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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE
KARNATAKA
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1 Name of the candidate and
address
DR.BIMBA
D/O G R KRISHNAPPA
“CHAYA”UDAYAGIRI EXTENSION ,
SECOND STAGE NEAR RING ROAD ,
HASSAN-573201
2 Name of the Institution
KEMPEGOWDA INSTITUTE OF MEDICAL
SCIENCES, BANGALORE.
3 Course of the study and
M.S. IN OBSTETRICS AND GYNAECOLOGY
subject
4 Date of admission to the
31st MAY 2011
course
5 Title of the topic
TO ASSESS THE EFFICACY OF INTRAVENOUS
LABETALOL VERSUS ORAL NIFEDIPINE IN
CONTROL OF ACUTE HYPERTENSION IN SEVERE
PREECLAMPSIA/ECLAMPSIA.
1
6
Brief resume of the intended work
6.1 Introduction and need for the study
Preeclampsia is the development of hypertension, proteinuria, or both
after 20 weeks of pregnancy in women with previously normal blood pressure. It is a
syndrome which may also be associated with myriad signs and symptoms such as
edema, visual disturbance, and headache and epigastric pain. It is also associated
with laboratory abnormalities like elevated liver enzymes and low platelet count
(HELLP syndrome) The incidence of pre eclampsia is 5-10%. Preeclampsia
accounts for 12-18% of maternal mortality. The highest maternal mortality rate
reported in developing countries is 0.4 %. Besides it is associated with a five fold
increase in perinatal mortality.1
Severe pre eclampsia/eclampsia with blood pressure readings ≥160/110
mmHg is associated with increased risks of complications like hypertensive
encephalopathy, intra-cranial hemorrhage and eclampsia .The reduction of blood
pressure to levels below 150/100 mmHg is necessary to reduce complications. The
first line anti-hypertensive medications recommended for acute control of blood
pressure in severe pre eclampsia are intravenous hydralazine ,oral or intravenous
labetalol and oral nifedipine.2
In India, nifedipine is the most commonly used antihypertensive for
blood pressure control in severe hypertension because of its easy availability, rapid
onset of action, ease of oral administration and satisfactory reduction in blood
pressure. It is however banned in certain countries like Australia in view its sudden
unpredictable fall of blood pressure and
cardiac side effects. An interaction
between nifedipine and magnesium sulphate may be associated with profound
muscle weakness and hypotension. Nifedipine and magnesium sulphate both have
tocolytic effect and can prolong the duration of labour.
Intravenous Labetalol is also recommended as one of the first line agents in the
management of acute severe hypertensive disorder of pregnancy along with
hydralazine. IV Labetalol can also be given where control of blood pressure is
required in labour prior to caesarean section or when the patient is in coma
To date, there have not been many randomized clinical trials comparing these 2
agents in pregnancy. Hence we would like to study the efficacy of intermittent
intravenous labetalol with oral nifedipine in the control of severe hypertension in
pregnancy.
2
6.2 Review of literature
The management goals in preeclampsia are to prevent seizures and control
hypertension.3 Magnesium sulfate is the medication of choice for the prevention of
eclamptic seizures in women with severe preeclampsia and for the treatment of
women with eclamptic seizures.4,5
Hydralazine, a potent arterial vasodilator, has long been the criterion standard of
therapy for the management of hypertensive emergencies complicating pregnancy.
Less obvious, however, are alternative therapies for the management of this disorder.
This question became even more important when intravenous hydralazine was
temporarily withdrawn from the market in the early 1990s. Alternative agents
suggested from the literature include nifedipine, a dihydropyridine (L-type) calcium
channel blocker, and labetalol hydrochloride, a unique alpha- and beta-adrenergic
receptor blocker. Both nifedipine and labetalol have demonstrated comparable
efficacy and a lower risk of overshoot hypotension and fetal distress when compared
with hydralazine in randomized clinical trials.6,7
Nifedipine is a Ca2+ channel blocker which is an important group of drugs
used for the treatment of hypertension. The basis for their use in hypertension comes
from the understanding that hypertension generally is the result of increased
peripheral vascular resistance, contraction of vascular smooth muscle is dependent
on the free intracellular concentration of Ca2+, inhibition of transmembrane
movement of Ca2+ through voltage-sensitive Ca2+ channels can decrease the total
amount of Ca2+ that reaches intracellular sites. Indeed, all of the Ca2+ channel
blockers lower blood pressure by relaxing arteriolar smooth muscle and decreasing
peripheral vascular resistance.8 As a consequence of a decrease in peripheral
vascular resistance, the Ca2+ channel blockers evoke a baroreceptor-mediated
sympathetic discharge. In the case of the dihydropyridines, tachycardia may occur
from the adrenergic stimulation of the SA node; this response is generally quite
modest except when the drug is administered rapidly. Indeed, the concurrent use of a
receptor antagonist drug may magnify negative chronotropic effects of these drugs
or cause heart block in susceptible patients.9
The pharmacokinetics of nifedipine includes rapid onset, long action, oral
bioavailabilty, and infrequent side effects. These characteristics theoretically make it
an ideal agent for hypertensive emergencies in pregnancy. In fact, previous
investigations have demonstrated that nifedipine effectively lowers blood pressure
without any apparent reduction in uteroplacental blood flow10,11 and without any
significant fetal heart rate abnormalities.12,13 These additional benefits are important
characteristics expected of an ideal therapeutic agent for the treatment of
hypertensive emergencies complicating pregnancy. It begins to act within 20 min.
Duration of action is 4-8 hrs. Half life is 2 hrs. Rare adverse effects include
peripheral oedema, dizziness, flushing, headache, heartburn, nausea.
3
Labetalol is representative of a class of drugs that act as competitive
antagonists at both α1and β receptors. Labetalol has two optical centers, and the
formulation used clinically contains equal amounts of the four diastereomers. The
pharmacological properties of the drug are complex, because each isomer displays
different relative activities. The properties of the mixture include selective blockade
of α1 receptors (as compared with the α2 subtype), blockade of β1 and β2 receptors,
partial agonist activity at β2 receptors, and inhibition of neuronal uptake of NE
(cocaine-like effect) The potency of the mixture for β receptor blockade is 5-10 fold
that for α1 receptor blockade.14
The actions of labetalol on both α 1 and β receptors contribute to the fall in
blood pressure observed in patients with hypertension. α 1 receptor blockade leads to
relaxation of arterial smooth muscle and vasodilation, particularly in the upright
position. The α1 blockade also contributes to a fall in blood pressure, in part by
blocking reflex sympathetic stimulation of the heart. In addition, the intrinsic
sympathomimetic activity of labetalol at β2 receptors may contribute to
vasodilation.14
Labetalol is available in oral form for therapy of chronic hypertension and as
an intravenous formulation for use in hypertensive emergencies. Labetalol has been
associated with hepatic injury in a limited number of patients.
Labetalol is one of the few β adrenergic antagonists that have been
recommended as treatment for acute severe hypertension (hypertensive emergency).
Its hypotensive action begins within 2-5 minutes after IV administration, reaching its
peak at 5-15 minutes and lasting ~2-4 hours. Heart rate is either maintained or
slightly reduced and cardiac output is maintained.
Labetalol reduces systemic vascular resistance without reducing total peripheral
blood flow. Cerebral, renal, and coronary blood flow is maintained. It can be used in
the setting of pregnancy-induced hypertensive crisis because little placental transfer
occurs due to the poor lipid solubility of labetalol.14
Rare adverse effects include fatigue, dizziness, light headedness, nausea,
tingling sensation of scalp, pruritis, diaphoresis, orthostatic hypotension,
bronchospasm and dyspnea.
Raheem I A, et al compared oral nifedipine versus intravenous labetalol for
acute blood pressure control in hypertensive emergencies of pregnancy and
concluded that oral nifedipine and intravenous labetalol regimens are similarly
effective in the acute control of severe hypertension in pregnancy .15
Vermillion et al compared the efficacies of oral nifedipine and intravenous
labetalol and found both drugs to be effective in the management of acute
hypertensive emergencies of pregnancy. Nifedipine controls hypertension more
rapidly and is associated with a significant increase in urinary output. 16
4
Paulino Vigil-De Gracia et al concluded that labetalol fulfills the criteria
required for an antihypertensive drug to treat severe hypertension in pregnancy.17
A prospective trial by C. A. Michael et al performed to evaluate the use of
diazoxide and labetalol given intravenously in the management of severe
hypertensive disease in pregnancy concluded that both drugs had an efficient
Hypotensive action. The reduction in blood pressure in the labetalol group was
better controlled and concluded that this may be a factor influencing perinatal
outcome. Because of the freedom of maternal and fetal side-effects, labetalol
given by intravenous infusion is a more appropriate drug for use in the
management of hypertensive crises occurring in pregnancy and labour.18
Duley et al compared different antihypertensive drugs for very high blood pressure
during pregnancy and concluded that, the choice of antihypertensive should depend
on the clinician's experience and familiarity with a particular drug and on what is
known about adverse effects. Exceptions are diazoxide, ketanserin, nimodipine and
magnesium sulphate, which are probably best avoided.19
6.3
Objective of the study
•
To assess the efficacy of intermittent intravenous labetalol versus oral
nifedipine capsules in the treatment of acute hypertension in severe pre
eclampsia /eclampsia with blood pressure ≥160/110 mm Hg.
•
The assess the time taken and the number of doses required to achieve target
blood pressure of ≤ 150/100 mmHg.
•
Maternal side effects
•
Fetal side effects
5
7
7.1 Materials and methods
All women with severe preeclampsia/eclampsia with BP readings ≥160/110
mm Hg, admitted to KIMS Labour room.
STUDY SUBJECTS
: 30 each for intravenous labetalol and oral nifedipine
STUDY DURATION
: December 2011 to June 2013
STUDY PLACE
: Kempegowda Institute of Medical Sciences.
STUDY DESIGN
: Comparative study
SAMPLE DESIGN
: Purposive sampling
7.2 INCLUSION CRITERIA:
•
Patients with severe preeclampsia / eclampsia and
mm Hg,
•
Medical decision to rapidly control blood pressure.
7.3 EXCLUSION CRITERIA:
•
Patients with essential hypertension.
•
H/O Cardiac disease.
•
H/O Bronchial asthma.
•
H/O Hematological disorder.
•
H/O Allergy to labetalol or nifedipine
•
Diabetic
•
Liver disorders
•
Maternal heart rate <60 or >120 beats per minute..
6
B P ≥160/100
7.4 PROCEDURE:
A total number of 60 patients of severe preeclampsia /eclampsia
with BP ≥ 160/110 mm Hg are included in the study. Severe
hypertension is taken as a sustained systolic blood pressure of 160 mm
Hg or diastolic blood pressure of 110 mm Hg on repeat measurements
15 minutes apart while the patient is in a lateral recumbent position.
Enrolled patients will be randomized to receive either oral nifedipine or
intravenous labetalol
Demographic and standard laboratory data will be collected on admission.
Magnesium sulphate (Zuspan’s regimen) is started if required
(impending eclampsia/eclampsia).
Patients are randomly assigned to be started either with intravenous
labetalol (Study Group) or oral nifedipine (Control Group) until
satisfactory BP control is achieved that is <150/100 mm Hg.
Study Group (Group A) : Injection labetalol 20 mg I V bolus over 10
minutes repeated every 20 min increasing to 40,80, 80, 80 to a maximum
of 300mg6,.20,21,22 Once blood pressures start rising more than 10 mm Hg
the patient is started on Tab Labetalol in Group A.
Control Group (Group B): Nifedipine 10 mg stat and then repeated at
45 minutes interval till satisfactory BP control is achieved. Maximum
dose of nifedipine which will be given is 5 doses.20, 21, 22 once target blood
pressure reached, patient started on tablet nifedipine SR, two hours later.
During the study period maternal blood pressures and are recorded at
every fifteen minutes interval till first 30 minutes after achieving target
blood pressure less than or equal to 150/100,then every thirty minutes for
next 2 hours then every hourly .
Continuous maternal vital parameters and electronic fetal monitoring
is done CTG trace is taken at the beginning and then one at the end of the
study/ two hours.
Treatment is considered as failure if blood pressure doesn’t decrease
even after increasing the dose to maximum. Additional antihypertensive
agent is added and is managed accordingly.
If patient develops hypotension B P ≤ 90/60 mmHg then the trial is
terminated and patient treated with intravenous fluids and ephedrine. If
bradycardia develops, the trial is terminated and patient treated with atropine
/epinephrine.
7
7.5 Does the study require any investigations or interventions to be conducted
on patients or other humans or animals?
ANIMALS :NIL
PATIENTS;YES
INVESTIGATIONS:
PATIENTS: Routine investigation for pregnancy and those for preeclampsia
Obstetric scan,ECG,continous electronic fetal monitoring
INTERVENTIONS:
Yes, the study requires intervention - Intravenous labetalol, oral nifedipine in
control of blood pressure, the consent for which will be taken.
7.4 Ethical Clearance
Has this study been approved by the Ethical Committee?
Yes
.
7.6 Statistical Analysis
Data will be analysed using student t-test
8
8
References
1 Guler Sahin, Gulmezoglu AM. Incidence, morbidity and mortality of pre
eclampsia and eclampsia. Geneva foundation for medical education and research
2 Royal college of obstetrics and gynecology ,[Guideline No. 10(A]
3 American college of obstetrics and gynaecology ,practice bulletin ,clinical
management guidelines for obstetrician sand gynaecologist, number 33,2002,reaffirmed in
2008.
4 Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and
eclampsia. Obstet Gynecol 1998; 92:883–9.
5
Magpie Trial Collaboration Group. Do women with preeclampsia, and their
babies, benefit from magnesium sulphate? The Magpie Trial: a randomized
placebo-controlled trial. Lancet 2002; 359:1877–90.
6 Fenakel K, Fenakel G, Appelman Z, Lurie S, Katz Z, Shoham Z. Nifedipine in
the treatment of severe preeclampsia. Obstet Gynecol 1991; 77:331-7.
7 Mabie WC, Gonzalez AR, Sibai BM, Amon E. A comparative trial of labetalol and
hydralazine in the acute management of severe hypertension complicating
pregnancy. Obstet Gynecol 1987; 70:328-33.
6 Witlin AG, Sibai BM. Magnesium sulphate therapy in preeclampsia and
eclampsia. Obstet Gynecol 1998; 92:883–9.
7 Magpie Trial Collaboration Group. Do women with preeclampsia, and
their
babies, benefit from magnesium sulphate? The Magpie Trial: a randomized
placebo-controlled trial. Lancet 2002; 359:1877–90.
8. Weber MA. Calcium channel antagonists in the treatment of hypertension. Am
J Cardiovasc Drugs, 2002, 2:415–431.[PMID: 14727956]
9. Goodman & Gilman's The Pharmacological Basis of Therapeutics.Section III.
Modulation of Cardiovascular Function. Treatment of Myocardial Ischemia
and Hypertension.17th edition; 27:
10. Lindow SW, Davies N, Davey DA, Smith SA. The effect of sublingual
nifedipine on uteroplacental blood flow in hypertensive pregnancy. Br J Obstet
Gynaecol 1988; 95:1276-81.
11. Moretti MM, Fairlie FM, Axl S, Khoury AD, Sibai BM. The effect of
nifedipine therapy on fetal placental Doppler waveforms in preeclampsia
remote from term. Am J Obstet Gynecol 1990; 163:1844-8.
9
12. Lurie S, Fenakel K, Freidman A. Effect of nifedipine on fetal heart rate in the
treatment of severe pregnancy induced hypertension. Am J Perinatol 1990;
7:285-6.
13. Walters NJ, Redman WG. Treatment of severe pregnancy associated with
hypertension with the calcium antagonist nifedipine. Br J Obstet Gynaecol
1987; 91:330-4.
14. Goodman & Gilman's The Pharmacological Basis of Therapeutics.Section III.
Modulation of Cardiovascular Function. Treatment of Myocardial Ischemia
and Hypertension.17th edition; 12:
15. Raheem I, Saaid R, Omar S, Tan P.(10 OCT OCT 2011) Oral nifedipine versus
intravenous labetalol for acute blood pressure control in hypertensive emergencies of
pregnancy ,DOI: 10.1111/j.1471-0528.2011.03151.x
16. Vermillion et al (1999) Am J Obstet Gynecol 1999;181:858-61
17. Inform healthcare 2007, Vol. 26, No. 2 , Pages 163-171
18. A prospective trial by C. A. Michael et al (February 1986), ANZJOG,
Volume 26, Issue 1, pages 26–29, Feb
19. Duley L, Henderson-Smart DJ, Meher S: Drugs for treatment of very high blood
pressure during pregnancy.Cochrane Database of Systematic Reviews 2006. (Issue
3): Art. No.:CD001449
20. AGOD BULLETIN Volume 10 January 2011 Monthly Issue 9
21. Tiina Podymow, Phyllis August, Update on the Use of Antihypertensive Drugs
in Pregnancy, Hypertension journal of American heart association, 2008.
22. Laura A.et al, approach to the diagnosis, evaluation and treatment of the
hypertensive disorders of pregnancy (HDP),JOGC, Volume 30, Number 3 • volume
30, numéro 3 March • mars 2008 Supplement 1
23. American college of obstetrics and gynecology ,practice bulletin ,clinical
management
guidelines
for
obstretician
sand
gynaecologist,number
33,2002,reaffirmed in 2008.
24 Williams obstetrics 23rd edition; 34:706-7092.
9 Signature of the candidate
10
10 Remark of the guide
This study will help to provide an alternative safe
drug for our use in acute hypertensive emergency of pregnancy where nifedipine
cannot be used.
11 Name and designation
11.1 Guide
Dr Suvarna. R
MDOBG
Professor,
Department of OBG,
KIMS,Bangalore-560 070
11.2 Signature
11.3. Co-guide (if any)
11.4 Signature
11.5 Head of the Department
Prof. Dr. Nirmala Shivalingaiah
MBBS, M.S OBG
Professor and Head,
Department of OBG
KIMS, Bangalore 560 070
11.6 Signature
11
12 12.1 Remarks of the dean and principal
12.2 Signature
12