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Background: The increasing use of flexible bronchoscopy for diagnostic and interventional purposes requires further knowledge on feasible sedation regimens. We investigated the potential benefit of Target- Controlled Infusion (TCI) of propofol on sedation depth. Methods: Fifty-four patients scheduled for elective flexible bronchoscopy were allocated to receive propofol sedation using either intermittent boluses or Target Controlled Infusion (TCI). Endpoints included Entropy monitoring to evaluate sedation depth, sedation quality and the total amount of propofol. Results: There were no significant differences between both cohorts regarding the number of adverse sedation-related events. The mean applied dose of propofol was significantly higher in the Target-Controlled Infusion group (405±249 mg vs. 324±94 mg, p=0.015). Until patients reached loss of consciousness (LOC), State Entropy (SE) and Response Entropy (RE) levels were comparable among both sedation regimens. During the procedure, both parameters decreased to significantly lower levels in the TCI-cohort (SE: 77.7±13.2 vs. 88.8±8.6 (p=0.002) and RE: 69±12.6 vs. 79±8.7 (p=0.005)). Examination conditions, as rated by proceduralists and assisting nurses, were superior in the TCI-cohort. In addition, restraining measurements, due to uncontrolled movement during the examination needed to be applied more often to patients in the bolus cohort (body restraint: 26 (96%) vs. 18 (67%), p=0.005). Conclusion: Target-Controlled Infusion of propofol complies with the requirements of flexible bronchoscopy by providing a deep and steady level of sedation without impairing patient’s safety. In addition, there is evidence that overall sedation quality is superior, both for bronchoscopist and assisting staff.

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Purpose:Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT).Patients and Methods:Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses.Results:The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood.Conclusions:Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Background Intraoperative patient monitoring using the electroencephalogram (EEG) can help to adequately adjust the anesthetic level. Therefore, the processed EEG (pEEG) provides the anesthesiologist with the estimated anesthesia level. The commonly used approaches track the changes from a fast- and a low-amplitude EEG during wakefulness to a slow- and a high-amplitude EEG under general anesthesia. However, besides these changes, another EEG feature, a strong oscillatory activity in the alpha band (8-12 Hz), develops in the frontal EEG. Strong alpha-band activity during general anesthesia seems to reflect an appropriate anesthetic level for certain anesthetics, but the way the common pEEG approaches react to changes in the alpha-band activity is not well explained. Hence, we investigated the impact of an artificial alpha-band modulation on pEEG approaches used in anesthesia research. Methods We performed our analyses based on 30 seconds of simulated sedation (n = 25) EEG, simulated anesthesia (n = 25) EEG, and EEG episodes from 20 patients extracted from a steady state that showed a clearly identifiable alpha peak in the density spectral array (DSA) and a state entropy (GE Healthcare) around 50, indicative of adequate anesthesia. From these traces, we isolated the alpha activity by band-pass filtering (8-12 Hz) and added this alpha activity to or subtracted it from the signals in a stepwise manner. For each of the original and modified signals, the following pEEG values were calculated: (1) spectral edge frequency (SEF95), (2) beta ratio, (3) spectral entropy (SpEntr), (4) approximate entropy (ApEn), and (5) permutation entropy (PeEn). Results The pEEG approaches showed different reactions to the alpha-band modification that depended on the data set and the amplification step. The beta ratio and PeEn decreased with increasing alpha activity for all data sets, indicating a deepening of anesthesia. The other pEEG approaches behaved nonuniformly. SEF95, SpEntr, and ApEn decreased with increasing alpha for the simulated anesthesia data (arousal) but decreased for simulated sedation. For the patient EEG, ApEn indicated an arousal, and SEF95 and SpEntr showed a nonuniform change. Conclusions Changes in the alpha-band activity lead to different reactions for different pEEG approaches. Hence, the presence of strong oscillatory alpha activity that reflects an adequate level of anesthesia may be interpreted differently, by an either increasing (arousal) or decreasing (deepening) pEEG value. This could complicate anesthesia navigation and prevent the adjustment to an adequate, alpha-dominant anesthesia level, when titrating by the pEEG values.

Background: Local anaesthesia of the pharynx (LAP) was introduced in the era of rigid bronchoscopy (which was initially a conscious procedure under local anaesthetic), and continued into the era of flexible bronchoscopy (FB) in order to facilitate introduction of the FB. LAP reduces cough and gagging reflex, but its post-procedural effect is unclear. This prospective multicentre trial evaluated the effect of LAP on coughing intensity/time and patient comfort after FB, and the feasibility of FB under propofol sedation alone, without LAP. Material and methods: FB was performed in 74 consecutive patients under sedation with propofol, either alone (35 patients, 47.3%) or with additional LAP (39 patients, 52.7%). A primary endpoint of post-procedural coughing duration in the first 10 min after awakening was evaluated. A secondary endpoint was the cough frequency, quality and development of coughing in the same period during the 10 min post-procedure. Finally, the ease of undertaking the FB and the patient’s tolerance and safety were evaluated from the point of view of the investigator, the assistant technician and the patient. Results: We observed a trend to a shorter cumulative coughing time of 48.6 s in the group without LAP compared to 82.8 s in the group receiving LAP within the first 10 min after the procedure, although this difference was not significant (p = 0.24). There was no significant difference in the cough frequency, quality, peri-procedural complication rate, nor patient tolerance or safety. FB, including any additional procedure, could be performed equally well with or without LAP in both groups. Conclusions: Our study suggests that undertaking FB under deep sedation without LAP does to affect post-procedural cough duration and frequency. However, further prospective randomised controlled trials are needed to further support this finding.

Background: Patients suffering from out-of-hospital cardiac arrest (OHCA) frequently receive a bronchoscopy after being admitted to the ICU. We investigated the optimal timing and the outcome in these patients. Methods: All patients who suffered from OHCA and were treated in our ICU from January 2013 to December 2018 were retrospectively analyzed. The data were collected from the patients’ medical files, and included duration of mechanical ventilation, antibiotics, microbiological test results and neurological outcome. The outcome was the effect of early bronchoscopy (≤48 h after administration) on the rate of intubated patients on day five and day seven. Results: From January 2013 to December 2018, 190 patients were admitted with OHCA. Bronchoscopy was performed in 111 patients out of the 164 patients who survived the first day. Late bronchoscopy &gt, 48 h was associated with higher rates of intubation on day five (OR 4.94, 95% CI 1.2–36.72, 86.7% vs. 55.0%, p = 0.036) and day seven (OR 4.96, 95% CI 1.38–24.69, 80.0% vs. 43.3%, p = 0.019). Conclusion: This study shows that patients who suffered from OHCA might have a better outcome if they receive a bronchoscopy early after hospital admission. Our data suggests an association of early bronchoscopy with a shorter intubation period.

Purpose: Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT). Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

Lungenkrebs gehort trotz der verbesserten Therapieoptionen zu den prognostisch ungunstigen Tumoren. Das lasst sich an einer niedrigen relativen 5-Jahres-Uberlebensrate von 21 % bei Frauen und 16 % bei Mannern ablesen [1]. Besonders bei Patienten mit lokal fortgeschrittener Erkrankung ist zur optimalen, individualisierten Therapie eine interdisziplinare Zusammenarbeit zwischen den verschiedenen Fachdisziplinen erforderlich.

Membrane-bound heat shock protein 70 (mHsp70) is indicative for high-risk tumors with negative prognosis but also serves as a target for NK cells that are stimulated with Hsp70 peptide TKD and low dose IL-2 (TKD/IL-2). Herein, the efficacy of ex vivo TKD/IL-2 activated, autologous NK cells was tested in a randomized, investigator initiated phase II clinical trial in patients with mHsp70 positive advanced stage NSCLC after radiochemotherapy (RCT, 60-70 Gy, platinum-based chemotherapy). The interventional (INT) group received 4 cycles TKD/IL-2 activated, autologous NK cells every 2-6 weeks subsequent to standard RCT and the control (CTRL) group received best supportive care. The primary objective of the study was to examine whether the adjuvant treatment of NSCLC patients with TKD/IL-2 activated NK cells is feasible and effective with respect to progression-free survival (PFS). Secondary objectives were the assessment of treatment and biological responses, toxicity, quality-of-life (QoL, QLQ-LC13). Eight patients were randomized into the INT and eight into the CTRL arm. None of the patients died between randomization and final tumor assessment 18 months after randomization. In the INT group one patient had complete response (CR), one patient partial response (PR), two patients stable disease (SD) and one patient progressive disease (PD) at the last documented visit, whereas in the CTRL group only 2 patients showed clinical responses (PR, SD) and five patients had PD. The clinical response of patients in the INT group appeared to be mediated by activated NK cells whereas in the CTRL group by CD8+ T cells. The NK cell therapy after RCT was well tolerated, no differences in QoL were observed between both study groups. Citation Format: Gabriele Multhoff, Stephanie E. Combs, Sophie Seier, Stefan Stangl, Wolfgang Sievert, Maxim Shevtsov, Christiane Blankenstein, Martin Hildebrandt, Konrad Kokowski, Matthias Hautmann, Hubert Hautmann, Claus Roedel, Rainer Fietkau, Rudolf M. Huber, Bernhard Haller, Christina Ertl, Michal Devecka, Robert Offner, Norbert Ahrens. Targeted Natural Killer (NK) cell based adoptive immunotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy - results of a randomized phase II clinical trial (NSCLC-TKD/IL-2) (Eudra-CT Number 2008-002130-30) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-076.

Background We investigated the correlation and agreement of three depth of anesthesia indices, Bispectral Index (BIS), qCON and state entropy (SE) during propofol sedation, because there is extensive literature that deals with the comparability of these indices during general anesthesia, but not during sedation. Methods We recorded electroencephalogram (EEG) and SE trend data, using the Entropy Module from 21 patients who underwent elective bronchoscopy with target-controlled infusion of propofol. EEG data were replayed to BIS and qCON with an EEG player. We calculated the Spearman correlation to evaluate similarities in index trend behavior and estimated the general index agreement of displaying the same anesthetic level, i.e., wakefulness, sedation and anesthesia. We used coughing episodes and the bronchoscope placement to investigate the index for possible arousal reactions. Results We found a high to very high correlation of the indices' trend during the procedure. Furthermore, qCON was significantly lower than BIS and SE. All indices increased significantly after bronchoscope placement and coughing. The agreement of BIS/SE was 68% and around 50% for BIS/qCON and qCON/SE. The median duration of disagreement by >10 points was 39 s for BIS/SE and around 75 s for qCON with BIS and SE. Conclusions The results indicate a high probability of similar index performance between SE, BIS and qCON with the caveat of a different index scaling for qCON. These results can help the user of these monitoring devices to translate findings from one index to the other.

Objectives: Bronchoscopy is an integral part of pulmonary medicine. In recent years, a series of new technologies have evolved. It is to assume that significant changes have also occurred in clinical practice. We conducted a nationwide survey to evaluate the current status of care and to compare it with earlier reports. Methods: A standard questionnaire was sent to 1875 institutions to assess the clinical practice of bronchoscopy in Germany with respect to general issues, education, sedation/anaesthesia and technical aspects. Results: The returned questionnaires cover 301,965 bronchoscopies, performed by 2158 physicians over 12 months, making it the largest survey to date. The proportion of rigid bronchoscopies has decreased and amounts to 7.3 % at present. Atropine as a premedication is hardly used any more. Sedation is routinely applied in 88 % of flexible bronchoscopies, for which a combination of propofol and midazolam is preferred by most institutions (41.3 %), followed by propofol monotherapy (28.3 %). 74.4 % of institutions accept aspirin for transbronchial biopsy, 8.1 % dual platelet inhibition. 62.4 % of all institutions perform airway recanalisation, favouring cryotherapy and argon plasma coagulation. 9.1 % of bronchoscopies are supported by endobronchial ultrasound. Conclusion: Compared to preceding surveys, the experience of bronchoscopists, especially regarding interventional procedures, has increased. Endobronchial ultrasound has become a standard of care, as has patient sedation with propofol.

Flexible bronchoscopy is a standard examination today and is conducted not only in nearly every hospital but also in privately owned practices. The vast majority of patients want sedation for this examination. Such a procedure is nearly always necessary in complex and interventional procedures, irrespective of the patient's wish. The recommendation at hand to use sedation measures for flexible bronchoscopy is based on the results of numerous clinical studies and also takes account of individual experiences in this area. The structural and procedural requirements and the requirements for staff training are defined and should describe the minimum standard when it comes to conducting a bronchoscopy under sedation. Furthermore the drugs recommended for sedation are discussed and their methods of application shown. Finally the recommendations also include suggestions for patient clarification, monitoring and discharge. They should provide the examiner with concrete operating options and therefore above all increase patient safety.

Bronchoscopic training courses are an essential part of the education in bronchoscopy for all kinds of specialisations and professions performing such investigations. All aspects of the application should be mentioned during a course. These recommendations are necessary because the number of bronchoscopies performed in the last years has increased due to the increasing number of patients, improved equipment and better availability. Courses should provide the basic knowledge including main points of indications, preconditions for the procedure and decisions of consequence after bronchoscopy. Participants should be trained in the skills of correct handling and performing flexible bronchoscopies in training dummies. Necessary competence requirements on the course instructor are adequate professional qualifications, paedagogic skills and the availability of appropriate teaching material. Quality assurance of the course should be achieved by consequent evaluation. A widely spread field of bronchoscopic applications can improve patient care in many medical specialisations.

Background and objective: The diagnostic yield from fluoroscopy-guided bronchoscopic transbronchial biopsy of small solitary pulmonary nodules is low. The hypothesis tested in the present study was that the diagnostic yield can be significantly increased by combining flexible bronchoscopy with CT-guidance using a dedicated low-dose protocol. Methods: CT-guided transbronchial biopsies were performed in 15 patients with a newly diagnosed solitary peripheral pulmonary nodule and negative conventional bronchoscopic biopsies under fluoroscopic guidance. For imaging, a multi-detector helical CT unit, adjusted at 120 kV, 15 mAs/slice, 4 × 5 mm collimation, 10 mm reconstructed slice thickness and a maximal scan length of 150 mm, was used. After advancing the biopsy forceps towards the lesion, a CT scan was obtained. When the tip of the forceps reached or penetrated the lesion a biopsy was taken, otherwise the procedure was repeated with a maximum of eight attempts. The effective radiation dose was calculated. Results: The average diameter of the nodules was 23 ± 6 mm (mean ± SD) with a maximum distance to the parietal pleura of 18 mm (mean 6.5 mm). A mean of 4.1 (range 2–8) CT scans was performed to localize the lesion. In four patients, the forceps only reached the periphery of the nodule. In one patient, the nodule was missed in all attempts. Histology was malignant in eight patients and benign in four patients. In three patients, biopsy results were false negative (benign or non-specific instead of malignant). The overall diagnostic yield was 73%. Complications consisted of two pneumothoraces, one of which necessitated a chest tube. Mean effective radiation dose was 0.55 mSv (range 0.3–1.0). Conclusions: CT-guided transbronchial biopsy can be a valuable diagnostic tool in evaluating solitary pulmonary nodules. This applies for selected patients when other diagnostic methods are either unavailable or inappropriate. The diagnostic yield is high and, when a low-dose protocol is used, radiation exposure can be kept at a minimum.

Background and objectives: Local anaesthesia of the pharynx (LAP) is traditionally used for flexible bronchoscopy (FB). Nevertheless, its additional benefit to sedation concerning the reduction of cough and gagging is unclear. This prospective multicenter trial evaluated the feasibility of FB under sedation alone versus in combination with LAP and tested for non-inferiority. Material and methods: FB was performed in 72 consecutive patients either under sedation with propofol alone (33 patients 45.8%) or with additional oxybuprocaine 1% for LAP (39 patients, 54.2%). Assessment of patient characteristics (including sex, age, preexisting disease and smoking), periinterventional cardiorespiratory monitoring and sedation, and postinterventional coughing, (recorded with a microphone over 10 minutes as the primary objective) were conducted. Results: Demographic data (age, body mass index, preexisting lung disease and smoking history) were balanced between both groups. FB could be carried out in all patients as previously planned. Sedation dose, duration of the procedure and vital parameters did not differ between the groups. Within the first 10 minutes postintervention we observed a shorter cumulative coughing time of 51.4 s in the group without LAP compared to 79.7 s in the group receiving LAP. However, this difference was not significant (p = 0.46). In addition, there was no difference in complication rate and patient discomfort. Conclusions: FB under sedation without LAP can be adequately performed without disadvantages. Furthermore, it seems to be associated with less postinterventional coughing when compared to FB with additional LAP.

Whole-body plethysmography (WBP) with bronchial challenge testing to measure the (specific) airway resistance, (s)R(AW), is considered to be a more sensitive diagnostic procedure than spirometry, which can only measure the forced expiratory volume in one second (FEV1). The evidence for the added diagnostic value of WBP is not yet conclusive.In a prospective diagnostic study, we carried out WBP with bronchial challenge testing as well as a bronchodilation test in 400 patients with suspected asthma from June 2010 to October 2011. The bronchial provocation test was considered positive if the FEV1 fell by at least 20% and/or the airway resistance doubled, with an increase of the sR(AW) to at least 2.0 kPA × s and/or of the R(AW) to 0.5 kPA × s/L. Follow-up evaluation was performed one year later.The prevalence of asthma in the 302 patients who completed follow-up was 27.5%. The sensitivity of WBP with sR(AW) measurement for asthma was 95.2% (95% confidence interval [CI] 88.3%-98.1%), and its specificity was 81.7% (95% CI 76.1%-86.3%). The sensitivity of FEV1 was 44.6% (95% CI 34.4%-55.3%), and its specificity was 91.3% (95% CI 86.6%-94.4%). The negative predictive value (NPV) of WBP with sR(AW) measurement was 97.8% (95% CI 94.5%-99.1%), while that of FEV1 was 81.3% (95% CI 76.0%-85.7%). The positive predictive value (PPV) of WBP with sR(AW) measurement was 66.4% (95% CI 57.5%-74.2%), while that of FEV1 was 66.1% (95% CI 53.0%-77.1%).With sR(AW) measurement, asthma can be ruled out with high certainty. Improving the positive predictive value of testing for asthma remains a challenge, however, as sR(AW) measurement does not yield any increase in specificity.

Background Electromagnetic navigation in bronchoscopy is a novel method for assisting in the localization of peripheral lung lesions. Study objective To assess the usability, accuracy, and safety of electromagnetic navigation during flexible bronchoscopy in a clinical setting. Design Prospective evaluation. Patients Consecutive patients referred to the bronchoscopy unit for the diagnosis of peripheral infiltrates or solitary pulmonary nodules (SPNs). Methods Navigation was performed using an electromagnetic tracking system with a position sensor encapsulated in the tip of a flexible catheter that was pushed through the working channel of the bronchoscope. Real-time, multiplanar reconstruction of a previously acquired CT data set provided three-dimensional views for localization of the catheter. To match the position of the sensor with the CT scan, four anatomic landmarks were used for registration. The sensor position generated in the navigation system was controlled by fluoroscopy, and the corresponding error distances were measured. This was performed with all SPNs and at two different peripheral locations of the right upper lobe (RUL). Results Sixteen patients (10 men and 6 women; mean age, 63.7 years) were studied. Navigation prolonged bronchoscopy by 3.9 ± 1.3 min (mean ± SD). The navigation system identified all lesions. The position sensor achieved a direct hit in three of five SPNs. Fluoroscopy failed to recognize three SPNs (60%) and three infiltrates (38%). The mean error distances between sensor tip position and fluoroscopically verified RUL reference position were 10.4 mm (lateral position) and 12.5 mm (apical position) respectively. The mean error distances between the sensor tip and two endobronchial registration points at the end of the procedure were 4.2 mm and 5.1 mm, respectively. Conclusion Electromagnetic navigation is useful, accurate, and safe in the localization of peripheral lung lesions and may help to improve the yield of diagnostic bronchoscopic procedures.

Electromagnetical tracking devices have become so small, that tracking of flexible instruments is possible. Because of the low diagnostic yield of flexible bronchoscopy, we assembled and evaluated a system for navigation of the bronchoscopes tip. In order to evaluate the exactness of the electromagnetical tracking system in a preoperative CT-Scan, 16 patients underwent diagnostic flexible bronchoscopy with fluoroscopic guidance. Deviation was measured and computed.

We assessed safety and efficacy of creatine monohydrate (Cr) in myotonic dystrophy (DM1) in a double-blind, cross-over trial. Thirty-four patients with defined DM1 were randomized to receive Cr and placebo for eight weeks (10.6 g day 1–10, 5.3 g day 11–56) in one of 2 treatment sequences. There was no significant improvement using manual and quantitative muscle strength, daily-life activities, and patients' own global assessment comparing verum with placebo administration. Cr supplementation was well tolerated without clinically relevant side effects, but did not result in significant improvement of muscle strength or daily-life activities.

Study objectives: Bronchoscopic balloon dilatation (BBD) has become a valuable tool in the treatment of benign tracheobronchial stenoses. The objective of this study was to assess indications for and results of fiberoptic BBD in treating malignant lesions. Design: One hundred twenty-six balloon dilatation procedures were performed in 78 patients with predominantly bronchial carcinoma. BBD was only performed when alternative modes of local treatment (eg, laser therapy or stent implantation) were not indicated or were inappropriate. Indications were symptomatic stenoses of the tracheobronchial tree: dyspnea or stridor (52%), retention pneumonia (15%), atelectasis (10%), retention of secretions (21%), or lung abscess (2%). Results: Fifty-five percent of all procedures consisted of dilatations of tracheal or bronchial lesions (group 1). In 22% of procedures, a stent was dilated (group 2). In 13%, BBD was used to facilitate stent placement (group 3), and in 10% to enable the correct positioning of irradiation probes for brachytherapy (group 4). In group 1 and group 2, 2 of 2 lung abscesses resolved, 5 of 8 atelectases resolved, and 11 of 12 retention pneumonias resolved. Dyspnea improved in only 12 of 32 patients. No abscess recurred. Two pneumonias and two atelectases reappeared due to restenosis. Stent implantation and brachytherapy procedures were facilitated in 90% of cases. In 52% of cases, BBD was supported by high-frequency jet ventilation. Complications consisted of one fatal hemoptysis caused by a lacerated pulmonary artery, and minor bleeding not necessitating specific therapy. Conclusions: Fiberoptic BBD is useful in the management of airway stents prior to and postimplantation, as well as in the placement of brachytherapy catheters. BBD is also successful in the resolution of poststenotic lung abscesses, retention pneumonias, and atelectases. (CHEST 2001; 120:43‐ 49)

High frequency jet ventilation (HFJV) is a well accepted method for securing ventilation in rigid and interventional bronchoscopy. We describe a technique of HFJV using a 14F nylon insufflation catheter placed in the trachea to support stent implantation or endobronchial balloon dilation in endobronchial stenoses with the flexible fiberscope. One hundred sixty-one cases were treated with either a metal wire stent (n = 105) or with balloon dilation (n = 56). In addition to HFJV, IV anesthesia was applied in 132 cases. Driving pressure was 1125-1275 mm Hg, frequency 80-100/min, and inspiratory:expiratory ratio of 1:2. Fraction of inspired oxygen ranged from 0.3-1.0. The effects on alveolar ventilation were assessed by using blood-gas analysis and continuous monitoring of transcutaneous oxygen and carbon dioxide tension (P(tc)CO(2)). Complications consisted of hypertension (n = 8), hypotension (n = 6), bronchospasm (n = 5), and hypoxia (n = 6). In 52% of the cases, mild hypercarbia (P(tc)CO2 50-60mm Hg) was observed. In two cases, a P(tc)CO(2)80 mm Hg resolved spontaneously when the patients returned to normal breathing after intermittent superimposed ventilation with a face mask. During placement of stents in the proximal trachea, the jet catheter had to be withdrawn, resulting in displacement of the catheter into the pharynx in one case, which was managed safely with the bronchoscope. In conclusion, HFJV achieves satisfactory operating conditions and provides adequate gas exchange for interventional bronchoscopic procedures with the fiberscope.Safe ventilation is desired when performing tracheobronchial stent implantation and balloon dilation with the fiberscope. High frequency jet ventilation, applied with a 14F insufflation catheter through the nasotracheal route, offers safe ventilatory support with minimal complications. This was evaluated in 161 procedures treating benign and malignant airway stenoses.

Hypoxic pulmonary vasoconstriction is associated with but may not be sufficient for the development of high-altitude pulmonary oedema (HAPO). Hypoxia is known to induce an inflammatory response in immune cells and endothelial cells. It has been speculated that hypoxia-induced inflammatory cytokines at high altitude may contribute to the development of HAPO by causing capillary leakage in the lung. We were interested if such an inflammatory response, possibly involved in a later development of HAPO, is detectable at high altitude in individuals without HAPO. We examined the plasma levels of interleukin 6 (IL-6), interleukin 1 receptor antagonist (IL-1ra) and C-reactive protein (CRP) in two independent studies: study A, Jungfraujoch, Switzerland, three overnight stays at 3458 m, n=12; study B: Capanna Regina Margherita, Italy, 3 overnight stays at 3647 m and one overnight stay at 4559 m, n=10. In both studies, probands showed symptoms of acute mountain sickness but no signs of HAPO. At the Jungfraujoch, IL-6 increased from 0.1+/-0.03 pg/ml to 2. 0+/-0.5 pg/ml (day 2, P=0.03), IL-1ra from 101+/-21 to 284+/-73 pg/ml (day 2, P=0.01), and CRP from 1.0+/-0.4 to 5.8+/-1.5 micrograms/ml (day 4, P=0.01). At the Capanna Margherita, IL-6 increased from 0. 5+/-0.2 pg/ml to 2.0+/-0.8 pg/ml (P=0.02), IL-1ra from 118+/-25 to 213+/-28 pg/ml (P=0.02), and CRP from 0.4+/-0.03 to 3.5+/-1.1 micrograms/ml (P=0.03). IL-8 was below the detection limit of the ELISA (

Purpose: To evaluate the long-term mechanical behavior in vivo f expandable endobronchial wire stents, we imaged three different prostheses in the treatment of tracheobronchial disease. Methods: Six patients with bronchial stenoses (three benign, three malignant) underwent insertion of metallic stents. Two self-expandable Wallstents, two balloon-expandable tantalum Strecker stents and two self-expandable nitinol Accuflex stents were used. Measurements of deformation properties were performed during voluntary cough by means of fluoroscopy, at 1 month and 7–10 months after implantation. The procedures were videotaped, their images digitized and the narrowing of stent diameters calculated at intervals of 20 msec. Results: After stent implantation all patients improved with respect to ventilatory function. Radial stent narrowing during cough reached 53% (Wallstent), 59% (tantalum Strecker stent), and 52% (nitinol Accuflex stent) of the relaxed post-implantation diameter. Stent compression was more marked in benign compared with malignant stenoses. In the long term permanent deformation occurred with the tantalum Strecker stents; the other stents were unchanged. Conclusion: Endobronchial wire stents can be helpful in the treatment of major airway collapse and obstructing bronchial lesions. However, evidence of material fatigue as a possible effect of exposure to recurrent mechanical stress on the flexible mesh tube may limit their long-term use. This seems to be predominantly important in benign bronchial collapse.

PURPOSE Endobronchial brachytherapy has become more widely used to increase the total local dose of irradiation ("boost") applied for the treatment of lung cancer. Apart from treatment for local stenosis, endobronchial brachytherapy in combination with external irradiation (EI) has the potential to improve local tumor control and perhaps prolong survival, but the real benefit has not been proven yet. To evaluate the possible effects of external irradiation with an additional boost of high dose rate (HDR) brachytherapy, we conducted a prospective randomized study. METHODS AND MATERIALS Design-two groups were compared: Group 1 was treated with external radiotherapy alone (planned dose 60 Gy); Group 2 received an additional boost of HDR brachytherapy of scheduled 4.8 Gy each (at 10 mm from the source axis) before and after external irradiation. Patients-98 patients with advanced inoperable lung cancer were included in the study, 42 in Group 1 and 56 in Group 2. Both groups were comparable with respect to age, sex, tumor stage, Karnofsky performance status (KPS), and histology. RESULTS A mean total external irradiation dose of 50.5 +/- 14.1 Gy in Group 1 and 50 +/- 12.5 Gy in Group 2 was applied. Group 2 received an additional dose of 7.44 +/- 2.6 Gy (at 10 mm depth) through brachytherapy. The median survival time in both groups was comparable (28 weeks and 27 weeks, respectively). In patients with squamous cell carcinoma (68 patients) Group 2 showed an advantage in median survival with borderline significance (40 vs. 33 weeks, p = 0.09). Group 2 showed also a better local tumor control in all patients; patients with squamous cell carcinoma had a significantly longer period of local tumor control. Fatal hemoptysis was the cause of death in 6 (14.2%) patients in Group 1 and 11 (18.9%) in Group 2 (p = 0.53). CONCLUSIONS High dose rate brachytherapy in patients with inoperable lung cancer increased local control in our randomized study when used in combination with external irradiation. Survival time was also longer, but with no clear statistical significance. This applied especially to patients with squamous cell carcinomas. There was no statistically significant difference in the incidence of fatal hemoptysis between the two groups.

Flexible fiber-optic bronchoscopy is a widespread medical procedure for the diagnosis and treatment of lung diseases. Navigation systems are needed to track the flexible endoscope within the bronchial tree. Electromagnetic (EM) tracking is currently the only technology used clinically for this purpose. The registration between EM tracking and patient anatomy may become inaccurate due to breathing motion, so the addition of image-based tracking has been proposed as a hybrid EM-image-based system.When EM tracking is used as an initialization for image registration, small changes in the initialization may lead to different local minima and noise is amplified by hybrid tracking. The tracking output is modeled as continuous and uses splines for interpolation, thus smoothness is greatly improved. The bronchoscope pose relative to computed tomography data is interpolated using Catmull-Rom splines for position and spherical linear interpolation (SLERP) for orientation.The hybrid method was evaluated using ground truth poses manually selected by experts, where mean inter-expert agreement was determined as 1.26 mm. Using four dynamic phantom data sets, the accuracy was 4.91 mm, which is equivalent to previous methods. Compared to state-of-art methods, inter-frame smoothness was improved from 2.77-3.72 to 1.24 mm.Hybrid image and electromagnetic endoscope guidance provides a more realistic and physically plausible solution with significantly less jitter. This quantitative result is confirmed by visual comparison of real and virtual video, where the virtual video output is much more consistent and robust, with fewer occasions of tracking loss or unexpected movement compared with previous methods.

Navigated bronchoscopy provides benefits for endoscopists and patients, but accurate tracking information is needed. We present a novel real-time approach for bronchoscope tracking combining electromagnetic (EM) tracking, airway segmentation, and a continuous model of output. We augment a previously published approach by including segmentation information in the tracking optimization instead of image similarity. Thus, the new approach is feasible in real-time. Since the true bronchoscope trajectory is continuous, the output is modeled using splines and the control points are optimized with respect to displacement from EM tracking measurements and spatial relation to segmented airways. Accuracy of the proposed method and its components is evaluated on a ventilated porcine ex-vivo lung with respect to ground truth data acquired from a human expert. We demonstrate the robustness of the output of the proposed method against added artificial noise in the input data. Smoothness in terms of inter-frame distance is shown to remain below 2 mm, even when up to 5 mm of Gaussian noise are added to the input. The approach is shown to be easily extensible to include other measures like image similarity.

We present a novel approach to motion compensation for bronchoscope navigation where the bronchoscope trajectory is modeled using a spline curve. Initial position and orientation measurements from electromagnetic tracking are refined using the distance of the trajectory from airways segmented in preoperative CT data, and similarity between real and virtual bronchoscopic images. We present an evaluation on a dynamic motion phantom and on a moving ex-vivo porcine lung. Ground truth data is provided by human experts.

We present a novel approach to tracking of flexible bronchoscopes by modeling the output as spatially continuous over time. Bronchoscopy is a widespread clinical procedure for diagnosis and treatment of lung diseases and navigation systems are highly needed. Tracking of the bronchoscope can be regarded as a deformable registration problem. In our approach we use hybrid image-based and electromagnetic tracking, and the bronchoscope pose relative to CT data is interpolated using Catmull-Rom splines for position and SLERP for orientation. We evaluate the method using ground truth poses manually selected by experts, where mean inter-expert agreement was determined as 1.26 mm. For four dynamic phantom data sets, the accuracy of our method is between 4.13 and 5.93 mm and shown to be equivalent to previous methods. We significantly improve inter-frame smoothness from 2.35-3.08 mm to 1.08-1.51 mm. Our method provides a more realistic and physically plausible solution with significantly less jitter. This quantitative result is confirmed by video output, which is much more consistent and robust, with fewer occasions of tracking loss or unexpected movement.

The diagnostic yield from fluoroscopy-guided bronchoscopic transbronchial biopsy of small solitary pulmonary nodules is low. The hypothesis tested in the present study was that the diagnostic yield can be significantly increased by combining flexible bronchoscopy with CT-guidance using a dedicated low-dose protocol.CT-guided transbronchial biopsies were performed in 15 patients with a newly diagnosed solitary peripheral pulmonary nodule and negative conventional bronchoscopic biopsies under fluoroscopic guidance. For imaging, a multi-detector helical CT unit, adjusted at 120 kV, 15 mAs/slice, 4 x 5 mm collimation, 10 mm reconstructed slice thickness and a maximal scan length of 150 mm, was used. After advancing the biopsy forceps towards the lesion, a CT scan was obtained. When the tip of the forceps reached or penetrated the lesion a biopsy was taken, otherwise the procedure was repeated with a maximum of eight attempts. The effective radiation dose was calculated.The average diameter of the nodules was 23 +/- 6 mm (mean +/- SD) with a maximum distance to the parietal pleura of 18 mm (mean 6.5 mm). A mean of 4.1 (range 2-8) CT scans was performed to localize the lesion. In four patients, the forceps only reached the periphery of the nodule. In one patient, the nodule was missed in all attempts. Histology was malignant in eight patients and benign in four patients. In three patients, biopsy results were false negative (benign or non-specific instead of malignant). The overall diagnostic yield was 73%. Complications consisted of two pneumothoraces, one of which necessitated a chest tube. Mean effective radiation dose was 0.55 mSv (range 0.3-1.0).CT-guided transbronchial biopsy can be a valuable diagnostic tool in evaluating solitary pulmonary nodules. This applies for selected patients when other diagnostic methods are either unavailable or inappropriate. The diagnostic yield is high and, when a low-dose protocol is used, radiation exposure can be kept at a minimum.

Background In the diagnosis of early-stage lung cancer photosensitizer-enhanced fluorescence bronchoscopy with inhaled 5-aminolevolinic acid (5-ALA) increases sensitivity when compared to white-light bronchoscopy. This investigation was to evaluate the in vivo tissue pharmacokinetics of inhaled 5-ALA within the bronchial mucosa in order to define the time optimum for its application prior to bronchoscopy. Methods Patients with known or suspected bronchial carcinoma were randomized to receive 200 mg 5-ALA via inhalation 1, 2, 3, 4 or 6 hours before flexible fluorescence bronchoscopy was performed. Macroscopically suspicious areas as well as areas with visually detected porphyrin fluorescence and normal control sites were measured spectroscopically. Biopsies for histopathology were obtained from suspicious areas as well as from adjacent normal areas. Results Fluorescence bronchoscopy performed in 19 patients reveals a sensitivity for malignant and premalignant changes (moderate dysplasia) which is almost twice as high as that of white-light bronchoscopy, whereas specificity is reduced. This is due to false-positive inflammatory lesions which also frequently show increased porphyrin fluorescence. Malignant and premalignant alterations produced fluorescence values that are up to 5 times higher than those of normal tissue. According to the pharmacokinetics of porphyrin fluorescence measured by spectroscopy, the optimum time range for 5-ALA application is 80–270 min prior to fluorescence bronchoscopy, with an optimum at 160 min. Conclusion According to our results we propose inhalation of 5-ALA 160 min prior to fluorescence bronchoscopy, suggesting that this time difference provides the best tumor/normal tissue fluorescence ratio.

Navigated bronchoscopy has been developed by various groups within the last decades. Systems based on CT data and electromagnetic tracking enable the visualization of the position and orientation of the bronchoscope, forceps, and biopsy tools within CT data. Therefore registration between the tracking space and the CT volume is required. Standard procedures are based on point-based registration methods that require selecting corresponding natural landmarks in both coordinate systems by the examiner. We developed a novel algorithm for a fully automatic registration procedure in navigated bronchoscopy based on the trajectory recorded during routine examination of the airways at the beginning of an intervention. The proposed system provides advantages in terms of an unchanged medical workflow and high accuracy. We compared the novel method with point-based and ICP-based registration. Experiments demonstrate that the novel method transforms up to 97% of tracking points inside the segmented airways, which was the best performance compared to the other methods.

Implantation of endobronchial stents for treatment of dynamic airway collapse represents a suitable therapeutic option to alleviate distressing symptoms. We report the case of a 43 year old patient suffering from progressive respiratory distress 2 weeks after insertion of a balloon-expandable radial noncompliant Palmaz stent in an unstable segment of the left main bronchus, with the aim of preventing symptomatic airway collapse. Bronchial instability had developed following sleeve resection of the right lung due to adenoid cystic carcinoma. Explanation revealed compression and deformation of the stent. Peak expiratory flow (PEF) had declined a low of 1.38 L.s-1 (forced expiratory volume in one second (FEV1) 1.02 L). With placement of a Strecker stent, having the ability to re-expand within certain limits, bronchial collapse could be avoided and marked clinical improvement as well as expiratory flow increase was noted (PEF 7.10 L.s-1; FEV1 = 2.03 L). At 13 months follow-up, clinical status was unchanged. A decline in forced expiratory flow (PEF 5.96 L.s-1; FEV1 1.69 L), however, indicated a possible change in the structural integrity of the Strecker stent. We conclude that physical properties of endobronchial stents may be crucial for good functional results in major airway collapse. Stiff prostheses, when compressed, can induce severe airway obstruction.

To determine the response to treatment and the long-term outcome of patients with the antisynthetase syndrome associated with anti-Jo-1-antibodies. A total of 12 patients with histologically proven myositis and anti-Jo-1-autoantibodies were evaluated over a mean follow-up period of 66.4 months. In all patients neuromuscular function tests, electromyographic examinations, pulmonary function tests and high-resolution-computed tomography of the lungs were performed regularly. Muscle function improved in all patients with treatment, and a complete clinical response was achieved in 5 patients. Pulmonary function worsened in 1 patient, who died from respiratory failure, but normalised in 4 patients. Arthropathy progressed despite improvement of myositis and pulmonary status in 2 patients. Discontinuation of treatment was facilitated in 1 patient, although long-term therapy was required in 10 patients. In 2 patients with refractory disease, treatment with intravenous immunoglobulins was successful. Severe side effects of treatment occurred in 7 patients and overall mortality rate was one of 12 (8 %). The antisynthetase syndrome associated with anti-Jo-1-antibodies requires long-term immunosuppressive therapy in most patients. Whereas a complete clinical response of muscular symptoms is frequent, continued deterioration of the pulmonary system may occur despite immunosuppressive treatment, and may lead to fatal outcome. An interdisciplinary therapeutic approach is necessary for best possible results in these patients.

Over the last few years various types of metal wire stents have been increasingly employed in the treatment of both malignant and benign tracheobronchial obstruction. To date, however, few studies have investigated the in vivo properties of different stent types. We implanted 26 balloon-expandable tantalum Strecker stents (18 patients) and 18 self-expandable Wallstents (16 patients) into the tracheobronchial system of 30 patients with combined stenting in 4 patients. Mean age was 51 years (range: 0.5-79 years). Malignant disease was present in 23 patients, benign disease in seven patients. Both patients and individual stents were monitored clinically and radiographically. The probability of stents remaining within the tracheobronchial system, and of their remaining undislocated and uncompressed was calculated using Kaplan-Meier analysis for both stent types. Average stent follow-up time was 112 days until explantation and 115 days until patients' death or discharge. Kaplan-Meier analysis revealed a higher probability for the Wallstent to remain within the tracheobronchial system. Dislocation and compression occurred more rarely. Explantation, however, if desired, was more difficult compared to the Strecker stent. The Wallstent also led to the formation of granulation tissue, especially at the proximal stent end, frequently requiring reintervention. Both stent types proved to be effective therapeutic options in the management of obstructive tracheobronchial disease. The mechanical properties of the Strecker stent seem to be less favorable compared to the Wallstent but removal is easy. For benign disease, however, the Wallstent reveals limitations due to significant side effects.

5-ALA-induced protoporphyrin IX (PPIX) fluorescence kinetics was quantified by fluorescence microscopy in three-dimensional organ co-cultures of human bronchial epithelium, which were infiltrated by four different lung tumour cell lines (EPLC-M31, LCLC-103H, NCI-H125 and NCI-H841). Corresponding fluorescence measurements were performed in monolayer cultures of these tumour cell lines and BEAS-2B cells as a model for normal bronchial epithelium by flow cytometry. Significant differences of fluorescence intensities (FI) between the tumours were detected in organ co-cultures as well as in single cell measurements. Relative FI values in organ co-cultures (FI(EPLC-32M1)>FI(LCLC-H103)>FI(NCI-H125)>FI(NCI-H841)) did not correspond to the measurements in single cells (FI(LCLC-H103)>FI(NCI-H125)>FI(NCI-H841)>FI(EPLC-32M1)). Histology of organ co-cultures revealed different patterns of invasion and tumour cell densities depending on the tumour type. After correction of FI in the co-cultures to tumour cell density the correlation coefficient for fluorescence values between both models increased considerably. Thus, additionally to distinctive features of 5-ALA metabolism, patterns of tumour invasion may be a factor determining 5-ALA-induced fluorescence. Considering these results, a pronounced heterogeneity of 5-ALA-induced fluorescence might be expected in different bronchial tumours in vivo. This could interfere with the diagnostic reliability of 5-ALA-induced fluorescence for early tumour detection.

We assessed safety and efficacy of creatine monohydrate (Cr) in myotonic dystrophy (DM1) in a double-blind, cross-over trial. Thirty-four patients with defined DM1 were randomized to receive Cr and placebo for eight weeks (10.6 g day 1-10, 5.3 g day 11-56) in one of 2 treatment sequences. There was no significant improvement using manual and quantitative muscle strength, daily-life activities, and patients' own global assessment comparing verum with placebo administration. Cr supplementation was well tolerated without clinically relevant side effects, but did not result in significant improvement of muscle strength or daily-life activities.

Background: 5-Aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX) fluorescence improves the differentiation of tumor and normal tissue in the bladder, skin and brain. Objective: The kinetics of 5-ALA-induced protoporphyrin IX (PPIX) fluorescence in organ cultures of normal human bronchial epithelium and cocultures of bronchial epithelium and tumor have been studied. Methods: Cultured biopsies of bronchial epithelium were exposed for 5 or 15 min, or continuously to 5-ALA. PPIX fluorescence was quantified for up to 300 min by spectroscopy. Cocultures of normal bronchial epithelium and a non-small-cell lung cancer cell line (EPLC-32M1) were incubated with 5-ALA. Space-resolved fluorescence microscopy was used to quantify PPIX fluorescence kinetics in the tumor and normal epithelium. Results: In cultures of normal epithelium, PPIX fluorescence kinetics were shown to depend on the duration of exposure to 5-ALA. There was a trend to higher fluorescence intensities with longer exposure times. In cocultures of bronchial epithelium and tumor, increases of fluorescence intensity were significantly greater in the tumor. Best tumor/normal tissue fluorescence ratios were found between 110 and 160 min after exposure to 5-ALA. Conclusion: Data obtained in this coculture system of bronchial epithelium and tumor is valuable to optimize modalities of fluorescence bronchoscopy for the diagnosis of early bronchial carcinoma.