[Clinical research in service of clinical medicine: Contexts, practice, methodology and theory of Paul Martinís "clinical proof" - part 3: Causally relevant elements of Martini's clinical proof and epistemological remarks]. / Klinische Forschung im Dienst der Heilkunde: Kontexte, Praxis, Methodik und Theorie des "klinischen Beweises" von Paul Martini. Beitrag 3: Kausalanalytisch relevante Elemente des klinischen Beweises und epistemologische Kommentare.

In the third part of our quadripartite series on Paul Martini and his concept of clinical proof we shortly present the mostly procedural elements of his test of treatment. We discuss their causal conduciveness: what do they contribute to infer causality from effect? Finally we comment on some of Martini's epistemological assumptions and methodological decisions that underpin his method of proof.

[Clinical research in service of clinical medicine: Contexts, practice, methodology and theory of Paul Martini's "clinical proof" - part 2: Martini's early therapeutic research]. / Klinische Forschung im Dienst der Heilkunde: Kontexte, Praxis, Methodik und Theorie des "klinischen Beweises" von Paul Martini ­ Beitrag 2: Martinis frühe Forschungspraxis.

This article aims to examine Paul Martini's early therapeutic research. It traces the development and early practice of his methodology by focussing on four clinical studies which Martini conducted in the years 1928 to 1932. The studies show a methodological transition from uncontrolled drug evaluation to systematic method-based drug testing and the production of increasingly valid results. In addition, we address Martini's inaugural lecture in Bonn (1932) as a source of important conceptual considerations. With its publication in 1932, the "Methodenlehre der therapeutischen Untersuchung" became a firm basis and standard for therapeutic research practice for Martini, which he applied not only to his own, but to all clinical studies.

Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate.

INTRODUCTION: The appropriate strategy for trauma-induced coagulopathy management is under debate. We report the treatment of major trauma using mainly coagulation factor concentrates. METHODS: This retrospective analysis included trauma patients who received >or= 5 units of red blood cell concentrate within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM). Fibrinogen concentrate was given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was <10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score. RESULTS: Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was 14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014). CONCLUSIONS: ROTEM-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to investigate this therapeutic alternative further appear warranted.

Pilot study on the effects of a 2-week hiking vacation at moderate versus low altitude on plasma parameters of carbohydrate and lipid metabolism in patients with metabolic syndrome.

BACKGROUND: Hypoxic and hypobaric conditions may augment the beneficial influence of training on cardiovascular risk factors. This pilot study aimed to explore for effects of a two-week hiking vacation at moderate versus low altitude on adipokines and parameters of carbohydrate and lipid metabolism in patients with metabolic syndrome. METHODS: Fourteen subjects (mean age: 55.8 years, range: 39 - 69) with metabolic syndrome participated in a 2-week structured training program (3 hours of guided daily hiking 4 times a week, training intensity at 55-65% of individual maximal heart rate; total training time, 24 hours). Participants were divided for residence and training into two groups, one at moderate altitude (1,900 m; n = 8), and the other at low altitude (300 m; n = 6). Anthropometric, cardiovascular and metabolic parameters were measured before and after the training period. RESULTS: In study participants, training overall reduced circulating levels of total cholesterol (p = 0.024), low-density lipoprotein cholesterol (p = 0.025) and adiponectin (p < 0.001). In the group training at moderate altitude (n = 8), lowering effects on circulating levels were significant not only for total cholesterol, low-density-lipoprotein cholesterol and adiponectin (all, p < 0.05) but also for triglycerides (p = 0.025) and leptin (p = 0.015), whereas in the low altitude group (n = 6), none of the lipid parameters was significantly changed (each p > 0.05). Hiking-induced relative changes of triglyceride levels were positively associated with reductions in leptin levels (p = 0.006). As compared to 300 m altitude, training at 1,900 m showed borderline significant differences in the pre-post mean reduction rates of triglyceride (p = 0.050) and leptin levels (p = 0.093). CONCLUSIONS: Preliminary data on patients with metabolic syndrome suggest that a 2-week hiking vacation at moderate altitude may be more beneficial for adipokines and parameters of lipid metabolism than training at low altitude. In order to draw firm conclusions regarding better corrections of dyslipidemia and metabolic syndrome by physical exercise under mild hypobaric and hypoxic conditions, a sufficiently powered randomized clinical trial appears warranted. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02013947 (first received November 6, 2013).

Factors associated with B-lines after exposure to hypobaric hypoxia.

AIMS: Increased extravascular lung water (EVLW) is seen as B-lines on chest ultrasonography. In lowlanders ascending to altitude the time course, relationship with the patient's clinical status and factors affecting B-lines are still unclear. The aim was to monitor B-lines, clinical status and N-terminal B-type natriuretic peptide (NT-proBNP) during exposure to high altitude. METHODS AND RESULTS: Chest ultrasonography, blood samples, cardiovascular parameters, and signs and symptoms of high altitude pulmonary oedema (HAPE) were prospectively assessed in 19 participants at baseline and after ascent to 3830 m (9, 24, 48, 72 h, and 8 days) by blinded investigators. Potential confounding factors (e.g. altitude variations, physical effort) were minimized. Generalized estimating equations were used to analyse factors associated with B-lines. B-lines changed with exposure to altitude (P = 0.006) in a parabolic-like pattern within the first 72 h; 10 of 18 participants (55.6%) had >5 B-lines at 24 h. B-lines were correlated with the number of signs and symptoms (partial coefficient = 0.372, P = 0.001). B-lines were associated with time (P = 0.038), sex (P = 0.013), and SpO2 (P = 0.042), but not with NT-proBNP (P = 0.546). The participant with a clinical diagnosis of HAPE had 23 B-lines. CONCLUSION: B-lines during exposure to altitude seem to reflect the individual response to hypobaric hypoxia and represent clinically relevant alterations at high altitude, also in patients with HAPE. Similar to previous studies, our results support a non-cardiogenic aetiology of B-lines.

Influence of low ambient temperature on epitympanic temperature measurement: a prospective randomized clinical study.

BACKGROUND: Epitympanic temperature (Tty) measured with thermistor probes correlates with core body temperature (Tcore), but the reliability of measurements at low ambient temperature is unknown. The aim of this study was to determine if commercially-available thermistor-based Tty reflects Tcore in low ambient temperature and if Tty is influenced by insulation of the ear. METHODS: Thirty-one participants (two females) were exposed to room (23.2 ± 0.4 °C) and low (-18.7 ± 1.0 °C) ambient temperature for 10 min using a randomized cross-over design. Tty was measured using an epitympanic probe (M1024233, GE Healthcare Finland Oy) and oesophageal temperature (Tes) with an oesophageal probe (M1024229, GE Healthcare Finland Oy) inserted into the lower third of the oesophagus. Ten participants wore ear protectors (Arton 2200, Emil Lux GmbH & Co. KG, Wermelskirchen, Switzerland) to insulate the ear from ambient air. RESULTS: During exposure to room temperature, mean Tty increased from 33.4 ± 1.5 to 34.2 ± 0.8 °C without insulation of the ear and from 35.0 ± 0.8 to 35.5 ± 0.7 °C with insulation. During exposure to low ambient temperature, mean Tty decreased from 32.4 ± 1.6 to 28.5 ± 2.0 °C without insulation and from 35.6 ± 0.6 to 35.2 ± 0.9 °C with insulation. The difference between Tty and Tes at low ambient temperature was reduced by 82% (from 7.2 to 1.3 °C) with insulation of the ear. CONCLUSIONS: Epitympanic temperature measurements are influenced by ambient temperature and deviate from Tes at room and low ambient temperature. Insulating the ear with ear protectors markedly reduced the difference between Tty and Tes and improved the stability of measurements. The use of models to correct Tty may be possible, but results should be validated in larger studies.

Factors associated with optic nerve sheath diameter during exposure to hypobaric hypoxia.

OBJECTIVE: To monitor the changes in optic nerve sheath diameter (ONSD) induced by acute exposure to hypobaric hypoxia and to investigate factors associated with these changes, including development of acute mountain sickness. METHODS: In this cohort study, neurologic signs and symptoms, cardiovascular parameters, and ultrasonography of ONSD were prospectively assessed in 19 healthy lowlanders at baseline and after ascent to 3,830 m (3 hours, 9 hours, 24 hours, 48 hours, 72 hours, and 8 days) by blinded investigators. Potential confounding factors (e.g., altitude variations, physical effort) were minimized. A multivariate analysis of factors associated with ONSD was performed by means of generalized estimating equations. RESULTS: ONSD increased with exposure to altitude in all participants (p < 0.001). The increase between 9 and 24 hours was larger in patients who developed acute mountain sickness (p = 0.001). There was no influence of sex, oxygen saturation, or acclimatization on ONSD. CONCLUSION: Both physiologic and pathologic responses to hypobaric hypoxia were independently associated with changes in ONSD. Studies on a larger cohort, at a range of altitudes, and with baseline neuroimaging techniques are necessary to further understand the clinical significance of increased ONSD during exposure to hypobaric hypoxia.