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Background:Obstetric hemorrhage is the leading cause of maternal mortality. Using a cluster randomized design, we investigated whether application of the Non-pneumatic Anti-Shock Garment (NASG) before transport to referral hospitals (RHs) from primary health care centers (PHCs) decreased adverse outcomes among women with hypovolemic shock. We hypothesized the NASG group would have a 50% reduction in adverse outcomes.Methods and Findings:We randomly assigned 38 PHCs in Zambia and Zimbabwe to standard obstetric hemorrhage/shock protocols or the same protocols plus NASG prior to transport. All women received the NASG at the RH. The primary outcomes were maternal mortality; severe, end-organ failure maternal morbidity; and a composite mortality/morbidity outcome, which we labeled extreme adverse outcome (EAO). We also examined whether the NASG contributed to negative side effects and secondary outcomes. The sample size for statistical power was not reached; of a planned 2400 women, 880 were enrolled, 405 in the intervention group. The intervention was associated with a non-significant 46% reduced odds of mortality (OR 0.54, 95% CI 0.14-2.05, p = 0.37) and 54% reduction in composite EAO (OR 0.46, 95% CI 0.13-1.62, p = 0.22). Women with NASGs recovered from shock significantly faster (HR 1.25, 95% CI 1.02-1.52, p = 0.03). No differences were observed in secondary outcomes or negative effects. The main limitation was small sample size.Conclusions:Despite a lack of statistical significance, the 54% reduced odds of EAO and the significantly faster shock recovery suggest there might be treatment benefits from earlier application of the NASG for women experiencing delays obtaining definitive treatment for hypovolemic shock. As there are no other tools for shock management outside of referral facilities, and no safety issues found, consideration of NASGs as a temporizing measure during delays may be warranted. A pragmatic study with rigorous evaluation is suggested for further research.Trial Registration:ClinicalTrials.gov NCT00488462. © 2013 Miller et al.
Institutional review boards affiliated with the following institutions reviewed and approved study protocols and the informed consent document and process: University of California, San Francisco (UCSF); University of Zambia, Lusaka; University of Zimbabwe-UCSF Collaborative Programme on Health Research; and the Department of Reproductive Health and Research of the World Health Organization. Written informed consent (signature from literate participants and thumb print from those who could not sign) was obtained from all study participants who were conscious and able to give consent. All ethics committees approved a waiver of consent for unconscious women; written consent for an unconscious woman was either obtained from a relative and/or the patient after she regained consciousness. No data were entered for data collection forms that were not accompanied by a signed consent form. Figure 1, a photograph of a model in an NASG, was not taken during the study, but is a similar image used for illustrative purposes only. The subject of the photograph has given written informed consent, as outlined in the PLOS consent form, to publication of her photograph. To test the efficacy and safety of the NASG, a cluster randomized control trial (CRCT) with PHCs as the cluster units was conducted in 38 PHCs referring to one of five Referral Hospitals (RHs) in Harare, Zimbabwe, and Lusaka and the Copperbelt Province, Zambia. (The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.) We chose a cluster randomized design because it is impossible to blind providers to the intervention or to develop a placebo garment. Furthermore, it is difficult to require providers to randomize individual patients once they have had the opportunity to use the NASG and see the apparent results (decreased bleeding and improved vital signs). The University of California, San Francisco (UCSF), University of Zambia, Lusaka, and University of Zimbabwe-UCSF Collaborative Programme on Health Research, Harare, conducted the study. The Department of Reproductive Health and Research of the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) served as the Data Coordinating Center (DCC). The Institute for Clinical Effectiveness and Health Policy (IECS), Buenos Aires, Argentina, conducted data monitoring and analysis. All institutional review boards/ethical committees approved the protocols. Because the sites were research naïve, lacked baseline data, and clinicians were unfamiliar with NASGs, the study was implemented in three phases. Although the timelines were slightly different, all sites conducted each phase. The first phase, 2007–2008, was an 11-month preparatory phase, to familiarize the clinicians/data collectors with accurate form completion and adherence to standardized protocols. In the second phase, 10 months in 2008–2009, we implemented the NASG at the RHs, to give clinicians experience with it and to collect baseline outcome data. In the final phase, 2009–2012, the PHCs were randomized and NASGs implemented in the intervention group. Based on baseline data, a covariate-constrained randomization procedure was used to ensure that intervention and control PHCs were balanced on number of deliveries, number of deliveries per midwife, distance to the RH, and proportion of OH cases expected [28]. The DCC allocated the PHCs to intervention or control group; allocation assignment was known by PHC staff and health authorities, but not by women in the PHC catchment communities. Because the NASG is visible, blinding of participants and clinicians/data collectors was impossible; the UCSF research team was blind to outcomes. Eligible PHCs were peri-urban, had at least 500 annual deliveries conducted by midwives, and referred OH cases (≥500 mL blood loss by visual estimation) to one of five study RHs. Lusaka and Harare began in 2007; the Copperbelt Province was added in 2008. PHCs each covered the public assistance population in a given geographic catchment area. All PHCs had a maternity department, where midwives attended deliveries; any woman >24 weeks gestation with bleeding would be seen in the maternity department. Midwives were trained to provide prophylactic uterotonics, treat PPH with uterotonics and IV fluids, repair first- and second-degree perineal lacerations, and refer any patient with estimated blood loss ≥500 mL to the RH. Women with early pregnancy bleeding of <24 weeks gestation (ectopic pregnancy, complications of abortion, trophoblastic/molar pregnancy) were seen in the outpatient department by either midwives or clinical officers; these women in early pregnancy were also referred to the RH for bleeding ≥500 mL. No PHC was equipped to provide blood transfusion, surgery, or manual vacuum aspiration (MVA). All PHCs had access to a shared ambulance dispatch system to request ambulance transfer for their patients to the designated RH. Participants were included in a cluster if they sought maternity care in a study PHC in their neighborhood. Participants were women with OH from any etiology and hypovolemic shock, with at least two of the following eligibility criteria: visually estimated blood loss ≥500 mL, pulse ≥100 BPM, systolic blood pressure ≤100 mm Hg. Women with antepartum hemorrhage were excluded if the fetus was viable. Participants were consented when they became eligible, if they were conscious and able to give consent. All ethics committees approved waiver of consent for unconscious women; consent for an unconscious women was either obtained from a relative and/or the patient after she regained consciousness. The main intervention was applying the NASG first-aid compression device (Zoex, Colma, CA, USA). The NASG was rapidly applied, sequentially starting at the ankles, as the first step in shock resuscitation, and an absorbent perineal pad (Stay Dry Briefs, McKesson, San Francisco, CA, USA) was applied for blood loss measurement. Control group patients also had absorbent perineal pads applied at study entry. Both groups received the same hemorrhage/hypovolemic shock protocol: intravenous (IV) fluids, uterotonics and uterine massage (for uterine atony), and suturing of first- and second-degree lacerations. Women in the control arm also received the NASG upon RH arrival; those in the intervention arm remained in the NASG. The rationale for giving all women in the study the NASG at the RH was a) by the start of the RCT in 2009, the RHs were using the NASG on OH patients in the facility, b) the providers would find it difficult to refrain from applying the NASG after seeing the benefits at the RH level, and c) the goal of the study was to determine the efficacy when applied earlier in the OH/shock trajectory. All women received standard shock/hemorrhage protocol: oxygen, IV fluids, uterotonics/uterine massage (for uterine atony), suturing of lacerations, manual removal of placenta or retained tissues, MVA, surgery, and blood transfusion, as necessary. The only differences in treatment received depended on hemorrhage etiologies, e.g. ruptured ectopic pregnancies required surgery. Upon RH arrival, all women had absorbent pads removed and weighed to determine blood loss during transport and had a calibrated blood measurement drape (Brass V Drape, Excellent Fixable Drapes, Madurai, India) placed. Staff at the RH removed the NASG when both criteria were met: the patient’s bleeding decreased to <50 mL per hour and the pulse was <100 BPM for two hours. Removal was incremental, beginning at the NASG ankle segments; vital signs were monitored for fifteen minutes to ensure hemodynamic stability before proceeding to subsequent segments. Data collected included reason for patient admission, age, gravidity, parity, weeks gestation, delivery information, prophylactic uterotonics, time hemorrhage started, treatment uterotonics, IV fluids, blood transfusions, and hemostatic procedures and/or surgeries. Blood loss in the drape and urine output in urine collection bags were recorded hourly, and vital signs were recorded every 15 minutes from study entry to NASG removal. Mean Arterial Pressure (MAP) <60 mmHg, ([(2 × diastolic)+systolic]/3), defined more serious shock [29]. Mortality, morbidities, diagnosis, and negative side effects that could potentially be attributed to the NASG (respiratory distress, reduced urine output, nausea, vomiting, abdominal pain) were recorded. In-facility clinicians/data collectors or study-funded midwives (when available) recorded data. Data forms were reviewed by study coordinators and checked against medical records to resolve inconsistencies. Annually, a random sample of 10% of data forms was checked against medical records to confirm accuracy. Data were double-entered in OpenClinica (Akaza Research, Waltham, MA, USA), queried and cleaned, and analyzed using SAS (SAS Institute, Cary, NC, USA) and STATA (STATA Corp, College Station, TX, USA). The primary outcomes of the trial were the frequency of maternal mortality; survival with severe maternal morbidity; and extreme adverse outcome (EAO), a composite outcome of the two. Mortality was defined as dying before hospital discharge, as women were not followed up after discharge. Severe morbidity was defined as end-organ failure (cardiac, pulmonary, renal, cerebral) persisting 24 hours or more beyond shock resuscitation [30]. Patients who were lost to follow-up between the PHC and the RH were tracked to determine if there were outcome data on mortality. (See Text S1 for a detailed description of the lost to follow-up protocol). Secondary outcomes included median blood loss measured by weighing the absorbent pad(s) upon RH admission; blood loss measured in the drape at the RH; blood loss during surgery; frequency of emergency hysterectomy for intractable uterine atony; and time to recovery from shock, defined as return to Shock Index (SI) <0.98 (SI = Heart Rate/Systolic Blood Pressure) [31]. Negative effects that might be attributable to the NASG included decreased urine output, respiratory difficulties, nausea, vomiting, and abdominal pain. Co-interventions included: IV fluids, blood transfusions, receipt of the NASG at the RH, and duration of NASG use. Sample size was estimated in Acluster (Metaxis, Inc., Vista, CA) using the incidence rate of the primary composite EAO, based on an NASG pilot study conducted in Nigeria in 2005 (9% incidence, 50% effect size reduction) [32]. A sample size of 2400 women was calculated based on a reduction in incidence of EAO from 9.0% to 4.5% in EAOs at 20 clinics, of varying sizes, 80% power, two-sided type 1 error rate of 5%, and an intra-cluster correlation coefficient of 0.01 [33]. Achieving this target required enrolling approximately 3.3 women per clinic per month over 3 years, which we felt was possible based on an assessment of delivery rates and reported OH rates in Harare and Lusaka conducted while writing the proposal. Initially, 12 clusters in Lusaka and 12 clusters in Harare were included with a planned enrollment period of three years. During the baseline period, an additional 14 clusters in the Copperbelt Province, Zambia were added in 2008 because the accrual rate was lower than expected, mainly due to lower than expected incidence of OH/shock and lower incidence of EAOs (5%). In 2008, prior to randomization, the Data Safety and Monitoring Board (DSMB) reviewed the enrollment and outcome rates from the baseline data collection phase and they changed the sample size target to 1944 women. The DSMB performed power calculations in April 2011 and February 2012. In both instances the DSMB noted that accrual was low, but recommended continuing the study and either increasing clusters or extending enrollment. However we were unable to secure additional funding; enrollment ended May 2012, approximately 30 months post-randomization. We undertook intention-to-treat analyses to compare treatment groups with a pretest-posttest design, where the outcome rates were measured at the cluster level prior to random assignment and again after randomization and implementation of intervention. As pre-specified in the protocol, two sets of analyses were conducted, both accounting for the cluster randomized study design: a) post-test observations only and b) post-test observations adjusted for baseline measurements. We estimated random effects logistic regression models for binary outcomes. To adjust for the outcome measurements at baseline, we included the logit of the cluster specific outcome rate as a covariate [34]. Diagnosis was entered in the regression model to adjust for an imbalance among participants recruited after randomization. The effect size was reported as OR with 95% CIs. For continuous outcomes, a random effects linear regression model was estimated. Measured blood loss values were transformed into the log metric for normality, and the ratio of the geometric mean and its 95% CI were reported. To compare SI recovery trajectories, Cox regression models were estimated to evaluate group differences accounting for study design effects by including a working correlation matrix to adjust the standard errors. Statistical tests were 2-sided and performed at the 5% significance level. This study is registered with ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00488462","term_id":"NCT00488462"}}NCT00488462.
