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Journal of Clinical and Diagnostic Research. 2019 Feb, Vol-13(2): QC01-QC04 11
DOI: 10.7860/JCDR/2019/39642.12596 Original Article
Miscellaneous
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Obstetrics and Gynaecology
Section
Comparison of Magnesium Sulphate
Protocols by Weight-Adjusted Versus Two
Grams Per Hour for Preventing Convulsion in
Preeclampsia: A Randomised Controlled Trial
INTRODUCTION
Hypertensive disorder of pregnancy is a leading cause of maternal
and perinatal mortality and morbidity worldwide with an incidence
rate of 5-10% of all pregnancies [1]. Preeclampsia is a severe form
which has multisystem involvement and fatal complication [1,2].
The main management of preeclampsia with severe features are
hospitalisation, seizure prevention, control blood pressure and
termination of pregnancy. Magnesium Sulphate (MgSO4) is the
most effective drug used for seizure prevention [3,4], as this drug
can reduce the risk of eclampsia by more than 50% [5,6]. The
dosage of MgSO4 is still in diverse however, two commonly used
MgSO4 infusions protocols are intravenous (Zuspan regimen) [7]
and intramuscular route (Pritchard regimen) [8]. For the intravenous
regimen, the recommended dose is 4-6 g intravenous loading
dose, followed by the maintenance dose of 1 to 3 g/hr until 24
hours after delivery [7]. For the intramuscular regimen, the dosage
is 4 g intravenous with 10 g intramuscular loading dose, then 5 g
intramuscular every four hours [8]. The therapeutic serum level of
MgSO4 for convulsion prevention is not clearly established, however
the recommended serum level, based on a retrospective study, is
4.8 to 8.4 mg/dL which has been used by many centres for safe
monitoring of this drug [1,9].
Many studies were conducted about the proper dosage of MgSO4
to achieve a therapeutic level. A 2 g/hr maintenance dose was
more likely to achieve a therapeutic level when compared to 1 g/
hr where only 18.6-45.9% of the cases reach a therapeutic level
[10-13]. However, a supra-therapeutic level of serum MgSO4 was
reported in 13.3% of the 2 g/hr protocol [10]. Another important
factor is maternal bodyweight which showed a significant effect
on the serum Mg level in many studies [12,14]. The high maternal
bodyweight subgroup had a higher proportion of subtherapeutic
level of MgSO4; however, there has not been any weight-adjusted
regimen of MgSO4 reported. A previous retrospective study at our
centre reported the optimum maintenance dose which achieved
the serum therapeutic level according to maternal bodyweight
[14]. Therefore, the objective of this study was to compare the
effectiveness of two protocols of MgSO4, a weight-adjusted dose
and the other used the standard 2 g/hr, for preventing convulsion in
preeclamptic women.
MATERIALS AND METHODS
This study was a randomised controlled trial which was conducted
from January 2018 to September 2018 at Udonthani Hospital,
Thailand. The study was conducted after the approval by the
Udonthani Research Ethics Committee (number 1/2561). Pregnant
women with preeclampsia with severe features who met the
inclusion criteria were counselled and invited to participate in this
study. An informed consent was obtained after explanation of the
SAOWANEE TANGMANOWUTTHIKUL1, RAWISARA CHAMPAWONG2, SRISUDA SONGTHAMWAT3, METHA SONGTHAMWAT4
Keywords: Anticonvulsant, Eclampsia, Pregnancy induced hypertension, Serum magnesium, Therapeutic level
ABSTRACT
Introduction: Magnesium Sulphate (MgSO4) is the most effective
drug used for seizure prevention in preeclampsia; however, the
dosage of MgSO4 is still in controversy. Maternal weight is an
important factor for the serum MgSO4 level; however, there has
not been any weight-adjusted regimen of MgSO4 reported.
Aim: To compare the effectiveness of weight-adjusted versus
standard two grams per hour (g/hr) protocols of intravenous
MgSO4 for preventing convulsion in preeclampsia.
Materials and Methods: A randomised controlled trial was
conducted with 86 preeclamptic women from January 2018 to
September 2018. The study group (43 cases) received MgSO4
4 g loading followed by a weight-adjusted protocol starting with
1.2-1.5 g/hr depending on maternal weight. The control group
(43 cases) received MgSO4 4 g loading followed by 2 g/hr. The
serum Mg level was monitored at two and four hours after MgSO4
injection. The MgSO4 dosage was adjusted and continued until
24 hours after delivery. The percentages of those who achieved a
therapeutic level of MgSO4 (4.8-8.4 mg/dL) in the first four hours
were compared between the two groups. Clinical signs of Mg
toxicity were monitored. Maternal and neonatal outcomes were
evaluated.
Results: At four hours after treatment, the proportion of
participants who achieved a therapeutic level were 11.6% in the
study group and 41.9% in the control group (RR 0.28, 95% CI 0.11
to 0.68, p-value <0.01). The 2 g/hr protocol for those participants
whose maternal weight was <80 kg had a higher proportion who
achieved a therapeutic level (p-values >0.001). However, both
protocols had similar low proportions who achieved a therapeutic
level for those whose maternal weight was ≥80 kg (8% in maternal
weight 80-99.9 kg, 0% in maternal weight ≥100 kg). No clinical
MgSO4 toxicity was observed. Maternal and neonatal outcome
were not statistically significant.
Conclusion: Maternal bodyweight is important for MgSO4
dosage adjustment. In those patients whose maternal bodyweight
is <80 kg, a 2 g/hr maintenance dose is more effective than a
lower dose; however, in patients whose maternal bodyweight is
≥80 kg, higher dose is required for achieving therapeutic level. A
low dose is not sufficient for any weight range. At least 2 g/hr is
minimum required for preventing convulsion in preeclampsia.
Saowanee Tangmanowuthikul et al., Weight-adjusted Protocol of Magnesium Sulfate www.jcdr.net
Journal of Clinical and Diagnostic Research. 2019 Feb, Vol-13(2): QC01-QC04
22
Characteristics Weight-adjusted
Group (n=43)
2 grams/hour
Group (n=43) p-value
Age (year), range 29.2±7.3 (16-44) 27.8±7.3 (15-42) 0.41
Primigravida, n (%) 13 (30.2%) 22 (51.2%) <0.05*(a)
Nullipara, n (%) 18 (41.9%) 29 (67.4%) 0.02*(a)
Gestational age (weeks),
range
36.4±3.2 (27-41) 36.1±3.5 (26-41) 0.75
BMI (kg/m2) 31.9±5.5 30.2±5.8 0.18
<18.5, n (%) 0 0 0.32(b)
18.5 to <25, n (%) 3 (7.0%) 9 (20.9%)
25 to <30, n (%) 15 (34.9%) 13 (30.2%)
30 to <40, n (%) 23 (53.5%) 19 (44.2%)
≥40, n (%) 2 (4.7%) 2 (4.7%)
MAP (mmHg) 128.5±9.18 127.9±10.6 0.79
GFR (mL/min) 174.0±55.6 173.1±50.7 0.94
Serum creatinine >1.1 mg/dL 1 (2.3%) 0 1.00(a)
Platelets < 100,000/μL 2 (4.7%) 2 (4.7%) 1.00(a)
Transaminase levels ≥2
time of upper normal limit 4 (9.3%) 2 (4.7%) 0.68(a)
Pulmonary oedema 1 (2.3%) 1 (2.3%) 1.00(a)
Cerebral or visual symptoms 10 (23.3%) 7 (16.3%) 0.42(a)
Medical disease
Chronic hypertension 7 (16.3%) 5 (11.6%) 0.53(a)
Gestational DM 6 (14.0%) 6 (14.0%) 1.00(a)
Autoimmune disease 0 1 (2.3%) 1.00(a)
[Table/Fig-2]: Comparison of epidemiological characteristics, data was presented
in term of mean±standard deviation unless specified otherwise.
p-value was calculated by Student t-test, Pearson chi-square (a) or Fisher-exact test (b);
*statistical significance (p-value<0.05); MAP: Mean arterial pressure; GFR: Glomerular filtration rate;
DM: Diabetes mellitus
range or mean±standard deviation. The groups were compared using
an unpaired Student’s t-test for continuous variables. Chi-square and
Fisher’s-exact tests were used for categorical variables. The mean
difference and relative risk with a 95% CI was calculated for the
magnitude of effect. Statistical analysis was performed using Stata
version13. A p-value <0.05 was considered statistically significant.
RESULTS
A total of 86 participants were included in this study with 43 in each
group. All continued until the study completed and were included
in the data analysis [Table/Fig-1]. The participants’ characteristics
in both groups are shown in [Table/Fig-2]. The mean maternal
bodyweight was 76.5 kg (range 50.3-126 kg). Both groups were
comparable in terms of age, gestational age, body mass index,
study’s method and side effects on the participants. The parent or
legal guardian provided their written informed consent for all patients
under the age of 18.
The inclusion criteria were pregnant preeclamptic women with severe
features who were admitted with gestational age ≥24 weeks. The
preeclampsia was diagnosed according to American College of
Obstetrics and Gynaecology 2013 guideline. Criteria includes systolic
blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg
with proteinuria >300 mg in 24 hours or urine protein-creatinine ratio
>0.3 or proteinuria ≥1+ by urine protein dipstick. Severe features
were defined, as the patients who had one of the following; systolic
blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg,
serum creatinine >1.1 mg/dL or ≥2 time of baseline, transaminase
levels ≥2 time of upper normal limit, platelets <100,000/μL, pulmonary
oedema, cerebral symptoms such as persistent headache, visual
disturbances and right upper abdominal pain [15].
The exclusion criteria were participants, who had serum creatinine
>1.3, hypersensitivity to MgSO4, myocardial damage, diabetic coma,
heart block and myasthenia gravis. All participants were randomly
allocated into two groups using block randomisation by computer
generated random number which were sealed in opaque envelops.
Study and control drugs were prepared by ward nurses according
to the study protocol. All patients received 4 g intravenous loading
dose, and then the study group received a maintenance dose of
MgSO4 by weight-adjusted protocol according to our previous
report [14]. The weight-adjusted protocol was 1.2 g/hr for maternal
bodyweight <60 kg, 1.3 g/hr for maternal bodyweight 60-79.9
kg, 1.4 g/hr for maternal bodyweight 80-99.9 kg and 1.5 g/hr for
maternal bodyweight ≥100 kg. The control group received 2 g/hr
maintenance dose [1]. The serum Mg level was monitored at two
hours after loading dose and then every four hours and dosage of
MgSO4 was adjusted until the therapeutic level of serum Mg was
reached and then continued to 24 hours after delivery.
The blood samples were kept in a collection tube and sent to the
laboratory. The serum Mg level was measured by the Arsenazo method
and the creatinine level was measured by the enzymatic method
[16,17]. The creatinine result was then used to calculate the Glomerular
Filtration Rate (GFR) using the CKD-EPI GFR calculator program. Both
tests were done by an ARCHITECT machine modelC1600 (ABBOTT).
All participants were monitored for clinical magnesium toxicity such as
loss of patellar reflex, oliguria, apnea and drowsiness. A 10% calcium
gluconate was made available in all cases.
The characteristics of patients in both groups were recorded such as
age, gravida, parity, body weight and height. The body mass index
and mean arterial pressure in both groups were calculated and then
compared between groups. Maternal outcomes such as mortality,
eclampsia, intracranial haemorrhage, Disseminated Intravascular
Coagulopathy (DIC), cardiomyopathy, Intensive Care Unit (ICU)
admission, postpartum haemorrhage were recorded. Neonatal
outcomes such as preterm birth, intrauterine growth retardation, low
birth weight, abruption placenta, still birth, death foetus in utero and
Neonatal Intensive Care Unit (NICU) admission were recorded. The
serum Mg levels at two and four hours were compared between the
two groups. The primary outcome measurement was the proportion
of participants who achieved therapeutic level at four hours after the
loading dose, and secondary outcomes were the comparison of
maternal and neonatal complications between the two protocols.
STATISTICAL ANALYSIS
The sample size was calculated using the formula for randomised
controlled trial for binary data [18]. The proportion of successful
outcome from the pilot study data in the study group was 0.20, in
the control group was 0.45. A α was 0.1 and the power was 80%.
The calculated sample size was 43 participants in each group. A
total number of 86 participants, with 43 per group, was used. The
participants’ characteristics are presented in number, percentage,
[Table/Fig-1]: Consort diagram.
www.jcdr.net Saowanee Tangmanowuthikul et al., Weight-adjusted Protocol of Magnesium Sulfate
Journal of Clinical and Diagnostic Research. 2019 Feb, Vol-13(2): QC01-QC04 33
mean arterial pressure, glomerular filtration rate, serum creatinine,
serum transaminase, platelet count, maternal medical disease and
maternal complications such as pulmonary oedema, cerebral or
visual symptoms except gravida and parity.
The primary outcome was a comparison of the effectiveness of
achieving the therapeutic level between both groups. At two hours
after loading dose, the mean serum Mg was not significantly different
between both groups. The proportion of participants who achieved
therapeutic level was 10.8% in the study group and 28.2% in the
control group.
At four hours after the loading dose, the mean serum Mg was higher
in the control group (mean difference 0.63, 95% CI 0.27 to 0.98,
p-value<0.01). The proportion of patients who achieved therapeutic
level was 11.6% in the study group and 41.9% in the control group
(RR 0.28, 95% CI 0.11 to 0.68, p-value <0.01). Supra-therapeutic
level was not detected in either group [Table/Fig-3].
Variables Weight-adjusted 2 grams/hour p-value
Magnesium toxicity
Loss of patellar reflex 0 0 NA
Respiratory paralysis 0 0 NA
Cardiac arrest 0 0 NA
Maternal complication
Convulsion 0 0 NA
ICU admission 2 (4.7%) 2 (4.7%) 1.00
Route of delivery
Normal labour 10 (23.3%) 17 (39.5%) 0.12
Caesarean section 31 (72.1%) 26 (60.5%)
Vacuum extraction 2 (4.7%) 0
Neonatal complication
NICU admission 4 (9.52%) 5 (12.2%) 0.70
Perinatal death 0 0 NA
[Table/Fig-5]: Pregnancy outcome.
ICU: Intensive Care Unit; NICU: Neonatal Intensive Care Unit; p-value was calculated by Pearson
chi-square or Fisher-exact test; statistical significance (p-value<0.05)
Outcome
Weight-
adjusted
n (%)
2 grams/hour
n (%)
RR or
difference 95% CI p-value
Two hours after
loading
Mean serum
Mg (g/dL) 3.97±0.61 4.20±0.88 0.23 -0.12 to
0.57 0.20
Therapeutic
level 4 (10.8%) 11 (28.2%) 0.38 0.13 to
1.10 0.07
Subtherapeutic
level 33 (89.2%) 28 (71.8%) 1.24 0.99 to
1.56 0.06
Supra-
therapeutic level 0 0 NA NA NA
Four hours after
loading
Mean serum
Mg (g/dL) 4.00±0.68 4.63±0.95 0.63 0.27 to
0.98 <0.01*
Therapeutic
level 5 (11.6%) 18 (41.9%) 0.28 0.11 to
0.68 <0.01*
Subtherapeutic
level 38 (88.4%) 25 (58.2%) 1.52 1.15 to
2.00 <0.01*
Supra-
therapeutic level 0 0 NA NA NA
[Table/Fig-3]: Comparison of mean serum Mg and percentage of achieved
therapeutic level in weight-adjusted and 2 grams/hour group.
p-value was calculated by linear or logistic regression analysis; *statistical significance (p-value<0.05);
There was some missing data at 2 hours after loading
According to maternal bodyweight, 11 patients were in <60 kg
group, 42 patients were in 60-79.9 kg group, 27 patients were
in 80-99.9 kg group and 6 patients were in ≥100 kg group. The
proportions of subtherapeutic level of MgSO4 at two and four
hours were higher in the weight-adjusted regimen especially in the
maternal weight <80 kg. In the maternal bodyweight between 60-
79.9 kg at four hours, the relative risk was 2.16, 95% CI 1.23 to
3.79, p-value <0.01. The high maternal weight (≥80 kg), in both
regimens had very high proportion of subtherapeutic level of MgSO4
with 92% in 80-99.9 kg and 100% in ≥100 kg [Table/Fig-4].
The pregnancy outcome include maternal complications, route
of delivery, neonatal complications shown in [Table/Fig-5]. No Mg
toxicity or eclampsia was detected during study period. Maternal
complications, route of delivery and neonatal complications were
not significantly different between both groups.
DISCUSSION
Magnesium sulfate is proven to be the first line drug to prevent
seizure in preeclamptic women. However, the proper dosage of this
drug has not been clearly established. Many centres use the Zuspan
regimen by MgSO4 4-6 g intravenous loading dose, followed by an
infusion of the maintenance dose of 1-2 g/hr. The maintenance
dose was adjusted until the therapeutic level was reached then
continued until 24 hours after delivery [7]. The weight-adjusted
Outcome
Weight-
adjusted,
n (%)
2 grams/hour,
n (%) RR 95% CI p-value
BW<60 kg
Subtherapeutic
level at two
hours
2 (50.0%) 3 (42.86%) 1.17 0.32 to 4.28 0.82
Subtherapeutic
level at four
hours
3 (75.0%) 2 (28.57%) 2.63 0.72 to 9.64 0.15
BW 60-79.9 kg
Subtherapeutic
level at two
hours
18 (81.82%) 13 (65.00%) 1.26 0.86 to 1.84 0.23
Subtherapeutic
level at four
hours
19 (86.36%) 9 (42.11%) 2.16 1.23 to 3.79 <0.01*
BW 80-99.9 kg
Subtherapeutic
level at two
hours
10 (71.43%) 9 (69.23%) 1.03 0.63 to 1.69 0.90
Subtherapeutic
level at four
hours
13 (92.86%) 12 (92.31%) 1.01 0.81 to 1.25 0.96
BW≥100 kg
Subtherapeutic
level at two
hours
3 (100%) 3 (100%) NA NA NA
Subtherapeutic
level at four
hours
3 (100%) 3 (100%) NA NA NA
[Table/Fig-4]: Comparison of percentage of subtherapeutic level in weight-adjusted
and 2 grams/hour group in different weight groups.
BW: Body weight; p-value was calculated by logistic regression analysis; *statistical significance
(p-value<0.05)
maintenance dose in this study was derived from a retrospective
analysis of optimum maintenance dose which achieved therapeutic
level of serum Mg in preeclamptic women [14].
The comparison of both protocols in this study showed no
eclampsia in either protocol. Also the maternal bodyweight had
a significant effect on the serum Mg level. Many studies reported
a high proportion of subtherapeutic level of MgSO4 in 4 g loading
and 1 g/hr maintenance [12,13,19]. This study also shows with
either a 2 g/hr or a weight-adjusted maintenance dose there still
had a high proportion of subtherapeutic level of MgSO4, especially
in those with high maternal bodyweight. The proportion of those
who achieved therapeutic level at four hour in the weight-adjusted
group in this study was lower than the previous studies which used
Saowanee Tangmanowuthikul et al., Weight-adjusted Protocol of Magnesium Sulfate www.jcdr.net
Journal of Clinical and Diagnostic Research. 2019 Feb, Vol-13(2): QC01-QC04
44
PARTICULARS OF CONTRIBUTORS:
1. Department of Obstetrics and Gynecology, Udonthani Hospital, Udonthani, Thailand.
2. Department of Obstetrics and Gynecology, Udonthani Hospital, Udonthani, Thailand.
3. Department of Obstetrics and Gynecology, Udonthani Hospital, Udonthani, Thailand.
4. Department of Obstetrics and Gynecology, Udonthani Hospital, Udonthani, Thailand.
NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR:
Dr. Metha Songthamwat,
45/5, Phorniyomrd Muang, Udonthani-41000, Thailand.
E-mail: udonhome@yahoo.com
FINANCIAL OR OTHER COMPETING INTERESTS: None.
Date of Submission: Sep 17, 2018
Date of Peer Review: Oct 04, 2018
Date of Acceptance: Dec 06, 2018
Date of Publishing: Feb 01, 2019
the 1 g/hr regimen [10,20]. This might be due to the proportion of
high maternal bodyweight participants in this study, most of these
patients had their BMI ≥30.
The proportions of participants in the study group who achieved
therapeutic level in high maternal weight subgroups were 0-7.2%.
This is compatible with the previous study in which high body
mass index subgroup (≥30 kg/m2) achieved therapeutic level in
7.4% [20]. The result of the 2 g/hr protocol from this study also
had only 40.5% of participants who achieved therapeutic level.
This is lower than a previous study that reported 80% of the
participants who achieved therapeutic level, supra-therapeutic
level was reported in 13% in the previous study but none were
found in this study [10]. Other MgSO4 clinical toxicities such
as loss of patella reflex or respiratory depression were also not
detected in this study.
This study is first to report the weight-adjusted protocol of MgSO4
by prospective randomised controlled trial. The block randomisation
with opaque envelope made for a good representation of the
population.
LIMITATION
There are some limitations to this study. The first is the sample size
was calculated from the proportion of participants who achieved a
serum therapeutic level of MgSO4, not the incidence of eclampsia.
So the effectiveness of MgSO4 in eclampsia prevention needs a
larger sample size to be conclusive. Second, the sample size in
some maternal bodyweight groups, such as <60kg, was small, a
larger sample size is needed for the specific recommended dose
for lower weight patients with preeclampsia. Moreover, the loading
dose in this study was 4 g, the effect of higher loading dose to the
serum Mg still needs further evaluation.
The study implies that 2 g/hr regimen for maintenance dose is better
than a lower dose regimen, however further researches study, for
weight-adjusted dose in high maternal weight preeclamptic patients,
are needed.
CONCLUSION
Maternal bodyweight is important for MgSO4 dosage adjustment.
When the maternal bodyweight was <80 kg, a 2 g/hr maintenance
dose was more effective than a lower dose. However, when the
maternal bodyweight was ≥80 kg, a higher dose than 2 g/hr was
required for achieving therapeutic level.
ACKNOWLEDGEMENTS
We gratefully acknowledge Dr. Thammanoon Wisittanawat, director
of Udonthani Hospital for permission and grant support. Thanks to
the Udonthani Hospital staff and all participants who assisted in this
trial. None of the authors has any conflict of interest relative to this
work. This study did not receive pharmaceutical company support.
Clinical Trials registration number: TCTR20180122001
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