Hypertensive disorders of pregnancy are the most common direct cause of maternal mortality in the United States, responsible for 15% of deaths.1 Cerebrovascular complications are the most common cause of major disability and death in preeclampsia/eclampsia; hypertension and cerebral hyperperfusion-related vascular shear stress and vasogenic edema are postulated to cause stroke, cerebral edema, and eclampsia.2,3 Preeclamptic women suffering stroke have a poor prognosis. A retrospective case series published in 2005 reported <50% survival in which only a small percentage of surviving patients were not disabled.4 The American College of Obstetricians and Gynecologists guidelines recommend urgent treatment of systolic blood pressures exceeding 160 mm Hg or diastolic blood pressures exceeding 110 mm Hg.5,6 The Seventh and Eighth Confidential Enquiries into Maternal Deaths reports from the United Kingdom recommend treatment of systolic blood pressures exceeding 150 to 160 mm Hg, and emergent treatment of systolic blood pressures exceeding 180 mm Hg, to prevent intracranial hemorrhage.3,7
The cesarean delivery rate in the United States in 2012 was 32.8%8 and may be higher among patients with severe preeclampsia. Although the majority of cesarean deliveries are performed under neuraxial anesthesia, some patients receive general anesthesia for maternal or fetal indications. Laryngoscopy and tracheal intubation are often accompanied by increases in arterial blood pressure and heart rate,9–13 and such increases may enhance the risk of cerebrovascular or cardiovascular events in preeclamptic patients.2,3 Many strategies for controlling the hemodynamic response to laryngoscopy and intubation have been investigated in the general surgical population, with conflicting results. Fewer studies specifically address preeclamptic patients, and practice among anesthesiologists varies widely.14
An ideal induction technique for this patient population would have fast, predictable onset, allowing for a safe rapid-sequence induction and tracheal intubation followed immediately by surgical incision. Ideally, drugs should be quickly cleared, cause no serious maternal side effects, have minimal placental transfer or no significant fetal/neonatal effects, and be widely available and stable at room temperature without the need for reconstitution or dilution. There is no perfect medication or technique, but some drugs have more favorable pharmacodynamic and pharmacokinetic profiles than others. This review focuses on drugs used to control the hypertensive response to laryngoscopy and tracheal intubation in preeclamptic patients receiving general anesthesia.
β-Adrenergic Blocking Drugs
Depending on structure, β-adrenergic antagonists have activity at either β-1 or β-2 receptors, with variable onset and duration of action. Blockade of β-1 receptors causes decreased heart rate, cardiac contractility, and arterial blood pressure. Only esmolol and labetalol have been studied in women with preeclampsia.
Esmolol is a selective β-1 antagonist with short onset time and elimination half-life (Table 1).a Esmolol prevents the hemodynamic response to laryngoscopy and intubation in nonpregnant patients when administered as an infusion (50 µg/kg/min) or as a bolus (100–200 mg), after induction with thiopental 3 to 6 mg/kg.15–18 The combination of esmolol 1 to 2 mg/kg and lidocaine 1.5 mg/kg before induction with thiopental 4 mg/kg decreased the hypertensive response to intubation compared with saline placebo in nonpregnant healthy women undergoing gynecologic surgery, whereas either drug alone did not.19 In a randomized, blinded, controlled trial of 80 preeclamptic women undergoing cesarean delivery after induction with thiopental 5 mg/kg, esmolol 2 mg/kg suppressed both heart rate and arterial blood pressure increases during airway manipulation compared with saline placebo, whereas esmolol 1 mg/kg required the addition of lidocaine 1.5 mg/kg to be effective.20
Serious maternal side effects of esmolol are few, given its short half-life. However, transient maternal bradycardia or heart block can occur, and the drug should be used cautiously in patients with heart failure.
Esmolol’s low lipid solubility and rapid plasma inactivation predict limited placental transfer, and it has a low fetal/maternal (F/M) ratio of 0.2.21 However, there are several case reports of decreases in fetal heart rate after maternally administered esmolol infusion.22,23 In contrast, favorable Apgar scores and no instances of fetal bradycardia were reported with peri-induction bolus doses ranging from 1 to 2 mg/kg in 80 patients with preeclampsia.20
Labetalol is a mixed β-1 and β-2 receptor antagonist, with some α-adrenergic receptor antagonism (1:7 α/β). It is relatively rapid-acting with an effect onset time of several minutes and effect duration of 2 to 3 hours after an IV bolus (Table 1).1 Labetalol is recommended as a first-line therapy for emergency treatment of elevated arterial blood pressures in preeclamptic patients5,7 and does not compromise placental blood flow in the setting of preeclampsia.24 A small (n = 25) randomized controlled trial in preeclamptic patients reported that IV labetalol 20 mg followed by incremental doses of 10 mg up to a total dose of 1 mg/kg, titrated to achieve a diastolic blood pressure <100 mm Hg or decrease in mean arterial blood pressure (MAP) of 20% before induction with thiopental 4 mg/kg, was effective at blunting heart rate and blood pressure responses to laryngoscopy and tracheal intubation.25
Potential serious maternal side effects of labetalol administered in the peri-induction period include postinduction hypotension due to its intermediate effect duration and bronchospasm due to β-2 antagonism.
Labetalol crosses the placenta, with an F/M ratio of 0.38.26 Transient mild neonatal hypotension27,28 or mild hypotension and bradycardia29 have been reported after maternal use of labetalol, of unclear clinical significance. Despite theoretical concerns about hypoglycemia with β-adrenergic blockade, no differences in neonatal glycemic values were reported in the reviewed studies.25,27–30
Esmolol and labetalol in appropriate doses (Table 1), which are notably higher than doses typically administered perioperatively to treat hypertension, have been shown to be effective at preventing a hemodynamic response to laryngoscopy and tracheal intubation. Labetalol’s longer onset time and effect duration make it less attractive than esmolol in emergency situations. β-Adrenergic blockade should likely only be used in settings where peri- and postnatal fetal monitoring is available.
Nitroglycerin (NTG) is a rapid-acting direct vasodilator with a long record of safe use in obstetric anesthesia. NTG decreases arterial blood pressure by smooth muscle relaxation via the nitric oxide/cyclic GMP pathway. Onset time after an IV bolus is almost immediate, and effect duration is 3 to 5 minutes (Table 1).a
After induction with thiopental 5 mg/kg, an NTG bolus of 1.5 to 2.5 µg/kg immediately before laryngoscopy attenuated the hypertensive response to intubation in nonpregnant patients compared with saline placebo.31 An NTG infusion (25–300 µg/min), titrated to decrease MAP by 20% immediately before induction with thiopental 4 mg/kg, resulted in improved peri-induction arterial blood pressure control in a small (n = 19) randomized controlled trial in preeclamptic patients.32 One prospective blinded trial in 120 patients with severe preeclampsia compared NTG infusion (5 µg/min) with oral nifedipine 10 mg, or IV hydralazine 5 to 10 mg, titrated to achieve a systolic blood pressure between 120 and 140 mm Hg and a diastolic blood pressure between 80 and 100 mm Hg just before induction of anesthesia with thiopental 5 mg/kg. The authors found better hemodynamic control and less postinduction hypotension with NTG.33 Transdermal NTG 0.4 mg/h decreases umbilical and uterine artery resistance and pulsatility indices in in vivo human studies34,35 and induces human umbilical artery vasodilation in vitro.36
NTG crosses the placenta with an F/M ratio of 0.18.26 No adverse fetal effects have been noted with peri-induction doses.32,37,38 Maternal side effects of bolus-dose NTG are usually transient but include tachycardia, brief hypotension, or ventilation/perfusion mismatch. With prolonged high-dose infusion, methemoglobinemia is possible. NTG is stable at room temperature, widely available, and included in many emergency drug trays, in particular in the labor and delivery suite, but it requires dilution to make clinically relevant concentrations.
Nitroprusside is a direct vasodilator with rapid onset and offset used for hypertensive emergencies. It is administered via infusion and can be used as second-line therapy for arterial blood pressure control in preeclampsia.39,40 No data regarding nitroprusside’s peri-induction use are available. The F/M ratio is reported as 1.0 in sheep models,21 but no data regarding fetal safety are available. Potential maternal side effects include undesirable hypotension; prolonged administration at infusion rates more rapid than 2 µg/kg/min may be associated with tachyphylaxis and cyanide toxicity. Nitroprusside is unstable in light and is usually not readily available in the labor and delivery suite.
Hydralazine is a direct vasodilator with mainly peripheral arterial effects; its use is well established in preeclampsia.5 Hydralazine has an onset time of 5 to 20 minutes and effect duration of 1 to 4 hours.a Hydralazine crosses the placenta with an F/M ratio of 0.72.21 Potential maternal side effects include tachycardia and delayed hypotension. One prospective randomized trial comparing hydralazine to NTG infusion and oral nifedipine in preeclamptic patients found hydralazine ineffective at controlling the hemodynamic response to intubation; additionally, it was associated with later hypotension.33
Mu-opioid receptor agonists have many systemic effects, the most important being analgesia. Depending on structure, opioids have variable onset, effects, solubility, duration, and clearance; only fentanyl, alfentanil, and remifentanil have been studied specifically for the prevention of hypertension on induction of anesthesia in women with preeclampsia.
Fentanyl and alfentanil are rapidly acting semisynthetic opioids with time to peak effect 5 and 2 minutes, respectively, and effect durations between 30 and 60 minutes.a Fentanyl (2–8 µg/kg) before induction of anesthesia with thiopental 3 to 5 mg/kg has been shown in multiple studies to suppress the hemodynamic response to laryngoscopy and intubation in general surgical patients.41–43 Alfentanil (10–30 µg/kg) before induction with thiopental 4 to 5 mg/kg, similarly has been shown to blunt the hemodynamic response to intubation in nonpregnant surgical patients.44 Alfentanil 10 µg/kg, given before thiopental 3.5 to 5 mg/kg in healthy women undergoing elective cesarean delivery reduced arterial blood pressure response after intubation.45–47 Alfentanil has also been shown to provide stable hemodynamics in the setting of preeclampsia either in combination with a magnesium bolus 30 mg/kg48 or alone49 after induction with thiopental 5 mg/kg.
In a study of 40 severely preeclamptic patients undergoing general anesthesia that compared fentanyl 2.5 µg/kg to alfentanil 10 µg/kg given before induction of anesthesia with lidocaine 1 mg/kg and etomidate 0.3 mg/kg, no difference in hemodynamic variables between the 2 groups was observed. Patients’ peri- and postintubation arterial blood pressures were not significantly different from the baseline pressures in either group.50
Fentanyl and alfentanil in analgesic doses offer little serious maternal risk; rarely, respiratory depression, bradycardia, and chest wall rigidity can occur.
Fentanyl crosses the placenta, with an F/M ratio of 0.37.21 Only 1 study has assessed neonatal outcome after peri-induction low-dose fentanyl (1 µg/kg) compared with placebo in healthy women undergoing elective cesarean delivery under general anesthesia. There were no differences in Apgar scores, umbilical artery blood gas values, or need for naloxone.51 A prospective trial of 24 term parturients assessed biophysical variables of fetuses exposed to maternally administered fentanyl for early labor analgesia compared with an unexposed control group. After receiving fentanyl 50 µg, heart rate variability was reduced, body movements were less, and breathing was absent at 10 minutes in the exposed fetuses.52 Alfentanil also crosses the placenta, with an F/M ratio of 0.3,21 and studies of neonatal effects have had conflicting results; some studies report neonatal depression.45–47,49
Remifentanil is a potent synthetic opioid agonist with rapid onset of <60 seconds and context-insensitive half-life of 3 minutes due to its metabolism by nonspecific plasma esterases.a Remifentanil is available as a concentrated powder that must be reconstituted and diluted. Since its introduction 15 years ago, several case reports have appeared in the literature demonstrating its use in high-risk patients with preeclampsia and concomitant cardiac disease53 or hemolysis–elevated liver enzymes–low platelets (HELLP) syndrome.54,55 Given immediately before induction of anesthesia with thiopental 4 mg/kg, remifentanil 1 µg/kg decreased the hypertensive response to laryngoscopy and tracheal intubation compared with saline placebo in a randomized, blinded, controlled trial of 40 healthy pregnant patients undergoing cesarean delivery with general anesthesia.56
Two randomized controlled trials involving peri-induction bolus remifentanil in preeclamptic women have been reported.57,58 Yoo et al.57 found that remifentanil 1 µg/kg significantly decreased immediate postintubation arterial blood pressure compared with saline placebo when administered just before induction with thiopental 4 mg/kg. Park et al. compared remifentanil 0.5 µg/kg with 1 µg/kg administered immediately before induction of anesthesia with thiopental 5 mg/kg and found postintubation systolic blood pressure to be within baseline range in both groups. Arterial blood pressure control was better with the larger dose of remifentanil at the expense of postinduction hypotension requiring vasopressor treatment in some patients.58
Serious potential maternal side effects of remifentanil include chest wall rigidity and hypotension. Remifentanil readily crosses the placenta, with an F/M ratio of 0.88.21,26 Despite remifentanil’s short half-life, several studies have noted transient respiratory depression, need for naloxone, or lower Apgar scores in neonates whose mothers received remifentanil during anesthesia induction.57,59
Fentanyl, alfentanil, and remifentanil all are effective in preventing the hypertensive response to laryngoscopy and intubation in preeclamptic patients. Transient fetal respiratory depression has been associated with all 3 drugs; therefore, the neonatal resuscitation team must be immediately available and made aware that the mother received opioids. Because opioids are controlled substances, they may not be rapidly available in emergency situations. Additionally, remifentanil must be reconstituted and diluted. For these reasons, use of opioids for the prevention of hypertension may be less attractive than antihypertensive drugs.
Calcium Channel Blocking Drugs
Calcium channel blocking drugs cause cardiac and vascular smooth muscle relaxation. The dihydropyridine subtype primarily causes peripheral vasodilation with few effects on cardiac function.
Nifedipine is used for tocolysis as well as to treat hypertension during pregnancy. It is available only for oral administration and has a long effect duration, limiting its use in the setting of anesthesia induction.
Nicardipine is a rapid-acting dihydropyridine calcium channel blocking drug with a primarily peripheral vasodilatory effect, often accompanied by reflex increases in heart rate and cardiac output. After IV administration, onset time is <1 minute, with a peak effect at 2.5 minutes.a,60 Nicardipine bolus (15–30 µg/kg) 1 minute before induction of anesthesia with thiamylal 5 mg/kg decreased the hypertensive response to laryngoscopy and tracheal intubation compared with placebo in several studies in healthy nonpregnant patients.61,62 Although its use has been reported for resistant hypertension in severe preeclampsia,63–65 there are no efficacy data for nicardipine given peri-induction to prevent hypertension in healthy or preeclamptic pregnant patients. Potential serious maternal effects include tachycardia, hypotension, and uterine atony.65
Nicardipine is highly protein bound in maternal plasma, with low placental transfer and an F/M ratio of 0.15.66 Fetal and neonatal effects have not been noted after infusion of nicardipine 1 to 10 µg/min over 1 to 2 days for arterial blood pressure control in patients with severe preeclampsia.65,66
Lidocaine is an amide local anesthetic that may decrease the hemodynamic response to laryngoscopy and tracheal intubation by central sodium channel blockade. Onset time after IV administration is 1 to 2 minutes, and the clinical effect duration is 10 to 20 minutes.a
Efficacy studies in the general surgical population demonstrate conflicting results, likely due to differences in methodology, dose, or patient selection.67–71 One investigation in preeclamptic patients compared lidocaine 1.5 mg/kg to alfentanil 10 µg/kg and magnesium 40 mg/kg given before induction of anesthesia with thiopental 5 mg/kg and found systolic, diastolic blood pressures and MAP to be significantly higher in the lidocaine group.49 No serious maternal side effects were reported, although the safe maximal dose may be lower in preeclamptic patients.
Lidocaine crosses the placenta, with an F/M ratio of 0.5 to 0.7.26 In addition, fetal/neonatal lidocaine levels may be elevated in acidotic fetuses due to ion trapping.21 No data regarding neonatal outcome are available when lidocaine is administered as the only adjunct to an induction drug.
Magnesium is an electrolyte with many systemic effects; it is a direct vasodilator, a skeletal and smooth muscle relaxant, and an anticonvulsant. Magnesium infusion is recommended by the American College of Obstetricians and Gynecologists for the treatment of severe preeclampsia, including during cesarean delivery, to prevent eclampsia.5,6 Because of this recommendation, most severely preeclamptic women receive magnesium during cesarean delivery, which may affect these patients’ responses to other medications. After an IV bolus, magnesium has an onset of <30 seconds, effect duration of 30 minutes, and variable elimination half-life depending on renal function.a
Two randomized controlled trials compared magnesium 40 mg/kg, alfentanil 10 µg/kg, or combined magnesium 30 mg/kg and alfentanil 7.5 µg/kg and found all 3 techniques offered stable hemodynamics in preeclamptic patients undergoing nonemergent cesarean delivery under general anesthesia. No placebo group was used for comparison.48,49 Maternal serum magnesium levels after bolus were assessed in both studies, and mean values varied, depending on whether the patient had received magnesium therapy for seizure prophylaxis. In those who had received magnesium infusion before anesthesia induction, the mean serum magnesium level was 4.01 mmol/L, with a maximal level of 6.6 mmol/L.48
Serious potential maternal toxicity with magnesium is possible, particularly in patients already receiving an infusion or in those with renal insufficiency. Sedation, neurologic depression, muscle weakness, hypotension, respiratory depression, and cardiovascular collapse have all been associated with toxic magnesium levels. Magnesium enhances neuromuscular blockade and may increase the sedative effects of other medications. Tachycardia is a common side effect of magnesium bolus and was noted in both randomized trials.48,49
Magnesium crosses the placenta, with fetal serum levels approximating maternal serum levels.72 Administered maternal magnesium is associated with both fetal and neonatal depression; a large retrospective review reported lower 1- and 5-minute Apgar scores and higher rates of tracheal intubation, hypotonia, and requirement for neonatal intensive care in neonates as maternal magnesium levels increased.73
Anesthesia Induction Drugs
Numerous sedative–hypnotic drugs are used for induction; however, in obstetric anesthesia, historically thiopental and currently propofol are the most commonly used drugs. Ketamine and etomidate are used occasionally for induction of anesthesia for cesarean delivery, but their hemodynamic profiles make them less attractive for prevention of hypertension during laryngoscopy and tracheal intubation. Thiopental is a barbiturate with onset time of 30 to 60 seconds, effect duration of 5 to 30 minutes, and elimination half-life of 3 to 8 hrs.a Thiopental crosses the placenta with a wide range of reported F/M ratios (0.4–1.1).26 Serious maternal side effects include depression of myocardial contractility and decrease in systemic vascular resistance, causing hypotension and tachycardia, or histamine release, causing bronchospasm. Thiopental is no longer available in the United States but was commonly used for induction of anesthesia until 5 years ago. Therefore, most studies of hemodynamic control during intubation in preeclamptic patients used thiopental, not propofol, as the induction drug.
Propofol is a general anesthetic with unknown mechanism of action, possibly due to γ-aminobutyric acid receptor agonism or glutamate receptor antagonism. Onset time is 30 to 60 seconds, effect duration 3 to 10 minutes, with an elimination half-life of 40 minutes.a The most serious maternal side effect of propofol is a decrease in systemic vascular resistance, causing hypotension. Propofol crosses the placenta with an F/M ratio range of 0.65 to 0.85.26 The primary neonatal side effect of both thiopental and propofol is sedation, the degree of which may vary depending on induction to delivery time and fetal and maternal protein binding. Neonatal outcomes after exposure to thiopental and propofol were compared in several studies, with most studies showing comparable Apgar scores.74–78 In addition, 1 study found no difference in neurologic and adaptive capacity scores between the 2 drugs.77
Safety studies comparing thiopental with propofol in healthy women undergoing cesarean delivery showed lower blood pressures during and after tracheal intubation with propofol 2 to 2.5 mg/kg compared with thiopental 4 to 5 mg/kg.76–78 No investigation into varying the doses of thiopental or propofol has been done in healthy pregnant or preeclamptic patients. It is likely that both the timing and dose of induction drug significantly affect the hemodynamic response to laryngoscopy and tracheal intubation.
In summary, there is scant literature regarding optimal pharmacologic drugs for control of arterial blood pressure during the rapid-sequence induction of general anesthesia in preeclamptic women. There are no trials available that compare the medications used in current practice, in particular with propofol as the induction drug, and there is insufficient evidence to support one drug as first-line therapy. It may be that a combination of drugs from different classes, along with a patient-specific dose of induction drug, leads to optimal hemodynamic stability. Given their favorable pharmacologic profiles, wide availability, and predictability with few reports of serious maternal or neonatal effects, esmolol 1.5 mg/kg or NTG 2 µg/kg, combined with propofol 2 mg/kg, is used by the authors of this review, depending on maternal hemodynamic variables at the time of anesthesia induction. The effect duration of these drugs is short in neonates; therefore, their use should not preclude admission of otherwise healthy term infants to the general care nursery. Labetalol and remifentanil are also reasonable options in nonemergency situations for practitioners who are comfortable with their use. Nicardipine may be useful; however, data are lacking. Lidocaine, calcium channel blocking drugs other than nicardipine, hydralazine, and magnesium bolus are not recommended given their lack of efficacy and/or potential serious maternal or fetal side effects. In all cases, a neonatal resuscitation team should be present at delivery and made aware of any maternally administered medications. Further prospective trials comparing these drugs and varying doses of anesthesia induction drugs are needed.
Name: Melissa Pant, MD.
Contribution: This author helped prepare the manuscript.
Attestation: Melissa Pant approved the final manuscript.
Name: Robert Fong, MD.
Contribution: This author helped prepare the manuscript.
Attestation: Robert Fong approved the final manuscript.
Name: Barbara Scavone, MD.
Contribution: This author helped prepare the manuscript.
Attestation: Barbara Scavone approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
a Lexi Drugs Online. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6847. Accessed January 15, 2013.
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