Randomized Controlled Trial Comparing Zuspan Regime With The Alternative Regime In The Maintenance Therapy Of Magnesium Sulphate In Severe Pre-Eclampsia

doi:10.21203/rs.3.rs-1535945/v1

Download PDF

Study protocol

Randomized Controlled Trial Comparing Zuspan Regime With The Alternative Regime In The Maintenance Therapy Of Magnesium Sulphate In Severe Pre-Eclampsia

https://doi.org/10.21203/rs.3.rs-1535945/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Hypertensive disorder of pregnancy causes 14% mortality and is considered second common direct cause for maternal mortality. Pre-eclampsia is a new onset of hypertension detected after 20 weeks of pregnancy with proteinuria. It is categorised as severe and non severe. The definitive management of severe preclampsia is termination of pregnancy but prevention of seizures is most important part of management. The anticonvulsant of choice is magnesium sulphate (MgSO4 ). The doses of magnesium sulphate are given as per the regimens of Pritchard or Zuspan regimen which are accepted as standard regimen globally. There is narrow therapeutic window of magnesium sulphate and can cause life threatening complications. Thus, considering the complications of magnesium sulphate in women of low BMI and difficulty in monitoring the magnesium levels in low resourse settings, many modified and alternate regimens have been developed. Rationale: In treatment of severe preclampsia, 24 hours maintenance therapy of magnesium sulphate is considered as standard regimen but no justification is given for this duration in present literature.

Aims and objective: To develop a short duration regimen of maintenance dose of anticonvulsive magnesium sulphate therapy and compare with the standard regimen for treatment of severe pre-eclampsia in an effort to reduce adverse events and improve early recovery without compromising the effectiveness.

Material and methods: This will be a randomised controlled trial, total 54 cases will be recruited in the case and control group each as per inclusion and exclusion criteria. All enrolled patients of study will receive loading dose of MgSO4, 4 gm intravenously. Maintenance dose will be given as 1gm/hour as continuous intravenous infusion with infusion pump for 12hours in study group and for 24 hours in control group. The primary outcome will be the occurrence of a seizure any time after the completion of treatment in both groups and secondary outcome will be maternal health outcomes and magnesium sulphate toxicities.

Results-The result would be undertaken in SPSS software.

Conclusion-The conclusion will be based on finding of study. Ethical clearance: Ethical approval was obtained from Institutional ethics committee.

severe preeclampsia

maintenance therapy

magnesium sulphate

short duration

Hypertensive disorder of pregnancy converts 3-10% pregnancy into high risk obstetrics and causes around 30,000 maternal and 500,000 perinatal mortality annually in the world(1). It causes 14% mortality and is considered second common direct cause for maternal mortality (2,3). Hypertensive disorder of pregnancy is a multisystem disorder attributed to the abnormal interaction between maternal decidua and fetal trobhoblastic invasion(4). Incidence of hypertensive disorders in pregnancy was around 10.08 % in India, as per the National Eclampsia Registry (NER) in 2014 and incidence of eclampsia was found to be 1.09 % (4,5). Hypertensive disorder in pregnancy has a broad spectrum and gestational hypertension, pre-eclampsia and eclampsia are spectrum of these disorder. Pre-eclampsia is a new onset of hypertension detected after 20 weeks of pregnancy with proteinuria. It is categorised as severe and non severe. Eclampsia is defined as generalized convulsions in pregnancy without previous history of epilepsy, unless proved otherwise (3). Severe preeclmpsia can be defined when blood pressure is more or equal to 160/110 mm Hg, measured on two different occasions, 4-6 hours apart, proteinuria of 3+ on dipstick or 5 gm in 24 hours urine sample, with one or more of the following features like epigastric pain or right upper quadrant pain, oliguria of less than 500ml/24 hour, impaired liver function, thrombocytopenia, fetal growth restriction, pulmonary edema or cyanosis, cerebral or visual disturbances(6–8). Severe preeclampsia can lead to various complications like convulsions, abruption of placenta, pulmonary edema, aspiration pneumonia, acute renal failure neurological deficits, and cardiopulmonary arrest(8). It also causes fetal complications like intrauterine death, still births, preterm birth, and admissions to neonatal intensive care unit (NICU) (2,7).

The definitive management of severe preclampsia is termination of pregnancy but prevention of seizures is most important part of management. The anticonvulsant of choice for control and prevention of seizures is magnesium sulphate (MgSO4 ) (9). The mechanism of magnesium sulphate for control of seizures is not understood clearly but it is suggested that it causes blockage of NMDA receptors (N-methyl D-aspartate), involved in genesis of seizures or it acts by blocking calcium channels which prevents cerebral vasospasm. (10) The doses of magnesium sulphate are given as per the regimens of either Pritchard or Zuspan regimen which are accepted as standard regimen globally on basis of two largest MgSO4 trial (9,11,12). Although these are internationally accepted regimens, the present literature did not give minimum effective dose, optimal duration and or optimal therapeutic window of magnesium sulphate. Because many times, clinical improvement is shown in patients even it fails to reach the minimum therapeutic threshold as per given in standard literature (11,13). Since the standard regimens developed after MgSO4 trial were conducted in the Western countries and the BMI of the women of many Asian countries are about only two-third of the western women, thus considering the narrow therapeutic window of magnesium sulphate, it can cause life threatening complications like respiratory depression or renal failure in small size Asian women.(14). Thus, considering the complications of magnesium sulphate in women of low BMI and difficulty in monitoring the magnesium levels in low resourse settings, many modified and alternate regimens have been proposed like lowering the maintenance doses, single loading dose without maintenance or reducing the duration of maintenance doses, etc.(6,7,10,15,16).

Our study seeks to compare the efficacy, safety and early recovery of patients of severe preeclampsia when maintenance doses of magnesium sulphate is reduced to 12 hours from 24 hours duration, thus, helping in formulating the new treatment protocol for prevention of seizures and medical management of patients of severe preclampsia with similar efficacy, minimal side effects and cost effective treatment in low resource settings of developing countries like India.

Rationale:

In treatment of severe preclampsia, 24 hours maintenance therapy of magnesium sulphate is considered as standard regimen but no justification is given for this duration in present literature. Although different studies of alternate regimens have shown promising results in terms of effectiveness and safety, smaller sample size and lack of standardized protocols inhibits the formulation of standard guidelines particularly for Asian women

Aim and objective

Aim

To develop a short duration regimen of maintenance dose of anticonvulsive magnesium sulphate therapy for treatment of severe pre-eclampsia in an effort to reduce adverse events and improve early recovery without compromising the effectiveness

Objectives

To study occurrence of seizures, adverse events and early postnatal recovery when short duration (12 hours) maintenance therapy magnesium sulphate is used in severe pre-eclampsia management .
To study occurrence of seizures, adverse events and early postnatal recovery when standard duration (24 HOURS) maintenance therapy magnesium sulphate is used in severe pre-eclampsia management
To compare between the above two

Outcome to be measured in terms of:

Primary outcome:

Efficacy: Occurence of seizures in next 24 hours after completion of intervention in both groups

Secondary outcome:

1. Need to prolong therapy of magnesium sulfate for 24 hours

2. Safety: Adverse events/side effects in both groups

3. Recovery (first 48 hours) in both groups :

Length of HDU stay

Early ambulation

Duration of indwelling catheter

Mother to baby caring/rooming

Study design: This is Randomised Controlled Trial

(CTRI registration number: CTRI/2022/01/039776)

Study site: This study will be conducted at obstetric unit of JNMC (Jawaharlal Nehru Medical College) and AVBRH (Acharya Vinoba Bhave Rural Hospital), Sawangi, Wardha

Study duration: 2 years

Sample size: Assuming that the proportion of severe pre-eclamptic women experiencing seizure in both 12-hour and 24-hour arm to be 1%, inferiority margin of 5%, with a statistical power of 80% and a two-sided p value of 0.05, 49 women are needed per group. Considering loss to follow up of 10%, the final sample size resulted in a total of 54 women per group.

Final sample size: 108 (54 in each group)

Criteria for inclusion

1. Age of patient >=18 years.

2. Patients of severe preeclampsia based on:

Increased blood pressures of 160/110mm Hg or more after 20 weeks of gestation on two different occasions at least 4 hours apart and
Proteinuria of 3+ on dipstick or 5 gm in 24 hours urine sample

3. Singleton pregnancy

4. who give consent for participation in study

Criteria for exclusion

Age of patient < 18 years
Patients with either antepartum or intrapartum or postpartum convulsions(before enrollment)
Patients with known case of epilepsy
Patients with renal or liver disorder, not attributed to preeclampsia
Central Nervous System disorder
Chronic kidney disease
Seizures due to metabolic disturbances, space occupying lesions or intra cerebral infections
Cardiac patients
Contraindications to MgSO4 i.e. drug hypersensitivity, myasthenia gravis, anuria or oliguria
Prior intake of any other anticonvulsant

Statistical methods :Chisquare test and Student’s unpaired t test

Software’s Used in the study : SPSS 24.0 version, EPI-INFO 7.0 version and GraphPad Prism7.0 version.

Enrollment

All women admitted to the obstetric (ANC) ward of hospital with diagnosis of severe preclampsia, will be screened by on duty gynae doctor and if found eligible i.e. meeting inclusion and exclusion criteria, patient will be then enrolled in study. Diagnosis of severe preclampsia will be done on the basis of blood pressure more or equal to 160/110 mm Hg, measured on two different occasions, 4-6 hours apart, proteinuria of 3+ on dipstick or 5 gm in 24 hours urine sample, with one or more of the following features like epigastric pain or right upper quadrant pain, oliguria of less than 500ml/24 hour, impaired liver function, thrombocytopenia, fetal growth restriction, pulmonary edema or cyanosis, visual disturbances(6–8).

Patient information sheet will be given to patient and relative and informed consent will be taken and patient will be randomised to either short duration therapy or standard duration therapy (Figure 1). All required blood investigations like complete blood count, blood group, viral markers for HIV, HbsAg, VDRL, Sickling (if not done prior), coagulation profile including bedside bleeding time and clotting time(BT and CT), kidney function test (KFT) and liver function test (LFT) will be sent. Baseline serum magnesium levels will be measured and will be repeated after 4 hours of loading dose and 4 hours of completion of maintenance therapy.

Intervention Protocol

All enrolled patients of study will receive loading dose of MgSO4, 4 gm intravenously. The dose will be constituted by diluting 8 mL of 50% MgSO4 solution with 12 mL of normal saline to obtain 20 mL of 20% 4gm MgSO4 which will be administered slowly over 15–20min. Maintenance dose will be given as 1gm/hour as continuous intravenous infusion with infusion pump. Patient randomized to 12hours therapy group will be given maintenance therapy for 12 hours, and those randomized to 24 hours therapy will be given maintenance therapy for 24 hours. In study group of 12 hours, if there is persistent severe hypertension/ appearance of signs or symptoms of impending convulsions, the maintenance dose will be continued for 24 hours. If any patients develops seizures during maintenance therapy or after completion of therapy then patients will be given 2 gm of 20% MgSO4 intravenously as a repeat loading dose and her maintenance dose will then be continued for 24 hours. If a patient develops second recurrent episode of convulsions during therapy then anticonvulsant medicine (phenytoin) will be started after discussion with physician. Patients developing seizures after 48-72 hours after delivery, will be evaluated for other causes of convulsions (17).

Clinical monitoring protocol:

During the entire duration of treatment, all patients will be in the high dependency unit (HDU) and will be monitored hourly for blood pressure, deep tendon reflexes (patellar reflex), urine output, respiratory rate and occurrence of seizures. Patients will be catheterised by Foleys catheter, and strict input and output charting will be done. Catheter will be retained till the last dose of magnesium sulphate. All details of magnesium sulphate treatment like timing, doses will be recorded, serum magnesium levels will be measured at baseline, after 4 hours of loading dose and 4 hours after cessation of therapy. Features of magnesium toxicity, if any will be noted. All patients will be followed up till discharge.

Obstetric management

Apart from magnesium sulphate treatment, other management of study patients will be done as per institutional protocol, like antihypertensive medicine for raised blood pressure, decision on mode of delivery, induction of labour, fetal heart rate monitoring. Mode of delivery, duration of labour, maternal complications if any, will be recorded. All neonatal details like gestational age at delivery, baby weight at birth, APGAR score at 1 and 5 minutes, need of admission in neonatal intensive care unit (NICU) will be noted. After delivery all necessary postpartum care will be provided to patients and baby care will be done as per hospital protocol, till discharge.

Since it will be a single centre trial, sample size is less as it is influenced by the number of admission to the institute and other co-related factors.

Interpretation

By using this study, we can develop a valuable data which will help to design the alternate therapy for the maintenance dose of magnesium sulphate in patients of severe preeclampsia without compromising its effectiveness, in patients of low BMI( like Indian population)

Data availability

Data supporting the findings and results of the study will be discussed and shared with the research committee of the institute time to time (every 6 monthly) and also with the clinical trial registry, under which this trial is registered. However, raw data that support the findings of this study will be available from corresponding author, upon reasonable request.

Contributors:

AC is a principal investigator of study and drafted the final protocol manuscript. NA is the supervisor of the study and guided in designing the study protocol and helped in drafting the manuscript. SI involved in editing and finalisation of the protocol. SA involved in editing the protocol. All authors (AC, NA, SI, SA) reviewed the final protocol manuscript

Ethical approval

This is a randomised controlled trial and it is approved by the ethical committee of the institute of DMIMS with Re-regd no.ECR/440/Inst/MH/2013/RR-2019 and has been performed with the ethical standards described in an appropriate version of the 1975 Declaration of Helsinki, as revised in 2000.

Clinical trial registration

Registered under clinical trial registry of India with registration number: CTRI/2022/01/039776

Informed consent

We have taken informed consent of patients for including them in our study and using their treatment details for publishing in journal, without breaching the respect and confidentiality of our case. We have not caused any harm to the patients.

Conflict of interest

The authors declare that they have no conflict of interest for this study.

Source of Funding

The authors declare that they have no funding support for this study

Acknowledgement

Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.

Ukah UV, De Silva DA, Payne B, Magee LA, Hutcheon JA, Brown H, et al. Prediction of adverse maternal outcomes from pre-eclampsia and other hypertensive disorders of pregnancy: A systematic review. Pregnancy Hypertens. 2018 Jan;11:115–23.
Abalos E, Cuesta C, Carroli G, Qureshi Z, Widmer M, Vogel JP, et al. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG Int J Obstet Gynaecol. 2014 Mar;121 Suppl 1:14–24.
Pratt JJ, Niedle PS, Vogel JP, Oladapo OT, Bohren M, Tunçalp Ö, et al. Alternative regimens of magnesium sulfate for treatment of preeclampsia and eclampsia: a systematic review of non-randomized studies. Acta Obstet Gynecol Scand. 2016 Feb;95(2):144–56.
Gupte S, Wagh G. Preeclampsia–Eclampsia. J Obstet Gynaecol India. 2014 Feb;64(1):4–13.
Nobis PN, Hajong A. Eclampsia in India Through the Decades. J Obstet Gynaecol India. 2016 Oct;66(Suppl 1):172–6.
Unwaha EA, Bello FA, Bello OO, Oladokun A. Intravenous magnesium sulfate in the management of severe pre-eclampsia: A randomized study of 12-hour versus 24-hour maintenance dose. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet. 2020 Apr;149(1):37–42.
Nagaria T, Mitra S, Banjare SP. Single Loading Low Dose MgSo4 Regimen: A Simple, Safe and Effective Alternative to Pritchard’s Regimen for Indian Women. J Clin Diagn Res JCDR. 2017 Aug;11(8):QC08-QC12.
Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for maternal morbidity. Am J Obstet Gynecol. 2000 Feb;182(2):307–12.
Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, et al. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet Lond Engl. 2002 Jun 1;359(9321):1877–90.
Ekele BA, Muhammed D, Bello LN, Namadina IM. Magnesium sulphate therapy in eclampsia: the Sokoto (ultra short) regimen. BMC Res Notes. 2009 Aug 19;2:165.
Okusanya BO, Oladapo OT, Long Q, Lumbiganon P, Carroli G, Qureshi Z, et al. Clinical pharmacokinetic properties of magnesium sulphate in women with pre-eclampsia and eclampsia. BJOG Int J Obstet Gynaecol. 2016 Feb;123(3):356–66.
Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial - PubMed [Internet]. [cited 2020 Dec 27]. Available from: https://pubmed.ncbi.nlm.nih.gov/7769899/
Aali BS, Khazaeli P, Ghasemi F. Ionized and total magnesium concentration in patients with severe preeclampsia-eclampsia undergoing magnesium sulfate therapy. J Obstet Gynaecol Res. 2007 Apr;33(2):138–43.
Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: evaluation of 245 cases. Am J Obstet Gynecol. 1984 Apr 1;148(7):951–63.
Begum R, Begum A, Johanson R, Ali MN, Akhter S. A low dose (“Dhaka”) magnesium sulphate regime for eclampsia. Acta Obstet Gynecol Scand. 2001 Nov;80(11):998–1002.
Maia SB, Katz L, Neto CN, Caiado BVR, Azevedo APRL, Amorim MMR. Abbreviated (12-hour) versus traditional (24-hour) postpartum magnesium sulfate therapy in severe pre-eclampsia. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet. 2014 Sep;126(3):260–4.
ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019 Jan;133(1):e1–25.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Randomized Controlled Trial Comparing Zuspan Regime With The Alternative Regime In The Maintenance Therapy Of Magnesium Sulphate In Severe Pre-Eclampsia

Status:

Version 1

Abstract

Figures

Introduction

Material And Methods

Limitation Of The Study

Declarations

References

Additional Declarations

Status:

Version 1