Effect of Zolpidem on nocturnal arousals and susceptibility to central sleep apnea.

PURPOSE: Arousals may contribute to the pathogenesis of sleep-disordered breathing (SDB) and central sleep apnea (CSA). We aimed to determine the effect of the nonbenzodiazepine hypnotic zolpidem on the frequency of respiratory-related arousals and central apnea in patients with moderate-to-severe SDB. We hypothesized that zolpidem decreases the severity of SDB by decreasing the frequency of respiratory-related arousals. METHODS: Patients with apnea-hypopnea index ≥ 15 events/hour and central apnea-hypopnea index ≥ 5 events/hour underwent a sleep study on zolpidem 5 mg and a sleep study with no medication in a randomized order. The respiratory arousal index was compared between the two studies using a randomized crossover design. Sleep, respiratory, and physiologic parameters, including the CO2 reserve and the respiratory arousal threshold, were also compared. RESULTS: Eleven participants completed the study. Compared to no treatment, zolpidem reduced the respiratory arousal index (39.7 ± 7.7 vs. 23.3 ± 4.4 events/h, P = 0.031). Zolpidem also lowered the total apnea-hypopnea index (55.6 ± 8.5 vs. 41.3 ± 7.5 events/hour, P = 0.033) but did not affect other clinical and physiologic parameters. Compared to control, zolpidem did not widen CO2 reserve (- 0.44 ± 1.47 vs. - 0.63 ± 0.86 mmHg, P = 0.81). The respiratory arousal threshold did not show a significant change on zolpidem compared to control (- 8.72 ± 2.1 vs. - 8.25 ± 2.81 cmH2O, P = 0.41). CONCLUSION: Nocturnal arousals and overall SDB severity were reduced with a single dose of zolpidem in patients with moderate-to-severe sleep-disordered breathing with increased susceptibility for central apnea. Zolpidem did not widen the CO2 reserve or increase the arousal threshold. TRIAL REGISTRATION: Clinicaltrials.gov. Sleep and Breathing in the General Population - Chemical Stimuli (NCT04720547).

Prevalence of central sleep apnea among veterans and response rate to continuous positive airway pressure therapy.

Study Objectives: Sleep-disordered breathing (SDB) is common in the Veteran population. In this retrospective study, we investigated the prevalence of comorbid central and obstructive SDB and the response rate to PAP among Veterans. Methods: Veterans were screened from a single VA medical center who had polysomnography (PSG) study from 2017 to 2021 to ascertain the presence, severity, and type of SDB by measuring the apnea-hypopnea index (AHI) and central apnea index (CAI). Patients were excluded if they did not have complete studies (diagnostic and PAP titration studies). The inclusion criteria for these analyses were central sleep apnea (CSA) defined as AHI ≥ 10 events/hour and CAI ≥ 5 events/hour. Diagnostic "CSA only" was defined as AHI ≥ 10 events/hour and CAI ≥ 50% of AHI. "OSA only" was defined if AHI ≥ 10 events/hour and CAI < 5 events/hour. Comorbid central and obstructive sleep apnea (COSA) was defined if AHI ≥ 10 events/hour and CAI > 5 events/hour but < 50% of AHI. The responsiveness to PAP therapy was determined based on the CAI < 5 events/hour on the titration study. Results: A total of 90 patients met the inclusion criteria and from those 64 Veterans were found to have COSA (71%), 18 (20%) were CSA only, and 8 (9%) were OSA only. A total of 22 (24.4%) Veterans diagnosed with CSA or COSA were responsive to PAP therapy. Sixty days after treatment initiation, both responsive and nonresponsive groups had significant decreases in AHI and CAI (p < 0.05). Conclusions: Comorbid central and obstructive SDB is common among Veterans. The response to PAP therapy is suboptimal but improves over time.

Sleep and Daytime Function in People with Spinal Cord Injury.

Study Design: Cross-sectional cohort study. Objectives: To determine the role of sleep-disordered breathing (SDB), insomnia symptoms and sleep quality in the daytime function and quality of life of veterans with spinal cord injury (SCI). Setting: A Veterans Administration (VA) medical center in the Midwestern US. Methods: Thirty-eight male veterans with SCI (22 cervical, 16 thoracic; mean [SD] age = 62.9[9.5] years) completed baseline assessments within a larger clinical trial. Measures assessed sleep apnea severity (apnea-hypopnea index, AHI), insomnia symptoms (Insomnia Severity Index, ISI), self-reported sleep quality (Pittsburg Sleep Quality Index, PSQI), daytime sleepiness (Epworth Sleepiness Scale, ESS), fatigue (Flinders Fatigue Scale, FFS), depression (Patient Health Questionnaire-9 item, PHQ-9 excluding sleep item), functioning (Spinal Cord Independence Measure, SCIM), and quality of life (World Health Organization Quality of Life, WHOQOL-BREF). Bivariate correlations (alpha p<.05) were used to assess relationships between sleep (AHI, ISI, PSQI, ESS) and function (FFS, PHQ-9, SCIM, WHOQOL-BREF). Results: Mean AHI was 29.9(26.6), mean ISI was 9.38(6.2), mean PSQI was 9.0(4.6), and mean ESS was 7.0(5.2). There were no significant relationships between AHI and function measures. Significant relationships emerged between ISI and PHQ-9, some WHOQOL-BREF subscales, and SCIM as well as between PSQI and FFS, PHQ-9, and some WHOQOL-BREF subscales. Conclusions: Among Veterans with SCI, insomnia symptom severity and poor sleep quality were associated with worse functioning, whereas SDB severity was not. Insomnia and poor sleep quality represent modifiable contributors to poor daytime function. Research evaluating the impact of evidence-based insomnia treatments among individuals living with SCI is warranted.

Intensive support does not improve positive-airway pressure use in spinal cord injury/disease: a randomized clinical trial.

STUDY OBJECTIVE: Treatment of sleep-disordered breathing (SDB) with positive airway pressure (PAP) therapy has unique clinical challenges in individuals living with spinal cord injuries and diseases (spinal cord injury [SCI]/D). Interventions focused on increasing PAP use have not been studied in this population. We aimed to evaluate the benefits of a program to increase PAP use among Veterans with SCI/D and SDB. METHODS: Randomized controlled trial comparing a behavioral Intervention (n = 32) and educational control (n = 31), both including one face-to-face and five telephone sessions over 3 months. The intervention included education about SDB and PAP, goal setting, troubleshooting, and motivational enhancement. The control arm included non-directive sleep education only. RESULTS: Primary outcomes were objective PAP use (nights ≥4 hours used within 90 days) and sleep quality (Pittsburgh Sleep Quality Index [PSQI] at 3 months). These did not differ between intervention and control (main outcome timepoint; mean difference 3.5 [-9.0, 15.9] nights/week for PAP use; p = .578; -1.1 [-2.8, 0.6] points for PSQI; p = .219). Secondary outcomes included fatigue, depression, function, and quality of life. Only fatigue improved significantly more in the intervention versus the control group (p = .025). Across groups, more PAP use was associated with larger improvements in sleep quality, insomnia, sleepiness, fatigue, and depression at some time points. CONCLUSIONS: PAP use in Veterans with SCI/D and SDB is low, and a 3-month supportive/behavioral program did not show significant benefit compared to education alone. Overall, more PAP use was associated with improved symptoms suggesting more intensive support, such as in-home assistance, may be required to increase PAP use in these patients. CLINICAL TRIALS INFORMATION: Title: "Treatment of Sleep Disordered Breathing in Patients with SCI." Registration number: NCT02830074. Website: https://clinicaltrials.gov/study/NCT02830074?cond=Sleep%20Apnea&term=badr&rank=5.

Insomnia severity predicts depression, anxiety, and posttraumatic stress disorder in veterans with spinal cord injury or disease: a cross-sectional observational study.

STUDY OBJECTIVES: To assess the association of insomnia symptoms and psychiatric symptoms in patients with spinal cord injury or disease (SCI/D). METHODS: In this cross-sectional observational study, veterans with SCI/D (n = 72; mean = 59.85 ± 10.4 years; 92% male) completed baseline measures, including the Insomnia Severity Index (ISI) during the baseline phase of a clinical trial on treatment of sleep disorders in veterans with SCI/D. Depression severity was measured by the Patient Health Questionnaire (PHQ-9; sleep items excluded), anxiety severity was measured by the Generalized Anxiety Disorder screener (GAD-7), and probable posttraumatic stress disorder (PTSD) was measured by the Primary Care PTSD screener. Blocked regression was used to evaluate the impact of insomnia symptoms (ISI) on mental health measures after accounting for demographics and level of spinal cord injury/disease. RESULTS: On average, participants scored in the mild range for depression (PHQ-9 = 7.4 ± 5.9) and anxiety severity (GAD-7 = 6.1 ± 6.1). In total, 36.1% (n = 26) screened positive for probable PTSD. ISI explained 19% of the variance in PHQ-9 and 20% of the variance in GAD-7 (P < .001) over and above demographics and SCI/D level of injury/disease. Odds of probable PTSD were increased 1.22-fold for each 1 unit increase in ISI (P = .001) after accounting for demographics and level of injury/disease. CONCLUSIONS: In veterans with SCI/D, insomnia severity was linked to depression and anxiety symptom severity and risk of PTSD. Study results warrant further research to evaluate the impact of insomnia treatment on depression, anxiety, and PTSD in patients with SCI/D. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Treatment of Sleep-disordered Breathing in Patients With SCI; URL: https://clinicaltrials.gov/ct2/show/NCT02830074; Identifier: NCT02830074. CITATION: Kelly MR, Zeineddine S, Mitchell MN, et al. Insomnia severity predicts depression, anxiety, and posttraumatic stress disorder in veterans with spinal cord injury or disease: a cross-sectional observational study. J Clin Sleep Med. 2023;19(4):695-701.

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep.

People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short- and long-term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2 ) and 40% carbon dioxide (CO2 ) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2 ). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V.E. ), tidal volume (V.T. ), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short-term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long-term facilitation following AIH in either group.

Sleep disorders, daytime symptoms, and quality of life in veterans with multiple sclerosis: preliminary findings.

Study Objectives: Multiple sclerosis (MS) is an autoimmune disease impacting the central nervous system. A hallmark symptom of MS is fatigue, which impairs daytime function and quality of life (QOL). Sleep disorders and disturbances are common in persons with MS and exacerbate fatigue. We evaluated relationships between sleep-disordered breathing (SDB), insomnia symptoms, sleep quality, and daytime functioning in veterans with MS participating in a larger study. Methods: Twenty-five veterans with clinically diagnosed MS were included (average age = 57 ± 11, 80% male). One had a co-occurring thoracic spinal cord injury. Twenty-four participants completed in-laboratory polysomnography (PSG) to measure apnea-hypopnea index (AHI) and sleep efficiency (PSG-SE). Insomnia Severity Index (ISI) and Pittsburg Sleep Quality Index (PSQI) were used to measure sleep subjectively. The Flinders Fatigue Scale (FFS), Epworth Sleepiness Scale (ESS), PHQ-9 depression scale, and GAD-7 anxiety scale assessed daytime symptoms. The World Health Organization Quality of Life (WHOQOL) was used to assess quality of life. Relationships between sleep (AHI, PSG-SE, ISI, PSQI), daytime symptoms (ESS, FFS, PHQ-9, and GAD-7), and quality of life (WHOQOL) were evaluated with bivariate correlations. Results: Higher ISI (r = 0.78, 95% CI = [0.54, 0.90], p < .001), higher PSQI (r = 0.51, 95% CI = [0.10, 0.77], p = .017), and lower PSG-SE (r = -0.45, 95% CI = [-0.74, -0.02], p = .041) were associated with worse fatigue (FFS). Higher ISI was also associated with worse WHOQOL (Physical Domain; r = -0.64, 95% CI = [-0.82, -0.32], p = .001). There were no other significant relationships. Conclusion: In veterans with MS, more severe insomnia and worse sleep quality may be associated with more fatigue and lower quality of life. Recognition and management of insomnia should be considered in future studies of sleep in MS.

Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure.

RATIONALE: There is increasing evidence of increased ventilatory instability in patients with obstructive sleep apnea (OSA), but previous investigations have not studied whether the hypocapnic apneic threshold is altered in this group. OBJECTIVES: To compare the apneic threshold, CO2 reserve, and controller gain between subjects with and without OSA matched for age, sex, and body mass index. METHODS: Hypocapnia was induced via nasal mechanical ventilation for 3 minutes. Cessation of mechanical ventilation resulted in hypocapnic central hypopnea or apnea depending upon the magnitude of the hypocapnia. The apnea threshold (Pet(CO2)-AT) was defined as the measured Pet(CO2) at which the apnea closest to the last hypopnea occurred. The CO2 reserve was defined as the change in Pet(CO2) between eupneic Pet(CO2) and Pet(CO2)-AT. Controller gain was defined as the ratio of change in Ve between control and hypopnea or apnea to the DeltaPet(CO2). MEASUREMENTS AND MAIN RESULTS: Eleven pairs of subjects were studied. There was no difference in the Pet(CO2)-AT between the two groups. However, the CO2 reserve was smaller in the subjects with OSA (2.2 +/- 0.6 mm Hg) compared with the control subjects (4.5 +/- 1.4 mm Hg; P < 0.001). The controller gain was increased in the subjects with OSA (3.7 +/- 1.3 L/min/mm Hg) compared with the control subjects (1.6 +/- 0.5 L/min/mm Hg; P < 0.001). Controller gain decreased and CO2 reserve increased in seven subjects restudied after using continuous positive airway pressure for 1 month. CONCLUSIONS: Ventilatory instability is increased in subjects with OSA and is reversible with the use of continuous positive airway pressure.

Effect of acetazolamide on susceptibility to central sleep apnea in chronic spinal cord injury.

Spinal cord injury (SCI) is an established risk factor for central sleep apnea. Acetazolamide (ACZ), a carbonic anhydrase inhibitor, has been shown to decrease the frequency of central apnea by inducing mild metabolic acidosis. We hypothesized that ACZ would decrease the propensity to develop hypocapnic central apnea and decrease the apneic threshold. We randomized 16 participants with sleep-disordered breathing (8 SCI and 8 able-bodied controls) to receive ACZ (500 mg twice a day for 3 days) or placebo with a 1-wk washout before crossing over to the other drug arm. Study nights included polysomnography and determination of the hypocapnic apneic threshold and CO2 reserve using noninvasive ventilation. For participants with spontaneous central apnea, CO2 was administered until central apnea was abolished, and CO2 reserve was measured as the difference in end-tidal Pco2 (PETCO2) before and after. Steady-state plant gain, the response of end-tidal Pco2 to changes in ventilation, was calculated from PETCO2 and V̇e ratio during stable sleep. Controller gain, the response of ventilatory drive to changes in end-tidal Pco2, was defined as the ratio of change in V̇e between control and hypopnea to the ΔCO2 during stable non-rapid eye movement sleep. Treatment with ACZ for three days resulted in widening of the CO2 reserve (-4.0 ± 1.2 vs. -3.0 ± 0.7 mmHg for able-bodied, -3.4 ± 1.9 vs. -2.2 ± 2.2 mmHg for SCI, P < 0.0001), and a corresponding decrease in the hypocapnic apnea threshold (28.3 ± 5.2 vs. 37.1 ± 5.6 mmHg for able-bodied, 29.9 ± 5.4 vs. 34.8 ± 6.9 mmHg for SCI, P < 0.0001), respectively. ACZ significantly reduced plant gain when compared with placebo (4.1 ± 1.7 vs. 5.4 ± 1.8 mmHg/L min for able-bodied, 4.1 ± 2.0 vs. 5.1 ± 1.7 mmHg·L-1·min for SCI, P < 0.01). Acetazolamide decreased apnea-hypopnea index (28.8 ± 22.9 vs. 39.3 ± 24.1 events/h; P = 0.05), central apnea index (0.6 ± 1.5 vs. 6.3 ± 13.1 events/h; P = 0.05), and oxyhemoglobin desaturation index (7.5 ± 8.3 vs. 19.2 ± 15.2 events/h; P = 0.01) compared with placebo. Our results suggest that treatment with ACZ decreases susceptibility to hypocapnic central apnea due to decreased plant gain. Acetazolamide may attenuate central sleep apnea and improve nocturnal oxygen saturation, but its clinical utility requires further investigation in a larger sample of patients.NEW & NOTEWORTHY Tetraplegia is a risk factor for central sleep-disordered breathing (SDB) and is associated with narrow CO2 reserve (a marker of susceptibility to central apnea). Treatment with high-dose acetazolamide for 3 days decreased susceptibility to hypocapnic central apnea and reduced the frequency of central respiratory events during sleep. Acetazolamide may play a therapeutic role in alleviating central SDB in patients with cervical spinal cord injury, but larger clinical trials are needed.

Aging is associated with increased propensity for central apnea during NREM sleep.

The reason for increased sleep-disordered breathing with predominance of central apneas in the elderly is unknown. We hypothesized that the propensity to central apneas is increased in older adults, manifested by a reduced carbon-dioxide (CO2) reserve in older compared with young adults during non-rapid eye movement sleep. Ten elderly and 15 young healthy adults underwent multiple brief trials of nasal noninvasive positive pressure ventilation during stable NREM sleep. Cessation of mechanical ventilation (MV) resulted in hypocapnic central apnea or hypopnea. The CO2 reserve was defined as the difference in end-tidal CO2 ([Formula: see text]) between eupnea and the apneic threshold, where the apneic threshold was [Formula: see text] that demarcated the central apnea closest to the eupneic [Formula: see text]. For each MV trial, the hypocapnic ventilatory response (controller gain) was measured as the change in minute ventilation (V̇e) during the MV trial for a corresponding change in [Formula: see text]. The eupneic [Formula: see text] was significantly lower in elderly vs. young adults. Compared with young adults, the elderly had a significantly reduced CO2 reserve (-2.6 ± 0.4 vs. -4.1 ± 0.4 mmHg, P = 0.01) and a higher controller gain (2.3 ± 0.2 vs. 1.4 ± 0.2 l·min-1·mmHg-1, P = 0.007), indicating increased chemoresponsiveness in the elderly. Thus elderly adults are more prone to hypocapnic central apneas owing to increased hypocapnic chemoresponsiveness during NREM sleep. NEW & NOTEWORTHY The study describes an original finding where healthy older adults compared with healthy young adults demonstrated increased breathing instability during non-rapid eye movement sleep, as suggested by a smaller carbon dioxide reserve and a higher controller gain. The findings may explain the increased propensity for central apneas in elderly adults during sleep and potentially guide the development of pathophysiology-defined personalized therapies for sleep apnea in the elderly.

Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin.

OBJECTIVES: To compare the rates of bleeding complications in patients with renal insufficiency who receive anticoagulation therapy with the full therapeutic dose, unfractionated heparin (UFH), or with twice-daily enoxaparin. SETTING: A 325-bed community teaching hospital. STUDY TYPE: Retrospective cohort study. METHODS: The medical records of all patients with renal insufficiency who received anticoagulation therapy with UFH or enoxaparin during a 13-month period were reviewed for the occurrence of major and minor bleeding. Incidence rates were computed per 1,000-person days of anticoagulation therapy. Comparisons were made across categories of renal insufficiency and other potential confounders. RESULTS: A total of 620 patients with estimated glomerular filtration rates of < 60 mL/min were studied. Of these, 331 received anticoagulation therapy with UFH, 250 with enoxaparin, and 39 with both (not simultaneously). The major bleeding rates were 26.3 per 1,000 person-days for UFH and 20.7 per 1,000 person-days for enoxaparin. Major bleeding complications were similarly increased for both UFH and enoxaparin therapy across categories of worsening renal insufficiency. Patients with severe renal insufficiency while receiving enoxaparin had a 154% excess incidence of minor bleeding compared to those receiving UFH (incidence ratio, 2.54; 95% confidence interval, 1.01 to 6.36). Worsening renal insufficiency, female gender, and prolonged duration of anticoagulation therapy emerged as the main determinants for bleeding complications. CONCLUSION: Both the twice-daily enoxaparin and UFH regimens are associated with comparable increases in major bleeding complications in patients with renal dysfunction receiving full-dose anticoagulation therapy. Both agents should be used with caution in anticoagulation therapy for patients with renal insufficiency.

Mycobacterium marinum infection in Connecticut: report of four cases.

Mycobacterium marinum is emerging as an important human pathogen in the United States. We report four cases incidentally diagnosed from culture of biopsy specimens of wrist lesions at a Connecticut inner city hospital between 1996 and 1999. There was no clear association with aquatic exposure and only one patient recalled prior trauma. All were successfully treated with ethambutol and rifampicin. The current literature on the epidemiology, clinical characteristics and management of Mycobacterium marinum infections is reviewed.

Pulmonary complications following hematopoietic stem cell transplantation: diagnostic approaches.

Pulmonary complications are a significant cause of morbidity and mortality in hematopoietic stem cell transplant recipients. Pulmonary infiltrates in such patients pose a major challenge for clinicians because of the wide differential diagnosis of infectious and noninfectious conditions. It is rare for the diagnosis to be made by chest radiograph, and commonly these patients will need further invasive and noninvasive studies to confirm the etiology of the pulmonary infiltrates. This review describes the role of the different diagnostic tools available to reach a diagnosis in a timely manner in this patient population.