopy (HVM) has recently allowed identification of hemodynamic alterations in the microcirculation associated with COVID-19. In the present study we hypothesized that supervised deep machine learning could be used to identify previously unknown microcirculatory alterations, and combination with algorithmically quantified functional variables increases the model's performance to differentiate critically ill COVID-19 patients from healthy volunteers. METHODS: Four international, multi-central cohorts of critically ill COVID-19 patients and healthy volunteers (n = 59/n = 40) were used for neuronal network training and internal validation, alongside quantification of functional microcirculatory hemodynamic variables. Independent verification of the models was performed in a second cohort (n = 25/n = 33). RESULTS: Six thousand ninety-two image sequences in 157 individuals were included. Bootstrapped internal validation yielded AUROC(CI) for detection of COVID-19 status of 0.75 (0.69-0.79), 0.74 (0.69-0.79) and 0.84 (0.80-0.89) for the algorithm-based, deep learning-based and combined models. Individual model performance in external validation was 0.73 (0.71-0.76) and 0.61 (0.58-0.63). Combined neuronal network and algorithm-based identification yielded the highest externally validated AUROC of 0.75 (0.73-0.78) (P < 0.0001 versus internal validation and individual models). CONCLUSIONS: We successfully trained a deep learning-based model to differentiate critically ill COVID-19 patients from heathy volunteers in sublingual HVM image sequences. Internally validated, deep learning was superior to the algorithmic approach. However, combining the deep learning method with an algorithm-based approach to quantify the functional state of the microcirculation markedly increased the sensitivity and specificity as compared to either approach alone, and enabled successful external validation of the identification of the presence of microcirculatory alterations associated with COVID-19 status.

Near real-time observation reveals increased prevalence of young patients in the ICU during the emerging third SARS-CoV-2 wave in Switzerland.

AIMS OF THE STUDY: During the ongoing COVID-19 pandemic, the launch of a large-scale vaccination campaign and virus mutations have hinted at possible changes in transmissibility and the virulence affecting disease progression up to critical illness, and carry potential for future vaccination failure. To monitor disease development over time with respect to critically ill COVID-19 patients, we report near real-time prospective observational data from the RISC-19-ICU registry that indicate changed characteristics of critically ill patients admitted to Swiss intensive care units (ICUs) at the onset of a third pandemic wave. METHODS: 1829 of 3344 critically ill COVID-19 patients enrolled in the international RISC-19-ICU registry as of 31 May 2021 were treated in Switzerland and were included in the present study. Of these, 1690 patients were admitted to the ICU before 1 February 2021 and were compared with 139 patients admitted during the emerging third pandemic wave RESULTS: Third wave patients were a mean of 5.2 years (95% confidence interval [CI] 3.2–7.1) younger (median 66.0 years, interquartile range [IQR] 57.0–73.0 vs 62.0 years, IQR 54.5–68.0; p <0.0001) and had a higher body mass index than patients admitted in the previous pandemic period. They presented with lower SAPS II and APACHE II scores, less need for circulatory support and lower white blood cell counts at ICU admission. P/F ratio was similar, but a 14% increase in ventilatory ratio was observed over time (p = 0.03) CONCLUSION: Near real-time registry data show that the latest COVID-19 patients admitted to ICUs in Switzerland at the onset of the third wave were on average 5 years younger, had a higher body mass index, and presented with lower physiological risk scores but a trend towards more severe lung failure. These differences may primarily be related to the ongoing nationwide vaccination campaign, but the possibility that changes in virus-host interactions may be a co-factor in the age shift and change in disease characteristics is cause for concern, and should be taken into account in the public health and vaccination strategy during the ongoing pandemic. (ClinicalTrials.gov Identifier: NCT04357275).

Machine learning using the extreme gradient boosting (XGBoost) algorithm predicts 5-day delta of SOFA score at ICU admission in COVID-19 patients.

Background: Accurate risk stratification of critically ill patients with coronavirus disease 2019 (COVID-19) is essential for optimizing resource allocation, delivering targeted interventions, and maximizing patient survival probability. Machine learning (ML) techniques are attracting increased interest for the development of prediction models as they excel in the analysis of complex signals in data-rich environments such as critical care. Methods: We retrieved data on patients with COVID-19 admitted to an intensive care unit (ICU) between March and October 2020 from the RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry. We applied the Extreme Gradient Boosting (XGBoost) algorithm to the data to predict as a binary outcome the increase or decrease in patients' Sequential Organ Failure Assessment (SOFA) score on day 5 after ICU admission. The model was iteratively cross-validated in different subsets of the study cohort. Results: The final study population consisted of 675 patients. The XGBoost model correctly predicted a decrease in SOFA score in 320/385 (83%) critically ill COVID-19 patients, and an increase in the score in 210/290 (72%) patients. The area under the mean receiver operating characteristic curve for XGBoost was significantly higher than that for the logistic regression model (0.86 vs. 0.69, P < 0.01 [paired t-test with 95% confidence interval]). Conclusions: The XGBoost model predicted the change in SOFA score in critically ill COVID-19 patients admitted to the ICU and can guide clinical decision support systems (CDSSs) aimed at optimizing available resources.

Automated Algorithm Analysis of Sublingual Microcirculation in an International Multicentral Database Identifies Alterations Associated With Disease and Mechanism of Resuscitation.

OBJECTIVES: Reliable automated handheld vital microscopy image sequence analysis and the identification of disease states and effects of therapy are prerequisites for the routine use of quantitative sublingual microcirculation measurements at the point-of-care. The present study aimed to clinically validate the recently introduced MicroTools software in a large multicentral database of perioperative and critically ill patients and to use this automatic algorithm to data-mine and identify the sublingual microcirculatory variable changes in response to disease and therapy. DESIGN: Retrospective algorithm-based image analysis and data-mining within a large international database of sublingual capillary microscopy. Algorithm-based analysis was compared with manual analysis for validation. Thereafter, MicroTools was used to identify the functional microcirculatory alterations associated with disease conditions and identify therapeutic options for recruiting functional microcirculatory variables. SETTING: Ten perioperative/ICU/volunteer studies in six international teaching hospitals. PATIENTS: The database encompass 267 adult and pediatric patients undergoing surgery, treatment for sepsis, and heart failure in the ICU and healthy volunteers. INTERVENTIONS: Perioperative and ICU standard of care. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred twenty-five handheld vital microscopy image sequences containing 149,257 microscopy images were analyzed. 3.89 × 10 RBC positions were tracked by the algorithm in real time, and offline manual analysis was performed. Good correlation and trending ability were found between manual and automatic total and functional capillary density (r = 0.6-0.8; p < 0.0001). RBC tracking within the database demonstrated changes in functional capillary density and/or RBC velocity in septic shock, heart failure, hypovolemia, obstructive shock, and hemodilution and thus detected the presence of a disease condition. Therapies recruiting the microcirculatory diffusion and convection capacity associated with systemic vasodilation and an increase in cardiac output were separately identified. CONCLUSIONS: Algorithm-based analysis of the sublingual microcirculation closely matched manual analysis across a broad spectrum of populations. It successfully identified a methodology to quantify microcirculatory alterations associated with disease and the success of capillary recruitment, improving point-of-care application of microcirculatory-targeted resuscitation procedures.

Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe: Initial report of the international RISC-19-ICU prospective observational cohort.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with a high disease burden with 10% of confirmed cases progressing towards critical illness. Nevertheless, the disease course and predictors of mortality in critically ill patients are poorly understood. METHODS: Following the critical developments in ICUs in regions experiencing early inception of the pandemic, the European-based, international RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry was created to provide near real-time assessment of patients developing critical illness due to COVID-19. FINDINGS: As of April 22, 2020, 639 critically ill patients with confirmed SARS-CoV-2 infection were included in the RISC-19-ICU registry. Of these, 398 had deceased or been discharged from the ICU. ICU-mortality was 24%, median length of stay 12 (IQR, 5-21) days. ARDS was diagnosed in 74%, with a minimum P/F-ratio of 110 (IQR, 80-148). Prone positioning, ECCO2R, or ECMO were applied in 57%. Off-label therapies were prescribed in 265 (67%) patients, and 89% of all bloodstream infections were observed in this subgroup (n = 66; RR=3·2, 95% CI [1·7-6·0]). While PCT and IL-6 levels remained similar in ICU survivors and non-survivors throughout the ICU stay (p = 0·35, 0·34), CRP, creatinine, troponin, d-dimer, lactate, neutrophil count, P/F-ratio diverged within the first seven days (p<0·01). On a multivariable Cox proportional-hazard regression model at admission, creatinine, d-dimer, lactate, potassium, P/F-ratio, alveolar-arterial gradient, and ischemic heart disease were independently associated with ICU-mortality. INTERPRETATION: The European RISC-19-ICU cohort demonstrates a moderate mortality of 24% in critically ill patients with COVID-19. Despite high ARDS severity, mechanical ventilation incidence was low and associated with more rescue therapies. In contrast to risk factors in hospitalized patients reported in other studies, the main mortality predictors in these critically ill patients were markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. Elevated risk of bloodstream infections underscores the need to exercise caution with off-label therapies.

Resuscitation with PEGylated carboxyhemoglobin preserves renal cortical oxygenation and improves skeletal muscle microcirculatory flow during endotoxemia.

PEGylated carboxyhemoglobin (PEGHbCO), which has carbon monoxide-releasing properties and plasma expansion and oxygen-carrying properties, may improve both skeletal microcirculatory flow and renal cortical microcirculatory Po2 (CµPo2) and, subsequently, limit endotoxemia-induced acute kidney injury. Anesthetized, ventilated Wistar albino rats (n = 44) underwent endotoxemic shock. CµPo2 was measured in exposed kidneys using a phosphorescence-quenching method. Rats were randomly assigned to the following five groups: 1) unresuscitated lipopolysaccharide (LPS), 2) LPS + Ringer's acetate (RA), 3) LPS + RA + 0.5 µg·kg·-1min-1 norepinephrine (NE), 4) LPS + RA + 320 mg/kg PEGHbCO, and 5) LPS + RA + PEGHbCO + NE. The total volume was 30 mL/kg in each group. A time control animal group was used. Skeletal muscle microcirculation was assessed by handheld intravital microscopy. Kidney immunohistochemistry and myeloperoxidase-stained leukocytes in glomerular and peritubular areas were analyzed. Endotoxemia-induced histological damage was assessed. Plasma levels of IL-6, heme oxygenase-1, malondialdehyde, and syndecan-1 were assessed by ELISA. CµPo2 was higher in the LPS + RA + PEGHbCO-resuscitated group, at 35 ± 6mmHg compared with 21 ± 12 mmHg for the LPS+RA group [mean difference: -13.53, 95% confidence interval: (-26.35; -0.7156), P = 0.035]. The number of nonflowing, intermittent, or sluggish capillaries was smaller in groups infused with PEGHbCO compared with RA alone (P < 0.05), while the number of normally perfused vessels was greater (P < 0.05). The addition of NE did not further improve CµPo2 or microcirculatory parameters. Endotoxemia-induced kidney immunohistochemistry and histological alterations were not mitigated by PEGHbCO 1 h after resuscitation. Renal leukocyte infiltration and plasma levels of biomarkers were similar across groups. PEGHbCO enhanced CµPo2 while restoring skeletal muscle microcirculatory flow in previously nonflowing capillaries. PEGHbCO should be further evaluated as a resuscitation fluid in mid- to long-term models of sepsis-induced acute kidney injury.

MicroTools enables automated quantification of capillary density and red blood cell velocity in handheld vital microscopy.

Direct assessment of capillary perfusion has been prioritized in hemodynamic management of critically ill patients in addition to optimizing blood flow on the global scale. Sublingual handheld vital microscopy has enabled online acquisition of moving image sequences of the microcirculation, including the flow of individual red blood cells in the capillary network. However, due to inherent content complexity, manual image sequence analysis remained gold standard, introducing inter-observer variability and precluding real-time image analysis for clinical therapy guidance. Here we introduce an advanced computer vision algorithm for instantaneous analysis and quantification of morphometric and kinetic information related to capillary blood flow in the sublingual microcirculation. We evaluated this technique in a porcine model of septic shock and resuscitation and cardiac surgery patients. This development is of high clinical relevance because it enables implementation of point-of-care goal-directed resuscitation procedures based on correction of microcirculatory perfusion in critically ill and perioperative patients.

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.

Preserving fertility in an unconscious patient with Goodpasture syndrome-medicolegal and ethical aspects.

BACKGROUND: Every day in the ICU, legal issues arise while treating sedated, unconscious, and legally incapacitated patients. Whenever a life-saving treatment cannot be discussed in a timely manner with an unconscious patient, doctors are required by law to act according to the substituted judgment standard. However, if it is not survival that is at stake, but conservation of reproduction and the potential side effects are significant, the decision-making process becomes much more difficult. Legal issues associated with possible harm to the patient on the one hand and ethical issues with presumable benefit of the intervention on the other hand give rise to difficult decisions. CASE PRESENTATION: We present the case of a 24-year-old patient with Goodpasture syndrome. Because of rapid aggravation of kidney function and alveolar hemorrhage-the latter requiring an urgent initiation of mechanical ventilation-therapy with steroids, plasmapheresis, and cyclophosphamide was immediately required. Knowledge of the negative impact on fertility brought up the question about sperm cryopreservation. According to the substituted judgment standard, together with the mother of the patient and based on interdisciplinary evaluation of the situation with specialists from the reproductive endocrinology and urology department, the decision for a testicular sperm extraction in the absence of the possibility to obtain the patient's informed consent was made. Immediate chemotherapy was initiated and continued after the procedure. The patient recovered from the acute illness and was informed retrospectively about the testicular sperm extraction, which he received extremely positively. CONCLUSION: Our aim is to highlight the legal objectives and ethical aspects of a non-lifesaving but fertility-preserving intervention in an unconscious patient. The need for decision-making in this kind of situation is rare and therefore challenging. The present case may serve to encourage and guide other doctors in similar situations.

Validation of transpulmonary thermodilution variables in hemodynamically stable patients with heart diseases.

BACKGROUND: Transpulmonary thermodilution is recommended in the treatment of critically ill patients presenting with complex shock. However, so far it has not been validated in hemodynamically stable patients with heart disease. METHODS: We assessed the validity of cardiac output, global end-diastolic volume index (GEDVI), an established marker of preload thought to reflect the volume of all four heart chambers, global ejection fraction (GEF) and cardiac function index (CFI) as variables of cardiac function, and extravascular lung water index (EVLWI) as indicator of pulmonary edema in 29 patients undergoing elective left and right heart catheterization including left ventricular angiography with stable coronary heart disease and normal cardiac function (controls, n = 11), moderate-to-severe aortic valve stenosis (AS, n = 10), or dilated cardiomyopathy (DCM, n = 8). RESULTS: Cardiac output was similar in controls, AS, and DCM, with good correlation between transpulmonary thermodilution and pulmonary artery catheter using the Fick method (r = 0.69, p < 0.0001). Left ventricular end-diastolic volume was normal in controls and AS, but significantly higher in DCM (104 ± 37 vs 135 ± 63 vs 234 ± 24 ml, p < 0.01). GEDVI did not differentiate between patients with normal and patients with enlarged left ventricular end-diastolic volume (848 ± 128 vs 882 ± 213 ml m-2, p = 0.60). No difference in GEF and CFI was found between patients with normal and patients with reduced left ventricular ejection fraction. Patients with AS but not DCM had higher EVLWI than controls (9 ± 2 vs 12 ± 4 vs 11 ± 3 ml kg-1, p = 0.04), while there was only a trend in pulmonary artery occlusion pressure (8 ± 3 vs 10 ± 5 vs 14 ± 7 mmHg, p = 0.05). CONCLUSIONS: Cardiac output measurement by transpulmonary thermodilution is unaffected by differences in ventricular size and outflow obstruction. However, GEDVI did not identify markedly enlarged left ventricular end-diastolic volumes, and neither GEF nor CFI reflected the increased heart chamber volumes and markedly impaired left ventricular function in patients with DCM. In contrast, EVLWI is probably a sensitive marker of subclinical pulmonary edema particularly in patients with elevated left-ventricular-filling pressure irrespective of differences in left ventricular function.

Assessment of endothelial cell function and physiological microcirculatory reserve by video microscopy using a topical acetylcholine and nitroglycerin challenge.

BACKGROUND: Assessment of the microcirculation is a promising target for the hemodynamic management of critically ill patients. However, just as the sole reliance on macrocirculatory parameters, single static parameters of the microcirculation may not represent a sufficient guide. Our hypothesis was that by serial topical application of acetylcholine (ACH) and nitroglycerin (NG), the sublingual microcirculation can be challenged to determine its endothelial cell-dependent and smooth muscle-dependent physiological reserve capacity. METHODS: In 41 healthy subjects, sublingual capillary microscopy was performed before and after topical application of ACH and NG. Total vessel density (TVD) was assessed in parallel using manual computer-assisted image analysis as well as a fully automated analysis pathway utilizing a newly developed computer algorithm. Flow velocity was assessed using space-time diagrams of the venules as well as the algorithm-based calculation of an average perfused speed indicator (APSI). RESULTS: No change in all measured parameters was detected after sublingual topical application of ACH. Sublingual topical application of NG however led to an increase in TVD, space-time diagram-derived venular flow velocity and APSI. No difference was detected in heart rate, blood pressure, and cardiac output as measured by echocardiography, as well as in plasma nitric oxide metabolite content before and after the topical application of ACH and NG. CONCLUSIONS: In healthy subjects, the sublingual microcirculatory physiological reserve can be assessed non-invasively by topical application of nitroglycerin without affecting systemic circulation.