Refractory Hypotension During General Anesthesia Despite Withholding Telmisartan

Abstract

Angiotensin receptor blockers (ARBs) are commonly used to treat hypertension. However, similar to angiotensin-converting enzyme inhibitors, ARBs can also cause refractory hypotension during general anesthesia. Therefore, it has been recommended that ARBs be withheld for 24 hours prior to the induction of anesthesia. This is a case report of refractory hypotension requiring the administration of potent vasopressors after the induction of general anesthesia despite withholding telmisartan for 24 hours. In the same patient undergoing a subsequent general anesthetic, telmisartan was withheld for 5 days before induction, leading to mild intraoperative hypotension that responded adequately to phenylephrine. The primary cause of refractory hypotension during the first general anesthetic was suspected to be an insufficient telmisartan washout period. Telmisartan's half-life of 24 hours is notably the longest of all ARBs in current use. This case report demonstrates that refractory hypotension during general anesthesia cannot always be avoided by withholding telmisartan for 24 hours before the induction of anesthesia. Therefore, a washout period greater than 24 hours is preferable for patients taking telmisartan.

Angiotensin receptor blockers (ARBs) are commonly prescribed for the management of hypertension. However, refractory hypotension during general anesthesia caused by renin-angiotensin system blockade is a well-known potential complication in patients concurrently taking ARBs or angiotensin-converting enzyme inhibitors.^1–5 Therefore, it has been recommended that ARBs preferably be withheld for 24 hours prior to the induction of general anesthesia.^1–5 However, some reports suggest that continued preoperative administration of ARBs does not cause refractory hypotension on induction of general anesthesia.^6,7 In any case, the washout periods of individual ARBs with known differences in their half-lives have not been taken into consideration for avoiding ARB-induced refractory hypotension. Herein we describe a case of refractory hypotension occurring during general anesthesia despite the ARB (telmisartan) having been withheld for 24 hours prior to induction.

CASE REPORT

A 48-year-old man (height 174 cm, weight 67.6 kg, body mass index 22.3 kg/m²) was scheduled for resection of oral squamous cell carcinoma under general anesthesia. His vital signs were stable during the preoperative evaluation; his blood pressure was 117/81 mmHg, heart rate was 69 beats per minute (bpm), and oxygen saturation as measured by pulse oximetry in room air was 98%. His medical history was significant for hypertension, angina pectoris, and paroxysmal supraventricular tachycardia. All medical comorbidities were well controlled with medications, including telmisartan (Micardis tablets; 40 mg/d), atenolol (Tenormin tablets; 50 mg/d), and aspirin (Bayaspirin tablets; 100 mg/d). The patient was instructed to withhold only the telmisartan for 24 hours prior to the scheduled operation.

On the day of surgery, the patient confirmed adherence to all preoperative instructions including withholding the telmisartan. Standard anesthetic monitors were placed upon arrival to the operating room, consisting of a noninvasive blood pressure cuff, 5-lead electrocardiograph, capnography, and a pulse oximeter. Baseline vital signs obtained immediately before induction of general anesthesia were stable with a noted blood pressure of 131/79 mmHg, heart rate of 86 bpm, and oxygen saturation as measured by pulse oximetry 100% on room air. General anesthesia was induced by intravenous boluses of fentanyl (100 μg), propofol (140 mg), and rocuronium (50 mg). Following mask ventilation with sevoflurane (5%) and oxygen (6 L/min), direct laryngoscopy was performed, and the patient was subsequently intubated without any difficulty with a 7.5-mm preformed nasal endotracheal tube. General anesthesia was maintained with sevoflurane (reduced to 1.5%), oxygen (1 L/min), and air (2 L/min), plus a continuous infusion of remifentanil (0.1 μg/kg/min).

Shortly after intubation, profound hypotension was noted, with the patient's blood pressure falling to 56/26 (32) mmHg and heart rate decreasing to 68 bpm despite repeated intravenous boluses of ephedrine (total dose 36 mg) and phenylephrine (total dose 1.5 mg). Because of the patient's inadequate response to the vasopressors, a continuous infusion of dopamine (2–4 μg/kg/min) was started along with a 1500-mL infusion of a colloid solution (Voluven, 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride) prior to insertion of a central venous catheter. Sevoflurane was further reduced (1.0%) and a central venous catheter was inserted into the femoral vein to facilitate continued administration of potent vasopressors. The patient's blood pressure remained below 80/40 (55) mmHg for more than 1 hour, then recovered to 90/48 (60) mmHg or higher after infusion of dopamine (5 μg/kg/min) and dobutamine (5 μg/kg/min). Thereafter, intraoperatively, his blood pressure was maintained at ∼100/60 (70) mmHg, with a heart rate ∼80 bpm. After concluding the surgical procedure and emerging from anesthesia, the patient was extubated without difficulty and transferred out of the operating room to continue recovering, during which time no additional complications were noted.

Postoperative histopathological examinations of the surgical specimen indicated the need for additional resection due to unclear surgical margins. The second operation was scheduled 5 days after the first surgery. While discussing the anesthetic plan for the second operation, it was felt that the telmisartan washout period (24 hours) utilized initially was likely insufficient to avoid ARB-related refractory hypotension. Therefore, the patient was instructed to withhold telmisartan as long as possible prior to the second operation. Accordingly, the patient abstained from taking any telmisartan for the 5 days prior to the second scheduled operation. Also, the atenolol was held for the same period as the telmisartan, and the inhalational agent for anesthetic maintenance was changed from sevoflurane to desflurane. The anesthetic course throughout the second operation proceeded without any recurrence of the ARB-induced refractory hypotension, and all minor instances of hypotension were successfully managed requiring only phenylephrine (total dose 0.55 mg). From a cardiovascular standpoint, the patient was stable during the second operation, with a blood pressure and pulse maintained at ∼110/65 (80) mmHg and ∼70 bpm.

DISCUSSION

The patient described herein likely developed ARB-induced refractory hypotension, as evident by the profound hypotension and lack of vasoconstrictor response during the first operation, which was attributed to an insufficient washout period for the telmisartan. It has been reported that long-term ARB administration can be associated with a reduced response to alpha₁ adrenergic agonists during general anesthesia.^3,8 In the first general anesthetic, administration of the vasoconstrictors phenylephrine and ephedrine to treat hypotension had no effect despite withholding the ARB for 24 hours prior to induction. During the second surgery, however, withholding the ARB (telmisartan) and the beta blocker (atenolol) for 5 days preoperatively permitted an effective response to phenylephrine and adequate hemodynamic control during general anesthesia. This suggests that the lack of response to the vasoconstrictors was due to ARB-induced refractory hypotension, likely as a result of an insufficient washout period for the telmisartan.

Refractory hypotension under general anesthesia is a significant perioperative complication that can be attributed to blockade of the renin-angiotensin system and the development of vasoplegic syndrome, characterized by profound hypotension that fails to respond to the administration of normal catecholamines. This state of autonomic dysfunction is referred to as vasoplegia, in which the patient experiences low systemic vascular resistance.⁹ Normally patients have 3 main separate systems that help regulate blood pressure: the sympathetic nervous system, the renin-angiotensin system, and the vasopressinergic system. General anesthesia interferes with the sympathetic system, creating a higher dependence on the other 2 systems to maintain blood pressure.⁹ Angiotensin-converting enzyme inhibitors and ARBs, which inhibit the normal renin-angiotensin system response to hypotension, also reduce the sensitivity of adrenergic receptors, thereby limiting clinical effects of adrenergic agonists.^8,9 Therefore, ARB-induced refractory hypotension is likely to occur during general anesthesia.

A recent meta-analysis concluded that withholding ARBs for 24 hours prior to induction of general anesthesia was an effective strategy for avoiding severe hypotension.⁵ At present, however, a uniform ARB washout period of 24 hours is generally recommended to avoid refractory hypotension despite the known differences in half-lives of various ARBs.^1–5 Notably, telmisartan has the longest half-life (24 hours) of all the ARBs currently in use (Table).¹⁰ It has also been reported that the half-life of telmisartan becomes prolonged with regular use.¹⁰ Therefore, there is a high possibility that the 24-hour washout period utilized for the telmisartan in the first presented case was insufficient.

Table.

Half-Lives of Angiotensin Receptor Blockers (ARBs)¹⁰

ARB	t1/2, h
Losartan	2
Valsartan	6
Candesartan	9
Olmesartan	13
Azilsartan	13
Irbesartan	11–15
Eprosartan	20
Telmisartan	24

Nabbi et al³ reported a case of refractory hypotension during general anesthesia despite valsartan, an ARB, having been withheld for 24 hours prior to induction. That patient successfully underwent a subsequent operation without refractory hypotension following a 5-day valsartan washout period in the same fashion as the patient presented in this case report. Of the ARBs characterized to date, valsartan has a relatively short half-life of approximately 6 hours. Notably, marked variations in the half-lives of different ARBs suggest that it may be appropriate to investigate optimal washout periods for each individual ARB. In the present case and in Nabbi et al,³ subsequent general anesthetics were performed after substantially prolonged washout periods of 5 days; however, no conclusions can likely be drawn regarding “optimal” or “minimally sufficient” washout periods based only on these 2 individual case reports. The establishment of appropriate washout periods for individual ARBs will likely require knowledge derived from future case reports and/or prospective studies.

Vasopressin has been reported as an effective agent for the management of refractory hypotension.⁹ Its primary functions are to increase the reabsorption of water in the kidneys and to constrict blood vessels.⁹ Reports indicate that the vasopressin system is the only endogenous vasopressor system that is not inhibited during general anesthesia in patients receiving angiotensin-converting enzyme inhibitors or ARBs.⁹ Unfortunately, health insurance in Japan does not cover the use of vasopressin to treat refractory hypotension. Therefore, vasopressin could not be used in this case. Approval for use of vasopressin to treat refractory hypotension in Japan is desired.

Continued administration of beta blockers is known to reduce the risk of cardiovascular complications during the perioperative period.¹¹ Notably, however, sustained beta blocker administration before surgery can be associated with hypotension during general anesthesia.¹² A recent report highlighted the importance of weighing the risks and benefits of withholding beta blockers before surgery depending on the underlying degree of cardiac risk.¹² In this case, the beta blocker (atenolol) was withheld before the second operation in an effort to avoid hypotension.

It is reported that, unlike sevoflurane, high-concentration desflurane increases sympathetic nervous system activity, leading to potential increases in blood pressure and heart rate.¹³ Desflurane has been recommended for use in the induction of general anesthesia in patients using ARBs.⁸ Therefore, the inhalational anesthetic agent used during the second general anesthetic in the present patient was changed from sevoflurane to desflurane (7%) in an effort to avoid refractory hypotension.

CONCLUSION

In patients taking an ARB, especially one with a long half-life like telmisartan, refractory hypotension during general anesthesia may not be avoided by withholding the ARB for 24 hours prior to induction. A prolonged washout period longer than 24 hours should be considered to adequately reduce the risk of ARB-induced refractory hypotension.