Incidence of postoperative opioid-induced respiratory depression episodes in patients on room air or supplemental oxygen: a post-hoc analysis of the PRODIGY trial.

BACKGROUND: Supplemental oxygen (SO) potentiates opioid-induced respiratory depression (OIRD) in experiments on healthy volunteers. Our objective was to examine the relationship between SO and OIRD in patients on surgical units. METHODS: This post-hoc analysis utilized a portion of the observational PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial dataset (202 patients, two trial sites), which involved blinded continuous pulse oximetry and capnography monitoring of postsurgical patients on surgical units. OIRD incidence was determined for patients receiving room air (RA), intermittent SO, or continuous SO. Generalized estimating equation (GEE) models, with a Poisson distribution, a log-link function and time of exposure as offset, were used to compare the incidence of OIRD when patients were receiving SO vs RA. RESULTS: Within the analysis cohort, 74 patients were always on RA, 88 on intermittent and 40 on continuous SO. Compared with when on RA, when receiving SO patients had a higher risk for all OIRD episodes (incidence rate ratio [IRR] 2.7, 95% confidence interval [CI] 1.4-5.1), apnea episodes (IRR 2.8, 95% CI 1.5-5.2), and bradypnea episodes (IRR 3.0, 95% CI 1.2-7.9). Patients with high or intermediate PRODIGY scores had higher IRRs of OIRD episodes when receiving SO, compared with RA (IRR 4.5, 95% CI 2.2-9.6 and IRR 2.3, 95% CI 1.1-4.9, for high and intermediate scores, respectively). CONCLUSIONS: Despite oxygen desaturation events not differing between SO and RA, SO may clinically promote OIRD. Clinicians should be aware that postoperative patients receiving SO therapy remain at increased risk for apnea and bradypnea. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02811302, registered June 23, 2016.

Nocturnal Oxygen Desaturation Index Correlates with Respiratory Depression in Post-Surgical Patients Receiving Opioids - A Post-Hoc Analysis from the Prediction of Opioid-Induced Respiratory Depression in Patients Monitored by Capnography (PRODIGY) Study.

Purpose: Postoperative monitoring of respiratory status on general care wards typically consists of intermittent checks of oxyhemoglobin saturation and respiratory rate, allowing substantial unmonitored time for severe opioid induced respiratory depression (RD) to develop unnoticed. Oxygen desaturation index (ODI) can be computed solely by continuous pulse oximetry monitoring. In this post-hoc analysis, we evaluate whether nocturnal ODI correlates with RD. Patients and Methods: The PRODIGY trial (NCT02811302) was a multinational study conducted where adult patients receiving parenteral opioids on the general care floor were continuously monitored by blinded pulse oximetry and capnography monitoring to detect episodes of RD. An RD episode was defined as: respiratory rate ≤5 breaths/min (bpm) for ≥3 minutes, oxygen saturation (SpO2) ≤85% for ≥3 minutes, end-tidal carbon dioxide (EtCO2) ≤15 or ≥60 mm Hg for ≥3 minutes, apnea episode lasting >30 seconds, or any respiratory opioid-related adverse event. Data were used to calculate nocturnal (00:00 ─ 06:00) ODI4% based on desaturation episodes (4% decrease from mean oxyhemoglobin saturation in the past 120 seconds, lasting ≥10 seconds). Continuous monitoring began after a patient received parenteral opioids, allowing identification of potential RD and ODI4% episodes during opioid therapy. The average number of ODI4% episodes (≥1, ≥5, ≥10, ≥15 episodes/hour) were analyzed. Logistic regression and area under the receiver operating characteristic curve (AUC) were computed. Results: A final cohort of 1072 (out of 1335) patients had sufficient data, with 76% (N=817/1072) having ≥1 episode of ODI4%. Multivariable logistic regression showed that ODI4% was strongly associated with RD, with greater risk for higher ODI4% scores: ≥5 episodes/hour odds ratio 2.59 (95% CI 1.72-3.89, p<0.0001); ≥10 episodes/hour 3.39 (95% CI 1.80-6.39, p=0.0002); ≥15 episodes/hour 4.71 (95% CI 1.93-11.47, p=0.0006).There was no significant association between ODI4% and respiratory adverse events. Conclusion: Nocturnal ODI4% was highly correlated with RD among hospitalized patients receiving parenteral opioids. Patients with a high ODI4%, especially with ≥15 episodes/hour, are more likely to experience RD and should be evaluated for the need of closer monitoring after opioid administration.

Association Between Race and Opioid-Induced Respiratory Depression: An International Post Hoc Analysis of the Prediction of Opioid-induced Respiratory Depression In Patients Monitored by Capnography Trial.

BACKGROUND: Opioid-induced respiratory depression (OIRD) is common on the medical and surgical wards and is associated with increased morbidity and health care costs. While previous studies have investigated risk factors for OIRD, the role of race remains unclear. We aim to investigate the association between race and OIRD occurrence on the medical/surgical ward. METHODS: This is a post hoc analysis of the PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial; a prospective multinational observational blinded study of 1335 general ward patients who received parenteral opioids and underwent blinded capnography and oximetry monitoring to identify OIRD episodes. For this study, demographic and perioperative data, including race and comorbidities, were analyzed and assessed for potential associations with OIRD. Univariable χ 2 and Mann-Whitney U tests were used. Stepwise selection of all baseline and demographic characteristics was used in the multivariable logistic regression analysis. RESULTS: A total of 1253 patients had sufficient racial data (317 Asian, 158 Black, 736 White, and 42 other races) for inclusion. The incidence of OIRD was 60% in Asians (N = 190/317), 25% in Blacks (N = 40/158), 43% in Whites (N = 316/736), and 45% (N = 19/42) in other races. Baseline characteristics varied significantly: Asians were older, more opioid naïve, and had higher opioid requirements, while Blacks had higher incidences of heart failure, obesity, and smoking. Stepwise multivariable logistic regression revealed that Asians had increased risk of OIRD compared to Blacks (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.54-4.04; P = .0002) and Whites (OR, 1.38; 95% CI, 1.01-1.87; P = .0432). Whites had a higher risk of OIRD compared to Blacks (OR, 1.81; 95% CI, 1.18-2.78; P = .0067). The model's area under the curve was 0.760 (95% CI, 0.733-0.787), with a Hosmer-Lemeshow goodness-of-fit test P value of .23. CONCLUSIONS: This post hoc analysis of PRODIGY found a novel association between Asian race and increased OIRD incidence. Further study is required to elucidate its underlying mechanisms and develop targeted care pathways to reduce OIRD in susceptible populations.

Initial rhythm control with cryoballoon ablation vs drug therapy: Impact on quality of life and symptoms.

BACKGROUND: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized. METHODS: Patients aged 18 to 75 with symptomatic paroxysmal AF naïve to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary. RESULTS: Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs AAD (all P <0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5 -14.2, P <0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P <0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs 15.2 days/year post-blanking; IRR: 0.30, P <0.001). CONCLUSIONS: In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01803438.

Modeling the Cost Savings of Continuous Pulse Oximetry and Capnography Monitoring of United States General Care Floor Patients Receiving Opioids Based on the PRODIGY Trial.

INTRODUCTION: Despite the high incidence of respiratory depression on the general care floor and evidence that continuous monitoring improves patient outcomes, the cost-benefit of continuous pulse oximetry and capnography monitoring of general care floor patients remains unknown. This study modeled the cost and length of stay savings, investment break-even point, and likelihood of cost savings for continuous pulse oximetry and capnography monitoring of general care floor patients at risk for respiratory depression. METHODS: A decision tree model was created to compare intermittent pulse oximetry versus continuous pulse oximetry and capnography monitoring. The model utilized costs and outcomes from the PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial, and was applied to a modeled cohort of 2447 patients receiving opioids per median-sized United States general care floor annually. RESULTS: Continuous pulse oximetry and capnography monitoring of high-risk patients is projected to reduce annual hospital cost by $535,531 and cumulative patient length of stay by 103 days. A 1.5% reduction in respiratory depression would achieve a break-even investment point and justify the investment cost. The probability of cost saving is ≥ 80% if respiratory depression is decreased by ≥ 17%. Expansion of continuous monitoring to high- and intermediate-risk patients, or to all patients, is projected to reach a break-even point when respiratory depression is reduced by 2.5% and 3.5%, respectively, with a ≥ 80% probability of cost savings when respiratory depression decreases by ≥ 27% and ≥ 31%, respectively. CONCLUSION: Compared to intermittent pulse oximetry, continuous pulse oximetry and capnography monitoring of general care floor patients receiving opioids has a high chance of being cost-effective. TRIAL REGISTRATION: www.clinicaltrials.gov , Registration ID: NCT02811302.

Frequency and Temporal Distribution of Postoperative Respiratory Depressive Events.

BACKGROUND: The frequency and temporal distribution of postoperative respiratory depression (RD) events are not completely understood. This study determined the temporal distribution and frequency of RD episodes in postsurgical patients continuously monitored by bedside capnography and pulse oximetry. METHODS: This was a post hoc study of a subset of postsurgical patients enrolled in The PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial from 2 sites in the United States. These patients had undergone continuous bedside monitoring on general care wards. These data were adjudicated for potential RD episodes. The number of RD episodes per patient and the time of each RD episode were determined. The first RD episode experienced by a patient was classified as an "initial" episode, and the initial and all subsequent RD episodes experienced by a patient were classified as "all" episodes. A PRODIGY risk score was calculated. RESULTS: Data analyzed from 250 patients contained 2539 RD episodes in 155 (62.0%, 95% confidence interval, 55.7-68.0) patients with median 2 [0-8], range of 0-545 RD episodes per patient, with a PRODIGY risk score distribution of 100 (40.0%) low, 79 (31.6%) intermediate, 70 (28.0%) high (missing data from 1 patient). Median time to the initial RD episode was 8.8 [5.1-18.0] hours postoperatively. There was a peak occurrence of initial RD events between 14:00 and 20:00 on the day of surgery, and these were associated with a large number of subsequent events in the same timeframe. The peak time of all RD episodes occurred from 02:00 to 06:00. Patients with high PRODIGY risk scores had higher incidence and greater number of RD episodes per patient (P < .001, overall comparisons between groups for both incidence [χ2] and number of episodes [Kruskal-Wallis test]). CONCLUSIONS: Continuous monitoring of surgical patients demonstrates that RD episodes are common, and risk increases with higher PRODIGY scores. In this patient cohort, the rate of initial RD episodes peaked in the afternoon to early evening, while peak rate of all RD episodes occurred in early morning. Further, among patients with RD episodes, the number of episodes increased with higher PRODIGY scores.

Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation.

AIMS: Treatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF). METHODS AND RESULTS: A total of 218 treatment naive patients with symptomatic PAF were randomized (1 : 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was ≥1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) >30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P < 0.001). CONCLUSIONS: Cryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.

Postoperative opioid administration characteristics associated with opioid-induced respiratory depression: Results from the PRODIGY trial.

STUDY OBJECTIVE: Opioid administration for pain in general care floor patients remains common, and can lead to adverse outcomes, including respiratory compromise. The PRODIGY trial found that among ward patients receiving parenteral opioids, 46% experienced ≥1 respiratory depression episode. The objective of this analysis was to evaluate the geographic differences of opioid administration and examine the association between opioid administration characteristics and the occurrence of respiratory depression. DESIGN: Prospective observational trial. SETTING: 16 general care medical and surgical wards in Asia, Europe, and the United States. PATIENTS: 1335 patients receiving parenteral opioids. INTERVENTIONS: Blinded, alarm-silenced continuous capnography and pulse oximetry monitoring. MEASUREMENTS: Opioid-induced respiratory depression, defined as respiratory rate ≤ 5 bpm, SpO2 ≤ 85%, or ETCO2 ≤ 15 or ≥ 60 mmHg for ≥3 min; apnea episode lasting >30 s; or any respiratory opioid-related adverse event. RESULTS: Across all patients, 58% received only long-acting opioids, 16% received only short-acting (<3 h) opioids, and 21% received a combination of short- and long-acting (≥3 h) opioids. The type and median total morphine milligram equivalent (MME) of opioid administered varied significantly by region, with 31.5 (12.5-76.7) MME, 31.0 (6.2-99.0) MME, and 7.2 (1.7-18.7) MME in the United States, Europe, and Asia, respectively (p < 0.001). Considering only postoperative opioids, 54% (N = 119/220) and 45% (N = 347/779) of patients receiving only short-acting opioids or only long-acting opioids experienced ≥1 episode of opioid-induced respiratory depression, respectively. Multivariable analysis identified post-procedure tramadol (OR 0.62, 95% CI 0.424-0.905, p = 0.0133) and post-procedure epidural opioids (OR 0.485, 95% CI 0.322-0.731, p = 0.0005) being associated with a significant reduction in opioid-induced respiratory depression. CONCLUSIONS: Despite varying opioid administration characteristics between Asia, Europe, and the United States, opioid-induced respiratory depression remains a common global problem on general care medical and surgical wards. While the use of post-procedure tramadol or post-procedure epidural opioids may reduce the incidence of respiratory depression, continuous monitoring is also necessary to ensure patient safety when receiving postoperative opioids. REGISTRATION NUMBER: www.clinicaltrials.gov, ID: NCT02811302.

Subretinally injected semiconducting polymer nanoparticles rescue vision in a rat model of retinal dystrophy.

Inherited retinal dystrophies and late-stage age-related macular degeneration, for which treatments remain limited, are among the most prevalent causes of legal blindness. Retinal prostheses have been developed to stimulate the inner retinal network; however, lack of sensitivity and resolution, and the need for wiring or external cameras, have limited their application. Here we show that conjugated polymer nanoparticles (P3HT NPs) mediate light-evoked stimulation of retinal neurons and persistently rescue visual functions when subretinally injected in a rat model of retinitis pigmentosa. P3HT NPs spread out over the entire subretinal space and promote light-dependent activation of spared inner retinal neurons, recovering subcortical, cortical and behavioural visual responses in the absence of trophic effects or retinal inflammation. By conferring sustained light sensitivity to degenerate retinas after a single injection, and with the potential for high spatial resolution, P3HT NPs provide a new avenue in retinal prosthetics with potential applications not only in retinitis pigmentosa, but also in age-related macular degeneration.

Safety and efficacy of polymer-free biolimus-eluting stents versus ultrathin stents in unprotected left main or coronary bifurcation: A propensity score analysis from the RAIN and CHANCE registries.

OBJECTIVES: Evaluate safety and efficacy of polymer-free biolimus-eluting stents (PF-BESs) versus ultrathin stents in unprotected left main (ULM) or bifurcation. BACKGROUND: PF-BESs due to reduced length of dual antiplatelet therapy (DAPT) are increasingly used. However, there are limited data about safety and efficacy for ULM or bifurcation. METHODS: We selected all-patients treated for ULM or bifurcation from two multicenter real life registries (RAIN [NCT03544294] evaluating ultrathin stents, CHANCE [NCT03622203] appraising PF-BES). After propensity score with matching, the primary endpoint was major adverse cardiac events (MACE; a composite of all-cause death, myocardial infarction, target lesion revascularization [TLR], and stent thrombosis [ST]), while its components along with target vessel revascularization (TVR) secondary endpoints. RESULTS: Three thousand and three patients treated with ultrathin stents and 446 with PF-BESs, resulting respectively in 562 and 281 after propensity score with matching (33 and 22%, respectively, with ULM disease). After 12 (8-20) months, rates of MACE were similar (9 vs. 8%, p = 0.56) without difference in TLR and ST (3.0 vs. 1.7%, p = .19 and 1.8 vs. 1.1%, p = .42). These results were consistent for ULM group (3 vs. 1.7% and 1.8 vs. 1.1%, p = .49 and .76), for non-ULM group (2.1 vs. 3.4%, p = .56 and 1.2 vs. 1.7%, p = .78) and for two-stent strategy (8.7 vs. 4.5% and 4.3 vs. 3.2%, p = .75 and .91). Among patients treated with 1 month of DAPT in both groups, those with ultrathin stents experienced higher rates of MACE related to all-cause death (22 vs. 12%, p = .04) with higher although not significant rates of ST (3 vs. 0%, p = .45). CONCLUSIONS: PF-BES implanted on ULM or BiF offered freedom from TLR and ST comparable to ultrathin stents. PF-BESs patients assuming DAPT for 1 month experienced a lower despite not significant incidence of ST.

[A case of anomalous origin of the left coronary artery from the pulmonary artery in the elderly]. / Origine anomala dell'arteria coronaria sinistra dall'arteria polmonare: un caso diagnosticato nell'età anziana.

The anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) syndrome is a rare congenital coronary artery anomaly. The development of acquired collateral circulation between the right coronary artery and the left coronary artery allows, sometimes, survival until adulthood. In our clinical practice, we came across an exceptional case for the advanced age, 75 years. Coronary computed tomography, associated with other imaging modalities, has played a crucial role in accurately defining the origin, the course and the connection of the coronary arteries.

Cost-effectiveness in transient hypocalcemia post-thyroidectomy.

BACKGROUND: Three different strategies to manage transient hypocalcemia after total thyroidectomy were compared to evaluate cost-effectiveness. The reliability of total serum calcium (TSCa), ionized calcium (ICa), and intact parathyroid hormone (iPTH) were investigated to achieve this goal. METHODS: A multicenter, prospective randomized study was carried out with 169 patients. The strategies were "preventive" (oral calcium + vitamin D supplementation), "reactive" (therapy in hypocalcemia), and "predictive" (therapy if iPTH <10 pg/mL). RESULTS: TSCa had higher accuracy in identifying patients who developed hypocalcemia-related symptoms than ICa (84.6% vs 50.0%). TSCa 24 h after surgery showed 24.8% of patients with hypocalcemia, whereas TSCa 48 h after surgery identified a further 10.6% with hypocalcemia (only in the "reactive" and "predictive" groups). iPTH showed low sensitivity as a predictor of hypocalcemia. Between the 3 groups, there was no significant difference in hospitalization time or number of symptomatic hypocalcemic patients. Interestingly, the cost-per-patient was significantly different among the groups. CONCLUSIONS: None of the discussed strategies allowed for early discharge of patients without any risk of transient hypocalcemia. The "preventive" strategy was the most cost-effective, despite overtreatment.

Optimal medical therapy vs. coronary revascularization for patients presenting with chronic total occlusion: A meta-analysis of randomized controlled trials and propensity score adjusted studies.

INTRODUCTION: The optimal management of patients with coronary chronic total occlusions (CTO) remains controversial. This meta-analysis aims to compare percutaneous coronary intervention of CTO (CTO-PCI) versus optimal medical therapy (OMT) in CTO patients. METHODS: A literature search with highly specific terms was conducted using MEDLINE, EMBASE, and Web of Science to identify most relevant randomized controlled trials (RCTs) and observational studies with propensity score matching (PSM) evaluating differences in between CTO-PCI versus OMT. The primary endpoint was the incidence of major adverse cardiac events (MACEs, composite of cardiovascular death, acute coronary syndrome, and repeat PCI, re-PCI) while its single components were defined as secondary endpoints. RESULTS: A total of eight studies was included, four RCTs and four PSMs. 3,971 patients were included in the analysis (2,050 CTO-PCI versus 1,921 OMT) with a mean follow-up of 3 years. No significant differences were found regarding overall MACE, re-PCI and AMI. Regarding CV-death, CTO-PCI was associated with a better outcome compared with OMT driven by PSMs (OR 0.52, 0.0.81, P < 0.01). CONCLUSIONS: As compared to OMT, CTO-PCI was associated with similar MACE rate; however, CTO-PCI may be associated with reduced CV death, mainly due to PSMs effect.

Network meta-analysis of studies comparing closure devices for femoral access after percutaneous coronary intervention.

INTRODUCTION: Different devices have been released for closure of femoral vascular access after coronary angiography or percutaneous coronary intervention, whereas evidence about their efficacy and safety when compared with manual compression or head to head is lacking, especially across different diameters of sheaths, age and sex. RESULTS: A total of 30 studies were included in the analysis. Manual compression was evaluated as the control group in all of the included studies (5620 patients), Angioseal in 15 studies (17-29) (1812 patients), Exoseal in two studies (30-31) (1773 patients), Perclose in six (29, 32-37) (849 patients), Vasoseal in eight (36, 38-43) (699 patients), DUETT in one study (44) (392 patients), StarClose in two studies (23, 45) (334 patients), Techstar in two studies (37, 46) (252 patients) and extravascular staple in one study (47) (242 patients). At network meta-analysis, all the devices resulted as not superior to manual compression to reduce all vascular complications, and these results did not vary at metaregression for age, sex and diameter of sheaths. Manual compression significantly increased time to hemostasis when compared with Femoseal (5.72; 1.91-19.10), Vasoseal (5.11; 2.32-11.33), Perclose (3.46; 1.70-7.06), Angioseal (14.95; 7.84-28.57) and Techstar (9.78; 1.81-53.65), while was similar to StarClose, DUETT and Exoseal. CONCLUSION: Different vascular devices for closure of femoral access did not results superior to manual compression to reduce complications, whereas offered a shorted time to hemostasis. StarClose was the device with the highest probability to perform best in terms of complication, whereas Angioseal was superior in terms of reduction of time to hemostasis.