Hemodynamic Consequences of Continuing Angiotensin Converting Enzyme Inhibitors

or Angiotensin II Receptor Blockers Perioperatively in Non-cardiac Elective Surgery

(HeCCA)

Sarah Kolshuk, BScPhm, ACPR; Steve Celetti, MSc, BScPhm, ACPR; Ihab Asaad MD, FRCPC

Abstract

Background: Despite widespread use of angiotensin converting enzyme inhibitors and

angiotensin II receptor antagonists (ACEI/ARBs), controversy exists on the optimal

perioperative management of these agents due to their association with post-induction

hypotension during non-cardiac surgery. Additionally, it is unknown if elderly patients taking

ACEI/ARBs are at increased risk of this adverse event compared to younger surgical patients.

Objectives: To determine if ACEI/ARBs should be continued or held on the morning of non-

cardiac surgery. Primary outcome was post-induction hypotension rates within 30 minutes taken

at 5 minute intervals. Secondary outcomes were vasopressor use at 0-15 or 16-30 minutes and

death by any cause, cardiac events, or stroke occurring during surgery or until time of hospital

discharge. Outcomes for patients less than 65 years were compared to patients 65 years of age

or older.

Methods: A retrospective chart review was performed at Trillium Health Partners – Credit

Valley Hospital from October 2014 to June 2015. Adult patients taking chronic ACEI/ARBs

therapy and undergoing elective surgery with post-surgical admission to an inpatient ward were

included.

Results: A total of 395 patients were included. Hypotension rates in patients who received

ACEI/ARBs prior to surgery were 34.8% compared to 26.7%, in patients who had their

ACEI/ARB held prior to surgery (P=0.068). Continuation of ACEI/ARBs on the morning of

surgery was not associated with increased vasopressor use (P= 0.151), cardiac events, stroke,

or death (P=0.268). There were no differences in primary or secondary outcomes based on

patient age. Previously published hypotension rates were higher than collected rates suggesting

the study was underpowered to detect statistically significant differences in outcomes.

Vasopressor use increased when systolic blood pressure was less than 90 mmHg.

Conclusion: In patients who continued ACEI/ARBs on the morning of surgery, there was a

non- significant trend towards an increased risk of post-induction hypotension. With continued

data collection, this study has the potential to optimize perioperative management of

ACEI/ARBs and prevent adverse outcomes.

INTRODUCTION:

In Canada, 23% of adults are diagnosed with hypertension and this incidence increases

with age, reaching a prevalence of 60-80% in elderly patients [1, 2]. Two medication classes

that are commonly used to treat hypertension include angiotensin converting enzyme inhibitors

(ACEIs) and angiotensin II receptor antagonists (ARBs).

Medications that affect the angiotensin cascade (ACEI/ARBs) are commonly indicated in

a multitude of medical conditions including hypertension, renal disease, diabetes, heart failure,

and post-myocardial infarction. While the development of hypertension is highly complex and

multifactorial, ACEI/ARBs inhibit the downstream responses of the renin angiotensin system

(RAS) pathway that contribute to hypertension [3]. On the other hand, the RAS system plays a

crucial role in maintaining regular intraoperative blood pressures (BP) during surgery. However,

when blunted by ACEI/ARBs, patients are at risk of vasopressor-refractory hypotension,

particularly during the induction phase of anesthesia [4, 5].

Ensuring tissue perfusion with adequate oxygen and blood supply is critical during

surgery to minimize and prevent post-surgical ischemic complications, such as organ damage. It

was shown that a surgical MAP less than 50 mmHg, a 40% decrease in MAP from baseline, or

an episode of HR greater than 100 beats per minute (BPM) was linked to increased cardiac

adverse events (cardiac arrest, non ST elevation MI, cardiac dysrhythmia) [6].

Physiologic changes that occur naturally with aging can increase susceptibility and

decrease tolerance to medication side effects, especially in the elderly. For example, the

clearance of medications can naturally decrease with age, extending the drug half-life and

duration of action. Second, hypotensive episodes can occur easier due to slower baroreceptor

and sympathetic nervous system responses in the elderly [7]. Finally, older individuals require

more medical services including surgical procedures, relative to a younger population [8];

advanced age is an independent predictor for experiencing cardiac adverse events in non-

cardiac surgery [6]. Given the high prevalence of hypertension in an elderly population and their

increased likelihood of surgical procedures, many elderly patients undergoing elective surgery

may be at risk of perioperative complications if ACEI/ARBs are continued on the day of surgery.

Regional anaesthesia techniques are becoming increasingly recognized as an

alternative to general anaesthesia in patients with significant comorbid diseases [9].

Mechanisms for reduced complications include a decreased need for intubation and ventilation,

reduction in opioid analgesic and muscle relaxant requirements leading to improved post-

operative pain management [10, 11]). Furthermore, a small reduction in mortality (1.7% vs 2%,

RR: 0.89, CI: 0.81–0.91, P=0.02) was also found in a non-cardiac surgical population with

regional compared to general anaesthesia [12]. This growing body of literature suggests that

regional anaesthesia may positively affect perioperative outcomes. Literature reviews examining

both general and regional anaesthesia populations have shown a possibility for increased post-

induction hypotension. However, a difference in the rate of ACEI/ARB post-induction

hypotension between these two anaesthetic techniques had not yet been evaluated.

Rationale for Study:

Current recommendations for the perioperative management of ACEI/ARBs in non-

cardiac surgery are conflicting. The American College of Cardiology (ACC) guidelines state that

ACEI/ARBs should be continued, while the European guidelines recommend transient

discontinuation of ACEI/ARBs on the morning of surgery [13, 14]. Practices between THP

hospital sites also differ on this issue; consensus between sites differed given the conflicting

guideline recommendations and outcome of individual studies. This study builds upon the

current literature to help clarify if ACEI/ARB therapy should be continued or held on the morning

of surgery to reduce post-induction hypotension rates and vasopressor use. No previous studies

in the available literature have evaluated these risks in an elderly population compared to a

younger population. This study aims to examine if post induction hypotension rates can be

prevented, thereby reducing poor surgical outcomes and subsequent vasopressor medication

use.

METHODS

Study Design

The research questions were addressed using a retrospective review of electronic charts

to evaluate the rates of hypotension in patients who did or did not receive a preoperative dose

of an ACEI/ARB on the morning of elective non-cardiac surgery utilizing general or regional

anesthesia at THP – Credit Valley Hospital (CVH)between October 31st 2014 and November 1st

2015.

Study Population

Inclusion Criteria:

- Age ≥18 years old

- Have undergone elective non-cardiac surgery with general or regional anesthesia between

the dates of October 31st 2014 and November 1st 2015

- Best Possible Medication History (BPMH) performed by pre-surgery pharmacist

- Post-surgical admission to inpatient ward

- American Society of Anesthesiologists (ASA) status 1-4

Exclusion Criteria:

- Patients on both an ACEI and ARB

- Scheduled cardiac surgery

- Emergency surgery

- ASA status 5 or 6

- Pregnancy

- Anesthetic techniques other than general or regional anesthesia

Patients were required to have had a pre-surgical appointment with the clinic pharmacist

where a BPMH was completed. This confirmed if a patient was taking an ACEI/ARB chronically.

As well, a requirement for post-surgical admission to inpatient ward allowed for longer follow-up

and monitoring of patients. Cardiac surgical procedures were excluded since the practice of

holding ACEI/ARBs before surgery is established in the literature and between surgical sites at

THP. Patients taking both ACEI and ARB were excluded as there is limited benefit for the

concomitant use and this combination has been shown to increase risk of hypotension,

hyperkalemia, and kidney problems [15].

Sample size was determined for a dichotomous endpoint, in two independent study groups.

Based on previous literature, we assumed 60.4% of patients taking an ACEI/ARB would

experience hypotension after anesthetic induction. It was determined that a sample size of 195

patients per group would provide 80% power to detect a 30% difference in the rate of

hypotension, defined as SBP less than 80 mmHg or a decrease in MAP greater than 40% from

baseline (two tailed test, alpha = 0.05) [16].

Study Outcomes

Table 1 lists the patient demographics collected for each eligible patient.

Table 1: Patient Demographics

Age (years)

- Less than 65 years

- Equal to or greater than 65 years

Sex (male, female)

ASA status (1-4)

Pre surgical induction SBP and MAP (mmHg)

Pre-existing medical conditions:

- Total number of pre-existing medical conditions

- Hypertension

- Diabetes

- Smoking

- Hyperlipidemia

- Ischemic heart disease

- Angina

- Chronic heart failure and NYHA Class

Medications being taken prior to surgery that can influence blood pressure: (n)

- Diuretics

- Alpha blockers,

- Beta blockers,

- Calcium Channel Blockers

- Pramipexole / Levodopa

- Vasodilators (hydralazine, nitrates, nitroglycerin, isosorbide dinitrate, etc).

ACEI or ARB therapy

Surgical Procedure

- Gynecological surgery

- Gastrointestinal surgery

- Orthopedic surgery

- Genitourinary surgery

- Thoracic surgery

- Head and neck surgery

- Endoscopic procedures

- Superficial surgery

- Other surgery

Perioperative positioning

- Supine

- Decubitus

- Lithotomy

- Other

Anaesthesia technique (general, regional, combination)

Primary Outcome

To determine the rate of the following outcomes in patients less than 65 years of age and 65

years of age or older:

1) Percent (%) occurrence of post-induction hypotension within the first 30 minutes of

surgery

Secondary outcomes:

To determine the rate of the following outcomes in patients less than 65 years of age and 65

years of age or older:

1) Percent (%) occurrence of post-induction hypotension requiring vasopressor use

2) Associated blood pressure (SBP, DBP and MAP) at the time of vasopressor

administration

3) Percent (%) occurrence of death by any cause, cardiac events, or stroke during surgery

or until time of hospital discharge.

Study Definitions:

Hypotension:

1) Systolic blood pressure (SBP) less than 80 mmHg

- Predefined on the “Trillium Health Partners (THP) Anesthesia Record” form filled

by anesthesiology during surgery.

2) Mean arterial pressure (MAP) decrease of greater than 40% from baseline

- Previously linked to increased incidences of cardiac adverse events [17].

3) Both above definitions concurrently

Hypertension: defined as a diastolic blood pressure (DBP) greater than 105 mmHg.

- Predefined on the “Trillium Health Partners Anesthesia Record” form filled by anesthesiology

during surgery.

Baseline blood pressure (BP): First blood pressure recording on the patient’s anesthesiology

record taken prior to induction.

Post-induction: Events occurring within the first 30 minutes of anesthesia administration, which

may or may not include surgical incision.

- Immediately post-induction is when ACEI/ARBs have been shown to have the greatest

impact on blood pressure hemodynamics. Previous studies have shown rates for

hypotension beyond 30 minutes were not clinically significant [16]

Post-operative cardiac events: Experiencing congestive heart failure, cardiac death, or

myocardial infarction.

ASA status: American Society of Anesthesiologist status classification system for assessing the

fitness of patients prior to surgery on a scale of 1-6. With one being a healthy patient, and six

being a patient that is brain dead.

RESULTS:

1677 patient charts from October 2014 - June 2015, were screened for eligibility and 395

patients met inclusion criteria. Inclusion and exclusion criteria are outlined in Table 1.There

were an equal number of patients in the group that held ACEI/ARBs when compared to the

group that continued ACEI/ARBs pre-operatively, and data collection stopped when adequate

enrollment in each group was reached. Patient selection with study numbers is detailed in

Figure 1.

Figure 1: Patient Selection

Baseline patient characteristics were very similar in both groups. More than half of the

patients had an ASA status of 3, were greater than or equal to 65 years, and were placed in a

supine body position during surgery. Continuation of diuretics on the morning of surgery was

significantly higher in the group that received pre-op ACEI/ARBs (17.3% vs. 3%). However, in

the ACEI/ARB held group, higher rates of general anesthesia (57.6 % vs. 50.3%) and lower

rates of regional anesthesia (42.4% vs. 48.7%) were seen compared to the continued group.

1677 patient charts reviewed

for possible study inclusion

(patients undergoing non-

cardiac surgery at THP-CVH)

198 patients HELD

ACEI/ARBs on the morning

of surgery

197 patients CONTINUED

ACEI/ARBs on the morning

of surgery

cardiac surgery at THP-

395 patients eligible for

inclusion

Table 2: Patient Baseline Characteristics (n=395)

Characteristic: ACEI/ARB Continued

(n=197), %

ACEI/ARB Held

(n=198), %

ACEI, n (%) 98 (49.8) 97 (49)

Gender, male, n (%) 88 (44.8) 99 (50)

Age, yrs (SD)

Greater than or equal to 65 yrs, n (%)

68.3 (+/- 9.9)

136 (69)

67.5 (+/- 9.7)

130 (65.7)

Pre-surgery SBP, mmHg (SD)

Pre-surgery MAP, mmHg (SD)

133.9 (+/-20.6)

98.4 (+/-46.6)

134.1 (+/-18.5)

97.4 (+/-31)

ASA status 2, n (%)

ASA status 3, n (%)

ASA status 4, n (%)

50 (25.4)

119 (60.4)

27 (13.7)

57 (28.7)

111 (59.5)

29 (14.6)

Other BP medications, n (%)

- Alpha blockers

- Beta blockers

- Calcium channel blockers

- Diuretics

4 (2)

42 (21.3)

48 (24.4)

34 (17.3)

5 (2.5)

40 (20.2)

39 (19.7)

6 (3)

Pre-existing medical conditions, n (SD) 2.3 (+/- 1.1) 2.4 (+/-1.1)

Anesthesia, n (%)

- General

- Regional

- Both

99 (50.3)

96 (48.7)

3 (2)

114 (57.6)

84 (42.4)

6 (3)

Perioperative position, n (%)

- Supine

- Decubitus

- Lithotomy

- Other

126 (64)

26 (13.2)

18 (9.1)

27 (13.7)

112 (56.6)

33 (16.7)

38 (19.3)

15 (7.6)

Primary Outcome:

Total post-induction hypotension rates between ACEI/ARBs continued and held groups

were 34.8% and 26.7%, respectively. These differences were not statistical significance

(P=0.068), however, there was a trend towards increased risk of hypotension when ACEI/ARBs

were continued on the morning of surgery. Hypotension rates of patients less than 65 years

were very similar to those of patients 65 years of age and older. Although not significant, these

results hypothesize that patients of any age are at an increased risk of hypotension.

Table 3: Primary outcome - Instances of post induction hypotension

Total

Hypotension

n=122 (%)

No hypotension

n=273 (%) P-value

Continued 69 (56.6) 129 (34.8) 0.068

Held 53 (43.4) 145 (26.7)

Patients less than 65 years

Hypotension

n=44 (%)

No hypotension

n=88 (%) P-value

Continued 25 (56.8) 39 (44) 0.176

Held 19 (43.2) 49 (55.7)

Patients 65 years and older

Hypotension

n=78 (%)

No hypotension

n=186 (%) P-value

Continued 44 (56.4) 90 (48.4) 0.234

Held 34 (43.6) 96 (51.6)

Note: ACEI/ARBs Continued (n=197), ACEI/ARBs Held (n=198)

Table 4: Primary outcome - Breakdown of hypotension rates based on definition

Variable n (%) p-value

Hypotension: Total

Continued

Held

69 (34.8)

53 (26.7) 0.068

Hypotension: >40% decrease in MAP from baseline

Continued

Held

38 (19.3)

34 (17.2) 0.364

Hypotension: SBP <80 mmHg

Continued

Held

10 (5.1)

6 (3) 0.221

Hypotension: Both hypotension definitions concurrently

Continued

Held

21 (10.7)

13 (6.7) 0.092

Note: ACEI/ARBs Continued (n=197), ACEI/ARBs Held (n=198)

Secondary Outcomes:

Rates of vasopressor use was higher in ACEI/ARBs continued group compared to ACEI/ARBs

held group, at 34.5% and 24.7% respectively, however, was statistically non-significant

(P=0.151). Interestingly, vasopressor administration increased in response to low BP when SBP

was less than 90 mmHg, or MAP was less than 65 mmHg. Rates of death by any cause, cardiac

events or stroke were higher in the ACEI/ARBs held group, although the study was not

adequately powered to detect this difference. Within the held group there were 2 cases of

sudden cardiac arrest, 2 cases of stroke, and 1 death. In the continued group there were 2

cases of cardiac arrest. There were no differences in any secondary outcomes based on patient

age.

Table 5: Secondary outcome: Instances of vasopressor use and other adverse events

Total

Vasopressor

n=117 (%)

No Vasopressor

n=278 (%) P-value

Continued 68 (34.5) 129 (46.4) 0.151

Held 49 (24.7) 149 (53.6)

Patients less than 65 years

Vasopressor

n=122 (%)

No Vasopressor

n=273 (%) P-value

Continued 17 (13.9) 44 (16.1) 0.418

Held 14 (11.5) 54 (19.8)

Patients 65 years and older

Vasopressor

n=79 (%)

No Vasopressor

n=185 (%) P-value

Continued 45 (57) 89 (48.1) 0.201

Held 34 (43) 96 (51.9)

Adverse events:

Occurrence of death by any cause, cardiac events, or stroke

Adverse event

n=7 (%)

No adverse events

N=388 (%) P-value

Continued 2 (1) 195 (99) 0.268

Held 5 (2.5) 198 (97.5)

Note: ACEI/ARBs Continued (n=197), ACEI/ARBs Held (n=198)

Graph 1: Vasopressor Use in Response to Blood Pressure Readings

DISCUSSION:

This retrospective chart review attempted to determine if continuing or holding

ACEI/ARBS on the morning of surgery resulted in significant changes to patient hemodynamics

during surgical post anesthesia induction. Furthermore, this study was the first to compare a

younger population to a more elderly population for differences in hemodynamic stability and

risk of developing hypotension. However, given that this study had less than optimal enrolment,

until further data collection is completed, it is difficult to draw firm conclusions from the results.

Our primary finding was a trend towards increased post induction hypotension when

ACEI/ARBs were continued on the morning of surgery. These results are similar to previous

literature findings. Using a hypotension definition of SBP less than 85 mmHg, Comfere, et al.

demonstrated in a retrospective review (n=267) hypotension rates of 60.4% versus 46.3% in

continued versus held groups (P= 0.02) [16]. Additionally, Calloway et al, completed a

retrospective analysis of 114 elderly patients (age greater than 60 years) undergoing elective

0

5

10

15

20

25

30

Pa

tie

nts

(n

)

Blood Pressure (mmHg)

MAP

SBP

orthopedic knee surgery with regional anesthesia. They found statistically significant increases

in hypotension (defined as SBP less than 85 mmHg), and vasopressor requirements in the

ACEI/ARB continued group (OR 5.813; 95% CI: 1.046 - 32.258) [17]. In this study there appears

to be a 13% higher risk for development of post induction hypotension in those patients that do

not interrupt their chronic ACEI/ARB therapy on the morning of surgery. The majority of

hypotension cases arose from a greater than 40% decrease in MAP from baseline, followed by

both hypotension definitions occurring concurrently (Table 4). Rationale is that patients are often

anxious and nervous prior to surgery resulting in high baseline blood pressure readings

immediately prior to anesthesia induction. Drastic changes in blood pressure can result in

inadequate tissue perfusion, oxygen and blood supply to vital organs, and has been linked to

cardiovascular complications [18]. Hypotension rates in ACEI/ARBs continued versus held

groups were 56% and 43% respectively, in both age subgroups. This suggests that an elderly

population is not necessarily at a higher risk of adverse events compared to a younger

population. An increase in sample size is needed to confirm these findings.

Comfere, et al. also demonstrated that taking ACEI/ARBs 10 hours or less before

anaesthetic induction, compared to greater than 10 hours, was an independent risk factor for

developing moderate hypotension within 30 minutes of induction [16]. In this study, 30 minutes

post induction was chosen as the cut off period for data collection as blood pressure readings

past this point become increasingly confounded due to vasopressor and fluid administration.

There is evidence-based consensus to continue beta-blockers, alpha-2-agonists and

calcium channel blockers perioperatively for non-cardiac surgery [18]. There is no firm evidence

to support continuation or discontinuation of both thiazide and loop diuretics pre-operatively [18]

[19]. However, theoretical risk of hypotension, hypokalemia due to hypovolemia leads to

recommendations that diuretics used to treat hypertension be held on the morning of surgery

[20]. It is unknown to what degree concurrent use of other antihypertensive medications had on

the incidence of hypotension due to inadequate sample size collection. However, it has been

suggested that patients taking multiple antihypertensive medications have increased incidences

of hypotension [21].

Rates of vasopressor use appeared to be higher when ACEI/ARBs were continued on

the morning of surgery. Although not a secondary endpoint, potential cost savings of reducing

reactive vasopressor use for ACEI/ARB induced hypotension, could allow for more optimal use

of institution resources. Rates of death by any cause, cardiac events or stroke did not seem to

be directly associated with hemodynamic instability. Additionally an association between age

and any secondary outcome was not observed, although the study was not adequately powered

to detect these differences.

This study had several limitations. The chief limitation was that our study was

underpowered to detect statistically significant differences in outcomes. The predicted sample

size required was derived from prior literature defining hypotension as SBP less than 85 mmHg

[16] [17] [22]. Our definition of hypotension as SBP less than 80 mmHg was more strict and

diverged from previous studies definition of SBP less than 85 mmHg. Additionally, since the

threshold for treatment of hypotension is dependent upon the practicing anesthesiologist, we

may have underestimated the incidence of hypotensive episodes, as some practitioners use

vasopressors and fluids prior to development of hypotension. Figure 1 suggests that the general

consensus for concern of hypotension occurs when the SBP drops below 90 mmHg or when the

MAP is less than 65 mmHg. Patients with a drop in SBP between 80 – 90 mmHg would not

have been captured due to our strict hypotension definitions. Having a retrospective research

design with non-standardized anaesthetic induction limited the ability to control for all

confounding variables. Within THP, blood pressure recordings are hand written, with 5 minute

intervals between recordings. This may have led to inconsistencies in completeness and

accuracy of data documentation between physicians and inability to reliably capture true blood

pressure variation. Continued diuretic use appeared higher in ACEI/ARBs continued patients

and may have been a caveat to study findings, emphasizing a greater increase in hypotension

than truly present. Secondary outcomes of death by any cause, cardiac events, or stroke were

limited to hospitalization time, likely missing complications that may have occurred days to

weeks post-surgery and discharge.

CONCLUSION:

In conclusion, patients who continued ACEI/ARBs on the morning of surgery had a non-

significant trend towards an increased risk of post-induction hypotension. This interim analysis

also suggests that patients less than 65 years of age versus 65 years of age and older are at

similar risk rates for development of hypotension. Results from this preliminary analysis suggest

a new calculated sample size of 762 patients is required to detect a 30% difference in frequency

of hypotension. With continued data collection, this study has the potential to optimize and

standardize perioperative management of ACEI/ARBs across THP sites, prevent adverse

outcomes, and minimize vasopressor usage. No concrete recommendations can be made at

this time for the holding of continuation of ACEI/ARBs on the morning of non-cardiac surgery.

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