Community Level Interventions for Pre-eclampsia (CLIP)

• ClinicalTrials.gov Identifier: NCT01911494
• Recruitment Status: Completed
• First Posted: July 30, 2013
• Last Update Posted: June 27, 2019
• Sponsor: University of British Columbia
• Collaborators: Bill and Melinda Gates Foundation; Olabisi Onabanjo University; Centro de Investigacao em Saude de Manhica; Aga Khan University; Jawaharlal Nehru Medical College
• Information provided by (Responsible Party): Peter von Dadelszen, University of British Columbia

Study Description

Brief Summary:

This project is being undertaken to test the hypothesis that implementing a community based package of care for women with hypertensive disorders of pregnancy will result in overall improvement in maternal and neonatal outcomes. This is based on the premise that there are three main modifiable reasons why women (and their fetuses/newborns) die due to pregnancy complications: 1) delays by the woman herself in recognizing the seriousness of her condition; 2) delays in her being assessed and then transported to a center capable of providing effective and life-saving interventions; and 3) delays in the health facility in providing those interventions. The treatments for pre-eclampsia that are poorly accessed in LMIC are 1) magnesium sulfate (MgSO4) for prevention and treatment of the grand mal seizures of eclampsia; 2) oral antihypertensive medication to lower maternal BP to reduce the risk of stroke.

The CLIP pilot and definitive cRCT will investigate whether the community level intervention including implementation of the CLIP package (oral antihypertensive therapy when indicated, intramuscular (i.m.) MgSO4 when indicated; and appropriate referral to an CEmOC facility when indicated) of care will reduce the incidence of all-cause maternal morbidity and mortality.

Condition or disease	Intervention/treatment	Phase
Pre-eclampsia; Hypertension, Pregnancy Induced	Behavioral: Community Engagement; Device: PIERS on the Move mHealth decision aid; Drug: Magnesium Sulfate; Drug: Methyldopa	Not Applicable

Detailed Description:

We have designed a two-phased community (including PHC-level) cRCT encompassing both rural and urban settings to be fully powered in each of:

• Ogun State, Nigeria
• Maputo and Gaza Province, Mozambique
• Hyderabad and Matiari districts in Sindh Province, Pakistan.
• Belgaum and Bagalkot districts in Karnataka State, India The trial will be phased from the Pilot CLIP trial to Definitive CLIP trial on the basis of a satisfactory rate of use (≥50%) of the CLIP 'package of care' in appropriate women in all countries but Mozambique. Mozambique will be unique in that they will rely on an extended period of feasibility to pilot test all Trial systems and tools before directly beginning a definitive trial. Foregoing the Pilot in Mozambique was felt to be appropriate based on their experience with community-based surveillance and will ensure timelines of the trial are met within a manageable budget.

For all other countries, use of the package in the Pilot phase will be defined as appropriate referral (urgent or non-urgent) to a facility able to provide comprehensive emergency obstetric care (CEmOC) in appropriate women during the first six months of the Pilot CLIP trial.

A primary component of the CLIP intervention is antenatal risk assessment guided by the PIERS on teh Move mHealth decision aid. The CLIP version of the PIERS on the Move tool (CLIP POM) integrates the miniPIERS predictive score and a clinical data collection system into a single application. Community health workers in each country will assess women according to the visit protocol, entering clinical data into the CLIP POM mobile application. The application will provide recommendations for care according to meeting one of the trigger events listed below, as per this protocol. Triggers identified that will indicate treatment and/or transport (urgently, defined as within 4hrs) to a CEmOC facility are as follows:

1. Unconsciousness (MgSO4 if sBP ≥160 mmHg [to be reasonably sure that the unconsciousness is associated with severe pre-eclampsia and not due to obstetric sepsis], urgent transport)
2. Signs of recent stroke or seizure (methyldopa if sBP ≥160 mmHg [to ensure BP is not lowered too much], MgSO4, urgent transport)
3. Significant vaginal bleeding (MgSO4 if sBP ≥140 mmHg [presumed abruption associated with severe pre-eclampsia], urgent transport).
4. No fetal movements felt in the previous 12 hrs (urgent transport [a threshold for identifying at risk fetuses that are alive at the time of screening] 39)
5. sBP ≥160 mmHg (or dBP ≥ 110 mmHg in Nigeria only) (methyldopa, MgSO4, urgent transport [consistent with severe pre-eclampsia])
6. Heavy proteinuria (≥4+ by dipstick - predictive of stillbirth in miniPIERS cohort, urgent transport)
7. miniPIERS predicted probability ≥25% (MgSO4, urgent transport)
8. Shock index >1.7 in Nigeria only (the Shock index is a ratio of pulse/sBP; high shock index is an indication of poor prognosis in women with postpartum haemorrhage) Non-urgent transport (by non-ambulance services), meaning assessment at a CEmOC facility within 24 hours, will be advised for all women with non-severe hypertension (sBP 140-159 mmHg) who do not meet criteria for one of the above 7/8 triggers.

In Mozambique and Pakistan additional CLIP triggers based on use of the audio oximeter will also be included in the POM decision aid. As with the original miniPIERS model, the enhanced model including SpO2 uses a risk threshold of ≥25% predicted probability to identify high-risk cases. Recommendations based on the updated miniPIERS model will include treatment with MgSO4 and urgent referral. An additional independent trigger of SpO2<93% will also be used in Mozambique and Pakistan to indicate urgent referral.

In Nigeria where the updated Microlife CRADLE VSA blood pressure device is being used additional triggers will be included for severe diastolic blood pressure or severe shock index to coincide with the traffic light warning signs included in this device.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 87500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: The CLIP (Community Level Interventions for Pre-eclampsia) Cluster Randomized Controlled Trial
• Study Start Date: September 2013
• Actual Primary Completion Date: May 2018
• Actual Study Completion Date: June 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intervention; The CLIP intervention consists of (i) community engagement including community leaders, the women of the communities themselves, and their mothers, husbands, and mothers-in-law, regarding pre-eclampsia, its origins, symptoms, signs, and potential consequences, pre-permissions for maternal transport, and fundraising activities around transport and treatment costs; (ii) provision of HDP oriented antenatal care through CLIP visits and use of CLIP "PIERS on the Move" mHealth tool (for risk stratification), and (iii) use of the CLIP package for women with a CLIP 'trigger' (i.e., oral antihypertensive therapy (methyldopa) when indicated, intramuscular (i.m.) magnesium sulfate when indicated; and appropriate referral to an CEmOC facility when indicated)	Behavioral: Community Engagement; The primary objective of the community engagement activities in CLIP will be to create awareness and action around the prevention of maternal morbidity and mortality due to pre-eclampsia/eclampsia. Community engagement involves the collective action of individuals, families, religious leaders, policy makers,; Device: PIERS on the Move mHealth decision aid; This mHealth application is to be used by community health workers in intervention clusters to guide collection of relevant clinical data during antenatal visits. This clinical data is used to generate a risk estimate for any women with hypertension based on the miniPIERS (Pre-eclampsia Integrated Estimate of Risk) clinical risk prediction model. This risk estimate in combination with other pre-defined treatment triggers (severe hypertension (>160mmHg systolic) or proteinuria (>3+ dipstick); absence of fetal movements for greater than 12 hours; signs of recent stroke of seizure) are collected in the app and based on this data recommendations for care of the woman are provided.; Other Name: CLIP mHealth tool; Drug: Magnesium Sulfate; Women identified in intervention clusters by the community health worker during a study visit as being at high risk of- or having recently experienced- an eclamptic seizure will be given 10 g intramuscular magnesium sulfate prior to transfer to a nearby facility for further care.; Other Name: MgSO4; Drug: Methyldopa; Women identified in intervention clusters as having severe hypertension (systolic greater than 160 mmHg) by the community health worker during a study visit will be given 750 mg of oral methyldopa prior to transfer to a nearby facility for further care.; Other Name: Aldomet
No Intervention: Control; Current standard of antenatal care

Outcome Measures

Primary Outcome Measures :

1. Maternal or Perinatal death or morbidity [ Time Frame: within 42 days of pregnancy ]

   Combined outcome including any one of the following:

   1. Maternal death (number of deaths during or within 42d of pregnancy or last contact day if contact not maintained to 42d/1000 identified pregnancies); termed Maternal Death Rate.
   2. Maternal morbidity (number of women with ≥1 life-threatening complication of pregnancy (ie eclampsia, major PPH requiring surgical intervention, obstetric sepsis, stroke, etc) during or within 42d of pregnancy or last contact day if contact not maintained to 42d) / 1000 identified pregnancies
   3. Perinatal death (stillbirth [≥20+0 and/or ≥500g], early neonatal mortality [d0-7 of postnatal life] and late neonatal mortality [d8-28 of postnatal life] /1000 identified pregnancies)
   4. Neonatal morbidity (occurrence of any non-lethal morbidity (ie severe breathing difficulty, severe feeding difficulty, seizure, lethargy, coma, hypothermia, skin or umbilical stump infection, jaundice, etc) during 0-28d of postnatal life /1000 identified pregnancies)

Secondary Outcome Measures :

1. Birth preparedness and complication readiness [ Time Frame: from 20 weeks gestation to delivery ]
   as measured by any three of the following: (1) arranged for transport; (2) obtained prior permission for transport should emergency arise; (3) saved money for obstetric care; (4) identified skilled birth attendant; (5) identified facility for delivery. This will evaluate the success of community engagement.
2. Facility births [ Time Frame: from 20 weeks gestation to delivery ]
   number of women presenting for delivery in a CEmONC facility in control vs intervention clusters

Other Outcome Measures:

1. Pre-eclampsia knowledge [ Time Frame: from 20 weeks gestation to time of delivery ]
2. Post-trial seizures [ Time Frame: within 42 days of pregnancy ]
   Assessment of post-trial start eclamptic seizures in control vs intervention clusters to assess effectiveness of community dosing of magnesium sulfate
3. Cost-effectiveness [ Time Frame: within 42 days of pregnancy ]
   Of the CLIP package against QALYs
4. Adverse effects [ Time Frame: within 42 days of pregnancy ]
   Adverse effects of magnesium include injection site hematoma or infection, and respiratory depression
5. Functional disability [ Time Frame: within 6 months of delivery ]
   Index measurement of functional ability, including ability to care for baby, do household chores and return to work within 6 months of delivery measured at two to four week intervals postpartum.

Eligibility Criteria

• Ages Eligible for Study: 15 Years to 49 Years (Child, Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• all consenting pregnant women

Exclusion Criteria:

• non-pregnant

Contacts and Locations

Locations

India

Jawaharlal Nehru Medical College, Karnataka Lingayat Education University

Belgaum, Karnataka, India

Mozambique

Centro de Investigacaoem Saude de Manhica (CISM)

Maputo, Mozambique

Nigeria

Centre for Research in Reproductive Health, Olabisi Onabanjo University

Sagamu, Ogun State, Nigeria

Pakistan

Aga Khan University

Karachi, Sindh, Pakistan

Sponsors and Collaborators

University of British Columbia

Bill and Melinda Gates Foundation

Olabisi Onabanjo University

Centro de Investigacao em Saude de Manhica

Aga Khan University

Jawaharlal Nehru Medical College

Investigators

• Principal Investigator: Peter von Dadelszen, MBChB, DPhil; University of British Columbia

More Information

Additional Information:

CLIP trial website 

Publications:

Payne BA, Hutcheon JA, Ansermino JM, Hall DR, Bhutta ZA, Bhutta SZ, Biryabarema C, Grobman WA, Groen H, Haniff F, Li J, Magee LA, Merialdi M, Nakimuli A, Qu Z, Sikandar R, Sass N, Sawchuck D, Steyn DW, Widmer M, Zhou J, von Dadelszen P; miniPIERS Study Working Group. A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study. PLoS Med. 2014 Jan;11(1):e1001589. doi: 10.1371/journal.pmed.1001589. Epub 2014 Jan 21.

von Dadelszen P, Firoz T, Donnay F, Gordon R, Justus Hofmeyr G, Lalani S, Payne BA, Roberts JM, Teela KC, Vidler M, Sawchuck D, Magee LA. Preeclampsia in low and middle income countries-health services lessons learned from the PRE-EMPT (PRE-Eclampsia-Eclampsia Monitoring, Prevention and Treatment) project. J Obstet Gynaecol Can. 2012 Oct;34(10):917-926. doi: 10.1016/S1701-2163(16)35405-6. Review.

Dunsmuir DT, Payne BA, Cloete G, Petersen CL, Görges M, Lim J, von Dadelszen P, Dumont GA, Ansermino JM. Development of mHealth applications for pre-eclampsia triage. IEEE J Biomed Health Inform. 2014 Nov;18(6):1857-64. doi: 10.1109/JBHI.2014.2301156.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hoodbhoy Z, Sheikh SS, Qureshi R, Memon J, Raza F, Kinshella MW, Bone JN, Vidler M, Sharma S, Payne BA, Magee LA, von Dadelszen P, Bhutta ZA; CLIP Pakistan Working Group*. Role of community engagement in maternal health in rural Pakistan: Findings from the CLIP randomized trial. J Glob Health. 2021 Jul 17;11:04045. doi: 10.7189/jogh.11.04045. eCollection 2021.

Bone JN, Magee LA, Singer J, Nathan H, Qureshi RN, Sacoor C, Sevene E, Shennan A, Bellad MB, Goudar SS, Mallapur AA, Munguambe K, Vidler M, Bhutta ZA, von Dadelszen P; CLIP study group. Blood pressure thresholds in pregnancy for identifying maternal and infant risk: a secondary analysis of Community-Level Interventions for Pre-eclampsia (CLIP) trial data. Lancet Glob Health. 2021 Aug;9(8):e1119-e1128. doi: 10.1016/S2214-109X(21)00219-9. Epub 2021 Jul 5. Erratum in: Lancet Glob Health. 2021 Nov;9(11):e1507.

Bone JN, Khowaja AR, Vidler M, Payne BA, Bellad MB, Goudar SS, Mallapur AA, Munguambe K, Qureshi RN, Sacoor C, Sevene E, Frederix GWJ, Bhutta ZA, Mitton C, Magee LA, von Dadelszen P; CLIP Trials Working Group. Economic and cost-effectiveness analysis of the Community-Level Interventions for Pre-eclampsia (CLIP) trials in India, Pakistan and Mozambique. BMJ Glob Health. 2021 May;6(5). pii: e004123. doi: 10.1136/bmjgh-2020-004123.

Makacha L, Makanga PT, Dube YP, Bone J, Munguambe K, Katageri G, Sharma S, Vidler M, Sevene E, Ramadurg U, Charantimath U, Revankar A, von Dadelszen P. Is the closest health facility the one used in pregnancy care-seeking? A cross-sectional comparative analysis of self-reported and modelled geographical access to maternal care in Mozambique, India and Pakistan. Int J Health Geogr. 2020 Feb 3;19(1):1. doi: 10.1186/s12942-020-0197-5.

Magee LA, Sharma S, Nathan HL, Adetoro OO, Bellad MB, Goudar S, Macuacua SE, Mallapur A, Qureshi R, Sevene E, Sotunsa J, Valá A, Lee T, Payne BA, Vidler M, Shennan AH, Bhutta ZA, von Dadelszen P; CLIP Study Group. The incidence of pregnancy hypertension in India, Pakistan, Mozambique, and Nigeria: A prospective population-level analysis. PLoS Med. 2019 Apr 12;16(4):e1002783. doi: 10.1371/journal.pmed.1002783. eCollection 2019 Apr.

Makanga PT, Sacoor C, Schuurman N, Lee T, Vilanculo FC, Munguambe K, Boene H, Ukah UV, Vidler M, Magee LA, Sevene E, von Dadelszen P, Firoz T; CLIP Working Group. Place-specific factors associated with adverse maternal and perinatal outcomes in Southern Mozambique: a retrospective cohort study. BMJ Open. 2019 Feb 19;9(2):e024042. doi: 10.1136/bmjopen-2018-024042.

Sharma S, Adetoro OO, Vidler M, Drebit S, Payne BA, Akeju DO, Adepoju A, Jaiyesimi E, Sotunsa J, Bhutta ZA, Magee LA, von Dadelszen P, Dada O. A process evaluation plan for assessing a complex community-based maternal health intervention in Ogun State, Nigeria. BMC Health Serv Res. 2017 Mar 28;17(1):238. doi: 10.1186/s12913-017-2124-4.

Bellad MB, Vidler M, Honnungar NV, Mallapur A, Ramadurg U, Charanthimath U, Katageri G, Bannale S, Kavi A, Karadiguddi C, Sharma S, Lee T, Li J, Payne B, Magee L, von Dadelszen P, Derman R, Goudar SS; CLIP Working Group. Maternal and Newborn Health in Karnataka State, India: The Community Level Interventions for Pre-Eclampsia (CLIP) Trial's Baseline Study Results. PLoS One. 2017 Jan 20;12(1):e0166623. doi: 10.1371/journal.pone.0166623. eCollection 2017.

Akeju DO, Vidler M, Sotunsa JO, Osiberu MO, Orenuga EO, Oladapo OT, Adepoju AA, Qureshi R, Sawchuck D, Adetoro OO, von Dadelszen P, Dada OA; CLIP Nigeria Feasibility Working Group. Human resource constraints and the prospect of task-sharing among community health workers for the detection of early signs of pre-eclampsia in Ogun State, Nigeria. Reprod Health. 2016 Sep 30;13(Suppl 2):111.

Salam RA, Qureshi RN, Sheikh S, Khowaja AR, Sawchuck D, Vidler M, von Dadelszen P, Zaidi S, Bhutta Z; CLIP working group. Potential for task-sharing to Lady Health Workers for identification and emergency management of pre-eclampsia at community level in Pakistan. Reprod Health. 2016 Sep 30;13(Suppl 2):107.

Ramadurg U, Vidler M, Charanthimath U, Katageri G, Bellad M, Mallapur A, Goudar S, Bannale S, Karadiguddi C, Sawchuck D, Qureshi R, von Dadelszen P, Derman R; Community Level Interventions for Pre-eclampsia (CLIP) India Feasibility Working Group. Community health worker knowledge and management of pre-eclampsia in rural Karnataka State, India. Reprod Health. 2016 Sep 30;13(Suppl 2):113.

Sotunsa JO, Vidler M, Akeju DO, Osiberu MO, Orenuga EO, Oladapo OT, Qureshi R, Sawchuck D, Adetoro OO, von Dadelszen P, Dada OA; CLIP Nigeria Feasibility Working Group. Community health workers' knowledge and practice in relation to pre-eclampsia in Ogun State, Nigeria: an essential bridge to maternal survival. Reprod Health. 2016 Sep 30;13(Suppl 2):108.

Sheikh S, Qureshi RN, Khowaja AR, Salam R, Vidler M, Sawchuck D, von Dadelszen P, Zaidi S, Bhutta Z; CLIP Working Group. Health care provider knowledge and routine management of pre-eclampsia in Pakistan. Reprod Health. 2016 Sep 30;13(Suppl 2):104.

Vidler M, Charantimath U, Katageri G, Ramadurg U, Karadiguddi C, Sawchuck D, Qureshi R, Dharamsi S, von Dadelszen P, Derman R, Goudar S, Mallapur A, Bellad M; Community Level Interventions for Pre-eclampsia (CLIP) India Feasibility Working Group. Community perceptions of pre-eclampsia in rural Karnataka State, India: a qualitative study. Reprod Health. 2016 Jun 8;13 Suppl 1:35. doi: 10.1186/s12978-016-0137-9.

Boene H, Vidler M, Sacoor C, Nhama A, Nhacolo A, Bique C, Alonso P, Sawchuck D, Qureshi R, Macete E, Menéndez C, von Dadelszen P, Sevene E, Munguambe K. Community perceptions of pre-eclampsia and eclampsia in southern Mozambique. Reprod Health. 2016 Jun 8;13 Suppl 1:33. doi: 10.1186/s12978-016-0135-y.

Akeju DO, Vidler M, Oladapo OT, Sawchuck D, Qureshi R, von Dadelszen P, Adetoro OO, Dada OA; CLIP Nigeria Feasibility Working Group. Community perceptions of pre-eclampsia and eclampsia in Ogun State, Nigeria: a qualitative study. Reprod Health. 2016 Jun 8;13 Suppl 1:57. doi: 10.1186/s12978-016-0134-z.

Khowaja AR, Qureshi RN, Sawchuck D, Oladapo OT, Adetoro OO, Orenuga EA, Bellad M, Mallapur A, Charantimath U, Sevene E, Munguambe K, Boene HE, Vidler M, Bhutta ZA, von Dadelszen P; CLIP Working Group. The feasibility of community level interventions for pre-eclampsia in South Asia and Sub-Saharan Africa: a mixed-methods design. Reprod Health. 2016 Jun 8;13 Suppl 1:56. doi: 10.1186/s12978-016-0133-0.

Munguambe K, Boene H, Vidler M, Bique C, Sawchuck D, Firoz T, Makanga PT, Qureshi R, Macete E, Menéndez C, von Dadelszen P, Sevene E. Barriers and facilitators to health care seeking behaviours in pregnancy in rural communities of southern Mozambique. Reprod Health. 2016 Jun 8;13 Suppl 1:31. doi: 10.1186/s12978-016-0141-0.

Qureshi RN, Sheikh S, Khowaja AR, Hoodbhoy Z, Zaidi S, Sawchuck D, Vidler M, Bhutta ZA, von Dadeslzen P; CLIP Working Group. Health care seeking behaviours in pregnancy in rural Sindh, Pakistan: a qualitative study. Reprod Health. 2016 Jun 8;13 Suppl 1:34. doi: 10.1186/s12978-016-0140-1.

Akeju DO, Oladapo OT, Vidler M, Akinmade AA, Sawchuck D, Qureshi R, Solarin M, Adetoro OO, von Dadelszen P; CLIP Nigeria Feasibility Working Group. Determinants of health care seeking behaviour during pregnancy in Ogun State, Nigeria. Reprod Health. 2016 Jun 8;13 Suppl 1:32. doi: 10.1186/s12978-016-0139-7.

Vidler M, Ramadurg U, Charantimath U, Katageri G, Karadiguddi C, Sawchuck D, Qureshi R, Dharamsi S, Joshi A, von Dadelszen P, Derman R, Bellad M, Goudar S, Mallapur A; Community Level Interventions for Pre-eclampsia (CLIP) India Feasibility Working Group. Utilization of maternal health care services and their determinants in Karnataka State, India. Reprod Health. 2016 Jun 8;13 Suppl 1:37. doi: 10.1186/s12978-016-0138-8.

Khowaja AR, Mitton C, Bryan S, Magee LA, Bhutta ZA, von Dadelszen P. Economic evaluation of Community Level Interventions for Pre-eclampsia (CLIP) in South Asian and African countries: a study protocol. Implement Sci. 2015 May 26;10:76. doi: 10.1186/s13012-015-0266-5.

• Responsible Party: Peter von Dadelszen, Study Principal Investigator, University of British Columbia
• ClinicalTrials.gov Identifier: NCT01911494
• Other Study ID Numbers: H12-03497; F12-01593 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation )
• First Posted: July 30, 2013
• Last Update Posted: June 27, 2019
• Last Verified: June 2019

Keywords provided by Peter von Dadelszen, University of British Columbia:

cluster randomized controlled trial; pre-eclampsia; eclampsia; maternal mortality

Additional relevant MeSH terms:

Eclampsia; Pre-Eclampsia; Hypertension, Pregnancy-Induced; Hypertension; Vascular Diseases; Cardiovascular Diseases; Pregnancy Complications; Magnesium Sulfate; Methyldopa; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics; Central Nervous System Depressants; Anti-Arrhythmia Agents; Anticonvulsants; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Tocolytic Agents; Reproductive Control Agents; Antihypertensive Agents; Sympatholytics; Autonomic Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents