Rainald Fischer

Five-year outcomes of severe acute kidney injury requiring renal replacement therapy

BACKGROUND Current research priorities in critical care medicine are focusing on long-term outcomes of survivors of critical illness. Severe acute kidney injury (AKI) is a common occurrence in intensive care. However, few studies have followed up these patients beyond 12 months after hospital discharge. METHODS Of a cohort of 425 patients, 226 survivors with severe AKI necessitating renal replacement therapy (RRT) were followed up for 60 months after hospital discharge. None of these patients had pre-existing kidney disease. Vital status and renal function were documented annually for 5 years. RESULTS None of the discharged or transferred patients was dependent on RRT; 57% had complete recovery and 43% had partial recovery of renal function. During the first year after hospital discharge, 18% of survivors died, during the second year 4% and during the third to fifth year 2% per year. At 5 years, 25% of the cohort were still alive. Further improvement in renal function (eGFR) was noted in 26 patients within the first year only. Deterioration of renal function occurred in eight patients. At 5 years, renal function was normal in 86% of the remaining survivors, it was impaired in 9% and 5% of the patients alive needed dialysis again. The proportional Cox regression analysis model showed that pre-existing extrarenal comorbidity, surgery and partial recovery of renal function were independent determinants of long-term survival. CONCLUSIONS This prospective observational study indicates that severe AKI is not only a determinant of excess in-hospital case fatalities of critically ill patients, but it also carries significant implications for long-term mortality.

Levofloxacin Inhalation Solution (MP-376) in Patients with Cystic Fibrosis with Pseudomonas aeruginosa

RATIONALE Lower respiratory tract infection with Pseudomonas aeruginosa (PA) is associated with increased morbidity in patients with cystic fibrosis (CF). Current treatment guidelines for inhaled antibiotics are not universally followed due to the perception of decreased efficacy, increasing resistance, drug intolerance, and high treatment burden with current aerosol antibiotics. New treatment options for CF pulmonary infections are needed. OBJECTIVES This study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin (MP-376, Aeroquin) in a heavily treated CF population with PA infection. METHODS This study randomized 151 patients with CF with chronic PA infection to one of three doses of MP-376 (120 mg every day, 240 mg every day, 240 mg twice a day) or placebo for 28 days. The primary efficacy endpoint was the change in sputum PA density. Secondary endpoints included changes in pulmonary function, the need for other anti-PA antimicrobials, changes in patient-reported symptom scores, and safety monitoring. MEASUREMENTS AND MAIN RESULTS All doses of MP-376 resulted in reduced sputum PA density at Day 28, with MP-376 240 mg twice a day showing a 0.96 log difference compared with placebo (P = 0.001). There was a dose-dependent increase in FEV(1) for MP-376, with a difference of 8.7% in FEV(1) between the 240 mg twice a day group and placebo (P = 0.003). Significant reductions (61-79%) in the need for other anti-PA antimicrobials were observed with all MP-376 treatment groups compared with placebo. MP-376 was generally well tolerated relative to placebo. CONCLUSIONS Nebulized MP-376was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection. Clinical trial registered with www.clinicaltrials.gov (NCT00677365).

Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: A comparative efficacy trial

BACKGROUND Open-label, parallel-group, international trial comparing aztreonam for inhalation solution (AZLI) and tobramycin nebulizer solution (TNS) for cystic fibrosis patients with airway Pseudomonas aeruginosa. METHODS 273 patients (≥ 6 years); randomized to three 28-day courses (AZLI 75 mg [three-times/day] or TNS 300 mg [twice/day]); 28 off-days separated each course. RESULTS 268 patients were treated (AZLI/TNS: 136/132). Mean baseline FEV1 was 52% predicted. Mean relative changes after 1 course (AZLI: 8.35%; TNS: 0.55%; p<0.001) and mean actual changes across 3 courses (AZLI: 2.05%; TNS: -0.66%; p=0.002) indicated AZLI statistical superiority vs. TNS. AZLI-treated patients had fewer respiratory hospitalizations (p=0.044) and respiratory events requiring additional antipseudomonal antibiotics (p=0.004); both treatments were well tolerated. 133 patients received 1 to 3 courses of AZLI treatment in the open-label extension-period (28-day courses separated by 28 days off-treatment); lung function improvements were comparable regardless of whether patients had received TNS or AZLI in the preceding comparative period. CONCLUSIONS AZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

Hypobaric Hypoxia Causes Body Weight Reduction in Obese Subjects

The reason for weight loss at high altitudes is largely unknown. To date, studies have been unable to differentiate between weight loss due to hypobaric hypoxia and that related to increased physical exercise. The aim of our study was to examine the effect of hypobaric hypoxia on body weight at high altitude in obese subjects. We investigated 20 male obese subjects (age 55.7 ± 4.1 years, BMI 33.7 ± 1.0 kg/m2). Body weight, waist circumference, basal metabolic rate (BMR), nutrition protocols, and objective activity parameters as well as metabolic and cardiovascular parameters, blood gas analysis, leptin, and ghrelin were determined at low altitude (LA) (Munich 530 m, D1), at the beginning and at the end of a 1‐week stay at high altitude (2,650 m, D7 and D14) and 4 weeks after returning to LA (D42). Although daily pace counting remained stable at high altitude, at D14 and D42, participants weighed significantly less and had higher BMRs than at D1. Food intake was decreased at D7. Basal leptin levels increased significantly at high altitude despite the reduction in body weight. Diastolic blood pressure was significantly lower at D7, D14, and D42 compared to D1. This study shows that obese subjects lose weight at high altitudes. This may be due to a higher metabolic rate and reduced food intake. Interestingly, leptin levels rise in high altitude despite reduced body weight. Hypobaric hypoxia seems to play a major role, although the physiological mechanisms remain unclear. Weight loss at high altitudes was associated with clinically relevant improvements in diastolic blood pressure.

Theophylline and acetazolamide reduce sleep-disordered breathing at high altitude.

A randomised, double-blind, placebo-controlled study was conducted to evaluate the effects of theophylline and acetazolamide in the treatment of sleep-disordered breathing (SDB) after fast ascent to high altitude (3,454 m). The study was conducted at a high-altitude research laboratory and included 30 healthy male volunteers. Study medication was either oral slow release theophylline (2×250 mg·day−1), oral acetazolamide (2×250 mg·day−1) or a matched placebo tablet. Polysomnographic measurements were performed during two consecutive nights, and acute mountain sickness, pulse rate, oxyhaemoglobin saturation and arterial blood gases were assessed three times a day. Without active medication, the apnoea/hypopnoea index (AHI) was highly pathological (median 16.2·h−1, range 2–92). Both theophylline and acetazolamide normalised SDB (median AHI 2.5·h−1, range 0–11; 4.2·h−1, range 0–19, respectively) and reduced oxyhaemoglobin desaturations during sleep (median desaturation index placebo 41.5·h−1, range 6–114; acetazolamide 6.5·h−1, range 3–28; theophylline 8.5·h−1, range 3–32). Compared with the high amount of central apnoeas or hypopnoeas, the number of obstructive events during sleep was very low in all groups (<4·h−1). In contrast to theophylline, acetazolamide significantly improved basal oxyhaemoglobin saturation during sleep (86.2±1.7% versus 81.0±3.0%). The authors conclude that both oral slow release theophylline and acetazolamide are effective to normalise high-altitude sleep-disordered breathing.

No Evidence of Cerebral Oedema in Severe Acute Mountain Sickness

In a randomized, double-blind cross-over study 10 subjects were exposed to a simulated altitude of 4500 m for 10 h after administration of placebo, acetozolamide (250 mg bid) or theophylline (250 mg bid). T2-weighted magnetic resonances images (MRI) and diffusion weighted MRI were obtained directly after exposure to altitude under hypoxic conditions. Although eight of 10 subjects had moderate to severe acute mountain sickness (AMS), we found no evidence of cerebral oedema, irrespective of the medication taken. Almost all subjects showed a decrease in inner cerebrospinal fluid (iCSF) volumes (placebo −10.3%, P = 0.02; acetazolamide −13.2%, P = 0.008, theophylline −12.2%, n.s.). There was no correlation between AMS symptoms and fluid shift. However, we found a significantly positive correlation of large (>10 ml) iCSF volume and more severe AMS after administration of placebo (r = 0.76, P = 0.01). Moderate to severe AMS after high altitude exposure for 10 h is associated with a decreased iCSF-volume independent of AMS severity or medication without signs of cerebral oedema.

Regional ventilation in cystic fibrosis measured by electrical impedance tomography

BACKGROUND The feasibility of electrical impedance tomography (EIT) as an alternative examination tool in cystic fibrosis (CF) was examined. METHODS 14 CF patients and 14 healthy volunteers were studied. Spirometry and EIT measurements were performed simultaneously. The global inhomogeneity (GI) index was applied to assess the degree of ventilation homogeneity at different levels of maximum inspiratory volume. Ratios of maximum expiratory flow at 25% and 75% of vital capacity (MEF(25)/MEF(75)) were calculated for both global lung and regional areas in EIT images. RESULTS Significant differences among GI values at various lung volumes were found in CF patients (P<0.01) but not in healthy subjects. Global MEF(25)/MEF(75) measured with spirometry and with EIT were highly correlated for all subjects (r(2)=0.69, P<0.01). Significant difference in global MEF(25)/MEF(75) was found between CF patients and healthy volunteers with both spirometer (CF: 0.15±0.09; healthy: 0.46±0.15; P<0.001) and EIT (CF: 0.14±0.09; healthy: 0.42±0.08; P<0.001). Regional airway obstruction was identified in the MEF(25)/MEF(75) maps in CF patients. CONCLUSIONS Compared to the global parameters provided by spirometry, EIT is able to deliver both global and regional information to assess the airway obstruction in CF patients.

Theophylline improves acute mountain sickness

A randomized two-part study was conducted in order to determine the efficacy of theophylline in the treatment of acute mountain sickness during fast ascent to altitudes >2,500 m. Fourteen healthy male subjects participated in a randomized single-blind placebo-controlled crossover study carried out in a decompression chamber (simulated altitude 4,500 m). A second randomized single-blind, placebo-controlled study was conducted at a high-altitude research laboratory (3,454 m) and included 21 healthy male subjects. The study medication was either 375 mg oral slow-release theophylline (250 mg if <70 kg) or a matched placebo tablet taken twice daily. The acute mountain sickness score (AMSS) was assessed three times a day, beginning 18 h prior to altitude exposure and continuing for 18 h after altitude exposure. In addition, measurements of respiratory frequency, pulse rate, oxygen saturation and arterial blood gas levels were performed. Acute mountain sickness was significantly reduced by theophylline during the decompression chamber study (mean+/-SD 1.2+/-0.9) with placebo versus 3.6+/-0.8 with theophylline; p=0.03). During the high-altitude study, subjects with theophylline showed a significantly lower AMSS on arrival and after 18 h at altitude (0.6 versus 2.3, p=0.03). Oxygenation was improved in both parts of the study. In conclusion, oral slow-release theophylline improves acute mountain sickness.

Lung function in adults with cystic fibrosis at altitude: impact on air travel

Current guidelines for air travel state that patients with chronic respiratory diseases are required to use oxygen if their in-flight arterial oxygen tensions (Pa,O2) drop below 6.6 kPa. This recommendation may not be strictly applicable to cystic fibrosis patients, who may tolerate lower Pa,O2 for several hours without clinical symptoms. Lung function, symptoms, blood gas levels and signs of pulmonary hypertension were studied in 36 cystic fibrosis patients at altitudes of 530 m and, after 7 h, 2,650 m. A hypoxia inhalation test (inspiratory oxygen fraction 0.15) was performed at low altitude in order to predict high-altitude hypoxaemia. Median Pa,O2 dropped from 9.8 kPa at low altitude to 7.0 kPa at high altitude. Mild exercise at a workload of 30 W further decreased Pa,O2. Two-thirds of all patients exhibited Pa,O2 of <6.6 kPa during exercise and, except for one patient, were asymptomatic. Patients were significantly less obstructed at an altitude of 2,650 m. Low forced expiratory volume in one second at baseline was associated with a low Pa,O2 at altitude. It is concluded that cystic fibrosis patients with baseline arterial oxygen tensions of >8.0 kPa safely tolerate an altitude of 2,650 m for several hours under resting conditions. The risk assessment of low in-flight oxygenation should encompass the whole clinical situation of cystic fibrosis patients, with special attention being paid to the presence of severe airway obstruction.

A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients

BACKGROUND Inhaled antibiotics are standard of care for persons with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infection. APT-1026 (levofloxacin inhalation solution, LIS) is fluoroquinolone in development. We compared the safety and efficacy of LIS to tobramycin inhalation solution (TIS) in persons ≥12 years old with CF and chronic P. aeruginosa infection. METHODS This multinational, randomized (2:1), non-inferiority study compared LIS and TIS over three 28-day on/off cycles. Day 28 FEV(1) % predicted relative change was the primary endpoint. Time to exacerbation and patient-reported quality of life were among secondary endpoints. RESULTS Baseline demographics for 282 subjects were comparable. Non-inferiority was demonstrated (1.86% predicted mean FEV(1) difference [95% CI -0.66 to 4.39%]). LIS was well-tolerated, with dysgeusia (taste distortion) as the most frequent adverse event. CONCLUSIONS LIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection.