A Randomized Noninferiority Trial to Compare Enteral to Parenteral Phosphate Replacement on Biochemistry, Waste, and Environmental Impact and Healthcare Cost in Critically Ill Patients With Mild to Moderate Hypophosphatemia.

OBJECTIVES: Hypophosphatemia occurs frequently. Enteral, rather than IV, phosphate replacement may reduce fluid replacement, cost, and waste. DESIGN: Prospective, randomized, parallel group, noninferiority clinical trial. SETTING: Single center, 42-bed state trauma, medical and surgical ICUs, from April 20, 2022, to July 1, 2022. PATIENTS: Patients with serum phosphate concentration between 0.3 and 0.75 mmol/L. INTERVENTIONS: We randomized patients to either enteral or IV phosphate replacement using electronic medical record-embedded program. MEASUREMENT AND MAIN RESULTS: Our primary outcome was serum phosphate at 24 hours with a noninferiority margin of 0.2 mmol/L. Secondary outcomes included cost savings and environmental waste reduction and additional IV fluid administered. The modified intention-to-treat cohort comprised 131 patients. Baseline phosphate concentrations were similar between the two groups. At 24 hours, mean ( sd ) serum phosphate concentration were enteral 0.89 mmol/L (0.24 mmol/L) and IV 0.82 mmol/L (0.28 mmol/L). This difference was noninferior at the margin of 0.2 mmol/L (difference, 0.07 mmol/L; 95% CI, -0.02 to 0.17 mmol/L). When assigned IV replacement, patients received 408 mL (372 mL) of solvent IV fluid. Compared with IV replacement, the mean cost per patient was ten-fold less with enteral replacement ($3.7 [$4.0] vs. IV: $37.7 [$31.4]; difference = $34.0 [95% CI, $26.3-$41.7]) and weight of waste was less (7.7 g [8.3 g] vs. 217 g [169 g]; difference = 209 g [95% CI, 168-250 g]). C O2 emissions were 60-fold less for comparable phosphate replacement (enteral: 2 g producing 14.2 g and 20 mmol of potassium dihydrogen phosphate producing 843 g of C O2 equivalents). CONCLUSIONS: Enteral phosphate replacement in ICU is noninferior to IV replacement at a margin of 0.2 mmol/L but leads to a substantial reduction in cost and waste.

Novel Methods of Measuring Adherence Patterns Reveal Adherence Phenotypes with Distinct Asthma Outcomes.

Rationale: Poor adherence with asthma controller medication contributes to worse symptom control and increased exacerbation risk. Adherence is often expressed as the mean proportion of prescribed doses taken over a period of 6-12 months. New metrics may capture individual day-to-day variability patterns linked with distinct clinical outcomes. Objectives: To test the hypotheses that novel time- and dose-based adherence variability metrics offer independent value to mean adherence in identifying distinct adherence patterns that are associated with symptom control (Asthma Control Test [ACT] score) and exacerbation risk, using electronically recorded medication data from a 6-month cluster randomized trial examining the effect of inhaler reminders on adherence. Methods: Adherence metrics were calculated from the first 2 months (Months 0-2) of the study period. In addition to mean adherence (percentage prescribed puffs/day taken), we examined novel metrics, including time adherence area under the curve (T-AUC), reflecting cumulative gaps in adherence over time; entropy, reflecting disorder in the ways in which a patient changed their medication dose adherence from day to day; and standard deviation of the percentage prescribed puffs/day taken. Dominant metrics identified from factor analysis were included in hierarchical clustering analysis. We compared the resultant clusters in terms of outcomes over Months 2-6 and exacerbation risk over the entire study period. Results: Two factors explained >65% of the total variance in adherence, primarily driven by T-AUC and entropy. Two main patient clusters based on their adherence metrics were identified: cluster 1 (high time adherence, n = 75) had better T-AUC (i.e., fewer gaps between medication-taking days) than cluster 2 (low time adherence, n = 23). Though both clusters had similar symptom control at 2 months, cluster 1 showed less subsequent decline in ACT over Months 2-6 (median [interquartile range] change in ACT score: 1 [-1 to 4] vs. -2 [-3.75 to 0.75]; P = 0.012), and had better symptom control at 6 months (ACT score: 20 [17-23] vs. 17 [15-20]; P = 0.034). There were no significant differences between the clusters in terms of proportion of exacerbators or time to exacerbation. Conclusions: Novel metrics showed that low time adherence was associated with greater risk of decline in asthma symptom control. Adherence patterns may exhibit "memory" relevant to future clinical status, warranting validation in a larger dataset.

Using mobile multimedia platforms in teaching dental diagnosis.

OBJECTIVE: Mobile Multimedia Platforms (MMPs) are prolific tools that can be used by individuals and corporations to share content. However, few studies have shown the effectiveness of MMPs as educational tools. Through this study, we aimed to evaluate the effectiveness of MMPs in improving basic dental diagnostic skills. In addition, we captured student feedback on the use of MMPs in a dental curriculum. METHOD: In this voluntary interventional study on 89 senior dental students, we created pilot learning modules through an MMP called Instagram Stories to teach dental diagnosis. We evaluated the efficacy of the modules through diagnostic tests that were given to dental students who were close to graduating. RESULTS: The students showed a significant increase in diagnostic test scores from 49% to 73% (p < 0.05) after the use of an MMP. Furthermore, the students' feedback on the MMP indicated that most students found it easy and enjoyable to use. CONCLUSION: Our study data show that MMPs may be used to improve training in basic dental diagnostic skills and can serve as an adjunct teaching tool. Moreover, MMP modules can potentially enrich professional education in developing countries where access to educational resources is limited.

Day-to-day variability of forced oscillatory mechanics for early detection of acute exacerbations in COPD.

BACKGROUND: Telemonitoring trials for early detection of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have provided mixed results. Day-to-day variations in lung function measured by the forced oscillation technique (FOT) may yield greater insight. We evaluated the clinical utility of home telemonitoring of variability in FOT measures in terms of 1) the relationship with symptoms and quality of life (QoL); and 2) the timing of variability of FOT measures and symptom changes prior to AECOPD. METHODS: Daily FOT parameters at 5 Hz (resistance (R) and reactance (X); Resmon Pro Diary, Restech Srl, Milan, Italy), daily symptoms (COPD Assessment Test (CAT)) and 4-weekly QoL data (St George's Respiratory Questionnaire (SGRQ)) were recorded over 8-9 months from chronic obstructive pulmonary disease (COPD) patients. Variability of R and X was calculated as the standard deviation (sd) over 7-day running windows and we also examined the effect of varying window size. The relationship of FOT versus CAT and SGRQ was assessed using linear mixed modelling, daily changes in FOT variability and CAT prior to AECOPD using one-way repeated measures ANOVA. RESULTS: Fifteen participants with a mean±sd age of 69±10 years and a % predicted forced expiratory volume in 1 s (FEV1) of 39±10% had a median (interquartile range (IQR)) adherence of 95.4% (79.0-98.8%). Variability of the inspiratory component of X (indicated by the standard deviation of inspiratory reactance (SDXinsp)) related to CAT and weakly to SGRQ (fixed effect estimates 1.57, 95% CI 0.65-2.49 (p=0.001) and 4.41, 95% CI -0.06 to 8.89 (p=0.05), respectively). SDXinsp changed significantly on the same day as CAT (1 day before AECOPD, both p=0.02) and earlier when using shorter running windows (3 days before AECOPD, p=0.01; accuracy=0.72 for 5-day windows). CONCLUSIONS: SDXinsp from FOT telemonitoring reflects COPD symptoms and may be a sensitive biomarker for early detection of AECOPD.

The effect of acute exposure to morphine on breathing variability and cardiopulmonary coupling in men with obstructive sleep apnea: A randomized controlled trial.

Opioid-related deaths from respiratory depression are increasing but there is only limited information on the effect of morphine on breathing during sleep. This study aimed to detect and quantify opioid-induced cardiorespiratory pattern changes during sleep in obstructive sleep apnea (OSA) patients using novel automated methods and correlate these with conventional polysomnography (PSG) measures. Under a randomized double-blind placebo-controlled crossover design, 60 male OSA patients attended two one-night visits to the sleep laboratory, at least a week apart. Either a 40-mg controlled-release oral morphine dose or placebo was administered. Breathing during sleep was measured by standard in-laboratory PSG. We analysed the inter-breath interval (IBI) from the PSG flow channel to quantify breathing irregularity. Cardiopulmonary coupling (CPC) was analysed using the PSG electrocardiogram (ECG) channel. Following the consumption of morphine, the 60 OSA patients had fewer breaths (p = .0006), a longer inter-breath interval (p < .0001) and more irregular breathing with increased IBI coefficient of variation (CV) (p = .0015) compared to the placebo night. A higher CPC sleep quality index was found with morphine use. The change of key IBI and CPC parameters was significantly correlated with the change of key PSG sleep-disordered breathing parameters. In conclusion, 40 mg controlled-release morphine resulted in a longer breathing cycle and increased breathing irregularity but generally more stable sleep in OSA patients. The significant links between the IBI and CPC techniques and a range of PSG sleep-disordered breathing parameters may suggest a practical value as surrogate overnight cardiorespiratory measurements, because both respiratory flow and ECG can be detected by small portable devices.

An automated and reliable method for breath detection during variable mask pressures in awake and sleeping humans.

Accurate breath detection is crucial in sleep and respiratory physiology research and in several clinical settings. However, this process is technically challenging due to measurement and physiological artifacts and other factors such as variable leaks in the breathing circuit. Recently developed techniques to quantify the multiple causes of obstructive sleep apnea, require intermittent changes in airway pressure applied to a breathing mask. This presents an additional unique challenge for breath detection. Traditional algorithms often require drift correction. However, this is an empirical operation potentially prone to human error. This paper presents a new algorithm for breath detection during variable mask pressures in awake and sleeping humans based on physiological landmarks detected in the airflow or epiglottic pressure signal (Pepi). The algorithms were validated using simulated data from a mathematical model and against the standard visual detection approach in 4 healthy individuals and 6 patients with sleep apnea during variable mask pressure conditions. Using the flow signal, the algorithm correctly identified 97.6% of breaths with a mean difference±SD in the onsets of respiratory phase compared to expert visual detection of 23±89ms for inspiration and 6±56ms for expiration during wakefulness and 10±74ms for inspiration and 3±28 ms for expiration with variable mask pressures during sleep. Using the Pepi signal, the algorithm correctly identified 89% of the breaths with accuracy of 31±156ms for inspiration and 9±147ms for expiration compared to expert visual detection during variable mask pressures asleep. The algorithm had excellent performance in response to baseline drifts and noise during variable mask pressure conditions. This new algorithm can be used for accurate breath detection including during variable mask pressure conditions which represents a major advance over existing time-consuming manual approaches.

Respiratory Variability during Sleep in Methadone Maintenance Treatment Patients.

STUDY OBJECTIVES: Methadone maintenance treatment (MMT) patients have a high prevalence of central sleep apnea and ataxic breathing related to damage to central respiratory rhythm control. However, the quantification of sleep apnea indices requires laborious manual scoring, and ataxic breathing pattern is subjectively judged by visual pattern recognition. This study proposes a semi-automated technique to characterize respiratory variability in MMT patients. METHODS: Polysomnography, blood, and functional outcomes of sleep questionnaire (FOSQ) from 50 MMT patients and 20 healthy subjects with matched age, sex, and body mass index, were analyzed. Inter-breath intervals (IBI) were extracted from the nasal cannula pressure signal. Variability of IBI over 100 breaths was quantified by standard deviation (SD), coefficient of variation (CV), and scaling exponent (α) from detrended fluctuation analysis. The relationships between these variability measures and blood methadone concentration, central sleep apnea index (CAI), apnea-hypopnea index (AHI), and clinical outcome (FOSQ), were then examined. RESULTS: MMT patients had significantly higher SD and CV during all sleep stages. During NREM sleep, SD and CV were correlated with blood methadone concentration (Spearman R = 0.52 and 0.56, respectively; p < 0.01). SD and CV were also correlated with CAI (R = 0.63 and 0.71, p < 0.001, respectively), and AHI (R = 0.45 and 0.58, p < 0.01, respectively). Only α showed significant correlation with FOSQ (R = -0.33, p < 0.05). CONCLUSIONS: MMT patients have a higher respiratory variability during sleep than healthy controls. Semi-automated variability measures are related to apnea indices obtained by manual scoring and may provide a new approach to quantify opioid-related sleep-disordered breathing.

Mild Airflow Limitation during N2 Sleep Increases K-complex Frequency and Slows Electroencephalographic Activity.

STUDY OBJECTIVES: To determine the effects of mild airflow limitation on K-complex frequency and morphology and electroencephalogram (EEG) spectral power. METHODS: Transient reductions in continuous positive airway pressure (CPAP) during stable N2 sleep were performed to induce mild airflow limitation in 20 patients with obstructive sleep apnea (OSA) and 10 healthy controls aged 44 ± 13 y. EEG at C3 and airflow were measured in 1-min windows to quantify K-complex properties and EEG spectral power immediately before and during transient reductions in CPAP. The frequency and morphology (amplitude and latency of P200, N550 and N900 components) of K-complexes and EEG spectral power were compared between conditions. RESULTS: During mild airflow limitation (18% reduction in peak inspiratory airflow from baseline, 0.38 ± 0.11 versus 0.31 ± 0.1 L/sec) insufficient to cause American Academy of Sleep Medicine-defined cortical arousal, K-complex frequency (9.5 ± 4.5 versus 13.7 ± 6.4 per min, P < 0.01), N550 amplitude (25 ± 3 versus 27 ± 3 µV, P < 0.01) and EEG spectral power (delta: 147 ± 48 versus 230 ± 99 µV(2), P < 0.01 and theta bands: 31 ± 14 versus 34 ± 13 µV(2), P < 0.01) significantly increased whereas beta band power decreased (14 ± 5 versus 11 ± 4 µV(2), P < 0.01) compared to the preceding non flow-limited period on CPAP. K-complex frequency, morphology, and timing did not differ between patients and controls. CONCLUSION: Mild airflow limitation increases K-complex frequency, N550 amplitude, and spectral power of delta and theta bands. In addition to providing mechanistic insight into the role of mild airflow limitation on K-complex characteristics and EEG activity, these findings may have important implications for respiratory conditions in which airflow limitation during sleep is common (e.g., snoring and OSA).

The effect of sigh on cardiorespiratory synchronization in healthy sleeping infants.

STUDY OBJECTIVES: Sighs are thought to have a role in regulating breathing control. They may preceed a central apnea (sigh-CA) or a pause (sigh-P), particularly in quiet sleep. Recent techniques characterizing cardiorespiratory synchronization (CRS) provide sensitive measures of cardiorespiratory coupling, which is an important factor in breathing control. We speculated that the strength of CRS and direction of cardiorespiratory coupling (DC), would differ between sigh-P and sigh-CA; before and after a sigh; and with maturation. DESIGN: Prospective study. CRS and DC were calculated from the respiratory signal and heart rate before and after sighs recorded during overnight polysomnography. SETTING: Sleep laboratory. PARTICIPANTS: The data were selected from 15 subjects of a prospective cohort of 34 healthy infants at ages 2 weeks, 3 months and 6 months. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Both CRS and respiratory modulation on heart rate (RMH) (negative DC index) were decreased around sigh-CA compared with sigh-P at all ages. Short-term CRS decreased after both sigh-P and sigh-CA in infants aged 2 weeks and 3 months. Long term CRS did not change before and after sigh-P or sigh-CA. CRS and RMH were increased at 3 months and 6 months compared to 2 weeks. CONCLUSIONS: A sigh was not found to be associated with apparent resetting of breathing control in healthy infants less than 6 months of age. Cardiorespiratory coupling appears to be a leading marker of changes in breathing control, preceding central apnea associated with a sigh. CITATION: Nguyen CD; Dakin C; Yuill M; Crozier S; Wilson S. The effect of sigh on cardiorespiratory synchronization in healthy sleeping infants. SLEEP 2012;35(12):1643-1650.