Winfried Randerath

Non-CPAP therapies in obstructive sleep apnoea

In view of the high prevalence and the relevant impairment of patients with obstructive sleep apnoea syndrome (OSAS) lots of methods are offered which promise definitive cures for or relevant improvement of OSAS. This report summarises the efficacy of alternative treatment options in OSAS. An interdisciplinary European Respiratory Society task force evaluated the scientific literature according to the standards of evidence-based medicine. Evidence supports the use of mandibular advancement devices in mild to moderate OSAS. Maxillomandibular osteotomy seems to be as efficient as continuous positive airway pressure (CPAP) in patients who refuse conservative treatment. Distraction osteogenesis is usefully applied in congenital micrognathia or midface hypoplasia. There is a trend towards improvment after weight reduction. Positional therapy is clearly inferior to CPAP and long-term compliance is poor. Drugs, nasal dilators and apnoea triggered muscle stimulation cannot be recommended as effective treatments of OSAS at the moment. Nasal surgery, radiofrequency tonsil reduction, tongue base surgery, uvulopalatal flap, laser midline glossectomy, tongue suspension and genioglossus advancement cannot be recommended as single interventions. Uvulopalatopharyngoplasty, pillar implants and hyoid suspension should only be considered in selected patients and potential benefits should be weighed against the risk of long-term side-effects. Multilevel surgery is only a salvage procedure for OSA patients.

A Novel Extracorporeal CO2 Removal System: Results of a Pilot Study of Hypercapnic Respiratory Failure in Patients With COPD

BACKGROUND Hypercapnic respiratory failure in patients with COPD frequently requires mechanical ventilatory support. Extracorporeal CO2 removal (ECCO2R) techniques have not been systematically evaluated in these patients. METHODS This is a pilot study of a novel ECCO2R device that utilizes a single venous catheter with high CO2 removal rates at low blood flows. Twenty hypercapnic patients with COPD received ECCO2R. Group 1 (n = 7) consisted of patients receiving noninvasive ventilation with a high likelihood of requiring invasive ventilation, group 2 (n = 2) consisted of patients who could not be weaned from noninvasive ventilation, and group 3 (n = 11) consisted of patients on invasive ventilation who had failed attempts to wean. RESULTS The device was well tolerated, with complications and rates similar to those seen with central venous catheterization. Blood flow through the system was 430.5 ± 73.7 mL/min, and ECCO2R was 82.5 ± 15.6 mL/min and did not change significantly with time. Invasive ventilation was avoided in all patients in group 1 and both patients in group 2 were weaned; PaCO2 decreased significantly (P < .003) with application of the device from 78.9 ± 16.8 mm Hg to 65.9 ± 11.5 mm Hg. In group 3, three patients were weaned, while the level of invasive ventilatory support was reduced in three patients. One patient in group 3 died due to a retroperitoneal bleed following catheterization. CONCLUSIONS This single-catheter, low-flow ECCO2R system provided clinically useful levels of CO2 removal in these patients with COPD. The system appears to be a potentially valuable additional modality for the treatment of hypercapnic respiratory failure.

Non-CPAP therapies in obstructive sleep apnoea mandibular advancement device therapy

Mandibular advancement devices (MADs) represent the main non-continuous positive airway pressure (non-CPAP) therapy for patients with obstructive sleep apnoea (OSA). The aim of the European Respiratory Society Task Force was to review the evidence in favour of MAD therapy. Effects of tongue-retaining devices are not included in this report. Custom-made MADs reduce apnoea/hypopnoea index (AHI) and daytime sleepiness compared with placebo devices. CPAP more effectively diminishes AHI, while increasing data suggest fairly similar outcomes in relation to symptoms and cardiovascular health from these treatments. Patients often prefer MADs to CPAP. Milder cases and patients with a proven increase in upper airway size as a result of mandibular advancement are most likely to experience treatment success with MADs. A custom-made device titrated from an initial 50% of maximum mandibular advancement has been recommended. More research is needed to define the patients who will benefit from MAD treatment compared with CPAP, in terms of the effects on sleep-disordered breathing and on other diseases related to OSA. In conclusion, MADs are recommended for patients with mild to moderate OSA (Recommendation Level A) and for those who do not tolerate CPAP. The treatment must be followed up and the device adjusted or exchanged in relation to the outcome.

Long-term Auto-Servoventilation or Constant Positive Pressure in Heart Failure and Coexisting Central With Obstructive Sleep Apnea

BACKGROUND The coexistence of obstructive sleep apnea (OSA) and central sleep apnea (CSA) and Cheyne-Stokes respiration (CSR) is common in patients with heart failure (HF). While CPAP improves CSA/CSR by about 50%, maximal suppression is crucial in improving clinical outcomes. Auto-servoventilation (ASV) effectively suppresses CSA/CSR in HF, but few trials have been performed in patients with coexisting OSA and CSA/CSR. Our objective was to evaluate a randomized, controlled trial to compare the efficacy of ASV and CPAP in reducing breathing disturbances and improving cardiac parameters in patients with HF and coexisting sleep-disordered breathing. METHODS Both modes were delivered using the BiPAP autoSV (Philips Respironics) over a 12-month period. Seventy patients (63 men, 66.3 ± 9.1 y, BMI 31.3 ± 6.0 kg/m(2)) had coexisting OSA and CSA/CSR, arterial hypertension, coronary heart disease, or cardiomyopathy and clinical signs of heart failure New York Heart Association classes II-III. Polysomnography, brain natriuretic peptide (BNP), spiroergometry, and echocardiography were performed at baseline and after 3 and 12 months of treatment. RESULTS Both modes of therapy significantly improved respiratory disturbances, oxygen desaturations, and arousals over the study period. ASV reduced the central apnea hypopnea index (baseline CPAP, 21.8 ± 11.7; ASV, 23.1 ± 13.2; 12 months CPAP, 10.7 ± 8.7; ASV, 6.1 ± 7.8, P < .05) and BNP levels (baseline CPAP, 686.7 ± 978.7 ng/mL; ASV, 537.3 ± 891.8; 12 months CPAP, 847.3 ± 1848.1; ASV, 230.4 ± 297.4; P < .05) significantly more effectively as compared with CPAP. There were no relevant differences in exercise performance and echocardiographic parameters between the groups. CONCLUSIONS ASV improved CSA/CSR and BNP over a 12-month period more effectively than CPAP.

Adaptive servo-ventilation in patients with coexisting obstructive sleep apnoea/hypopnoea and Cheyne-Stokes respiration.

OBJECTIVE The coexistence of obstructive (OSAS) and central sleep apnoea (CSA) and Cheyne-Stokes respiration (CSR) is common in patients with and without underlying heart diseases. CPAP has been shown to improve CSA/CSR by about 50%, but recent data suggest maximal suppression of CSA is important in improving clinical outcomes in heart failure patients. Adaptive servo-ventilation (ASV) effectively suppresses CSA/CSR in heart failure, but only few trials have considered patients with coexisting OSAS and CSA/CSR. METHODS Prospective, observational pilot study to evaluate the efficacy of a new ASV device, the BiPAP AutoSV, in 10 male consecutive patients with coexisting OSAS and CSA/CSR with and without heart failure over eight weeks. Six had stable heart failure. MEASUREMENTS AND RESULTS The total AHI improved from 48.9+/-20.6/h to 8.7+/-7.4, the obstructive AHI from 15.8+/-16.2/h to 2.6+/-2.5/h and the central AHI from 33.1+/-10.8/h to 6.1+/-5.9/h (all p<0.01). Furthermore, there was a significant improvement in sleep profile and respiratory related arousals. The six patients with cardiovascular disease, including three with congestive heart failure, showed similar improvements in all parameters. CONCLUSIONS BiPAP AutoSV was effective in reducing all types of respiratory disturbances in coexisting OSAS and CSA/CSR with and without heart failure. Further studies comparing the long-term clinical efficacy of this device against CPAP are warranted.

Combined adaptive servo-ventilation and automatic positive airway pressure (anticyclic modulated ventilation) in co-existing obstructive and central sleep apnea syndrome and periodic breathing

BACKGROUND The co-existence of obstructive and central sleep apnea/hypopnea syndrome (OSAS) and periodic breathing is common in patients with and without underlying heart diseases. While automatic continuous positive airway pressure (APAP) has proven to effectively treat OSAS, the adaptive servo-ventilation (ASV) sufficiently improves periodic breathing. This is the first trial on a device which combines both treatment modes. METHODS Pilot study on a two-week treatment in patients with co-existing obstructive and central and periodic breathing disturbances during sleep. Twelve consecutive patients (9 male, 3 female, age 56.9+/-10.6 years, BMI 32.4+/-5.5 kg/m(2)) were treated with a new algorithm which combines APAP and ASV (also called anticyclic modulated ventilation (ACMV), SOMNOventCR, Weinmann, Hamburg, Germany). Seven suffered from arterial hypertension, coronary heart disease and mitral regurgitation, none from congestive heart failure. RESULTS The total apnea-hypopnea index (AHI) improved from 43.8+/-24.0/h to 2.1+/-2.4 (p<0.01), the obstructive AHI from 12.8+/-14.3/h to 0.3+/-0.6/h (p<0.01) and the central AHI from 31.0+/-17.5/h to 1.7+/-2.0/h (p<0.01). Moreover, there was a significant improvement in the total number of arousals, respiratory induced arousals, oxygen saturation and sleep profile. CONCLUSION The algorithm combining automatic continuous positive airway pressure (CPAP) and ASV normalizes all types of co-existing obstructive and central apnea/hypopnea and periodic breathing.

A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.

Positive airway pressure therapy with adaptive servoventilation: part 1: operational algorithms.

The beginning of the 21st century witnessed the advent of new positive airway pressure (PAP) technologies for the treatment of central and complex (mixtures of obstructive and central) sleep apnea syndromes. Adaptive servoventilation (ASV) devices applied noninvasively via mask that act to maintain a stable level of ventilation regardless of mechanism are now widely available. These PAP devices function by continually measuring either minute ventilation or airflow to calculate a target ventilation to be applied as needed. The apparatus changes inspiratory PAP on an ongoing basis to maintain the chosen parameter near the target level, effectively controlling hypopneas of any mechanism. In addition, by applying pressure support levels anticyclic to the patients own respiratory pattern and a backup rate, this technology is able to suppress central sleep apnea, including that of Hunter-Cheyne-Stokes breathing. Moreover, ASV units have become available that incorporate autotitration of expiratory PAP to fully automate the treatment of all varieties of sleep-disordered breathing. Although extremely effective in many patients when used properly, these are complex devices that demand from the clinician a high degree of expertise in understanding how they work and how to determine the proper settings for any given patient. In part one of this series we detail the underlying technology, whereas in part two we will describe the application of ASV in the clinical setting.

Upper Airway Stimulation for Obstructive Sleep Apnea: Durability of the Treatment Effect at 18 Months.

OBJECTIVE To determine the stability of improvement in polysomnographic measures of sleep disordered breathing, patient reported outcomes, the durability of hypoglossal nerve recruitment and safety at 18 months in the Stimulation Treatment for Apnea Reduction (STAR) trial participants. DESIGN Prospective multicenter single group trial with participants serving as their own controls. SETTING Twenty-two community and academic sleep medicine and otolaryngology practices. MEASUREMENTS Primary outcome measures were the apnea-hypopnea index (AHI) and the 4% oxygen desaturation index (ODI). Secondary outcome measures were the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire (FOSQ), and oxygen saturation percent time < 90% during sleep. Stimulation level for each participant was collected at three predefined thresholds during awake testing. Procedure- and/or device-related adverse events were reviewed and coded by the Clinical Events Committee. RESULTS The median AHI was reduced by 67.4% from the baseline of 29.3 to 9.7/h at 18 mo. The median ODI was reduced by 67.5% from 25.4 to 8.6/h at 18 mo. The FOSQ and ESS improved significantly at 18 mo compared to baseline values. The functional threshold was unchanged from baseline at 18 mo. Two participants experienced a serious device-related adverse event requiring neurostimulator repositioning and fixation. No tongue weakness reported at 18 mo. CONCLUSION Upper airway stimulation via the hypoglossal nerve maintained a durable effect of improving airway stability during sleep and improved patient reported outcomes (Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire) without an increase of the stimulation thresholds or tongue injury at 18 mo of follow-up.

SERVE-HF: More Questions Than Answers

The recent online publication of the SERVE-HF trial that evaluated the effect of treating central sleep apnea (CSA) with an adaptive servoventilation (ASV) device in patients with heart failure and reduced ejection fraction (HFrEF) has raised serious concerns about the safety of ASV in these patients. Not only was ASV ineffective but post hoc analysis found excess cardiovascular mortality in treated patients. The authors cited as one explanation an unfounded notion that CSA is a compensatory mechanism with a protective effect in HFrEF patients. We believe that there are several possible considerations that are more likely to explain the results of SERVE-HF. In this commentary, we consider methodological issues including the use of a previous-generation ASV device that constrained therapeutic settings to choices that are no longer in wide clinical use. Patient selection, data collection, and treatment adherence as well as group crossovers were not discussed in the trial as potential confounding factors. We have developed alternative reasons that could potentially explain the results and that can be explored by post hoc analysis of the SERVE-HF data. We believe that our analysis is of critical value to the field and of particular importance to clinicians treating these patients.