|Year : 2016 | Volume
| Issue : 1 | Page : 34-37
Life threatening adverse reaction following prostaglandin analogue use in obstetric and gynecological practice
Anitha Prashanth, Murali Chakravarthy, Pavani Maddirala
Department of Anesthesia, Critical Care and Pain Relief, Fortis Hospitals, Bangalore, Karnataka, India
|Date of Web Publication||22-Apr-2016|
Dr. Anitha Prashanth
Consultant Anaesthesiologist, Fortis Hospitals, BG road, Bangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Prostaglandin analogues are the most commonly used drugs by the obstetricians because of its favorable actions on the uterus and cervix. Although considered safe, this drug is associated with various adverse side effects. Here, we report two cases that became hemodynamically unstable after the administration of this drug.
Keywords: Adverse reaction, hysteroscopy, misoprostol
|How to cite this article:|
Prashanth A, Chakravarthy M, Maddirala P. Life threatening adverse reaction following prostaglandin analogue use in obstetric and gynecological practice. J Obstet Anaesth Crit Care 2016;6:34-7
|How to cite this URL:|
Prashanth A, Chakravarthy M, Maddirala P. Life threatening adverse reaction following prostaglandin analogue use in obstetric and gynecological practice. J Obstet Anaesth Crit Care [serial online] 2016 [cited 2019 Dec 8];6:34-7. Available from: http://www.joacc.com/text.asp?2016/6/1/34/181077
| Introduction|| |
Misoprostol is a synthetic analogue of prostaglandin E1. It has actions on the gastrointestinal tract, uterus, and cervix. Due to its uterotonic and cervical priming actions, it is widely used by obstetricians and gynecologists for various purposes as follows: medical termination of pregnancy, cervical priming before hysteroscopy, induction of labor, and management of postpartum hemorrhage (PPH). It is generally considered safe however many complications have been reported. Fatal complications have also been reported. , Maternal mortality was attributed to uterine hyperstimulation and amniotic fluid embolism. Other nonfatal complications, such as diarrhea, pyrexia, shivering, hypotension, vasodilation, and bronchospasm, have been noted with misoprostol.  Here we report two cases that reacted severely to misoprostol.
| Case Reports|| |
Case report 1
A 24-year-old primigravida, at risk of PPH, delivered a healthy baby at our institute. As per the request of the treating obstetrician, the patient was administered 600 μg of misoprostol rectally to prevent the anticipated hemorrhage. Despite this prophylactic treatment, an hour later she developed atonic PPH with a sudden blood loss of about 500 mL. At that time, 250 μg prostaglandin F2alpha was administered intramuscularly, and 0.2 mg methylergometrine was administered intravenously. Fifteen minutes later, the patient became restless, hypotensive (blood pressure decreased from 130/80 mmHg to 90/60 mmHg), with increased heart rate (HR) (80 beats-180 beats/min), and developed hyperpyrexia (105° F). Her peripheral pulses were not palpable. She was transferred to the intensive care unit (ICU).
In the ICU, noninvasive blood pressure and pulse oximeter plethysmogram were unmeasurable. Rapid infusion of crystalloids was started and at the same time an intravenous infusion of noradrenaline (0.05 μg/kg/min) was commenced to treat hypotension. Mechanical ventilation was instituted in view of impending cardiac arrest. Midazolam (2 mg) and rocuronium (50 mg) were administered to facilitate endotracheal intubation. The patient was managed with a working diagnosis of acute hemorrhagic shock. The central line was inserted to guide fluid resuscitation. It was difficult to cannulate the radial artery as it was not felt. After rapid fluid administration, feeble femoral pulses became palpable, and it was cannulated under ultrasound guidance. Surprisingly, the invasive arterial pressures was noted to be 190/120 mmHg; this found to be correct after repeatedly checking the zeroing of the transducer and the level of the transducer. Then the working diagnosis was revised to hypovolemia and severe vasoconstriction (probably drug induced). Further intravenous fluid was administered and the administration of inotropic agent was ceased. The arterial blood gas (ABG) analysis showed pH 7.226 and bicarbonate 10.5 mEq. The patient gradually improved over the next few hours after which she was gradually weaned from the ventilator and extubated. She required two unit of packed red blood cell transfusion because hemoglobin level decreased from 10.5-6.6 G%. The remaining course of her treatment and hospitalization was uneventful, and she was discharged after 4 days.
Case report 2
A 32-year-old lady, weighing 69 kg, 155-cm tall (body mass index of 28), being worked up for infertility was found to have two submucosal fibroids. She was electively scheduled for hysteroscopic resection of submucosal fibroids under general anesthesia and was accepted for the procedure under American Society of Anaesthesiologists (ASA) 1. She had undergone hysterosalpingography and medical termination of pregnancy 4 years ago under general anesthesia. To facilitate hysteroscopy, the patient was administered 200 μg of misoprostol vaginally 30 min prior to the procedure. Her baseline parameters were as follows: HR 53 beats/min and blood pressure of 118/70 mmHg, and oxygen saturation 100%. A peripheral venous cannula 18G was inserted. General anesthesia was induced with intravenous administration of fentanyl 100 μg, propofol 100 mg, and atracurium 20 mg. Laryngeal mask airway (LMA) #3 was inserted and controlled ventilation initiated with a tidal volume of 500 mL and frequency of 12/min. The airway pressures were normal. Anesthesia was maintained with sevoflurane in a mixture of air and oxygen. The patient was positioned in lithotomy position. Warm air was blown over the patient using Bair hugger as per the institutional protocol.
During resection of the second fibroid, there was profuse hemorrhage (loss of about 800 mL). The loss was replaced with intravenous crystalloids and on request of the gynecologist, and tranexamic acid (1 gm) administered intravenously.
Uterine perforation was suspected by the gynecologist and hemorrhage was suspected to be ongoing from the perforated uterine wall. The gynecologist decided to convert to emergency laparotomy. The patient's vital parameters were as follows: HR of 95 beats/min and blood pressure of 136/75 mmHg. Anticipating longer duration of surgery, LMA was replaced by #7 cuffed endotracheal tube. A second 16G peripheral line was inserted to facilitate rapid fluid resuscitation. Misoprostol (600 μg) was inserted rectally to facilitate contraction of the uterus and to reduce the bleeding prior to starting the laparotomy.
Laparotomy confirmed the perforation of uterus, but there was no major bleeder around the perforation. At this time, it was found that the peripheral arteries (radial and femoral) were not palpable and pulsation could not be located even with the use of color Doppler ultrasound. However, we noticed that the noninvasive blood pressure reading was 204/144 mmHg, the HR was 80 beats/min, and the peak airway pressure was 45 cm of H 2 O. A little later, blood stained secretion, suggestive of pulmonary edema, appeared in the endotracheal tube. Non invasive blood pressure (NIBP) showed an increasing trend of blood pressure to 224/168 mmHg. As the pulses were not felt on the background of acute blood loss it was difficult to believe the NIBP readings. Although the features were of acute hemorrhage, we did not consider any vasopressors as the NIBP readings were high and also because of our previous experience. After fluid resuscitation, the right femoral artery could be visualized using Doppler ultrasound; a catheter was inserted and the invasive pressure was found to be 201/105 mmHg. It was presumed that the hypertensive crisis was caused by severe vasospasm, possibly occurring due to the administration of misoprostol. The indwelling tablet of misoprostol in the rectum was removed and the anesthetic depth was increased. Over time, the BP decreased to 120 mmHg systolic. ABG analysis revealed persistence of metabolic acidosis (pH of 7.326), and the partial pressure of oxygen was 78.8 mmHg and that of carbon dioxide was 34.6 mmHg. Transthoracic echocardiogram showed good left ventricular function and hyper dynamic left ventricle probably due to hypovolemia. The surgery was completed without events. Overall blood loss was about 2 L; that was replaced with crystalloids. The patient was transferred to ICU for ventilator support and further management. The peripheral pulses remained feeble for about 2 h thereafter, but became palpable after further fluid resuscitation. She was extubated after 24 h. She received two units of packed cells as the hemoglobin had decreased to 6.7 g%. Further hospital stay was uneventful and the patient was discharged on day 7.
| Discussion|| |
Prostaglandins are hormone-like compounds that are derived from fatty acids; they have autocrine action (they are produced at various places but act on cells at their site of secretion). There are currently 10 known prostaglandin receptors on various cell types with varying actions. On the vascular smooth muscle it may either produce constriction or dilatation.  The cardiovascular effects can thus vary with the use of synthetic prostaglandins also.
The most commonly used prostaglandins in obstetrics and gynecology are prostaglandin E1 analogue (misoprostol) and prostaglandin F2 alpha (carboprost tromethamine). While misoprostol can be administered through various routes - oral, sublingual, buccal, vaginal, and rectal, carboprost can be administered only via intramuscular and intramyometrial routes.
The bioavailability of misoprostol varies with route of administration. When administered vaginally, the plasma concentration increases gradually reaches its maximum level in about 70 min, but with the rectal route, it peaks by about 40-65 min. ,, Although the bioavailability of the drug is less when administered rectally, it is preferred at times because the adverse events are lesser via this route.  Both the patients in our report had adverse reaction an hour after the drug administration. In the first case, it was after per rectal misoprostol and vaginal misoprostol in the second case. The use of other uterotonics, such as methylergometrine intravenously and carboprost intramuscularly, further contributed to the adverse profile in our first case. Also, the lady had significant hyperpyrexia (temperature 105 degree Farenheit) probably due to carboprost. In the second case, it was per vaginal misoprostol that was administered before the surgery and it was aggravated with per rectal misoprostol administered intraoperatively.
User instructions for misoprostol suggest that its use could cause chest pain, diaphoresis, hypotension, hypertension, arrhythmias, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and cerebrovascular accident). Both the cases under discussion here had hypertensive crisis probably attributable to misoprostol.
Both our cases had a few things in common; both suffered from significant blood loss, received prostaglandin analogs twice via different routes, peripheral pulses were absent, and systemic hypertension was noted. Although these reactions have not been observed in the past many adverse reactions to misoprostol have been reported. 
In a study on the effects of oral misoprostol (400 μg) versus placebo on 20 volunteers, decrease in leg blood flow volume occurred and a corresponding increase in leg peripheral vascular resistance in the misoprostol group, which were deemed insignificant by the authors.  In both our cases, we noted significant increase in peripheral vascular resistance probably because of higher dose of prostaglandins that our patients had received. The other common observation of significance in both the cases was significant blood loss that had occurred either before or after the administration of prostaglandins.
In a bulletin of the World Health Organization about the adverse effects of misoprostol 46 trials were included in the analysis.  Deaths were reported in five trials. ,,,, Misoprostol recipients experienced more adverse events in contrast to the recipients of placebo. Pyrexia was more than twice frequent among women who received more than 600 μg rather than 400 μg of misoprostol.
Considering the near-fatal experience that our patients encountered, we opine that misoprostol may be administered in the smallest effective dose with utmost care while monitoring hemodynamic parameters. This is especially required because the medication has the scope of being administered via multiple routes, elevated plasma levels may exert adverse reactions that could be life threatening. If combination of prostaglandin analogues is required, it should be administered judiciously.
| Conclusion|| |
Prostaglandin analogues are generally considered safe and are used widely in obstetric and gynecological practices; however, adverse events are known to occur. Though sweeping remarks cannot be made based on two cases, it may be reasonable to conclude that when misoprostol is administered in a hypovolemic patient, severe vasoconstriction and hypertensive crisis might occur and hence to minimize the side effects, minimum effective dose may be administered.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: Pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet 2007;99(Suppl 2):S160-7.
Hausknecht R. Mifepristone and misoprostol for early medical abortion: 18 months experience in the United States. Contraception 2003;67:463-5.
Wagner M. Adverse events following misoprostol induction of labor. Midwifery Today Int Midwife 2004;9-12.
Randy NF. Prostaglandin. In: Randy NF, editor. An Introduction to Behavioral Endocrinology. 3 rd
ed. Sunderland, Mass: Sinauer Associates; 2005. p. 100.
Meckstroth KR, Whitaker AK, Bertisch S, Goldberg AB, Darney PD. Misoprostol administered by epithelial routes: Drug absorption and uterine response. Obstet Gynecol 2006;108:582-90.
Khan RU, El-Refaey H. Pharmacokinetics and adverse-effect profile of rectally administered misoprostol in the third stage of labor. Obstet Gynecol 2003;101:968-74.
Hofmeyr GJ, Gülmezoglu AM, Novikova N, Linder V, Ferreira S, Piaggio G. Misoprostol to prevent and treat postpartum haemorrhage: A systematic review and meta-analysis of maternal deaths and dose-related effects. Bull World Health Organ 2009;87:666-77.
Brecht T. Effects of misoprostol on human circulation. Prostaglandins 1987;33(Suppl):51-60.
Høj L, Cardoso P, Nielsen BB, Hvidman L, Nielsen J, Aaby P. Effect of sublingual misoprostol on severe postpartum haemorrhage in a primary health centre in Guinea-Bissau: Randomised double blind clinical trial. BMJ 2005;331:723.
Derman RJ, Kodkany BS, Goudar SS, Geller SE, Naik VA, Bellad MB, et al
. Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: A randomised controlled trial. Lancet 2006;368:1248-53.
Walraven G, Blum J, Dampha Y, Sowe M, Morison L, Winikoff B, et al
. Misoprostol in the management of the third stage of labour in the home delivery setting in rural Gambia: A randomised controlled trial. BJOG 2005;112:1277-83.
Hofmeyr GJ, Ferreira S, Nikodem VC, Mangesi L, Singata M, Jafta Z, et al
. Misoprostol for treating postpartum haemorrhage: A randomized controlled trial. BMC Pregnancy Childbirth 2004;4:16.
Gülmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, et al
.; WHO Collaborative Group To Evaluate Misoprostol in the Management of the Third Stage of Labour. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet 2001;358:689-95.