Too little, too late : the recurrent theme in maternal deaths due to sepsis

BACKGROUND : Maternal sepsis accounts for 11% of direct obstetric deaths, making it the third commonest cause of death, after obstetric hemorrhage and hypertensive disorders. OBJECTIVE : To evaluate the risk factors and quality of care for maternal deaths due to sepsis. METHODS : Detailed secondary file review for all maternal deaths classified as pregnancy-related sepsis in South Africa between 2014-2016 and comparison of management with the Surviving Sepsis guidelines. RESULTS : There were 158 maternal deaths from sepsis. The postpartum period carried the greatest risk (94% of deaths), especially after caesarean delivery (50%). Adequate fluid resuscitation was done in only 25 cases (16%) and initiation of empiric antibiotics was often delayed (48% of those receiving antibiotics). Only 28% of women with possible source of infection in the uterus had a hysterectomy (39 cases). CONCLUSION : Healthcare professionals often underestimate the severity of maternal sepsis and poorly adhere to treatment guidelines.http://www.journals.co.za/content/journal/medogam2019Obstetrics and Gynaecolog

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Frequency and management of maternal infection in health facilities in 52 countries (GLOSS): a 1-week inception cohort study

Background Maternal infections are an important cause of maternal mortality and severe maternal morbidity. We report the main findings of the WHO Global Maternal Sepsis Study, which aimed to assess the frequency of maternal infections in health facilities, according to maternal characteristics and outcomes, and coverage of core practices for early identification and management. Methods We did a facility-based, prospective, 1-week inception cohort study in 713 health facilities providing obstetric, midwifery, or abortion care, or where women could be admitted because of complications of pregnancy, childbirth, post-partum, or post-abortion, in 52 low-income and middle-income countries (LMICs) and high-income countries (HICs). We obtained data from hospital records for all pregnant or recently pregnant women hospitalised with suspected or confirmed infection. We calculated ratios of infection and infection-related severe maternal outcomes (ie, death or near-miss) per 1000 livebirths and the proportion of intrahospital fatalities across country income groups, as well as the distribution of demographic, obstetric, clinical characteristics and outcomes, and coverage of a set of core practices for identification and management across infection severity groups. Findings Between Nov 28, 2017, and Dec 4, 2017, of 2965 women assessed for eligibility, 2850 pregnant or recently pregnant women with suspected or confirmed infection were included. 70·4 (95% CI 67·7–73·1) hospitalised women per 1000 livebirths had a maternal infection, and 10·9 (9·8–12·0) women per 1000 livebirths presented with infection-related (underlying or contributing cause) severe maternal outcomes. Highest ratios were observed in LMICs and the lowest in HICs. The proportion of intrahospital fatalities was 6·8% among women with severe maternal outcomes, with the highest proportion in low-income countries. Infection-related maternal deaths represented more than half of the intrahospital deaths. Around two-thirds (63·9%, n=1821) of the women had a complete set of vital signs recorded, or received antimicrobials the day of suspicion or diagnosis of the infection (70·2%, n=1875), without marked differences across severity groups. Interpretation The frequency of maternal infections requiring management in health facilities is high. Our results suggest that contribution of direct (obstetric) and indirect (non-obstetric) infections to overall maternal deaths is greater than previously thought. Improvement of early identification is urgently needed, as well as prompt management of women with infections in health facilities by implementing effective evidence-based practices