Isolated Systolic Hypertension Is Associated with Adverse Outcomes from Coronary Artery Bypass Grafting Surgery Solomon Aronson,

MD, FACC, FACCP*,

Denis Boisvert,

MSc†,

and William Lapp,

PhD†

*Department of Anesthesia and Critical Care, University of Chicago Medical Center, Chicago, Illinois; and †The Ischemia Research and Education Foundation, San Francisco, California

Isolated systolic blood pressure has not been sufficiently studied in the perioperative setting and may contribute to morbidity and mortality after coronary artery bypass grafting (CABG) surgery. Our objective was to determine the prevalence of isolated systolic hypertension among patients who had CABG surgery and to assess whether isolated systolic hypertension is associated with perioperative and postoperative in-hospital morbidity or mortality. Patients who underwent CABG were selected from a prospective epidemiological study involving 2417 patients in 24 medical centers. Patients were classified as having normal preoperative blood pressure, isolated systolic hypertension (systolic blood pressure ⬎140 mm Hg), diastolic hypertension (diastolic blood pressure ⬎90 mm Hg), or a combination of these. Demographic risk factors (age, sex, and ethnicity), clinical risk factors (diabetes mellitus, increased cholesterol, antihypertensive medications, history of congestive heart failure, myocardial infarction, hypertension, and neurological deficits), and behavioral risk factors (smoking and heavy drinking) were

T

he importance of isolated systolic hypertension in the perioperative setting has not been appreciated, nor have its consequences been examined as extensively as those of diastolic hypertension. Despite our understanding that blood pressure (BP) remains a strong modifiable risk factor for cardiovascular morbidity, the increasing incidence of stroke, renal disease, and heart failure suggests that control of BP has been inadequate (1– 4). Isolated systolic hypertension, the presence of increased systolic BP (SBP) in the absence of increased diastolic BP (DBP), has emerged

Supported by grants from the Ischemia Research and Education Foundation. Presented in part at the 75th Clinical and Scientific Congress of the International Anesthetic Research Society, Fort Lauderdale, FL, March, 2001 (selected as Best Abstract Presentation). Accepted for publication December 11, 2001. Address correspondence and reprint requests to Solomon Aronson, MD, FACC, FACCP, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637. Address e-mail to [email protected]. ©2002 by the International Anesthesia Research Society 0003-2999/02

controlled for statistically. Adverse outcomes included left ventricular dysfunction, cerebral vascular dysfunction or events, renal insufficiency or failure, and all-cause mortality. Isolated systolic hypertension was found in 29.6% of patients. Unadjusted isolated systolic hypertension was associated with a 40% increased risk of adverse outcomes (odds ratio, 1.4; confidence interval, 1.1–1.7). After adjusting for other potential risk factors, the increased risk of adverse outcomes with isolated systolic hypertension was 30%. We conclude that isolated systolic hypertension is associated with a 40% increase in the likelihood of cardiovascular morbidity perioperatively in CABG patients. This increase remains present regardless of antihypertensive medications, anesthetic techniques, and other perioperative cardiovascular risk factors (e.g., age older than 60 yr or history of congestive heart failure, myocardial infarction, or diabetes). (Anesth Analg 2002;94:1079 –84)

as an important predictor of cardiovascular morbidity in large epidemiological studies (5,6). In the sixth report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (7), isolated systolic hypertension was defined as SBP ⬎140 mm Hg with DBP ⬍90 mm Hg. Our study determined the prevalence and investigated the effect of isolated systolic hypertension on perioperative cardiovascular morbidity among patients who had coronary artery bypass grafting (CABG) surgery.

Methods This prospective, observational study included patients scheduled for elective CABG surgery with or without concurrent procedures at 24 centers in the United States, including academic, federal, private, and health maintenance organizations (Appendix 1). After approval by each center’s IRB, patients were Anesth Analg 2002;94:1079–84

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enrolled over 2 yr by using a systematic sampling scheme at each site (every nth patient, up to 100 patients per site, with n based on the expected number of CABG surgeries performed annually at that site) [n ⫽ (expected annual cardiac volume ⫻ 2)/100]. A structured questionnaire with approximately 1500 data fields was used to obtain demographic, clinical, and laboratory data in the hospital and at discharge. Preoperative data included physical examination, BP, heart rate, height and weight, medical history, and medications. Perioperative hemodynamic data were obtained. Outcome end points included cardiac, pulmonary, infectious, gastrointestinal, neurologic, and renal problems. Random chart reviews were initiated at each site several months after the database was closed to validate the process. A total of 2069 patients were selected from the 2417 patients enrolled in this project. Patients were included if they had all BP values recorded (6 patients had missing values) and were excluded if they were previously diagnosed with diastolic hypertension (n ⫽ 342). Systolic and diastolic hypertension were defined according to the recommendations of the Joint National Committee on the Detection, Evaluation, and Treatment of Hypertension. Diastolic hypertension was defined as DBP ⬎90 mm Hg, whereas systolic hypertension was defined as SBP ⬎140 mm Hg on a single preoperative measurement. Isolated systolic hypertension refers to cases in which DBP ⬍90 mm Hg and SBP ⬎140 mm Hg, i.e., systolic hypertension in the absence of diastolic hypertension. BP readings were measured by trained personnel using standardized equipment and techniques. The SBP was defined as the reading at the first Korotkoff sound. A combined adverse outcome variable was created to code for death, left ventricular dysfunction, renal failure or insufficiency, and deficits in the functioning of the central nervous system (CNS). Death was defined as mortality due to any and all causes. Left ventricular dysfunction was indicated by perioperative congestive heart failure (CHF), hemodynamic CHF, or the need for three or more inotropes. Perioperative CHF was defined by chest radiograph criteria, jugular venous distention, rales, or an audible S3. Hemodynamic CHF was defined as a cardiac index ⬍1.5 L · min⫺1 · m⫺2. Renal failure or insufficiency was defined as an increase in serum creatinine ⱖ0.7 mg/dL from preoperative to maximal postoperative values and a postoperative value of ⱖ2 mg/dL, or the need for dialysis. CNS dysfunction included cerebrovascular accident, transient ischemic attack, coma at discharge, stupor, or CNS death. Stupor was defined as a clinician choice between coma, stupor, and conscious. New deterioration in intellectual function, confusion, agitation, disorientation, memory deficits, and seizures were also considered to be indications of CNS dysfunction. All adverse CNS outcomes

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were reviewed by a panel of five investigators, including a neurologist and four cardiac anesthesiologists, and were determined by consensus. Several confounding factors were treated as covariates in a multiple regression analysis to control for known predictors of adverse outcome. Age, sex, and ethnicity are associated with cardiovascular complications, renal failure, and CNS dysfunction after CABG surgery (8,9). Body mass index (weight/height2) (10), previous myocardial infarction (MI), serum cholesterol, family coronary artery disease, a history of hypertension, neurological disorders, renal problems, diabetes mellitus, cigarette smoking, and alcohol abuse are known risk factors for adverse outcomes such as mortality, cardiac events, and stroke. All of these factors, along with the use of ␤-adrenergic blockers, calcium channel blockers, or angiotensin-converting enzyme inhibitors and intraoperative hypotension (mean arterial BP [MAP] ⬍40 mm Hg) or hypertension, (MAP ⬎100 mm Hg) were considered. Bivariate analyses were computed by using contingency table and ␹2 analyses. Multiple logistic regression analyses were performed to assess the effect of isolated systolic hypertension on the incidence of postoperative ischemia, and variables that would confound or independently predict its occurrence were taken into consideration. Anesthetic technique and preoperative medications were covariates in the equation. Age ⱖ60 yr, MAP ⬍40 mm Hg on the day of surgery or during cardiopulmonary bypass, and a history of CHF or MI were also analyzed as predictors.

Results Of the 2417 patients enrolled, 2069 qualified for analysis. Of the 2069 who qualified for analysis, 612 had isolated systolic hypertension. Among the 612 patients with systolic hypertension, 318 (52%) had SBP between 140 and 150 mm Hg, 156 (25%) had SBP between 150 and 160 mm Hg, 71 (12%) had SBP between 160 and 170 mm Hg, and 67 (11%) had SBP ⬎170 mm Hg. The patients were from 28 to 90 yr old (mean, 65 yr); 76% were men, and 89% were Caucasian (versus 5% African American and 6% other). Most patients were receiving some type of a medication with a potential effect on BP; however, only 24% received medications specifically intended as antihypertensive drugs. Seven percent of patients did not take any medications. Among the 348 patients who were excluded, 342 were already classified as hypertensive by DBP measurement, and 6 others were excluded because their BP values were missing. Patients who had diastolic hypertension did not have an increased risk of adverse outcomes regardless of whether or not they also had systolic hypertension (odds ratio [OR], 1.0; 95% confidence interval [CI], 0.6–1.7).

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Table 1. Associations Between Isolated SBP Hypertension and Individual and Combined Adverse Outcomes

Outcome

Patients without isolated SBP HTN (n ⫽ 1457)a

Patients with isolated SBP HTN (n ⫽ 612)a

Odds ratio and 95% CI

Death (n ⫽ 83) Renal (n ⫽ 152) Cerebral vascular accident (n ⫽ 154) Left ventricular dysfunction (n ⫽ 634) Combined (n ⫽ 733)

4.1 (59) 6.7 (98) 6.3 (92) 29.1 (424) 33.2 (483)

3.9 (24) 8.8 (54) 10.1 (62) 34.3 (210) 40.9 (250)

1.0 (0.6–1.6) 1.3 (0.9–1.9) 1.7 (1.2–2.3) 1.3 (1.0–1.6) 1.4 (1.1–1.7)

SBP ⫽ systolic blood pressure; HTN ⫽ hypertension; CI ⫽ confidence interval. a Data are presented as n (%).

However, patients who did not have diastolic hypertension did have an increased risk of having an adverse outcome when they had systolic hypertension (OR, 1.4; 95% CI, 1.1–1.7). Table 1 illustrates that although death was not significantly associated with the presence or absence of isolated SBP, the presence of isolated SBP was associated with an increase in renal failure or insufficiency, cerebrovascular accident, left ventricular dysfunction, and combined adverse outcomes. Isolated systolic hypertension combined with other risk factors was associated with an increased risk of combined adverse outcomes (Table 2). Patients ⱖ60 yr of age had a 150% increased risk of adverse outcome (OR, 2.5; 95% CI, 2.0 –3.1), and women were at 40% increased risk of postoperative ischemia compared with men (OR, 1.4; 95% CI, 1.2–1.8). A history of diabetes or hypertension increased the risk by 30% (OR, 1.3; 95% CI, 1.1–1.5), a history of MI increased the risk by 40% (OR, 1.4; 95% CI, 1.1–1.6), and a neurological condition increased the risk by 70% (OR, 1.7; 95% CI, 1.4 –2.2). Preexisting CHF was associated with a 140% increase in risk of adverse outcome (OR, 2.4; 95% CI, 2.0 –2.9). A 120% increase in risk was associated with the occurrence of severe intraoperative hypotension (OR, 1.4; 95% CI, 1.4 –3.3). The results of the multiple logistic regression analysis showed that anesthetic technique and preoperative or perioperative medications did not affect adverse outcomes (Table 3). The prediction power of isolated systolic hypertension after controlling for covariates was a 30% increase in the likelihood of an adverse outcome, similar to the effect seen for a history of MI (OR, 1.3; 95% CI, 1.1–1.6).

Discussion Hypertension affects approximately 25% of the adult population in the United States, or 50 million people (7,11). In our study, approximately 30% (612 of 2069) of the patients who had CABG surgery also had isolated systolic hypertension. The common clinical practice of restricting a diagnosis of hypertension to increased DBP misses a large segment of hypertensive patients. Although increased DBP has traditionally

been associated with increased cardiovascular adverse outcomes, the data that led to those conclusions were derived primarily from patients without adequately distinguishing systolic and pulsatile components of BP (12–15). The data supporting the relationship between hypertension and risk were further strengthened by subsequent therapeutic trials demonstrating the benefits of treating hypertension defined essentially on the basis of DBP (16 –18). Several studies have evaluated the relative risk of specific components of BP (e.g., SBP, DBP, pulse pressure, and MAP) in highrisk older patients (1,2,4,6,7). These data in the ambulatory population are consistent with our data in the surgical population and indicate that there is indeed a negative association of increased DBP with outcome. This suggests to us that a J-curve phenomenon may be in effect (19). At the very least it indicates that hypertension is a complex disease with multiple components deserving a critical reevaluation in the perioperative period. The relationship between specific indices of pressure (each reflecting a manifestation of peripheral vascular pathology, whether microcirculatory disease or central aortic compliance) and perioperative risk stratification, we believe, is noteworthy and requires reevaluation. We here have provided evidence to support further work in this area. Although the long-term risk associated with systolic hypertension has yet to be established, our results show that it is associated with acute perioperative risk for adverse outcomes that is not explained by other risk factors. Understanding the relevance of isolated systolic hypertension as a perioperative cardiovascular risk factor is important (20–24). This common form of hypertension in the elderly may become the most common form of hypertension in the perioperative population, given the rapidly expanding elderly population referred for surgery. SBP is affected by stroke volume, rate of systolic ejection, and the distensibility of the arterial tree (25). Increases in pressure decrease distensibility, which is turn has adverse effects on circulation. Pulsatile energy (approximately 15% of cardiac work) accounts for up to 30% of left ventricular oxygen consumption (26). Increased BP occurs initially because of arterial

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ANESTH ANALG 2002;94:1079 –84

Table 2. Demographic and Perioperative Characteristics by Status of Isolated SBP Hypertension and Their Bivariate Associations with the Combined Adverse Outcome (n [%])

Variable Demographic Age ⬎60 yr ⬍60 yr Sex Female Male Medical history CHF Yes No MI Yes No Hypertension Yes No Neurological Yes No Diabetes Yes No Smoking Yes No Alcohol Yes No Preoperative Laboratory cholesterol ⱖ265 mg/dL ⬍265 mg/dL Isolated SBP HTN (⬎140 mm Hg) Yes No Intraoperative MAP ⬍40 mm Hg Yes No Preoperative preadministered medication Antihypertensive Yes No ␤-blockers Yes No Calcium channel blockers Yes No Diuretics Yes No Anesthetic technique (primary) Inhaled Yes No IV Yes No Both Yes No

Prevalence among nonisolated SBP hypertensive patients (n ⫽ 1457)

Prevalence among isolated SBP hypertensive patients (n ⫽ 612)

73 (1509) 27 (560)

69 (1003)

24 (491) 76 (1578)

Prevalence among all patients (n ⫽ 2069)

Incidence of CAO

Odds ratio and 95% CI

83 (612)*

41 (613) 21 (120)

2.5 (2.0–3.1)

21 (302)

31 (189)*

42 (205) 33 (528)

1.4 (1.2–1.8)

31 (636) 69 (1409)

32 (460)

29 (176)

49 (313) 29 (408)

2.4 (2.0–2.9)

55 (1114) 45 (922)

58 (838)

46 (276)*

38 (426) 31 (288)

1.4 (1.1–1.6)

55 (1112) 45 (907)

48 (683)

72 (429)*

38 (422) 33 (296)

1.3 (1.1–1.5)

15 (317) 85 (1750)

14 (211)

17 (106)

47 (148) 33 (584)

1.7 (1.4–2.2)

26 (530) 74 (1536)

23 (336)

32 (194)*

40 (210) 34 (523)

1.3 (1.0–1.6)

67 (1361) 33 (679)

68 (980)

63 (381)*

34 (467) 37 (254)

0.9 (0.7–1.1)

41 (806) 59 (1154)

43 (590)

38 (216)*

34 (276) 35 (407)

1.0 (0.8–1.2)

6 (118) 94 (1950)

5 (76)

7 (42)

28 (33) 36 (700)

0.7 (0.5–1.0)

30 (612) 70 (1457)

0 (0) 100 (1457)

100 (612) 0 (0)

41 (250) 33 (483)

1.4 (1.1–1.7)

5 (96) 95 (1940)

5 (67)

5 (29)

53 (51) 34 (666)

2.6 (1.4–3.3)

24 (492) 76 (1577)

23 (331)

26 (161)

44 (218) 33 (515)

1.6 (1.3–2.0)

49 (1006) 51 (1063)

51 (739)

44 (267)*

34 (341) 37 (392)

0.9 (0.7–1.1)

65 (1343) 35 (726)

63 (915)

70 (428)*

35 (470) 36 (263)

0.9 (0.8–1.1)

30 (616) 70 (1453)

28 (406)

34 (210)*

48 (298) 30 (435)

2.2 (1.8–2.7)

9 (177) 91 (1892)

8 (111)

11 (66)*

32 (57) 36 (676)

0.9 (0.6–1.2)

92 (1898) 8 (171)

92 (1345)

90 (553)

36 (683) 29 (50)

1.4 (1.0–1.9)

2 (33) 98 (2036)

1 (20)

2 (13)

39 (13) 35 (720)

1.2 (0.6–2.4)

CAO ⫽ combined adverse outcomes; CHF ⫽ congestive heart failure; MI ⫽ myocardial infarction; MAP ⫽ mean arterial blood pressure; SBP ⫽ systolic blood pressure; HTN ⫽ hypertension; CI ⫽ confidence interval. * Prevalence among patients with or without isolated SBP hypertension was significantly different (P ⬍ 0.05).

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Table 3. Multiple Logistic Regression Results for Combined Adverse Outcome Type of predictor Primary SBP ⱖ140 mm Hg Secondary Age ⱖ60 yr MAP ⬍40 mm Hg (CPBS) History of CHF History of MI Covariates Anesthetic technique Preoperative medications

OR

CI

P value

0.29

1.3

1.1–1.6

0.008

0.86 0.82 0.81 0.28

2.4 2.3 2.3 1.3

1.9–3.0 1.5–3.5 1.8–2.8 1.1–1.6

0.0001 0.0002 0.0001 0.006

0.84 1.24

0.6–1.2 0.8–1.9

0.35 0.29

Coefficient

⫺0.02 0.22

SBP ⫽ systolic blood pressure; MAP ⫽ mean arterial blood pressure; CHF ⫽ congestive heart failure; MI ⫽ myocardial infarction; OR ⫽ odds ratio; CI ⫽ confidence interval; CPB ⫽ cardiopulmonary bypass.

stiffness or increased stroke volume. It is only later, when stroke volume returns to normal, that increased BP is a consequence of systemic vascular resistance and cardiovascular risk is related to MAP or DBP. If, however, arterial distensibility decreases while stroke volume and rate of systolic ejection remain constant, then the result is increased SBP, decreased DBP, wider pulse pressure, and unchanged MAP. Therefore, cardiac output, MAP, and systemic vascular resistance alone do not adequately describe the contribution of arterial compliance to blood flow and cardiac work. The relationship of SBP to left ventricular hypertrophy (27,28) and the relationship of left ventricular hypertrophy to perioperative morbidity (27,28) suggest that SBP is a significant independent risk factor for cardiac adverse outcomes. These findings furthermore may suggest that cerebrovascular risk stratification should be readdressed. Morbidity traditionally associated with atherosclerosis of the aorta and emboli (29) may be alternatively postulated to be associated with the decreased central aortic distensibility without atheromatous emboli. The need to develop riskreduction strategies in high-risk populations thus completely depends on defining the problem as well as understanding the risks and benefits of treatment. We have provided evidence that isolated systolic hypertension increases the risk of perioperative cardiovascular morbidity in patients who have CABG surgery. Questions raised about treatment of isolated systolic hypertension in the nonsurgical population also apply in a perioperative setting (30). Can we modify risk with treatment? If so, what treatment strategy should we use? What should the BP goals of treatment be? What are the real or potential risks of treatment? We did not answer these questions in our descriptive analysis. Although previous studies have considered the effect of BP on perioperative outcome, systolic and diastolic hypertension were not differentiated in their analyses (31–34). A limitation of our study was reliance on a single preoperative measurement of BP. This measurement

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was made at the preoperative visit or at the time of admission. We believe that a single measurement, however, would underestimate the cardiovascular risk associated with systolic hypertension because BP would probably be decreased, not increased, with repeated measurements because of the “white coat” effect (35). Our database was large, and the measurements were taken by physicians who were blinded with respect to the hypothesis. It is recommended that multiple preoperative measurements of BP be taken at sufficient intervals between measurements in future studies that include a treatment limb. Isolated SBP is an increasingly important modifiable risk factor for cardiovascular morbidity among patients who are ambulatory (7,22,36 – 41). It seems that future study is indicated to determine the specific relationship between perioperative BP management and adverse outcomes, recognizing that isolated systolic hypertension portends a different pathophysiology of the peripheral vascular system than diastolic hypertensive disease alone.

Appendix 1 The following institutions and people coordinated the Multicenter Study of Perioperative Ischemia-I study. Study Chairman: D. Mangano; Coordinating Center: Ischemia Research and Education Foundation—C. Dietzel, V. Katseva, E. Kwan, A. Herskowitz, C. Ley, L. Ngo, D. Boisvert; Outcome Editorial/Administrative Group: D. Beatty, I. Deem, I. Asturias, B. Xavier. The following institutions and persons participated in the Multicenter Study of Perioperative Ischemia-I study. Centers and Investigators: University of Alabama at Birmingham—W. Lell; Baylor College of Medicine—S. Shenaq, R. Clark; Cedars-Sinai Medical Center, California—A. Friedman; University of Chicago—M. Trankina, W. Ruo; Cleveland Clinic Foundation—C. Koch, N. Starr; Cornell University—O. Patafio, R. Fine; Duke University—T. Stanley, M. Newman; Emory University—C. Mora Mangano, J. Ramsay; Harvard University/Beth Israel Hospital—M. Comunale; Brigham and Women’s Hospital—S. Body, R. Maddi; Massachusetts General Hospital—M. D’Ambra; University of Iowa—A. Ross; Kaiser-Permanente Medical Center, San Francisco—G. Roach, W. Bellows; University of Michigan—J. Wahr; New York University—M. Kanchuger, K. Marschall; University of Pennsylvania—J. Savino; Rush Presbyterian, St. Luke’s Medical Center—K. Tuman; Stanford University—E. Stover, L. Siegel; Texas Heart Institute—S. Slogoff, M. Goldstein; Milwaukee Veterans Administration Medical Center—A. Aggarwal; San Francisco Veterans Administration Medical Center—G. Ozanne, D. Mangano; Medical College of Virginia—J. Fabian, R. Wolman; University of Washington—B. Spiess; Yale Medical Center—J. Mathew.

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