Search

Background: Serotonin-norepinephrine reuptake inhibitors inhibit the reuptake of serotonin and noradrenalin and are used in the treatment of neuropathic pain. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of μ-opioid receptor agonists. This study hypothesized that co-administration of milnacipran and buprenorphine would have a synergistic effect in evoked pain models in healthy subjects., Methods: This was a randomized double-blinded, placebo-controlled, four-way cross-over, multiple dose clinical trial to investigate the analgesic effects of buprenorphine (placebo, 0.5, 1 and 3 μg/kg) in combination with milnacipran (placebo, 25 and 50 mg) in healthy subjects., Results: 11 healthy men were enrolled in the study. Buprenorphine alone showed a dose-response relationship indicative of anti-nociception in the pain tests. Following milnacipran administration, no changes were seen in the pharmacodynamic measurements for pain, psychomotor function, body stability or eye movements. For the electrical tests, cold pressor test and pressure pain test, buprenorphine alone was superior when compared with buprenorphine plus milnacipran. No differences in pharmacodynamic variables, besides an increase in pupil/iris ratio, were observed after repeated administration of milnacipran 50 mg. Single and multiple doses of 25 or 50 mg milnacipran did not further potentiate the anti-nociceptive effects of buprenorphine., Conclusions: Buprenorphine showed dose-dependent effects consistent with its pharmacological profile. Milnacipran alone did not affect any of the pain variables. The combination of both buprenorphine and milnacipran did not potentiate or show a synergistic effect on the pain models used in this study., Significance: Buprenorphine is known to be a potent opioid agonist. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of μ-opioid receptor agonists. Here, we found that buprenorphine showed a dose-dependent analgesic effect, but that no potentiation or synergy on a battery of evoked pain tasks could be observed after co-administration of both milnacipran and buprenorphine., (© 2016 European Pain Federation - EFIC®.)

Therapeutics promoting myelin synthesis may enhance recovery in demyelinating diseases, such as multiple sclerosis. However, no suitable method exists to quantify myelination. The turnover of galactosylceramide (myelin component) is indicative of myelination in mice, but its turnover has not been determined in humans. Here, six healthy subjects consumed 120 mL 70% D 2 O daily for 70 days to label galactosylceramide. We then used mass spectrometry and compartmental modeling to quantify the turnover rate of galactosylceramide in cerebrospinal fluid. Maximum deuterium enrichment of body water ranged from 1.5-3.9%, whereas that of galactosylceramide was much lower: 0.05-0.14%. This suggests a slow turnover rate, which was confirmed by the model-estimated galactosylceramide turnover rate of 0.00168 day -1 , which corresponds to a half-life of 413 days. Additional studies in patients with multiple sclerosis are needed to investigate whether galactosylceramide turnover could be used as an outcome measure in clinical trials with remyelination therapies., (© 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The development of a new medicine is a risky and costly undertaking that requires careful planning. This planning is largely applied to the operational aspects of the development and less so to the scientific objectives and methodology. The drugs that will be developed in the future will increasingly affect pathophysiological pathways that have been largely unexplored. Such drug prototypes cannot be immediately introduced in large clinical trials. The effects of the drug on normal physiology, pathophysiology, and eventually the desired clinical effects will need to be evaluated in a structured approach, based on the definition of drug development as providing answers to important questions by appropriate clinical studies. This review describes the selection process for biomarkers that are fit-for-purpose for the stage of drug development in which they are used. This structured and practical approach is widely applicable and particularly useful for the early stages of innovative drug development.

Background: Evidence is weak for the ability of long-term non-invasive positive pressure ventilation (NPPV) to improve survival in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD). Previous prospective studies did not target a reduction in hypercapnia when adjusting ventilator settings. This study investigated the effect of long-term NPPV, targeted to markedly reduce hypercapnia, on survival in patients with advanced, stable hypercapnic COPD., Methods: This investigator-initiated, prospective, multicentre, randomised, controlled clinical trial enrolled patients with stable GOLD stage IV COPD and a partial carbon dioxide pressure (PaCO2) of 7 kPa (51.9 mm Hg) or higher and pH higher than 7.35. NPPV was targeted to reduce baseline PaCO2 by at least 20% or to achieve PaCO2 values lower than 6.5 kPa (48.1 mm Hg). Patients were randomly assigned (in a 1:1 ratio) via a computer-generated randomisation sequence with a block size of four, to continue optimised standard treatment (control group) or to receive additional NPPV for at least 12 months (intervention group). The primary outcome was 1-year all-cause mortality. Analysis was by intention to treat. The intervention was unblinded, but outcome assessment was blinded to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT00710541., Findings: Patients were recruited from 36 respiratory units in Germany and Austria, starting on Oct 29, 2004, and terminated with a record of the vital status on July 31, 2011. 195 patients were randomly assigned to the NPPV group (n=102) or to the control group (n=93). All patients from the control group and the NPPV group were included in the primary analysis. 1-year mortality was 12% (12 of 102 patients) in the intervention group and 33% (31 of 93 patients) in the control group; hazard ratio 0.24 (95% CI 0.11-0.49; p=0.0004). 14 (14%) patients reported facial skin rash, which could be managed by changing the type of the mask. No other intervention-related adverse events were reported., Interpretation: The addition of long-term NPPV to standard treatment improves survival of patients with hypercapnic, stable COPD when NPPV is targeted to greatly reduce hypercapnia., Funding: German Lung Foundation; ResMed, Germany; Tyco Healthcare, Germany; and Weinmann, Germany., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The use of cyanoacrylate followed by fluorescent reagents is well known in the field of fingermark visualisation. Treatment with fluorescent reagents that stain the cyanoacrylate deposits will not only enhance the visibility of fingermarks previously thought unusable, but also reveal previously unseen marks. Downside of this approach is the exposure of the evidential material to large amounts of solvent, such as water, methanol and ethanol, thereby potentially destroying other forensic traces. New cyanoacrylate derivates with fluorescent and UV-active properties can be used for one step dual action visualisation of latent fingermarks. Increased optical properties can be achieved by addition of functional groups via the Steglich esterification of cyanoacetic acid with N-(3-dimetylaminopropyl)-N'-ethylcarbodiimide (EDC). The UV-active ester can be created via the Knoevenagel condensation with formaldehyde to form poly-cyanoacrylate. These poly-cyanoacrylates can be depolymerised to form monomer cyanoacrylates. In this paper we compare these ethylcyanoacrylate derivatives with commercially available cyanoacrylate formulations. We have shown that the use of poly-cyanoacrylate derivatives can yield fully developed fingerprints. The initiator of the polymerisation reaction towards novel reagents can be altered according to the need for particular optical properties., (© 2013.)

Background: Homecare for mechanically ventilated patients is complex and challenging for homecare institutions. The framework conditions of homecare are regulated by a likewise complex social legislation. The German Respiratory Society (DGP) and the German Interdisciplinary Society for Home Care Ventilation (DIGAB) have published recommendations on the structure of homecare for ventilated patients in their recent guideline and recommended a certification of homecare nursing services., Rationale: Prior to a certification process, the homecare task force of the DIGAB conducted a survey in order to compare the current structures with the guideline recommendations., Methods: Voluntary disclosure of information by means of a written questionnaire consisting of eleven items was requested., Results: 37 homecare institutions with a total of 78 subsidiaries providing service all over Germany returned their questionnaires. While educational standards are mostly in line with the guideline recommendation, it was found that only 43 % of 812 recorded patients followed up with a specialised weaning centre or centre for ventilation. 84 % of these patients were ventilated invasively. In spite of the fact that all homecare institutions took care of invasively ventilated patients, there was a lack of company-owned standards for specific nursing measures., Conclusions: Homecare for ventilated patients in Germany has reached a decent degree of organisation, while follow-up with specialised centres for ventilation, and with that medical specialist care appears to be underserved. The certification process for homecare institutions should be pursued with emphasis in order to create uniform quality standards. The number of invasively ventilated patients in homecare settings is probably higher than previously estimated and could be the result of a lack of weaning capacity., (© Georg Thieme Verlag KG Stuttgart · New York.)

Patients with amyotrophic lateral sclerosis (ALS) who are treated with the antiglutamatergic drug riluzole receive a fixed-dose regimen of 50 mg b.i.d. The drug has been shown to increase tracheostomy-free survival by 3-6 months. The pharmacokinetics of riluzole show a high interindividual variability. Riluzole serum concentrations are associated with side effects and ALS symptoms, but the effect of the actual blood level of riluzole on disease progression and survival is unknown. We measured trough and peak serum concentrations of riluzole in 160 patients with ALS, and estimated the area under the curve for one dosage interval (AUCi) using a Bayesian method. We then determined the association between riluzole AUCi and survival over a 5-year period, and between riluzole AUCi and disease progression, defined by the rates of decline of arm strength and vital lung capacity. No significant association was found between riluzole AUCi and survival or disease progression.

Pharmacokinetic studies of riluzole show a large inter-individual variability of the drug's clearance and serum concentrations. Optimizing the individual dosage of riluzole may have the potential to improve the effect of riluzole treatment on survival of patients with amyotrophic lateral sclerosis (ALS). Limited data are available on the in vivo metabolic elimination of riluzole. From in vitro experiments, CYP1A2 seems to be mainly involved in riluzole clearance. However, in vitro studies suggest that formation of riluzole-glucuronide plays a role and may determine the drug's pharmacokinetic variability in patients to some extent. In the current study the formation of riluzole-glucuronide was examined in amyotrophic lateral sclerosis (ALS) patients. It also aimed at relating glucuronidation of riluzole to differential UGT1A1*28 genotypes. The formation of riluzole-glucuronide was confirmed in serum from a group of 14 ALS patients taking riluzole. Riluzole-glucuronide concentrations were positively associated with those of riluzole. In a separate group of 131 ALS patients taking riluzole, the UGT1A1*28 genotype was not associated with trough or peak serum concentrations of riluzole. This study provides evidence that the in vivo metabolic elimination of riluzole in ALS patients involves glucuronidation. The results do not indicate that glucuronidation of riluzole highly contributes to the drug's inter-individual pharmacokinetic variability.

We report on a 65-year-old female who complained of recurrent bronchopulmonary infections since 1999. She suffered from permanent cough and progressive dyspnea. The diagnosis of amyloidosis was made by bronchoscopic tissue biopsies, during which severe bleeding occurred. Argon-plasma-laser treatment stopped the bleeding and resulted in a successful recanalization of the left main bronchus. The patient noticed a decrease in dyspnea shortly after the intervention. Further diagnostic procedures did not show any signs of systemic or malignant disease. This led us to the diagnosis of a rare form of isolated tracheobronchial amyloidosis.

We attempted to decrease PCO2 during noninvasive ventilation (NIV) and studied he effects of this therapy both in acute exacerbations of chronic obstructive pulmonary disease (COPD) and in its chronic state. Ninety six patients (63% male) with COPD and hypercapnia above 6.7 kPa were investigated. The mode and setting of the ventilator had to be chosen to achieve normocapnia. The subgroup of acute exacerbated COPD was separated by pH (<7.35=acute), by HCO3- (<26 mmol/l=acute), and by history (acute=history of recent deterioration). Ventilator settings were the following: tidal volume-972+/-137 ml and frequency-20+/-2.2 (volume preset). Inspiratory pressure was 33.6+/-14.2 mbar and frequency-19.7+/-5.1 (pressure preset). The preference of volume preset ventilators resulted from insufficient maximal pressures of the pressure preset devices. Eighty three percent of the patients became normocapnic while on NIV after 6.8+/-5.7 days. The mean PCO2 decreased from 64+/-13 mmHg to 41+/-6 mmHg (P<0.001). After 4 weeks, 72% of the patients were normocapnic while breathing spontaneously (P<0.001). The subgroups of acute exacerbation were the following: pH 28%, HCO3- 3.1%, and history 68%. All three indicators together were present in 2% of patients. Normocapnia under ventilation and during spontaneous breathing was independent from the subgroup. In conclusion, the study showed that normocapnia can be achieved in COPD under the ventilator and while breathing spontaneously in chronic and acute disease.

Patients suffering from advanced chronic thoracic disorders are at higher risk to develop respiratory failure, requiring mechanical ventilation. Forty seven patients acutely decompensated were investigated. Twenty nine of them were primarily ventilated noninvasively, 7 were intubated and 11 had been intubated and tracheotomized prior to arriving at the weaning center. All intubated patients were transferred to noninvasive ventilation within 24 h after arrival. Ten of the 11 tracheotomizd patients were transferred to noninvasive ventilation before discharge. One remained tracheotomized because of severe tracheal stenosis, despite being able to breathe spontaneously for several hours. Mortality was 14.2% in the intubated, 9% in the tracheotomized, and 10.2% in the primarily nasally ventilated. One patient refused to go on with mechanical ventilation and died. Hospital stay ranged between 4 and 24 days in the nasally ventilated. The intubated were ventilated invasively between 3 and 16 days and thereafter 4 to 17 days noninvasively on a regular ward. Tracheotomized patients were treated in intensive care for 7 to 32 days and in the weaning unit for 7 to 39 days. We conclude that patients either ventilated nasally or intubated or tracheotomized can be prepared for home mechanical ventilation in a weaning unit with similar outcome. Noninvasive ventilation is highly important in such patients as only one remained on invasive ventilation. This may implicate that transfer to noninvasive ventilation prior to tracheotomy might be appropriate.

Background: Gemcitabine/carboplatin is a convenient and effective treatment for advanced-stage non-small-cell lung cancer (NSCLC), but modification of the schedule to diminish thrombocytopenia is worthwhile., Patients and Methods: One hundred fifty-eight chemotherapy-naive patients with stage IIIB/IV NSCLC were randomized from 15 centers in Germany to receive gemcitabine 1250 mg/m(2) on days 1 and 8 plus carboplatin area under the curve 5 on day 1 (arm A) or carboplatin area under the curve 2.5 on days 1 and 8 (arm B), every 21 days for 4 cycles., Results: The 2 arms (A vs. B) were well balanced with regard to patient baseline characteristics: stage IV 72.5% versus 69%, median Eastern Cooperative Oncology Group performance status 1 versus 1. The incidence of grade 3/4 hematologic toxicity was as follows (percentage of patients in arm A vs. B): leukopenia 37.5% versus 27% (P = 0.075), granulocytopenia 36% versus 36%, and thrombocytopenia 51% versus 35% (P = 0.017). Nonhematologic toxicity was modest and comparable with both schedules. The overall response rate was 46% versus 36% (P = 0.12), and 24% versus 42% had stable disease. Median progression-free survival (5.8 months vs. 6.1 months) and overall survival (11.7 months vs. 10.7 months) were not significantly different between arms A and B., Conclusion: Splitting the dose of carboplatin between days 1 and 8 on the same days as gemcitabine results in a significantly decreased incidence of severe thrombocytopenia, without compromising the activity of the combination.

Aims: Riluzole is used in a fixed dosing schedule of 50 mg twice daily to treat patients with amyotropic lateral sclerosis (ALS), one form of motor neurone disease. The large variability in the pharmacokinetics of riluzole may be a factor contributing to its limited therapeutic benefit. Riluzole is assumed to be mainly metabolized by the cytochrome P450 enzyme 1A2 (CYP1A2). The aim of the study was to investigate the relationship between CYP1A2 activity and riluzole clearance with a view to optimize drug treatment., Methods: A group of 30 ALS patients participated in the study. In each patient the CYP1A2 activity was determined using caffeine as a metabolic probe. Riluzole clearance was estimated from serum drug concentration measurements followed by Bayesian fitting., Results: Riluzole clearance and the serum paraxanthine : caffeine (P/C) ratio showed a positive correlation (r = 0.693; P = 0.0002). Linear regression analysis identified the P/C ratio (beta: 1.16) and height (beta: 0.027) as independent predictors of riluzole clearance (adjusted r2 = 0.369)., Conclusions: The P/C ratio, used as measure of CYP1A2 activity, significantly correlated with the riluzole clearance, although only 37% of the observed variability could be explained.

A specific, accurate and precise high-performance liquid chromatographic assay was developed for the determination of riluzole, a drug used to treat patients with amyotrophic lateral sclerosis. Samples were treated by extraction with dichloromethane followed by reversed-phase chromatography with ultraviolet detection at 260 nm. Preset validation criteria were met from 20 to 2000 ng/mL with a linear response curve. Extraction recovery of riluzole was 65-76%. The accuracy of the method was 102-103%. Intra- and inter-day coefficients of variation were in the ranges 2.8-4.9% and 1.8-9.7%. A detection limit of 5 ng/mL was found. Determination of concentrations in serum and plasma resulted in similar results below 500 ng/mL. At higher values a matrix effect cannot be excluded. This presented method can be used to monitor plasma or serum levels in ALS patients treated with riluzole., (2004 John Wiley & Sons, Ltd.)

The incidence of amyotrophic lateral sclerosis (ALS) is higher among men than women but rises in women after the menopause. Estrogens may play a protective role. Treatment with estrogens has been shown to be neuroprotective in models of several neurodegenerative diseases. We therefore determined the effect of ovariectomy on female G93A mSOD1 transgenic mice, and the effect of subsequent treatment with 17beta-estradiol (E2). Ovariectomy led to a significant acceleration of disease progression of the mice, and high-dose E2 treatment significantly delayed disease progression of ovariectomized G93A mSOD1 transgenic mice. We conclude that treatment with E2 may also delay disease progression of post-menopausal women with ALS.

Non-invasive ventilation is applied with increasing frequency in patients with chronic hypercapnic COPD and insufficiency of the ventilatory pump. In the few existing clinical trials on long-term use of NIV, no significant improvement on survival could be proven, mainly due to methodical reasons. The "National Task Force for Non-invasive ventilation and weaning" plans to study patients with severe COPD and hypercapnic ventilatory pump insufficiency in a prospective, randomised, multicentre clinical trial over one year. In the intervention group, NIV will be applied for at least six hours per day in addition to standard COPD-treatment. The target of mechanical ventilation is a reduction of PCO (2) during spontaneous breathing by at least 20 %, or into the normal range. The main outcome parameter is all-cause mortality, secondary outcome parameters are course of the disease, exercise capacity, quality of life and consumption of medical resources. The sample size is estimated on 300 patients (150 control group, 150 intervention group). The whole study will take approximately three years.

A 48-year-old woman with right-sided hemiplegia by embolic occlusion of the left middle cerebral artery was treated with alteplase. A pre- and post-treatment CT angiography scan showed the vanishing blood clot.

Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure. In a transgenic mouse model of ALS, creatine monohydrate showed a promising increase in survival. We performed a double-blind, placebo-controlled, sequential clinical trial to assess the effect of creatine monohydrate on survival and disease progression in patients with ALS. Between June 2000 and December 2001, 175 patients with probable, probable-laboratory supported, or definite ALS were randomly assigned to receive either creatine monohydrate or placebo 10 gm daily. A sequential trial design was used with death, persistent assisted ventilation, or tracheostomy as primary end points. Secondary outcome measurements were rate of decline of isometric arm muscle strength, forced vital capacity, functional status, and quality of life. The trial was stopped when the null hypothesis of indifference was accepted. Creatine did not affect survival (cumulative survival probability of 0.70 in the creatine group vs 0.68 in the placebo group at 12 months, and 0.52 in the creatine group vs 0.47 in the placebo group at 16 months), or the rate of decline of functional measurements. Creatine intake did not cause important adverse reactions. This placebo-controlled trial did not find evidence of a beneficial effect of creatine monohydrate on survival or disease progression in patients with ALS.

A 52-year-old woman was in a confused state and had difficulty walking and swallowing, as well as dysarthria. That same day she had consumed some berries, which she thought were bilberries, but she had instead eaten Atropa belladonna (deadly nightshade). She made a spontaneous and full recovery within a few days. A 3-year-old boy, with amblyopia, was vomiting, had difficulty walking and had a temperature of 39 degrees C. He was agitated and had a warm, red skin and dilated pupils that did not respond to light. A suspected intoxication with a parasympathicolytic agent was confirmed upon an empty bottle of atropine eye drops being found at his home. The boy made a full recovery following treatment with physostigmine. It is important to consider an anticholinergenic intoxication in the case of patients who are confused, have difficulty speaking, large fixed pupils and fever. A specific anamnesis with respect to medicines, eye drops and berries or plants consumed can confirm the diagnosis. It is important to recognise an anticholinergic intoxication because without treatment, the outcome can be fatal.

The authors evaluated response, time to progression (TTP), survival, prognostic factors, and toxicity in 63 patients with a recurrent glioblastoma multiforme treated with procarbazine, lomustine, and vincristine (PCV) chemotherapy. Complete and partial response was observed in two (3%) and five patients (8%). In 16 patients (25%), stable disease was observed. Median TTP and survival were 13 and 33 weeks. Age < 40 years and Karnofsky Performance Status > or = 90 were associated with longer TTP and survival. PCV treatment was generally well tolerated.

Methods: Five patients with chronic ventilatory failure demonstrated by arterial hyperkapnia and overloaded respiratory muscles under spontaneous ventilation (P01/P01 max) were adapted to passive noninvasive ventilation (ISB). Three of them suffered from severe COPD (FEV1 < 50%), two patients from severe restriction (VC < 30%). These patients had to undergo a bicycle ergometer exercise with and without nasal ventilation until they reached physical exhaustion with standardised incremental increase in external workload., Results: In both settings all patients were able to manage exercise up to their physical exhaustion. The anaerobic limit was exceeded each time. The total ventilation volume had to be increased two- to threefold during exercise with nasal ventilation to maintain the passive ventilation. The reduced load on the respiratory muscles was generally proven by lower pCO2 and higher pH levels. Without ventilation discontinuation of the exercise was caused by dyspnoea, whereas this was due to weakness in the legs under ventilation. In all five cases the achieved level of external workload was higher when supporting the respiratory muscles (43 watts vs. 36 watts) at lower lactate levels., Conclusion: On a bicycle ergometer the respiratory muscles can be sufficiently relieved using noninvasive nasal ventilation. A higher level of workload, longer duration and a higher quality of exercise can be achieved thereby. The fact that patients without relief of load of the respiratory muscles complained of dyspnoea, whereas the fact that patients with ventilation complained of weakness in their legs indicates the high efficiency of this method, although the tested patients are severely handicapped individuals who usually do not undergo comparable physical exercise in their daily activities.

Background: Patients suffering from amyotrophic lateral sclerosis (ALS) can profit from nasal mechanical ventilation and improve in the quality of life., Patients and Methods: Thirty-eight patients were introduced to nasal mechanical ventilation, using pressure- and volume-cycled respirators. The daily periods of mechanical ventilation varied from 8 to 24 hours., Results: Twelve women and 26 men with ALS mostly with severe symptoms were adapted to the intermittent nasal ventilation. 80% had bulbar symptoms. Nineteen patients died till now. Even when complications occurred it was possible to use the noninvasive ventilation., Conclusions: Noninvasive mechanical ventilation is possible in spite of complications and improves the quality of life in ALS.

Background: Since the first publication by Cooper et. al. in 1994 of lung volume reduction surgery (LVRS) of emphysema a marked respiratory failure with hyperkapnia (PaCO2 > 55 Torr) has been regarded as an exclusion criterion for LVRS., Patients and Method: In a survey in German hospitals the question was asked whether non-invasive nasal ventilation (NIPPV) has a role in the management of LVRS. Of 12 hospitals 6 had experience with NIPPV and LVRS in a total of 19 patients with a mean FEV1 of 0.64 +/- 0.101., Results: LVRS improved FEV1 by 0.20 +/- 0.181. Preoperative NIPPV was short (< 6 months) in 8 patients and resulted in improvement of physical condition and getting the patient used to NIPPV for better perioperative management. In 5 cases NIPPV was used on a long-term basis in order to allow the patient to be included in the LVRS program. In fact 7 of these 13 patients needed ventilation perioperatively, and 4 had to continue long-term NIPPV after surgery. In further 3 patients NIPPV was applied only perioperatively. One patient had to resume NIPPV after 15 months. Two patients started NIPPV 1 resp. 12 months after surgery. Two patients had bronchial cancer which was resected. Four patients died: 1 perioperatively after intubation, 2 after 3 resp. 13 months due to respiratory failure, 1 for cancer relapse after 20 months., Conclusion: NIPPV may be helpful in the planning and management of LVRS in patients with ventilatory failure with hypercarbia.

Background: Nasal mechanical ventilation is not only applicable to adults but also in childhood when necessary., Patients and Methods: Thirty-six children suffering from various neuromuscular diseases were brought up by their parents to learn nasal mechanical ventilation. Thirty children had to be ventilated, because of symptomatic ventilatory failure, reduced ventilatory muscle capacity or hypercapnia., Results: Thirty-five children could be adapted to nasal mechanical ventilation, 1 girl needed a naso-oral mask. All children wanted to continue with ventilation because they realized the benefit. Their symptoms disappeared., Conclusions: The management of ventilatory failure should be the same in adults and children. Nasal mechanical ventilation is indeed a good possibility for children even in early childhood. Children should be introduced to mechanical ventilation at the beginning of the symptoms of ventilatory failure.

Background: The ventilatory and the pressure response to CO2 in patients with advanced thoracic disorders are critically dependent on the mechanics of the lung and the respiratory muscles. Changes in drive, therefore, can not be directly assessed with that method. However during changes as a result of intermittent mechanical ventilation, changes in drive can be assessed, if lung and muscle mechanics remain unaffected. In addition, to study changes in ventilatory drive independently in patients successfully treated by intermittent mechanical ventilation, we determined the recruitment threshold, pCO2RT, of the unloaded ventilatory pump to CO2., Patients: 16 patients with various disorders (4 COPD, 4 COPD and sleep apnoea, 7 scoliosis, 1 fibrothorax) were studied, 14 during nasal IPPV and 2 during mechanical ventilation via tracheostomy., Results: After they had been successfully adapted to the ventilator, they were entered into the study. The apnoea threshold in all cases had already been reached during the adaptation period. pCO2AT was determined 32 +/- 5 mm Hg. While the patients were passively ventilated, the inspiratory CO2 was increased every 5 minutes, resulting in a stepwise increase in arterial pCO2 by 3 mm Hg. The recruitment threshold pCO2RT was then defined as the lowest pCO2, which resulted in a deformation of the inspiratory pressure curve by the patients own inspiratory efforts. pCO2RT was reproducible within trials and in different trials with a standard error of 1.2 mm Hg. It was found 6 +/- 4 mm Hg above the pCO2 during spontaneous breathing (p < 0.01) in all patients. pCO2RT decreased from 58 +/- 10 to 47 +/- 4 mm Hg during intermittent IPPV and so did the threshold during CO2 rebreathing, while spontaneous pCO2 decreased from 53 +/- 12 to 42 +/- 5 mm Hg. The slope, reflecting drive was decreased to 0.28 compared to normals but remained unchanged 0.32 (n. s.) during the study. Lung function did not change. A highly significant increase in the indices of maximal inspiratory force was observed (p < 0.002) and as a result a decrease in the inspiratory demand (p < 0.008)., Conclusion: Intermittent IPPV does efficiently suppress phasic respiratory drive via thoracic afferent inhibition and therefore effectively unloads the ventilatory pump. The CO2 threshold is increased in patients with hypercapnic ventilatory failure, probably to minimise the load to the ventilatory muscles. With the increase in inspiratory capacity the pCO2 threshold can be restored to normal by intermittent noninvasive or invasive IPPV.

Background: The purpose of this study is to assess quality of life in patients with chronic respiratory failure who require home mechanical ventilation (HMV)., Patients and Methods: Patients with COPD (n = 20), scoliosis (n = 20), neuromuscular diseases (n = 20) and others (n = 7) were examined. A specific questionnaire containing forms for the patient, the physician and for the relatives was developed according to the formulation of the question (Fragebogen zur chronischen Heimbeatmung = FCH, Interview zur chronischen Heimbeatmung = ICH). In addition to that the Hospital Anxiety and Depression Scale (HAD) and the Asthma Quality of Life Questionnaire were used. Arterial blood gas tensions, pulmonary function and inspiratory mouth occlusion pressure were studied., Results: Quality of life in patients with scoliosis and neuromuscular diseases is improved during HMV compared to patients with COPD who especially are impaired with regard to psychological and functional conditions. Correlations with physiological parameters and with the compliance could not be observed., Conclusion: Despite progression of the disease HMV enhances quality of life in patients with scoliosis and neuromuscular diseases. The outcome in COPD is less evident. Therefore the indication must be considered more critically.

The purpose of the lung is intrapulmonary gas exchange. The circulatory system delivers the respiratory gases to the tissue. The ventilatory pump however is responsible for the circulation of air between the lungs and the ambient atmosphere. Due to better diffusing capabilities, hypercapnia always is a result of pump failure and little dependent on the lung. Ventilatory failure, either compensated with an increased demand on the muscles or decompensated with an additional increase in pCO2, should be separated from lung failure where primarily oxygen exchange is involved. Decompensated hypercapnic ventilatory failure is then the indication for intermittent mechanical ventilation. The pCO2, either arterial or transcutaneously registered together with the noninvasive evaluation of the mouth occlusion pressures during tidal breathing and during a maximal inspiratory effort, define well the severity of ventilatory failure. In acute on chronic ventilatory failure, noninvasive mechanical ventilation in three randomised and controlled studies resulted in a better survival compared to intubation. To fulfil certain weaning criteria is no longer required in difficult to wean patients, as a transfer from invasive to noninvasive mechanical ventilation can be performed if only cooperativity is preserved together with a minimal capacity of spontaneous breathing. Weaning will thereafter occur by progressive relief from intermittent noninvasive ventilation. 2300 difficult to wean patients in Germany should profit from this approach. Chronic ventilatory failure as a result of neuromuscular disease or scoliosis of the thoracic spine are the classical indications. COPD and myasthenia gravis are under discussion as indications for intermittent mechanical ventilation with an increasing tendency to ventilate. Epidemiological data however can only be roughly estimated due to the heterogeneity of indication and selection of the patients.

Background: Fully informed patients were willing to start with IPPV., Patients and Methods: Twenty-three patients with amyothropic lateral sclerosis (ALS) were treated with noninvasive intermittent mechanical ventilation (7 women, 16 men, mean age 59 years). The major symptoms were dyspnoe, heavy sleep disruption resulting in severely reduced quality of life., Results: Their symptoms improved. The blood gases normalized during spontaneous breathing. They remained stable, despite a rapid decrease in respiratory force. Thirteen patients died, 6 during an acute event, 4 during bronchopulmonary infection and 3 stopped therapy, when they were fully ventilator dependent., Conclusion: We conclude that respiratory symptoms and quality of life can be improved by home intermittent mechanical ventilation. Indication should therefore be made earlier.

Background: Non-invasive mechanical ventilation is used with success for ventilatory failure due to derangements of the respiratory pump. Efficacy in pulmonary diseases is controversial. Still non-invasive intermittent ventilation is reported as a mean of bridging the period till lung transplantation can be performed., Patients and Methods: We report of 20 patients from 5 centers who were treated with non-invasive intermittent ventilation while lung transplantation was planned., Results and Conclusion: Non-invasive intermittent ventilation was seen as successful in 14 patients. Of these 4 are transplanted after up to 2 years, 4 are still waiting, 2 have not yet entered a lung transplantation program, 1 continued non-invasive intermittent ventilation after refusal to be enlisted, 3 meanwhile died. In the group of non-successful non-invasive intermittent ventilation 2 patients were transplanted after a short waiting period. All remaining 4 patients died. It seems that non-invasive intermittent ventilation may be helpful in prolonging the period of survival while waiting for lung transplantation.

Background: A chronic hypercapnic ventilatory failure appears in patients with restrictive chest wall disorders, chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (OSA), but it can also appear in patients with a disorder of the central respiratory drive., Patients and Method: We studied the lung function, the respiratory muscle function and the PCO2 recruitment threshold (pCO2RT) during nasal intermittent positive pressure ventilation (IPPV) in 16 chronic hypercapnic patients (scoliosis = 8, COPD = 4, OSA = 4)., Results: The pCO2RT decreased from 61 +/- 6 mm Hg to 48 +/- 4 mm Hg (p < 0.0001) during intermittent IPPV, while spontaneous pCO2 decreased from 55 +/- 6 mm Hg to 42 +/- 5 mm Hg (p < 0.0001). The load of the respiratory pump decreased (P0.1/P0.1 max:0.27 +/- 0.18 before, 0.15 +/- 0.08 after intermittent IPPV; p < 0.04)., Conclusion: We conclude, that the pCO2RT can be normalized by intermittent nasal IPPV as well as the pCO2 under spontaneous breathing. The load of the respiratory pump decreases due to an increase of the inspiratory muscle strength.

Patients and Methods: 381 patients were treated by intermittent ventilation for up to 6 years, when ventilatory failure and symptoms persisted despite efficient medical treatment. Patients with chest wall disorders (COPD) were in hospital for 19 +/- 10 (21 +/- 14) days during the first and for 6 +/- 10 (14 +/- 12) days in the following years., Results: Survival was found above 95% in chest wall disorders. In COPD survival ranged 75% in the 2nd and 59% in the 4th years., Conclusion: Intermittent mechanical ventilation, therefore, can restore hypercapnic ventilatory failure to normal. Survival is improve similar to a control group without ventilatory failure.

Objective: We investigated the effects of continuous positive airway pressure (CPAP) and pressure support ventilation (PSV) on the oxygen cost of breathing (VO2resp) for different states of pulmonary function. Additionally VO2resp was measured during spontaneous breathing., Design: This was done in a controlled and prospective study. Ventilatory modes were applied randomly., Setting: Measurements were performed in a quiet room on volunteers (VOL) and inpatients treated for chronic obstructive pulmonary disease (COPD). Post-operative patients after aortocoronary bypass surgery (ACB) were studied on the cardio-thoracic intensive care unit just before and after extubation., Patients: Healthy volunteers (n = 14), postoperative patients after aorto-coronary bypass surgery (n = 15) and patients with COPD (n = 9, xFEV1 47.7%) were the objects of study., Interventions: Demand flow CPAP (5 mbar) and PSV (7 mbar, PEEP 5 mbar), using the Hamilton Veolar ventilator, were investigated in comparison to spontaneous breathing., Measurements and Results: VO2 was measured by a Datex Deltatrac metabolic monitor. VO2resp was calculated by subtraction of total oxygen uptake (VO2tot) in controlled mode ventilation (CMV) from that in the respective spontaneous breathing mode. For VOL and COPD patients who were not intubated, a CPAP facemask connected to a short 7.5 mm tube was used as connection to the ventilator. Breathing spontaneously under a canopy system VOL showed a VO2resp of 4.5 +/- 4.0% compared to 9.2 +/- 3.5% for ACB and 15.4 +/- 7.7% for COPD. CPAP changed the VO2resp to 7.8 +/- 3.9%, 12.0 +/- 4.0% and 9.1 +/- 3.6% respectively. PSV reduced the VO2resp to 7.9 +/- 3.8% in ACB and 7.7 +/- 5.5% in COPD., Conclusions: This investigation confirms findings that postoperative patients have a mild increase in VO2resp. COPD exhibit the highest increase in VO2resp. Tracheal tubes, masks and CPAP on a demand flow apparatus increases VO2resp in volunteers and postoperative patients after cardiac surgery. The same amount of CPAP in contrary reduces VO2resp in patients with COPD. Pressure support ventilation can offset the additional VO2resp induced by CPAP but at the same level does not further reduce VO2resp in COPD patients.

Noninvasive intermittent ventilation (NIV) is performed as controlled mechanical ventilation to put the inspiratory muscles at rest and to normalize the arterial blood gases. As access to the airways an individual nasal mask was used. weaning from tracheostoma ventilation had failed after 74 days on average. 27 patients were treated, when hypercapnic ventilatory failure had not improved within three weeks of conventional therapy (eight patients with kyphoscoliosis, 15 COPD, six neuromuscular disease, three sequelas of tbc). During NIV, there was an increase in inspiratory muscle force, indicated by an increase in maximal inspiratory mouth occlusion from 42 to 58 cm H2O (p less than 0.01). With this increase in muscular force, spontaneous minute volume increased, resulting in an increase in pO2 from 56 to 70 mm Hg (p less than 0.001) and a decrease in pCO2 from 53 to 43 mm Hg (p less than 0.001), as well as an increase in exercise capacity. NIV therefore can improve hypercapnic ventilatory failure effectively. It can be used early in chronic respiratory failure, during weaning from mechanical ventilation, allowing the early and costsaving discharge from the ICU.

Non-invasive intermittent "self-ventilation" employing a nose mask is considered to be an efficient means of treating chronic respiratory failure. After several hours of treatment with a respirator, 10 patients (four with kyphoscoliosis, three with COLD, two with neuromuscular disorders, and one with sequela of Tbc) experienced reversal of the chronic respiratory failure and an improvement in respiratory muscle force.

In 38 patients with chronic obstructive lung disease (COLD), lung function tests, blood gas analysis, catheterisation examination of the right heart, and long-term (Holter) ECG were performed. In comparison with normal subjects, all the patients had a higher mean 24-hour heart rate of 97 +/- 11/minute, and a disturbance of the physiological day/night rhythmicity. Seventeen patients (group I) revealed no major arrhythmias (Lown I to III). More than 50 per cent of the patients (group II) were found to have complex arrhythmias (Lown IV), together with an elevated incidence of polymorphic ventricular and superventricular extrasystoles. A significant correlation of the arrhythmias with the severity of the obstruction or pulmonary hypertension was not observed. Only the long-term follow-up of these patients will provide us with information about the prognostic significance of the complex arrhythmias and about indications for anti-arrhythmic treatment.