Marco Maggiorini

Prevention of High-Altitude Pulmonary Edema by Nifedipine

Abstract Background. Exaggerated pulmonary-artery pressure due to hypoxic vasoconstriction is considered an important pathogenetic factor in high-altitude pulmonary edema. We previously found that nifedipine lowered pulmonary-artery pressure and improved exercise performance, gas exchange, and the radiographic manifestations of disease in patients with high-altitude pulmonary edema. We therefore hypothesized that the prophylactic administration of nifedipine would prevent its recurrence. Methods. Twenty-one mountaineers (1 woman and 20 men) with a history of radiographically documented high-altitude pulmonary edema were randomly assigned to receive either 20 mg of a slow-release preparation of nifedipine (n = 10) or placebo (n = 11) every 8 hours while ascending rapidly (within 22 hours) from a low altitude to 4559 m and during the following three days at this altitude. Both the subjects and the investigators were blinded to the assigned treatment. The diagnosis of pulmonary edema was based on chest radio...

High-Altitude Pulmonary Edema Is Initially Caused by an Increase in Capillary Pressure

BackgroundHigh-altitude pulmonary edema (HAPE) is characterized by severe pulmonary hypertension and bronchoalveolar lavage fluid changes indicative of inflammation. It is not known, however, whether the primary event is an increase in pressure or an increase in permeability of the pulmonary capillaries. Methods and ResultsWe studied pulmonary hemodynamics, including capillary pressure determined by the occlusion method, and capillary permeability evaluated by the pulmonary transvascular escape of 67Ga-labeled transferrin, in 16 subjects with a previous HAPE and in 14 control subjects, first at low altitude (490 m) and then within the first 48 hours of ascent to a high-altitude laboratory (4559 m). The HAPE-susceptible subjects, compared with the control subjects, had an enhanced pulmonary vasoreactivity to inspiratory hypoxia at low altitude and higher mean pulmonary artery pressures (37±2 versus 26±1 mm Hg, P <0.001) and pulmonary capillary pressures (19±1 versus 13±1 mm Hg, P <0.001) at high altitude. Nine of the susceptible subjects developed HAPE. All of them had a pulmonary capillary pressure >19 mm Hg (range 20 to 26 mm Hg), whereas all 7 susceptible subjects without HAPE had a pulmonary capillary pressure <19 mm Hg (range 14 to 18 mm Hg). The pulmonary transcapillary escape of radiolabeled transferrin increased slightly from low to high altitude in the HAPE-susceptible subjects but remained within the limits of normal and did not differ significantly from the control subjects. ConclusionsHAPE is initially caused by an increase in pulmonary capillary pressure.

Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes

OBJECTIVES We sought to assess the mechanism and prognostic value of elevated troponins in patients without acute coronary syndromes (ACS). BACKGROUND Cardiac troponins are used as specific markers for the diagnosis of ACS. Recent studies reported a considerable number of critically ill patients without ACS as being troponin-positive, especially patients with sepsis, pulmonary embolism, renal failure, and stroke. METHODS We analyzed 58 consecutive, critically ill patients admitted for reasons other than ACS, according to their troponin status. Thirty-day mortality, left ventricular ejection fraction (LVEF), and a panel of inflammatory cytokines were compared between troponin-positive and troponin-negative patients. Relevant coronary artery disease was excluded either by stress echocardiography or autopsy. RESULTS Of the 58 critically ill patients, 32 (55%) without evidence of ACS were troponin-positive. Positive troponin levels were associated with higher mortality (22.4% vs. 5.2%, p < 0.018) and a lower LVEF (p = 0.0006). Troponin-positive patients had significantly higher median levels of tumor necrosis factor (TNF)-alpha, its soluble receptor, and interleukin (IL)-6. A subgroup of 10 aplastic patients was troponin-negative at study entry. Three became troponin-positive during leukocyte recovery and subsequently died, whereas all the others stayed troponin-negative and survived. Flow-limiting coronary artery disease was not demonstrable at autopsy or stress echocardiography in 72% of troponin-positive patients. CONCLUSIONS Elevated troponin is a mortality risk factor for medical intensive care patients admitted for reasons other than ACS. It is associated with decreased left ventricular function and higher levels of TNF-alpha and IL-6.

Clinical review: Update on hemodynamic monitoring - a consensus of 16

Hemodynamic monitoring plays a fundamental role in the management of acutely ill patients. With increased concerns about the use of invasive techniques, notably the pulmonary artery catheter, to measure cardiac output, recent years have seen an influx of new, less-invasive means of measuring hemodynamic variables, leaving the clinician somewhat bewildered as to which technique, if any, is best and which he/she should use. In this consensus paper, we try to provide some clarification, offering an objective review of the available monitoring systems, including their specific advantages and limitations, and highlighting some key principles underlying hemodynamic monitoring in critically ill patients.

Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.

Context Very few trials have evaluated ways to prevent high-altitude pulmonary edema (HAPE). Contribution In this double-blind trial, 29 adults with a history of HAPE were randomly assigned to receive prophylactic tadalafil, dexamethasone, or placebo during a 24-hour ascent and 2-day stay at 4559 m. Compared with placebo recipients, adults taking dexamethasone less often experienced acute mountain sickness and those taking either dexamethasone or tadalafil less often had HAPE. Cautions The trial involved a small number of selected adults who rapidly ascended to a high altitude. Implications Either tadalafil or dexamethasone might help prevent HAPE in mountaineers with a history of pulmonary edema. The Editors Rapid ascent to altitudes greater than 2500 m may cause acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE). In nonacclimatized mountaineers, the prevalences of AMS and HAPE at 4559 m are approximately 50% and 4%, respectively (1). Individual susceptibility, rate of ascent, and preexposure to high altitude are major, independent determinants of the prevalence of AMS (2). Acute mountain sickness is not a prerequisite for HAPE. Acetazolamide (3, 4) or dexamethasone (5, 6) prophylaxis can prevent AMS, whereas nifedipine prophylaxis can prevent HAPE (7). Whether acetazolamide or dexamethasone also prevents HAPE has not been studied. Exaggerated hypoxic pulmonary vasoconstriction leading to elevated pulmonary capillary pressure (8) is the major pathophysiologic mechanism of HAPE. This elevated pulmonary capillary pressure may be caused by inhomogeneous hypoxic pulmonary vasoconstriction (9), which leads to areas that are subjected to high pressure and flow, consequent mechanical overdistention of pulmonary capillaries, and injury of the bloodgas barrier (10). This phenomenon causes extravasation of fluid, plasma proteins, and blood cells into the interstitial and alveolar spaces (11). Decreased bioavailability of nitric oxide might explain the elevated pulmonary artery pressure (12, 13). Therefore, phosphodiesterase-5 inhibitors are an attractive option to restore impaired effects of nitric oxide in persons susceptible to HAPE (1416). Constitutively impaired sodium and water transport in the lung has been thought to be an additional factor in the pathogenesis of HAPE (17, 18). Hypoxia also decreases water reabsorption from the alveolar space. Direct experimental evidence has been obtained from hypoxia-exposed rats (19), and indirect evidence derives from decreased sodium transport activity in cultured alveolar epithelial cells (20). Prophylactic inhalation of the 2-adrenergic agonist salmeterol to stimulate alveolar sodium transport (17) decreased the incidence of HAPE in susceptible persons. However, other mechanisms of action may also contribute to the preventive effects of salmeterol, because -adrenergics tighten the endothelial barrier and decrease pulmonary artery pressure (21). Dexamethasone may be an alternative therapy to prevent HAPE because it stimulates alveolar sodium and water reabsorption (22); may enhance nitric oxide availability in pulmonary vessels (23, 24); and is effective against AMS (5, 6), which may develop despite use of nifedipine as prophylaxis against HAPE (25). However, HAPE has occurred in persons who received dexamethasone for AMS (26, 27). We sought to test whether prophylaxis with dexamethasone or tadalafil reduces the risk for HAPE in adults with a history of HAPE on rapid ascent to 4559 m. Methods Sample and Setting Mountaineers with a history of HAPE were recruited through announcements in the journals of the Swiss Alpine Club and the German Alpine Club. Four women and 25 men with at least 1 documented episode of HAPE participated after providing written informed consent. Table 1 shows the age and average number of HAPE episodes for each participant. No participant spent more than 4 nights above 2500 m within 30 days before ascent to the Capanna Regina Margherita, Italy (altitude, 4559 m). Table 1. Participant Characteristics Two to 4 weeks before the study at the Capanna Regina Margherita, baseline evaluations were performed in Zrich, Switzerland (altitude, 490 m). For ascent, participants traveled to Alagna, Italy (altitude, 1100 m), ascended to 3200 m by cable car, and continued by foot to the Capanna Gnifetti (altitude, 3600 m), where they spent 1 night. The journey from the cable car arrival station (3200 m) to the Capanna Gnifetti took about 1.5 hours. The next morning, the participants continued to the Capanna Regina Margherita (about 4 hours), where they spent 2 nights. Figure 1 shows the study design. The institutional ethics boards of the University Hospital Zrich and University Hospital Heidelberg approved the study and its protocol, which was consistent with the principles of the Declaration of Helsinki. Figure 1. Flow diagram of the study. Twenty-nine participants were recruited and underwent prealtitude tests, after which they were randomly assigned to treatment groups. *Two participants in the tadalafil group were withdrawn from the study early because they required treatment for severe acute mountain sickness (AMS) with oxygen and dexamethasone before the first night at 4559 m, but high-altitude pulmonary edema (HAPE) was not diagnosed at the time of withdrawal. However, the duration of exposure to 4559 m may not have been long enough to develop HAPE. Randomization and Interventions Medication consisted of white gelatin capsules, identical in appearance, containing placebo; tadalafil, 10 mg (Cialis [Eli Lilly, Geneva, Switzerland]); or dexamethasone, 8 mg (Fortecortin [Merck, Dietikon, Switzerland]). Before the study, the pharmacist at the University Hospital Zrich packaged the medication into numbered bottles, which were assigned to individual participants according to a computer-generated list. Randomization was stratified by the number of previous episodes of HAPE (1 or 2) without blocking. Participants started taking the medication twice daily on the morning of the day before ascent to high altitude and continued intake until the end of the study. Primary End Point and Assessment of HAPE and AMS The primary end point was development of HAPE, which was assessed by clinical examination and chest radiography in each participant after the first and second nights at 4559 m or when HAPE or severe AMS occurred (Figure 1). Two physicians who were blinded to treatment assignment performed clinical examinations according to a predefined checklist in the mornings after the first and second night at 4559 m or when severe AMS or HAPE occurred. High-altitude pulmonary edema was clinically suspected at the appearance of dry cough, orthopnea, or pulmonary rales in at least 1 lung area. A posteroanterior thorax radiograph was then obtained by using a mobile unit (TRS [Siemens, Stockholm, Sweden]) at a fixed distance of 1.4 m at 95 kV and a charge of 3 to 6 mAs. Radiographs were scored retrospectively by a second radiologist who was blinded to other study results. After the lung was divided into 4 quadrants, the following scores were assigned: 1 for a questionable infiltrate, 2 for interstitial edema in less than 50% of the quadrant area, 3 for interstitial edema on 50% or more of the quadrant area, and 4 for alveolar edema. A radiograph showing interstitial or alveolar edema (score >1) in at least 1 quadrant (28) confirmed the diagnosis of HAPE. The severity of AMS was evaluated by clinical examination and was quantified by using the Lake Louise scoring protocol (29). Each participant answered the first 5 questions of the protocol that asked about the severity of headache, gastrointestinal symptoms, fatigue, lightheadedness or dizziness, and insomnia. A score of 0 to 3 points (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms) was assigned for each item. In clinical examination, a score of 0 (normal) to 4 points was given for mental status (for which 4 points indicated coma) and ataxia (for which 4 points indicated inability to stand on the heel-to-toe walking test). A score of 1 was given for peripheral edema in 1 location, and a score of 2 was given for edema in more than 1 location. The sum of all points yielded the Lake Louise score (maximum score, 25 points). A Lake Louise score greater than 4 defined AMS (30). To assess possible side effects of the study medications, we separately evaluated the Lake Louise score question that asked for information on headache severity and the degree of insomnia, and we measured blood glucose levels in addition to vital signs. To test for adherence, participants were requested to document medication intake and investigators counted the remaining capsules at each visit. Blood and urine samples were collected to measure cortisol and tadalafil, respectively. Treatment of HAPE and AMS consisted of nifedipine for HAPE, dexamethasone for AMS, and supplemental oxygen for both disorders. Participants who required treatment were withdrawn from the study. Echocardiography and Measurement of Cardiac Output Doppler echocardiography was performed by using an integrated color Doppler system with a 4.0-MHz transducer (Aplio 80 [Toshiba-Medical Systems, Oetwil am See, Switzerland]) while participants were lying in a semi-supine, left-lateral position. Systolic pulmonary artery pressure was calculated from the pressure gradient across the tricuspid valve and measured with continuous-wave Doppler echocardiography by using the modified Bernoulli equation and an estimated right atrial pressure of 7 mm Hg (8). Color flow imaging was used for alignment. The recordings were stored on magneto-optical disk for evaluation by 2 investigators who were blinded to all other data. Averages of at least 3 cardiac cycles were used. Cardiac output was measured by using beat-to-beat stroke volume measurement with impedance cardiography (Task Force Monitor [CNSystems, Graz, Austria]). Nasal Potential Measurements Diffe

Nifedipine for high altitude pulmonary oedema

In a laboratory at 4559 m six subjects with high altitude pulmonary oedema (HAPO) characterised by clinical signs, severe hypoxaemia, widened alveolar-arterial oxygen gradient, pulmonary hypertension, and alveolar oedema on chest radiography were treated with nifedipine. Despite continued exercise at the same altitude this treatment, without supplementary oxygen, resulted in clinical improvement, better oxygenation, reduction of alveolar arterial oxygen gradient and pulmonary artery pressure, and progressive clearing of alveolar oedema. Nifedipine offers a potential emergency treatment for HAPO when descent or evacuation is impossible and oxygen is not available. The findings also suggest that hypoxic pulmonary hypertension is essential in the pathogenesis of HAPO.

Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure.

Objective:B-type natriuretic peptide (BNP) and N-terminal pro-BNP measurements are used for the diagnosis of congestive heart failure (HF). However, the diagnostic value of these tests is unknown under septic conditions. We compared patients with severe sepsis or septic shock and patients with acute HF to unravel the influence of the underlying diagnosis on BNP and N-terminal pro-BNP levels. Design:Prospective, clinical study. Setting:Academic medical intensive care unit (ICU). Patients:A total of 249 consecutive patients were screened for the diagnosis of sepsis or HF. Sepsis was defined according to published guidelines. HF was diagnosed in the presence of an underlying heart disease and congestive HF, pulmonary edema, or cardiogenic shock. Interventions:BNP and N-terminal pro-BNP were measured from blood samples that were drawn daily for routine analysis. Measurements and Main Results:We identified 24 patients with severe sepsis or septic shock and 51 patients with acute HF. At admission, the median (range) BNP and N-terminal pro-BNP levels were 572 (13–1,300) and 6,526 (198–70,000) ng/L in patients with sepsis and 581 (6–1,300) and 4,300 (126–70,000) ng/L in patients with HF. The natriuretic peptide levels increased during the ICU stay, but the differences between the groups were not significant. Nine patients with sepsis and eight patients with HF were monitored with a pulmonary artery catheter. Mean (sd) pulmonary artery occlusion pressure were 16 (4.2) and 22 (5.3) mm Hg (p = .02), and cardiac indexes were 4.6 (2.8) and 2.2 (0.6) L/min/m2 (p = .03) in patients with sepsis and HF, respectively. Despite these clear hemodynamic differences BNP and N-terminal pro-BNP levels were not statistically different between the two groups. Conclusion:In patients with severe sepsis or septic shock, BNP and N-terminal pro-BNP values are highly elevated and, despite significant hemodynamic differences, comparable with those found in acute HF patients. It remains to be determined how elevations of natriuretic peptide levels are linked to inflammation and sepsis-associated myocardial dysfunction.

Measurement of quality of life in pulmonary hypertension and its significance.

Until recently, assessment of patients with pulmonary hypertension has mainly relied on functional and haemodynamic parameters. Health-related quality of life (HRQOL), however, has become increasingly important in defining overall health status. The present study investigated the performance and clinical relevance of the Minnesota Living with Heart Failure (MLHF) questionnaire by prospectively studying 48 patients with either pulmonary arterial hypertension (n = 26) or chronic thromboembolic pulmonary hypertension (n = 22). The MLHF scores were correlated to various clinical and haemodynamic parameters. Prognostic outcome was evaluated by calculating the time taken to reach an adverse clinical event defined as death, lung transplantation or pulmonary endarterectomy. The reliability of test–re-test and internal consistency of this HRQOL tool was high. The MLHF score and its physical subscore correlated moderately to well with functional and haemodynamic parameters, except in the case of pulmonary artery pressures. Both scores significantly improved during vasodilator therapy. This figure was surpassed only by the New York Heart Association/World Health Organization functional class. A multivariate analysis of all variables revealed that the MLHF score was the sole factor predicting subsequent outcome. The Minnesota Living with Heart Failure questionnaire is highly reproducible, consistent, and a moderately valid and responsive tool in assessing health-related quality of life in pulmonary hypertension. Moreover, it is a significant predictor of outcome in these patients.

“Live high–train low” using normobaric hypoxia: a double-blinded, placebo-controlled study

The combination of living at altitude and training near sea level [live high-train low (LHTL)] may improve performance of endurance athletes. However, to date, no study can rule out a potential placebo effect as at least part of the explanation, especially for performance measures. With the use of a placebo-controlled, double-blinded design, we tested the hypothesis that LHTL-related improvements in endurance performance are mediated through physiological mechanisms and not through a placebo effect. Sixteen endurance cyclists trained for 8 wk at low altitude (<1,200 m). After a 2-wk lead-in period, athletes spent 16 h/day for the following 4 wk in rooms flushed with either normal air (placebo group, n = 6) or normobaric hypoxia, corresponding to an altitude of 3,000 m (LHTL group, n = 10). Physiological investigations were performed twice during the lead-in period, after 3 and 4 wk during the LHTL intervention, and again, 1 and 2 wk after the LHTL intervention. Questionnaires revealed that subjects were unaware of group classification. Weekly training effort was similar between groups. Hb mass, maximal oxygen uptake (VO(2)) in normoxia, and at a simulated altitude of 2,500 m and mean power output in a simulated, 26.15-km time trial remained unchanged in both groups throughout the study. Exercise economy (i.e., VO(2) measured at 200 W) did not change during the LHTL intervention and was never significantly different between groups. In conclusion, 4 wk of LHTL, using 16 h/day of normobaric hypoxia, did not improve endurance performance or any of the measured, associated physiological variables.

Toxoplasmosis in heart transplant recipients

In cardiac transplant recipients, infection withToxoplasma gondii may be transmitted with the transplanted organ to immunosuppressed recipients or may be due to reactivation under immunosuppression in cases of pretransplant infection. In the present study the incidence of infection withToxoplasma gondii and the clinical presentation of the infection in 121 consecutive heart transplant recipients were investigated. Data on IgG and IgM antibodies forToxoplasma gondii measured by a semiquantitative microparticle immunoassay of donors and recipients were collected prospectively in 121 patients. Infection withToxoplasma gondii was defined as IgM seroconversion with proven pretransplant seronegativity (primary infection) or at least a fourfold increase of IgG antibodies (reactivation). Infection withToxoplasma gondii occurred in 16 of 121 patients (13%), whereas overt clinical disease occurred in 5 of 121 patients (4%). Organ-transmitted infection was more frequent (11/18, 61%) and more often associated with acute disease than reactivation of latent infection (5/69 patients, 7%) (p < 0.01), although one case ofToxoplasma retinochoroiditis occurred in a patient with recrudescence of latent pretransplant infection. Treatment with pyrimethamine and sulfadiazine was efficient in all patients with acute disease and in controlling disease in patients with evidence of acute infection.