ACE-Inhibitor or ARB-Induced Refractory Hypotension Treated With Vasopressin in Patients Undergoing General Anesthesia for Dentistry: Two Case Reports
Two case reports present the use of vasopressin for treating refractory hypotension associated with continued angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy prior to general anesthesia for oral surgery. Both patients were treated in an ambulatory dental surgery clinic and took either their ACEI or ARB medication for hypertension within 24 hours prior to undergoing an intubated general anesthetic. Persistent profound hypotension was encountered intraoperatively that was refractory to treatment with traditional methods. However, the ACEI- or ARB-induced refractory hypotension was successfully managed with the administration of vasopressin.
Hypertension (HTN) affects ∼1 billion individuals worldwide.1 It is estimated that there are ∼72 million patients with HTN in the United States, affecting 30% of people over the age of 20 and 60% to 70% of people over 70 years of age.2 The World Health Organization predicts that one-third of the world's population will have HTN by 2025.1 A variety of medications including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed for treating HTN. Due to the increasing number of individuals on antihypertensive therapy, consideration should be given to patients taking ACEIs or ARBs who present for ambulatory dental surgery under general anesthesia. Continued perioperative use of ACEIs and ARBs has been associated with reduced or abnormal physiological responses to common intraoperative vasopressors, such as ephedrine, phenylephrine, and epinephrine, and is otherwise known as refractory hypotension.3
We present the cases of 2 patients taking an ACEI or ARB with refractory hypotension successfully managed with the addition of vasopressin. Both patients provided written consent prior to publication of these case reports.
CASE PRESENTATIONS
Case 1
A class 3 or severely obese 58-year-old female (height 163 cm; weight 150 kg; body mass index [BMI] 56.6 kg/m2) presented to the University of Pittsburgh School of Dental Medicine outpatient center for extraction of 22 teeth and 2 quadrants of alveoloplasty under general anesthesia. Her medical history was significant for primary HTN for which she was taking losartan 50 mg once daily. She also had arthritis but did not report taking any medication for treatment.
Preoperative instructions given over the phone the day before her appointment included directions to take the losartan that evening with dinner as normal. It is worth noting that she required assistance with her activities of daily living, and it was perceived by the resident interviewer that she may struggle with intellectual challenges, which was not reported. On the day of surgery, the patient confirmed adherence to all preoperative instructions including fasting from solids for 8 hours and liquids for 6 hours. Her last losartan dose was taken at ∼7 PM the evening prior to surgery. Despite her severely elevated BMI, her airway was deemed a Mallampati Class II, and a routine induction and intubation with a nasal endotracheal tube (NETT) was planned using video laryngoscopy. All risks, benefits, and alternatives for general anesthesia were explained and written consent obtained.
Upon entering the dental operatory room, she experienced significant anxiety and was unable to cooperate for monitor placement or intravenous (IV) catheter insertion without her sister being present. Standard American Society of Anesthesiologists (ASA) monitors were then applied, and a 20-gauge IV was placed in the dorsum of her hand and attached to a 500-mL bag of Lactated Ringer's (LR).
The patient was preoxygenated via face mask with 100% O2 in preparation for induction, and fentanyl 50 mcg IV bolus was administered. Her blood pressure (BP) at that time was 139/88 mm Hg (mean arterial pressure [MAP] 105 mm Hg), and her heart rate (HR) was 96 beats per minute (bpm). General anesthesia was induced with an additional bolus of fentanyl 50 mcg and propofol 200 mg, followed by a defasciculating dose of rocuronium 5 mg and succinylcholine 200 mg. Due to patient size, patient was kept in a 45-degree semirecumbent position during induction to aid with ventilation. Positive pressure ventilation with easy bag valve mask was confirmed before paralysis with IV succinylcholine. A cuffed size 6.0 preformed NETT was inserted into the right naris, and intubation was completed on the first attempt using video laryngoscopy. Anesthesia was maintained with 2% sevoflurane in 2 L/min of a 50/50% nitrous oxide/oxygen mix. The patient was artificially ventilated using volume control with a 400-mL tidal volume and a rate of 12 breaths per minute. Immediately following intubation, a BP of 67/47 mm Hg (MAP 52 mm Hg) was obtained along with a HR of 75 bpm. An IV bolus of ephedrine 10 mg was administered to treat the hypotension while the local anesthetic injections proceeded. The subsequent BP was 123/72 mm Hg (MAP 89 mm Hg) with a HR of 85 bpm, although fluctuations in BP persisted throughout the case (Figure 1).
Citation: Anesthesia Progress 69, 3; 10.2344/anpr-69-02-06
Repeated incidents of hypotension continued but failed to respond successfully to treatment. A 500 mL fluid bolus along with intermittent vasopressor boluses consisting of ephedrine 40 mg total, phenylephrine 200 mcg total, and epinephrine 20 mcg total produced only transient effects while her MAP continued to trend downward (Figure 1). Sevoflurane was discontinued to reduce the potential profound vasodilation, and a propofol infusion 100 mcg/kg/min was substituted for maintenance in the hope that it may have a less profound vasodilatory effect.
Due to the continuing significant BP fluctuations and hypotension, vasopressin was administered via a 1-unit loading dose followed by a continuous infusion titrated to effect. The infusion was started at 0.03 units/min and titrated up to 0.05 units/min over a 30-minute period to maintain a target MAP >65 mm Hg. The entire case lasted 2.5 hours, and the NETT was removed without complication once the patient met all awake extubation criteria. She recovered satisfactorily from anesthesia and met discharge criteria prior to being released into her sister's care. The patient was recovered in the dental operatory for ∼30 minutes following extubation. Her BP readings remained stable during the recovery period and were comparable with baseline, and she was discharged in stable condition.
Case 2
A borderline class 3 or severely obese 53-year-old female (height 170 cm; weight 110 kg; BMI 38.9 kg/m2) presented for extraction of 27 teeth and 4 quadrants of alveoloplasty under general anesthesia. Her medical history was significant for diabetes mellitus type 1, HTN, hyperlipidemia, rheumatoid arthritis, fibromyalgia, and anxiety/depression. All medical comorbidities were controlled, with her last HbA1c being ∼6%, and she reported taking the following medications: lisinopril 20 mg once daily along with insulin glargine, insulin lispro, bupropion, alprazolam, hydroxyzine, simvastatin, etanercept, and pregabalin.
Preoperative instructions were given over the phone the day before her appointment, and the patient was informed to withhold her insulin lispro but continue taking her other morning medications including the lisinopril as usual before arrival. The morning of surgery, she confirmed adherence to these instructions as well as appropriate fasting guidelines. Although the patient reported her blood glucose as 135 mg/dL earlier that morning, we obtained another blood glucose reading of 138 mg/dL preoperatively. Physical examination revealed a Mallampati Class III airway, a thyromental distance equal to 3 fingerbreadths, and that the patient was able to easily bite her upper lip with her lower mandibular incisors. Considering the patient's airway examination and surgical needs, the plan to proceed with general anesthesia was confirmed. All risks, benefits, and alternatives for general anesthesia were explained and written consent was obtained.
Upon arrival to the dental operatory room and after placement of standard ASA monitors, her initial vital signs were as follows: BP 118/82 mm Hg (MAP 94 mm Hg), pulse 90 bpm. A 22-gauge peripheral IV catheter was placed in her antecubital fossa, connected to 500 mL of LR, and midazolam 2 mg IV was administered. After sufficiently preoxygenating the patient with 100% O2 via face mask, general anesthesia was induced with sufentanil 5 mcg and propofol 200 mg, followed by a defasciculating dose of rocuronium 5 mg and succinylcholine 140 mg. Positive pressure ventilation with easy bag valve mask was confirmed before paralysis with IV succinylcholine. Due to patient size, patient was kept in 45-degree semirecumbent position during induction to aid with ventilation. The first intubation attempt was successful using video laryngoscopy and cuffed size 6.5 preformed NETT atraumatically inserted through the right naris. Anesthesia was maintained with 2% sevoflurane in 2 L/min of a 50/50% nitrous oxide/oxygen mix. The patient was artificially ventilated using volume control with a 400-mL tidal volume and a rate of 12 breaths per minute.
Shortly after intubation, profound hypotension, a BP of 82/55 mm Hg (MAP 64 mm Hg), and a HR 84 bpm was noted and treated with intermittent 100 mcg phenylephrine boluses (total of 1 mg) with transient increases in BP, followed by 500 mL bolus of IV fluid. Ephedrine and epinephrine were avoided because the patient was taking bupropion. Due to the limited improvement following phenylephrine and the fluid bolus, the sevoflurane concentration was reduced as the patient's MAP trended downward from 65 to 48 mm Hg over the next 15 minutes (Figure 2). Sevoflurane was then discontinued, and a continuous infusion of propofol 50 mcg/kg/min was initiated for anesthetic maintenance to minimize any vasodilatory effects.
Citation: Anesthesia Progress 69, 3; 10.2344/anpr-69-02-06
Following limited improvement, a vasopressin loading dose of 1 unit was administered followed by an infusion at 0.03 units/min. The patient's BP gradually stabilized with a MAP ranging from 68 to 92 mm Hg (Figure 2). The vasopressin infusion continued for a total of 70 minutes, and the case was completed in 2.5 hours at which point the propofol and vasopressin were discontinued. The patient was extubated without complications after emerging smoothly from anesthesia. She was recovered for ∼30 minutes following extubation. Once she recovered fully and appropriately met discharge criteria, the patient was discharged from the clinic. Her hemodynamic vital signs returned to baseline and remained stable throughout recovery.
DISCUSSION
Both patients were middle-aged females on antihypertensives who reported taking either an ACEI or ARB within 24 hours of general anesthesia for dental surgery. As noted previously, this can lead to intraoperative hypotension refractory to traditional interventions like vasopressors and fluid boluses.4 Maintaining adequate BP and organ perfusion is critical for any patient under general anesthesia. However, those with existing cardiac and/or renal comorbidities are at greater risk of suffering acute injury from extended periods of severe hypotension.5
Hypotension is best characterized by either an absolute threshold or a relative decrease from baseline. For example, a MAP >65 mm Hg may be considered an absolute threshold for preserving autoregulation of end organ perfusion, while maintaining a MAP within 20% of the patient's baseline is a relative threshold.6 Patients with preexisting renal dysfunction, coronary artery disease, diabetes mellitus, and/or HTN may require a higher relative MAP to adequately perfuse organs habituated to the higher pressures.6 However, the absolute vs relative hypotension related to organ injury is unknown.5 Salmasi et al6 showed that intraoperative BPs falling below the absolute MAP threshold of 65 mm Hg or relative threshold >20% of baseline were both related to myocardial and kidney injury, although neither demonstrated a stronger association than the other. Patients with MAPs <65 mm Hg for longer than 13 minutes were at significantly higher odds of myocardial and kidney injury, and the lower the MAPs, the less time required (even just 1 minute) to increase the risk for such injuries.
Transient periods of hypotension under anesthesia, especially following induction, are relatively common and typically respond effectively to basic measures such as decreasing the anesthetic depth, administering IV fluids, and/or pharmacologic support. Vasopressors (eg, ephedrine, phenylephrine, and epinephrine) are typically used due to their rapid onset and hemodynamic predictability.7 Due to fasting requirements prior to anesthesia, patients typically experience a relative decrease in intravascular volume. This relative hypovolemia can be exacerbated during appointments later in the day, particularly if patients are instructed to have, “Nothing by mouth after midnight.” Additionally, most anesthetic agents cause some degree of vasodilation, which can further exaggerate intraoperative hypotension.
The most recent Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery was developed in 2014 by the American College of Cardiology and the American Heart Association. It states that, “Continuation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers perioperatively is reasonable.”8 While there is well-documented evidence of refractory hypotension in patients continuing ACEI and ARB therapy for noncardiac surgery under general anesthesia, one must consider the risk of discontinuing any such medications.9 A systematic review from 2018 by Hollmann et al10 looked at a total of 6022 patients on chronic ACEI or ARB therapy. There was no difference in mortality, major cardiac events, heart failure, acute kidney injury, or cerebral vascular accidents between patients who held or continued their ACEI or ARB preoperatively. However, continuing such antihypertensives on the morning of surgery was associated with an ∼30% increase in relative risk of intraoperative hypotension. Intraoperative hypotension was associated with adverse renal and cardiac outcomes, although it remains unclear if continuation of ACEI or ARB and associated hypotension is correlated to these adverse outcomes. Ultimately the decision to continue or withhold these medications is left to the discretion of the clinician. However, it appears that primarily for general anesthesia, the benefits of holding ACEIs or ARBs in hopes of preventing dramatic, and possibly refractory, intraoperative hypotension outweigh the risks of continuing these medications. If these antihypertensives are withheld preoperatively, they must be resumed as soon as reasonably possible to minimize risk of harm from existing comorbidities.
In both cases, each patient's hypotension was treated by decreasing the inhalational anesthetic and administering fluid boluses and vasopressors for ∼1 hour with limited improvement. Additionally, maintenance using inhalational anesthesia (sevoflurane) was changed to a total IV anesthetic (propofol) during that hour. However, that decision was more empirical than evidence based with the idea that propofol may produce less profound vasodilation than sevoflurane in each patient. The hypotension that occurred was more likely related to anesthetic depth than the agents used, and one can assume there may have been less hypotension if moderate sedation had been utilized in place of intubated general anesthesia.
The sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and the vasopressinergic system (VS) are the 3 primary regulatory systems that control vascular tone.11 General anesthesia can blunt the SNS, which negatively impacts vascular tone and increases dependence on the RAAS and VS to maintain BP.12 The RAAS blockade produced by ACEIs or ARBs inhibits the short-term hormonal regulation of BP (Figure 3). Additionally, the efficacy of sympathetic adrenoceptor agonists can be limited in patients taking ACEIs and ARBs.3,12 With the impairment of both the SNS and RAAS, only the VS is left uninhibited,13 which explains the effectiveness of vasopressin and vasopressin-receptor agonists for treating intraoperative refractory hypotension when other treatment modalities are ineffective (Figure 4).
Citation: Anesthesia Progress 69, 3; 10.2344/anpr-69-02-06
Citation: Anesthesia Progress 69, 3; 10.2344/anpr-69-02-06
Vasopressin
Arginine vasopressin (AVP), also known as antidiuretic hormone, is an endogenous hormone made in the hypothalamus and released by the posterior pituitary in response to elevations in plasma osmolarity and decreases in intravascular volume.14 A synthetic version of AVP (vasopressin injection) can be used to stimulate the vasopressin (V1) receptors and treat decreased MAPs.14 V1 receptors are found on vascular smooth muscle and cardiomyocytes. Activation of V1 receptors triggers a short-term vasoconstrictor response in arterial smooth muscle, increasing vascular resistance and MAP14 (Figure 4). Case studies have shown support for the use of a V1 receptor agonist in patients with severe hypotension and RAAS blockade when conventional treatment strategies fail.15
Vasopressin injection is available for IV use and is commonly packaged as 20 units/mL in a 1-mL vial. According to the package insert, it must be diluted with normal saline or 5% dextrose in water (D5W) to either 0.1 units/mL or 1 unit/mL for IV administration. It should be infused over time with a starting rate between 0.01 and 0.03 units/min and titrated up by 0.005 units/min at 10- to 15-minute intervals. The vasopressor effect is rapid, peaking within 15 minutes, and the effects fade within 20 minutes of ending the infusion.18 One may question whether vasopressin should be a required medication for the management of intraoperative refractory HTN in the office-based environment. Acceptable possible alternatives may include terminating the procedure and allowing the patient to recover from the anesthetic effects or performing the procedure with moderate/deep sedation instead. Further studies are indicated to determine the frequency of ACEI- or ARB-induced refractory hypotension in an office setting and therefore the need for additional nonsympathomimetic vasopressors.
CONCLUSION
The patients in these 2 case reports took either an ACEI or an ARB prior to undergoing intubated general anesthesia for the extraction of remaining teeth with alveoloplasty. Intraoperatively, both developed refractory hypotension that failed to respond to standard treatment that included decreasing the depth of anesthesia, IV fluid administration, and repeated doses of multiple common vasopressors. Vasopressin administration successfully stabilized systemic BP in each case. While the administration of vasopressin is not without risk, its use should be considered during ACEI- or ARB-induced refractory hypotension.
Trend of cardiovascular vitals for case 1. Vasopressin stabilized labile hypotension unresponsive to standard vasopressors in a patient who continued angiotensin receptor blocker (ARB) therapy preoperatively.
Trend of cardiovascular vitals for case 2. Vasopressin stabilized labile hypotension unresponsive to standard vasopressors in a patient who continued angiotensin-converting enzyme inhibitor (ACEI) therapy preoperatively.
Effects of angiotensin-converting enzyme inhibitor (ACEIs) and angiotensin receptor blockers (ARBs) on vasoconstriction. Inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACEIs or ARBs inhibits hormonal regulation of blood pressure (BP), leaving only the vasopressinergic system fully functional during general anesthesia.
Mechanism of vasopressinergic vs adrenergic vasoconstriction. Vasopressin (V1) receptor activation by vasopressin produces short-term vasoconstriction that increases vascular resistance and mean arterial pressure (MAP).14 V1 receptor agonists are effective in patients with severe hypotension and renin-angiotensin-aldosterone system (RAAS) blockade when conventional adrenergic treatment fails.15
Contributor Notes