- Email: [email protected]
Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial
Original Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
ajog.org
OBSTETRICS
Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial Q16
Chanderdeep Sharma, MD (OBG), DNB (OBG); Anjali Soni, MD (OBG); Amit Gupta, MD (OBG); Ashok Verma, MD (OBG); Suresh Verma, MD (OBG)
Q2
OBJECTIVE: We sought to compare the efficacy of intravenously administered hydralazine and oral nifedipine for acute blood pressure control in acute hypertensive emergency of pregnancy. STUDY DESIGN: In this double-blind, randomized, controlled trial, pregnant women (24 weeks POG) with sustained increase in systolic blood pressure of 160 mm Hg or diastolic blood pressure of 110 mm Hg were randomized to receive intravenous hydralazine injection in doses of 5, 10, 10, and 10 mg and a placebo tablet or oral nifedipine (10 mg tablet up to 4 doses) and intravenous saline injection every 20 minutes until the target blood pressure of 150 mm Hg systolic and 100 mm Hg diastolic was achieved. Crossover treatment was administered if the initial treatment failed. The primary outcome of the study was time necessary to achieve target blood pressure. The secondary outcomes were the number of dosages required, adverse maternal and neonatal effects, and perinatal outcome. RESULTS: From December 2014 through September 2015, we enrolled 60 patients. The median time to achieve target blood pressure
Q3
Introduction Hypertension is one of the most common medical disorders during pregnancy.1 Hypertensive disorders of pregnancy constitute one of the major causes of maternal and fetal morbidity and mortality worldwide.2 The American Congress of Obstetricians and Gynecologists (ACOG) defines systolic blood pressure (BP) 160 mm Hg or diastolic BP 110 mm Hg as one of the severe features of preeclampsia. BP readings should preferably be taken on 2 occasions with an interval of at least 4 hours between them. Nonetheless, diagnosis can be confirmed within a shorter interval (even minutes) to facilitate timely antihypertensive therapy. Increased BP is associated with increased risk of morbidity and mortality in preeclamptic women.2 ACOG Task Cite this article as: Sharma C, Soni A, Gupta A, et al. Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial. Am J Obstet Gynecol 2017;volume:x.ex-x.ex. 0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.08.018
was 40 minutes in both groups (intravenous hydralazine and oral nifedipine) (interquartile interval 5 and 40 minutes, respectively, P value .809). The median dose requirement in both groups was 2 (intravenous Q4 hydralazine and oral nifedipine) (interquartile range 1 and 2 doses, Q5 respectively, P value .625). Intravenous hydralazine was associated with statistically significantly higher occurrence of vomiting (9/30 vs 2/30, respectively, P value .042). No serious adverse maternal or perinatal side effects were witnessed in either group. CONCLUSION: Both intravenous hydralazine and oral nifedipine are equally effective in lowering of blood pressure in acute hypertensive emergency of pregnancy. Key words: acute hypertensive emergency of pregnancy, blood
pressure, critical care, double blind, hypertension, intravenous hydralazine, maternal morbidity, maternal mortality, oral nifedipine, preeclampsia
Force recommends use of antihypertensive therapy to lower severe hypertension in preeclamptic women during pregnancy.2 Cochrane meta-analysis on drugs for the treatment of very high BP during pregnancy states that until better evidence is available, the choice of antihypertensive should depend on clinician experience and women’s preferences.3 Commonly used agents for acute lowering of BP in preeclamptic women with severe hypertension in pregnancy are intravenous hydralazine, intravenous labetalol, and oral nifedipine.3,4 However, there is limited evidence with respect to nature of drug to be used. Cochrane meta-analysis found no significant difference regarding efficacy between various agents (hydralazine, labetalol, or nifedipine). Recently there was concern regarding use of hydralazine for acute BP control in preeclamptic women with severe hypertension.1,4 Use of intravenous hydralazine for acute BP control in pregnant women with severe sustained hypertension has been implicated with increased risk of cesarean delivery, placental abruption, maternal overshoot hypotension, and low Apgar scores in neonates.4-6
Additionally, on detailed evaluation of available evidence7-13 comparing hydralazine with nifedipine for acute BP control in women with severe hypertension during pregnancy, it is observed that the majority of these studies actually used short-acting sublingual nifedipine,7,8,11,13 which was withdrawn because of concerns of excessive cardiovascular morbidity and mortality.4 From 1995 through 2013 a PubMed database search for trials comparing hydralazine and nifedipine BP control in pregnant preeclamptic women with severe hypertension using key words “severe hypertension,” “pregnancy,” “nifedipine,” and “hydralazine” revealed only 1 randomized controlled trial10 that had compared nifedipine and intravenous hydralazine for the lowering of BP during hypertensive emergency in pregnancy. Hence, in the present era of evidencebased medicine there is a paucity of good-quality evidence on the better option between 2 commonly used agents, ie, intravenous hydralazine and oral nifedipine, for the control of acute BP control in women with severe preeclampsia during pregnancy.
MONTH 2017 American Journal of Obstetrics & Gynecology FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
1.e1
56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110
111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
ajog.org
OBSTETRICS
With this objective in mind, we conducted this double-blind randomized controlled trial to evaluate which of the 2 drugseintravenous hydralazine or oral nifedipineehas better efficacy in controlling acute severe hypertension in pregnant women with preeclampsia.
Materials and Methods We conducted this randomized, doubleblind, controlled trial for acute lowering of BP during hypertensive emergency of pregnancy. The trial was conducted in the labor ward of the Department of Obstetrics and Gynecology of Dr Rajendra Prasad Government Medical College and Hospital, Tanda, India, a tertiary care teaching and referral hospital. The recruitment took place from December 2014 through September 2015 after obtaining approval from the institutional ethics committee. The trial was also registered with the Trial Registry Q6 of India (vide no. CTRI/2014/12/ 005285). All pregnant women with sustained severe hypertension (defined as systolic BP 160 mm Hg or diastolic BP 110 mm Hg on 2 separate occasions, at least 30 minutes apart) were approached for enrollment. Women were eligible for inclusion if they were between 18-45 years of age, they were at 24 weeks of gestation, their heart rate was between 60 and <120 beat/min, and they had a reassuring fetal heart rate (120-160 beat/ min, with no abnormality detected on admission cardiotocography). The exclusion criteria were a known atrial-ventricular heart block or history of heart failure, moderate to severe bronchial asthma provoked by either drug under study, exposure to any antihypertensive medication within the past 24 hours, and nonpregnancy-related hypertension (diagnosed cases of chronic or secondary hypertension). Consolidated Standards of Reporting Trials (CONSORT) guidelines were strictly followed throughout the trial. Written informed consent was obtained from the participating women. The randomization sequence was computer-generated in blocks of 4 or 8. Study medications were placed in sequentially numbered sealed envelopes.
FIGURE 1 ---
Assessed for Eligibility (n = 132) Excluded • Not meeting inclusion criteria(n=36) • Declined to participate (n=46)
ENROLLMENT
print & web 4C=FPO
Original Research
RANDOMIZED (60)
ALLOCATION Allocated to intervention NIFEDIPINE (n=30)
Allocated to intervention HYDRALAZINE (n=30)
FOLLOW UP & ANALYSIS
ANALYSED = 30 (LOST TO FOLLOW UP;NONE)
ANALYSED = 30 (LOST TO FOLLOW UP; NONE)
Consolidated Standards of Reporting Trials (CONSORT) flow chart of participants.
Q15
Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017.
Each envelope contained 2 packages. One was labeled as package A and the other was labeled as package B. Package A contained either intravenous hydralazine vials (total 10 mL as hydralazine, 5 mg/mL) (Dralgeen; Bharat Serums and Vaccines Ltd) and 4 placebo tablets or intravenous saline (10 mL as 0.9%) and 4 10-mg nifedipine tablets (Zydus Cadila). Package B contained the opposite regimen if treatment crossover was required. These envelopes were opened by an investigator, and package A was administered first to the participant. Oral nifedipine and placebo tablets were identical in appearance. Each tablet contained 10 mg nifedipine or placebo. Colorless intravenous study solution (hydralazine or saline) was placed into a 10-mL syringe by the investigator and was labeled as “A,” then given to the physician (resident doctor) for intravenous administration, along with 4 tablets (nifedipine or placebo) from package A.
Intravenous study solution was administered through an intravenous line secured as soon as the women were enrolled in the trial. In case of crossover to regimen B, the contents of package B were prepared in a manner similar as described for regimen A, and the syringe Q7 was labeled “B.” Thus, the physician and the participant were blinded regarding the treatment administered. The women Q8 rested in bed in the semirecumbent position. The physicians were instructed to administer 1 tablet to be swallowed from package A and to administer 1 mL intravenously from syringe A over 1 minute as the initial treatment (ie, 5 mg of intravenous hydralazine or 1 mL saline). After 20 minutes, if the systolic BP was >150 mm Hg or if the diastolic BP was >100 mm Hg, the second tablet was administered and 2 mL intravenous solution from syringe A was administered over 1 minute (ie, 10 mg of intravenous hydralazine or 2 mL of saline). If the target BP was not achieved even after
1.e2 American Journal of Obstetrics & Gynecology MONTH 2017 FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222
ajog.org 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278
OBSTETRICS
another 20 minutes, the third tablet was administered, along with intravenous administration of 2 mL solution from syringe A. This was repeated for 1 more cycle of treatment if required to lower BP to the target range (ie, hydralazine in doses of 5 mg, 10 mg, 10 mg, and 10 mg and a flat dose of nifedipine 10 mg each every 20 minutes to a maximum of 4 doses). Crossover to regimen B occurred if target BP was not achieved after 4 cycles of regimen A. Regimen B was administered in a fashion identical to that of regimen A. If the target BP was still not achieved, open-label treatment was performed according to the preference of the provider. The BP was measured with mercury sphygmomanometer as per standard recommendations, using Korotkoff sound 5 for diastolic BP. The BP was measured every 20 minutes for at least 100 minutes until the target BP of 150 mm Hg systolic and 100 mm Hg diastolic was achieved. Once the target BP was achieved, no further trial medication was administered. During the course of treatment, continuous electronic fetal heart monitoring was performed. In the event of nonreassuring fetal or maternal status, the trial protocol was abandoned and appropriate measures such as open antihypertensive treatment or expedited delivery were instituted. If clinically significant maternal hypotension occurred, appropriate measures were suggested for the provider’s consideration. After completion of the trial protocol, women were requested to complete a questionnaire regarding occurrence of side effects during the trial period (ie, nausea, vomiting, headache, dizziness, urticaria, flushing, pruritus, nasal congestion, conjunctivitis, palpitations). After successfully lowering the BP to target range, further antihypertensive therapy was started 2 hours after the last trial medication as per discretion of the provider. As per the standard protocol, the delivery of the neonate was performed as a definite treatment for severe pregnancy-induced hypertension. As per the institutional protocol all women after admission received magnesium sulfate. The primary outcome measured was time needed to achieve target
Original Research
279 280 281 Demographic characteristics of women in both groups 282 Hydralazine, Nifedipine, 283 n ¼ 30 n ¼ 30 P value 284 24.2 6.3 23.4 2.6 .163 Age,a y 285 b 286 Gravida 2 (1) 2 (1) .280 287 1 16 22 288 2 8 4 289 3 5 2 290 291 4 1 2 a 2 292 BMI, kg/m 21.8 3.2 22.5 2.8 .776 293 Heart rate,a beat/min 78 7 86 6 .279 294 POG,a d 257 28 258 17 .856 295 a 296 Systolic BP at enrollment, mm Hg 177 18 168 6 .064 297 Diastolic BP at enrollment, mm Hga 109 11 107 8 .307 298 Mean arterial pressure at enrollmenta 127 14 125 9 .492 299 Women with systolic BP 160 mm Hg, n 26 21 .209 300 301 Women with diastolic BP 110 mm Hg, n 19 18 .989 302 Neonatal sex, n 303 Male 15 13 .605 304 Female 15 17 305 306 Antenatal steroid given, n 4 3 .688 307 BMI, body mass index; BP, blood pressure. 308 a Mean SD; b Median (interquartile interval). 309 Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017. 310 311 312 systolic BP of 150 mm Hg and diastolic nonparametric testing, we randomized a 313 BP of 100 mm Hg (both targets had to total of 60 women (30 in each group). 314 be fulfilled). Secondary outcomes The data were entered into software 315 included total number of antihyperten- (SPSS 17; IBM Corp, Armonk, NY). The 316 sive dosages required to achieve the analysis was based on the intention to 317 target BP (ie, systolic 150 mm Hg and treat. One-sample Kolmogorov-Smir318 diastolic 100 mm Hg), maternal heart nov test was used to check normal dis319 rate profile during the first 100 minutes, tribution of continuous data. Student t 320 maternal hypotension (BP <90/60 mm test was used to analyze the normally 321 Hg), side-effects profile, and perinatal distributed data and ordinal data were 322 outcome. analyzed by Mann-Whitney U test. Cat323 Sample size calculations are based on a egorical data sets were analyzed with 324 previous study by Rezaei et al.10 Taking Fisher exact test. All tests were 2-sided 325 mean time interval required to achieve and P < .05 was considered significant. 326 target BP from nifedipine and hydral- Participants were analyzed on the 327 Q9 azine as 24.0 10 and 34.8 18.8, intention-to-treat basis. 328 respectively, assuming 2-sided signifi329 cance with a ¼ 0.05 and b ¼ 0.2, 28 Results 330 women are required in each group. Figure 1 shows the CONSORT flow ½F1 331 Statulator beta software was used to es- chart of participants after enrollment. Q10 332 Sixty women were enrolled into the timate the sample size. Giving due 333 consideration for attrition and possible study, and divided into 2 groups of 30 334 skewed distributions that might require each. Each group of 30 was randomized TABLE 1
MONTH 2017 American Journal of Obstetrics & Gynecology FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
1.e3
Original Research
ajog.org
OBSTETRICS
335 336 TABLE 2 337 Outcomes of randomized trial comparing intravenous hydralazine with oral 338 nifedipine for acute blood pressure control in pregnancy 339 Hydralazine, Nifedipine, 340 n ¼ 30 n ¼ 30 P value 341 Primary outcome 342 343 40 (5) 40 (40) .809 Time for BP control,a min 344 Secondary outcomes 345 No. of doses,a n 2 (1) 2 (2) .625 346 Maternal side effects 347 348 Nausea 3 5 .706 349 Vomiting 9 2 .042 350 Overshoot hypotension 1 nil .998 351 Tachycardia (>90 beat/min) nil 2 .491 352 353 Elective cesarean delivery, n 3 2 .986 354 Induction of labor, n 27 28 .998 355 Emergency cesarean delivery 6 5 .898 356 Apgar score <7 357 358 1 min 2 3 .640 359 5 min 1 2 .554 360 NICU admission, n 1 2 .978 361 Neonatal birthweight, g 2280 628 2544 514 .079 362 363 BP, blood pressure; NICU, neonatal intensive care unit. a 364 Median (interquartile interval). Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017. 365 366 367 368 to receive either intravenous hydralazine the target BP. Repeated measures analysis 369 ½T1 or oral nifedipine. As shown in Table 1, of the variance of BP for the first 80 370 both groups were similar with respect to minutes indicated that both systolic and 371 maternal age, gravidity, period of gestadiastolic BP decreased significantly with 372 tion, systolic and diastolic BP at enrollthe passage of time in both groups 373 ment, and use of antenatal steroids. (Figure 2). 374 Median time to achieve target BP The Figure 3 shows the cumulative 375 (defined as systolic BP <150 and diapercentage of patients who happened to 376 stolic BP <100 mm Hg, both conditions achieve the target BP in both groups over 377 fulfilled) was 40 minutes in both groups the specified time. The mean maternal 378 (intravenous hydralazine vs oral nifediheart rate at the beginning of the treat379 pine; interquartile interval 5 and 40 miment was 88 beat/min in the hydralazine 380 Q11 nutes, respectively, P value .809). All group and 86 beat/min in the nifedipine 381 group (P value .279). The corresponding women in the study required a median of 382 2 doses for acute control of BP (intra- values at the end of the treatment were 383 venous hydralazine and oral nifedipine; 78 and 88 beat/min in the hydralazine 384 interquartile range 1 and 2 doses, and nifedipine groups, respectively. Two 385 women had tachycardia (heart rate >90 ½T2 respectively, P value .625) (Table 2). No 386 beat/min), both in the nifedipine group. woman in the study required the cross387 Both of them were managed conserva½F2 over treatment. Figure 2 shows decrease 388 Q12 of BP in 2 groups under the study over tively without any additional treatment. 389 Repeated measures analysis of variance the specified period of time. In the first 390 80 minutes, 100% of women achieved of maternal heart rate for the first 80
391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 Comment 423 In this double-blinded, randomized 424 controlled trial, we found intravenous 425 hydralazine and oral nifedipine to have 426 similar efficacy for acute BP control in 427 pregnant women with severe sustained 428 hypertension. 429 There is a paucity of literature with 430 respect to these 2 agents for acute BP ½F3 431 control in pregnant women with severe 432 sustained hypertension. Several studies 433 compared sublingual nifedipine with 434 intravenous hydralazine.7,8,11,13 How435 ever, the use of sublingual nifedipine 436 has been abandoned due to serious 437 associated cardiovascular complica438 tions.4 To our knowledge, only 1 study 439 by Rezaei et al10 compared oral nifed440 ipine with intravenous hydralazine and 441 they observed that oral nifedipine had 442 better efficacy (mean time required for 443 BP control oral nifedipine vs intrave444 nous hydralazine: 24 vs 35 minutes, P 445 value .016). This could be due to 446 higher dose of nifedipine used, ie,
minutes revealed a significant increase with time in the nifedipine group (P < .001). However, there was no statistically significant difference in mean heart rate of women in the hydralazine group. As shown in Table 2, there was no statistically significant difference in maternal or neonatal outcomes in either group except for maternal vomiting, which was significantly more frequent in the hydralazine group (hydralazine vs nifedipine 9 vs 2, P value .042). There was 1 case of precipitous decrease in maternal BP during the trial period (although she did not meet the initial defined criteria of hypotension, ie, BP <90 mm Hg). This woman was in the hydralazine group. She received a second dose of hydralazine when she developed significant decrease in BP (systolic BP 110 mm Hg). She reported uneasiness. Intravenous fluids were administered and no fetal heart rate abnormality was detected. Her BP was normalized in 20 minutes after intravenous hydration with 0.9% normal saline. Subsequently after induction of labor she had normal vaginal delivery of a healthy neonate. There was no maternal or fetal death during the study.
1.e4 American Journal of Obstetrics & Gynecology MONTH 2017 FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
ajog.org
FIGURE 2
Blood pressure in mm of Hg
web 4C=FPO
---
200 180 160 140 120 100 80 60 40 20 0
HYDRALAZINE SBP NIFEDIPINE SBP HYDRALAZINE DBP NIFEDIPINE DBP
0
20
40
60
80
Time taken for blood pressure control (min)
Profiles of mean SD systolic blood pressure (SBP) and diastolic blood pressure (DBP) during treatment. Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017.
initial 10 mg dose followed by 20 mg every 20 minutes to a total of 5 doses or target BP achieved. Additionally, there is slight variation in the target BP range in their study as they used systolic BP <150 mm Hg and diastolic BP 90-100 mm Hg as the target. One major drawback of the study by Rezaei et al10 was that there was no blinding
of patients or treating physicians. Not doing so is a well-known confounding factor in randomized trials and, as such, has been mandated as an essential criterion by CONSORT guidelines worldwide.14 Nonetheless, they reported 100% efficacy of both drugs for achieving target BP within the stipulated time period
FIGURE 3 ---
web 4C=FPO
447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
OBSTETRICS
100 90 80 70 60 50 Hydralazine
40
Nifedipine
30 20 10 0 20
40
60
80
(x-axis: Time taken for BP control, minutes, y-axis: Cumulative percentage of women who achieved target blood pressure of 150/100 mm Hg or less)
Cumulative percentage of women who achieved target blood pressure (BP) during specified time period. Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017.
Original Research
and this finding is similar to our observation as no woman required crossover treatment in either group in our study. None of the women had any major side effects in our study. However, intravenous hydralazine was statistically more significantly associated with vomiting as compared to oral nifedipine (P value .042). We did not observe any statistically significant difference with respect to maternal or neonatal effects in either group. There has been much controversy regarding the use of intravenous hydralazine as first-line agent due to increased need for cesarean delivery, placental abruption, overshoot hypotension, and low 5-minute Apgar scores.4-6 There has been some speculation regarding safety profile of oral nifedipine especially with respect to overshoot hypotension, synergistic effect with concurrent use of magnesium sulfate, and risk of prolonged labor (as nifedipine has also been used for tocolysis). Nonetheless, these concerns have been satisfactorily proven wrong by various trials15-22 and the safety of nifedipine has been well documented as antihypertensive agent12,15,16 as well as with respect to tocolysis17-21 or synergistic action with magnesium sulfate.22 In our study, there was no case of overshoot hypotension with use of oral nifedipine. All women received magnesium sulfate and no case of neuromuscular blockade was observed. The majority of women required 2-4 doses of nifedipine to achieve target BP and were exposed to much lesser doses in comparison to what is used for tocolysis. The questions can, however, be raised regarding different dosing schedule of both intravenous hydralazine and oral nifedipine. We preferred lower dosage of hydralazine as initial dose (5 mg), and subsequently it was followed by the higher dose (10 mg), as advised by the standard textbook by Cunningham et al.23 Additionally, we followed the protocol of Shekhar et al1 with respect to the dosage of nifedipine to have a flat dose of 10 mg, which was to be repeated every 20 minutes thereby keeping the dosing interval similar for 2 drugs.
MONTH 2017 American Journal of Obstetrics & Gynecology FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
1.e5
503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558
Original Research 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614
Regarding the side-effect profile; vomiting was statistically more significantly common in hydralazine group (9 vs 2, P value .042). There was 1 case of precipitous decrease in maternal BP in the hydralazine group and 2 cases of tachycardia in the nifedipine group. However, these were transient and responded to routine maneuvers and there was no major maternal or fetal side effect in our study. Nonetheless, it is prudent to mention that our study lacked adequate power to assess the safety profile of these drugs conclusively. Our observation of equal efficacy of both these agents is slightly at variance with the observations of Rezaei et al.10 However, it does establish oral nifedipine as first-line agent, which is better tolerated as compared to intravenous hydralazine for acute BP control in hypertensive emergency of pregnancy. Therefore, a larger, well-controlled, adequately powered study, especially with respect to the maternal and fetal side effects, is the need of the hour. Until then, we completely agree with Shekhar et al1 that “oral nifedipine may be preferred because of flat dosing regimen, ease of oral administration, wide availability, and low cost.” n References
Q13
ajog.org
OBSTETRICS
1. Shekhar S, Sharma C, Thakur S, Verma S. Oral nifedipine or intravenous labetalol for hypertensive emergency in pregnancy: a randomized controlled trial. Obstet Gynecol 2013;122:1057-63. 2. ACOG Task Force. Hypertension in pregnancy. Available at: https://www.acog.org/ w/media/Task%20Force%20and%20Work% 20Group%20Reports/public/Hypertensionin Pregnancy.pdf.
3. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev 2013;7: CD001449. 4. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ 2003;327:955-60. 5. Vink GJ, Moodley J, Philpott RH. Effect of dihydralazine on the fetus in the treatment of maternal hypertension. Obstet Gynecol 1980;55:519-22. 6. Vink GJ, Moodley J. The effect of low-dose dihydralazine on the fetus in the emergency treatment of hypertension in pregnancy. S Afr Med J 1982;62:475-7. 7. Aali B, Nejad SS. Nifedipine or hydralazine as a first-line agent to control hypertension in severe pre-eclampsia. Acta Obstet Gynecol Scand 2002;81:25-30. 8. Walss Rodriguez RJ, Flores Padilla LM. Management of severe pre-eclampsia/ eclampsia. Comparison between nifedipine and hydralazine as antihypertensive drugs. Ginecol Obstet Mex 1993;61:76-9. 9. Martins-Costa S, Ramos JG, Barros E, Bruno RM, Costa CA. Randomized, controlled trial of hydralazine versus nifedipine in preeclamptic women with acute hypertension. Clin Exp Hypertens 1992;B11:25-44. 10. Rezaei Z, Sharbaf FR, Pourmojieb M, et al. Comparison of the efficacy of nifedipine and hydralazine in hypertensive crisis in pregnancy. Acta Med Iran 2011;49:701-6. 11. Kwawukume EY, Ghosh TS. Oral nifedipine therapy in the management of severe preeclampsia. Int J Gynaecol Obstet 1995;49: 265-9. 12. Seabe SJ, Moodley J, Becker P. Nifedipine in acute hypertensive emergencies in pregnancy. S Afr Med J 1989;76:248-50. 13. 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. 14. Schulz KF, Altman DG, Moher D; for the CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol 2010;115: 1063-70.
15. Barton JR, Hiett AK, Conover WB. The use of nifedipine during the postpartum period in patients with severe preeclampsia. Am J Obstet Gynecol 1990;162:788-92. 16. Scardo JA, Vermillion ST, Hogg BB, Newman RB. Hemodynamic effects of oral nifedipine in preeclamptic hypertensive emergencies. Am J Obstet Gynecol 1996;175: 336-8. 17. Meyer W, Randall HW, Graves WL. Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 1990;35: 649-53. 18. Ferguson JE, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol 1990;163:105-11. 19. Bracero LA, Leikin E, Kirshenbaum N, Tejani N. Comparison of nifedipine and ritodrine for the treatment of preterm labor. Am J Perinatol 1991;8:365-9. 20. Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labor. Br J Obstet Gynaecol 1993;100:1090-4. 21. Papatsonis DNM, van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol 1997;90:230-4. 22. Magee LA, Miremadi S, Li J, et al. Therapy with both magnesium sulfate and nifedipine does not increase the risk of serious magnesium-related maternal side effects in women with preeclampsia. Am J Obstet Gynecol 2005;193:153-63. 23. Cunningham FG, Leveno KJ, Bloom SL, et al. Williams obstetrics. 24th ed. McGraw Hill; Q14 2014:762.
Author and article information From the Dr Rajendra Prasad Government Medical Q1 College, Tanda, India. Received June 28, 2017; revised Aug. 12, 2017; accepted Aug. 23, 2017. The authors report no conflict of interest. Corresponding author: Chanderdeep Sharma, MD (OBG), DNB (OBG). [email protected]
1.e6 American Journal of Obstetrics & Gynecology MONTH 2017 FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670
ajog.org
OBSTETRICS
Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial Q16
Chanderdeep Sharma, MD (OBG), DNB (OBG); Anjali Soni, MD (OBG); Amit Gupta, MD (OBG); Ashok Verma, MD (OBG); Suresh Verma, MD (OBG)
Q2
OBJECTIVE: We sought to compare the efficacy of intravenously administered hydralazine and oral nifedipine for acute blood pressure control in acute hypertensive emergency of pregnancy. STUDY DESIGN: In this double-blind, randomized, controlled trial, pregnant women (24 weeks POG) with sustained increase in systolic blood pressure of 160 mm Hg or diastolic blood pressure of 110 mm Hg were randomized to receive intravenous hydralazine injection in doses of 5, 10, 10, and 10 mg and a placebo tablet or oral nifedipine (10 mg tablet up to 4 doses) and intravenous saline injection every 20 minutes until the target blood pressure of 150 mm Hg systolic and 100 mm Hg diastolic was achieved. Crossover treatment was administered if the initial treatment failed. The primary outcome of the study was time necessary to achieve target blood pressure. The secondary outcomes were the number of dosages required, adverse maternal and neonatal effects, and perinatal outcome. RESULTS: From December 2014 through September 2015, we enrolled 60 patients. The median time to achieve target blood pressure
Q3
Introduction Hypertension is one of the most common medical disorders during pregnancy.1 Hypertensive disorders of pregnancy constitute one of the major causes of maternal and fetal morbidity and mortality worldwide.2 The American Congress of Obstetricians and Gynecologists (ACOG) defines systolic blood pressure (BP) 160 mm Hg or diastolic BP 110 mm Hg as one of the severe features of preeclampsia. BP readings should preferably be taken on 2 occasions with an interval of at least 4 hours between them. Nonetheless, diagnosis can be confirmed within a shorter interval (even minutes) to facilitate timely antihypertensive therapy. Increased BP is associated with increased risk of morbidity and mortality in preeclamptic women.2 ACOG Task Cite this article as: Sharma C, Soni A, Gupta A, et al. Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial. Am J Obstet Gynecol 2017;volume:x.ex-x.ex. 0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.08.018
was 40 minutes in both groups (intravenous hydralazine and oral nifedipine) (interquartile interval 5 and 40 minutes, respectively, P value .809). The median dose requirement in both groups was 2 (intravenous Q4 hydralazine and oral nifedipine) (interquartile range 1 and 2 doses, Q5 respectively, P value .625). Intravenous hydralazine was associated with statistically significantly higher occurrence of vomiting (9/30 vs 2/30, respectively, P value .042). No serious adverse maternal or perinatal side effects were witnessed in either group. CONCLUSION: Both intravenous hydralazine and oral nifedipine are equally effective in lowering of blood pressure in acute hypertensive emergency of pregnancy. Key words: acute hypertensive emergency of pregnancy, blood
pressure, critical care, double blind, hypertension, intravenous hydralazine, maternal morbidity, maternal mortality, oral nifedipine, preeclampsia
Force recommends use of antihypertensive therapy to lower severe hypertension in preeclamptic women during pregnancy.2 Cochrane meta-analysis on drugs for the treatment of very high BP during pregnancy states that until better evidence is available, the choice of antihypertensive should depend on clinician experience and women’s preferences.3 Commonly used agents for acute lowering of BP in preeclamptic women with severe hypertension in pregnancy are intravenous hydralazine, intravenous labetalol, and oral nifedipine.3,4 However, there is limited evidence with respect to nature of drug to be used. Cochrane meta-analysis found no significant difference regarding efficacy between various agents (hydralazine, labetalol, or nifedipine). Recently there was concern regarding use of hydralazine for acute BP control in preeclamptic women with severe hypertension.1,4 Use of intravenous hydralazine for acute BP control in pregnant women with severe sustained hypertension has been implicated with increased risk of cesarean delivery, placental abruption, maternal overshoot hypotension, and low Apgar scores in neonates.4-6
Additionally, on detailed evaluation of available evidence7-13 comparing hydralazine with nifedipine for acute BP control in women with severe hypertension during pregnancy, it is observed that the majority of these studies actually used short-acting sublingual nifedipine,7,8,11,13 which was withdrawn because of concerns of excessive cardiovascular morbidity and mortality.4 From 1995 through 2013 a PubMed database search for trials comparing hydralazine and nifedipine BP control in pregnant preeclamptic women with severe hypertension using key words “severe hypertension,” “pregnancy,” “nifedipine,” and “hydralazine” revealed only 1 randomized controlled trial10 that had compared nifedipine and intravenous hydralazine for the lowering of BP during hypertensive emergency in pregnancy. Hence, in the present era of evidencebased medicine there is a paucity of good-quality evidence on the better option between 2 commonly used agents, ie, intravenous hydralazine and oral nifedipine, for the control of acute BP control in women with severe preeclampsia during pregnancy.
MONTH 2017 American Journal of Obstetrics & Gynecology FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
1.e1
56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110
111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
ajog.org
OBSTETRICS
With this objective in mind, we conducted this double-blind randomized controlled trial to evaluate which of the 2 drugseintravenous hydralazine or oral nifedipineehas better efficacy in controlling acute severe hypertension in pregnant women with preeclampsia.
Materials and Methods We conducted this randomized, doubleblind, controlled trial for acute lowering of BP during hypertensive emergency of pregnancy. The trial was conducted in the labor ward of the Department of Obstetrics and Gynecology of Dr Rajendra Prasad Government Medical College and Hospital, Tanda, India, a tertiary care teaching and referral hospital. The recruitment took place from December 2014 through September 2015 after obtaining approval from the institutional ethics committee. The trial was also registered with the Trial Registry Q6 of India (vide no. CTRI/2014/12/ 005285). All pregnant women with sustained severe hypertension (defined as systolic BP 160 mm Hg or diastolic BP 110 mm Hg on 2 separate occasions, at least 30 minutes apart) were approached for enrollment. Women were eligible for inclusion if they were between 18-45 years of age, they were at 24 weeks of gestation, their heart rate was between 60 and <120 beat/min, and they had a reassuring fetal heart rate (120-160 beat/ min, with no abnormality detected on admission cardiotocography). The exclusion criteria were a known atrial-ventricular heart block or history of heart failure, moderate to severe bronchial asthma provoked by either drug under study, exposure to any antihypertensive medication within the past 24 hours, and nonpregnancy-related hypertension (diagnosed cases of chronic or secondary hypertension). Consolidated Standards of Reporting Trials (CONSORT) guidelines were strictly followed throughout the trial. Written informed consent was obtained from the participating women. The randomization sequence was computer-generated in blocks of 4 or 8. Study medications were placed in sequentially numbered sealed envelopes.
FIGURE 1 ---
Assessed for Eligibility (n = 132) Excluded • Not meeting inclusion criteria(n=36) • Declined to participate (n=46)
ENROLLMENT
print & web 4C=FPO
Original Research
RANDOMIZED (60)
ALLOCATION Allocated to intervention NIFEDIPINE (n=30)
Allocated to intervention HYDRALAZINE (n=30)
FOLLOW UP & ANALYSIS
ANALYSED = 30 (LOST TO FOLLOW UP;NONE)
ANALYSED = 30 (LOST TO FOLLOW UP; NONE)
Consolidated Standards of Reporting Trials (CONSORT) flow chart of participants.
Q15
Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017.
Each envelope contained 2 packages. One was labeled as package A and the other was labeled as package B. Package A contained either intravenous hydralazine vials (total 10 mL as hydralazine, 5 mg/mL) (Dralgeen; Bharat Serums and Vaccines Ltd) and 4 placebo tablets or intravenous saline (10 mL as 0.9%) and 4 10-mg nifedipine tablets (Zydus Cadila). Package B contained the opposite regimen if treatment crossover was required. These envelopes were opened by an investigator, and package A was administered first to the participant. Oral nifedipine and placebo tablets were identical in appearance. Each tablet contained 10 mg nifedipine or placebo. Colorless intravenous study solution (hydralazine or saline) was placed into a 10-mL syringe by the investigator and was labeled as “A,” then given to the physician (resident doctor) for intravenous administration, along with 4 tablets (nifedipine or placebo) from package A.
Intravenous study solution was administered through an intravenous line secured as soon as the women were enrolled in the trial. In case of crossover to regimen B, the contents of package B were prepared in a manner similar as described for regimen A, and the syringe Q7 was labeled “B.” Thus, the physician and the participant were blinded regarding the treatment administered. The women Q8 rested in bed in the semirecumbent position. The physicians were instructed to administer 1 tablet to be swallowed from package A and to administer 1 mL intravenously from syringe A over 1 minute as the initial treatment (ie, 5 mg of intravenous hydralazine or 1 mL saline). After 20 minutes, if the systolic BP was >150 mm Hg or if the diastolic BP was >100 mm Hg, the second tablet was administered and 2 mL intravenous solution from syringe A was administered over 1 minute (ie, 10 mg of intravenous hydralazine or 2 mL of saline). If the target BP was not achieved even after
1.e2 American Journal of Obstetrics & Gynecology MONTH 2017 FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222
ajog.org 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278
OBSTETRICS
another 20 minutes, the third tablet was administered, along with intravenous administration of 2 mL solution from syringe A. This was repeated for 1 more cycle of treatment if required to lower BP to the target range (ie, hydralazine in doses of 5 mg, 10 mg, 10 mg, and 10 mg and a flat dose of nifedipine 10 mg each every 20 minutes to a maximum of 4 doses). Crossover to regimen B occurred if target BP was not achieved after 4 cycles of regimen A. Regimen B was administered in a fashion identical to that of regimen A. If the target BP was still not achieved, open-label treatment was performed according to the preference of the provider. The BP was measured with mercury sphygmomanometer as per standard recommendations, using Korotkoff sound 5 for diastolic BP. The BP was measured every 20 minutes for at least 100 minutes until the target BP of 150 mm Hg systolic and 100 mm Hg diastolic was achieved. Once the target BP was achieved, no further trial medication was administered. During the course of treatment, continuous electronic fetal heart monitoring was performed. In the event of nonreassuring fetal or maternal status, the trial protocol was abandoned and appropriate measures such as open antihypertensive treatment or expedited delivery were instituted. If clinically significant maternal hypotension occurred, appropriate measures were suggested for the provider’s consideration. After completion of the trial protocol, women were requested to complete a questionnaire regarding occurrence of side effects during the trial period (ie, nausea, vomiting, headache, dizziness, urticaria, flushing, pruritus, nasal congestion, conjunctivitis, palpitations). After successfully lowering the BP to target range, further antihypertensive therapy was started 2 hours after the last trial medication as per discretion of the provider. As per the standard protocol, the delivery of the neonate was performed as a definite treatment for severe pregnancy-induced hypertension. As per the institutional protocol all women after admission received magnesium sulfate. The primary outcome measured was time needed to achieve target
Original Research
279 280 281 Demographic characteristics of women in both groups 282 Hydralazine, Nifedipine, 283 n ¼ 30 n ¼ 30 P value 284 24.2 6.3 23.4 2.6 .163 Age,a y 285 b 286 Gravida 2 (1) 2 (1) .280 287 1 16 22 288 2 8 4 289 3 5 2 290 291 4 1 2 a 2 292 BMI, kg/m 21.8 3.2 22.5 2.8 .776 293 Heart rate,a beat/min 78 7 86 6 .279 294 POG,a d 257 28 258 17 .856 295 a 296 Systolic BP at enrollment, mm Hg 177 18 168 6 .064 297 Diastolic BP at enrollment, mm Hga 109 11 107 8 .307 298 Mean arterial pressure at enrollmenta 127 14 125 9 .492 299 Women with systolic BP 160 mm Hg, n 26 21 .209 300 301 Women with diastolic BP 110 mm Hg, n 19 18 .989 302 Neonatal sex, n 303 Male 15 13 .605 304 Female 15 17 305 306 Antenatal steroid given, n 4 3 .688 307 BMI, body mass index; BP, blood pressure. 308 a Mean SD; b Median (interquartile interval). 309 Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017. 310 311 312 systolic BP of 150 mm Hg and diastolic nonparametric testing, we randomized a 313 BP of 100 mm Hg (both targets had to total of 60 women (30 in each group). 314 be fulfilled). Secondary outcomes The data were entered into software 315 included total number of antihyperten- (SPSS 17; IBM Corp, Armonk, NY). The 316 sive dosages required to achieve the analysis was based on the intention to 317 target BP (ie, systolic 150 mm Hg and treat. One-sample Kolmogorov-Smir318 diastolic 100 mm Hg), maternal heart nov test was used to check normal dis319 rate profile during the first 100 minutes, tribution of continuous data. Student t 320 maternal hypotension (BP <90/60 mm test was used to analyze the normally 321 Hg), side-effects profile, and perinatal distributed data and ordinal data were 322 outcome. analyzed by Mann-Whitney U test. Cat323 Sample size calculations are based on a egorical data sets were analyzed with 324 previous study by Rezaei et al.10 Taking Fisher exact test. All tests were 2-sided 325 mean time interval required to achieve and P < .05 was considered significant. 326 target BP from nifedipine and hydral- Participants were analyzed on the 327 Q9 azine as 24.0 10 and 34.8 18.8, intention-to-treat basis. 328 respectively, assuming 2-sided signifi329 cance with a ¼ 0.05 and b ¼ 0.2, 28 Results 330 women are required in each group. Figure 1 shows the CONSORT flow ½F1 331 Statulator beta software was used to es- chart of participants after enrollment. Q10 332 Sixty women were enrolled into the timate the sample size. Giving due 333 consideration for attrition and possible study, and divided into 2 groups of 30 334 skewed distributions that might require each. Each group of 30 was randomized TABLE 1
MONTH 2017 American Journal of Obstetrics & Gynecology FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
1.e3
Original Research
ajog.org
OBSTETRICS
335 336 TABLE 2 337 Outcomes of randomized trial comparing intravenous hydralazine with oral 338 nifedipine for acute blood pressure control in pregnancy 339 Hydralazine, Nifedipine, 340 n ¼ 30 n ¼ 30 P value 341 Primary outcome 342 343 40 (5) 40 (40) .809 Time for BP control,a min 344 Secondary outcomes 345 No. of doses,a n 2 (1) 2 (2) .625 346 Maternal side effects 347 348 Nausea 3 5 .706 349 Vomiting 9 2 .042 350 Overshoot hypotension 1 nil .998 351 Tachycardia (>90 beat/min) nil 2 .491 352 353 Elective cesarean delivery, n 3 2 .986 354 Induction of labor, n 27 28 .998 355 Emergency cesarean delivery 6 5 .898 356 Apgar score <7 357 358 1 min 2 3 .640 359 5 min 1 2 .554 360 NICU admission, n 1 2 .978 361 Neonatal birthweight, g 2280 628 2544 514 .079 362 363 BP, blood pressure; NICU, neonatal intensive care unit. a 364 Median (interquartile interval). Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017. 365 366 367 368 to receive either intravenous hydralazine the target BP. Repeated measures analysis 369 ½T1 or oral nifedipine. As shown in Table 1, of the variance of BP for the first 80 370 both groups were similar with respect to minutes indicated that both systolic and 371 maternal age, gravidity, period of gestadiastolic BP decreased significantly with 372 tion, systolic and diastolic BP at enrollthe passage of time in both groups 373 ment, and use of antenatal steroids. (Figure 2). 374 Median time to achieve target BP The Figure 3 shows the cumulative 375 (defined as systolic BP <150 and diapercentage of patients who happened to 376 stolic BP <100 mm Hg, both conditions achieve the target BP in both groups over 377 fulfilled) was 40 minutes in both groups the specified time. The mean maternal 378 (intravenous hydralazine vs oral nifediheart rate at the beginning of the treat379 pine; interquartile interval 5 and 40 miment was 88 beat/min in the hydralazine 380 Q11 nutes, respectively, P value .809). All group and 86 beat/min in the nifedipine 381 group (P value .279). The corresponding women in the study required a median of 382 2 doses for acute control of BP (intra- values at the end of the treatment were 383 venous hydralazine and oral nifedipine; 78 and 88 beat/min in the hydralazine 384 interquartile range 1 and 2 doses, and nifedipine groups, respectively. Two 385 women had tachycardia (heart rate >90 ½T2 respectively, P value .625) (Table 2). No 386 beat/min), both in the nifedipine group. woman in the study required the cross387 Both of them were managed conserva½F2 over treatment. Figure 2 shows decrease 388 Q12 of BP in 2 groups under the study over tively without any additional treatment. 389 Repeated measures analysis of variance the specified period of time. In the first 390 80 minutes, 100% of women achieved of maternal heart rate for the first 80
391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 Comment 423 In this double-blinded, randomized 424 controlled trial, we found intravenous 425 hydralazine and oral nifedipine to have 426 similar efficacy for acute BP control in 427 pregnant women with severe sustained 428 hypertension. 429 There is a paucity of literature with 430 respect to these 2 agents for acute BP ½F3 431 control in pregnant women with severe 432 sustained hypertension. Several studies 433 compared sublingual nifedipine with 434 intravenous hydralazine.7,8,11,13 How435 ever, the use of sublingual nifedipine 436 has been abandoned due to serious 437 associated cardiovascular complica438 tions.4 To our knowledge, only 1 study 439 by Rezaei et al10 compared oral nifed440 ipine with intravenous hydralazine and 441 they observed that oral nifedipine had 442 better efficacy (mean time required for 443 BP control oral nifedipine vs intrave444 nous hydralazine: 24 vs 35 minutes, P 445 value .016). This could be due to 446 higher dose of nifedipine used, ie,
minutes revealed a significant increase with time in the nifedipine group (P < .001). However, there was no statistically significant difference in mean heart rate of women in the hydralazine group. As shown in Table 2, there was no statistically significant difference in maternal or neonatal outcomes in either group except for maternal vomiting, which was significantly more frequent in the hydralazine group (hydralazine vs nifedipine 9 vs 2, P value .042). There was 1 case of precipitous decrease in maternal BP during the trial period (although she did not meet the initial defined criteria of hypotension, ie, BP <90 mm Hg). This woman was in the hydralazine group. She received a second dose of hydralazine when she developed significant decrease in BP (systolic BP 110 mm Hg). She reported uneasiness. Intravenous fluids were administered and no fetal heart rate abnormality was detected. Her BP was normalized in 20 minutes after intravenous hydration with 0.9% normal saline. Subsequently after induction of labor she had normal vaginal delivery of a healthy neonate. There was no maternal or fetal death during the study.
1.e4 American Journal of Obstetrics & Gynecology MONTH 2017 FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
ajog.org
FIGURE 2
Blood pressure in mm of Hg
web 4C=FPO
---
200 180 160 140 120 100 80 60 40 20 0
HYDRALAZINE SBP NIFEDIPINE SBP HYDRALAZINE DBP NIFEDIPINE DBP
0
20
40
60
80
Time taken for blood pressure control (min)
Profiles of mean SD systolic blood pressure (SBP) and diastolic blood pressure (DBP) during treatment. Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017.
initial 10 mg dose followed by 20 mg every 20 minutes to a total of 5 doses or target BP achieved. Additionally, there is slight variation in the target BP range in their study as they used systolic BP <150 mm Hg and diastolic BP 90-100 mm Hg as the target. One major drawback of the study by Rezaei et al10 was that there was no blinding
of patients or treating physicians. Not doing so is a well-known confounding factor in randomized trials and, as such, has been mandated as an essential criterion by CONSORT guidelines worldwide.14 Nonetheless, they reported 100% efficacy of both drugs for achieving target BP within the stipulated time period
FIGURE 3 ---
web 4C=FPO
447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
OBSTETRICS
100 90 80 70 60 50 Hydralazine
40
Nifedipine
30 20 10 0 20
40
60
80
(x-axis: Time taken for BP control, minutes, y-axis: Cumulative percentage of women who achieved target blood pressure of 150/100 mm Hg or less)
Cumulative percentage of women who achieved target blood pressure (BP) during specified time period. Sharma et al. Hypertensive emergency: hydralazine vs nifedipine. Am J Obstet Gynecol 2017.
Original Research
and this finding is similar to our observation as no woman required crossover treatment in either group in our study. None of the women had any major side effects in our study. However, intravenous hydralazine was statistically more significantly associated with vomiting as compared to oral nifedipine (P value .042). We did not observe any statistically significant difference with respect to maternal or neonatal effects in either group. There has been much controversy regarding the use of intravenous hydralazine as first-line agent due to increased need for cesarean delivery, placental abruption, overshoot hypotension, and low 5-minute Apgar scores.4-6 There has been some speculation regarding safety profile of oral nifedipine especially with respect to overshoot hypotension, synergistic effect with concurrent use of magnesium sulfate, and risk of prolonged labor (as nifedipine has also been used for tocolysis). Nonetheless, these concerns have been satisfactorily proven wrong by various trials15-22 and the safety of nifedipine has been well documented as antihypertensive agent12,15,16 as well as with respect to tocolysis17-21 or synergistic action with magnesium sulfate.22 In our study, there was no case of overshoot hypotension with use of oral nifedipine. All women received magnesium sulfate and no case of neuromuscular blockade was observed. The majority of women required 2-4 doses of nifedipine to achieve target BP and were exposed to much lesser doses in comparison to what is used for tocolysis. The questions can, however, be raised regarding different dosing schedule of both intravenous hydralazine and oral nifedipine. We preferred lower dosage of hydralazine as initial dose (5 mg), and subsequently it was followed by the higher dose (10 mg), as advised by the standard textbook by Cunningham et al.23 Additionally, we followed the protocol of Shekhar et al1 with respect to the dosage of nifedipine to have a flat dose of 10 mg, which was to be repeated every 20 minutes thereby keeping the dosing interval similar for 2 drugs.
MONTH 2017 American Journal of Obstetrics & Gynecology FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
1.e5
503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558
Original Research 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614
Regarding the side-effect profile; vomiting was statistically more significantly common in hydralazine group (9 vs 2, P value .042). There was 1 case of precipitous decrease in maternal BP in the hydralazine group and 2 cases of tachycardia in the nifedipine group. However, these were transient and responded to routine maneuvers and there was no major maternal or fetal side effect in our study. Nonetheless, it is prudent to mention that our study lacked adequate power to assess the safety profile of these drugs conclusively. Our observation of equal efficacy of both these agents is slightly at variance with the observations of Rezaei et al.10 However, it does establish oral nifedipine as first-line agent, which is better tolerated as compared to intravenous hydralazine for acute BP control in hypertensive emergency of pregnancy. Therefore, a larger, well-controlled, adequately powered study, especially with respect to the maternal and fetal side effects, is the need of the hour. Until then, we completely agree with Shekhar et al1 that “oral nifedipine may be preferred because of flat dosing regimen, ease of oral administration, wide availability, and low cost.” n References
Q13
ajog.org
OBSTETRICS
1. Shekhar S, Sharma C, Thakur S, Verma S. Oral nifedipine or intravenous labetalol for hypertensive emergency in pregnancy: a randomized controlled trial. Obstet Gynecol 2013;122:1057-63. 2. ACOG Task Force. Hypertension in pregnancy. Available at: https://www.acog.org/ w/media/Task%20Force%20and%20Work% 20Group%20Reports/public/Hypertensionin Pregnancy.pdf.
3. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev 2013;7: CD001449. 4. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ 2003;327:955-60. 5. Vink GJ, Moodley J, Philpott RH. Effect of dihydralazine on the fetus in the treatment of maternal hypertension. Obstet Gynecol 1980;55:519-22. 6. Vink GJ, Moodley J. The effect of low-dose dihydralazine on the fetus in the emergency treatment of hypertension in pregnancy. S Afr Med J 1982;62:475-7. 7. Aali B, Nejad SS. Nifedipine or hydralazine as a first-line agent to control hypertension in severe pre-eclampsia. Acta Obstet Gynecol Scand 2002;81:25-30. 8. Walss Rodriguez RJ, Flores Padilla LM. Management of severe pre-eclampsia/ eclampsia. Comparison between nifedipine and hydralazine as antihypertensive drugs. Ginecol Obstet Mex 1993;61:76-9. 9. Martins-Costa S, Ramos JG, Barros E, Bruno RM, Costa CA. Randomized, controlled trial of hydralazine versus nifedipine in preeclamptic women with acute hypertension. Clin Exp Hypertens 1992;B11:25-44. 10. Rezaei Z, Sharbaf FR, Pourmojieb M, et al. Comparison of the efficacy of nifedipine and hydralazine in hypertensive crisis in pregnancy. Acta Med Iran 2011;49:701-6. 11. Kwawukume EY, Ghosh TS. Oral nifedipine therapy in the management of severe preeclampsia. Int J Gynaecol Obstet 1995;49: 265-9. 12. Seabe SJ, Moodley J, Becker P. Nifedipine in acute hypertensive emergencies in pregnancy. S Afr Med J 1989;76:248-50. 13. 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. 14. Schulz KF, Altman DG, Moher D; for the CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol 2010;115: 1063-70.
15. Barton JR, Hiett AK, Conover WB. The use of nifedipine during the postpartum period in patients with severe preeclampsia. Am J Obstet Gynecol 1990;162:788-92. 16. Scardo JA, Vermillion ST, Hogg BB, Newman RB. Hemodynamic effects of oral nifedipine in preeclamptic hypertensive emergencies. Am J Obstet Gynecol 1996;175: 336-8. 17. Meyer W, Randall HW, Graves WL. Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 1990;35: 649-53. 18. Ferguson JE, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol 1990;163:105-11. 19. Bracero LA, Leikin E, Kirshenbaum N, Tejani N. Comparison of nifedipine and ritodrine for the treatment of preterm labor. Am J Perinatol 1991;8:365-9. 20. Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labor. Br J Obstet Gynaecol 1993;100:1090-4. 21. Papatsonis DNM, van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol 1997;90:230-4. 22. Magee LA, Miremadi S, Li J, et al. Therapy with both magnesium sulfate and nifedipine does not increase the risk of serious magnesium-related maternal side effects in women with preeclampsia. Am J Obstet Gynecol 2005;193:153-63. 23. Cunningham FG, Leveno KJ, Bloom SL, et al. Williams obstetrics. 24th ed. McGraw Hill; Q14 2014:762.
Author and article information From the Dr Rajendra Prasad Government Medical Q1 College, Tanda, India. Received June 28, 2017; revised Aug. 12, 2017; accepted Aug. 23, 2017. The authors report no conflict of interest. Corresponding author: Chanderdeep Sharma, MD (OBG), DNB (OBG). [email protected]
1.e6 American Journal of Obstetrics & Gynecology MONTH 2017 FLA 5.5.0 DTD YMOB11812_proof 8 September 2017 1:07 pm ce
615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670