The Study of Magnesium Sulphate Vs Diazepam in Eclampsia

Eclampsia is a life threatening condition with highest mortality and morbidity characterized by uncontrolled hypertension un-consciousness fits albumin urea in the setting the of Pre Eclampsia. Study: An extensive elaborative study carried out from 2005 to 2009, to study the therapeutic and prophylactic role of Magnesium Sulphate and Diazepam in Eclampsia. Study Period: Four Years 2005 to 2009. Objective: To study MgSo4 Vs Diazepam reducing MMR, NMR in Eclampsia. Study Design: This was a comparative study. Total 500 patients of fulminent preEclampsia / Eclampsia were studied included booked / un-booked patients attending Lady Willingdon Hospital were admitted evaluated assessed and put on MgSo4 Vs Diazepam divided in two groups. The results were compared which showed of MgSo4 as superior in efficacy of compared to Diazepam in improving overall mortality morbidity in Eclampsia. Material and Methods: Total 500 patients of Eclampsia admitted and studied in Unit – 2 Lady Willingdon Teaching Hospital of King Edward Medical University Lahore managed in ICU according to a specially design proforma, protocol and were given MgSo4 and Diazepam for control of fits, Hydralazine, Labetalol and Isoket infusions for lowering – blood pressure (MgSO4) A+B. (Diazepam) with multi disciplinary involvement divided in two groups compared and followed up. Results: In Group-A there were 20 mothers and in Group-B 40 mothers died. It was observed that maternal mortality was significantly higher in Group-B women as compared to that of Group-A. i.e. (p-value=0.005) In Group-A there were 20 mothers and in Group-B 40 mothers died. It was observed that maternal mortality was significantly higher in Group-B women as compared to that of Group-A. i.e. (p-value=0.005) Conclusion: The comparative study and of role of MgSO4 Vs Diazepam in reducing Mortality, morbidity in maternities, neoneties, efficacy showed the superiorness of Magnesium Sulphate as compared to Diazepam without any doubt.


Introduction
Eclampsia is defined as the onset of convulsions seizures activity during pregnancy or post partum in a patient who have signs and symptoms of Fulminent Pre-eclampsia eclampsia i.e. hypertension & albuminuria mostly after the 20 th week of Pregnancy. Eclampsia is a life threatening emergency that continues to be a major cause of serious maternal neonatal morbidity and mortality worldwide. In developing countries eclampsia accounts for about one third of maternal deaths. Complicated cases and mismanaged cases are responsible for most maternal deaths which are usually due to cerebrovascular accidents, pulmonary oedema, renal hepatic, or respiratory failure, or multi system failure, DIC, Hypertensive encephalopathy/ Aspiration, Mendleson Aspiration Syndrome. Pulmonary Embolism etc.
In addition it is associated with high perinatal mortality and neonatal morbidity. The pathophysiology of eclamptic seizures is not understood. The main causes of perinatal mortality and neonatal morbidity from Eclampsia are pre-term delivery, fetal growth retardation and abruption placenta. Fetal distress, pre-maturity, Asphyxia, Neonatorum. Our objective of study was to study Magnesium Sulphate Vs Diazepam in reducing mother and child mortality in Pre-Eclampsia and Eclampsia. Urgent interventions are required to manage patients / and increase public awareness, the need for case referral and to raise the level of understanding, improving attitudes and practice in relation to Eclampsia. Pre-eclampsia / Eclampsia has been recognized as a clinical entity since the time of Hippocrates. In1916 zweifel first termed "toxemia the disease of theories".
Many of the theories attributed to pre-eclampsia/eclampsia describe pathological features of clinical presentation which are the result rather than the cause of the disease process. It has been thought to be a neurological, renal, hepatic, hypertensive and more recently a placental disorder. It is the result of both pathological change and maternal response. In different women, the rate of progression and the organ systems affected can be different. There needs to be an initial placental trigger but it is the maternal response that probably modifies the disease presentation and progression. By trying to understand the variations of disease presentation and progression, management of the affected women can become clearer and outcomes are predictable. One thing, that is agreed by all, is that placenta is required for the development and maintenance of pre-eclampsia/eclampsia and delivery, with removal of placenta-remains the ultimate cure and is evidenced based that the role of Magnesium Sulphate Vs Diazepam remains superior to Diazepam in both reducing maternal/neonatal morbidity/mortality. Evidence in support of the multiple modular approaches to pre-eclampsia includes.   Diagram of components of the pathophysiology of preeclampsia/eclampsia that make up the multi system disorder. Pre-eclampsia/eclampsia only occurs in the presence of placenta. It usually but not always associated with placental insufficiency and intra uterine growth restriction IUGR. Hypertension in Pregnancy does not cause growth retardation but co-events with placental functions resulting in the restriction of growth. Both normal and abnormal implantation is likely to be influenced by maternal/fetal immunological interactions. Large granular Macrophages and lymphocytes, as they are important to mother's ability to recognize the invading trophoblast and respond appropriately to it. An abnormal or excessive maternal immunological response may lead to deficient implantation and poor placenta ion.

Maternal Immunology
Evidence for and against an immunological basis to pre-eclampsia. c. Similar placental findings are found in IUGR The "utero-placental ischemia is responsible for pre-eclampsia." It is believed that placental ischemia results in the release of a substance "Factor X". It is the maternal reaction to any placental factor that produces the signs & symptoms of preeclampsia.

The Maternal Debus Theory
The substance responsible for the systematic reaction may be pregnancy placental villi.

Maternal immunology
Immunocytes-clinical studies have localized neutrophil diastase in term placenta, decidua and myometrium in women with PET. The cell adhesion molecule V-cam is elevated in peripheral circulation. TNFX has been shown to be increased in PET.
a. Abnormalities in various cell types could explain the immunological activity red cell fragility, platelet activation, hepatocyte dysfunctions, glomerular endotheliosis and neuronal sensitivity. Therefore all the clinical manifatestations of pre-eclampsia can be explained by cellular dysfunction secondary to response to circulating factors in maternal blood.
b. Alterations in the membrane of the red cell can alter blood physiology and tendency to lyse and can explain many of the clinical finding in this condition.
c. The red cell in women with pre-eclampsia is deficient in intracellular free radical scavengers, opening them to increased damage and membrane stability. Levels of antioxidant activity correlate with plasma levels of prostacyclin and thromboxanes are common with pregnancy induced hypertension. These changes particularly those found with superoxide dismutase (SOD) have been found in neutrophils. This decreased SOD activity would appear to be a secondary phenomenon.
d. The most common physical presentation of the eclampsia is hypertension. Vascular endothelial cell dysfunctions is certainly part of the disease process, though not permanent endothelial damage.

Hereditary factors
Multiple studies have suggested that pre-eclampsia is a familial disease. It seems likely that there may be genetic factors that modulate the process, the so called MODULATOR GENES. Recent studies confirmed this family linkage and results are consistent with single gene dominance with 48% inheritance.
i. Gene linkage with in Family groups is being investigated ii. Angio Tensinogen: a candidate gene involved in preeclampsia.
Arngrusson et al. in a study of several generations of women found evidence for role of AGT on neighbouring gene in predisposition to pre-eclampsia. This was true for women with both Proteinuric and non pre-Proteinuric and especially with Proteinuric hypertension having increased significant level.
iii. This suggests that genetic factor may be related to hypertension of PET and risk of convulsions is related to another, may be genetic cause.

TNF & Gene in pre-eclampsia
TNF can affect cells in many ways including (1) altering the balance between oxidant and antioxidant.

MGSO 4 VS Diazepam
Though MgSO 4 is the drug of choice for fulminent preeclampsia and eclampsia, with a very narrow range of safety margins, monitoring of drug levels is mandatory, with the 3R Parameters, Renal output more than 30ml/hr, diminished/respiratory rate less than 12/min, then reduce or stop altogether Reduce or absent reflex activity 0.5gm/ hr. 1-2 gm /hr is the maintenance dose MgSO 4 is given as Proplylactic and therapeutic dose, Diazepam the drug, is given very slowly, as it can depress respiratory rate, MgSO 4 52% better than Diazepam and 67% than phonation. The level of MgSO 4 is in maintenance 4-7 in Eq / lit, as there is narrow therapeutic range, so MgSO 4 level be monitored critically.

Historical background
Despite lack of complete understanding, preeclampsia and eclampsia have been recognized and described many centuries ago. Hippocrates observed that headaches, convulsions, fits and drowsiness are ominous signs in association with pregnancy. In his treatise on gynecology varandeous coined the term eclampsia in 1619. Evidence exist that ancient civilization of China, Egypt and India have all recognized and narrated this disease as well as the bleak maternal and fetal prognosis it has Association with hypertension and proteinuria, the two cardinal features were noted in mid to late 19 th century (hypertension) and the early 20 th century proteinuria. Delivery was further identified as the key and salient feature of management in the 20 th century. Notwithstanding the extensive literature and progress in our understanding, these facts still remains the basis of our management of preeclampsia and eclampsia [1,2].

Epidemiology
Eclampsia is defined as the onset of seizures / fits in the setting of preeclampsia and without another neurologic or medical causes or condition. The spectrum of hypertensive disease in pregnancy, which includes preeclampsiaeclampsia, is one of the leading causes of maternal morbidity and mortality both in the United States and worldwide, resulting in 10-15% of maternal deaths [3][4][5].
Eclampsia is further associated with increased morbidity due to risks of hypoxic-ischemic brain damage and intracranial hemorrhage from seizure activity [6]. Of eclampsia cases, 2-20% are complicated by perinatal loss, while 1-20% are complicated by maternal fatality, with the highest rates of morbidity and mortality in developing countries [5,7,8]. The risk of eclamptic seizures is approximately 2% in patients with untreated severe preeclampsia, while it is roughly 0.5% in patients with mild preeclampsia [9]. Eclampsia may occur antenatally, intrapartum, or postnatally. The incidence of eclampsia is cited to be on the order of 2-8 cases per 10,000 deliveries in developed countries and up to 16-69 cases per 10,000 in developing countries. Several recent studies from Canada and Ireland have demonstrated a decline in eclampsia incidence over time [7,10]. Liu et al. [7] found a decline from 12.4 per 10,000 to 5.9 from 2003 through 2009 in Canada, while O'Connor et al. [5] found a decline from 5.4 per 10,000 to 3.5 over a span of 30 years in Ireland. It is believed that the use of magnesium sulfate prophylactically has been associated with a decrease in incidence of eclampsia [5,7,10,11].

Etiologic and risk factors for eclampsia
Genetic predisposition, immunology, endocrinology, nutrition, abnormal trophoblastic invasion, coagulation abnormalities, vascular endothelial damage, cardiovascular maladaptation, dietary deficiencies or excess, and infection have been proposed as etiologic factors for preeclampsia/ eclampsia. Imbalanced prostanoid production and increased plasma antiphospholipids have also been implicated in eclampsia [1, 12,13].

Risk factors for eclampsia
I. The following are considered risk factors for eclampsia a. Nulliparity b. Family history of preeclampsia, previous preeclampsia and eclampsia [13] c. In addition, it is believed that antiangiogenic factors, such as placental protein fms-like tyrosine kinase 1 (sFlt-1) and activin A, antagonize vascular endothelial growth factor (VEGF) [7]. Elevated levels of these proteins cause a reduction of VEGF and induce systemic and local endothelial cell dysfunction [11]. Leakage of proteins from the circulation and generalized edema are sequelae of the endothelial dysfunction and thus a defining factor associated with preeclampsia and eclampsia [1].
Oxidative stress: Evidence indicates that leptin molecules increase in the circulation of women with eclampsia, inducing oxidative stress, another factor in eclampsia, on cells [13,15]. (The leptin increase also results in platelet aggregation, most likely contributing to the coagulopathy associated with eclampsia.) Oxidative stress has been found to stimulate the production and secretion of the antiangiogenic factor activin A from placental and endothelial cells [16]. Studies in pregnant mouse models have proposed that there is a dysregulation in the reactive oxygen species (ROS) signaling pathway [15][16][17]. Studies also suggest that increased systemic leukocyte activity plays a role in the mediation of oxidative stress, inflammation, and endothelial cell dysfunction. Histochemistry studies indicate that there is predominantly an increase in neutrophil infiltration of vasculature in patients with eclampsia [1,17].

Time of Onset of Eclampsia
The onset of eclamptic convulsions can be antepartum, intrapartum, or postpartum. The reported frequency of antepartum convulsions among recent series has ranged from 38% to 53%. The frequency of postpartum eclampsia has ranged from 11% to 44%. Although most cases of postpartum eclampsia occur within thefirst 48 h, some cases can develop beyond 48 h postpartum and have been reported as late as 23 days postpartum [8,14,[18][19][20][21].
The cases of eclampsia that occur after 48 h postpartum, but less than 4 weeks after delivery, are defined as late postpartum eclampsia. These women will have signs and symptoms consistent with preeclampsia in association with convulsions. Some of these women will demonstrate a clinical picture of preeclampsia during labor or immediately postpartum (56%), whereas others will demonstrate these clinical findings for the first time more than 48 h after delivery (44%) [19,21,22]. Of interest is the fact that late postpartum eclampsia developed despite the use of prophylactic magnesium during labor and for at least 24 h postpartum in previously diagnosed preeclampsia women [19,21]. Therefore, women in whom convulsions develop in association with hypertension and/or proteinuria or with headaches or blurred vision after 48 h of delivery should be considered to have eclampsia and initially treated as such [22].

Differential diagnosis
The presenting symptoms, clinical findings, and many of the laboratory findings overlap with a number of medical and surgical conditions [21,[23][24][25]. The most common cause of convulsions developing in association with hypertension and/ or proteinuria during pregnancy or immediately postpartum is eclampsia. Rarely, other etiologies producing convulsions in pregnancy or postpartum may mimic eclampsia. These diagnoses are particularly important in the presence of focal neurologic deficits, prolonged coma, or atypical eclampsia. In addition, in some patients gestational hypertension or preeclampsia may develop in association with these disorders (connective tissue disease, thrombophilias, seizure disorder, hypertensive encephalopathy), further contributing to the diagnostic difficulty [23]. Therefore, an effort should be made to identify an accurate diagnosis, given that management strategies may differ among these conditions. The diagnosis and management of the conditions that mimic eclampsia are beyond the scope of this report [26].

Maternal-Perinatal Complications
Although eclampsia is associated with an increased risk of maternal death in developed countries (0-1.8%), the mortality rate is as high as 14% in developing countries. In developed countries, hemorrhagic stroke is the most common cause of death in patients with eclampsia and resulted in as many as 60% of all eclampsia-related deaths [8,18,19,[27][28][29][30]. The high maternal mortality reported from developing countries is noted primarily among patients who had multiple seizures outside the hospital and those without prenatal care [18]. In addition, this high mortality rate could be attributed to the lack of resources and intensive care facilities needed to manage maternal complications from eclampsia [31]. Pregnancies complicated by eclampsia are also associated with increased rates of maternal morbidities, such as abruptio placentae (7-10%), disseminated intravascular coagulopathy (7-11%), pulmonary edema (3-5%), acute renal failure (5-9%), aspiration pneumonia (2-3%), and cardiopulmonary arrest (2-5%).The risks of diffuse intravascular coagulation (8%); hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (10-15%); and liver hematoma (1%) are similar in eclamptic and severely preeclampsia patients. It is important to note that maternal complications are significantly higher among women who develop antepartum eclampsia, particularly among those who develop eclampsia remote from term [8,14,28]. Perinatal mortality and morbidities remain high in eclamptic pregnancies. The reported perinatal death rate in recent series ranged from 5.6% to 11.8%.77 this high perinatal death rate is related to prematurity, abruptio placentae, and severe fetal growth restriction. 65, 66 the rate of preterm delivery is approximately 50%, with approximately 25% of these occurring before 32 weeks of gestation [8,19,27,31].

Evaluation
Eclampsia always should be considered in a pregnant patient with a seizure episode. A pregnant patient who has been involved in an unexplained trauma (such as a single-vehicle auto accident) and has exhibited seizure activity should be evaluated for eclampsia.

Management
The first priority in the management of eclampsia is to prevent maternal injury and to support respiratory and cardiovascular functions. During or immediately after the acute convulsive episode, supportive care should be given to prevent serious maternal injury and aspiration, assess and establish airway potency, and ensure maternal oxygenation. During this time, the bed's side rails should be elevated and padded, a padded tongue blade should be inserted between the teeth (avoid inducing gag reflex), and physical restraints may be needed. To minimize the risk of aspiration, the patient should lie in lateral decubitus position, and vomitus and oral secretion are suctioned as needed. During the convulsive episode, hypoventilation and respiratory acidosis often occur. Although the initial seizure lasts only a few minutes, it is important to maintain oxygenation by supplemental oxygen administration via a face mask with or without oxygen reservoir at 8-10 L/min [22]. After the convulsion has ceased, the patient begins to breathe again and oxygenation is rarely a problem. However, maternal hypoxemia and acidosis may develop in women who have had repetitive convulsions and in those with aspiration pneumonia, pulmonary edema, or a combination of these factors. It is recommended using transcutaneous pulse oximetry to monitor oxygenation in all eclamptic patients [22].
Arterial blood gas analysis is required if the pulse oximetry results are abnormal (oxygen saturation at or below 92%). The next step in the management of eclampsia is to prevent recurrent convulsions. Magnesium sulfate is the drug of choice to treat and prevent subsequent convulsions in women with eclampsia [11,34,35]. It is recommend giving a loading dose of 6 g over 15-20 min, followed by a maintenance dose of 2 g/h as a continuous intravenous infusion. Approximately seminars inperinatology 37 (2013) 207-224 214, 10% of eclamptic women will have a second convulsion after receiving magnesium sulfate [36]. In these women, another bolus of 2g magnesium sulfate can be given intravenously over 3-5min. An occasional patient will have recurrent convulsions while receiving adequate doses of magnesium sulfate. In this patient, recurrent seizures can be treated with sodium amobarbital, given 250mg intravenously over 3-5min. Serum magnesium levels are not monitored during the infusion because there is no established serum magnesium level that is considered "therapeutic." Patients should be monitored for signs and symptoms of magnesium toxicity by serial evaluations of reflexes, respiratory rate, and urinary output. The signs and symptoms of magnesium toxicity in relationship to the magnesium level [37,38]. In case of magnesium toxicity, management is described. The next step in the management of eclampsia is to reduce the blood pressure, if hypertensive emergency is present. A hypertensive emergency is defined as sustained (430 min), severe hypertension (≥160 mmHg systolic or ≥110 mmHg diastolic) [37][38][39].
The objective of treating severe hypertension is to avoid the loss of cerebral autoregulation and to prevent congestive heart failure without compromising cerebral perfusion or jeopardizing uteroplacental blood flow that is already reduced in many women with eclampsia. If not treated expeditiously, it can result in complications such as cerebral hemorrhage and maternal death. Thus, morbidity and mortality risk reduction for women with eclampsia requires management and avoidance of severe systolic and diastolic hypertension. The aim of blood pressure management is to keep the BP in a safe range but at the same time to avoid significant hypotension. We recommend a target systolic blood pressure between 140 and 160 mmHg and diastolic blood pressure between 90 and 105 mmHg. The rationale for keeping maternal blood pressures at these levels is to avoid potential reduction in either uteroplacental blood flow or cerebral perfusion pressure. Acutefirst-line therapy includes IV labetalol and hydralazine as well as oral nifedipine [39].
Guideline recommendations for the dosing of IV labetalol are to begin with 20 mg intravenously followed at 10-min intervals by doses of 40 mg, then 80 mg, and then 80 mg for a total of 220-300 mg. A fall in blood pressure within 5-10 min is expected. If desired blood pressure levels are not achieved after 220 mg, switch to another drug. Intravenous hydralazine is also recommended, although a meta analysis has demonstrated a slight increase in adverse events compared with labetalol, but without sufficient data to recommend one drug over the other [39][40][41]. Hydralazine dosing begins with 5mg intravenously followed at 20-min intervals by a 5-10-mg bolus depending upon the initial response. A drop in blood pressure within 10-30 min is expected. If there is no success with a total of 25 mg intravenously, consider using another antihypertensive medication. A recent, double-blind, randomized controlled trial demonstrated similar effectiveness with oral nifedipine and intravenous labetalol regimens in the acute control of severe hypertension [42]. Oral rapid acting nifedipine dosing begins with 10-20 mg orally and continued every 30 min for a maximum dose of 50 mg in 1h. Other potent antihypertensive medications such as sodium nitroprusside or nitroglycerine are rarely needed in eclampsia. Diuretics are not used except in the presence of pulmonary edema. The introduction of guidelines in both the United States and the United Kingdom for the management of patients with eclampsia and increased awareness of the importance of blood pressure reduction has been associated with a decrease in the incidence of adverse maternal outcomes [43][44][45][46].
The next step in the management of a patient with eclampsia is to manage associated complications, such as disseminated intravascular coagulopathy (DIC) and pulmonary edema. If DIC is suspected, it is important to maintain blood volume and blood pressure with aggressive replacement with crystalloids and/or blood products as indicated. In general, the treatment of DIC is mainly supportive in nature. Specific details regarding the management of DIC are beyond the scope of this discussion. Initial management of pulmonary edema includes administration of oxygen and stimulating greater urine output by giving 20-40 mg of IV furosemide over 1-2 min. Further details regarding management of pulmonary edema is beyond the scope of this discussion. The next step in the management of an eclamptic patient is to begin induction/delivery within 24 h of the onset of eclampsia. Maternal hypoxemia and hypercarbia cause fetal heart rate and uterine activity changes during and immediately following a convulsion. Fetal heart rate changes can include bradycardia, transient late decelerations, decreased beatto-beat variability, and compensatory tachycardia. Changes in uterine activity can include increased frequency and tone [47]. These changes usually resolve spontaneously within 3-10 min after the termination of convulsions and the correction of maternal hypoxemia. The patient should not be rushed for an emergency cesarean delivery based on these findings, especially if the maternal condition is not stable. It is considered to be advantageous to the fetus to allow in utero recovery from hypoxia and hypercarbia due to maternal convulsions. However, if the bradycardia and/or recurrent late decelerations persist beyond 10-15 min despite all resuscitive efforts, then a diagnosis of abruptio placentae or no reassuring fetal status should be considered. The presence of eclampsia is not an indication for cesarean delivery. The decision to perform cesarean delivery should be based on fetal gestational age, fetal condition, presence of labor, and cervical Bishop Score. We recommend cesarean delivery for those with eclampsia before 30 weeks of gestation who are not in labor and whose Bishop score is below 5 [22].
Patients having labor or rupture of membranes are allowed to deliver vaginally in the absence of obstetric complications. When labor is indicated, it is initiated with either oxytocin infusions or prostaglandins in all patients with a gestational age of 30 weeks or more, irrespective of the Bishop score.
A similar approach is used for those before 30 weeks of gestation if the cervical Bishop score is at least 5. Maternal pain relief during labor and delivery can be provided by either systemic opioids or epidural anesthesia as recommended for women with severe preeclampsia. Epidural, spinal, or combined techniques of regional anesthesia can be used for cesarean delivery. Regional anesthesia is contraindicated in the presence of coagulopathy or severe thrombocytopenia (platelet count less than 50,000/mm3) [22]. In women with eclampsia, general anesthesia increases the risk of aspiration and failed intubation due to airway edema and is associated with marked increases in systemic and cerebral pressures during intubation and extubation. Women with airway or laryngeal edema may require awake intubation underfiber optic observation with the availability of immediate tracheostomy. Changes in systemic or cerebral pressures may be attenuated by pretreatment with labetalol or nitroglycerine injections.

The Use of Magnesium Sulphate for the Treatment of Eclampsia the Magpie Trial
Magnesium sulphate (MgSO 4 ) was first introduced to control convulsions in 1925, but it was the Collaborative Eclampsia Trial in 1995 that confirmed the efficacy of MgSO 4 in the treatment of severe preeclampsia and eclampsia. The trial (also called Magpie trial) was a randomized, placebo controlled study that enrolled over 10,000 women in 33 countries and across a wide variety of clinical settings. Four centers in Nigeria Ibadan, Sagamu, Port Harcourt and Sokoto participated in the study [48,49]. Women treated with MgSO 4 had a 52% and 67% lower recurrence of convulsions than those treated with diazepam and phonation, respectively. Use of MgSO 4 in patients with severe pre-eclampsia reduced the risk of progression to eclampsia by more than half and reduced maternal mortality. The effect of MgSO 4 on perinatal outcomes was also studied, demonstrating significantly improved outcomes for newborns compared to phenytoin. Recently, the 2-year outcome following the use of MgSO 4 in the Magpie trial was published. The reduction in the risk of eclampsia following prophylaxis with MgSO 4 was not associated with an excess of death or disability for the women after 2 years in the group that had MgSO 4 compared to placebo. The children whose mothers were treated with MgSO 4 were also studied at the age of 18 months. The use of the MgSO 4 was not associated with a difference in the risk of death or disability for the children at 18 months of age compared to those whose mothers were treated with placebo [29,34,49].

Mechanism of Action
The mechanism of action of MgSO 4 is not completely understood. It is thought to cause dilatation of cerebral blood vessels thus reducing cerebral ischemia. It is also thought that the magnesium blocks calcium receptors by inhibiting N-methyl-Daspartate receptors in the brain [50]. Magnesium also produces a peripheral (predominantly arteriolar) vasodilatation thus reducing the blood pressure [51]. It also acts competitively in blocking the entry of calcium into synaptic endings thus altering neuromuscular transmission. This transmission is affected by a preponderant presynaptic as well as a postsynaptic effect. The presynaptic release of acetylcholine is also reduced thus altering neuromuscular transmission [52]. The precise mechanism of action for the tocolytic effects of MgSO 4 is not clearly defined but may be related to the action of magnesium as a calcium blocker thus inhibiting muscle contractions [53]. 4 On the basis of the available evidence, The World Health Organization (WHO) has recommended MgSO4 as the most effective, safe, and low-cost drug for the treatment of severe pre-eclampsia and eclampsia. There are indeed several reports of its successful introduction in several countries including Nigeria and its effectiveness and safety for mother and baby [54][55][56][57]. However, the drug has remained largely unavailable in several developing countries where it is incidentally needed the most. Leading advocates, researchers, non-governmental organizations, representatives of the WHO and national health ministry's from all over the world recently met and identified the main barriers to the use and availability of MgSO4. These included the lack of guidelines on its use, non-inclusion in many national essential drug lists, the wrong perception that the drug is meant for use only at the highest level of facilities (such as those with intensive care facilities), lack of training of health workers on its use, little incentive for pharmaceutical companies to commercialize the drug, and ready availability of prepackaged forms of less effective drugs [58].

MgSO 4 regimens
There are principally two main regimens available for the administration of MgSO 4 . In the Pritchard Regimen, the loading bolus dose of 4 g of MgSO 4 is given slowly intravenously over 5-10 min and this is followed by 10 g given intramuscularly (5 g in each buttock). Subsequently, 5 g is given intramuscularly into alternate buttocks every 4 h. In the Zuspan regimen, the loading dose consists of an initial intravenous dose of 4 g slowly over 5-10 min followed by a maintenance dose of 1-2 g every hour given by an infusion pump [59]. A gravity fed infusion set can be used in the absence of the pump especially in the developing countries. It should be noted that for the 50% MgSO 4 , 1 ml of the solution contains 0.5 g of MgSO 4 , while for the 20% solution, 1 ml contains 0.2 g of MgSO 4 . Monitoring is important to ensure that the right doses are administered and this is not an easy task. Whatever regimen chosen, the drug should be administered till 24 h after delivery or after the last fit (whichever comes last). The choice of which regimen to use depends on a number of factors such as availability of staff to monitor the drug as well as the expertise of the staff. In resource-constrained settings, the Pritchard regimen may be easier to administer since it is given intramuscularly (could thus be administered by lower cadre of health workers). It, however, has the disadvantage of being very painful, a situation which is not desired for a patient on whom efforts are been made to lower the blood pressure. To counteract this, the intramuscular dose could be administered with about 2 ml of 1% xylocaine in the same syringe. Some workers have reported modifications in the above-mentioned regimens. MgSO 4 has been used with the dose reduced to a loading dose of 4.5 g intravenously and maintained on intramuscular 1.5 g every 4 h until 12 h after delivery or the last fit [60].
In another study, the loading dose was 10g intramuscularly followed by a maintenance dose of 2.5 g intramuscularly every 4 h for 24 h. The drug has been used as in Pritchard regime, but the duration of its administration reduced to 12 h after the initial loading dose. The fetomaternal outcome was similar to the two more famous regimens (Pritchard and Zuspan) [61,62].

Clinical Detection of Toxicity
The main fear of toxicity was also laid to rest with the Magpie trial. Toxicity of the drug was monitored using clinical parameters. The parameters that need to be monitored are the knee jerk (should be present), respiratory rate (should be more than 16/minute), and urine output (should be more than 25 ml/min). These clinical parameters have been compared with serum levels of MgSO 4 . The first warning sign of toxicity is loss of the knee jerk which occurs at serum magnesium level of 3.5ñ5 mmol/l. Respiratory paralysis occurs at 5-6.5 mmol/, cardiac conduction is altered at more than 7.5 mmol/ while cardiac arrest occurs when serum magnesium exceeds 12.5 mmol/l However, with the above-mentioned protocols, the expected serum range of magnesium is 2-3.5 mmol/l10. Using the Pritchard regimen, a mean serum magnesium level of 2.1 mmol/l was found. Should toxicity be detected, however, the antidote is 1 g of 10% calcium gluconate given intravenously slowly over 10 minutes [48,63,64].

Training on MgSO 4
The need has now emerged for refresher trainings for health workers in the use of MgSO 4 . Clinical protocols are particularly useful in guiding such workers. The Federal Ministry of Health has developed a national clinical service protocol for obstetric care. The protocol outlines the management of eclampsia and how MgSO 4 can be used and monitored. There is need to distribute this protocol and train health workers all over the country on its use. It is also recommended that the protocol should be utilized nationally as a guideline thus ensuring universal dosage regimen that will also help in uniform studies and research. Some workers have also reported the utilization of the protocol to suite the working environment in respect of the available facilities, staff, investigations, and even the regimen of MgSO 4 used. In Kano state, for example, the protocol was institutionalized under the guidance of the state safe motherhood committee to incorporate the role played by no physicians in the care of patients with eclampsia including referral where necessary [65]. c. To study materno-foetal outcome by using MgSO 4 Vs Diazepam.

Procedure of Data Collection
All the patients of pregnancy between 28 weeks to 39 weeks with Eclampsia were admitted in ICU and managed according to set protocol and were given MgSO 4 and Diazepam divided in two groups and their role compared. Blood Pressure was controlled with Hydralazine, Labetalol, Isoket infusion. Results were given in table form. Of the total patients 50 were excluded from the study, 10 of them could not be traced in the follow up and their outcome is not known. 20 had been induced, pre-term delivery due to medical conditions i.e. uncontrolled hypertension & albuminuria due to eclampsia.
All patents were examined and investigated thoroughly, managed and regular follow up ensured while comparison is made between the role of MgSO 4 & Diazepam in patients. The study conducted in accordance with standard criteria / protocols set up and Data analyzed by recording on a especially designed proforma for evaluation and later analysis and comparison made between when the acute emergency is over, the patients are stabilized managed accordingly till convalescence and followed regularly.
The maternal fetal outcome / prognosis depend upon the severity of signs and Gestational age. Mostly the uncomplicated pregnancy were carried to the terms also if maternal and fetal condition allows i.e. 37 completed weeks and the 34 completed week was taken a cutoff point to prematurity and role & comparison of use of MgSO 4 Vs Diazepam in eclampsia, analyzed. Regular antenatal care in high risk pregnancy admission of Eclampsia use of MgSO 4 Vs Diazepam control of blood pressure by Hydralazine and Labetalol and urgent delivery markedly reduces MMR, NMR. All women fulfilling the study criteria were counseled especially the OPD patients and meet the average ages between the age (28 -39) of gestation. Complete set of history as shown in the Performa, including precious, obstetric, Gynecological/ medical/especially previous history of hypertension/PIH, Fits unconsciousness. PET/ Eclampsia/ surgical/drug and psychological history was obtained at first antenatal or first emergency admission (in case of coma from the relatives available) and entered on to a proforma. Gestational age was determined from menstrual history and confirmed by: As part of routine/emergency care, full thorough and detailed General physical examination was conducted followed by systemic examinations of CVS, GIT, respiratory and special emphasis was laid on CNS examination and Fundo-Scopic points to be particularly important were following points.

Data Analysis
Identifying the risk factors during meticulous antenatal screening and looking for increase in hypertension, proteinuria and evaluating the warning signs of pre-eclampsia and eclampsia. The drugs are the MgSO 4 and Diazepam for control of fits, control of blood pressure Hydralazine, Labetalol, Isoket infusion and study of MgSO 4 and Diazepam already discussed in details.

Group-B= Diazepam
In Group-A there were 150 women who had booked for their delivery while the remaining 100 women were un-booked for their delivery. In Group-B there were 180 women were who had booked for their delivery while 70 women were not booked for their delivery.   In Group-A perinatal mortality was seen in 25 neonates while in Group-B perinetal mortality was seen in 45 neonates. According to p-value it was observed that perinatal mortality was significantly lower in Group-A as compared to Group-B. i.e. (p-value=0.002).

Figure 1: Mortality status in patients.
Maternal mortality was seen in 12% women

Discussion
Pre-eclampsia is a condition unique to pregnancy that is characterized by new onset of hypertension and proteinuria [66]. Pre-eclampsia is a relatively common complication of pregnancy, and can occur at any time during the second half of pregnancy or in the first few weeks after delivery. For many women who have pre-eclampsia the maternal outcome is good, but severe disease can lead to death or serious problems for the woman. Severe pre-eclampsia is associated with multiple organ system involvement including renal failure, cerebral hemorrhage and edema, hepatic failure and rupture, and thrombocytopenia in addition to pre-eclampsia [67]. Pre-eclampsia and eclampsia are not distinct disorders but the manifestations of the same condition. In pre-eclampsia, hypertension and proteinuria are present, and when convulsions occur after other causes of convulsion are excluded in addition to these signs, the condition is referred to as eclampsia [66]. Eclampsia is a serious complication increasing the risk of maternal morbidity and mortality [68]. Current strategies for prevention of pre-eclampsia can be broadly classified as antenatal surveillance, modification of lifestyle, nutritional supplementation, and pharmacological therapy. The only definitive treatment for pre-eclampsia or eclampsia is to end the pregnancy. The aim of interventions for women with eclampsia is to prevent further seizures, to minimize and treat any complications and, if not delivered, to optimize the timing of birth for the baby. Currently, standard care for women with severe pre-eclampsia/eclampsia is to use an anticonvulsant drug to control the immediate fit, and to continue maintenance treatment to prevent further seizures [68].
The principal goals of treatment in eclampsia are stopping the convulsions and preventing further fits which are associated with reduction in adverse outcome. This has been reported to depend on the type of anticonvulsant used. It has also been revealed, in a typical systematic quantitative review and analysis, that magnesium sulphate was more effective than other interventions in preventing recurrent seizures in eclampsia and in preventing the first seizure in pre-eclampsia. Another meta-analysis by Duley et al. [34] has reported a substantial reduction in the risk recurrence of further fits (RR=0.44, 95%CI 0.34 to 0.57) in eclamptic pregnant women [34,69]. In this study it was observed that maternal and perinetal mortality was high in Group-B (diazepam) however In Group-A (MgSO4) maternal and perinetal mortality was low. This difference in mortality in both treamtent groups was statistically significant. According to Khan, magnesium sulphate was the better anticonvulsant than diazepam infusion in terms of total morbidity and maternal deaths (Null versus 5%) [70].
A Randomized Double Blind Trial of Magnesium Sulphate and Diazepam in Lagos, Nigeria also showed that the use of magnesium sulphate was found to be significantly associated with less serious morbidity in comparison to diazepam use [71]. A similar significant reduction in maternal deaths was reported in Tanzania [72]. Gizat M Kassie in his study evaluated maternal outcomes of magnesium sulphate and diazepam use in the management of severe pre-eclampsia and eclampsia in Jimma University Specialized Hospital.
In his results he reported that Three pregnant women from the magnesium sulphate treated group and eleven pregnant women from diazepam treated group had at least one convulsion after taking the drug. Greater proportion of patients in the magnesium sulphate treated group had less than four days postpartum stay as compared to the diazepam treated patients (82.3% versus 66.2%). Seizure occurrence, duration of postpartum hospital stays and birth outcome had a statistically significant association with the type of anticonvulsant used [73].
Chaudhary P [57] in his study determined the incidence and impact of changes in the intervention strategy for the management of eclampsia in a maternity hospital on maternal and perinatal outcome. In his results he reported that marked improvement was noticed in terms of recurrence of fit (19.13% vs 73.91%) with change in the intervention strategy. Perinatal deaths were fewer in study period B (20% vs 33%). Overall, it seems that care of eclamptic patients and use of magnesium sulphate as anticonvulsant has resulted in positive impact on maternal outcome. Eclampsia is still commonly perceived as the end of a linear spectrum that stretches from normal pregnancy, through mild hypertension, pre-eclampsia and finally eclampsia. However, eclampsia may precede pre-eclampsia and an alternative view is that seizures are one of the range of signs and symptoms caused by the widespread endothelial cell damage secondary to an ischaemic placenta. Preeclampsia is a multisystem disease of poorly understood etiology and the extent of involvement of various organs are unpredictable. Another important fact is that treatment of this disease is entirely empirical and symptomatic and controversy still exists in the choice of the most appropriate treatment especially for prevention and control of fits. It is understood that treatment of eclampsia is symptomatic as underlying cause is unknown. Most clinicians agree that diazepam should be used to abort initial fit as it is effective, inexpensive, and easily available and can be used by nursing staff. However, the risks include respiratory depression, respiratory arrest and aspiration pneumonia. The general aim of treatment in eclampsia is prevention of further fits as it is the recurrent fits that leads to significant cerebral anoxia and its associated adverse outcome. The greater efficacy of magnesium sulphate compared to diazepam or phenytoin for prevention of recurrence of fits is now accepted worldwide in many studies. • Least 24 hours if poor arterial blood gases.
• Laryngeal oedema. • Hypertension may not be the primary presenting symptom.

Anti Hypertensive in Eclampsia
• The placenta is the initial trigger to disease development.
• The presentation of pre-eclampsia is very varied and any body system can be affected.
• Maternal response is the main controller of disease severity.
• Upper abdominal pain is a concerning feature suggestive of HELLP syndrome.
• Eclampsia is not an inevitable progression from pre-eclampsia.
• Pulmonary oedema can occur with a normal CVP due to capillary leak.

Recommendations for Management Key Point For Clinical Practice
We make the following recommendations for the management of patients with eclampsia and severe pre-eclampsia: • All severe Fulminent pre-eclamptics and eclamptics should be managed in special regional centers with the appropriate expertise.
• Continuous monitoring of blood pressure pulse rate, ECG and central venous pressure is required as the cardiovascular system is extremely labile in this condition and can deteriorate in seconds.
• Magnesium Sulphate is the drug of choice, in fulminent pre eclampsia / eclampsia.
• The airway should be maintained and protected. Any patient with a Glasgow Coma Scale of less than 9 should be intubated. Nursing staff at district hospitals and community clinics should be taught how to position an unconscious patient, insert oral airway and administer oxygen.
• An arterial partial pressure of oxygen of at least 100 mmHg should be maintained. Mechanical ventilation may be necessary.
• Blood pressure should be carefully and slowly lowered the diastolic pressure should be lowered by not more than 30 mmHg in order to maintain cerebral perfusion.
• Seziures should be prevented or terminated as soon as possible MgSO4 is the anticonvulsant of choice for this purpose. Efficient transport facilities must be available and personnel at district hospitals and community clinics should be capable of administering anticonvulsants.
• The fetus should be delivered within 6-12 hrs of admission: Caesarean section is often indicated. General anesthesia, administered by skilled anesthetist, is recommended. Where these facilities are not available, epidural anesthesia would be adequate, provided a hypertensive episode is prevented with sufficient intravenous pre-loading and coagulopathy is excluded by estimation of crude clotting time, fibrinogen levels and platelet counts.
• An eclampsia team should be organized, since the problems developed by these patients are multifactorial. Personnel (an obstetrician, obstetric anesthetist and critical care nurse) experienced in the specific obstetric management of these patients need to work together, in order to improve patient outcome. While prevention of pre-eclampsia/eclampsia must await an understanding of its etiology, improvement in antenatal care, together with active management of the disease when it develops, will improve both fetal and maternal prognosis.

Key Points -MgSO 4 Vs Diazepam
• Eclampsia is an obstetrical emergency that occurs in 4 to 5 per 10,000 live births in developed countries, with higher rates in under developing countries.
• Approximately one-third of cases are not preventable.
• Both the fetus and the mother are at immediate risk of death or life-long neurologic disability.
• The goals of management are to stabilize the mother, prevent recurrent convulsions, treat severe hypertension, and initiate delivery of the fetus.
• Delivery is the only curative treatment, but immediate cesarean birth is not usually necessary.
• Maternal prognosis is good with prompt treatment and in the absence of cerebrovascular hemorrhage. The fetal prognosis is primarily dependent upon the gestational age at delivery.
• Two percent of women will experience an eclamptic seizure in a future pregnancy, 9 to 25 percent will develop severe preeclampsia, and up to 65 percent will develop preeclampsia.
• Magnesium sulfate is the drug of choice for prevention of both primary and recurrent eclamptic seizures as compared to diazepam Phenytoin.