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Sickle cell anemia : Current Treatment and Drugs

Wednesday, April 17, 2013


Bone marrow transplant offers the only potential cure for sickle cell anemia. But, finding a donor is difficult and the procedure has serious risks associated with it, including death.
As a result, treatment for sickle cell anemia is usually aimed at avoiding crises, relieving symptoms and preventing complications. If you have sickle cell anemia, you'll need to make regular visits to your doctor to check your red blood cell count and monitor your health. Treatments may include medications to reduce pain and prevent complications, blood transfusions and supplemental oxygen, as well as bone marrow transplant.
Medications
Medications used to treat sickle cell anemia include:
  • Antibiotics. Children with sickle cell anemia may begin taking the antibiotic penicillin when they're about 2 months of age and continue taking it until they're 5 years old. Doing so helps prevent infections, such as pneumonia, which can be life-threatening to an infant or child with sickle cell anemia. Antibiotics may also help adults with sickle cell anemia fight certain infections.
  • Pain-relieving medications. To relieve pain during a sickle crisis, your doctor may advise over-the-counter pain relievers and application of heat to the affected area. You may also need stronger prescription pain medication.
  • Hydroxyurea (Droxia, Hydrea). When taken daily, hydroxyurea reduces the frequency of painful crises and may reduce the need for blood transfusions. It may be an option for adults with severe disease. Hydroxyurea seems to work by stimulating production of fetal hemoglobin — a type of hemoglobin found in newborns that helps prevent the formation of sickle cells. Hydroxyurea increases your risk of infections, and there is some concern that long-term use of this drug may cause tumors or leukemia in certain people. Your doctor can help you determine if this drug may be beneficial for you.
Assessing stroke risk
Using a special ultrasound machine (transcranial), doctors can learn which children have a higher risk of stroke. This test can be used on children as young as 2, and those who are found to have a high risk of stroke are then treated with regular blood transfusions.
Immunizations to prevent infections
Because infections can be very serious in children with sickle cell anemia, your doctor will likely recommend your child receive the available vaccinations.
Blood transfusions
In a red blood cell transfusion, red blood cells are removed from a supply of donated blood. These donated cells are then given intravenously to a person with sickle cell anemia.
Blood transfusions increase the number of normal red blood cells in circulation, helping to relieve anemia. In children with sickle cell anemia at high risk of stroke, regular blood transfusions can decrease their risk of stroke.
Blood transfusions carry some risk. Blood contains iron. Regular blood transfusions cause an excess amount of iron to build up in your body. Because excess iron can damage your heart, liver and other organs, people who undergo regular transfusions may need treatment to reduce iron levels. Deferasirox (Exjade) is an oral medication that can reduce excess iron levels.
Supplemental oxygen
Breathing supplemental oxygen through a breathing mask adds oxygen to your blood and helps you breathe easier. It may be helpful if you have acute chest syndrome or a sickle cell crisis.
Stem cell transplant
A stem cell transplant, also called a bone marrow transplant, involves replacing bone marrow affected by sickle cell anemia with healthy bone marrow from a donor. A stem cell transplant is recommended only for people who have significant symptoms and problems from sickle cell anemia.
If a donor is found, the diseased bone marrow in the person with sickle cell anemia is first depleted with radiation or chemotherapy. Healthy stem cells from the donor are filtered from the blood. The healthy stem cells are injected intravenously into the bloodstream of the person with sickle cell anemia, where they migrate to the bone marrow cavities and begin generating new blood cells. The procedure requires a lengthy hospital stay. After the transplant, you'll receive drugs to help prevent rejection of the donated stem cells.
A stem cell transplant carries risks. There's a chance that your body may reject the transplant, leading to life-threatening complications. In addition, not everyone is a candidate for transplantation or can find a suitable donor.
Treating complications
Doctors treat most complications of sickle cell anemia as they occur. Treatment may include antibiotics, vitamins, blood transfusions, pain-relieving medicines, other medications and possibly surgery, such as to correct vision problems or to remove a damaged spleen.
Experimental treatments
Scientists are studying new treatments for sickle cell anemia, including:
  • Gene therapy. Because sickle cell anemia is caused by a defective gene, researchers are exploring whether inserting a normal gene into the bone marrow of people with sickle cell anemia will result in the production of normal hemoglobin. Scientists are also exploring the possibility of turning off the defective gene while reactivating another gene responsible for the production of fetal hemoglobin — a type of hemoglobin found in newborns that prevents sickle cells from forming.
  • Nitric oxide. People with sickle cell anemia have low levels of nitric oxide in their blood. Nitric oxide is a gas that helps keep blood vessels open and reduces the stickiness of red blood cells. Treatment with nitric oxide may prevent sickle cells from clumping together.
  • Drugs to boost fetal hemoglobin production. Researchers are studying various drugs to devise a way to boost the production of fetal hemoglobin. This is a type of hemoglobin that stops sickle cells from forming.

Travelling During pregnancy


Generally, commercial air travel during pregnancy is considered safe for women who have healthy pregnancies. Still, if you're pregnant, it's best to check with your health care provider before you fly.
Your health care provider might caution against air travel if your pregnancy is considered high risk or you're at risk of preterm labor. Similarly, your health care provider might restrict travel of any type after 36 weeks of pregnancy.
If your health care provider approves air travel and you have flexibility in your travel plans, the best time to fly might be in the middle of your pregnancy — about weeks 14 to 28. This is when you're likely to feel your best, and the risks of miscarriage and premature labor are the lowest.
When you fly:
  • Check the airline's policy about air travel during pregnancy.Guidelines for pregnant women might vary by carrier and destination.
  • Choose your seat carefully. For the most space and comfort, consider requesting an aisle seat.
  • Buckle up. During the trip, fasten the lap belt under your abdomen.
  • Promote circulation. If possible, take occasional walks up and down the aisle. If you must remain seated, flex and extend your ankles often.
  • Drink plenty of fluids. Low humidity in the cabin can lead to dehydration.
Decreased air pressure during flight can slightly reduce the amount of oxygen in your blood, but this doesn't pose risks if you're otherwise healthy.
Likewise, the radiation exposure associated with air travel at high altitudes isn't thought to be problematic for most business or leisure travelers who fly during pregnancy.
There's a caveat for frequent fliers, though.
Pilots, flight attendants and others who fly steadily might be exposed to a level of cosmic radiation that raises questions during pregnancy. If you must fly frequently during your pregnancy, discuss it with your health care provider. He or she might limit your total flight time during pregnancy.

Clinical review: The management of hypertensive crises, Sublingual Nifidipine Abandoned in Hypertensive emergencies

Monday, August 27, 2012


Treatment of Hypertension (High Blood Pressure)


Summaries of the latest research concerning treatment of hypertension
By Hans R. Larsen MSc ChE


Treating hypertension helps prevent atrial fibrillation
GENEVA, SWITZERLAND. There is increasing evidence that essential hypertension (high blood pressure) is an important risk factor in the development of atrial fibrillation. What is less clear is whether treating the hypertension lessens the risk of afib. Swiss researchers now report that appropriate treatment does indeed reduce the risk and that the risk reduction is independent of the type of blood pressure reducing agent used. The study involved a group of 597 patients who, after having been diagnosed with hypertension (systolic blood pressure equal to or greater than 140 mm Hg and/or diastolic pressure equal to or greater than 90 mm Hg), were placed on antihypertensive therapy using ACE inhibitors (46%), angiotensin II receptor blockers (23%), calcium channel blockers (52%), and beta-blockers (21%) either alone or in combination.
After a 7-year follow-up the researchers found that the risk of developing atrial fibrillation decreased by 24% with a 12 mm Hg drop in systolic pressure after adjusting for age, gender, body mass, and pulse pressure (systolic blood pressure minus diastolic pressure). All blood pressure measurements were averages of 24-hour ambulatory measurements. Those of the patients who did develop atrial fibrillation were slightly older than those who did not, were more likely to be men, and to be overweight or obese. A decrease in pulse pressure also correlated with a decrease in AF risk, but this trend was not statistically significant. There was no indication that one class of blood pressure medications was superior in preventing the development of AF. The researchers conclude that an increased systolic pressure and pulse pressure may promote the onset of atrial fibrillation by modification of left ventricular diastolic function.
Ciaroni, S, et al. Prognostic value of 24-hour ambulatory blood pressure measurement for the onset of atrial fibrillation in treated patients with essential hypertension. American Journal of Cardiology, Vol. 94, December 15, 2004, pp. 1566-69
Olive oil lowers blood pressure
NAPLES, ITALY. Several studies have shown that replacing saturated fat with unsaturated fat in the diet can help lower blood pressure in hypertensive individuals. Research has shown that some unsaturated fats (oils) are more effective in lowering blood pressure than others. Fish oils containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for example, have been found quite effective in lowering both blood pressure and triglyceride levels. Now researchers at the University of Naples report that olive oil is also highly effective in lowering blood pressure.
Their one-year study involved 23 men and women with mild hypertension (systolic pressure less than 165 mm Hg and diastolic pressure less than 104 mm Hg at the start of the study). The participants were randomized into two groups. One group was told to add olive oil to their food after cooking while the other group was told to add sunflower oil (a rich source of linoleic acid). Men added 40 grams/day (approx. four spoonfuls) and women added 30 grams/day (approx. three spoonfuls) to arrive at a diet containing 8368 kJ and 6276 kJ respectively. The overall composition of the diet was 17 per cent protein, 57 per cent carbohydrates, and 26 per cent fat.
The participants' blood pressures were measured every two months. After six months the average systolic blood pressure in the olive oil group had dropped to 127 mm Hg from the 134 mm Hg recorded at the start and the diastolic pressure had dropped from 90 mm Hg to 84 mm Hg. There were no significant changes in the sunflower oil group.
The level of antihypertensive medication was adjusted during the experiment by a separate group of doctors who did not know which diet their patients were following. The ones in the olive oil group were able to reduce their medication use by an average 48 per cent and eight of them were able to discontinue their medications completely. None of the ones in the sunflower oil group were able to discontinue their medications and the average reduction in medication usage was only 4 per cent.
The researchers conclude that a reduction in saturated fat intake combined with the increased use of extra-virgin olive oil lowers the need for antihypertensive medication. They speculate that the high content of polyphenols in olive oil may be a major factor in its beneficial effects.
Ferrara, L. Aldo, et al. Olive oil and reduced need for antihypertensive medications. Archives of Internal Medicine, Vol. 160, March 27, 2000, pp. 837-42
Fish oil supplementation reduces blood pressure
CINCINNATI, OHIO. Conventional blood pressure lowering medications often have detrimental effects on quality of life and may lead to unfavourable changes in cholesterol levels. Several studies have found that supplementation with large amounts of fish oil (5-15 grams/day) lowers blood pressure significantly in hypertensive individuals. Whether smaller amounts are equally effective has been open to question.
Researchers at the University of Cincinnati (Ohio) College of Medicine now report that daily supplementation with low doses of fish oil is indeed effective in lowering blood pressure in mildly hypertensive patients. Their study involved 33 patients (men and women) with a diastolic pressure between 90 and 104 mm Hg. After a four-week washout period during which the participants discontinued all medications the patients were randomly allocated to one of two groups. Group 1 supplemented with 2.04 grams/day of fish oil containing 410 mg of eicosapentaenoic acid and 285 mg of docosahexaenoic acid. Group 2 was given a placebo capsule daily containing safflower oil (80% linoleic acid). After 12 weeks and a four-week washout period the groups switched supplementation so that group 1 now received the placebo. Blood pressure, heart rate, and body weight were recorded at two-week intervals during the study and blood samples were collected and analyzed at the beginning and end of each treatment period.
The researchers found that fish oil supplementation reduced diastolic pressure (sitting) by an average of approximately 4.4 mm Hg and systolic pressure by an average of 6.5 mm Hg when compared to values obtained prior to the start of treatment. There were no adverse effects on cholesterol levels. They conclude that fish oil supplementation is a safe and effective way of lowering blood pressure in mildly hypertensive subjects, but noted that the beneficial effects wear off relatively quickly once supplementation is discontinued. NOTE: This study was funded by a grant from RP Scherer Ltd. a manufacturer of fish oil products.
Radack, Kenneth, et al. The effects of low doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects. Archives of Internal Medicine, Vol. 151, June 1991, pp. 1173- 80
Salt restriction and fish oil supplementation lower blood pressure
ADELAIDE, AUSTRALIA. Salt (sodium) restriction can help lower blood pressure in people with hypertension, but is less effective in people with normal pressure. Blood pressure tends to rise with age and there is some evidence that sodium restriction may help reduce this age-related increase. Fish oil supplementation is also effective in lowering blood pressure in hypertensive individuals, but its effect on people with normal pressure is unclear.
Australian researchers report that a combination of fish oil supplementation and salt restriction is highly effective in lowering both systolic and diastolic blood pressure in elderly people with normal pressures. Their study involved 50 healthy volunteers aged 60 to 80 years whose mean initial systolic and diastolic blood pressures were 133 and 77 mm Hg respectively. The participants were randomly assigned to one of four groups. Group 1 supplemented with 8 fish oil capsules per day (providing 4.2 g of omega-3 fatty acids) while maintaining a normal sodium intake. Group 2 supplemented with fish oil while consuming a low-sodium diet. Group 3 supplemented with sunflower oil combined with normal sodium intake while group 4 took sunflower oil while consuming a low-sodium diet. After 4 weeks the mean systolic blood pressure in group 1 had decreased by 8.9 mm Hg and the diastolic pressure by 6.0 mm Hg. There were no significant changes in blood pressure in the group supplementing with fish oil while maintaining a normal sodium intake. The researchers conclude that sodium restriction combined with fish oil supplementation effectively lowers blood pressure. They suggest that this finding may be of particular relevance in the treatment of hypertension in the elderly.
Cobiac, Lynne, et al. Effects of dietary sodium restriction and fish oil supplements on blood pressure in the elderly. Clinical and Experimental Pharmacology and Physiology, Vol. 18, 1991, pp. 265-68
Controlled trials confirm blood pressure reduction with fish oils
BOSTON, MASSACHUSETTS. Numerous studies have concluded that fish oil consumption lowers blood pressure, but a few have found no effect and others have been inconclusive. Researchers at the Harvard Medical School have just completed a major evaluation of the results of 31 placebo-controlled trials involving 1356 subjects. They found that fish oil supplementation (mean dose of 5.6 grams/day) lowers systolic blood pressure (first [highest] reading of blood pressure measurement) by an average of 3.4 mm Hg and diastolic pressure (second [lowest] reading) by an average of 2.0 mm Hg. The effect is highly dose-dependent with 1 gram/day of fish oil lowering systolic pressure by an average of 0.66 mm Hg and diastolic pressure by an average of 0.35 mm Hg. Fish oil supplementation does not affect blood pressure in people with normal blood pressure, but relatively dramatic effects are seen in patients with high cholesterol levels and in patients with atherosclerosis. Both eicosapentaenoic and docosahexaenoic acids (the main components of fish oils) are effective in blood pressure reduction with docosahexaenoic acid being slightly superior. The Harvard researchers conclude that supplementation with 7.7 to 9 grams/day of fish oils will reduce systolic blood pressure by 4 mm Hg and diastolic pressure by 3 mm Hg in hypertensive individuals. Blood pressure reductions may be substantially larger among patients with atherosclerosis or high cholesterol levels.
Morris, Martha Clare, et al. Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation, Vol. 88, No. 2, August 1993, pp. 523-33
Vitamin C combats hypertension
BOSTON, MASSACHUSETTS. There is increasing evidence that free radicals (reactive oxygen species) play a significant role in essential hypertension (high blood pressure). Now researchers at the Boston University School of Medicine report that daily supplementation with vitamin C (ascorbic acid) can significantly reduce blood pressure in people suffering from hypertension. Their randomized, placebo-controlled study involved 39 patients (average age of 49 years) 29 of whom were taking antihypertensive medication.
The study participants had diastolic blood pressure between 90 and 110 mm Hg and did not suffer from diabetes, coronary artery disease or heart failure. They also did not take estrogens or antioxidants within one month of the start of the study. After fasting overnight the patients had their blood pressures (systolic, mean, and diastolic) measured and had urine and blood samples collected. The measurements were repeated two hours after receiving a 2-gram oral dose of ascorbic acid or placebo and again after 30 days of oral supplementation with 500 mg/day of ascorbic acid or placebo.
The researchers found that blood pressures were similar at baseline and after the acute treatment (2-gram dose). At the end of the 30-day period, however, the average systolic pressure in the vitamin C group had decreased from 155 mm Hg to 142 mm Hg and the mean pressure had decreased from 110 to 100 mm Hg. No changes were observed in the placebo group. The average diastolic pressure in the vitamin C group also decreased, but the difference from the placebo group was not statistically significant. Blood plasma levels of ascorbic acid increased significantly in the vitamin C group during the study; from 50 micromol/L to 149 micromol/L two hours after ingesting the 2-gram dose and levelling out at 99 micromol/L at the end of the 30-day test period. The researchers conclude that oral supplementation with 500 mg/day of ascorbic acid is useful for blood pressure control in patients with high blood pressure.
Duffy, Stephen J., et al. Treatment of hypertension with ascorbic acid. The Lancet, Vol. 354, December 11, 1999, pp. 2048-49 (research letter)
Beta-blockers may be a poor choice as an antihypertensive medication for patients who engage in vigorous exercise
ALBUQUERQUE, NEW MEXICO. This review of the effect of blood-pressure-lowering drugs on exercise performance found that the converting enzyme inhibitors, calcium channel blockers, and alpha-blockers have the least potential for adverse effects. Beta-blockers and the CCB, verapamil, were found to impair left ventricular function during exercise. The CCB's nifedipine and diltiazem preserved myocardial contractility better while other antihypertensive agents had negligible effects. Beta-blockers and CCB's (verapamil and diltiazem) have mild antiarrhythmic properties and may provide some protection against ventricular tachycardia. Beta-blockers however, reduce time to exhaustion - nonselective beta-blockers to a greater extent than selective beta-blockers.
Chick, Thomas W., et al. The effect of antihypertensive medications on exercise performance: a review. Medicine and Science in Sports and Exercise, Vol. 20, No. 5, October 1988, pp.447- 52
Cigarette smoking may interfere with treatment of hypertension
MIAMI, FLORIDA. A comparative study of the efficacy of propranolol and hydrochlorothiazide in treatment of hypertension was analyzed to determine if patients who were non-smokers reacted differently than did smokers. The study involved 105 smokers, 81 former smokers, and 147 who never smoked. It was found that smokers responded less to propranolol than did non-smokers; however, further stratification of the data showed that most of the effect was attributable to black patients. A similar trial involving nadolol and bendroflumethiazide showed no difference between smokers and non-smokers in their response to nadolol. This study involved 96 smokers and 187 non-smokers.
Materson, Barry J., et al. Cigarette smoking interferes with treatment of hypertension. Archives of Internal Medicine, Vol. 148, No. 10, October 1988, pp. 2116-19
Potassium proves effective in lowering blood pressure
NAPLES, ITALY. Researchers at the University of Naples have concluded a one-year trial to determine if an increased potassium intake decreases the need for anti-hypertensive medication. A group of 54 patients who were all controlling their high blood pressure with medication participated in the study. Half of the group maintained their regular diet while the diet of the other half was modified to increase the amount of potassium-rich food. The extent of the dietary modification was such that the sodium to potassium ratio was 1:1 rather than the customary 3.5:1. At the end of the trial period the group on the high potassium diet consumed less medication than the other group and 38% of them had discontinued medication altogether. The group on the potassium-rich diet also reported a significant (55%) reduction in symptoms related to their hypertension. NOTE: Increasing potassium intake may be dangerous when taking certain diuretics such as spironolactone.
Supplemental dietary potassium reduced the need for antihypertensive drug therapy. Nutrition Reviews, Vol. 50, No. 5, May 1992, pp. 144-5
Fish oils reduce blood pressure
BALTIMORE, MARYLAND. The daily consumption of fish oils (omega-3 polyunsaturated fatty acids) can significantly lower blood pressure in people suffering from hypertension. The benefit of the fish oils is comparable to that obtainable by sodium reduction and weight loss. A group of medical researchers at the Johns Hopkins Medical School evaluated the results of 17 clinical trials involving supplementation with fish oils for periods of three months or less. They found that the consumption of 3 grams per day of fish oil (6-10 capsules) or more led to impressive reductions in the blood pressure of hypertensive individuals. Systolic pressure was lowered by an average of 5.5 mm Hg and diastolic pressure was lowered by 3.5 mm Hg. The effect was found to be more pronounced at higher blood pressures and no significant effects were noted in people with normal blood pressure. Twenty-eight percent of the participants in the trials reported side effects such as a fishy taste or belching. The doctors suggest that fish oil supplementation may be a valuable therapy in patients with borderline hypertension who would otherwise be candidates for conventional drug therapy. They point out that the effects of long term (> 3 months) supplementation are unknown and that lower dosages than 3 g/day may be desirable and perhaps as effective. NOTE: Systolic pressure is the first (highest) reading given for a blood pressure measurement, diastolic is the second (lowest) reading, i.e. 120/80.
Appel, Lawrence J., et al. Does supplementation of diet with "fish oil" reduce blood pressure? Archives of Internal Medicine, Vol. 153, June 28, 1993, pp. 1429-38
Vitamin C lowers blood pressure
AUGUSTA, GEORGIA. Researchers at the Medical College of Georgia have confirmed that people with a high vitamin C concentration in their blood have lower blood pressures than do people with little vitamin C. They tested 168 healthy people, 56 of which were taking supplements containing ascorbic acid. Among their findings: plasma ascorbic acid levels were 11% higher in supplement users than in non-users; both diastolic and systolic blood pressure were about 5 mm lower in people having a high plasma level of vitamin C than in people having a low level. Blood levels of selenium, vitamin A and vitamin E were not found to affect blood pressure, but both obesity and smoking had a significant adverse effect.
Moran, John P., et al. Plasma ascorbic acid concentrations relate inversely to blood pressure in human subjects. American Journal of Clinical Nutrition, Vol. 57, March 1993, pp. 213-17
Magnesium supplement lowers blood pressure
ROTTERDAM, THE NETHERLANDS. A double-blind controlled trial was recently carried out by Dutch and Belgian researchers in order to determine if oral supplementation with magnesium is an effective way of lowering blood pressure in women suffering from mild to moderate hypertension. Their experiment involved 91 women between 35 and 77 years of age who did not take anti-hypertensive medication. All the women had a systolic blood pressure between 140 and 185 mm Hg and a diastolic pressure between 90 and 105 mm Hg. After a two-week period where all subjects received a placebo, the participants were randomly assigned to two groups. One group continued to receive the placebo while the other group received 485 mg per day of magnesium aspartate-HCl. Both the placebo and the magnesium supplement were supplied in the form of four packets of water-soluble powder per day to be taken with meals. At the end of the six-month trial period the systolic blood pressure in the magnesium supplementation group had decreased by 2.7 mm Hg and the diastolic pressure by 3.4 mm Hg when compared to the placebo group. The researchers conclude that oral supplementation with magnesium aspartate- HCl may be effective in lowering blood pressure in people suffering from mild to moderate hypertension who are not taking anti-hypertensive drugs.
Witteman, Jacqueline C.M., et al. Reduction of blood pressure with oral magnesium supplementation in women with mild to moderate hypertension. American Journal of Clinical Nutrition, Vol. 60, July 1994, pp. 129-35

Natural mineral salt lowers blood pressure
ROTTERDAM, THE NETHERLANDS. Medical researchers at the Erasmus University Medical School have discovered a natural mineral salt that significantly lowers blood pressure in people suffering from mild to moderate hypertension. The salt, "Saga Salt" (Akzo Nobel, Netherlands) occurs naturally in Iceland and contains 41 per cent sodium chloride, 41 per cent potassium chloride, 17 per cent magnesium salts and 1 per cent trace minerals. The researchers tested the salt in a randomized double blind placebo controlled trial involving 100 men and women aged 55 to 75 years. The participants had systolic blood pressures between 140 and 200 mm Hg or diastolic pressures between 85 and 100 mm Hg. Half the group used the mineral salt in food preparation and at the table while the other half used common table salt (sodium chloride). Blood pressures were measured at the start of the experiment and after 8, 16 and 24 weeks. After eight weeks the average blood pressure in the mineral salt group had fallen significantly. The systolic blood pressure (mean of measurement at weeks 8, 16 and 24) fell by 7.6 mm Hg and the diastolic pressure by 3.3 mm Hg in the mineral salt group as compared with the control group. After 24 weeks all participants went back to using common table salt and at week 25 there was no longer any difference in blood pressures between the two groups. The researchers conclude that replacing common table salt with a low sodium, high potassium, high magnesium mineral salt is an effective way of lowering blood pressure in older people suffering from mild to moderate hypertension. NOTE: Systolic pressure is the first (highest) reading given in a blood pressure measurement, diastolic is the second (lowest) reading, i.e. 120/80
Geleijnse, J.M., et al. Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension. British Medical Journal, Vol. 309, August 13, 1994, pp. 436-40
Calcium combats high blood pressure
PORTLAND, OREGON. Researchers at the Oregon Health Sciences University have just published a major overview on the current knowledge concerning the effect of dietary minerals on high blood pressure. They conclude that the effect of sodium intake on blood pressure is still not clear. It may be that only a subset of people with a genetic defect is sensitive to salt intake. The chloride ion in itself does not seem to increase blood pressure, but when combined with sodium it does cause hypertension in salt-sensitive individuals. A four-year study of 60,000 nurses concluded that women who have a calcium intake of 800 mg/day or more have a 23 per cent lower risk of developing high blood pressure than women with an intake of 400 mg/day or less. The benefits of calcium are even greater among pregnant women. Controlled trials have found that women who consume between 1500 - 2000 mg/day of calcium reduce their risk of developing pregnancy-induced hypertension by as much as 50 per cent.
It has also been shown that maternal calcium intake directly affects the infant's blood pressure. Women with a high calcium intake gave birth to babies with higher birth weights and lower blood pressures. This lower pressure persisted throughout at least the first five years of life. The effect of potassium on blood pressure is still being actively investigated. One trial found that a 50 per cent increase in potassium from natural foods lowered blood pressure and dramatically reduced the need for blood pressure-lowering drugs. Another trial found that supplementation with potassium lowered blood pressure by 10 - 14 mm Hg. Several studies suggest that a low magnesium intake is associated with hypertension, stroke, and ischemic heart disease. It has been proposed that supplementation with about 900 mg/day of magnesium, about 2.5 times the RDA, is required in order to effectively lower blood pressure. (71 references)
Reusser, Molly E. and McCarron, David A. Micronutrient effects on blood pressure regulation. Nutrition Reviews, Vol. 52, No. 11, November 1994, pp. 367-75
Fish oils recommended for diabetes and hypertension 
TROMSO, NORWAY. Fish and fish oils help protect against the development of atherosclerosis and heart disease. It is believed that fish oils exert their protective effect by lowering blood pressure and the levels of triglycerides and very-low-density lipoprotein (VLDL). Fish oils are also believed to reduce platelet aggregation and to suppress the growth of smooth-muscle cells in the arterial walls. Many people with hypertension also suffer from diabetes and there has been concern that fish oil supplementation may aggravate problems with glucose intolerance. Researchers at the University of Tromso now report that fish oil supplementation lowers blood pressure significantly in people with hypertension and has no effect on glucose control even in people with mild diabetes. The study involved 78 obese volunteers with essential hypertension. The participants were randomly assigned to one of two equal-sized groups. The fish oil group received four fish oil capsules a day (containing a total of 3.4 grams of a mixture of eicosapentaenoic acid and docosahexaenoic acid) for a period of 16 weeks. The control group received four corn oil capsules a day.
At the end of the test period the average (mean) systolic blood pressure had dropped by 4.4 mm Hg and the diastolic pressure by 3.2 mm Hg in the fish oil group. The average blood pressure in the control group did not change. The researchers also found that plasma triglyceride and VLDL levels in the fish oil group decreased significantly (by about 9 per cent) while they increased significantly (by about 12 per cent) in the control group. There were no changes in total or low- density-lipoprotein levels in either group. Extensive tests (oral glucose tolerance, hyperglycemic and hyperinsulemic clamps) were done to evaluate the effect of fish oil supplementation on glucose control. No adverse effects were found. An editorial accompanying the research report concludes that fish or fish oil is useful in the prevention of vascular disease in diabetics. Patients with diabetes should eat fish two to three times a week or, as an alternative, supplement with two to three one gram capsules of fish oil per day.
Toft, Ingrid, et al. Effects of n-3 polyunsaturated fatty acids on glucose homeostasis and blood pressure in essential hypertension. Annals of Internal Medicine, Vol. 123, No. 12, December 15, 1995, pp. 911-18
Connor, William E. Diabetes, fish oil, and vascular disease. Annals of Internal Medicine, Vol. 123, No. 12, December 15, 1995, pp. 950-52

Qigong effective in treatment of many illnesses 
SAN FRANCISCO, CALIFORNIA. Qigong is an integral part of Traditional Chinese Medicine and has been used for over 3,000 years to improve health and achieve longer life. The types of qigong used for healing and health maintenance involve meditation, breathing exercises, and physical movements. It is estimated that 60 million Chinese practice qigong daily. Reports of long-term scientific studies of the medical benefits of qigong are beginning to appear. Researchers at the Shanghai Institute of Hypertension recently released the results of a 30-year study of the benefits of qigong in combating hypertension. Their investigation involved 242 patients with high blood pressure who were randomly assigned to one of two groups. One group of 122 patients, the qigong group, performed Yan Jing Yi Shen Gong for 30 minutes twice a day; the other group of 120 patients was used as a control group. Both groups received standard drug therapy to control blood pressure. At the end of the 30-year period 32.5 per cent of the members of the control group had died from a stroke compared to only 15.6 per cent in the qigong group. The researchers also found that the blood pressure of the qigong group stabilized over the study period whereas that of the control group kept increasing. Required dosages of anti-hypertensive drugs decreased for the qigong group and were completely eliminated for 30 per cent of the patients. Required drug dosages for members of the control group generally increased throughout the study period.
The regular practice of qigong has also been found to increase bone density in men, to reverse the unfavourable shift in the production of sex hormones caused in aging, to improve heart function, and to effectively combat many of the side effects of cancer. Studies have also shown that drug therapy combined with qigong exercises is more effective than drug therapy on its own.
Sancier, Kenneth M. Medical applications of qigong. Alternative Therapies, Vol. 2, No. 1, January 1996, pp. 40-46
Relaxation therapy controls high blood pressure 
TAIPEI, TAIWAN. Hypertension (diastolic blood pressure of 90 mm Hg or higher or systolic pressure of 140 mm Hg or higher) is widespread in northern Taiwan. A recent survey found that 27.2 per cent of males and 13.6 per cent of females suffer from this condition. A team of researchers from the National Taiwan University and the University of Hawaii now reports that relaxation techniques, frequent blood pressure measurements, and educational techniques are all effective in controlling hypertension. Their experiment involved 590 patients. The patients were randomly assigned to practise relaxation techniques at home, to have frequent, routine blood pressure measurements by health professionals, to read information packages about hypertension control or to receive no treatment (control group). The relaxation techniques involved one-on-one instruction sessions, taped messages of progressive relaxation procedures, and encouragement to perform Buddhist meditation. At the end of the two-month test period the average drop in systolic pressure in the relaxation group was 11 mm Hg and the drop in diastolic pressure was 4.7 mm Hg greater than in the control group. The patients who participated in the frequent blood pressure measurement program also lowered their pressure significantly as did the self-learning group. Almost 50 per cent of the members of the relaxation and self-learning groups achieved a drop in systolic pressure of 10 mm Hg or more and a drop in diastolic pressure of 5 mm Hg or more as a result of the program.
Yen, Lee-Lan, et al. Comparison of relaxation techniques, routine blood pressure measurements, and self-learning packages in hypertension control. Preventive Medicine, Vol. 25, No. 3, May/June 1996, pp. 339-45
Blood pressure drugs increase risk of heart attack 
MALMOE, SWEDEN. It is generally accepted practice to treat people with high blood pressure with antihypertensive drugs in order to prevent heart attacks (myocardial infarctions). This despite the fact that clinical trials and recent population studies have both raised serious questions about the effectiveness of antihypertensive drugs in reducing the incidence of heart attacks. Nevertheless, the prescription of antihypertensive drugs for the prevention of heart attacks continues and there is an increasing trend to prescribe them for people having only a marginal elevation above normal. Now Swedish researchers report that treating elderly men who have a diastolic blood pressure less than 90 mm Hg with antihypertensive drugs increases their risk of having a heart attack by a factor of four. The study involved 484 Swedish men born in 1914. The men were first examined in 1969-70 and again in 1982-83. They were followed-up until December 31, 1992. In 1969-70 only about 3 per cent of the men were taking antihypertensive drugs, in 1982-83 over 23 per cent were doing so. Thirty-six men (13 per cent) with a diastolic pressure below 90 mm Hg were taking antihypertensive drugs while 231 men were not.
During the follow-up period the incidence of heart attacks in the men taking antihypertensive drugs was 3.9 times greater than among the men not taking blood pressure medication. This significantly increased risk remained even when the data was adjusted for the presence of heart disease, diabetes, smoking, high cholesterol, etc. The risk of having a heart attack among men with a diastolic blood pressure greater than 90 mm Hg was twice as high among men taking antihypertensive drugs; however, this increased risk largely disappeared when other cardiovascular risk factors were taken into account. The researchers conclude that treating men with a diastolic blood pressure of 90 mm Hg or less with antihypertensive drugs significantly increases their risk of having a heart attack.
Merlo, Juan, et al. Incidence of myocardial infarction in elderly men being treated with antihypertensive drugs: population based cohort study. British Medical Journal, Vol. 313, August 24, 1996, pp. 457-61
Popular hypertension drug is dangerous 
NEW ORLEANS, LOUISIANA. An international team of medical researchers strongly recommend that the use of short-acting nifedipine be abandoned as a treatment for emergencies involving hypertension. Nifedipine capsules have, over the past two decades, become a very popular treatment option in emergency situations brought on by high blood pressure. It is widely used in hospitals and doctors' offices to swiftly lower an excessively high blood pressure brought on by such conditions as renal failure and pregnancy-induced hypertension. The popularity of short-acting nifedipine has continued despite the fact that its use has been linked to serious adverse effects such as stroke, heart attacks, arrhythmias, foetal distress, uncontrollable fall in blood pressure, and even death. The drug has never been approved by the Food and Drug Administration (FDA) for use in hypertensive emergencies. It is often given in the form of sublingual capsules that the research team found to be next to useless unless swallowed. Apparently the drug is only absorbed in the intestine not in the mouth. The use of short-acting nifedipine for hypertensive emergencies was condemned as early as 1985 by the Cardiorenal Advisory Committee of the FDA. The committee concluded that the use of the drug should be abandoned because it is neither safe nor efficacious. The researchers believe that the reason short-acting nifedipine is still being used to treat hypertensive emergencies is that the manufacturers of the drug have not informed physicians that it is highly dangerous. The research team points out that while the approval of a drug is usually rapidly brought to the attention of physicians, the denial of approval because of lack of efficacy or safety concerns is not. NOTE: The concerns about short-acting nifedipine do not apply to time-release versions of the drug (Procardia XL, Adalat CC).
Grossman, Ehud, et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? Journal of the American Medical Association, Vol. 276, No. 16, October 23/30, 1996, pp. 1328-31
Sour milk reduces blood pressure 
TOKYO, JAPAN. Calpis sour milk has been used traditionally in Japan for many years. It is prepared by fermenting skim milk with a starter culture containing Lactobacillus helveticus and Saccharomyces cerevisiae. The fermented milk contains about 0.7 billion L. helveticus and 2.5 million S. cerevisiae cells per millilitre. Researchers at the Kyorin University School of Medicine have discovered that Calpis sour milk is effective in lowering blood pressure in patients with hypertension. Their experiment involved 30 hypertensive patients, 26 of which were receiving antihypertensive medication such as calcium antagonists, beta-blockers, diuretics, and ACE inhibitors. Seventeen of the patients were fed 95 ml of Calpis sour milk daily for an eight-week period. The remaining 13 patients were given a placebo sour milk prepared by adding lactic acid to skim milk. At the end of the trial period the systolic blood pressure in the Calpis milk group had decreased by an average of 14.1 mm Hg and diastolic pressure by 6.9 mm Hg. No significant blood pressure changes were observed in the placebo group. The blood pressure decreases in the Calpis milk group remained four weeks after the end of treatment. The researchers conclude that daily supplementation with sour milk is a useful and practical way of reducing blood pressure in patients with hypertension. NOTE: This work was done in cooperation with Calpis Food Industry Co., the manufacturer of Calpis sour milk.
Hata, Yoshiya, et al. A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. American Journal of Clinical Nutrition, Vol. 64, November 1996, pp. 767- 71
Potassium supplementation lowers blood pressure 
BALTIMORE, MARYLAND. Researchers at the Johns Hopkins University School of Medicine have come out in favour of using supplementation with potassium in the treatment and prevention of hypertension (high blood pressure). A group of seven medical researchers reviewed 33 randomized, controlled supplementation trials involving over 2600 participants. They conclude that potassium supplementation is effective in lowering both systolic and diastolic blood pressure. The average observed decrease in hypertensive patients was 4.4 mm Hg and 2.5 mm Hg for systolic and diastolic pressure respectively. In people with normal blood pressure the observed decreases were 1.8 mm and 1.0 mm. The amount of elemental potassium used in the studies varied from 60 mmol (2.5 grams) to 120 mmol (5.0 grams) daily. Sixty mmol of potassium is equivalent to 4.5 grams of potassium chloride, 6 grams of potassium bicarbonate or 20 grams of potassium citrate. Oral potassium supplementation appeared to be well tolerated in all the studies examined. The researchers conclude that potassium supplementation "should be considered as part of recommendations for prevention and treatment of hypertension." Potassium supplementation is particularly important in people who are unable to reduce their intake of sodium.
Whelton, Paul K., et al. Effects of oral potassium on blood pressure. Journal of the American Medical Association, Vol. 277, May 28, 1997, pp. 1624-32
Combination diet lowers blood pressure 
BALTIMORE, MARYLAND. High blood pressure (hypertension) is a major problem in the United States. It is estimated that 24 per cent of all American adults (about 43 million people) have high blood pressure, i.e. systolic pressure greater than 120 mm Hg and diastolic pressure greater than 80 mm Hg. Among older adults the proportion of people with hypertension is substantially higher. It is clear that diet affects blood pressure. Vegetarians, for example, tend to have lower blood pressures than non-vegetarians. Now researchers at the Johns Hopkins Medical School report that a diet rich in fruits, vegetables and low-fat dairy products is highly effective in lowering blood pressure. Their study involved 459 adults with systolic blood pressures below 160 mm Hg and diastolic pressures between 80 and 95 mm Hg. For the first three weeks of the experiment the participants were fed a control diet typical of the average diet in the United States (high in fat, low in fruits, vegetables, and dairy products). They were then randomly assigned to three groups. One group continued on the control diet, another group consumed a diet similar to the control diet except it provided more fruits and vegetables and less sweets and snacks, and the third group received a combination diet with reduced amounts of fats and cholesterol and increased amounts of fruits, vegetables and low-fat dairy foods. The calorie content of all diets was identical as was the sodium content at about three grams per day.
After eight weeks on the three diets the participants' blood pressures were again measured. The combination diet resulted in an average (mean) drop in systolic and diastolic blood pressure of 5.5 mm Hg and 4.0 mm Hg respectively when compared to the control diet. The fruits and vegetables diet (modified control diet) produced a drop in systolic and diastolic blood pressure of 2.8 mm Hg and 1.1 mm Hg respectively. The reduction in blood pressure began to take effect within two weeks and was maintained for the next six weeks. The combination diet provided a daily intake of saturated fat of seven per cent of energy, a potassium intake of 4.4 g/day, magnesium 480 mg/day, and calcium 1265 mg/day. In contrast, the control diet provided a saturated fat intake equalling 14 per cent of energy, potassium 1.89 g/day, magnesium 176 mg/day, and calcium 443 mg/day. The researchers conclude that the combination diet may help reduce blood pressure and could serve as an effective alternative to drug therapy in people with mild (stage 1) hypertension.
Appel, Lawrence J., et al. A clinical trial of the effects of dietary patterns on blood pressure. New England Journal of Medicine, Vol. 336, April 17, 1997, pp. 1117-24
L-arginine and heart disease 
STANFORD, CALIFORNIA. The inside of blood vessels is lined with a layer of single cells called the endothelium. Among other functions, the endothelium produces nitric oxide that serves to relax (vasodilate) the blood vessels so as to facilitate the flow of blood. It is now generally accepted that many heart problems involve a dysfunction of the endothelial vasodilator mechanism. Antioxidants, estrogen, exercise, folic acid, and fish oils can in a number of cases, reverse this dysfunction. Now researchers at the Stanford University School of Medicine report that supplementation with the amino acid L-arginine is highly effective in reversing endothelial dysfunction. It has been established that L-arginine is the precursor for endothelium-derived nitric oxide (EDNO). EDNO, in turn, is a potent vasodilator and inhibits platelet aggregation and the adherence of circulating blood cells to blood vessel walls. L-arginine administration, either orally or intravenously, has been found useful in preventing and reversing atherosclerosis, in increasing coronary blood flow in heart disease patients, in alleviating intermittent claudication, and in improving functional status of heart failure patients. L-arginine infusions have been found to lower blood pressure and to inhibit restenosis (reclosing of arteries) after balloon angioplasty. The most common used dosage of L-arginine is between six and thirty grams per day (113 references).

Clinical review: The management of hypertensive crises, Sublingual Nifidipine Abandoned in Hypertensive emergencies


Clinical review: The management of hypertensive crises

Abstract

Hypertension is an extremely common clinical problem, affecting approximately 50 million people in the USA and approximately 1 billion individuals worldwide. Approximately 1% of these patients will develop acute elevations in blood pressure at some point in their lifetime. A number of terms have been applied to severe hypertension, including hypertensive crises, emergencies, and urgencies. By definition, acute elevations in blood pressure that are associated with end-organ damage are called hypertensive crises. Immediate reduction in blood pressure is required only in patients with acute end-organ damage. This article reviews current concepts, and common misconceptions and pitfalls in the diagnosis and management of patients with acutely elevated blood pressure.
Keywords: aortic dissection, β-blockers, calcium channel blockers, fenoldopam, hypertension, hypertensive crises, hypertensive encephalopathy, labetalol, nicardipine, nitroprusside, pregnancy

Introduction

Hypertension is an exceedingly common disorder in Western societies, and as such practitioners of most clinical specialties are likely to encounter patients with acute, severe elevations in blood pressure. In particular, hypertensive emergencies and hypertensive urgencies (see the section on Teminology, definitions, and misconceptions, below) are commonly encountered in the emergency department, operating room, postanaesthesia care unit, and intensive care units [-]. The most important factor that limits morbidity and mortality from these disorders is prompt and carefully considered therapy []. Unfortunately, hypertensive emergencies and urgencies are among the most misunderstood and mismanaged of acute medical problems seen today. Indeed, the reflex of rapidly lowering an elevated blood pressure is associated with significant morbidity and death. Clinicians dealing with hypertensive emergencies and urgencies should be familiar with the pathophysiology of the disease and the principles of treatment. This article reviews current concepts, and common misconceptions and pitfalls in the diagnosis and management of patients with severe hypertension.

Terminology, definitions, and misconceptions

Efforts to classify hypertension on the basis of specific values have existed for the past 100 years. In the USA, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has classified hypertension according to the degree of elevation in blood pressure [,]. According to the most recent report by this committee (the JNC 7 Report []), patients with stage 1 hypertension have a systolic blood pressure of 140–159 mmHg or a diastolic blood pressure of 90–99 mmHg. Those patients with stage 2 hypertension have a systolic blood pressure greater than 160 mmHg or a diastolic blood pressure greater than 100 mmHg. Although not specifically addressed in the JNC 7 Report, patients with a systolic blood pressure greater than 179 mmHg or a diastolic blood pressure that is greater than 109 mmHg are usually defined as having 'severe or accelerated' hypertension.
A number of different terms have been applied to acute severe elevations in blood pressure, and the current terminology is somewhat confusing. However, most authorities have defined hypertensive crises or emergencies as a sudden increase in systolic and diastolic blood pressures associated with 'acute end-organ damage' (i.e. cardiovascular, renal, central nervous system) that requires immediate management. On the other hand, the term 'hypertensive urgency' has been used for patients with severely elevated blood pressure without acute end-organ damage [-,,,]. It is important to emphasize that the clinical distinction between hypertensive emergencies (crises) and hypertensive urgencies depends on the presence of acute target organ damage, rather than the absolute level of blood pressure. Table Table11 lists those clinical conditions that meet the diagnostic criteria for hypertensive emergencies. The term 'malignant hypertension' has been used to describe a syndrome characterized by elevated blood pressure accompanied by encephalopathy or acute nephropathy [,]. However, this term has been removed from national and international blood pressure control guidelines [,], and this condition is best referred to as a hypertensive emergency or crisis.
Table 1

Table 1

Hypertensive emergencies/crises
The dynamic physiologic changes that occur in the early postoperative period deserve special mention. Postoperative hypertension has arbitrarily been defined as a systolic blood pressure greater than 190 mmHg and/or diastolic blood pressure greater than 100 mmHg on two consecutive readings following surgery [,]. Postoperative hypertension may have significant adverse sequelae in both cardiac and non-cardiac patients []. The transient but potentially life-threatening nature of postoperative hypertension and the unique clinical factors present in the postoperative period require that this clinical syndrome be given individual consideration. Another group of patients that requires special mention is those pregnant patients who develop elevations in blood pressure during, immediately before, or after delivery. The presence of a systolic pressure greater than 169 mmHg or a diastolic pressure greater than 109 mmHg in a pregnant woman is considered a hypertensive emergency that requires immediate pharmacologic management [,,].

Epidemiology

Hypertension is an extremely common clinical problem in the Western countries. Hypertension affects approximately 50 million people in the USA and approximately 1 billion individuals worldwide [,,]. Most of these patients have essential hypertension and approximately 30% are undiagnosed [,,]. Furthermore, only between 14% and 29% of American patients with hypertension have adequate blood pressure control []. The incidence of hypertension increases with age. In the Framingham heart study [] the incidence of hypertension increased in men from 3.3% at age 30–39 years to 6.2% at age 70–79 years. Overall, the prevalence and incidence of hypertension are slightly higher in men than in women [,,,]. The incidence of hypertension in African-Americans is about twofold higher than in whites [,,,]. The prevalence and incidence of hypertension in Mexican-Americans are similar to or lower than those in non-Hispanic whites [,,].
The syndrome of hypertensive emergency was first described by Volhard and Fahr in 1914 and was characterized by severe accelerated hypertension, accompanied by evidence of renal disease and by signs of vascular injury to the heart, brain, retina and kidney, and by a rapidly fatal course ending in heart attack, renal failure, or stroke []. The first large study of the natural history of malignant hypertension was published in 1939 before the widespread use of antihypertensive agents []. In that seminal report by Keith and colleagues, untreated malignant hypertension had a 1-year mortality of 79% and a median survival of 10.5 months.
It has been estimated that approximately 1% of patients with hypertension will develop a hypertensive crises at some point during their lives [,]. Before the advent of antihypertensive therapy, this complication occurred in up to 7% of the hypertensive population []. The epidemiology of hypertensive crises parallels the distribution of essential hypertension in the community, being much higher among African-Ameri-cans and the elderly; however, men are affected two times more frequently than are women [,,,]. Most patients who present with a hypertensive crisis have previously been diagnosed as hypertensive and many have been prescribed antihypertensive therapy with inadequate blood pressure control [,,]. The lack of a primary care physician and failure to adhere to prescribed antihypertensive regimens are major risk factors for hypertensive emergencies []. Tumlin and colleagues [] reported that only 51 of 94 (54%) patients presenting to an emergency room with a hypertensive emergency had taken their hypertensive medication in the preceding week. Illicit drug use has also been reported to be a major risk factor for the development of hypertensive emergency [].
Despite the development of increasingly effective antihypertensive treatments over the past 4 decades, the incidence of hypertensive crisis has increased. Hospital admissions for hypertensive emergency more than tripled between 1983 and 1990, from 23 000/year to 73 000/year in the USA []. The reported incidence of postoperative hypertensive crisis varies depending on the population examined, with most studies reporting an incidence of between 4% and 35% [,,]. Like other forms of accelerated hypertension, patients with postoperative hypertensive crisis usually have a prior history of poorly controlled hypertension []. Pregnancy-related hypertension (pre-eclampsia) is a form of hypertension that deserves special mention. Pre-eclampsia occurs in about 7% of all pregnancies but the incidence varies according to the patient population, with 70% being nulliparous and 30% parous [].

Etiology and pathophysiology

Malignant hypertension can develop de novo or can complicate underlying essential or secondary hypertension (Table (Table2).2). In white patients, essential hypertension accounts for 20–30% of malignant hypertension. In blacks, however, essential hypertension is the predominant cause of malignant hypertension, accounting for approximately 80% of all cases [,]. Renal parenchymal disease accounts for up to 80% of all secondary causes, with chronic pyelonephritis and glomerulonephritis being the most common diagnoses []. The average age of presentation of essential malignant hypertension tends to be higher than that for secondary causes. Secondary causes are almost always found in white patients presenting under the age of 30 years, whereas black patients can present with essential hypertension at a younger age.
Table 2

Table 2

Secondary causes of malignant hypertension
The factors that lead to the severe and rapid elevation of blood pressure in patients with malignant hypertension are poorly understood. The rapidity of onset suggests a triggering factor superimposed on pre-existing hypertension. The risks for developing malignant hypertension are related to the severity of the underlying hypertension, and therefore the role of mechanical stress on the vessel wall appears to be critical in its pathogenesis. The release of humoral vasoconstrictor substances from the stressed vessel wall is thought to be responsible for the initiation and perpetuation of the hypertensive crisis [,]. Increased blood pressure results in endothelial damage, with local intravascular activation of the clotting cascade, fibrinoid necrosis of small blood vessels, and release of vasoconstrictor substances [,]. This leads to a vicious cycle of further vascular injury, tissue ischemia, and release of vasoconstrictor substances [,]. The volume depletion that results from pressure natriuresis further simulates the release of vasoconstrictor substances from the kidney. The release of vasoconstrictor substances from the kidney has long been postulated to play a central role in the pathophysiology of malignant hypertension []. Activation of the renin–angiotensin system has been strongly implicated in the initiation and perpetuation of the vascular injury associated with malignant hypertension [,-]. In addition to activation of the renin–angiotensin system vasopressin, endothelin and catecholamines are postulated to play important roles in the pathophysiology of hypertensive emergencies [-].

Clinical manifestations of hypertensive crises

The clinical manifestations of hypertensive crises are those associated with end-organ dysfunction (Table (Table1).1). Organ dysfunction is uncommon with diastolic blood pressures less than 130 mmHg (except in children and in pregnancy) []. However, the absolute level of blood pressure may not be as important as the rate of increase [,,]. In patients with longstanding hypertension a systolic blood pressure of 200 mmHg or elevations in diastolic pressure up to 150 mmHg may be well tolerated without the development of hypertensive encephalopathy, whereas children or pregnant women may develop encephalopathy with a diastolic blood pressure of only 100 mmHg [].
The symptoms and signs of hypertensive crises vary from patient to patient. Headache, altered level of consciousness, and/or focal neurologic signs are seen in patients with hypertensive encephalopathy [,]. On physical examination, these patients may have retinopathy with arteriolar changes, hemorrhages and exudates, as well as papilledema. In other patients, the cardiovascular manifestations of hypertensive crises may predominate, with angina, acute myocardial infarction, or acute left ventricular failure [,]. In some patients, severe injury to the kidneys may lead to acute renal failure with oliguria and/or hematuria.
In pregnant patients, the acute elevations in blood pressure may range from a mild to a life-threatening disease process. The clinical features vary but may include visual field defects, severe headaches, seizures, altered mental status, acute cerebrovascular accidents, severe right upper quadrant abdominal pain, congestive heart failure, and oliguria. In the vast majority of cases, this process can only be terminated by delivery. The decision to continue the pregnancy or to deliver should be made following consultation between medical and obstetric personnel [,,,].
One syndrome that warrants special consideration is aortic dissection. Approximately 2000 new cases occur in the USA each year [,]. Aortic dissection should be considered a likely diagnostic possibility in patients presenting to the emergency department with acute chest pain and elevated blood pressure. Left untreated, about three-quarters of patients with type A dissection die within 2 weeks of an acute episode, but with successful initial therapy the 5-year survival rate increases to 75% [,]. Hence, timely recognition of this disease entity coupled with urgent and appropriate management is the key to a successful outcome in a majority of patients. It is important to understand that the propagation of the dissection is dependent not only on the elevation in blood pressure itself but also on the velocity of left ventricular ejection [-]. For this reason, the aim of antihypertensive therapy is to lessen the pulsatile load or aortic stress by lowering the blood pressure. Specific targets are the blood pressure and rate of pressure rise.

Evaluation and management of hypertensive crises

A targeted medical history and physical examination supported by appropriate laboratory evaluation is required in patients presenting with a possible hypertensive crisis [,]. The patient's hypertensive history and prior blood pressure control should be ascertained, as should any history of renal and cardiac disease. The use of prescribed or nonprescribed medications, and recreational drugs should be determined. The blood pressure in both arms should be measured by the physician. In obese patients appropriately sized cuffs should be used. Physical examination should include palpation of pulses in all extremities, auscultation for renal bruits, a focused neurologic examination, and a funduscopic examination.
A complete blood count and smear (to exclude a microangiopathic anemia), electrolytes, blood urea nitrogen, creatinine, urinalysis, and electrocardiogram should be obtained in all patients. A chest radiograph should be obtained in patients with shortness of breath or chest pain, and a head computed tomography scan should be obtained in patients with neurologic symptoms [,]. In patients with unequal pulses and/or evidence of a widened mediastinum on the chest radiograph a chest computed tomography or magnetic resonance imaging scan should be considered [,]. Patients in whom an aortic dissection is considered should not undergo transesophageal echocardiography until the blood pressure has been adequately controlled. One the basis of the clinical evaluation, the physician should be able to make the distinction between a hypertensive emergency/crisis and a hypertensive urgency [].

Initial therapeutic approach

The majority of patients with severe hypertension (diastolic pressure > 109 mmHg) will have no acute end-organ damage (hypertensive urgencies). In these patients the blood pressure should be lowered gradually over a period of 24–48 hours, usually with oral medication. Rapid reduction in blood pressure in these patients may be associated with significant morbidity [-]. In patients with true hypertensive emergencies, rapid but controlled lowering of blood pressure is indicated to limit and prevent further organ damage [,,,,]. However, the blood pressure should not be lowered to normal levels [-,,]. Most patients with hypertensive emergencies are chronically hypertensive and will have a rightward shift of the pressure–flow (cerebral, renal, and coronary) autoregulation curve (Fig. (Fig.1)1) []. Rapid reduction in blood pressure below the cerebral, renal, and/or coronary autoregulatory range will result in a marked reduction in organ blood flow, leading to ischemia and infarction []. For this reason all patients with a hypertensive emergency should be managed in an intensive care unit, where the patient can be closely monitored. Intra-arterial blood pressure monitoring may be required in patients with blood pressure that is labile and difficult to control.
Figure 1

Figure 1

Cerebral autoregulation in normotensive and chronically hypertensive patient.
A variety of different antihypertensive agents are available for use in patients with hypertensive crises. The agent(s) of choice will depend on the end-organ involved as well as the monitoring environment (Table (Table3).3). Rapid acting intravenous agents should not be used outside the intensive care unit because a precipitous and uncontrolled fall in blood pressure may have lethal consequences. Reductions in diastolic blood pressure by 10–15% or to about 110 mmHg is generally recommended. This is best achieved by an continuous infusion of a short acting, titratable, parenteral antihypertensive agent []. In patients with a dissecting aneurysm this goal should be achieved within 5–10 min. In all other patients, this endpoint should be achieved within 1 hour. Once the end-points of therapy have been reached, the patient can be started on oral maintenance therapy and the intravenous agent weaned off. It should be noted that most patients with hypertensive emergencies are volume depleted. Volume repletion with intravenous crystalloid will serve to restore organ perfusion and prevent the precipitous fall in blood pressure that may occur with antihypertensive therapy.
Table 3

Table 3

Recommended antihypertensive agents for hypertensive crises
It should be emphasized that only patients with hypertensive emergencies require immediate reduction in markedly elevated blood pressure. In all other patients the elevated blood pressure can be lowered slowly using oral agents. Lowering the blood pressure in patients with ischemic strokes may reduce cerebral blood flow, which because of impaired autoregulation may result in further ischemic injury. The common practice of 'normalizing' blood pressure following a cerebrovascular accident is potentially dangerous. When a proximal arterial obstruction results in a mild stroke, a fall in blood pressure may result in further infarction involving the entire territory of that artery. The current recommendation of the American Heart Association is that hypertension in the setting of acute ischemic stroke should only be treated 'rarely and cautiously' [,]. It is generally recommended that antihypertensive therapy be reserved for patients with a diastolic pressure greater than 120–130 mmHg, aiming to reduce the pressure by no more than an arbitrary figure of 10–15% in the first 24 hours. This approach is supported by a study reported by Semplicini and colleagues []. Those investigators demonstrated that a higher initial blood pressure was associated with a better neurologic outcome following an acute ischemic stroke. They suggested that hypertension may be protective during an acute ischemic stroke and that lowering the blood pressure may be potentially harmful. In patients with intracerebral hematomas there is almost always a rise in intracranial pressure with reflex systemic hypertension. There is no evidence that hypertension provokes further bleeding in patients with intracranial hemorrhage. However, a precipitous fall in systemic blood pressure will compromise cerebral perfusion. The controlled lowering of the blood pressure is currently recommended only when the systolic blood pressure is greater than 200 mmHg or the diastolic pressure is greater than 110 mmHg [-]. This recommendation is supported by a recent study that demonstrated that the rapid decline in blood pressure within the first 24 hours after presentation was associated with increased mortality in patients with an intracranial hemorrhage []. The rate of decline in blood pressure was independently associated with increased mortality.
Pregnant patients with hypertensive crises represent a special group of patients. In these patients, intravenous drug therapy is reserved for those patients with systolic blood pressure persistently greater than 180 mmHg or diastolic blood pressure persistently greater than 110 mmHg (105 mmHg in some institutions) []. Before delivery it is desirable to maintain the diastolic blood pressure greater than 90 mmHg because this pressure allows for adequate utero-placental perfusion. If the diastolic blood pressure decreases to below 90 mmHg, then decreased uteroplacental perfusion may precipitate acute fetal distress progressing to an in utero death or to perinatal asphyxia [].

Pharmacologic agents used in the treatment of hypertensive crises

The ideal pharmacologic agent for the management of hypertensive crises would be fast-acting, rapidly reversible, and titratable without significant side effects. Although no single ideal agent exists, a growing number of drugs are available for the management of hypertensive crises. The agent of choice in any particular situation will depend upon the patient's clinical presentation. The preferred agents include esmolol, labetalol, fenoldopam, and nicardipine. Phentolamine and trimethaphan camsylate are less commonly used today; however, they may be useful in particular situations such as catecholamine-induced hypertensive crises (i.e. pheochromocytoma) [,,,,,]. Sodium nitroprusside may be used in patients with acute pulmonary edema and/or severe left ventricular dysfunction and in patients with aortic dissection. However, because sodium nitroprusside is extremely rapid acting and a potent antihypertensive agent, intra-arterial blood pressure monitoring is required; in addition, sodium nitroprusside requires special handling to prevent its degradation by light. These factors limit the use of this drug in the emergency department []. Oral and sublingual nifedipine are potentially dangerous in patients with hypertensive crises and are not recommended. Clonidine and angiotensin-converting enzyme inhibitors are long acting and poorly titratable, but these agents are particularly useful in the management of hypertensive urgencies [-]. Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy [,]. The recommended intravenous antihypertensive agents are reviewed briefly below.

Esmolol

Esmolol is an ultra-short-acting, cardioselective, β-adrenergic blocking agent [-]. The onset of action of this agent is within 60 s, with a duration of action of 10–20 min [-]. The metabolism of esmolol is via rapid hydrolysis of ester linkages by red blood cell esterases and is not dependant upon renal or hepatic function. Because of its pharmacokinetic properties, some authors consider it an 'ideal beta-adrenergic blocker' for use in critically ill patients []. This agent is available for intravenous use both as a bolus and as an infusion. Esmolol is particularly useful in severe postoperative hypertension [-]. It is a suitable agent in situations in which the cardiac output, heart rate, and blood pressure are increased. It has proven safe in patients with acute myocardial infarction, even those who have relative contraindications to β-blockers []. Typically, the drug is given as a 0.5–1 mg/kg loading dose over 1 min, followed by an infusion starting at 50 μg/kg per min and increasing up to 300 μg/kg per min as necessary.

Fenoldopam

Fenoldopam has recently been approved for the management of severe hypertension in the USA. It is a dopamine agonist (DA1 agonist) that is short acting and has the advantages of increasing renal blood flow and sodium excretion [,]. Fenoldopam has relatively unique actions and represents a new category of antihypertensive medication. Although the structure of fenoldopam is similar to that of dopamine, fenoldopam is highly specific for only DA1 receptors and is 10 times more potent than dopamine as a renal vasodilator []. Fenoldopam is rapidly and extensively metabolized by conjugation in the liver, without the participation of cytochrome P450 enzymes. The onset of action is within 5 min, with the maximal response being achieved by 15 min [-]. The duration of action is between 30 and 60 min, with the pressure gradually returning to pretreatment values without rebound once the infusion is stopped [-]. No adverse effects have been reported []. The dose rate of fenoldopam must be individualized according to body weight and according to the desired rapidity and extent of the pharmacodynamic effect. An initial starting dose of 0.1 μg/kg per min is recommended. Fenoldopam has been demonstrated to cause a consistent dose-related decrease in blood pressure in the dose range 0.03–0.3 μg/kg per min []. Fenoldopam has been demonstrated to improve creatinine clearance, urine flow rates, and sodium excretion in severely hypertensive patients with both normal and impaired renal function [,,]. It may therefore be the drug of choice in severely hypertensive patients with impaired renal function [].

Labetalol

Labetalol is a combined selective α1- and nonselective β-adrenergic receptor blocker with an α to β blocking ratio of 1 : 7 []. Labetalol is metabolized by the liver to form an inactive glucuronide conjugate []. The hypotensive effect of labetalol begins within 2–5 min after its intravenous administration, reaching a peak at 5–15 min after administration and lasting for about 2–4 hours [,]. Because of its β-blocking effects, the heart rate is either maintained or slightly reduced. Unlike pure β-adrenergic blocking agents, which decrease cardiac output, labetalol maintains cardiac output []. Labetalol reduces the systemic vascular resistance without reducing total peripheral blood flow. In addition, the cerebral, renal, and coronary blood flows are maintained [-]. This agent has been used in the setting of pregnancy-induced hypertensive crises because little placental transfer occurs, mainly due to the drug's negligible lipid solubility [].
Labetalol may be given as a loading dose of 20 mg, followed by repeated incremental doses of 20–80 mg given at 10-min intervals until the desired blood pressure is achieved. Alternatively, after the initial loading dose, an infusion commencing at 1–2 mg/min and uptitrated until the desired hypotensive effect is achieved is particularly effective. Bolus injections of 1–2 mg/kg have been reported to produce precipitous falls in blood pressure and should therefore be avoided [].

Nicardipine

Nicardipine is a second generation dihydropyridine derivative calcium channel blocker with high vascular selectivity and strong cerebral and coronary vasodilatory activities. It is 100 times more water soluble than is nifedipine, and therefore it can be administered intravenously, making nicardipine an easily titratable intravenous calcium channel blocker [,]. The onset of action of intravenous nicardipine is between 5 and 15 min with a duration of action of 4–6 hours. Once administered intravenously, nicardipine crosses the blood–brain barrier and reaches the nervous tissue, where it binds to calcium-channels of the L-type, acting primarily at the level of the hippocampus []. Intravenous nicardipine has been shown to reduce both cardiac and cerebral ischemia []. The appropriate dosage of nicardipine is independent of the patient's weight, with an initial infusion rate of 5 mg/hour, increasing by 2.5 mg/hour every 5 min to a maximum of 30 mg/hour until the desired blood pressure reduction is achieved [].

Nitroprusside

Sodium nitroprusside is an arterial and venous vasodilator that decreases both afterload and preload [-]. Nitroprusside decreases cerebral blood flow while increasing intracranial pressure – effects that are particularly disadvantageous in patients with hypertensive encephalopathy or following a cerebrovascular accident [-]. Nitroprusside is a very potent agent, with onset of action within seconds, a duration of action of 1–2 min, and a plasma half-life of 3–4 min [-,]. In patients with coronary artery disease a significant reduction in regional blood flow (coronary steal) can occur []. In a large randomized, placebo-controlled trial, nitroprusside was shown to increase mortality when infused in the early hours after acute myocardial infarction (mortality at 13 weeks, 24.2% versus 12.7%) [].
Nitroprusside contains 44% cyanide by weight []. Cyanide is released nonenzymatically from nitroprusside, the amount generated being dependent on the dose of nitroprusside administered. Cyanide is metabolized in the liver to thiocyanate []. Thiosulfate is required for this reaction [,]. Thiocyanate is 100 times less toxic than cyanide. The thiocyanate generated is excreted largely through the kidneys. Cyanide removal therefore requires adequate liver function, adequate renal function, and adequate bioavailability of thiosulfate.
Nitroprusside may cause cytotoxicity because of the release of cyanide with interference with cellular respiration [,]. Cyanide toxicity has been documented to result in 'unexplained cardiac arrest', coma, encephalopathy, convulsions, and irreversible focal neurologic abnormalities [,]. The current methods of monitoring for cyanide toxicity are insensitive. Metabolic acidosis is usually a preterminal event. In addition, a rise in serum thiocyanate levels is a late event and not directly related to cyanide toxicity. Red blood cell cyanide concentrations (although not widely available) may be a more reliable method of monitoring for cyanide toxicity []. A red blood cell cyanide concentration above 40 nmol/ml results in detectable metabolic changes. Levels above 200 nmol/ml are associated with severe clinical symptoms and levels greater than 400 nmol/ml are considered lethal []. Data suggest that nitroprusside infusion rates in excess of 4 μg/kg per min for as little as 2–3 hours may lead to cyanide levels that are within the toxic range []. The recommended doses of nitroprusside of up to 10 μg/kg per min result in cyanide formation at a far greater rate than human beings can detoxify. Sodium nitroprusside has also been demonstrated to cause cytotoxicity through the release of nitric oxide, with hydroxyl radical and peroxynitrite generation leading to lipid peroxidation [,-].
Recently, Khot and colleagues [] reported the use of nitroprusside in 25 normotensive patients with severe aortic stenosis and left ventricular dysfunction. After 24 hours of nitroprusside infusion (mean dose of 128 μg/min) there was a significant increase in the mean cardiac index to 2.52 ± 0.55 l/min per mfrom a baseline value of 1.60 ± 0.35 l/min per m2; this was associated with a significant increase in stroke volume and a significant fall in the systematic vascular resistance and pulmonary capillary wedge pressure. The nitroprusside was well tolerated, had minimal side effects, and was associated with an improvement in renal function. It should be emphasized that, in this study, the patients received the nitroprusside infusion for no longer than 24 hours and the maximum dose did not exceed 2 μg/kg per min.
Considering the potential for severe toxicity with nitroprusside, this drug should only be used when other intravenous antihypertensive agents are not available and then only in specific clinical circumstances and in patients with normal renal and hepatic function []. The duration of treatment should be as short as possible and the infusion rate should not exceed 2 μg/kg per min. An infusion of thiosulfate should be used in patients receiving higher dosages (4–10 μg/kg per min) of nitroprusside []. It has also been demonstrated that hydroxocobalamin (vitamin 12a) is safe and effective in preventing and treating cyanide toxicity associated with the use of nitroprusside. This may be given as a continuous infusion at a rate of 25 mg/hour. Hydroxocobalamin is unstable and should be stored dry and protected from light. Cyanocobalamin (vitamin B12), however, is ineffective as an antidote and is not capable of preventing cyanide toxicity.

Nifedipine, nitroglycerin, and hydralazine

Nifedipine, nitroglycerin, and hydralazine are not recommended in the management of hypertensive emergencies. The bases of these recommendations are discussed below.

Nifedipine

Nifedipine has been widely used via oral or sublingual administration in the management of hypertensive emergencies, severe hypertension associated with chronic renal failure, perioperative hypertension, and pregnancy induced hypertension [,-]. Although nifedipine has been given via the sublingual route, the drug is poorly soluble and is not absorbed through the buccal mucosa. However, it is rapidly absorbed from the gastrointestinal tract after the capsule is broken/dissolved []. This mode of administration has not been approved by the US Food and Drug Administration. A significant decrease in blood pressure is usually observed 5–10 min after nifedipine administration, with a peak effect at between 30 and 60 min and a duration of action of approximately 6–8 hours [].
Sudden uncontrolled and severe reductions in blood pressure accompanying the administration of nifedipine may precipitate cerebral, renal, and myocardial ischemic events, which have been associated with fatal outcomes [,,-,-]. Elderly hypertensive patients with underlying organ impairment and structural vascular disease are more vulnerable to the rapid and uncontrolled reduction in arterial pressure []. Given the seriousness of the reported adverse events and the lack of any clinical documentation attesting to a benefit, the use of nifedipine capsules for hypertensive emergencies and 'pseudo-emergencies' should be abandoned []. The Cardiorenal Advisory Committee of the US Food and Drug Adminsitration has concluded that the practice of administering sublingual/oral nifedipine should be abandoned because this agent is neither safe nor efficacious [].

Nitroglycerin, hydralazine, and diuretics

Nitroglycerin is a potent venodilator, and only at high doses does it affect arterial tone []. It causes hypotension and reflex tachycardia, which are exacerbated by the volume depletion characteristic of hypertensive emergencies. Nitroglycerin reduces blood pressure by reducing preload and cardiac output, which are undesirable effects in patients with compromised cerebral and renal perfusion. Low dose (60 mg/min) nitroglycerin may, however, be used as an adjunct to intravenous antihypertensive therapy in patients with hypertensive emergencies associated with acute coronary syndromes or acute pulmonary edema.
Hydralazine is a direct acting vasodilator. Following intramuscular or intravenous administration there is an initial latency period of 5–15 min followed by a progressive and often precipitous fall in blood pressure that can last up to 12 hours [,]. Although hydralazine's circulating half-life is only about 3 hours, the half-time of its effect on blood pressure is about 100 hours [-]. Because of hydralazine's prolonged and unpredictable antihypertensive effects and the inability to titrate the drug's hypotensive effect effectively, hydralazine is best avoided in the management of hypertensive crises.
Volume depletion is common in patients with malignant hypertension, and the administration of a diuretic together with a hypertensive agent can lead to a precipitous drop in blood pressure. Diuretics should be avoided unless specifically indicated for volume overload as occurs in renal parenchymal disease or coexisting pulmonary edema.

Conclusion

Patients with hypertensive crises may require immediate reduction in elevated blood pressure to prevent and arrest progressive end-organ damage. The best clinical setting in which to achieve this blood pressure control is in the intensive care unit, with the use of titratable intravenous hypotensive agents. There are several antihypertensive agents available for this purpose, including esmolol, nicardipine, labetalol, and fenoldopam. Although sodium nitroprusside is a rapid acting and potent antihypertensive agents, it may be associated with significant toxicity and should therefore only be used in select circumstances and at a dose that should not exceed 2 μg/kg per min. The appropriate therapeutic approach in each patient will depend on the clinical presentation. Agents such as nifedipine and hydralazine should be abandoned because these agents are associated with significant toxicities and/or side effects.

Conflict of interest

None declared.

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