Community-level interventions for pre-eclampsia (CLIP) in Pakistan: A cluster randomised controlled trial.

OBJECTIVES: To reduce all-cause maternal and perinatal mortality and major morbidity through Lady Health Worker (LHW)-facilitated community engagement and early diagnosis, stabilization and referral of women with preeclampsia, an important contributor to adverse maternal and perinatal outcomes given delays in early detection and initial management. STUDY DESIGN: In the Pakistan Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomized controlled trial (NCT01911494), LHWs engaged the community, recruited pregnant women from 20 union councils (clusters), undertook mobile health-guided clinical assessment for preeclampsia, and referral to facilities after stabilization. MAIN OUTCOME MEASURES: The primary outcome was a composite of maternal, fetal and newborn mortality and major morbidity. FINDINGS: We recruited 39,446 women in intervention (N = 20,264) and control clusters (N = 19,182) with minimal loss to follow-up (3∙7% vs. 4∙5%, respectively). The primary outcome did not differ between intervention (26·6%) and control (21·9%) clusters (adjusted odds ratio, aOR, 1∙20 [95% confidence interval 0∙84-1∙72]; p = 0∙31). There was reduction in stillbirths (0·89 [0·81-0·99]; p = 0·03), but no impact on maternal death (1·08 [0·69, 1·71]; p = 0·74) or morbidity (1·12 [0·57, 2·16]; p = 0·77); early (0·95 [0·82-1·09]; p = 0·46) or late neonatal deaths (1·23 [0·97-1·55]; p = 0·09); or neonatal morbidity (1·22 [0·77, 1·96]; p = 0·40). Improvements in outcome rates were observed with 4-7 (p = 0·015) and ≥8 (p < 0·001) (vs. 0) CLIP contacts. INTERPRETATION: The CLIP intervention was well accepted by the community and implemented by LHWs. Lack of effects on adverse outcomes could relate to quality care for mothers with pre-eclampsia in health facilities. Future strategies for community outreach must also be accompanied by health facility strengthening. FUNDING: The University of British Columbia (PRE-EMPT), a grantee of the Bill & Melinda Gates Foundation (OPP1017337).

Community level interventions for pre-eclampsia (CLIP) in India: A cluster randomised controlled trial.

OBJECTIVES: Pregnancy hypertension is associated with 7.1% of maternal deaths in India. The objective of this trial was to assess whether task-sharing care might reduce adverse pregnancy outcomes related to delays in triage, transport, and treatment. STUDY DESIGN: The Indian Community-Level Interventions for Pre-eclampsia (CLIP) open-label cluster randomised controlled trial (NCT01911494) recruited pregnant women in 12 clusters (initial four-cluster internal pilot) in Belagavi and Bagalkote, Karnataka. The CLIP intervention (6 clusters) consisted of community engagement, community health workers (CHW) provided mobile health (mHeath)-guided clinical assessment, initial treatment, and referral to facility either urgently (<4 h) or non-urgently (<24 h), dependent on algorithm-defined risk. Treatment effect was estimated by multi-level logistic regression modelling, adjusted for prognostically-significant baseline variables. Predefined secondary analyses included safety and evaluation of the intensity of mHealth-guided CHW-provided contacts. MAIN OUTCOME MEASURES: 20% reduction in composite of maternal, fetal, and newborn mortality and major morbidity. RESULTS: All 14,783 recruited pregnancies (7839 intervention, 6944 control) were followed-up. The primary outcome did not differ between intervention and control arms (adjusted odds ratio (aOR) 0.92 [95% confidence interval 0.74, 1.15]; p = 0.47; intraclass correlation coefficient 0.013). There were no intervention-related safety concerns following administration of either methyldopa or MgSO4, and 401 facility referrals. Compared with intervention arm women without CLIP contacts, those with ≥8 contacts suffered fewer stillbirths (aOR 0.19 [0.10, 0.35]; p < 0.001), at the probable expense of survivable neonatal morbidity (aOR 1.39 [0.97, 1.99]; p = 0.072). CONCLUSIONS: As implemented, solely community-level interventions focussed on pre-eclampsia did not improve outcomes in northwest Karnataka.

Community-level interventions for pre-eclampsia (CLIP) in Mozambique: A cluster randomised controlled trial.

OBJECTIVES: Pregnancy hypertension is the third leading cause of maternal mortality in Mozambique and contributes significantly to fetal and neonatal mortality. The objective of this trial was to assess whether task-sharing care might reduce adverse pregnancy outcomes related to delays in triage, transport, and treatment. STUDY DESIGN: The Mozambique Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trial (NCT01911494) recruited pregnant women in 12 administrative posts (clusters) in Maputo and Gaza Provinces. The CLIP intervention (6 clusters) consisted of community engagement, community health worker-provided mobile health-guided clinical assessment, initial treatment, and referral to facility either urgently (<4hrs) or non-urgently (<24hrs), dependent on algorithm-defined risk. Treatment effect was estimated by multi-level logistic regression modelling, adjusted for prognostically-significant baseline variables. Predefined secondary analyses included safety and evaluation of the intensity of CLIP contacts. MAIN OUTCOME MEASURES: 20% reduction in composite of maternal, fetal, and newborn mortality and major morbidity. RESULTS: 15,013 women (15,123 pregnancies) were recruited in intervention (N = 7930; 2·0% loss to follow-up (LTFU)) and control (N = 7190; 2·8% LTFU) clusters. The primary outcome did not differ between intervention and control clusters (adjusted odds ratio (aOR) 1·31, 95% confidence interval (CI) [0·70, 2·48]; p = 0·40). Compared with intervention arm women without CLIP contacts, those with ≥8 contacts experienced fewer primary outcomes (aOR 0·79 (95% CI 0·63, 0·99); p = 0·041), primarily due to improved maternal outcomes (aOR 0·72 (95% CI 0·53, 0·97); p = 0·033). INTERPRETATION: As generally implemented, the CLIP intervention did not improve pregnancy outcomes; community implementation of the WHO eight contact model may be beneficial. FUNDING: The University of British Columbia (PRE-EMPT), a grantee of the Bill & Melinda Gates Foundation (OPP1017337).

Temporal and external validation of the fullPIERS model for the prediction of adverse maternal outcomes in women with pre-eclampsia.

The fullPIERS model is a risk prediction model developed to predict adverse maternal outcomes within 48 h for women admitted with pre-eclampsia. External validation of the model is required before implementation for clinical use. We assessed the temporal and external validity of the fullPIERS model in high income settings using five cohorts collected between 2003 and 2016, from tertiary hospitals in Canada, the United States of America, Finland and the United Kingdom. The cohorts were grouped into three datasets for assessing the primary external, and temporal validity, and broader transportability of the model. The predicted risks of developing an adverse maternal outcome were calculated using the model equation and model performance was evaluated based on discrimination, calibration, and stratification. Our study included a total of 2429 women, with an adverse maternal outcome rate of 6.7%, 6.6%, and 7.0% in the primary external, temporal, and combined (broader) validation cohorts, respectively. The model had good discrimination in all datasets: 0.81 (95%CI 0.75-0.86), 0.82 (95%CI 0.76-0.87), and 0.75 (95%CI 0.71-0.80) for the primary external, temporal, and broader validation datasets, respectively. Calibration was best for the temporal cohort but poor in the broader validation dataset. The likelihood ratios estimated to rule in adverse maternal outcomes were high at a cut-off of ≥30% in all datasets. The fullPIERS model is temporally and externally valid and will be useful in the management of women with pre-eclampsia in high income settings although model recalibration is required to improve performance, specifically in the broader healthcare settings.

Development and internal validation of the multivariable CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) clinical risk prediction model.

BACKGROUND: Intensive care unit (ICU) outcome prediction models, such as Acute Physiology And Chronic Health Evaluation (APACHE), were designed in general critical care populations and their use in obstetric populations is contentious. The aim of the CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) study was to develop and internally validate a multivariable prognostic model calibrated specifically for pregnant or recently delivered women admitted for critical care. METHODS: A retrospective observational cohort was created for this study from 13 tertiary facilities across five high-income and six low- or middle-income countries. Women admitted to an ICU for more than 24 h during pregnancy or less than 6 weeks post-partum from 2000 to 2012 were included in the cohort. A composite primary outcome was defined as maternal death or need for organ support for more than 7 days or acute life-saving intervention. Model development involved selection of candidate predictor variables based on prior evidence of effect, availability across study sites, and use of LASSO (Least Absolute Shrinkage and Selection Operator) model building after multiple imputation using chained equations to address missing data for variable selection. The final model was estimated using multivariable logistic regression. Internal validation was completed using bootstrapping to correct for optimism in model performance measures of discrimination and calibration. RESULTS: Overall, 127 out of 769 (16.5%) women experienced an adverse outcome. Predictors included in the final CIPHER model were maternal age, surgery in the preceding 24 h, systolic blood pressure, Glasgow Coma Scale score, serum sodium, serum potassium, activated partial thromboplastin time, arterial blood gas (ABG) pH, serum creatinine, and serum bilirubin. After internal validation, the model maintained excellent discrimination (area under the curve of the receiver operating characteristic (AUROC) 0.82, 95% confidence interval (CI) 0.81 to 0.84) and good calibration (slope of 0.92, 95% CI 0.91 to 0.92 and intercept of -0.11, 95% CI -0.13 to -0.08). CONCLUSIONS: The CIPHER model has the potential to be a pragmatic risk prediction tool. CIPHER can identify critically ill pregnant women at highest risk for adverse outcomes, inform counseling of patients about risk, and facilitate bench-marking of outcomes between centers by adjusting for baseline risk.

Evaluation of cardiac modulation in children in response to apnea/hypopnea using the Phone Oximeter(™).

Individuals with sleep disordered breathing (SDB) can experience changes in automatic cardiac regulation as a result of frequent sleep fragmentation and disturbance in normal respiration and oxygenation that accompany most apnea/hypopnea events. In adults, these changes are reflected in enhanced sympathetic and reduced parasympathetic activity. In this study, we examined the autonomic cardiac regulation in children with and without SDB, through spectral and detrended fluctuation analysis (DFA) of pulse rate variability (PRV). PRV was measured from pulse-to-pulse intervals (PPIs) of the photoplethysmogram (PPG) recorded from 160 children using the Phone Oximeter(™) in the standard setting of overnight polysomnography. Spectral analysis of PRV showed the cardiac parasympathetic index (high frequency, HF) was lower (p < 0.01) and cardiac sympathetic indices (low frequency, LF and LF/HF ratio) were higher (p < 0.01) during apnea/hypopnea events for more than 95% of children with SDB. DFA showed the short- and long-range fluctuations of heart rate were more strongly correlated in children with SDB compared to children without SDB. These findings confirm that the analysis of the PPG recorded using the Phone Oximeter(™) could be the basis for a new screening tool for assessing PRV in non-clinical environment.

Assessing the incremental value of blood oxygen saturation (SpO(2)) in the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) Risk Prediction Model.

OBJECTIVE: To assess the incremental value of blood oxygen saturation (SpO(2)) as a predictor in the miniPIERS model, a risk prediction model for adverse outcomes among women with a diagnosis of hypertensive disorder of pregnancy (HDP) in low-resourced settings. METHODS: Using data from a prospective cohort including 852 women admitted to hospital for a HDP, the association between SpO(2) and adverse maternal outcome was assessed using logistic regression. The miniPIERS model was recalibrated and extended to include SpO(2). The incremental value of adding SpO(2) to the model was measured using a net reclassification index (NRI), sensitivity, specificity, positive and negative predictive values, and likelihood ratios. RESULTS: SpO(2) of < 93% was associated with a 30-fold increase in risk (95% CI 14 to 68) of adverse maternal outcome compared to women with SpO(2) > 97%. After recalibration and extension, the miniPIERS model including SpO(2) (vs. not including SpO(2)) had improved sensitivity (32.8% vs. 49.6%) at the cost of minimally decreased specificity (91.5% vs. 96.2%) with a NRI of 0.122. CONCLUSION: SpO(2) is a significant independent predictor of risk in women with a HDP. Adding SpO(2) to the miniPIERS model improved the model's ability to correctly identify high-risk patients who would benefit most from interventions.

Objectif : Évaluer la valeur cumulative de la saturation en oxygène (SaO2) à titre de facteur prédictif dans le cadre du modèle miniPIERS, soit un modèle de prévision des risques en ce qui concerne les issues indésirables chez les femmes ayant obtenu un diagnostic de trouble hypertensif de la grossesse (THG) dans des milieux qui ne disposent que de faibles ressources. Méthodes : Grâce à des données issues d'une cohorte prospective ayant porté sur 852 femmes hospitalisées en raison d'un THG, l'association entre la SaO2 et les issues indésirables maternelles a été évaluée au moyen d'une régression logistique. Le modèle miniPIERS a été recalibré et élargi de façon à inclure la SaO2. La valeur cumulative de l'ajout de la SaO2 à ce modèle a été mesurée en ayant recours à l'indice NRI (net reclassification index), à la sensibilité, à la spécificité, aux coefficients de prévision d'un test positif et d'un test négatif et aux rapports de vraisemblance. Résultats : La SaO2 < 93 % a été associée à un risque 30 fois plus élevé (IC à 95 %, 14 - 68) de constater une issue maternelle indésirable, par comparaison avec une SaO2 > 97 %. Après avoir été recalibré et élargi, le modèle miniPIERS comprenant la SaO2 (par comparaison avec le modèle ne comprenant pas la SaO2) présentait une sensibilité améliorée (32,8 % vs 49,6 %); cela a toutefois mené à une baisse minime de la spécificité (91,5 % vs 96,2 %) en présence d'un indice NRI de 0,122. Conclusion : La SaO2 constitue un facteur prédictif indépendant significatif pour ce qui est du risque auquel sont exposées les femmes qui présentent un THG. L'ajout de la SaO2 au modèle miniPIERS a mené à l'amélioration de la capacité de ce dernier à identifier correctement les patientes exposées à des risques élevés qui tireraient le plus avantage de la tenue d'interventions.

Pharmacodynamic modeling of propofol-induced tidal volume depression in children.

OBJECTIVE: This investigation aimed to develop a pediatric pharmacodynamic model of propofol-induced tidal volume depression towards an ultimate goal of developing a dosing schedule that would preserve spontaneous breathing following a loading dose of propofol. METHODS: Fifty two ASA 1 and 2 children aged 6-15 year presenting for gastrointestinal endoscopy were enrolled. Subjects were administered a loading dose of 4 mg/kg of propofol intravenously at a constant infusion rate determined by a randomization schedule. Respiratory parameters including tidal volume, respiratory rate, minute volume, and end-tidal CO(2) were recorded at 5 s intervals. Using the predicted plasma concentration, based on the Paedfusor pharmacokinetic model, propofol-induced tidal volume depression was modeled by 3 different approaches (2-stage, pooled, and mixed effects) and results were compared using prediction residual, median percentage errors, median absolute percentage errors, and root-mean-squared normalized errors. The effects of age and body weight as covariates were examined. RESULTS: Respiratory rate and end-tidal CO(2) did not show clear dependence on the predicted plasma concentration. The pharmacodynamic models for tidal volume derived from different modeling approaches were highly consistent. The 2-stage, pooled, and mixed effects approaches yielded k(e0) of 1.06, 1.24, and 0.72 min(-1); γ of 1.10, 0.83, and 0.93; EC50 of 3.18, 3.44, and 3.00 mcg/ml. Including age and body weight as covariates did not significantly improve the predictive performance of the models. CONCLUSIONS: A pediatric pharmacodynamic model of propofol-induced tidal volume depression was developed. Models derived from 3 different approaches were shown to be consistent with each other; however, the individual pharmacodynamic parameters exhibited significant inter-individual variability without strong dependence on age and body weight. This would suggest the desirability of adapting the pharmacodynamic model to each subject in real time.

PIERS proteinuria: relationship with adverse maternal and perinatal outcome.

OBJECTIVE: To examine the ability of three different proteinuria assessment methods (urinary dipstick, spot urine protein:creatinine ratio [Pr/Cr], and 24-hour urine collection) to predict adverse pregnancy outcomes. METHODS: We performed a prospective multicentre cohort study, PIERS (Preeclampsia Integrated Estimate of RiSk), in seven academic tertiary maternity centres practising expectant management of preeclampsia remote from term in Canada, New Zealand, and Australia. Eligible women were those admitted with preeclampsia who had at least one antenatal proteinuria assessment by urinary dipstick, spot urine Pr/Cr ratio, and/or 24-hour urine collection. Proteinuria assessment was done either visually at the bedside (by dipstick) or by hospital clinical laboratories for spot urine Pr/Cr and 24-hour urine collection. We calculated receiver operating characteristic area under the curve (95% CI) for each proteinuria method and each of the combined adverse maternal outcomes (within 48 hours) or adverse perinatal outcomes (at any time). Models with AUC ≥ 0.70 were considered of interest. Analyses were run for all women who had each type of proteinuria assessment and for a cohort of women ("ALL measures") who had all three proteinuria assessments. RESULTS: More women were proteinuric by urinary dipstick (≥ 2+, 61.4%) than by spot urine Pr/Cr (≥ 30 g/mol, 50.4%) or 24-hour urine collection (≥ 0.3g/d, 34.7%). Each proteinuria measure evaluated had some discriminative power, and dipstick proteinuria (categorical) performed as well as other methods. No single method was predictive of adverse perinatal outcome. CONCLUSION: The measured amount of proteinuria should not be used in isolation for decision-making in women with preeclampsia. Dipstick proteinuria performs as well as other methods of assessing proteinuria for prediction of adverse events.

Slower administration of propofol preserves adequate respiration in children.

BACKGROUND: Propofol is a versatile anesthetic agent used in pediatric practice to facilitate investigational and interventional procedures. Propofol can cause significant respiratory depression, the management of which may require advanced airway management skills. This investigation aimed to increase the safety of propofol administration by developing a dosing schedule that would preserve spontaneous respiration in at least 95% of subjects. METHODS: With Research Ethics Board approval and informed consent, American Society of Anesthesiologists' Status I and II children aged 6-15 years presenting for upper or lower gastrointestinal endoscopy were enrolled. An intravenous loading dose of propofol (4 mg·kg(-1) ) was administered at a rate determined by a randomization schedule in a two-phased study. Following the loading dose, additional propofol was infused at 200 mcg·kg(-1) ·min(-1) for 5 min or until respiratory insufficiency was observed. In Phase I, the infusion rate was modified by 100 mcg·kg(-1) ·min(-1) increments depending upon the respiratory response of the previous subject. In Phase II, the duration of infusion was randomized according to a Biased Coin Design principle to determine the 95% threshold for respiratory insufficiency. RESULTS: Fifty subjects were included in the analysis. Infusion rates ranged from 1000 to 2300 mcg·kg(-1) ·min(-1) . Seven subjects experienced respiratory insufficiency. The mean (sd) time to respiratory insufficiency was 104 (36) s and duration was 93 (51) s. A propofol loading dose administered over 3.0 min (CI = 1.9-3.4 min) maintained spontaneous respiration in 95% of subjects. CONCLUSIONS: The respiratory response to propofol is highly variable in children. Slower infusion of propofol will result in a lower risk of respiratory depression.

Comparison between a dorsal and a belt tactile display prototype for decoding physiological events in the operating room.

OBJECTIVE: Vibrotactile display technology represents an innovative method to communicate vital information on patients from physiological monitoring devices to clinicians. The increasing number of sensors used in clinical practice has increased the amount of information required to be communicated, overwhelming the capacity of visual and auditory displays. The capacity to communicate could be increased with the use of a tactile display. In this study, we have compared a dorsal (DTD) and belt tactile (TB) display prototype in terms of learnability, error rate, and efficiency. METHODS: We conducted a prospective randomized preclinical study with non-clinicians in a simulated clinical setting to compare the two tactile display prototypes. Information encoded in the tactile message included the type of physiological parameter monitored, the direction of change, and the magnitude of change. Following a period of training, 24 alerts were repeated three times for each display in random order. Each subject evaluated each display. Experiments were repeated with the addition of a distraction task. RESULTS: DTD stimuli were easier to learn (52 trials compared to 101 trials; P = 0.0003), but the accuracy in decoding following training did not differ between the two prototypes. The DTD took longer to display the information, resulting in a faster TB response time (start of stimulus to response; 9.3 +/- 1.4 s [mean +/- SD] vs. DTD, 10.0 +/- 1.4 s; F[1,27] = 4.66; P = 0.04). However, the DTD had a faster response interval (end of stimulus to response) compared to the TB (5.6 +/- 1.4 s vs. 8.0 +/- 1.4 s; F[1,27] = 47.91; P < 0.0001). Compared to the TB, performance was affected less by distraction with the DTD. CONCLUSIONS: The communication of information on physiological parameters by tactile displays was easy to learn and accurate for both prototypes. The DTD was easier to learn and affected less by distraction. Further evaluation is required in a clinical setting with expert users to determine the clinical applicability of these prototypes.

A Wavelet Approach to Detecting Electrocautery Noise in the ECG.

A software approach has been developed for detecting electrocautery noise in the electrocardiogram (ECG) using a wavelet decomposition of the signal. With this approach, a clinical monitoring expert system can be forewarned of potential artefacts in trend values derived from the ECG, allowing it to proceed with caution when making decisions based on these trends. In 15 operations spanning 38.5 hours of ECG data, we achieved a false positive rate of 0.71% and a false negative rate of 0.33%. While existing hardware approaches detect the source of the noise without any ability to assess its impact on the measured ECG, our software approach detects only the presence of noise in the signal itself. Furthermore, the software approach is cheaper and easier to implement in a clinical environment than existing hardware approaches.

Adaptive change point detection for respiratory variables.

Current alarm strategies for physiological monitoring depend on predetermined thresholds without consideration for the heterogeneity between patients or intraoperative variations. To improve upon this situation, we developed an adaptive change point detection scheme to automatically notify the clinician when a change of clinical significance has occurred in the respiratory variables. We modeled End-Tidal Carbon Dioxide, Expiratory Minute Volume, and Respiratory Rate using a dynamic linear growth model, whose noise covariances are estimated by an adaptive Kalman filter based on a recursive Expectation-Maximization method. Change points are detected by the CUSUM testing. The comparison of the results with post-hoc expert annotations demonstrates that the algorithm can accurately detect relevant changes in the respiratory signals.

A Wavelet Approach to Detecting Electrocautery Noise in the ECG.

A software approach has been developed for detecting electrocautery noise in the electrocardiogram (ECG) using a wavelet decomposition of the signal. With this approach, a clinical monitoring expert system can be forewarned of potential artefacts in trend values derived from the ECG, allowing it to proceed with caution when making decisions based on these trends. In 15 operations spanning 38.5 hours of ECG data, we achieved a false positive rate of 0.71% and a false negative rate of 0.33%. While existing hardware approaches detect the source of the noise without any ability to assess its impact on the measured ECG, our software approach detects only the presence of noise in the signal itself. Furthermore, the software approach is cheaper and easier to implement in a clinical environment than existing hardware approaches.