Lisinopril Pre-Surgery Hold Window: When to Stop, When to Continue

What the label says about surgery and anesthesia

The lisinopril prescribing information handles surgery in one paragraph inside its hypotension warning. In patients undergoing major surgery, or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release; if hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion [1]. No interval before surgery appears in that paragraph.

The same warning names the patients most exposed to excessive hypotension: heart failure with systolic pressure below 100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high-dose diuretic therapy, renal dialysis, and severe volume or salt depletion. For these patients the label says lisinopril should be started under very close medical supervision, with close follow-up for the first two weeks and after any dose increase [1].

What the perioperative studies found

A 2018 systematic review in Anesthesia & Analgesia (Hollmann and colleagues) pooled 9 studies, 5 randomized trials and 4 cohort studies, covering 6,022 adults on long-term ACE inhibitor or ARB therapy who had noncardiac surgery. Of those, 1,816 withheld therapy on the morning of surgery and 4,206 continued it. Withholding was not associated with a difference in mortality (odds ratio 0.97, 95% CI 0.62-1.52) or major adverse cardiac events (odds ratio 1.12, 95% CI 0.82-1.52), and it was associated with significantly less intraoperative hypotension [2]. The review pooled ACE inhibitors and ARBs and mixed trials with cohort studies, so it shows an association rather than proof that withholding caused the difference.

Comfere and colleagues retrospectively studied 267 hypertensive adults on long-term ACE inhibitor or ARB therapy having elective noncardiac surgery under general anesthesia. Patients had been asked either to take the last dose on the morning of surgery or to withhold it for up to 24 hours, and the hours from last dose to surgery were recorded. In the first 30 minutes after induction, moderate hypotension (systolic pressure at or below 85 mmHg) occurred in 60% of patients whose last dose was less than 10 hours before surgery and 46% of those at 10 hours or more (P=0.02), an adjusted odds ratio of 1.74 (95% CI 1.03-2.93) [3]. Severe hypotension (systolic pressure at or below 65 mmHg), vasopressor use and postoperative complications did not differ between the two groups [3].

Brabant and colleagues studied vascular surgery patients: 27 on an ACE inhibitor, 45 on a beta-blocker and/or calcium channel blocker, and 12 on an angiotensin receptor blocker, the last group treated until the morning of surgery. Hypotension after induction occurred in 18 of 27 on the ACE inhibitor, in 27 of 45 on a beta-blocker or calcium channel blocker, and in all 12 on the ARB. Hypotension refractory to repeated ephedrine or phenylephrine occurred in 1 of 27, 0 of 45 and 4 of 12 respectively, and a vasopressin-system agonist restored blood pressure in the refractory cases [5].

How long before surgery?

The available timing comparison is a last dose under 10 hours versus 10 hours or more before induction [3]. It does not establish whether a 12-hour or a 24-hour hold is better, and none of these studies tested lisinopril alone.

For context, the label says peak serum concentrations occur within about 7 hours and the effective half-life is about 12 hours with repeated dosing. Lisinopril is not metabolized, is not protein bound, and is excreted unchanged in urine [1]. Clinically important accumulation occurs when the glomerular filtration rate is below 30 mL/min; the label halves the usual initial dose at a creatinine clearance of 10 to 30 mL/min and gives 2.5 mg initially at a clearance below 10 mL/min or on hemodialysis [1].

Heart failure and other high-risk patients

Lisinopril is indicated to reduce the signs and symptoms of systolic heart failure, started at 5 mg once daily and increased as tolerated to a maximum of 40 mg once daily [1]. In ATLAS, 3,164 patients with NYHA class II to IV heart failure and an ejection fraction of 30% or less took 2.5 to 5 mg daily (n=1,596) or 32.5 to 35 mg daily (n=1,568) for 39 to 58 months; the high-dose group had a nonsignificant 8% lower risk of death (P=0.128) and a significant 12% lower risk of death or hospitalization for any reason (P=0.002) [4]. ATLAS tested dose, not holding the drug for surgery.

The label lists heart failure with systolic pressure below 100 mmHg among the conditions that raise the risk of excessive hypotension, alongside high-dose diuretic therapy, hyponatremia, dialysis and volume or salt depletion [1]. In the vascular surgery study, 1 of 27 ACE inhibitor patients had hypotension that did not respond to ephedrine or phenylephrine; those numbers are small [5].

When pressure falls after induction

In the vascular surgery study, the ACE inhibitor group needed less ephedrine on average than the beta-blocker/calcium channel blocker group (7±4 mg versus 10±6 mg) and far less than the ARB group (21±3 mg) [5]. Refractory cases responded to a vasopressin-system agonist [5].

Angioedema and the airway

The label says angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including fatal reactions, has occurred with ACE inhibitors at any time during treatment. Patients with tongue, glottis or larynx involvement are likely to experience airway obstruction, especially those with a history of airway surgery. The label says lisinopril should be promptly discontinued, with appropriate therapy and monitoring until the swelling has completely and persistently resolved [1]. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients [1]. In a large 24-week hypertension trial, angioedema occurred in 0.68% of patients on enalapril, another ACE inhibitor (these are enalapril data, not lisinopril), versus 2.17% on omapatrilat [6].

After surgery

The label says to consider withholding or discontinuing lisinopril in patients who develop a clinically significant decrease in renal function, and to monitor renal function periodically [1]. NSAIDs, including COX-2 inhibitors, may worsen kidney function in elderly, volume-depleted or renally impaired patients taking an ACE inhibitor, usually reversibly, and may reduce the blood-pressure effect [1]. Potassium is the other number to watch: 2.2% of hypertensive and 4.8% of heart failure patients in trials had serum potassium above 5.7 mEq/L. The label lists renal insufficiency, diabetes, potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes as risk factors, and says to monitor potassium periodically [1].