The key to the treatment of refractory hypertension is to identify the real causes of resistance to antihypertensive treatment and actively correct them, to remove the interfering factors affecting blood pressure control, to screen for secondary hypertension, to apply a reasonable combination of antihypertensive drugs, and to apply appropriate doses of diuretics and salt corticosteroid receptor antagonists, all of which are important aspects of the treatment of refractory hypertension
Patients with refractory hypertension tend to have higher blood pressure, longer disease duration, and more cardiovascular and cerebrovascular complications, which are the most dangerous components causing serious complications and death in the hypertensive population. Therefore, proper evaluation and treatment of refractory hypertension is necessary to improve the control of hypertension and reduce the disability and mortality rates of cardiovascular and cerebrovascular disease. The following steps may provide useful assistance in the management of refractory hypertension.
Step 1: Initial determination of possible refractory hypertension
Definition of refractory hypertension First, determine whether a patient has refractory hypertension according to the definition of refractory hypertension. The following are definitions of refractory hypertension from different academic organizations, which are similar and can be used for reference.
The 2003 JNC7 definition: Refractory hypertension generally refers to patients with hypertension whose blood pressure cannot be controlled at target blood pressure levels (<140 mmHg systolic and <90 mmHg diastolic, <130/80 mmHg in patients with diabetes or renal disease) despite the application of lifestyle modifications and the use of ≥3 full-dose antihypertensive medications with different mechanisms of action, as measured occasionally in clinics.
Refractory hypertension was defined again in the first scientific statement on the diagnosis, evaluation, and treatment of refractory hypertension issued by the Professional Education Committee of the Hypertension Research Council and the American Heart Association in 2008: the patient has applied 3 antihypertensive drugs with different mechanisms of action, 1 of which should be a diuretic, and the optimal dose of all 3 drugs has been reached and the blood pressure remains above target. If blood pressure is on target, but ≥4 antihypertensive drugs have been taken still defined as refractory hypertension.
The 2011 Chinese guidelines for the prevention and treatment of hypertension define refractory hypertension as a condition in which blood pressure is still above the target level or at least 4 drugs are required to achieve the target level after applying an adequate dose of a reasonable combination of 3 antihypertensive drugs (including diuretics) on the basis of lifestyle improvement.
There are several questions that primary care physicians are often confused about in the above definitions: What is the optimal dose of an “optimal dose” of antihypertensive medication? How long does it take to reach the target before it is initially judged as refractory hypertension? The concept is rather vague. The author believes that the optimal dose should be the maximum dose or close to the maximum dose in the pharmacopoeia or drug instructions (such as the emergence of adverse drug reactions and not up to this dose or discontinued), the application time should be > 2 weeks. If the patient is not suitable for diuretics (e.g., gout patients), but has applied 3 antihypertensive drugs other than diuretics and still cannot reach the target, he or she should also be initially judged to have refractory hypertension. If the above conditions are met, the patient should proceed to the next diagnostic process.
Step 2: Exclusion of pseudo-refractory hypertension
Before definitively diagnosing refractory hypertension, pseudo-refractory hypertension must be ruled out. Pseudo-refractory hypertension mainly includes: inaccurate blood pressure measurement due to technical problems in blood pressure measurement operations, poor patient cooperation, and white coat hypertension.
Whether blood pressure measurement is inaccurate Blood pressure measurement should follow the conditions and operational steps specified in the hypertension treatment guidelines. For proper blood pressure measurement, smoking and coffee should be avoided before blood pressure measurement, and after 5 minutes of quiet rest so that their arm is at the same level as the heart and the right size cuff is selected (Note: The problem of cuff is simple but not easy to solve, and few hospitals in China are currently equipped with different models of sphygmomanometer cuffs).
Is the patient poor compliance Poor patient compliance is also a common cause of pseudo-refractory hypertension, intermittent drug discontinuation, drug reduction and other inability to comply with medical advice until the blood pressure does not reach the standard, etc. It is not difficult to identify through detailed medical history questioning.
Whether it is white coat hypertension White coat hypertension is also the most common cause of pseudo-refractory hypertension. Compared with general hypertension, white coat hypertension accounts for a greater proportion of refractory hypertension, about 20% to 30%, so every patient with incidental blood pressure consistent with refractory hypertension must be monitored for 24-hour ambulatory blood pressure to avoid overtreatment of white coat hypertension.
If pseudohypertension is ruled out the patient may proceed to the next step.
Step 3: Identify and improve factors that are not conducive to blood pressure control
It has long been recognized that even when patients adhere to a reasonable and regular regimen of antihypertensive medications, there are many factors that can affect the effectiveness of antihypertensive therapy and manifest as poor outcomes.
Obesity is a very common cause of the effect of antihypertensive treatment. Obese patients who have excessive accumulation of fat mainly in the abdominal wall and abdominal cavity, called “central” or “centripetal” obesity, will have a great impact on metabolism. Central obesity is one of the most important risk factors for many chronic diseases. Body mass index (BMI) ≥ 24 kg/m2, the risk of hypertension is three to four times higher than that of people with normal weight (BMI = 18.5-23.9 kg/m2). Obesity is common in patients with severe hypertension, and obesity leads to an increase in the dose and quantity of antihypertensive drugs required and difficulty in achieving blood pressure targets. Therefore, obesity is a common feature of patients with refractory hypertension, and proper diet control and reasonable exercise can help to reduce weight.
Alcoholism Excessive alcohol consumption is also a cause of refractory hypertension, and blood pressure will gradually and easily drop to normal after reducing the amount of alcohol consumed.
High sodium diet Some scholars once conducted clinical observation of low sodium treatment for some refractory hypertension, strictly limiting salt intake to <3g/day, which not only refers to table salt, but also includes salt-containing seasonings such as MSG and soy sauce and salt-containing foods such as ham and luncheon meat, salt content of preserved products, as well as the content of natural salt in food, such as rice, noodles, vegetables and fruits containing about 0.05g of salt, calculated in 100g units. The amount of antihypertensive drugs can be reduced or even stopped after a few days of low-salt diet.
Smoking can also reduce the efficacy of antihypertensive drugs; chronic anxiety or stress, chronic pain, and lack of sleep can all make it difficult to control blood pressure.
Reduce or discontinue medications that affect blood pressure. Take a medical history to find out if any medications are being used that cause blood pressure to rise. Drugs that can raise blood pressure include licorice, oral contraceptives, steroids, NSAIDs, cocaine, amphetamines, erythropoietin, and cyclosporine. Specific analysis is as follows: ① NSAIDs can impair the diuretic effect of sodium ions and also inhibit the effect of prostaglandins, and have an effect against tachykinin and converting enzyme inhibitors (ACEI), especially captopril. ②Oral contraceptives, estrogen and progesterone can also elevate blood pressure. ③Adrenocorticotropic hormones can promote water and sodium retention, thus reducing the effects of diuretics and other antihypertensive drugs. ④Psychiatric drugs, including antidepressant tricyclics and monoamine oxidase inhibitors, can cause refractory hypertension by counteracting the anti-sympathetic effects of antihypertensive drugs. ⑤ Erythropoietin and cyclosporine in patients with end-stage renal failure can cause an increase in blood pressure and refractory hypertension. (6) Abuse of cocaine, amphetamines and catabolic steroids can increase blood pressure and make it refractory to treatment. (7) Clinical application of licorice is more common, such as compound licorice tablets or brown combination for cough. The main components of licorice are glycyrrhetinic acid and glycyrrhizic acid, both of which can lead to the accumulation of glucocorticoids in the body, causing sodium and water retention and increased blood pressure. Glycyrrhetinic acid can lead to a decrease in blood potassium and also increase vascular resistance, and the combined effect of the above factors leads to an increase in blood pressure. ⑧ Other drugs, some of which can directly raise blood pressure (such as ephedrine, epinephrine), some of which interfere with the antihypertensive effect (such as cholestyramine).
If lifestyle improvements, reduction or discontinuation of medications that interfere with the antihypertensive effect do not make the blood pressure easier to control, then you should move on to the next step.
Step 4: Look for evidence of secondary hypertension
Secondary hypertension was previously thought to account for 5% of the hypertensive population, and with advances in diagnostic techniques more and more secondary hypertension is being diagnosed. Common secondary hypertension: sleep apnea hypoventilation syndrome, substantial renal disease, primary aldosteronism, renal artery stenosis, depression, anxiety, and panic. Uncommon ones are: pheochromocytoma, Cushing’s syndrome, hyperparathyroidism, aortic constriction, etc.
In this step, primary care hospitals are not in a position to find “definitive evidence”, but they can make preliminary judgments, such as: ① Hypertensive patients who have poor results with conventional antihypertensive drugs or with excessive drinking and nocturia; especially when accompanied by clinical manifestations such as spontaneous hypokalemia and periodic paralysis; or those who are prone to hypokalemia with potassium-depleting diuretics. Primary aldosteronism should be highly suspected. Sleep apnea syndrome is characterized by snoring, apnea and daytime sleepiness. Pheochromocytoma is characterized by paroxysmal increase in blood pressure, palpitations, excessive sweating, and headache. ④Cushing’s syndrome presents with full-moon face, centripetal obesity, purple skin lines, and buffalo back. ⑤Aortic stenosis can be judged by the difference in blood pressure in the upper and lower extremities and systolic murmur. (6) The diagnosis of refractory hypertension due to anxiety, depression and panic is not easy, especially the episodic elevation of blood pressure due to panic attacks is highly diagnostic of pheochromocytoma. Some exogenous events may go unnoticed, and people often do not make causal connections between events spanning decades, leading to poor long-term misdiagnosis outcomes. Therefore, a careful history is required, and primary care physicians have an advantage in this regard.
In most cases, referral to a higher level hospital is required for confirmation of the diagnosis. If, after careful examination, secondary hypertension can be excluded, the diagnosis of refractory hypertension can be confirmed and the patient can proceed to the next step.
Step 5: Optimize the antihypertensive treatment plan and scientific drug administration
Diuretics are the cornerstone of treatment Because volume overload is a common phenomenon in refractory hypertension, diuretics are the cornerstone of treatment. Studies suggest that adjusting diuretics (adding 1 diuretic, increasing the dose of diuretics, or changing the type of diuretic according to the level of renal function) can bring more than 60% of refractory hypertension down to the target. For patients with normal renal function, the effective starting dose of thiazide diuretics is 12.5 mg/day, and for some patients, increasing to 50 mg/day can achieve greater blood pressure lowering effect. If the patient has chronic renal insufficiency, loop diuretics should be used.
Most patients need a combination of a renin-angiotensin system (RAS) inhibitor, a calcium antagonist (CCB) and a diuretic at the appropriate dose, each at an adequate dose (especially for obese patients) and at the appropriate frequency. To the above combination, a different type of CCB can also be added, for example, a long-acting diltiazem on top of nifedipine controlled-release tablets, which can further lower blood pressure. The combination of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) is not advocated because the combination of these two drugs is not significantly synergistic with antihypertensive drugs, does not further reduce cardiovascular and renal events compared with monotherapy, and has increased adverse effects. Studies have also shown that the synergistic antihypertensive effect of the combination of renin inhibitors and ARBs is also not significant. Therefore, dual blockade of the RAS system is not recommended in the treatment of patients with refractory hypertension.
Administration of salt corticosteroid receptor antagonists Aldosterone is the most potent salt corticosteroid in the body and plays an important role in the development of refractory hypertension. Studies have confirmed that the addition of spironolactone, a salt corticosteroid receptor antagonist, can significantly lower blood pressure in patients with refractory hypertension who are obese and have combined sleep apnea. It has also been shown that the combination of spironolactone with adequate amounts of thiazide diuretics or thiazide-like diuretics resulted in the greatest efficacy in the treatment of refractory hypertension and reduced the adverse effects of spironolactone-induced hyperkalemia. Amiloride, another salt corticosteroid receptor antagonist that blocks sodium channels in epithelial cells, can also be used to treat refractory hypertension, but is a potassium storage diuretic and still carries a risk of hyperkalemia. Close monitoring of potassium is required if patients with impaired renal function are treated with amiloride, especially in combination with ARB or ACEI.
If oral antihypertensive medication is not available, it can be combined with the administration of continuous intravenous antihypertensive medication such as sodium nitroprusside, the dose of which is adjusted according to blood pressure. plasma aldosterone concentrations. Low-calcium hemodialysis combined with hemoperfusion can significantly reduce the concentration of endothelin, angiotensin II, parathyroid hormone (PTH) and other hypertensive substances, which has a significant effect on lowering blood pressure and can reduce the use of antihypertensive drugs in patients; in addition, when meeting patients with refractory hypertension clinically, in addition to understanding whether they have inaccurate measurements, irregular medication, use of drugs that affect blood pressure and secondary hypertension, etc., we should also To understand whether the patient is accompanied by anxiety disorders and other emotional disorders, the appropriate use of biofeedback therapy, such as supplemented with psychological guidance is conducive to the ideal control of blood pressure.