Introduction
Hypertension affects about 1 billion people and is a leading cause of death worldwide. This global prevalence is likely to increase further as the population ages. The relationship between systemic hypertension and cardiovascular risk is continuous and independent of additional risk factors. The classification of adult blood pressure in the seventh report of the Joint National Committee recognized this important relationship by introducing the classification of prehypertension to signal a patient cohort at increased future cardiovascular risk who would benefit from early intervention ( Table 8-1 ). This guideline has also classified hypertension as either stage 1 or stage 2, depending on systolic or diastolic pressure profiles (see Table 8-1 ). Furthermore, there are multiple oral antihypertensive medications that are used alone or in combination for pharmacologic control of hypertension ( Table 8-2 and Box 8-1 ). The cumulative evidence from multiple clinical trials demonstrates that successful ambulatory management of hypertension significantly reduces cardiovascular mortality and morbidity rates. Furthermore, it is estimated that about 25% to 50% of surgical patients take long-term medications, in which antihypertensives as a group feature prominently. Given all these considerations, it follows that hypertensive patients with various medication regimens will commonly undergo surgical procedures and hence be a common and important part of daily anesthetic practice.
| Blood Pressure Classification | Systolic Blood Pressure | Diastolic Blood Pressure | Lifestyle Modification | Drug Therapy | |
|---|---|---|---|---|---|
| Normal | <120 mm Hg | and | <80 mm Hg | Encourage | None |
| Prehypertension | 120-139 mm Hg | or | 80-89 mm Hg | Yes | None |
| Stage 1 hypertension | 140-159 mm Hg | or | 90-99 mm Hg | Yes | Yes |
| Stage 2 hypertension | ≥160 mm Hg | or | ≥100 mm Hg | Yes | Yes |
| Antihypertensive Drug Class | Clinical Examples |
|---|---|
| Thiazide diuretics | Chlorothiazide; indapamide; metolazone |
| Loop diuretics | Bumetanide; furosemide |
| Potassium-sparing diuretics | Amiloride; triamterene |
| Aldosterone-receptor blockers | Spironolactone; eplerenone |
| Beta-blockers | Atenolol; bisoprolol; metoprolol; nadolol; propranolol; timolol |
| Beta-blockers with intrinsic sympathomimetic activity | Acebutolol; penbutolol; pindolol |
| Combined alpha- and beta-blockers | Carvedilol; labetalol |
| Angiotensin-converting enzyme inhibitors | Benazepril; captopril; enalapril; fosinopril; quinapril; ramipril; trandolapril |
| Angiotensin receptor blockers | Candesartan; eprosartan; irbesartan; losartan; valsartan |
| Calcium channel blockers (non-dihydropyridines) | Diltiazem; verapamil |
| Calcium channel blockers (dihydropyridines) | Amlodipine; felodipine; nicardipine; nifedipine; nisoldipine |
| Alpha-blockers | Phenoxybenzamine; doxazosin; prazosin; terazosin |
| Centrally acting agents | Clonidine; methyldopa; reserpine |
| Direct vasodilators | Hydralazine; minoxidil |
Angiotensin-converting enzyme inhibitors and calcium channel blockers
Angiotensin-converting enzyme inhibitors and diuretics
Angiotensin receptor blockers and diuretics
Beta-blockers and diuretics
Centrally acting antihypertensives and diuretics
Diuretic and diuretic
Options
Hypertensive patients undergoing surgery may or may not require adjustment of their antihypertensive regimen to optimize their perioperative management. This decision about perioperative continuity of antihypertensives depends on a risk–benefit analysis ( Box 8-2 ). The possible risks from continuation or discontinuation of ambulatory antihypertensive medication may be categorized as follows:
- 1.
The risk of inadequate control of hypertension with possible increased perioperative cardiovascular risk, if a particular agent is discontinued before surgery
- 2.
The risk of a clinically important withdrawal syndrome or increased perioperative cardiovascular risk if a particular agent is discontinued before surgery
- 3.
The risk of an adverse perioperative cardiovascular event such as hypotension, if a particular agent is continued until surgery
Is discontinuation of the antihypertensive agent associated with a clinically significant withdrawal syndrome?
Is discontinuation of the antihypertensive agent associated with improved perioperative hemodynamics?
Is discontinuation of the antihypertensive agent associated with increased perioperative cardiovascular risk?
Evidence
What Is the Perioperative Risk of Hypertension?
In the absence of concomitant cardiovascular disease or hypertensive end-organ damage (e.g., left ventricular hypertrophy [LVH] or renal dysfunction), stage 1 hypertension (systolic blood pressure < 160 mm Hg or diastolic blood pressure < 100 mm Hg) does not increase perioperative risk in noncardiac surgery. In a study of 4315 adults older than 50 years undergoing elective major noncardiac surgery, hypertension was not an independent predictor of postoperative cardiac complications. A meta-analysis of more than 30 observational studies found no clinically significant association between hypertension and perioperative complications.
However, the perioperative risk associated with hypertension appears to be significant in cardiovascular procedures and pheochromocytoma resection. Recent trials in adult cardiac surgery have demonstrated that systolic hypertension (defined as a systolic blood pressure > 140 mm Hg), systolic hypervariability (defined as a systolic blood pressure > 140 mm Hg and/or < 80 mm Hg), and pulse pressure hypertension (defined as a pulse pressure > 80 mm Hg) are significant risk factors for perioperative death, stroke, left ventricular dysfunction, and renal failure.
With respect to vascular procedures, perioperative hypertension was a significant risk factor for neurologic deficit in not only carotid endarterectomy but also carotid stenting. Furthermore, in 128 adults undergoing carotid endarterectomy, hypertension was a significant predictor of perioperative myocardial ischemia ( p < 0.05). In a recent study of 10,081 adults undergoing vascular surgery, hypertension was significantly associated with perioperative cardiac complications ( p < 0.005). In this massive trial, long-term beta-blocker therapy (frequently a surrogate for hypertension) was independently associated with perioperative cardiac complications (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0 to 1.8; p = 0.036). With respect to pheochromocytoma, progressive reduction in perioperative cardiovascular complications has been attributed to contemporary perioperative management of hypertension.
The presence of LVH adds significant additional perioperative cardiovascular risk in noncardiac surgery. In the absence of aortic outflow obstruction or hypertrophic cardiomyopathy, LVH typically is a result of systemic hypertension. In a prospective observational study of 405 patients undergoing major vascular surgery, LVH on preoperative electrocardiogram significantly predicted myocardial infarction and/or cardiac death (OR, 4.2; p = 0.001). In a study of 474 men with coronary artery disease undergoing major noncardiac surgery, LVH significantly predicted perioperative myocardial ischemia.
In the presence of severe baseline hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg), the relationship to perioperative cardiovascular risk is less clear. A recent meta-analysis demonstrated that these patients may be at more risk but that there was no evidence that delaying surgery reduces this risk. Despite the lack of evidence, expert opinion recommends that, when possible, surgery be delayed for medical control of baseline severe hyperetension.
Furthermore, “white coat hypertension” (short-term blood pressure elevation on the day of surgery due to anxiety) also confers no additional perioperative cardiovascular risk. This entity was the subject of a randomized controlled trial of 989 surgical patients with well-controlled baseline hypertension with diastolic blood pressures greater than 110 mm Hg on the day of surgery, despite anxiolysis with midazolam. Study patients were then randomly assigned to surgery after intranasal nifedipine or delayed surgery with further medical control of hypertension. No outcome difference was detected between groups. However, an important qualifier is that all patients in this study had no previous hypertensive end-organ damage, symptomatic atherosclerotic arterial disease, aortic stenosis, conduction system disease, or pregnancy-induced hypertension.
In summary, perioperative cardiovascular risk due to baseline hypertension alone is significant in the setting of LVH, cardiovascular procedures, pheochromocytoma resection, and possibly when persistently severe. Thus, for surgical patients without these qualifiers, there is minimal additional cardiovascular risk due to worsening hypertension from discontinuing their antihypertensive medications before surgery. Therefore, for most hypertensive patients, perioperative decisions about their antihypertensive regimen are not based on the intrinsic risk due to hypertension but rather on the considerations that follow.
Which Agents Decrease Risk If Continued Perioperatively?
Beta-Blockers (see Chapter 39 )
Perioperative beta-blockade has been extensively reviewed in multiple recent multisociety guidelines. Their consensus is that hypertensive patients receiving beta-blockers should continue to receive beta-blockade perioperatively (Class I recommendation; that is, this recommendation should be followed because the benefit far outweighs the risk). The evidence supporting this recommendation was ranked as level C; that is, the evidence is limited to expert opinion and case reports, mainly about beta-blocker withdrawal.
The beta-blocker withdrawal syndrome was first recognized with propranolol, the first widely available beta-blocker introduced into clinical practice in the 1970s. In a case series, perioperative withdrawal of propranolol was associated with significant myocardial ischemia. A recent prospective observational cohort study of 2588 adult outpatients found that the risk of myocardial infarction was further significantly increased by withdrawal of cardioselective beta-blockade. Because it is already clear that perioperative beta-blockade withdrawal is dangerous, this question is unlikely to be further studied in a prospective trial.
Perioperative beta-blockade in certain at-risk populations is associated with significant reduction in cardiovascular risk. The indications for beta-blockade in perioperative cardiovascular protection in patients with and without hypertension are explored in recent guidelines.
Given their cardiovascular risk of withdrawal and their perioperative cardiovascular benefit, existing beta-blockade in hypertensive surgical patients should be continued up to the day of surgery and throughout the perioperative period.
Alpha-2 Agonists (Clonidine)
Clonidine is a centrally acting alpha-agonist. It is available in oral, transdermal, and parenteral formulations. Recent high-quality evidence has demonstrated its significant perioperative cardiovascular benefit. In a 2003 meta-analysis of 23 trials (total N = 3395), perioperative alpha-2 agonists reduced mortality rate (relative risk, 0.76; 95% CI, 0.63 to 0.91), and myocardial infarction (relative risk, 0.66; 95% CI, 0.46 to 0.94). A subsequent randomized trial ( N = 190) showed that perioperative clonidine significantly reduced myocardial ischemia (from 31% to 14%; p = 0.01) and long-term mortality rate (relative risk, 0.43; 95% CI, 0.21 to 0.89). In a 2009 meta-analysis of 31 trials (total N = 4578), perioperative alpha-2 agonists reduced mortality rate (relative risk, 0.66; 95% CI, 0.44 to 0.98; p = 0.04) and myocardial infarction (relative risk, 0.68; 95% CI, 0.57 to 0.81; p < 0.0001).
The recent multisociety perioperative care guidelines have recommended alpha-2 agonists for control of hypertension in surgical patients with coronary artery disease (Class IIb recommendation, that is, benefit outweighs risk; level of evidence B, that is, evidence from trials that have evaluated limited populations). The perioperative cardiovascular benefits of alpha-2 agonists are reviewed comprehensively in a dedicated chapter in this textbook (see Chapter 32 ).
Perioperative discontinuation of alpha-2 agonists such as clonidine is, however, dangerous in hypertensive patients who have taken this drug class on a long-term basis. Perioperative clonidine withdrawal is associated with severe delirium, hypertension, and myocardial ischemia. Recent expert consensus has recommended careful supervision of perioperative clonidine therapy to avoid the deleterious effects of its withdrawal. Given the risks of withdrawal and the potential cardiovascular benefit, expert consensus recommends that existing therapy with alpha-2 agonists such as clonidine in hypertensive surgical patients should be continued up to the day of surgery and throughout the perioperative period.
Calcium Channel Blockers
Calcium channel blockers, including the dihydropyridines, are widely used for the pharmacologic management of hypertension. There are no described withdrawal syndromes related to perioperative discontinuation of calcium channel blockade. Furthermore, a recent meta-analysis (11 studies: total N = 1007) has demonstrated that in noncardiac surgery perioperative calcium channel blockade, especially diltiazem, significantly reduced myocardial ischemia (relative risk, 0.49; 95% CI, 0.30 to 0.80), supraventricular tachycardia (relative risk, 0.52; 95% CI, 0.37 to 0.72), and mortality and major morbidity rates (relative risk, 0.35; 95% CI, 0.15 to 0.86). A similar meta-analysis (41 studies: total N = 3327) in cardiac surgery demonstrated that perioperative calcium channel blockade significantly reduced myocardial infarction (OR, 0.58; 95% CI, 0.37 to 0.91; p = 0.02), myocardial ischemia (OR, 0.53; 95% CI, 0.39 to 0.72; p < 0.001), and supraventricular tachycardia (OR, 0.62; 95% CI, 0.41 to 0.93; p = 0.02). Calcium channel blockade was also associated with a trend toward reduced perioperative mortality after coronary artery bypass grafting (OR, 0.66; 95% CI, 0.26 to 1.70; p = 0.4). A recent meta-analysis (13 studies: total N = 724) has also demonstrated that in kidney transplantation, perioperative calcium channel blockade may significantly reduce the risk of postoperative acute tubular necrosis (relative risk, 0.62; 95% CI, 0.46 to 0.85) and delayed graft function (relative risk, 0.55; 95% CI, 0.42 to 0.73). These nephroprotective effects of calcium channel blockers for kidney transplant recipients were confirmed in a second larger meta-analysis (36 studies: total N = 2667), which demonstrated significantly reduced graft loss (risk ratio, 0.75; 95% CI, 0.57 to 0.99) and improved glomerular filtration (mean difference in glomerular filtration rate, 4.5 mL per minute; 95% CI, 2.2 to 6.7).
Therefore, because of the net perioperative outcome benefit, it follows that existing calcium channel blockade in hypertensive surgical patients should be continued throughout the perioperative period. This is the current recommendation from the American College of Physicians, as outlined in their physicians’ information and education resource.
Alpha-Blockers
Alpha-blockers are a mainstay of preoperative preparation of patients with pheochromocytoma and are credited with improved perioperative survival in resection of this tumor. Preoperative alpha-blockade, including that with the long-acting phenoxybenzamine, is titrated to control hypertension by peripheral catecholamine blockade. Frequently, beta-blockade is added subsequently for control of tachycardia and arrhythmia in the setting of epinephrine-secreting tumors. It is recommended to continue the antihypertensive regimen up to and including the day of surgical resection to minimize preoperative catecholamine-related adverse events. This is the current recommendation from the American College of Physicians, as outlined in their physicians’ information and education resource.
Regardless of the preoperative antihypertensive regimen, alpha-blockade and/or beta-blockade will persist after tumor resection, depending on the half-life of the agents chosen. Consequently, severe intraoperative hypotension may ensue after tumor removal due to significantly reduced catecholamine secretion, as well as residual alpha- and beta-blockade. This severe hypotension may require aggressive volume resuscitation and support of systemic vascular resistance with vasopressin adminstration. Because this intraoperative hypotension is readily managed, it is not an indication to recommend discontinuation of preoperative alpha-blockade on the morning of surgery for resection of pheochromocytoma. The resulting net perioperative benefit is the rationale for the expert recommendation to continue aggressive catecholamine blockade up to the morning of surgery.
Which Agents May Increase Risk If Continued Perioperatively?
Angiotensin System Inhibitors
Pharmacologic blockade of the angiotensin system may be associated with significant intraoperative hypotension, whether due to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers. This hypotensive risk may be significantly reduced by preoperative discontinuation of these agents. In a randomized trial of 51 vascular surgical patients, discontinuation of ACE inhibitors 12 to 24 hours before anesthetic induction significantly protected against hypotension ( p < 0.05). In a prospective case-controlled clinical trial of 72 vascular surgical patients, preoperative angiotensin receptor blockade significantly increased hypotension ( p < 0.05) and vasopressor requirement ( p < 0.001). A retrospective study of 267 hypertensive patients receiving both types of angiotensin inhibition demonstrated that discontinuation of the angiotensin blockade at least 10 hours before surgery was significantly associated with a reduced risk of intraoperative hypotension. Furthermore, recent randomized trials have demonstrated that intraoperative hypotension due to angiotensin inhibition may be treated effectively with ephedrine, norepinephrine, and/or vasopressin analogs such as terlipressin. Therefore, based on the cumulative evidence, the expert recommendation is that angiotensin blockade in hypertensive surgical patients be discontinued on the morning of surgery.
Diuretics
Hypokalemia is common in hypertensive patients receiving long-term diuretic therapy. In a randomized trial of 233 hypertensive adults managed with chronic diuretic therapy, the prevalence of hypokalemia (defined as a serum potassium level less than 3.5 mEq/L) was 25%. Perioperative hypokalemia, especially in cardiac surgery, is associated with an increased risk of arrhythmia. In a prospective multicenter trial of 2402 cardiac surgical patients, a serum potassium level less than 3.5 mEq/L significantly predicted serious arrhythmia (relative risk, 2.2; 95% CI, 1.2 to 4.0), intraoperative arrhythmia (relative risk, 2.0; 95% CI, 1.0 to 3.6), and postoperative atrial flutter/fibrillation (relative risk, 1.7; 95% CI, 1.0 to 2.7). Furthermore, a recent large observational trial ( N = 65043) demonstrated that in noncardiac surgery, diuretic therapy in combination with angiotensin blockade was significantly associated with intraoperative hypotension ( p < 0.05).
Therefore, because long-term diuretic therapy for hypertension perioperatively may aggravate hypokalemia, risk of arrhythmia, and risk of hypotension, it is reasonable to discontinue this therapy perioperatively, including the day of surgery. This is the current expert recommendation.
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