Hypertension and anesthesia Satoshi Hanada a, Hiromasa Kawakami a, Takahisa Goto b and Shigeho Morita a

Hypertension and anesthesia Satoshi Hanada a, Hiromasa Kawakami a, Takahisa Goto b and Shigeho Morita a Purpose of review There are still many controversies about perioperative management of hypertensive patients. This review aims to provide relevant instruction based on evidence regarding the treatment of those patients. Recent findings Mild to moderate hypertension is not independently responsible for perioperative cardiac complications. The position is less clear for severely hypertensive patients. A randomized study shows no benefit of the traditional practice of delaying elective surgery in severely hypertensive patients until better control of blood pressure is achieved. Perioperative use of β-blockers or α-2 agonists has been shown to maintain perioperative hemodynamic stability and thereby to prevent major cardiac complications. Summary Delaying surgery only for the purpose of blood pressure control may not be necessary, especially in the case of mild to moderate hypertension. Strict care, however, should be taken to ensure perioperative hemodynamic stability because labile hemodynamics, rather than preoperative hypertension per se, appears to be more closely associated with adverse cardiovascular complications. Delaying surgery in hypertensive patients may be justified if target organ damage exists that can be improved by such a delay or if (suspected) target organ damage should be evaluated further before the operation. Keywords anesthesia, complication, hypertension, perioperative Curr Opin Anaesthesiol 19:315 319. # 2006 Lippincott Williams & Wilkins. a Department of Anesthesiology, Teikyo University School of Medicine, Itabashi-ku, Tokyo and b Department of Anesthesiology, Yokohama City University, Graduate School of Medical Sciences and School of Medicine, Kanazawa-Ku, Yokohama- Shi, Japan Correspondence to Takahisa Goto, MD, Department of Anesthesiology, Yokohama City University, Graduate School of Medical Sciences and School of Medicine, 3 9 Fukuura, Kanazawa-Ku, Yokohama-Shi 236-0004, Japan Tel: +81 45 787 2918; e-mail: mitagoto@s4.dion.ne.jp Current Opinion in Anaesthesiology 2006, 19:315 319 Abbreviations ACC American College of Cardiology ACEI angiotensin-converting enzyme inhibitor AHA American Heart Association ARA angiotensin II receptor antagonist CAD coronary artery disease DBP diastolic blood pressure SBP systolic blood pressure # 2006 Lippincott Williams & Wilkins 0952-7907 Introduction Hypertension is one of the common diseases that are prevalent in a huge portion of global aging societies. In addition, improved surgical and anesthetic techniques result in the ability of older patients to have surgery. Anesthesiologists, therefore, now face a larger quantity of hypertensive patients. In the nonsurgical setting, it is generally recognized that tight control of blood pressure is very important in reducing cardiovascular complications. If such tight controls are also necessary in the acute perioperative setting is less clear. This review aims to provide relevant instruction based on recent evidence regarding the management of those patients. Hypertension and cardiovascular risk Hypertension is a common but serious health problem. It affects 1 billion people around the globe and is responsible for 7.1 million deaths per year [1]. Observational studies involving more than 1 million individuals demonstrate that death from ischemic heart disease and stroke increases constantly as blood pressure increases from as low as 115 mmhg systolic and 75 mmhg diastolic [2]. This result warranted the Seventh Report of the Joint National Committee (JNC) of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) to introduce a new classification called prehypertension [3], because the risk of cardiovascular complications increases even when blood pressure is within what had been previously considered normal. The term prehypertension was defined as systolic blood pressure (SBP) between 120 and 139 mmhg and/or diastolic blood pressure (DBP) between 80 and 89 mmhg. Individuals in this group are considered to be at high risk of developing hypertension. This concept of prehypertension urges both patients and physicians to be more conscious of the risk and to take actions for the prevention of true hypertension [3]. Treatment of hypertension Treating SBP and DBP to targets that are less than 140/90 mmhg reduces cardiovascular complications. In hypertensive patients with diabetes or renal disease, the treatment thresholds should be lowered [4,5]. The initial step of the treatment is lifestyle modification. When this alone is insufficient, pharmacological therapy is considered. A low dose of thiazide-type diuretics is appropriate as an initial therapy for most patients. This 315

316 Anaesthesia and medical disease therapy can be combined with other classes of drugs including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (ARAs), β- blockers, and calcium-channel blockers. Diuretics have been virtually unsurpassed in preventing cardiovascular complications in trials that compare them with other antihypertensive drugs [6]. The significance of systolic hypertension Blood pressure pattern changes with age. SBP continuously rises throughout a person s life, while DBP plateaus between the ages of 50 and 60 and then decreases. In this way, the prevalence of systolic hypertension increases with age, and for those older than 50, isolated systolic hypertension is the most common form of hypertension [7]. Traditionally, therapy has focused on the management of DBP rather than SBP. Data, however, from large observational studies [8,9] demonstrated a closer association of systolic hypertension with coronary artery disease (CAD) and stroke than diastolic hypertension. There is also evidence that those with a lower DBP (i.e. wider pulse pressure) are at risk [10,11]. As a result, many physicians recommend more aggressive treatment of isolated systolic hypertension [12]. Perioperative management of hypertensive patients In the long-term medical management, it has been proven that tight control of blood pressure is very important in reducing cardiac complications. Whether this holds true in the acute perioperative setting is less clear. Two questions appear relevant. Firstly, should elective surgery be postponed in patients with uncontrolled hypertension to achieve better blood pressure control preoperatively? Secondly, what is the goal of intraoperative blood pressure control? Should elective surgery be postponed in patients with uncontrolled hypertension to achieve better blood pressure control preoperatively? Traditional recommendation to postpone elective surgery in patients with uncontrolled hypertension comes from a series of studies in the 1970s by Prys-Roberts et al. [13 15] that demonstrated that poorly controlled hypertension was associated with greater hemodynamic lability and an increased risk of perioperative myocardial ischemia. In the late 1970s, however, Goldman et al. [16, 17] could not identify pre-existing hypertension as a major preoperative cardiac risk factor, especially when the DBP is less than 110 mmhg [18]. More recently, a meta-analysis of 30 observational studies [19] has shown that hypertensive patients are only 1.31-fold (95% confidence interval 1.13 1.51) more likely to experience adverse perioperative cardiac events than normotensive patients. These and other studies [20,21] complement the American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines published in 2002 [22], which states that mild to moderate hypertension (SBP below 180 mmhg and DBP below 110 mmhg) is not an independent risk factor for perioperative cardiovascular complications. These ACC/AHA guidelines also recommend that elective surgery should be postponed in severely hypertensive patients (SBP greater than or equal to 180 mmhg and DBP greater than or equal to 110 mmhg) in order to gain time to control blood pressure before surgery. No reference, however, is cited for this statement. Moreover, there is little evidence to support this statement in the currently available literature [23]. The number of severely hypertensive patients studied so far was too small to show clear benefit from delaying their surgeries in the face of the low frequency of adverse perioperative cardiac outcomes such as myocardial infarction or death. Weksler et al. [24] carried out a large, randomized, prospective sample study in patients with known and treated hypertension and with DBP remaining between 110 and 130 mmhg on arrival at the operating room. Those patients with evidence of target organ damage were excluded from this study. The participants were randomly allocated into two groups. In the control group, surgery was delayed until DBP remained less than 110 mmhg for a minimum of three consecutive days. In the study group, surgery was carried out after DBP was acutely reduced to less than 110 mmhg by intranasally administered nifedipine. The result showed that there was no major difference in the frequency of perioperative cardiac events between these two groups, and the investigators could not demonstrate any benefit of delaying surgery in patients with known and treated hypertension who were in severely hypertensive states prior to surgery. On the basis of the above-mentioned meta-analysis [19] and this randomized study [24], it appears that preoperative hypertension per se has limited significance in predicting perioperative risk of major cardiovascular complications, especially when the severity of hypertension is mild to moderate. In addition, it is not clear if delaying surgery in severely hypertensive patients reduces perioperative risk. One caution is worth mentioning here. Anesthesiologists should not ignore the target organ damage induced by hypertension, such as ischemic heart disease, heart failure, renal and cerebrovascular diseases. These are

Hypertension and anesthesia Hanada et al. 317 known predictors of perioperative cardiac complications [25] and many medical studies suggest that the higher the level of blood pressure, the higher the risk of target organ damage [2,26]. Although evidence is limited, therefore, we believe delaying surgery in order to reduce perioperative risk is justified in (1) hypertensive patients with target organ damage whose conditions can be improved by such postponement to the extent that the perioperative risk would be considerably decreased; (2) hypertensive patients with (suspected) target organ damage that should be evaluated by further examinations preoperatively and the results of such examinations could have an impact on the way the patient is managed. When delaying surgery is recommended, the urgency and benefit of the surgery should be taken into consideration. Further large, well designed trials and research are necessary to make more solid recommendations for perioperative management of patients with severe hypertension. What is the goal of intraoperative blood pressure control? It is well known that hypertensive patients are more likely to experience labile hemodynamics intraoperatively [13,18]. In addition, there is evidence that perioperative cardiac complications are more likely to occur in the presence of intraoperative hemodynamic instability. Goldman et al. [17] found that postoperative cardiac death was associated with a 33% or greater fall in the SBP for more than 10 min intraoperatively. Charlson et al. [27] suggest that fluctuation in mean arterial pressure of greater than 20% in a high-risk population of hypertensive and diabetic patients is associated with perioperative complications. Reich et al. [28] described a relationship between intraoperative hypertension, tachycardia, and adverse outcomes in long duration noncardiac surgery. These studies imply that, in order to minimize the risk of cardiovascular complications, achieving hemodynamic stability is more important than the absolute target values of intraoperative blood pressure control. Perioperative pharmacological interventions Several pharmacological interventions have been proven useful in order to maintain perioperative cardiovascular stability and, therefore, may offer benefits in reducing perioperative cardiac complications. Beta-blockers Two influential randomized controlled trials have shown a reduction in mortality in patients either at risk of, or with, CAD using perioperative β-blockers [29,30]. Although these two studies were criticized because of considerable methodological limitations [31], they show that hypertensive patients with a high risk of CAD seem to get some benefit when β-blockers are aggressively used in perioperative treatment. The 2002 ACC/AHA guidelines gave a class IIa recommendation to use perioperative β-blocker therapy in patients with preoperative untreated hypertension [22]. A class II recommendation refers to conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of performing the procedure/therapy. For a class IIa recommendation the weight of evidence/opinion is in favor of usefulness/efficacy. Beta-blockers are now widely used, because they appear efficacious, are inexpensive, and have few risks. It has recently begun to be appreciated that β-blockers may not be a panacea but may be efficacious in selected groups of patients. For example, Lindenauer et al. [32 ] carried out a retrospective cohort study of patients who underwent major noncardiac surgery at 329 hospitals throughout the USA and found that perioperative β- blockers reduced the risk of death among high-risk patients who underwent major noncardiac surgery. In contrast, in low risk patients, β-blockers had no benefit and might have possibly been harmful. We need to wait for a result from a large, ongoing, randomized trial [33] in order to get a more accurate idea of the effectiveness of β-blockers for preoperative hypertensive patients. For the present time, the perioperative use of β-blockers is recommended for hypertensive patients with a high risk of CAD and who undergo major surgeries. Alpha-2 adrenergic agonists The α-2 adrenergic agonists currently used in clinical practice include clonidine, dexmedetomidine, and mivazerol. These agents reduce the necessity for anesthetic drugs because of their sedative effects, and they provide more stable hemodynamics because of their sympatholytic effects. The use of α-2 adrenergic agonists for the perioperative control of hypertension constitutes a class IIb recommendation in the 2002 ACC/AHA guidelines [22]. For class IIb recommendations, the usefulness or efficacy is less well established by evidence and/or opinion. A recent meta-analysis of 23 studies by Wijeysundera et al. [34] has concluded that the perioperative use of α-2 agonists reduced perioperative mortality and myocardial ischemia following cardiac and noncardiac surgery. The patients who underwent vascular surgery got the most benefit. In most studies included in this meta-analysis, the subjects were patients with known CAD. Additional clarification for the potential to

318 Anaesthesia and medical disease improve perioperative outcomes would require large randomized controlled trials. Until results of such trials become available, perioperative use of α-2 agonists for hypertensive patients is warranted, especially those who are at risk of or with CAD and for those who undergo vascular surgeries. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists Patients with preoperative hypertension are more likely to develop intraoperative hypotension than normotensive patients [13]. This finding can be clearly seen in patients taking renin angiotensin system antagonists, either ACEIs or ARAs. Although continuation of antihypertensive medication through the perioperative period is an established principle, preoperative discontinuation of ACEI/ARA therapy has been suggested from reports on intraoperative hypotension [35,36]. A few small controlled, randomized studies [37,38] found that after the induction of anesthesia the frequency of hypotension was increased when ACEI/ARA therapy was continued through the morning of surgery compared with the preoperative withholding of the therapy. In addition, several authors [39] reported some difficulty treating hypotension that occurred among patients who continued to receive these drugs right up until their surgeries. Comfere et al. [40 ] retrospectively studied 267 hypertensive patients receiving chronic ACEI/ARA therapy undergoing elective noncardiac surgery under general anesthesia. They concluded that discontinuation of ACEI/ARA therapy at least 10 h before anesthesia was associated with a reduced risk of immediate postinduction hypotension. Although the long-term adverse effects of withholding those drugs in advance of surgery have not been assessed, preoperative withholding of these drugs is a reasonable option to prevent intraoperative hypotension. Conclusion A direct association between preoperative hypertension and perioperative cardiac complications is unclear. There appears to be general agreement that patients with mild to moderate hypertension may be allowed to proceed with surgery, because such hypertension poses little additional risk of perioperative cardiovascular complications. Regarding severe hypertension (SBP greater than or equal to 180 mmhg and DBP greater than or equal to 110 mmhg), the ACC/AHA guidelines recommend that elective surgery be postponed until better blood pressure control is obtained. We found no evidence, however, that definitely supports this statement. The urgency of surgery and the risk of cardiovascular complications should be balanced in each case. It is probably prudent to postpone elective surgery if hypertension-induced target organ damage is present. Available evidence suggests, however, that delaying surgery merely to achieve better blood pressure control in patients without target organ damage have a limited value. For the perioperative management, β-blockers or α-2 agonists may help to maintain perioperative hemodynamic stability and may prevent major cardiac complications. Further large, well designed trials and research are necessary to make more satisfactory conclusions about perioperative management of patients with severe hypertension. References and recommended reading. Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 355 358). 1 Guilbert JJ. The World Health Report 2002: reducing risks, promoting healthy life. Educ Health (Abingdon) 2003; 16:230. 2 Lewington S, Clarke R, Qizilbash N, et al. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903 1913. 3 Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560 2572. 4 American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care 2003; 26:S80 S82 (PR). 5 National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002; 39:S1 S246 (PR). 6 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981 2997. 7 Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension 2001; 37:869 874. 8 Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000; 355:865 872. 9 Kannel WB. Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol 2000; 85:251 255 (Review). 10 Gasowski J, Fagard RH, Staessen JA, et al. INDANA Project Collaborators. Pulsatile blood pressure component as predictor of mortality in hypertension: a meta-analysis of clinical trial control groups. J Hypertens 2002; 20: 145 151. 11 Blacher J, Staessen JA, Girerd X, et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med 2000; 160:1085 1089. 12 Kaplan NM. New issues in the treatment of isolated systolic hypertension. Circulation 2000; 102:1079 1081. 13 Prys-Roberts C, Meloche R, Foex P. Studies of anaesthesia in relation to hypertension I: cardiovascular responses on treated and untreated patients. Br J Anaesth 1971; 43:122 137. 14 Prys-Roberts C, Groere LT, Meloche R, Foex P. Studies of anaesthesia in relation to hypertension II: haemodynamic consequences of induction and endotracheal intubation. Br J Anaesth 1971; 43:531 547. 15 Prys-Roberts C, Foex P, Greene LT, Waterhouse TD. Studies of anaesthesia in relation to hypertension. IV. The effects of artificial ventilation on the circulation and pulmonary gas exchanges. Br J Anaesth 1972; 44:335 349.

Hypertension and anesthesia Hanada et al. 319 16 Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977; 297:845 850. 17 Goldman L, Caldera DL, Southwick FS, et al. Cardiac risk factors and complications in noncardiac surgery. Medicine (Baltimore) 1978; 57:357 370. 18 Goldman L, Caldera DL. Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979; 50:285 292. 19 Howell SJ, Sear JW, Foex P. Hypertension, hypertensive heart disease and perioperative cardiac risk. Br J Anaesth 2004; 92:570 583 (Review). 20 Howell SJ, Sear YM, Yeates D, et al. Risk factors for cardiovascular death after elective surgery under general anaesthesia. Br J Anaesth 1998; 80: 14 19. 21 Howell SJ, Sear JW, Sear YM, et al. Risk factors for cardiovascular death within 30 days after anaesthesia and urgent or emergency surgery: a nested case control study. Br J Anaesth 1999; 82:679 684. 22 Eagle KA, Berger PB, Calkins H, et al. ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery Executive Summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to update the 1996 guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg 2002; 94:1052 1064. 23 Spahn DR, Priebe HJ. Editorial II: Preoperative hypertension: remain wary? Yes cancel surgery? No. Br J Anaesth 2004; 92:461 464. 24 Weksler N, Klein M, Szendro G, et al. The dilemma of immediate preoperative hypertension: to treat and operate, or to postpone surgery? J Clin Anesth 2003; 15:179 183. 25 Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100:1043 1049. 26 Lawes CM, Rodgers A, Bennett DA, et al. Asia Pacific Cohort Studies Collaboration. Blood pressure and cardiovascular disease in the Asia Pacific region. J Hypertens 2003; 21:707 716. 27 Charlson ME, MacKenzie CR, Gold JP, et al. Intraoperative blood pressure: what patterns identify patients at risk for postoperative complications? Ann Surg 1990; 212:567 580. 28 Reich DL, Bennett-Guerrero E, Bodian CA, et al. Intraoperative tachycardia and hypertension are independently associated with adverse outcome in noncardiac surgery of long duration. Anesth Analg 2002; 95:273 277. 29 Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999; 341:1789 1794. 30 Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335:1713 1720. 31 Howell SJ, Sear JW, Foex P. Peri-operative beta-blockade: a useful treatment that should be greeted with cautious enthusiasm. Br J Anaesth 2001; 86: 161 164 (Review). 32 Lindenauer PK, Pekow P, Wang K, et al. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med 2005; 353:349 361. This article describes an observational study that analyses β-blocker therapy in a large number of varied patients. 33 Devereaux PJ, Yusuf S, Yang H, et al. Are the recommendations to use perioperative beta-blocker therapy in patients undergoing noncardiac surgery based on reliable evidence? CMAJ 2004; 171:245 247. 34 Wijeysundera DN, Naik JS, Beattie WS. Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis. Am J Med 2003; 114:742 752. 35 Brabant SM, Bertrand M, Eyraud D, et al. The hemodynamic effects of anesthetic induction in vascular surgical patients chronically treated with angiotensin II receptor antagonists. Anesth Analg 1999; 89:1388 1392. 36 Behnia R, Molteni A, Igic R. Angiotensin-converting enzyme inhibitors: mechanisms of action and implications in anesthesia practice. Curr Pharm Des 2003; 9:763 776 (Review). 37 Coriat P, Richer C, Douraki T, et al. Influence of chronic angiotensin-converting enzyme inhibition on anesthetic induction. Anesthesiology 1994; 81:299 307. 38 Bertrand M, Godet G, Meersschaert K, et al. Should the angiotensin II antagonists be discontinued before surgery? Anesth Analg 2001; 92:26 30. 39 Brabant SM, Eyraud D, Bertrand M, Coriat P. Refractory hypotension after induction of anesthesia in a patient chronically treated with angiotensin receptor antagonists. Anesth Analg 1999; 89:887 888. 40 Comfere T, Sprung J, Kumar MM, et al. Angiotensin system inhibitors in a general surgical population. Anesth Analg 2005; 100:636 644. This retrospective study analyzes the relationship between the timing of withholding of chronic ACEI/ARA therapy and hypotension after the induction of general anesthesia.