Since chronic diseases are largely self-managed, the family physician must work collaboratively with each patient to individualize therapy. One key consideration in individualizing therapy is patient gender, since men and women often manifest, deal with, and manage diseases differently. This supplement highlights these gender-related differences by focusing on the management of 6 diseases in men, including benign prostatic hyperplasia, gout, diabetes, acute coronary syndrome, coronary heart disease, and dyslipidemia.

Since chronic diseases are largely self-managed, the family physician must work collaboratively with each patient to individualize therapy. One key consideration in individualizing therapy is patient gender, since men and women often manifest, deal with, and manage diseases differently. This supplement highlights these gender-related differences by focusing on the management of 6 diseases in men, including benign prostatic hyperplasia, gout, diabetes, acute coronary syndrome, coronary heart disease, and dyslipidemia.

Since chronic diseases are largely self-managed, the family physician must work collaboratively with each patient to individualize therapy. One key consideration in individualizing therapy is patient gender, since men and women often manifest, deal with, and manage diseases differently. This supplement highlights these gender-related differences by focusing on the management of 6 diseases in men, including benign prostatic hyperplasia, gout, diabetes, acute coronary syndrome, coronary heart disease, and dyslipidemia.

Background

Gout is a heterogeneous disorder that peaks in incidence in the fifth decade. Gout is caused by hyperuricemia, generally as a result of reduced excretion of uric acid by the kidneys; hyperuricemia may also result from overproduction of uric acid. Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2008 indicate that the prevalence of gout continues to rise in the United States, likely related to the increasing frequency of adiposity and hypertension. Overall, about 75% of the 8.3 million people with gout are men.¹

Risk Factors

Clinically defined hyperuricemia—a serum urate (sUA) level greater than 6.8 mg/dL, the concentration at which urate exceeds its solubility in most biological fluids—is the major risk factor for gout. However, not all persons with hyperuricemia have gout. Data from NHANES 2007-2008, in which the definition of hyperuricemia was an sUA level greater than 7.0 mg/dL for men and greater than 5.7 mg/dL for women, showed the mean sUA level to be 6.1 mg/dL in men and 4.9 mg/dL in women, corresponding to hyperuricemia prevalences of 21.2% and 21.6%, respectively.¹

There are several other risk factors for gout, including hypertension, diabetes, hyperlipidemia, chronic kidney disease, cardiovascular disease (CVD), and metabolic syndrome.² For a man with hypertension, the relative risk (RR) of gout is 2.3 compared with a normotensive man.³ Furthermore, it is well established that the use of diuretics increases the risk of gout (RR, 1.8).³ Several other medications increase sUA level as well: aspirin (including low-dose), cyclosporine, pyrazinamide, ethambutol, and niacin.²

Lifestyle and diet also pose a risk for gout. The risk of gout increases with BMI such that, compared with a man with a BMI of 21 to 22.9 kg/m², the RR of gout is doubled for a man with a BMI of 25 to 29.9 kg/m²; for a man with a BMI of 35 kg/m² or more, the RR is tripled.³ Sugar-sweetened soft drinks (but not diet soft drinks) and fructose-rich fruits and fruit juices also increase the risk of gout, as do a high alcohol intake, particularly beer, and a diet rich in meat (especially organ meat, turkey, or wild game) or seafood.⁴ A moderate intake of purine-rich vegetables (eg, peas, beans, lentils, spinach, mushrooms, oatmeal, and cauliflower) or protein is not associated with an increased risk of gout, while a high consumption of dairy products is associated with a decreased risk.^5,6

Untreated or poorly treated gout usually leads to further acute attacks and progressive joint and tissue damage. In addition, gout and hyperuricemia serve as risk factors for other diseases. Adults with gout are 3 times as likely to develop metabolic syndrome as adults without gout.⁷ An elevated sUA level is also an independent risk factor for the development of hypertension (RR, 1.1), as well as myocardial infarction (MI; RR, 1.9), and stroke (RR, 1.6).^8,9 An increasing sUA level also increases the risk of renal failure.^10,11 In a study of 49,413 men followed for a mean of 5.4 years, the age-adjusted RR of renal failure was 1.5 in men with an sUA level of 6.5 to 8.4 mg/dL and 8.5 in men with an sUA level of 8.5 to 13.0 mg/dL compared with men with an sUA level of 5.0 to 6.4 mg/dL.¹¹

Clinical Presentation

The deposition of monosodium urate (MSU) crystals in joints and tissues is very common and typically causes no signs or symptoms in the majority of persons. Even in men with an sUA level of 9 mg/dL or greater, the cumulative incidence of gouty arthritis has been found to be 22% over 5 years.¹² However, as crystal deposition progresses, acute, painful attacks occur more frequently, with the development of chronic tophaceous gout after several years.¹³

Laboratory confirmation of hyperuricemia together with the pain, swelling, and tenderness of DB’s toe and ankle, other findings from his medical history and physical exam (eg, the use of aspirin daily), and exclusion of alternative diagnoses, such as septic arthritis, enable the family physician to arrive at a presumptive diagnosis of gouty arthritis. Aspiration of MSU crystals from DB’s toe or ankle is the gold standard and would allow for a definitive diagnosis. Although the sUA level was found to be high, it should be noted that a normal sUA level is often found during an acute attack; should this occur, the sUA level should be checked again 1 to 2 weeks after the acute attack has resolved.

Goals of Treatment

The cornerstone of gout management is daily, long-term treatment with urate-lowering therapy (ULT) combined with as-needed treatment for an acute attack. In addition, since initiation of ULT mobilizes MSU crystals, which often leads to a short-term increase in acute attacks, prophylaxis with an appropriate anti-inflammatory therapy is recommended at the time ULT is initiated.¹⁴

The therapeutic goals of gout treatment are 2-pronged: treatment of an acute gout attack and management of chronic gout. For an acute attack, the goals are to exclude a diagnosis of septic arthritis; reduce inflammation and terminate the attack; and seek, assess, and control associated diseases, such as diabetes mellitus, hypertension, hyperlipidemia, and CVD. If this latter goal is not possible during the acute attack, plans should be made to assess associated diseases once the acute attack has resolved.¹⁴ Lowering the sUA level is not a goal of therapy for an acute attack, but it is the primary goal of ULT for chronic gout. Lowering the sUA level to less than 6.0 mg/dL, which is well below the saturation point of urate in most biological fluids, is intended to prevent further acute attacks, tophus formation, and tissue damage.¹⁴

Treatment of an Acute Attack

The mainstay of treatment for an acute attack is anti-inflammatory therapy to reduce pain and inflammation.¹⁴ Therapy should be initiated at the onset of the attack and continued until the attack is terminated, which is typically 1 to 2 weeks. Anti-inflammatory therapy traditionally has in-cluded colchicine, a nonsteroidal anti-inflammatory drug (NSAID), or a corticosteroid.¹⁴

Nonsteroidal Anti-inflammatory Drugs

The NSAIDs are all thought to provide similar efficacy when used in maximum doses.^15,16 Since gastrointestinal toxicity is a concern with NSAIDs, coadministration of a proton pump inhibitor, H₂ antagonist, or misoprostol is advised for patients with an increased risk of peptic ulcers, bleeds, or perforations.¹⁷ The risk of MI, stroke, cardiovascular death, and atrial fibrillation/flutter with NSAID therapy should be considered, especially because gout often coexists with cardiovascular disorders.^15,18,19 Furthermore, NSAIDs are contraindicated in patients with heart failure or renal insufficiency.^20,21

Corticosteroids. A systematic review of clinical trials involving systemic corticosteroids that found a few prospective trials of low to moderate quality concluded that there was inconclusive evidence for the efficacy and effectiveness of corticosteroids in the treatment of acute gout.²² No serious adverse events (AEs) were reported. A more recent prospective trial found comparable pain reduction and incidence of AEs with naproxen 500 mg twice daily and prednisolone 35 mg once daily for 5 days in patients with monoarticular gout.²³ Furthermore, clinical experience indicates that intra-articular aspiration and injection of a long-acting corticosteroid is an effective and safe treatment for an acute attack.^14,15 Corticosteroids may be useful in patients who have an inadequate response to, are intolerant of, or have a contraindication to NSAIDs and colchicine.^14,15

Colchicine. Much of the recent clinical investigation regarding pharmacologic treatment of an acute gout attack has involved colchicine. To overcome the limitations of the standard dose-to-toxicity regimen of colchicine, a low-dose regimen of colchicine (1.2 mg followed by 0.6 mg 1 hour later) was investigated and subsequently approved by the US Food and Drug Administration (FDA).²⁴

Approval was based on a randomized, double-blind comparison with high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours) and placebo in 184 patients with an acute gout attack.²⁵ The primary endpoint, a 50% or greater reduction in pain at 24 hours without the use of rescue medication, was reached in 28 of 74 patients (38%) in the low-dose group, 17 of 52 patients (33%) in the high-dose group, and 9 of 58 patients (16%) in the placebo group (P = .005 and P = .034, respectively, versus placebo). An AE occurred in 36.5% and 76.9% of study participants in the low-dose and high-dose colchicine groups, respectively, and in 27.1% of participants in the placebo group. Gastrointestinal AEs (eg, diarrhea, nausea, and vomiting) were less common in the low-dose colchicine group ( FIGURE ). All AEs in the low-dose group were mild to moderate in intensity, while 10 of 52 patients (19.2%) in the high-dose group had an AE of severe intensity. Concomitant use of numerous drugs can increase the concentration of colchicine. Examples include atorvastatin, fluvastatin, pravastatin, simvastatin, fibrates, gemfibrozil, digoxin, clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, protease inhibitors, diltiazem, verapamil, and cyclosporine, as well as grapefruit juice.²⁶

FIGURE

Frequency of selected adverse events occurring over 24 hours with low-dose vs high-dose colchicine²⁵

TABLE

Care plan for a patient with gout²⁷

Urate-Lowering Therapy

Urate lowering therapy is indicated for most, but not all, patients with gout. ULT is generally not recommended for those who have suffered a single attack of gout and have no complications, since 40% of these patients will not experience another attack within a year. However, should a second attack occur within a year of the first attack, ULT is recommended. Some patients who have experienced a single attack may elect to initiate ULT after being educated about the risks of the disease and the risks and benefits of ULT.¹⁴ Patients who have had an attack of gout and also have a comorbidity (eg, visible gouty tophi, renal insufficiency, uric acid stones, or use of a diuretic for hypertension) should begin ULT, since the risk of further attacks is higher in these patients, and kidney or joint damage is more likely.¹⁷

Initiation of ULT should not occur until 1 to 2 weeks after an acute attack has resolved, since beginning ULT during an acute attack is thought to prolong the attack.¹⁷ Because gout is a chronic, largely self-managed disease, patient education is a cornerstone of successful long-term treatment. Implementation of a care plan for both an acute flare and chronic gout is recommended ( TABLE ).²⁷

Anti-inflammatory prophylaxis should begin at the same time that ULT is initiated, since an acute attack is likely due to a transient rise in the sUA level resulting from mobilization of MSU crystals. Colchicine, which is the only drug approved by the FDA for prophylaxis of an acute gout attack, can be used daily in a low-dose regimen (0.6 mg once or twice daily) for up to 6 months.^17,26 Alternatively, an NSAID can be used.¹⁷

One recent investigation pooled the results of 3 phase III clinical trials of ULT in 4101 patients with gout.²⁸ Patients received prophylaxis for 8 weeks or 6 months with low-dose colchicine 0.6 mg once daily or the combination of naproxen 250 mg twice daily with lansoprazole 15 mg once daily. The incidence of acute gout attacks increased sharply (up to 40%) at the end of 8 weeks of prophylaxis with either colchicine or naproxen and then declined steadily, whereas the rates of acute attacks were consistently low (3% to 5%) at the end of 6 months of prophylaxis with either colchicine or naproxen/lansoprazole. With the 8-week prophylaxis regimen, diarrhea was more common in the colchicine group (n = 993) than in the naproxen group (n = 829) (8.4% vs 2.7%, respectively; P < .001). With the 6-month prophylaxis regimen, liver function abnormalities (7.7% vs 4.3%; P = .023) and headache (2.8% vs 0.9%; P = .037) were more common with colchicine (n = 1807) than naproxen, while gastrointestinal/abdominal pains (3.2% vs 1.2%; P = .012) and dental/oral soft tissue infections (2.3% vs 0.6%; P = .006) were more common with naproxen (n = 346) than colchicine.

Uricostatic Agents

Uricostatic therapy with a xanthine oxidase inhibitor (ie, allopurinol or febuxostat) is the most commonly used ULT. Allopurinol is effective in lowering the sUA level and has been shown to lower the rates of all-cause mortality and cardiovascular events, and, in patients with chronic kidney disease, slow the progression of renal disease.^29,30 One key point that must be kept in mind is that the efficacy of allopurinol to lower the sUA level is dose-dependent, although limited safety data are available for doses >300 mg per day.^14,31,32 One recent prospective clinical trial showed that 26% of patients achieved an sUA level of 5 mg/dL or less following 2 months of treatment with allopurinol 300 mg per day compared with 78% of those who subsequently doubled the dose to 300 mg twice daily.³¹ Two patients discontinued treatment with allopurinol because of an AE. Finally, the dose of allopurinol must be adjusted based on renal function to minimize the risk of AEs, particularly skin rashes.³³

Febuxostat is also effective in lowering the sUA level. In patients with an sUA level of 8.0 mg/dL or higher and a creatinine clearance of 50 mL/min or higher at baseline, an sUA level of less than 6.0 mg/dL was achieved in 53% of patients treated with febuxostat 80 mg (n = 256) versus 21% of patients treated with allopurinol 300 mg once daily (n = 253) after 1 year (P < .001).³⁴ The most frequent treatment-related AE was liver function abnormality, which occurred in 4% of patients in each group. Results of a 6-month trial showed that achievement of an sUA level of less than 6.0 mg/dL was achieved in 45% and 67% of patients treated with febuxostat 40 mg or 80 mg daily, respectively, and 42% of those treated with allopurinol 300 mg (200 mg in moderate renal impairment) daily.³⁵ Febuxostat also has been shown to slow the progression of, or even stabilize, renal function.³⁶

Background

Gout is a heterogeneous disorder that peaks in incidence in the fifth decade. Gout is caused by hyperuricemia, generally as a result of reduced excretion of uric acid by the kidneys; hyperuricemia may also result from overproduction of uric acid. Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2008 indicate that the prevalence of gout continues to rise in the United States, likely related to the increasing frequency of adiposity and hypertension. Overall, about 75% of the 8.3 million people with gout are men.¹

Risk Factors

Clinically defined hyperuricemia—a serum urate (sUA) level greater than 6.8 mg/dL, the concentration at which urate exceeds its solubility in most biological fluids—is the major risk factor for gout. However, not all persons with hyperuricemia have gout. Data from NHANES 2007-2008, in which the definition of hyperuricemia was an sUA level greater than 7.0 mg/dL for men and greater than 5.7 mg/dL for women, showed the mean sUA level to be 6.1 mg/dL in men and 4.9 mg/dL in women, corresponding to hyperuricemia prevalences of 21.2% and 21.6%, respectively.¹

There are several other risk factors for gout, including hypertension, diabetes, hyperlipidemia, chronic kidney disease, cardiovascular disease (CVD), and metabolic syndrome.² For a man with hypertension, the relative risk (RR) of gout is 2.3 compared with a normotensive man.³ Furthermore, it is well established that the use of diuretics increases the risk of gout (RR, 1.8).³ Several other medications increase sUA level as well: aspirin (including low-dose), cyclosporine, pyrazinamide, ethambutol, and niacin.²

Lifestyle and diet also pose a risk for gout. The risk of gout increases with BMI such that, compared with a man with a BMI of 21 to 22.9 kg/m², the RR of gout is doubled for a man with a BMI of 25 to 29.9 kg/m²; for a man with a BMI of 35 kg/m² or more, the RR is tripled.³ Sugar-sweetened soft drinks (but not diet soft drinks) and fructose-rich fruits and fruit juices also increase the risk of gout, as do a high alcohol intake, particularly beer, and a diet rich in meat (especially organ meat, turkey, or wild game) or seafood.⁴ A moderate intake of purine-rich vegetables (eg, peas, beans, lentils, spinach, mushrooms, oatmeal, and cauliflower) or protein is not associated with an increased risk of gout, while a high consumption of dairy products is associated with a decreased risk.^5,6

Untreated or poorly treated gout usually leads to further acute attacks and progressive joint and tissue damage. In addition, gout and hyperuricemia serve as risk factors for other diseases. Adults with gout are 3 times as likely to develop metabolic syndrome as adults without gout.⁷ An elevated sUA level is also an independent risk factor for the development of hypertension (RR, 1.1), as well as myocardial infarction (MI; RR, 1.9), and stroke (RR, 1.6).^8,9 An increasing sUA level also increases the risk of renal failure.^10,11 In a study of 49,413 men followed for a mean of 5.4 years, the age-adjusted RR of renal failure was 1.5 in men with an sUA level of 6.5 to 8.4 mg/dL and 8.5 in men with an sUA level of 8.5 to 13.0 mg/dL compared with men with an sUA level of 5.0 to 6.4 mg/dL.¹¹

Clinical Presentation

The deposition of monosodium urate (MSU) crystals in joints and tissues is very common and typically causes no signs or symptoms in the majority of persons. Even in men with an sUA level of 9 mg/dL or greater, the cumulative incidence of gouty arthritis has been found to be 22% over 5 years.¹² However, as crystal deposition progresses, acute, painful attacks occur more frequently, with the development of chronic tophaceous gout after several years.¹³

Laboratory confirmation of hyperuricemia together with the pain, swelling, and tenderness of DB’s toe and ankle, other findings from his medical history and physical exam (eg, the use of aspirin daily), and exclusion of alternative diagnoses, such as septic arthritis, enable the family physician to arrive at a presumptive diagnosis of gouty arthritis. Aspiration of MSU crystals from DB’s toe or ankle is the gold standard and would allow for a definitive diagnosis. Although the sUA level was found to be high, it should be noted that a normal sUA level is often found during an acute attack; should this occur, the sUA level should be checked again 1 to 2 weeks after the acute attack has resolved.

Goals of Treatment

The cornerstone of gout management is daily, long-term treatment with urate-lowering therapy (ULT) combined with as-needed treatment for an acute attack. In addition, since initiation of ULT mobilizes MSU crystals, which often leads to a short-term increase in acute attacks, prophylaxis with an appropriate anti-inflammatory therapy is recommended at the time ULT is initiated.¹⁴

The therapeutic goals of gout treatment are 2-pronged: treatment of an acute gout attack and management of chronic gout. For an acute attack, the goals are to exclude a diagnosis of septic arthritis; reduce inflammation and terminate the attack; and seek, assess, and control associated diseases, such as diabetes mellitus, hypertension, hyperlipidemia, and CVD. If this latter goal is not possible during the acute attack, plans should be made to assess associated diseases once the acute attack has resolved.¹⁴ Lowering the sUA level is not a goal of therapy for an acute attack, but it is the primary goal of ULT for chronic gout. Lowering the sUA level to less than 6.0 mg/dL, which is well below the saturation point of urate in most biological fluids, is intended to prevent further acute attacks, tophus formation, and tissue damage.¹⁴

Treatment of an Acute Attack

The mainstay of treatment for an acute attack is anti-inflammatory therapy to reduce pain and inflammation.¹⁴ Therapy should be initiated at the onset of the attack and continued until the attack is terminated, which is typically 1 to 2 weeks. Anti-inflammatory therapy traditionally has in-cluded colchicine, a nonsteroidal anti-inflammatory drug (NSAID), or a corticosteroid.¹⁴

Nonsteroidal Anti-inflammatory Drugs

The NSAIDs are all thought to provide similar efficacy when used in maximum doses.^15,16 Since gastrointestinal toxicity is a concern with NSAIDs, coadministration of a proton pump inhibitor, H₂ antagonist, or misoprostol is advised for patients with an increased risk of peptic ulcers, bleeds, or perforations.¹⁷ The risk of MI, stroke, cardiovascular death, and atrial fibrillation/flutter with NSAID therapy should be considered, especially because gout often coexists with cardiovascular disorders.^15,18,19 Furthermore, NSAIDs are contraindicated in patients with heart failure or renal insufficiency.^20,21

Corticosteroids. A systematic review of clinical trials involving systemic corticosteroids that found a few prospective trials of low to moderate quality concluded that there was inconclusive evidence for the efficacy and effectiveness of corticosteroids in the treatment of acute gout.²² No serious adverse events (AEs) were reported. A more recent prospective trial found comparable pain reduction and incidence of AEs with naproxen 500 mg twice daily and prednisolone 35 mg once daily for 5 days in patients with monoarticular gout.²³ Furthermore, clinical experience indicates that intra-articular aspiration and injection of a long-acting corticosteroid is an effective and safe treatment for an acute attack.^14,15 Corticosteroids may be useful in patients who have an inadequate response to, are intolerant of, or have a contraindication to NSAIDs and colchicine.^14,15

Colchicine. Much of the recent clinical investigation regarding pharmacologic treatment of an acute gout attack has involved colchicine. To overcome the limitations of the standard dose-to-toxicity regimen of colchicine, a low-dose regimen of colchicine (1.2 mg followed by 0.6 mg 1 hour later) was investigated and subsequently approved by the US Food and Drug Administration (FDA).²⁴

Approval was based on a randomized, double-blind comparison with high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours) and placebo in 184 patients with an acute gout attack.²⁵ The primary endpoint, a 50% or greater reduction in pain at 24 hours without the use of rescue medication, was reached in 28 of 74 patients (38%) in the low-dose group, 17 of 52 patients (33%) in the high-dose group, and 9 of 58 patients (16%) in the placebo group (P = .005 and P = .034, respectively, versus placebo). An AE occurred in 36.5% and 76.9% of study participants in the low-dose and high-dose colchicine groups, respectively, and in 27.1% of participants in the placebo group. Gastrointestinal AEs (eg, diarrhea, nausea, and vomiting) were less common in the low-dose colchicine group ( FIGURE ). All AEs in the low-dose group were mild to moderate in intensity, while 10 of 52 patients (19.2%) in the high-dose group had an AE of severe intensity. Concomitant use of numerous drugs can increase the concentration of colchicine. Examples include atorvastatin, fluvastatin, pravastatin, simvastatin, fibrates, gemfibrozil, digoxin, clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, protease inhibitors, diltiazem, verapamil, and cyclosporine, as well as grapefruit juice.²⁶

FIGURE

Frequency of selected adverse events occurring over 24 hours with low-dose vs high-dose colchicine²⁵

TABLE

Care plan for a patient with gout²⁷

Urate-Lowering Therapy

Urate lowering therapy is indicated for most, but not all, patients with gout. ULT is generally not recommended for those who have suffered a single attack of gout and have no complications, since 40% of these patients will not experience another attack within a year. However, should a second attack occur within a year of the first attack, ULT is recommended. Some patients who have experienced a single attack may elect to initiate ULT after being educated about the risks of the disease and the risks and benefits of ULT.¹⁴ Patients who have had an attack of gout and also have a comorbidity (eg, visible gouty tophi, renal insufficiency, uric acid stones, or use of a diuretic for hypertension) should begin ULT, since the risk of further attacks is higher in these patients, and kidney or joint damage is more likely.¹⁷

Initiation of ULT should not occur until 1 to 2 weeks after an acute attack has resolved, since beginning ULT during an acute attack is thought to prolong the attack.¹⁷ Because gout is a chronic, largely self-managed disease, patient education is a cornerstone of successful long-term treatment. Implementation of a care plan for both an acute flare and chronic gout is recommended ( TABLE ).²⁷

Anti-inflammatory prophylaxis should begin at the same time that ULT is initiated, since an acute attack is likely due to a transient rise in the sUA level resulting from mobilization of MSU crystals. Colchicine, which is the only drug approved by the FDA for prophylaxis of an acute gout attack, can be used daily in a low-dose regimen (0.6 mg once or twice daily) for up to 6 months.^17,26 Alternatively, an NSAID can be used.¹⁷

One recent investigation pooled the results of 3 phase III clinical trials of ULT in 4101 patients with gout.²⁸ Patients received prophylaxis for 8 weeks or 6 months with low-dose colchicine 0.6 mg once daily or the combination of naproxen 250 mg twice daily with lansoprazole 15 mg once daily. The incidence of acute gout attacks increased sharply (up to 40%) at the end of 8 weeks of prophylaxis with either colchicine or naproxen and then declined steadily, whereas the rates of acute attacks were consistently low (3% to 5%) at the end of 6 months of prophylaxis with either colchicine or naproxen/lansoprazole. With the 8-week prophylaxis regimen, diarrhea was more common in the colchicine group (n = 993) than in the naproxen group (n = 829) (8.4% vs 2.7%, respectively; P < .001). With the 6-month prophylaxis regimen, liver function abnormalities (7.7% vs 4.3%; P = .023) and headache (2.8% vs 0.9%; P = .037) were more common with colchicine (n = 1807) than naproxen, while gastrointestinal/abdominal pains (3.2% vs 1.2%; P = .012) and dental/oral soft tissue infections (2.3% vs 0.6%; P = .006) were more common with naproxen (n = 346) than colchicine.

Uricostatic Agents

Uricostatic therapy with a xanthine oxidase inhibitor (ie, allopurinol or febuxostat) is the most commonly used ULT. Allopurinol is effective in lowering the sUA level and has been shown to lower the rates of all-cause mortality and cardiovascular events, and, in patients with chronic kidney disease, slow the progression of renal disease.^29,30 One key point that must be kept in mind is that the efficacy of allopurinol to lower the sUA level is dose-dependent, although limited safety data are available for doses >300 mg per day.^14,31,32 One recent prospective clinical trial showed that 26% of patients achieved an sUA level of 5 mg/dL or less following 2 months of treatment with allopurinol 300 mg per day compared with 78% of those who subsequently doubled the dose to 300 mg twice daily.³¹ Two patients discontinued treatment with allopurinol because of an AE. Finally, the dose of allopurinol must be adjusted based on renal function to minimize the risk of AEs, particularly skin rashes.³³

Febuxostat is also effective in lowering the sUA level. In patients with an sUA level of 8.0 mg/dL or higher and a creatinine clearance of 50 mL/min or higher at baseline, an sUA level of less than 6.0 mg/dL was achieved in 53% of patients treated with febuxostat 80 mg (n = 256) versus 21% of patients treated with allopurinol 300 mg once daily (n = 253) after 1 year (P < .001).³⁴ The most frequent treatment-related AE was liver function abnormality, which occurred in 4% of patients in each group. Results of a 6-month trial showed that achievement of an sUA level of less than 6.0 mg/dL was achieved in 45% and 67% of patients treated with febuxostat 40 mg or 80 mg daily, respectively, and 42% of those treated with allopurinol 300 mg (200 mg in moderate renal impairment) daily.³⁵ Febuxostat also has been shown to slow the progression of, or even stabilize, renal function.³⁶

Background

Gout is a heterogeneous disorder that peaks in incidence in the fifth decade. Gout is caused by hyperuricemia, generally as a result of reduced excretion of uric acid by the kidneys; hyperuricemia may also result from overproduction of uric acid. Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2008 indicate that the prevalence of gout continues to rise in the United States, likely related to the increasing frequency of adiposity and hypertension. Overall, about 75% of the 8.3 million people with gout are men.¹

Risk Factors

Clinically defined hyperuricemia—a serum urate (sUA) level greater than 6.8 mg/dL, the concentration at which urate exceeds its solubility in most biological fluids—is the major risk factor for gout. However, not all persons with hyperuricemia have gout. Data from NHANES 2007-2008, in which the definition of hyperuricemia was an sUA level greater than 7.0 mg/dL for men and greater than 5.7 mg/dL for women, showed the mean sUA level to be 6.1 mg/dL in men and 4.9 mg/dL in women, corresponding to hyperuricemia prevalences of 21.2% and 21.6%, respectively.¹

There are several other risk factors for gout, including hypertension, diabetes, hyperlipidemia, chronic kidney disease, cardiovascular disease (CVD), and metabolic syndrome.² For a man with hypertension, the relative risk (RR) of gout is 2.3 compared with a normotensive man.³ Furthermore, it is well established that the use of diuretics increases the risk of gout (RR, 1.8).³ Several other medications increase sUA level as well: aspirin (including low-dose), cyclosporine, pyrazinamide, ethambutol, and niacin.²

Lifestyle and diet also pose a risk for gout. The risk of gout increases with BMI such that, compared with a man with a BMI of 21 to 22.9 kg/m², the RR of gout is doubled for a man with a BMI of 25 to 29.9 kg/m²; for a man with a BMI of 35 kg/m² or more, the RR is tripled.³ Sugar-sweetened soft drinks (but not diet soft drinks) and fructose-rich fruits and fruit juices also increase the risk of gout, as do a high alcohol intake, particularly beer, and a diet rich in meat (especially organ meat, turkey, or wild game) or seafood.⁴ A moderate intake of purine-rich vegetables (eg, peas, beans, lentils, spinach, mushrooms, oatmeal, and cauliflower) or protein is not associated with an increased risk of gout, while a high consumption of dairy products is associated with a decreased risk.^5,6

Untreated or poorly treated gout usually leads to further acute attacks and progressive joint and tissue damage. In addition, gout and hyperuricemia serve as risk factors for other diseases. Adults with gout are 3 times as likely to develop metabolic syndrome as adults without gout.⁷ An elevated sUA level is also an independent risk factor for the development of hypertension (RR, 1.1), as well as myocardial infarction (MI; RR, 1.9), and stroke (RR, 1.6).^8,9 An increasing sUA level also increases the risk of renal failure.^10,11 In a study of 49,413 men followed for a mean of 5.4 years, the age-adjusted RR of renal failure was 1.5 in men with an sUA level of 6.5 to 8.4 mg/dL and 8.5 in men with an sUA level of 8.5 to 13.0 mg/dL compared with men with an sUA level of 5.0 to 6.4 mg/dL.¹¹

Clinical Presentation

The deposition of monosodium urate (MSU) crystals in joints and tissues is very common and typically causes no signs or symptoms in the majority of persons. Even in men with an sUA level of 9 mg/dL or greater, the cumulative incidence of gouty arthritis has been found to be 22% over 5 years.¹² However, as crystal deposition progresses, acute, painful attacks occur more frequently, with the development of chronic tophaceous gout after several years.¹³

Laboratory confirmation of hyperuricemia together with the pain, swelling, and tenderness of DB’s toe and ankle, other findings from his medical history and physical exam (eg, the use of aspirin daily), and exclusion of alternative diagnoses, such as septic arthritis, enable the family physician to arrive at a presumptive diagnosis of gouty arthritis. Aspiration of MSU crystals from DB’s toe or ankle is the gold standard and would allow for a definitive diagnosis. Although the sUA level was found to be high, it should be noted that a normal sUA level is often found during an acute attack; should this occur, the sUA level should be checked again 1 to 2 weeks after the acute attack has resolved.

Goals of Treatment

The cornerstone of gout management is daily, long-term treatment with urate-lowering therapy (ULT) combined with as-needed treatment for an acute attack. In addition, since initiation of ULT mobilizes MSU crystals, which often leads to a short-term increase in acute attacks, prophylaxis with an appropriate anti-inflammatory therapy is recommended at the time ULT is initiated.¹⁴

The therapeutic goals of gout treatment are 2-pronged: treatment of an acute gout attack and management of chronic gout. For an acute attack, the goals are to exclude a diagnosis of septic arthritis; reduce inflammation and terminate the attack; and seek, assess, and control associated diseases, such as diabetes mellitus, hypertension, hyperlipidemia, and CVD. If this latter goal is not possible during the acute attack, plans should be made to assess associated diseases once the acute attack has resolved.¹⁴ Lowering the sUA level is not a goal of therapy for an acute attack, but it is the primary goal of ULT for chronic gout. Lowering the sUA level to less than 6.0 mg/dL, which is well below the saturation point of urate in most biological fluids, is intended to prevent further acute attacks, tophus formation, and tissue damage.¹⁴

Treatment of an Acute Attack

The mainstay of treatment for an acute attack is anti-inflammatory therapy to reduce pain and inflammation.¹⁴ Therapy should be initiated at the onset of the attack and continued until the attack is terminated, which is typically 1 to 2 weeks. Anti-inflammatory therapy traditionally has in-cluded colchicine, a nonsteroidal anti-inflammatory drug (NSAID), or a corticosteroid.¹⁴

Nonsteroidal Anti-inflammatory Drugs

The NSAIDs are all thought to provide similar efficacy when used in maximum doses.^15,16 Since gastrointestinal toxicity is a concern with NSAIDs, coadministration of a proton pump inhibitor, H₂ antagonist, or misoprostol is advised for patients with an increased risk of peptic ulcers, bleeds, or perforations.¹⁷ The risk of MI, stroke, cardiovascular death, and atrial fibrillation/flutter with NSAID therapy should be considered, especially because gout often coexists with cardiovascular disorders.^15,18,19 Furthermore, NSAIDs are contraindicated in patients with heart failure or renal insufficiency.^20,21

Corticosteroids. A systematic review of clinical trials involving systemic corticosteroids that found a few prospective trials of low to moderate quality concluded that there was inconclusive evidence for the efficacy and effectiveness of corticosteroids in the treatment of acute gout.²² No serious adverse events (AEs) were reported. A more recent prospective trial found comparable pain reduction and incidence of AEs with naproxen 500 mg twice daily and prednisolone 35 mg once daily for 5 days in patients with monoarticular gout.²³ Furthermore, clinical experience indicates that intra-articular aspiration and injection of a long-acting corticosteroid is an effective and safe treatment for an acute attack.^14,15 Corticosteroids may be useful in patients who have an inadequate response to, are intolerant of, or have a contraindication to NSAIDs and colchicine.^14,15

Colchicine. Much of the recent clinical investigation regarding pharmacologic treatment of an acute gout attack has involved colchicine. To overcome the limitations of the standard dose-to-toxicity regimen of colchicine, a low-dose regimen of colchicine (1.2 mg followed by 0.6 mg 1 hour later) was investigated and subsequently approved by the US Food and Drug Administration (FDA).²⁴

Approval was based on a randomized, double-blind comparison with high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours) and placebo in 184 patients with an acute gout attack.²⁵ The primary endpoint, a 50% or greater reduction in pain at 24 hours without the use of rescue medication, was reached in 28 of 74 patients (38%) in the low-dose group, 17 of 52 patients (33%) in the high-dose group, and 9 of 58 patients (16%) in the placebo group (P = .005 and P = .034, respectively, versus placebo). An AE occurred in 36.5% and 76.9% of study participants in the low-dose and high-dose colchicine groups, respectively, and in 27.1% of participants in the placebo group. Gastrointestinal AEs (eg, diarrhea, nausea, and vomiting) were less common in the low-dose colchicine group ( FIGURE ). All AEs in the low-dose group were mild to moderate in intensity, while 10 of 52 patients (19.2%) in the high-dose group had an AE of severe intensity. Concomitant use of numerous drugs can increase the concentration of colchicine. Examples include atorvastatin, fluvastatin, pravastatin, simvastatin, fibrates, gemfibrozil, digoxin, clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, protease inhibitors, diltiazem, verapamil, and cyclosporine, as well as grapefruit juice.²⁶

FIGURE

Frequency of selected adverse events occurring over 24 hours with low-dose vs high-dose colchicine²⁵

TABLE

Care plan for a patient with gout²⁷

Urate-Lowering Therapy

Urate lowering therapy is indicated for most, but not all, patients with gout. ULT is generally not recommended for those who have suffered a single attack of gout and have no complications, since 40% of these patients will not experience another attack within a year. However, should a second attack occur within a year of the first attack, ULT is recommended. Some patients who have experienced a single attack may elect to initiate ULT after being educated about the risks of the disease and the risks and benefits of ULT.¹⁴ Patients who have had an attack of gout and also have a comorbidity (eg, visible gouty tophi, renal insufficiency, uric acid stones, or use of a diuretic for hypertension) should begin ULT, since the risk of further attacks is higher in these patients, and kidney or joint damage is more likely.¹⁷

Initiation of ULT should not occur until 1 to 2 weeks after an acute attack has resolved, since beginning ULT during an acute attack is thought to prolong the attack.¹⁷ Because gout is a chronic, largely self-managed disease, patient education is a cornerstone of successful long-term treatment. Implementation of a care plan for both an acute flare and chronic gout is recommended ( TABLE ).²⁷

Anti-inflammatory prophylaxis should begin at the same time that ULT is initiated, since an acute attack is likely due to a transient rise in the sUA level resulting from mobilization of MSU crystals. Colchicine, which is the only drug approved by the FDA for prophylaxis of an acute gout attack, can be used daily in a low-dose regimen (0.6 mg once or twice daily) for up to 6 months.^17,26 Alternatively, an NSAID can be used.¹⁷

One recent investigation pooled the results of 3 phase III clinical trials of ULT in 4101 patients with gout.²⁸ Patients received prophylaxis for 8 weeks or 6 months with low-dose colchicine 0.6 mg once daily or the combination of naproxen 250 mg twice daily with lansoprazole 15 mg once daily. The incidence of acute gout attacks increased sharply (up to 40%) at the end of 8 weeks of prophylaxis with either colchicine or naproxen and then declined steadily, whereas the rates of acute attacks were consistently low (3% to 5%) at the end of 6 months of prophylaxis with either colchicine or naproxen/lansoprazole. With the 8-week prophylaxis regimen, diarrhea was more common in the colchicine group (n = 993) than in the naproxen group (n = 829) (8.4% vs 2.7%, respectively; P < .001). With the 6-month prophylaxis regimen, liver function abnormalities (7.7% vs 4.3%; P = .023) and headache (2.8% vs 0.9%; P = .037) were more common with colchicine (n = 1807) than naproxen, while gastrointestinal/abdominal pains (3.2% vs 1.2%; P = .012) and dental/oral soft tissue infections (2.3% vs 0.6%; P = .006) were more common with naproxen (n = 346) than colchicine.

Uricostatic Agents

Uricostatic therapy with a xanthine oxidase inhibitor (ie, allopurinol or febuxostat) is the most commonly used ULT. Allopurinol is effective in lowering the sUA level and has been shown to lower the rates of all-cause mortality and cardiovascular events, and, in patients with chronic kidney disease, slow the progression of renal disease.^29,30 One key point that must be kept in mind is that the efficacy of allopurinol to lower the sUA level is dose-dependent, although limited safety data are available for doses >300 mg per day.^14,31,32 One recent prospective clinical trial showed that 26% of patients achieved an sUA level of 5 mg/dL or less following 2 months of treatment with allopurinol 300 mg per day compared with 78% of those who subsequently doubled the dose to 300 mg twice daily.³¹ Two patients discontinued treatment with allopurinol because of an AE. Finally, the dose of allopurinol must be adjusted based on renal function to minimize the risk of AEs, particularly skin rashes.³³

Febuxostat is also effective in lowering the sUA level. In patients with an sUA level of 8.0 mg/dL or higher and a creatinine clearance of 50 mL/min or higher at baseline, an sUA level of less than 6.0 mg/dL was achieved in 53% of patients treated with febuxostat 80 mg (n = 256) versus 21% of patients treated with allopurinol 300 mg once daily (n = 253) after 1 year (P < .001).³⁴ The most frequent treatment-related AE was liver function abnormality, which occurred in 4% of patients in each group. Results of a 6-month trial showed that achievement of an sUA level of less than 6.0 mg/dL was achieved in 45% and 67% of patients treated with febuxostat 40 mg or 80 mg daily, respectively, and 42% of those treated with allopurinol 300 mg (200 mg in moderate renal impairment) daily.³⁵ Febuxostat also has been shown to slow the progression of, or even stabilize, renal function.³⁶

Everyone should avoid overexposure to the sun’s rays. But the desire for the “perfect tan,” the belief that a tan enables one to spend more time in the sun, and a lack of awareness about the dangers of ultraviolet (UV) radiation are factors that contribute to UV-induced skin damage and to an increased risk of skin cancer. Physicians need to be prepared to counsel patients on why and how to avoid damaging UV radiation.

See the patient education handout

Some measures are straightforward, such as wearing protective clothing, limiting sun exposure during the peak daylight hours, and avoiding tanning booths. The issue of which sunscreen to use can be more difficult, given the quantity of sunscreen products and the confusing claims made on product labels.

In this article, we review UV radiation, the consequences of increased exposure to different parts of the UV spectrum, tanning, and the fundamentals of sunscreens. We also briefly review current guidelines from professional organizations and rulings on sunscreen products by the US Food and Drug Administration (FDA).

FACTORS AFFECTING UV EXPOSURE

UV radiation from the sun is strongest between 10:00 am and 4:00 pm at equatorial latitudes and during summer months.¹ Certain wavelengths of UV radiation have long been known to contribute to skin cancer in humans: the wavelengths considered most damaging are those from 320 to 400 nm, referred to as UV-A, and from 290 to 320 nm, referred to as UV-B.^1,2 The UV spectrum also includes UV-C and other subdivisions, but in this article we are mainly concerned with UV-A and UV-B. From 90% to 95% of UV radiation that reaches the earth’s surface is UV-A, and most of the rest is UV-B.

The different wavelengths of UV-A and UV-B have different effects on the skin. Much of the shorter-wavelength UV-B radiation is scattered by the atmospheric ozone layer, by clouds, by air pollution, and by glass; on the other hand, UV-B rays are the main cause of sunburn in humans. The longer-wavelength UV-A radiation penetrates more deeply into the skin and so may have greater destructive potential.^1,3

The daily UV index

The daily UV index of the US National Weather Service and the US Environmental Protection Agency (EPA) (www.epa.gov/sunwise/uvindex.html) offers a direct measurement of the level of UV radiation on a scale of 1 (low) to 11+ (extremely high). The higher the number, the greater the risk of sunburn for a fair-skinned person, even after allowing for cloud cover.

UV EXPOSURE RISKS ARE WELL KNOWN

The American Cancer Society has estimated that the annual incidence of nonmelanoma skin cancer is greater than 2 million, and the incidence of melanoma is from 65,000 to 70,000.⁴ The incidence of all types of skin cancer has been increasing for the last 30 years.^4,5

Exposure to UV radiation is the major environmental risk factor for nonmelanoma skin cancer.⁶ It is also believed to be a major risk factor for melanoma; although definitive evidence is still lacking, research is beginning to uncover mechanisms linking UV-related gene damage to melanoma.⁷

UV LIGHT’S EFFECTS ON THE SKIN

The effects of UV light on the skin can be immediate (eg, erythema) and long-term (eg, photoaging, immunosuppression, carcinogenicity).¹

Sunburn

Excessive UV damage creates a biochemical milieu that manifests grossly on the skin as a “sunburn.” Excessive UV exposure is damaging regardless of whether a sunburn occurs. Intensive intermittent UV exposure in childhood and teen years leading to blistering sunburn is a risk factor for basal cell carcinoma and malignant melanoma, whereas excessive chronic cumulative exposure is a risk factor for squamous cell carcinoma. In addition, both types of exposure can lead to photoaging.

Sunburn is noticeable 3 to 4 hours after exposure, peaking at around 24 hours.

Photoaging

A long-term effect of UV exposure is photoaging. Although how photoaging occurs is unclear, studies suggest that UV-A contributes more to photoaging, while UV-B contributes to burning, which results in extracellular matrix degradation and dysregulation of collagen metabolism. These changes in matrix and collagen may cause wrinkles and loss of skin turgor; increases in vascular growth factors may induce telangiectasia. All of these effects are characteristic of photoaging.^8,9

Immunosuppression, sun exposure, cancer

Profound systemic immunosuppression, such as in organ transplantation patients, can lead to an increased risk of skin cancer, as evidenced by the frequent development of nonmelanoma skin cancers in patients who have undergone organ transplantation, with reported incidence rates of 21% to 50%.^6,10

But sun exposure itself can also cause both local and systemic immunosuppression depending on the area of exposure and the dosage of UV radiation. The immunosuppressive and carcinogenic effects of UV light on the skin are complex, involving a variety of cell types, including antigen-presenting cells, lymphocytes, and cytokines. UV radiation can cause dysregulation of antigen-presenting cells such as Langerhans cells and dermal dendritic cells, which in turn can activate regulatory T cells to suppress the immune system. UV radiation can also induce keratinocytes to produce immunosuppressive cytokines that inhibit the production of a number of “repair cytokines” that fix UV-induced DNA damage. The repair cytokines can mitigate UV-induced immunosuppression.^6,11 These effects can suppress the induction of local, systemic, and memory immunity.

Both UV-A and UV-B interact to enhance UV-induced immunosuppression, and this can occur even at doses that do not cause erythema.¹² Profound immunosuppression—whether UV-induced or due to HIV infection or immunosuppressive drugs—can lead to an increased risk of skin cancer, as evidenced by the frequent development of nonmelanoma skin cancers in patients who have undergone organ transplantation, with reported incidence rates of 21% to 50%.^6,10

Animal studies linking UV-B exposure to skin cancer found that UV-B energy is directly absorbed by DNA, resulting in the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone photoproducts in the DNA, which block replication and transcription.⁶ The resulting mutations specifically occur in the tumor suppressor gene p53, and these mutations have been linked to squamous cell carcinoma.^13,14

UV-A light has also been reported to induce cyclobutane dimers, but via an indirect mechanism, since DNA does not directly absorb UV-A. Dimers induced by UV-A light are apparently cleared at a slower rate than those induced by UV-B, suggesting that UV-A may have a greater potential for carcinogenesis.¹⁵ UV-A light can also directly induce carcinogenesis through reactive oxygen species that cause tumorogenic modified bases in the DNA. These modified bases can be misread, leading to decreased DNA integrity.⁶

WHAT IS TANNING?

UV radiation produces darkening of the skin, or tanning. UV exposure results in both immediate and persistent pigment darkening. Immediate pigment darkening, which is visible and transient, occurs within seconds of UV exposure as a result of the formation of reactive oxygen species and photooxidation of preexisting melanin, and it resolves in a couple of hours. Persistent pigment darkening results from photooxidation and redistribution of preexisting melanin, occurring 2 to 24 hours after sun exposure. Neither type of pigment darkening protects the skin, since no new melanin is produced.^16,17

UV-B rays can induce skin erythema, edema, and sunburn, followed by skin desquamation and tanning. Its effects can be seen immediately, but typically the erythema reaches its peak 24 hours later.¹

“Delayed tanning” is an adaptive response seen about 3 days after sun exposure and is caused by increased melanocyte activity and new melanin formation in response to UV-B; this effect is considered mildly photoprotective, with a sun protection factor (SPF) of 3. In other words, there is a tiny bit of truth to the common belief that a tan that develops a few days after sun exposure (delayed tanning) can provide a small increase in protection from sunburn. However, the real health concern is not only sunburn, but increased cancer risk and photoaging from UV exposure.

INDOOR TANNING

Every year, nearly 28 million Americans use a sunbed or a sunlamp, and 2.3 million of them are teenagers.^18,19 Every day in the United States more than 1 million people use an indoor tanning device.²⁰ Nearly 70% of those who use tanning devices are white women ages 16 to 29.²¹

Tanning is big business. In 2010, there were 20,000 tanning salons in the United States, and the number of health clubs and spas with tanning beds was between 15,000 and 20,000. In 2010, the tanning industry generated an estimated $4.7 billion in revenue.²²

In their search for the perfect tan, people receive very large doses of UV light, and most tanning lamps emit 95% to 99% of their light as UV-A. In fact, the typical sunlamp user can receive an annual dose of UV-A that is 0.3 to 1.2 times the average annual cumulative dose received from sun exposure (7,700 kJ/m²).¹¹ A typical customer of a tanning salon in the course of 20 sessions is exposed to up to 1.2 times the average normal annual exposure from sunlight. Also, for a frequent tanner, the exposure can increase to 4.7 times the average normal annual exposure and up to 12 times the exposure if using high-pressure sunlamps.¹¹ Indoor tanners not only receive large doses of a known carcinogen, but the body’s pigmentary responses to a sunlamp’s UV-A (immediate and persistent pigment darkening) do not protect it from sunburn, cancer-inducing DNA damage, immunosuppression, or photoaging.

Additionally, even though tanning bed lamps only emit 1% to 5% of their light in the UV-B spectrum, one can still receive a very large dose of UV-B radiation with enough exposure.

The American Academy of Dermatology opposes indoor tanning and supports a ban on the nonmedical production and sale of indoor tanning devices. The World Health Organization classifies tanning lamps as carcinogenic and advises minors to avoid indoor tanning.²³

SUNSCREEN PROTECTION

Sunscreen products must contain an active sunscreen ingredient that absorbs radiation in the range of 290 to 400 nm. In “physical” sunscreens, the ingredient is an inorganic compound with particles that physically block out UV radiation; in “chemical” sunscreens, the ingredient is an organic compound that absorbs UV radiation.

Most organic UV filters absorb UV-B radiation, and a few act in the UV-A2 range (320–340 nm). Only one FDA-approved organic sunscreen, avobenzone, protects against UV-A1 (340–400 nm).

Inorganic compounds function by physically reflecting and scattering UV radiation from a film of inert metal particles, ie, in a manner similar to protective clothing.²⁴ Two FDA-approved inorganic sunscreens—titanium dioxide and zinc oxide—provide UV-A and UV-B protection. Zinc oxide and the non-micronized form of titanium dioxide provide UV-A1 and UV-A2 protection.

Inorganic sunscreens have a thick consistency and tend to clump. Advances in nanoparticle technology have improved their consistency,²⁵ but micronized titanium dioxide does not provide UV-A1 protection.

The FDA regulates the active ingredients in sunscreen products, determines the methods of testing them, and dictates labelling requirements.

CATEGORIES OF SUNSCREENS

Sunscreens are categorized according to their SPF,²⁶ UV-A protection,^27,28 substantivity, and stability.²⁹

Understanding the ‘sun protection factor’

SPF is a laboratory measure of sunscreen efficacy and is defined as the amount of UV radiation required to produce a sunburn on protected skin relative to that of unprotected skin. Since SPF assessment is based on erythema, it is mainly a measure of UV-B exposure, not UV-A exposure.

Contrary to popular belief, the SPF of a product is not related to the duration of UV exposure.³⁰ Also, the relationship between SPF and UV-B protection is not linear: a sunscreen with an SPF of 15 can filter 94% of UV-B radiation, whereas an SPF of 30 provides greater than 97% protection at an equal UV-B dosage. UV radiation dosage depends on both the duration of exposure and the intensity of the UV radiation. Thus, a sunscreen with twice the SPF does not necessarily mean one can stay out in the sun twice as long before developing a sunburn.

Ability to block UV-A radiation

As UV-A causes significant immunosuppression and is the major type of UV radiation reaching Earth, a systematic and repeatable method of measuring a sunscreen’s ability to block UV-A light is necessary.

For each sunscreen, laboratory testing generates a curve of the absorbance within the UV spectrum. The area under this curve is calculated, and a “critical wavelength” is defined as the wavelength where the area under the absorbance curve up to that value is 90% of the total area under the curve. A sunscreen with “broad-spectrum” UV-A protection is one for which the critical wavelength is greater than or equal to 370 nm. The critical wavelength measures the breadth of UV-A absorbance by a sunscreen and must be used in combination with the SPF value to provide a complete assessment of UV protection.^27,28,32,33

Substantivity

Substantivity is a sunscreen’s ability to remain effective under adverse conditions such as exposure to water and sweat. A water-resistant product maintains the indicated protection after 40 minutes of water immersion, whereas a very-water-resistant (formerly called “waterproof”) product maintains the indicated protection after 80 minutes of water immersion.^27,28,32,33

Stability

The stability of the sunscreen is important for long-lasting protection with continuous exposure to UV light, in particular to prevent photodegradation. The FDA has established maximum levels of each filter allowed in the sunscreen. Several filters can be combined to achieve a high SPF level, to provide broadspectrum UV-A and UV-B protection, and to prevent photodegradation. For example, octocrylene prevents the degradation of the photosensitive compound avobenzone, whereas ecamsule has been combined with avobenzone and octocrylene to provide broad-spectrum UV-A and UV-B protection. Ecamsule is currently patent-protected by L’Oreal and is found only in products produced by it and its subsidiaries.

SUNSCREEN USES AND ABUSES

Sunscreen use generally falls into three categories: daily use, short-term use (eg, for an activity involving increased sun exposure, such as outdoor exercise or work), and use for preventing sunburn during tan acquisition, ie, to increase the time of UV radiation exposure.

Most published studies report on the effects of daily sunscreen protection or on cutaneous immune responses to sunscreen use. However, the use of sunscreens to enhance tan acquisition and to increase sun exposure duration is an abuse of the product and can actually increase the risk of skin cancer. A common misperception is that sunscreens decrease the risk of burning and allow people to increase their exposure to UV radiation. This results in increased exposure to UV-A and thus increases the risk of skin cancers and facilitates photoaging.³⁴

In 2003, Baron et al³⁵ published a randomized trial evaluating the protective effects of UV-B sunscreens (SPF 15) and UV-A/UV-B sunscreens (SPF 15) against UV radiation, using contact hypersensitivity as a model for immunosuppression. The study involved 211 volunteers ages 18 to 59. Measuring skinfold thickness vs total UV dose to calculate an immune protection factor, they reported that the UV-A/UV-B sunscreens had a greater average immune protection factor than the UV-B sunscreen. They concluded that though both types of sunscreen can protect against immunosuppression, the addition of a UV-A filter provides greater protection against immunosuppression.³⁵

A French study³⁶ in 104 volunteers examined the immunoprotective effects of sunscreens with equal SPF but differing levels of UV-A protection after UV exposure, and used delayed-type hypersensitivity as a model for cutaneous immune response. Broader UV-A protection yielded smaller reductions in delayed-type hypersensitivity after UV exposure, leading to the conclusion that UV-A contributes greatly to cutaneous immunosuppression and that UV-A filters can mitigate some of these effects.³⁶

Sunscreens and photoaging

Only a few clinical studies have examined the effects of sunscreen use on photoaging.

In 1995, a randomized, double-blind, placebo-controlled trial involving 53 adults with previously diagnosed with actinic keratosis or skin cancer, or both, showed that those who applied a UV-A/UV-B sunscreen over a 24-month period had less solar elastosis on biopsy compared with controls.³⁷

In 2008, a French study of 12 volunteers showed that broad-spectrum UV protection prevented histologic changes attributed to 6 weeks of chronic UV exposure. The control group exhibited structural and molecular evidence of UV damage (eg, epidermal thickening, decreased procollagen expression, higher lysozyme-to-elastin ratio), whereas chronic use of a broad-spectrum sunscreen either minimized or abrogated these findings.¹²

Evidence also suggests that broad-spectrum sunscreens can prevent damage from suberythemal doses of UV. A study published in 2007³⁸ investigated whether broad-spectrum sunscreen use affects the development of genetic and cellular markers of UV damage after daily suberythemal UV exposure. It reported that unprotected individuals exhibited more thymine dimers, higher p53 expression, and loss of Langerhans cells compared with protected individuals.³⁸

Similarly, a study published in 2010¹² assessed cellular and molecular markers of photodamage after 19 daily suberythemal UV exposures with or without a broad-spectrum, low-SPF (SPF 8) sunscreen and found that consistent sunscreen use resulted in fewer p53-positive cells, a lower lysozyme-to-elastin ratio, a decreased number and size of melanocytes, and an increased number of Langerhans cells.

Thus, evidence supports the idea that consistent use of a broad-spectrum sunscreen can protect against photodamage, even at doses that do not cause erythema.¹²

Sunscreens and squamous cell carcinoma

Several large trials provide appreciable evidence that sunscreen is effective in preventing squamous cell carcinoma.

A randomized, controlled, 7-month trial in Australia of a broad-spectrum sunscreen with an SPF of 17 noted a dose-dependent reduction in the development of new actinic keratosis.³⁹ Another randomized, controlled trial from Australia showed a 40% reduction in the development of squamous cell carcinoma over a 4.5-year period in participants who applied a broad-spectrum SPF-16 sunscreen 3 to 4 days per week vs discretionary use.⁴⁰ Follow-up data at 8 years showed that daily sunscreen users continued to have a 40% lower incidence rate of squamous cell carcinoma than controls.⁴¹

Sunscreens and basal cell carcinoma

Although sunscreens appear to be effective in preventing actinic keratosis and squamous cell carcinoma, the evidence that they also prevent basal cell carcinoma and melanoma has been inconclusive.

Sunscreens and melanoma

Using a high number of nevi as a surrogate measure of the risk of developing melanoma, a randomized controlled trial of a broad-spectrum SPF-30 sunscreen in Canadian children over a 3-year period showed a slight decrease in the number of new nevi compared with controls. However, this effect was seen only in children with freckles.⁴²

In a large European study of white school-age children, sunscreen use was associated with an increased number of nevi compared with the use of clothing, which prevented new nevi.⁴³

A large meta-analysis of 18 case-controlled studies failed to show a protective association of sunscreen use with melanoma.⁴⁴ Postulated confounding factors in earlier studies included older sunscreen formulations with no UV-A protection, low SPF, and limited substantivity. In many cases, sunscreen users exposed themselves to higher doses of UV because of the perceived decreased risk of burning with sunscreen use. This is especially the case when sun exposure was intentional to acquire a tan.³⁴ Individuals who burn easily or may have had a family history of melanoma tended to use more sunscreen, thus creating another confounder. Finally, extrapolation of results from data performed in different geographic latitudes may not be appropriate.

Recently, Green et al⁴⁵ published a study using the same cohort from a previous study of sunscreens and nonmelanoma skin cancer to examine new primary melanomas as a secondary outcome. They reported that, during the 5-year trial period and during the 10-year follow-up, fewer participants in the intervention group developed primary melanoma compared with the control group (11 vs 21). They concluded that regular applications of a broad-spectrum SPF-16 sunscreen in white adults ages 25 to 75 can decrease the incidence of melanoma.⁴⁵ The study had serious limitations: the authors admitted that the results were marginally statistically significant; intervention sites of sunscreen application were chosen for nonmelanoma skin cancer and excluded the trunk and lower extremities, where melanomas often occur; and the entire body was analyzed for melanomas, not just the intervention site.⁴⁶ Thus, despite providing some of the first evidence supporting sunscreen’s ability to prevent melanoma, these results are controversial and are by no means conclusive.

HOW TO USE SUNSCREEN

The American Academy of Dermatology guidelines⁴⁷ recommend daily, year-round use of a broad-spectrum, water-resistant sunscreen with an SPF of at least 30, regardless of age or skin type. Cloud cover and windows block UV-B but not UV-A. Additionally, 80% of UV light can pass through cloud cover, while 25% is reflected by sand and 80% by snow. Thus, sunscreen should be used daily throughout the year.

Sunscreen should be applied to exposed dry skin 15 to 30 minutes before sun exposure, paying particular attention to common areas of nonmelanoma skin cancer, such as the face, ears, hands, arms, and lips. The standard amount of sunscreen used in SPF testing is 2 mg/cm², which is difficult to translate into real use; most people apply only 25% to 50% of the recommended amount of sunscreen.⁴⁸ According to the guidelines, 1 oz of sunscreen—2 tablespoons, or enough to fill a shot glass—is enough to cover sun-exposed parts of the adult body. Sunscreen should be reapplied every 2 hours or after swimming or heavy perspiration; many water-resistant sunscreens lose effectiveness after 40 minutes in the water.

Despite the protective effects of sunscreen, the following are still recommended:

• Seek shade or avoid exposure between 10:00 am and 4:00 pm, ie, when the sun’s rays are strongest
• Take caution around water, sand, and snow, which reflect UV radiation
• Wear protective clothing such as long-sleeved shirts, pants, sunglasses, and wide-brimmed hats
• Do not use tanning beds
• Do not use sunscreens to increase the time of UV exposure.

SPECIAL CONSIDERATIONS: INFANTS

Infants and toddlers are at higher risk of UV damage and skin cancer. Structurally, children’s skin is thinner than that of adults and has lower melanin concentrations. Thus, UV penetrates more deeply into skin that is less able to absorb UV radiation. Animal studies suggest that the skin of children, especially infants, is immunologically immature and less able to respond to UV damage than adult skin. Therefore, extra care must be taken to protect children from UV exposure.⁴⁹

The American Academy of Pediatrics recommends that infants under 6 months of age should be kept out of direct sunlight whenever possible. A broad-spectrum, water-resistant sunscreen with an SPF of at least 30 should be applied to skin that is not protected by clothing or shade (eg, face, hands, neck).⁵⁰

NEW FDA GUIDELINES AND OTHER PROPOSED CHANGES

The FDA’s SPF labeling requirements remained unchanged; however, the FDA instituted new regulations regarding UV-A protection. Sunscreens that qualify as broad-spectrum are to be labeled as such, indicating that they protect against radiation in the entire UV spectrum. Products that are “broad-spectrum SPF ≥ 15” can now include the following statement in the “drug facts” part of the label: “If used as directed with other sun protection measures, decreases the risk of skin cancer and early skin aging caused by the sun.”

The FDA now requires sunscreens that are not broad-spectrum or that have an SPF less than 15 to include the following alert: “Spending time in the sun increases your risk of skin cancer and early skin aging.”³³ These products can only claim protection from sunburn with the statement: “This product has been shown only to prevent sunburn, not skin cancer or early skin aging.”^27,28,32,33

In terms of water resistance, the FDA now bans the terms “sunblock,” “waterproof,” or “sweatproof,” as these claims cannot be substantiated. Instead, the label on the front of the package can only read either “water resistant (40 minutes)” or “water resistant (80 minutes).” Also, sunscreens may no longer claim to provide “instant protection,” nor can they claim to maintain efficacy for more than 2 hours without reapplication.^27,28,32,33

Some sunscreen products have been labeled with SPF values exceeding 100. The FDA decided that because there is insufficient evidence of clinical benefit for such SPFs, sunscreen product labels may claim a maximum SPF value of “50+.”^28,52

The FDA now also specifies approved formulations for sunscreen products. Oils, lotions, creams, gels, butters, pastes, and ointments are acceptable, and this applies to all products that contain sunscreens, including cosmetics. Wipes, towelettes, powders, body washes, and shampoos are not acceptable as sunscreen products. The FDA now considers the popular spray form as potentially acceptable; a final decision awaits the results of further testing.^28,53

Editor’s note: As this paper was being sent to press, the US Food and Drug Administration announced that sunscreen manufacturers would have an additional 6 months to comply with the new labeling rules for sunscreens. The new deadline is December 2012. Smaller companies have until December 2013 to implement the labeling changes.

Everyone should avoid overexposure to the sun’s rays. But the desire for the “perfect tan,” the belief that a tan enables one to spend more time in the sun, and a lack of awareness about the dangers of ultraviolet (UV) radiation are factors that contribute to UV-induced skin damage and to an increased risk of skin cancer. Physicians need to be prepared to counsel patients on why and how to avoid damaging UV radiation.

See the patient education handout

Some measures are straightforward, such as wearing protective clothing, limiting sun exposure during the peak daylight hours, and avoiding tanning booths. The issue of which sunscreen to use can be more difficult, given the quantity of sunscreen products and the confusing claims made on product labels.

In this article, we review UV radiation, the consequences of increased exposure to different parts of the UV spectrum, tanning, and the fundamentals of sunscreens. We also briefly review current guidelines from professional organizations and rulings on sunscreen products by the US Food and Drug Administration (FDA).

FACTORS AFFECTING UV EXPOSURE

UV radiation from the sun is strongest between 10:00 am and 4:00 pm at equatorial latitudes and during summer months.¹ Certain wavelengths of UV radiation have long been known to contribute to skin cancer in humans: the wavelengths considered most damaging are those from 320 to 400 nm, referred to as UV-A, and from 290 to 320 nm, referred to as UV-B.^1,2 The UV spectrum also includes UV-C and other subdivisions, but in this article we are mainly concerned with UV-A and UV-B. From 90% to 95% of UV radiation that reaches the earth’s surface is UV-A, and most of the rest is UV-B.

The different wavelengths of UV-A and UV-B have different effects on the skin. Much of the shorter-wavelength UV-B radiation is scattered by the atmospheric ozone layer, by clouds, by air pollution, and by glass; on the other hand, UV-B rays are the main cause of sunburn in humans. The longer-wavelength UV-A radiation penetrates more deeply into the skin and so may have greater destructive potential.^1,3

The daily UV index

The daily UV index of the US National Weather Service and the US Environmental Protection Agency (EPA) (www.epa.gov/sunwise/uvindex.html) offers a direct measurement of the level of UV radiation on a scale of 1 (low) to 11+ (extremely high). The higher the number, the greater the risk of sunburn for a fair-skinned person, even after allowing for cloud cover.

UV EXPOSURE RISKS ARE WELL KNOWN

The American Cancer Society has estimated that the annual incidence of nonmelanoma skin cancer is greater than 2 million, and the incidence of melanoma is from 65,000 to 70,000.⁴ The incidence of all types of skin cancer has been increasing for the last 30 years.^4,5

Exposure to UV radiation is the major environmental risk factor for nonmelanoma skin cancer.⁶ It is also believed to be a major risk factor for melanoma; although definitive evidence is still lacking, research is beginning to uncover mechanisms linking UV-related gene damage to melanoma.⁷

UV LIGHT’S EFFECTS ON THE SKIN

The effects of UV light on the skin can be immediate (eg, erythema) and long-term (eg, photoaging, immunosuppression, carcinogenicity).¹

Sunburn

Excessive UV damage creates a biochemical milieu that manifests grossly on the skin as a “sunburn.” Excessive UV exposure is damaging regardless of whether a sunburn occurs. Intensive intermittent UV exposure in childhood and teen years leading to blistering sunburn is a risk factor for basal cell carcinoma and malignant melanoma, whereas excessive chronic cumulative exposure is a risk factor for squamous cell carcinoma. In addition, both types of exposure can lead to photoaging.

Sunburn is noticeable 3 to 4 hours after exposure, peaking at around 24 hours.

Photoaging

A long-term effect of UV exposure is photoaging. Although how photoaging occurs is unclear, studies suggest that UV-A contributes more to photoaging, while UV-B contributes to burning, which results in extracellular matrix degradation and dysregulation of collagen metabolism. These changes in matrix and collagen may cause wrinkles and loss of skin turgor; increases in vascular growth factors may induce telangiectasia. All of these effects are characteristic of photoaging.^8,9

Immunosuppression, sun exposure, cancer

Profound systemic immunosuppression, such as in organ transplantation patients, can lead to an increased risk of skin cancer, as evidenced by the frequent development of nonmelanoma skin cancers in patients who have undergone organ transplantation, with reported incidence rates of 21% to 50%.^6,10

But sun exposure itself can also cause both local and systemic immunosuppression depending on the area of exposure and the dosage of UV radiation. The immunosuppressive and carcinogenic effects of UV light on the skin are complex, involving a variety of cell types, including antigen-presenting cells, lymphocytes, and cytokines. UV radiation can cause dysregulation of antigen-presenting cells such as Langerhans cells and dermal dendritic cells, which in turn can activate regulatory T cells to suppress the immune system. UV radiation can also induce keratinocytes to produce immunosuppressive cytokines that inhibit the production of a number of “repair cytokines” that fix UV-induced DNA damage. The repair cytokines can mitigate UV-induced immunosuppression.^6,11 These effects can suppress the induction of local, systemic, and memory immunity.

Both UV-A and UV-B interact to enhance UV-induced immunosuppression, and this can occur even at doses that do not cause erythema.¹² Profound immunosuppression—whether UV-induced or due to HIV infection or immunosuppressive drugs—can lead to an increased risk of skin cancer, as evidenced by the frequent development of nonmelanoma skin cancers in patients who have undergone organ transplantation, with reported incidence rates of 21% to 50%.^6,10

Animal studies linking UV-B exposure to skin cancer found that UV-B energy is directly absorbed by DNA, resulting in the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone photoproducts in the DNA, which block replication and transcription.⁶ The resulting mutations specifically occur in the tumor suppressor gene p53, and these mutations have been linked to squamous cell carcinoma.^13,14

UV-A light has also been reported to induce cyclobutane dimers, but via an indirect mechanism, since DNA does not directly absorb UV-A. Dimers induced by UV-A light are apparently cleared at a slower rate than those induced by UV-B, suggesting that UV-A may have a greater potential for carcinogenesis.¹⁵ UV-A light can also directly induce carcinogenesis through reactive oxygen species that cause tumorogenic modified bases in the DNA. These modified bases can be misread, leading to decreased DNA integrity.⁶

WHAT IS TANNING?

UV radiation produces darkening of the skin, or tanning. UV exposure results in both immediate and persistent pigment darkening. Immediate pigment darkening, which is visible and transient, occurs within seconds of UV exposure as a result of the formation of reactive oxygen species and photooxidation of preexisting melanin, and it resolves in a couple of hours. Persistent pigment darkening results from photooxidation and redistribution of preexisting melanin, occurring 2 to 24 hours after sun exposure. Neither type of pigment darkening protects the skin, since no new melanin is produced.^16,17

UV-B rays can induce skin erythema, edema, and sunburn, followed by skin desquamation and tanning. Its effects can be seen immediately, but typically the erythema reaches its peak 24 hours later.¹

“Delayed tanning” is an adaptive response seen about 3 days after sun exposure and is caused by increased melanocyte activity and new melanin formation in response to UV-B; this effect is considered mildly photoprotective, with a sun protection factor (SPF) of 3. In other words, there is a tiny bit of truth to the common belief that a tan that develops a few days after sun exposure (delayed tanning) can provide a small increase in protection from sunburn. However, the real health concern is not only sunburn, but increased cancer risk and photoaging from UV exposure.

INDOOR TANNING

Every year, nearly 28 million Americans use a sunbed or a sunlamp, and 2.3 million of them are teenagers.^18,19 Every day in the United States more than 1 million people use an indoor tanning device.²⁰ Nearly 70% of those who use tanning devices are white women ages 16 to 29.²¹

Tanning is big business. In 2010, there were 20,000 tanning salons in the United States, and the number of health clubs and spas with tanning beds was between 15,000 and 20,000. In 2010, the tanning industry generated an estimated $4.7 billion in revenue.²²

In their search for the perfect tan, people receive very large doses of UV light, and most tanning lamps emit 95% to 99% of their light as UV-A. In fact, the typical sunlamp user can receive an annual dose of UV-A that is 0.3 to 1.2 times the average annual cumulative dose received from sun exposure (7,700 kJ/m²).¹¹ A typical customer of a tanning salon in the course of 20 sessions is exposed to up to 1.2 times the average normal annual exposure from sunlight. Also, for a frequent tanner, the exposure can increase to 4.7 times the average normal annual exposure and up to 12 times the exposure if using high-pressure sunlamps.¹¹ Indoor tanners not only receive large doses of a known carcinogen, but the body’s pigmentary responses to a sunlamp’s UV-A (immediate and persistent pigment darkening) do not protect it from sunburn, cancer-inducing DNA damage, immunosuppression, or photoaging.

Additionally, even though tanning bed lamps only emit 1% to 5% of their light in the UV-B spectrum, one can still receive a very large dose of UV-B radiation with enough exposure.

The American Academy of Dermatology opposes indoor tanning and supports a ban on the nonmedical production and sale of indoor tanning devices. The World Health Organization classifies tanning lamps as carcinogenic and advises minors to avoid indoor tanning.²³

SUNSCREEN PROTECTION

Sunscreen products must contain an active sunscreen ingredient that absorbs radiation in the range of 290 to 400 nm. In “physical” sunscreens, the ingredient is an inorganic compound with particles that physically block out UV radiation; in “chemical” sunscreens, the ingredient is an organic compound that absorbs UV radiation.

Most organic UV filters absorb UV-B radiation, and a few act in the UV-A2 range (320–340 nm). Only one FDA-approved organic sunscreen, avobenzone, protects against UV-A1 (340–400 nm).

Inorganic compounds function by physically reflecting and scattering UV radiation from a film of inert metal particles, ie, in a manner similar to protective clothing.²⁴ Two FDA-approved inorganic sunscreens—titanium dioxide and zinc oxide—provide UV-A and UV-B protection. Zinc oxide and the non-micronized form of titanium dioxide provide UV-A1 and UV-A2 protection.

Inorganic sunscreens have a thick consistency and tend to clump. Advances in nanoparticle technology have improved their consistency,²⁵ but micronized titanium dioxide does not provide UV-A1 protection.

The FDA regulates the active ingredients in sunscreen products, determines the methods of testing them, and dictates labelling requirements.

CATEGORIES OF SUNSCREENS

Sunscreens are categorized according to their SPF,²⁶ UV-A protection,^27,28 substantivity, and stability.²⁹

Understanding the ‘sun protection factor’

SPF is a laboratory measure of sunscreen efficacy and is defined as the amount of UV radiation required to produce a sunburn on protected skin relative to that of unprotected skin. Since SPF assessment is based on erythema, it is mainly a measure of UV-B exposure, not UV-A exposure.

Contrary to popular belief, the SPF of a product is not related to the duration of UV exposure.³⁰ Also, the relationship between SPF and UV-B protection is not linear: a sunscreen with an SPF of 15 can filter 94% of UV-B radiation, whereas an SPF of 30 provides greater than 97% protection at an equal UV-B dosage. UV radiation dosage depends on both the duration of exposure and the intensity of the UV radiation. Thus, a sunscreen with twice the SPF does not necessarily mean one can stay out in the sun twice as long before developing a sunburn.

Ability to block UV-A radiation

As UV-A causes significant immunosuppression and is the major type of UV radiation reaching Earth, a systematic and repeatable method of measuring a sunscreen’s ability to block UV-A light is necessary.

For each sunscreen, laboratory testing generates a curve of the absorbance within the UV spectrum. The area under this curve is calculated, and a “critical wavelength” is defined as the wavelength where the area under the absorbance curve up to that value is 90% of the total area under the curve. A sunscreen with “broad-spectrum” UV-A protection is one for which the critical wavelength is greater than or equal to 370 nm. The critical wavelength measures the breadth of UV-A absorbance by a sunscreen and must be used in combination with the SPF value to provide a complete assessment of UV protection.^27,28,32,33

Substantivity

Substantivity is a sunscreen’s ability to remain effective under adverse conditions such as exposure to water and sweat. A water-resistant product maintains the indicated protection after 40 minutes of water immersion, whereas a very-water-resistant (formerly called “waterproof”) product maintains the indicated protection after 80 minutes of water immersion.^27,28,32,33

Stability

The stability of the sunscreen is important for long-lasting protection with continuous exposure to UV light, in particular to prevent photodegradation. The FDA has established maximum levels of each filter allowed in the sunscreen. Several filters can be combined to achieve a high SPF level, to provide broadspectrum UV-A and UV-B protection, and to prevent photodegradation. For example, octocrylene prevents the degradation of the photosensitive compound avobenzone, whereas ecamsule has been combined with avobenzone and octocrylene to provide broad-spectrum UV-A and UV-B protection. Ecamsule is currently patent-protected by L’Oreal and is found only in products produced by it and its subsidiaries.

SUNSCREEN USES AND ABUSES

Sunscreen use generally falls into three categories: daily use, short-term use (eg, for an activity involving increased sun exposure, such as outdoor exercise or work), and use for preventing sunburn during tan acquisition, ie, to increase the time of UV radiation exposure.

Most published studies report on the effects of daily sunscreen protection or on cutaneous immune responses to sunscreen use. However, the use of sunscreens to enhance tan acquisition and to increase sun exposure duration is an abuse of the product and can actually increase the risk of skin cancer. A common misperception is that sunscreens decrease the risk of burning and allow people to increase their exposure to UV radiation. This results in increased exposure to UV-A and thus increases the risk of skin cancers and facilitates photoaging.³⁴

In 2003, Baron et al³⁵ published a randomized trial evaluating the protective effects of UV-B sunscreens (SPF 15) and UV-A/UV-B sunscreens (SPF 15) against UV radiation, using contact hypersensitivity as a model for immunosuppression. The study involved 211 volunteers ages 18 to 59. Measuring skinfold thickness vs total UV dose to calculate an immune protection factor, they reported that the UV-A/UV-B sunscreens had a greater average immune protection factor than the UV-B sunscreen. They concluded that though both types of sunscreen can protect against immunosuppression, the addition of a UV-A filter provides greater protection against immunosuppression.³⁵

A French study³⁶ in 104 volunteers examined the immunoprotective effects of sunscreens with equal SPF but differing levels of UV-A protection after UV exposure, and used delayed-type hypersensitivity as a model for cutaneous immune response. Broader UV-A protection yielded smaller reductions in delayed-type hypersensitivity after UV exposure, leading to the conclusion that UV-A contributes greatly to cutaneous immunosuppression and that UV-A filters can mitigate some of these effects.³⁶

Sunscreens and photoaging

Only a few clinical studies have examined the effects of sunscreen use on photoaging.

In 1995, a randomized, double-blind, placebo-controlled trial involving 53 adults with previously diagnosed with actinic keratosis or skin cancer, or both, showed that those who applied a UV-A/UV-B sunscreen over a 24-month period had less solar elastosis on biopsy compared with controls.³⁷

In 2008, a French study of 12 volunteers showed that broad-spectrum UV protection prevented histologic changes attributed to 6 weeks of chronic UV exposure. The control group exhibited structural and molecular evidence of UV damage (eg, epidermal thickening, decreased procollagen expression, higher lysozyme-to-elastin ratio), whereas chronic use of a broad-spectrum sunscreen either minimized or abrogated these findings.¹²

Evidence also suggests that broad-spectrum sunscreens can prevent damage from suberythemal doses of UV. A study published in 2007³⁸ investigated whether broad-spectrum sunscreen use affects the development of genetic and cellular markers of UV damage after daily suberythemal UV exposure. It reported that unprotected individuals exhibited more thymine dimers, higher p53 expression, and loss of Langerhans cells compared with protected individuals.³⁸

Similarly, a study published in 2010¹² assessed cellular and molecular markers of photodamage after 19 daily suberythemal UV exposures with or without a broad-spectrum, low-SPF (SPF 8) sunscreen and found that consistent sunscreen use resulted in fewer p53-positive cells, a lower lysozyme-to-elastin ratio, a decreased number and size of melanocytes, and an increased number of Langerhans cells.

Thus, evidence supports the idea that consistent use of a broad-spectrum sunscreen can protect against photodamage, even at doses that do not cause erythema.¹²

Sunscreens and squamous cell carcinoma

Several large trials provide appreciable evidence that sunscreen is effective in preventing squamous cell carcinoma.

A randomized, controlled, 7-month trial in Australia of a broad-spectrum sunscreen with an SPF of 17 noted a dose-dependent reduction in the development of new actinic keratosis.³⁹ Another randomized, controlled trial from Australia showed a 40% reduction in the development of squamous cell carcinoma over a 4.5-year period in participants who applied a broad-spectrum SPF-16 sunscreen 3 to 4 days per week vs discretionary use.⁴⁰ Follow-up data at 8 years showed that daily sunscreen users continued to have a 40% lower incidence rate of squamous cell carcinoma than controls.⁴¹

Sunscreens and basal cell carcinoma

Although sunscreens appear to be effective in preventing actinic keratosis and squamous cell carcinoma, the evidence that they also prevent basal cell carcinoma and melanoma has been inconclusive.

Sunscreens and melanoma

Using a high number of nevi as a surrogate measure of the risk of developing melanoma, a randomized controlled trial of a broad-spectrum SPF-30 sunscreen in Canadian children over a 3-year period showed a slight decrease in the number of new nevi compared with controls. However, this effect was seen only in children with freckles.⁴²

In a large European study of white school-age children, sunscreen use was associated with an increased number of nevi compared with the use of clothing, which prevented new nevi.⁴³

A large meta-analysis of 18 case-controlled studies failed to show a protective association of sunscreen use with melanoma.⁴⁴ Postulated confounding factors in earlier studies included older sunscreen formulations with no UV-A protection, low SPF, and limited substantivity. In many cases, sunscreen users exposed themselves to higher doses of UV because of the perceived decreased risk of burning with sunscreen use. This is especially the case when sun exposure was intentional to acquire a tan.³⁴ Individuals who burn easily or may have had a family history of melanoma tended to use more sunscreen, thus creating another confounder. Finally, extrapolation of results from data performed in different geographic latitudes may not be appropriate.

Recently, Green et al⁴⁵ published a study using the same cohort from a previous study of sunscreens and nonmelanoma skin cancer to examine new primary melanomas as a secondary outcome. They reported that, during the 5-year trial period and during the 10-year follow-up, fewer participants in the intervention group developed primary melanoma compared with the control group (11 vs 21). They concluded that regular applications of a broad-spectrum SPF-16 sunscreen in white adults ages 25 to 75 can decrease the incidence of melanoma.⁴⁵ The study had serious limitations: the authors admitted that the results were marginally statistically significant; intervention sites of sunscreen application were chosen for nonmelanoma skin cancer and excluded the trunk and lower extremities, where melanomas often occur; and the entire body was analyzed for melanomas, not just the intervention site.⁴⁶ Thus, despite providing some of the first evidence supporting sunscreen’s ability to prevent melanoma, these results are controversial and are by no means conclusive.

HOW TO USE SUNSCREEN

The American Academy of Dermatology guidelines⁴⁷ recommend daily, year-round use of a broad-spectrum, water-resistant sunscreen with an SPF of at least 30, regardless of age or skin type. Cloud cover and windows block UV-B but not UV-A. Additionally, 80% of UV light can pass through cloud cover, while 25% is reflected by sand and 80% by snow. Thus, sunscreen should be used daily throughout the year.

Sunscreen should be applied to exposed dry skin 15 to 30 minutes before sun exposure, paying particular attention to common areas of nonmelanoma skin cancer, such as the face, ears, hands, arms, and lips. The standard amount of sunscreen used in SPF testing is 2 mg/cm², which is difficult to translate into real use; most people apply only 25% to 50% of the recommended amount of sunscreen.⁴⁸ According to the guidelines, 1 oz of sunscreen—2 tablespoons, or enough to fill a shot glass—is enough to cover sun-exposed parts of the adult body. Sunscreen should be reapplied every 2 hours or after swimming or heavy perspiration; many water-resistant sunscreens lose effectiveness after 40 minutes in the water.

Despite the protective effects of sunscreen, the following are still recommended:

• Seek shade or avoid exposure between 10:00 am and 4:00 pm, ie, when the sun’s rays are strongest
• Take caution around water, sand, and snow, which reflect UV radiation
• Wear protective clothing such as long-sleeved shirts, pants, sunglasses, and wide-brimmed hats
• Do not use tanning beds
• Do not use sunscreens to increase the time of UV exposure.

SPECIAL CONSIDERATIONS: INFANTS

Infants and toddlers are at higher risk of UV damage and skin cancer. Structurally, children’s skin is thinner than that of adults and has lower melanin concentrations. Thus, UV penetrates more deeply into skin that is less able to absorb UV radiation. Animal studies suggest that the skin of children, especially infants, is immunologically immature and less able to respond to UV damage than adult skin. Therefore, extra care must be taken to protect children from UV exposure.⁴⁹

The American Academy of Pediatrics recommends that infants under 6 months of age should be kept out of direct sunlight whenever possible. A broad-spectrum, water-resistant sunscreen with an SPF of at least 30 should be applied to skin that is not protected by clothing or shade (eg, face, hands, neck).⁵⁰

NEW FDA GUIDELINES AND OTHER PROPOSED CHANGES

The FDA’s SPF labeling requirements remained unchanged; however, the FDA instituted new regulations regarding UV-A protection. Sunscreens that qualify as broad-spectrum are to be labeled as such, indicating that they protect against radiation in the entire UV spectrum. Products that are “broad-spectrum SPF ≥ 15” can now include the following statement in the “drug facts” part of the label: “If used as directed with other sun protection measures, decreases the risk of skin cancer and early skin aging caused by the sun.”

The FDA now requires sunscreens that are not broad-spectrum or that have an SPF less than 15 to include the following alert: “Spending time in the sun increases your risk of skin cancer and early skin aging.”³³ These products can only claim protection from sunburn with the statement: “This product has been shown only to prevent sunburn, not skin cancer or early skin aging.”^27,28,32,33

In terms of water resistance, the FDA now bans the terms “sunblock,” “waterproof,” or “sweatproof,” as these claims cannot be substantiated. Instead, the label on the front of the package can only read either “water resistant (40 minutes)” or “water resistant (80 minutes).” Also, sunscreens may no longer claim to provide “instant protection,” nor can they claim to maintain efficacy for more than 2 hours without reapplication.^27,28,32,33

Some sunscreen products have been labeled with SPF values exceeding 100. The FDA decided that because there is insufficient evidence of clinical benefit for such SPFs, sunscreen product labels may claim a maximum SPF value of “50+.”^28,52

The FDA now also specifies approved formulations for sunscreen products. Oils, lotions, creams, gels, butters, pastes, and ointments are acceptable, and this applies to all products that contain sunscreens, including cosmetics. Wipes, towelettes, powders, body washes, and shampoos are not acceptable as sunscreen products. The FDA now considers the popular spray form as potentially acceptable; a final decision awaits the results of further testing.^28,53

Editor’s note: As this paper was being sent to press, the US Food and Drug Administration announced that sunscreen manufacturers would have an additional 6 months to comply with the new labeling rules for sunscreens. The new deadline is December 2012. Smaller companies have until December 2013 to implement the labeling changes.

Everyone should avoid overexposure to the sun’s rays. But the desire for the “perfect tan,” the belief that a tan enables one to spend more time in the sun, and a lack of awareness about the dangers of ultraviolet (UV) radiation are factors that contribute to UV-induced skin damage and to an increased risk of skin cancer. Physicians need to be prepared to counsel patients on why and how to avoid damaging UV radiation.

See the patient education handout

Some measures are straightforward, such as wearing protective clothing, limiting sun exposure during the peak daylight hours, and avoiding tanning booths. The issue of which sunscreen to use can be more difficult, given the quantity of sunscreen products and the confusing claims made on product labels.

In this article, we review UV radiation, the consequences of increased exposure to different parts of the UV spectrum, tanning, and the fundamentals of sunscreens. We also briefly review current guidelines from professional organizations and rulings on sunscreen products by the US Food and Drug Administration (FDA).

FACTORS AFFECTING UV EXPOSURE

UV radiation from the sun is strongest between 10:00 am and 4:00 pm at equatorial latitudes and during summer months.¹ Certain wavelengths of UV radiation have long been known to contribute to skin cancer in humans: the wavelengths considered most damaging are those from 320 to 400 nm, referred to as UV-A, and from 290 to 320 nm, referred to as UV-B.^1,2 The UV spectrum also includes UV-C and other subdivisions, but in this article we are mainly concerned with UV-A and UV-B. From 90% to 95% of UV radiation that reaches the earth’s surface is UV-A, and most of the rest is UV-B.

The different wavelengths of UV-A and UV-B have different effects on the skin. Much of the shorter-wavelength UV-B radiation is scattered by the atmospheric ozone layer, by clouds, by air pollution, and by glass; on the other hand, UV-B rays are the main cause of sunburn in humans. The longer-wavelength UV-A radiation penetrates more deeply into the skin and so may have greater destructive potential.^1,3

The daily UV index

The daily UV index of the US National Weather Service and the US Environmental Protection Agency (EPA) (www.epa.gov/sunwise/uvindex.html) offers a direct measurement of the level of UV radiation on a scale of 1 (low) to 11+ (extremely high). The higher the number, the greater the risk of sunburn for a fair-skinned person, even after allowing for cloud cover.

UV EXPOSURE RISKS ARE WELL KNOWN

The American Cancer Society has estimated that the annual incidence of nonmelanoma skin cancer is greater than 2 million, and the incidence of melanoma is from 65,000 to 70,000.⁴ The incidence of all types of skin cancer has been increasing for the last 30 years.^4,5

Exposure to UV radiation is the major environmental risk factor for nonmelanoma skin cancer.⁶ It is also believed to be a major risk factor for melanoma; although definitive evidence is still lacking, research is beginning to uncover mechanisms linking UV-related gene damage to melanoma.⁷

UV LIGHT’S EFFECTS ON THE SKIN

The effects of UV light on the skin can be immediate (eg, erythema) and long-term (eg, photoaging, immunosuppression, carcinogenicity).¹

Sunburn

Excessive UV damage creates a biochemical milieu that manifests grossly on the skin as a “sunburn.” Excessive UV exposure is damaging regardless of whether a sunburn occurs. Intensive intermittent UV exposure in childhood and teen years leading to blistering sunburn is a risk factor for basal cell carcinoma and malignant melanoma, whereas excessive chronic cumulative exposure is a risk factor for squamous cell carcinoma. In addition, both types of exposure can lead to photoaging.

Sunburn is noticeable 3 to 4 hours after exposure, peaking at around 24 hours.

Photoaging

A long-term effect of UV exposure is photoaging. Although how photoaging occurs is unclear, studies suggest that UV-A contributes more to photoaging, while UV-B contributes to burning, which results in extracellular matrix degradation and dysregulation of collagen metabolism. These changes in matrix and collagen may cause wrinkles and loss of skin turgor; increases in vascular growth factors may induce telangiectasia. All of these effects are characteristic of photoaging.^8,9

Immunosuppression, sun exposure, cancer

Profound systemic immunosuppression, such as in organ transplantation patients, can lead to an increased risk of skin cancer, as evidenced by the frequent development of nonmelanoma skin cancers in patients who have undergone organ transplantation, with reported incidence rates of 21% to 50%.^6,10

But sun exposure itself can also cause both local and systemic immunosuppression depending on the area of exposure and the dosage of UV radiation. The immunosuppressive and carcinogenic effects of UV light on the skin are complex, involving a variety of cell types, including antigen-presenting cells, lymphocytes, and cytokines. UV radiation can cause dysregulation of antigen-presenting cells such as Langerhans cells and dermal dendritic cells, which in turn can activate regulatory T cells to suppress the immune system. UV radiation can also induce keratinocytes to produce immunosuppressive cytokines that inhibit the production of a number of “repair cytokines” that fix UV-induced DNA damage. The repair cytokines can mitigate UV-induced immunosuppression.^6,11 These effects can suppress the induction of local, systemic, and memory immunity.

Both UV-A and UV-B interact to enhance UV-induced immunosuppression, and this can occur even at doses that do not cause erythema.¹² Profound immunosuppression—whether UV-induced or due to HIV infection or immunosuppressive drugs—can lead to an increased risk of skin cancer, as evidenced by the frequent development of nonmelanoma skin cancers in patients who have undergone organ transplantation, with reported incidence rates of 21% to 50%.^6,10

Animal studies linking UV-B exposure to skin cancer found that UV-B energy is directly absorbed by DNA, resulting in the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone photoproducts in the DNA, which block replication and transcription.⁶ The resulting mutations specifically occur in the tumor suppressor gene p53, and these mutations have been linked to squamous cell carcinoma.^13,14

UV-A light has also been reported to induce cyclobutane dimers, but via an indirect mechanism, since DNA does not directly absorb UV-A. Dimers induced by UV-A light are apparently cleared at a slower rate than those induced by UV-B, suggesting that UV-A may have a greater potential for carcinogenesis.¹⁵ UV-A light can also directly induce carcinogenesis through reactive oxygen species that cause tumorogenic modified bases in the DNA. These modified bases can be misread, leading to decreased DNA integrity.⁶

WHAT IS TANNING?

UV radiation produces darkening of the skin, or tanning. UV exposure results in both immediate and persistent pigment darkening. Immediate pigment darkening, which is visible and transient, occurs within seconds of UV exposure as a result of the formation of reactive oxygen species and photooxidation of preexisting melanin, and it resolves in a couple of hours. Persistent pigment darkening results from photooxidation and redistribution of preexisting melanin, occurring 2 to 24 hours after sun exposure. Neither type of pigment darkening protects the skin, since no new melanin is produced.^16,17

UV-B rays can induce skin erythema, edema, and sunburn, followed by skin desquamation and tanning. Its effects can be seen immediately, but typically the erythema reaches its peak 24 hours later.¹

“Delayed tanning” is an adaptive response seen about 3 days after sun exposure and is caused by increased melanocyte activity and new melanin formation in response to UV-B; this effect is considered mildly photoprotective, with a sun protection factor (SPF) of 3. In other words, there is a tiny bit of truth to the common belief that a tan that develops a few days after sun exposure (delayed tanning) can provide a small increase in protection from sunburn. However, the real health concern is not only sunburn, but increased cancer risk and photoaging from UV exposure.

INDOOR TANNING

Every year, nearly 28 million Americans use a sunbed or a sunlamp, and 2.3 million of them are teenagers.^18,19 Every day in the United States more than 1 million people use an indoor tanning device.²⁰ Nearly 70% of those who use tanning devices are white women ages 16 to 29.²¹

Tanning is big business. In 2010, there were 20,000 tanning salons in the United States, and the number of health clubs and spas with tanning beds was between 15,000 and 20,000. In 2010, the tanning industry generated an estimated $4.7 billion in revenue.²²

In their search for the perfect tan, people receive very large doses of UV light, and most tanning lamps emit 95% to 99% of their light as UV-A. In fact, the typical sunlamp user can receive an annual dose of UV-A that is 0.3 to 1.2 times the average annual cumulative dose received from sun exposure (7,700 kJ/m²).¹¹ A typical customer of a tanning salon in the course of 20 sessions is exposed to up to 1.2 times the average normal annual exposure from sunlight. Also, for a frequent tanner, the exposure can increase to 4.7 times the average normal annual exposure and up to 12 times the exposure if using high-pressure sunlamps.¹¹ Indoor tanners not only receive large doses of a known carcinogen, but the body’s pigmentary responses to a sunlamp’s UV-A (immediate and persistent pigment darkening) do not protect it from sunburn, cancer-inducing DNA damage, immunosuppression, or photoaging.

Additionally, even though tanning bed lamps only emit 1% to 5% of their light in the UV-B spectrum, one can still receive a very large dose of UV-B radiation with enough exposure.

The American Academy of Dermatology opposes indoor tanning and supports a ban on the nonmedical production and sale of indoor tanning devices. The World Health Organization classifies tanning lamps as carcinogenic and advises minors to avoid indoor tanning.²³

SUNSCREEN PROTECTION

Sunscreen products must contain an active sunscreen ingredient that absorbs radiation in the range of 290 to 400 nm. In “physical” sunscreens, the ingredient is an inorganic compound with particles that physically block out UV radiation; in “chemical” sunscreens, the ingredient is an organic compound that absorbs UV radiation.

Most organic UV filters absorb UV-B radiation, and a few act in the UV-A2 range (320–340 nm). Only one FDA-approved organic sunscreen, avobenzone, protects against UV-A1 (340–400 nm).

Inorganic compounds function by physically reflecting and scattering UV radiation from a film of inert metal particles, ie, in a manner similar to protective clothing.²⁴ Two FDA-approved inorganic sunscreens—titanium dioxide and zinc oxide—provide UV-A and UV-B protection. Zinc oxide and the non-micronized form of titanium dioxide provide UV-A1 and UV-A2 protection.

Inorganic sunscreens have a thick consistency and tend to clump. Advances in nanoparticle technology have improved their consistency,²⁵ but micronized titanium dioxide does not provide UV-A1 protection.

The FDA regulates the active ingredients in sunscreen products, determines the methods of testing them, and dictates labelling requirements.

CATEGORIES OF SUNSCREENS

Sunscreens are categorized according to their SPF,²⁶ UV-A protection,^27,28 substantivity, and stability.²⁹

Understanding the ‘sun protection factor’

SPF is a laboratory measure of sunscreen efficacy and is defined as the amount of UV radiation required to produce a sunburn on protected skin relative to that of unprotected skin. Since SPF assessment is based on erythema, it is mainly a measure of UV-B exposure, not UV-A exposure.

Contrary to popular belief, the SPF of a product is not related to the duration of UV exposure.³⁰ Also, the relationship between SPF and UV-B protection is not linear: a sunscreen with an SPF of 15 can filter 94% of UV-B radiation, whereas an SPF of 30 provides greater than 97% protection at an equal UV-B dosage. UV radiation dosage depends on both the duration of exposure and the intensity of the UV radiation. Thus, a sunscreen with twice the SPF does not necessarily mean one can stay out in the sun twice as long before developing a sunburn.

Ability to block UV-A radiation

As UV-A causes significant immunosuppression and is the major type of UV radiation reaching Earth, a systematic and repeatable method of measuring a sunscreen’s ability to block UV-A light is necessary.

For each sunscreen, laboratory testing generates a curve of the absorbance within the UV spectrum. The area under this curve is calculated, and a “critical wavelength” is defined as the wavelength where the area under the absorbance curve up to that value is 90% of the total area under the curve. A sunscreen with “broad-spectrum” UV-A protection is one for which the critical wavelength is greater than or equal to 370 nm. The critical wavelength measures the breadth of UV-A absorbance by a sunscreen and must be used in combination with the SPF value to provide a complete assessment of UV protection.^27,28,32,33

Substantivity

Substantivity is a sunscreen’s ability to remain effective under adverse conditions such as exposure to water and sweat. A water-resistant product maintains the indicated protection after 40 minutes of water immersion, whereas a very-water-resistant (formerly called “waterproof”) product maintains the indicated protection after 80 minutes of water immersion.^27,28,32,33

Stability

The stability of the sunscreen is important for long-lasting protection with continuous exposure to UV light, in particular to prevent photodegradation. The FDA has established maximum levels of each filter allowed in the sunscreen. Several filters can be combined to achieve a high SPF level, to provide broadspectrum UV-A and UV-B protection, and to prevent photodegradation. For example, octocrylene prevents the degradation of the photosensitive compound avobenzone, whereas ecamsule has been combined with avobenzone and octocrylene to provide broad-spectrum UV-A and UV-B protection. Ecamsule is currently patent-protected by L’Oreal and is found only in products produced by it and its subsidiaries.

SUNSCREEN USES AND ABUSES

Sunscreen use generally falls into three categories: daily use, short-term use (eg, for an activity involving increased sun exposure, such as outdoor exercise or work), and use for preventing sunburn during tan acquisition, ie, to increase the time of UV radiation exposure.

Most published studies report on the effects of daily sunscreen protection or on cutaneous immune responses to sunscreen use. However, the use of sunscreens to enhance tan acquisition and to increase sun exposure duration is an abuse of the product and can actually increase the risk of skin cancer. A common misperception is that sunscreens decrease the risk of burning and allow people to increase their exposure to UV radiation. This results in increased exposure to UV-A and thus increases the risk of skin cancers and facilitates photoaging.³⁴

In 2003, Baron et al³⁵ published a randomized trial evaluating the protective effects of UV-B sunscreens (SPF 15) and UV-A/UV-B sunscreens (SPF 15) against UV radiation, using contact hypersensitivity as a model for immunosuppression. The study involved 211 volunteers ages 18 to 59. Measuring skinfold thickness vs total UV dose to calculate an immune protection factor, they reported that the UV-A/UV-B sunscreens had a greater average immune protection factor than the UV-B sunscreen. They concluded that though both types of sunscreen can protect against immunosuppression, the addition of a UV-A filter provides greater protection against immunosuppression.³⁵

A French study³⁶ in 104 volunteers examined the immunoprotective effects of sunscreens with equal SPF but differing levels of UV-A protection after UV exposure, and used delayed-type hypersensitivity as a model for cutaneous immune response. Broader UV-A protection yielded smaller reductions in delayed-type hypersensitivity after UV exposure, leading to the conclusion that UV-A contributes greatly to cutaneous immunosuppression and that UV-A filters can mitigate some of these effects.³⁶

Sunscreens and photoaging

Only a few clinical studies have examined the effects of sunscreen use on photoaging.

In 1995, a randomized, double-blind, placebo-controlled trial involving 53 adults with previously diagnosed with actinic keratosis or skin cancer, or both, showed that those who applied a UV-A/UV-B sunscreen over a 24-month period had less solar elastosis on biopsy compared with controls.³⁷

In 2008, a French study of 12 volunteers showed that broad-spectrum UV protection prevented histologic changes attributed to 6 weeks of chronic UV exposure. The control group exhibited structural and molecular evidence of UV damage (eg, epidermal thickening, decreased procollagen expression, higher lysozyme-to-elastin ratio), whereas chronic use of a broad-spectrum sunscreen either minimized or abrogated these findings.¹²

Evidence also suggests that broad-spectrum sunscreens can prevent damage from suberythemal doses of UV. A study published in 2007³⁸ investigated whether broad-spectrum sunscreen use affects the development of genetic and cellular markers of UV damage after daily suberythemal UV exposure. It reported that unprotected individuals exhibited more thymine dimers, higher p53 expression, and loss of Langerhans cells compared with protected individuals.³⁸

Similarly, a study published in 2010¹² assessed cellular and molecular markers of photodamage after 19 daily suberythemal UV exposures with or without a broad-spectrum, low-SPF (SPF 8) sunscreen and found that consistent sunscreen use resulted in fewer p53-positive cells, a lower lysozyme-to-elastin ratio, a decreased number and size of melanocytes, and an increased number of Langerhans cells.

Thus, evidence supports the idea that consistent use of a broad-spectrum sunscreen can protect against photodamage, even at doses that do not cause erythema.¹²

Sunscreens and squamous cell carcinoma

Several large trials provide appreciable evidence that sunscreen is effective in preventing squamous cell carcinoma.

A randomized, controlled, 7-month trial in Australia of a broad-spectrum sunscreen with an SPF of 17 noted a dose-dependent reduction in the development of new actinic keratosis.³⁹ Another randomized, controlled trial from Australia showed a 40% reduction in the development of squamous cell carcinoma over a 4.5-year period in participants who applied a broad-spectrum SPF-16 sunscreen 3 to 4 days per week vs discretionary use.⁴⁰ Follow-up data at 8 years showed that daily sunscreen users continued to have a 40% lower incidence rate of squamous cell carcinoma than controls.⁴¹

Sunscreens and basal cell carcinoma

Although sunscreens appear to be effective in preventing actinic keratosis and squamous cell carcinoma, the evidence that they also prevent basal cell carcinoma and melanoma has been inconclusive.

Sunscreens and melanoma

Using a high number of nevi as a surrogate measure of the risk of developing melanoma, a randomized controlled trial of a broad-spectrum SPF-30 sunscreen in Canadian children over a 3-year period showed a slight decrease in the number of new nevi compared with controls. However, this effect was seen only in children with freckles.⁴²

In a large European study of white school-age children, sunscreen use was associated with an increased number of nevi compared with the use of clothing, which prevented new nevi.⁴³

A large meta-analysis of 18 case-controlled studies failed to show a protective association of sunscreen use with melanoma.⁴⁴ Postulated confounding factors in earlier studies included older sunscreen formulations with no UV-A protection, low SPF, and limited substantivity. In many cases, sunscreen users exposed themselves to higher doses of UV because of the perceived decreased risk of burning with sunscreen use. This is especially the case when sun exposure was intentional to acquire a tan.³⁴ Individuals who burn easily or may have had a family history of melanoma tended to use more sunscreen, thus creating another confounder. Finally, extrapolation of results from data performed in different geographic latitudes may not be appropriate.

Recently, Green et al⁴⁵ published a study using the same cohort from a previous study of sunscreens and nonmelanoma skin cancer to examine new primary melanomas as a secondary outcome. They reported that, during the 5-year trial period and during the 10-year follow-up, fewer participants in the intervention group developed primary melanoma compared with the control group (11 vs 21). They concluded that regular applications of a broad-spectrum SPF-16 sunscreen in white adults ages 25 to 75 can decrease the incidence of melanoma.⁴⁵ The study had serious limitations: the authors admitted that the results were marginally statistically significant; intervention sites of sunscreen application were chosen for nonmelanoma skin cancer and excluded the trunk and lower extremities, where melanomas often occur; and the entire body was analyzed for melanomas, not just the intervention site.⁴⁶ Thus, despite providing some of the first evidence supporting sunscreen’s ability to prevent melanoma, these results are controversial and are by no means conclusive.

HOW TO USE SUNSCREEN

The American Academy of Dermatology guidelines⁴⁷ recommend daily, year-round use of a broad-spectrum, water-resistant sunscreen with an SPF of at least 30, regardless of age or skin type. Cloud cover and windows block UV-B but not UV-A. Additionally, 80% of UV light can pass through cloud cover, while 25% is reflected by sand and 80% by snow. Thus, sunscreen should be used daily throughout the year.

Sunscreen should be applied to exposed dry skin 15 to 30 minutes before sun exposure, paying particular attention to common areas of nonmelanoma skin cancer, such as the face, ears, hands, arms, and lips. The standard amount of sunscreen used in SPF testing is 2 mg/cm², which is difficult to translate into real use; most people apply only 25% to 50% of the recommended amount of sunscreen.⁴⁸ According to the guidelines, 1 oz of sunscreen—2 tablespoons, or enough to fill a shot glass—is enough to cover sun-exposed parts of the adult body. Sunscreen should be reapplied every 2 hours or after swimming or heavy perspiration; many water-resistant sunscreens lose effectiveness after 40 minutes in the water.

Despite the protective effects of sunscreen, the following are still recommended:

• Seek shade or avoid exposure between 10:00 am and 4:00 pm, ie, when the sun’s rays are strongest
• Take caution around water, sand, and snow, which reflect UV radiation
• Wear protective clothing such as long-sleeved shirts, pants, sunglasses, and wide-brimmed hats
• Do not use tanning beds
• Do not use sunscreens to increase the time of UV exposure.

SPECIAL CONSIDERATIONS: INFANTS

Infants and toddlers are at higher risk of UV damage and skin cancer. Structurally, children’s skin is thinner than that of adults and has lower melanin concentrations. Thus, UV penetrates more deeply into skin that is less able to absorb UV radiation. Animal studies suggest that the skin of children, especially infants, is immunologically immature and less able to respond to UV damage than adult skin. Therefore, extra care must be taken to protect children from UV exposure.⁴⁹

The American Academy of Pediatrics recommends that infants under 6 months of age should be kept out of direct sunlight whenever possible. A broad-spectrum, water-resistant sunscreen with an SPF of at least 30 should be applied to skin that is not protected by clothing or shade (eg, face, hands, neck).⁵⁰

NEW FDA GUIDELINES AND OTHER PROPOSED CHANGES

The FDA’s SPF labeling requirements remained unchanged; however, the FDA instituted new regulations regarding UV-A protection. Sunscreens that qualify as broad-spectrum are to be labeled as such, indicating that they protect against radiation in the entire UV spectrum. Products that are “broad-spectrum SPF ≥ 15” can now include the following statement in the “drug facts” part of the label: “If used as directed with other sun protection measures, decreases the risk of skin cancer and early skin aging caused by the sun.”

The FDA now requires sunscreens that are not broad-spectrum or that have an SPF less than 15 to include the following alert: “Spending time in the sun increases your risk of skin cancer and early skin aging.”³³ These products can only claim protection from sunburn with the statement: “This product has been shown only to prevent sunburn, not skin cancer or early skin aging.”^27,28,32,33

In terms of water resistance, the FDA now bans the terms “sunblock,” “waterproof,” or “sweatproof,” as these claims cannot be substantiated. Instead, the label on the front of the package can only read either “water resistant (40 minutes)” or “water resistant (80 minutes).” Also, sunscreens may no longer claim to provide “instant protection,” nor can they claim to maintain efficacy for more than 2 hours without reapplication.^27,28,32,33

Some sunscreen products have been labeled with SPF values exceeding 100. The FDA decided that because there is insufficient evidence of clinical benefit for such SPFs, sunscreen product labels may claim a maximum SPF value of “50+.”^28,52

The FDA now also specifies approved formulations for sunscreen products. Oils, lotions, creams, gels, butters, pastes, and ointments are acceptable, and this applies to all products that contain sunscreens, including cosmetics. Wipes, towelettes, powders, body washes, and shampoos are not acceptable as sunscreen products. The FDA now considers the popular spray form as potentially acceptable; a final decision awaits the results of further testing.^28,53

Editor’s note: As this paper was being sent to press, the US Food and Drug Administration announced that sunscreen manufacturers would have an additional 6 months to comply with the new labeling rules for sunscreens. The new deadline is December 2012. Smaller companies have until December 2013 to implement the labeling changes.

• Seek shade or minimize your sun exposure between 10 am and 4 pm, when the sun’s rays are the most intense. Wear protective clothing such as a wide-brimmed hat and long sleeves. Wear UV-blocking sunglasses. Whenever possible, keep children under 6 months old out of direct sunlight.
• 
  Apply sunscreen to minimize UV damage when out in the sun. Choose a sunscreen that is broad-spectrum and water-resistant and with a sun protection factor—or SPF—of at least 30. This can be used all year long, regardless of your age or whether or not you are “fair-skinned.”
• Apply sunscreen to exposed dry skin 10–15 minutes before going out into the sun. The amount to use for an adult is about 2 tablespoons. Wear sunscreen even when the sky is overcast, as UV rays penetrate clouds and windows (unless the windows are treated to block UV light). Also, take cover and use sunscreen around water, sand, and snow: they reflect UV radiation.
• 
  Sunscreen is only effective for a limited time. Be sure to reapply sunscreen every 2 hours, or even sooner if you have been swimming or sweating heavily (eg, playing tennis or volleyball).
• 
  Don’t abuse sunscreen lotions. Don’t apply sunscreen so that you can stay longer in the sun—for example, in order to tan. They are not intended to let you stay in the sun for long periods. Long exposure to the sun’s damaging UV rays increases your risk of skin cancer and photoaging.
  
• Do not use tanning beds. They expose the skin to much larger amounts of damaging UV light than normal sun exposure. The American Dermatologic Association supports a ban on tanning beds, and the World Health Organization classifies them as carcinogenic.

   

  This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.
  
  This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.
  
  For patient information on hundreds of health topics, see the Patient Education and Health Information web site, www.clevelandclinic.org/health

• Seek shade or minimize your sun exposure between 10 am and 4 pm, when the sun’s rays are the most intense. Wear protective clothing such as a wide-brimmed hat and long sleeves. Wear UV-blocking sunglasses. Whenever possible, keep children under 6 months old out of direct sunlight.
• 
  Apply sunscreen to minimize UV damage when out in the sun. Choose a sunscreen that is broad-spectrum and water-resistant and with a sun protection factor—or SPF—of at least 30. This can be used all year long, regardless of your age or whether or not you are “fair-skinned.”
• Apply sunscreen to exposed dry skin 10–15 minutes before going out into the sun. The amount to use for an adult is about 2 tablespoons. Wear sunscreen even when the sky is overcast, as UV rays penetrate clouds and windows (unless the windows are treated to block UV light). Also, take cover and use sunscreen around water, sand, and snow: they reflect UV radiation.
• 
  Sunscreen is only effective for a limited time. Be sure to reapply sunscreen every 2 hours, or even sooner if you have been swimming or sweating heavily (eg, playing tennis or volleyball).
• 
  Don’t abuse sunscreen lotions. Don’t apply sunscreen so that you can stay longer in the sun—for example, in order to tan. They are not intended to let you stay in the sun for long periods. Long exposure to the sun’s damaging UV rays increases your risk of skin cancer and photoaging.
  
• Do not use tanning beds. They expose the skin to much larger amounts of damaging UV light than normal sun exposure. The American Dermatologic Association supports a ban on tanning beds, and the World Health Organization classifies them as carcinogenic.

   

  This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.
  
  This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.
  
  For patient information on hundreds of health topics, see the Patient Education and Health Information web site, www.clevelandclinic.org/health

• Seek shade or minimize your sun exposure between 10 am and 4 pm, when the sun’s rays are the most intense. Wear protective clothing such as a wide-brimmed hat and long sleeves. Wear UV-blocking sunglasses. Whenever possible, keep children under 6 months old out of direct sunlight.
• 
  Apply sunscreen to minimize UV damage when out in the sun. Choose a sunscreen that is broad-spectrum and water-resistant and with a sun protection factor—or SPF—of at least 30. This can be used all year long, regardless of your age or whether or not you are “fair-skinned.”
• Apply sunscreen to exposed dry skin 10–15 minutes before going out into the sun. The amount to use for an adult is about 2 tablespoons. Wear sunscreen even when the sky is overcast, as UV rays penetrate clouds and windows (unless the windows are treated to block UV light). Also, take cover and use sunscreen around water, sand, and snow: they reflect UV radiation.
• 
  Sunscreen is only effective for a limited time. Be sure to reapply sunscreen every 2 hours, or even sooner if you have been swimming or sweating heavily (eg, playing tennis or volleyball).
• 
  Don’t abuse sunscreen lotions. Don’t apply sunscreen so that you can stay longer in the sun—for example, in order to tan. They are not intended to let you stay in the sun for long periods. Long exposure to the sun’s damaging UV rays increases your risk of skin cancer and photoaging.
  
• Do not use tanning beds. They expose the skin to much larger amounts of damaging UV light than normal sun exposure. The American Dermatologic Association supports a ban on tanning beds, and the World Health Organization classifies them as carcinogenic.

   

  This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.
  
  This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.
  
  For patient information on hundreds of health topics, see the Patient Education and Health Information web site, www.clevelandclinic.org/health

A 64-year-old man with diabetes and hypertension presented with a 2-day history of sudden onset of acute pain and cyanosis on the sole of his right foot 4 days after undergoing cardiac catheterization and coronary angiography.

A few days later, the patient returned with abdominal pain, diarrhea, and acute renal injury with urinary eosinophils (7% of the white blood cells in the urine) and proteinuria.

Q: Which is the most likely diagnosis?

• Infective endocarditis
• Pernio (chilblain)
• Cholesterol crystal embolism
• Cutaneous small-vessel vasculitis

A: Cholesterol crystal embolism is the correct diagnosis.

Infective endocarditis is an infection of the endocardium, but systemic signs may be present, including cutaneous lesions such as Osler nodes (painful papules on the tips of the fingers and toes) and Janeway lesions (painless macules on the palms and soles). Histologic staining of skin biopsy specimens often shows vasculitis, occasionally with a positive Gram stain. Severe renal injury is not common, and the timing of the acute illness and skin lesion fits better with an acute embolic phenomenon.

Pernio is a form of cold injury, localized in peripheral parts of the body and occurring after exposure to cold temperatures in damp conditions. It usually manifests bilaterally as painful erythematous or purple lesions on the acral areas of the hands and feet, nose, ears, and, rarely, the thighs and buttocks. Pernio most commonly affects women between 20 and 40 years of age. It can be idiopathic or associated with a systemic disease such as systemic lupus erythematosus or Sjögren syndrome.

Cutaneous small-vessel vasculitis is a heterogeneous group of disorders with inflammation and damage of the blood vessels; it may be limited to the skin or it may involve multiple systems. Palpable or nonpalpable purpura and ulceration are common clinical findings, and histologic study shows an inflammatory infiltrate of vessel walls, fibrinoid necrosis, thrombosis, and extravasation of red blood cells.

While this patient’s problems are not consistent with small-vessel vasculitis, the single skin lesion, the timing after the catheterization, and the urinary eosinophils are best explained by cholesterol embolization.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol crystal embolism is commonly iatrogenic, a complication of mechanical damage to the arterial walls from vascular surgery or invasive percutaneous procedures. Material dislodged from atheromatous arterial plaques can occlude the small vessels of the feet, producing this syndrome.

The onset of the clinical disease is often delayed for days to weeks after an angiographic procedure.¹ Spontaneous hemorrhage, disruption of plaque, or drug therapy with an anticoagulant or a fibrinolytic can precipitate embolization of cholesterol crystals. The source of the emboli is atheromatous plaque in major blood vessels, particularly the abdominal aorta.

These emboli can affect many organs and systems: eg, the kidneys (causing hypertension and acute renal failure), the muscles (causing myalgias), gastrointestinal organs (causing bleeding, abdominal pain, and bowel infarction), the lungs (causing acute respiratory distress syndrome), the eyes (causing Hollenhorst plaques in retinal arteries), and the central nervous system (causing stroke, confusion, and delirium). Cardiac or central nervous system involvement is associated with a high risk of death.

After angiography, clinical manifestations of cholesterol embolization have been reported in 0.06% to 1.4% of patients,^2,3 although the finding of cholesterol emboli is more common in autopsy studies.⁴

Recognizing skin signs is the key

Cutaneous abnormalities are usually the earliest and often the only clinical manifestation of this syndrome. Findings on the lower limbs include blue toes, cutaneous nodules, and livedo reticularis, affecting the feet and legs and sometimes extending upward to the trunk. Other findings include digital infarcts, ulceration, gangrene, purpura, cyanosis, and splinter hemorrhages in the nail bed.

In our patient, microscopic study of skin biopsy specimens showed needle-shaped clefts within the lumen of blood vessels—ie, dissolved cholesterol crystals obstructing small arteries (Figure 2).

Biopsy studies of skin lesions are positive in a high percentage of cases, showing dissolved cholesterol crystals within the lumen of blood vessels, especially in the small to large arteries and arterioles of the deep dermis or subcutaneous fat. Deep biopsies and carefully examination are necessary, as emboli tend to be patchily distributed. Early recognition of cutaneous clinical findings is essential to establish the proper diagnosis and treatment.

The diagnostic triad of this disease includes blue toe syndrome, acute or subacute renal failure, and a temporal relation with an inciting event (particularly angiography). But despite these diagnostic criteria,² the diagnosis is often based on a combination of signs and symptoms specific to end-organ damage and a systemic inflammatory response.³

Histologic confirmation is considered essential to the diagnosis of cholesterol crystal embolism, and as the skin is the most accessible site, skin biopsy provides the best sample for histologic diagnosis.⁵

Postprocedural embolism of a blood clot, vasculitis, and infective endocarditis are the most important differential diagnoses.^6,7

Treatment is supportive, preventive

Treatment is mainly supportive with hemodynamic monitoring, nutritional and metabolic support, mechanical ventilation, and dialysis if necessary. The underlying atherosclerotic disease should be treated aggressively. Prevention of another episode involves modification of traditional risk factors such as serum cholesterol, diabetes, hypertension, and smoking. Additional vascular surgery procedures should be avoided, as they can induce new episodes.

A 64-year-old man with diabetes and hypertension presented with a 2-day history of sudden onset of acute pain and cyanosis on the sole of his right foot 4 days after undergoing cardiac catheterization and coronary angiography.

A few days later, the patient returned with abdominal pain, diarrhea, and acute renal injury with urinary eosinophils (7% of the white blood cells in the urine) and proteinuria.

Q: Which is the most likely diagnosis?

• Infective endocarditis
• Pernio (chilblain)
• Cholesterol crystal embolism
• Cutaneous small-vessel vasculitis

A: Cholesterol crystal embolism is the correct diagnosis.

Infective endocarditis is an infection of the endocardium, but systemic signs may be present, including cutaneous lesions such as Osler nodes (painful papules on the tips of the fingers and toes) and Janeway lesions (painless macules on the palms and soles). Histologic staining of skin biopsy specimens often shows vasculitis, occasionally with a positive Gram stain. Severe renal injury is not common, and the timing of the acute illness and skin lesion fits better with an acute embolic phenomenon.

Pernio is a form of cold injury, localized in peripheral parts of the body and occurring after exposure to cold temperatures in damp conditions. It usually manifests bilaterally as painful erythematous or purple lesions on the acral areas of the hands and feet, nose, ears, and, rarely, the thighs and buttocks. Pernio most commonly affects women between 20 and 40 years of age. It can be idiopathic or associated with a systemic disease such as systemic lupus erythematosus or Sjögren syndrome.

Cutaneous small-vessel vasculitis is a heterogeneous group of disorders with inflammation and damage of the blood vessels; it may be limited to the skin or it may involve multiple systems. Palpable or nonpalpable purpura and ulceration are common clinical findings, and histologic study shows an inflammatory infiltrate of vessel walls, fibrinoid necrosis, thrombosis, and extravasation of red blood cells.

While this patient’s problems are not consistent with small-vessel vasculitis, the single skin lesion, the timing after the catheterization, and the urinary eosinophils are best explained by cholesterol embolization.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol crystal embolism is commonly iatrogenic, a complication of mechanical damage to the arterial walls from vascular surgery or invasive percutaneous procedures. Material dislodged from atheromatous arterial plaques can occlude the small vessels of the feet, producing this syndrome.

The onset of the clinical disease is often delayed for days to weeks after an angiographic procedure.¹ Spontaneous hemorrhage, disruption of plaque, or drug therapy with an anticoagulant or a fibrinolytic can precipitate embolization of cholesterol crystals. The source of the emboli is atheromatous plaque in major blood vessels, particularly the abdominal aorta.

These emboli can affect many organs and systems: eg, the kidneys (causing hypertension and acute renal failure), the muscles (causing myalgias), gastrointestinal organs (causing bleeding, abdominal pain, and bowel infarction), the lungs (causing acute respiratory distress syndrome), the eyes (causing Hollenhorst plaques in retinal arteries), and the central nervous system (causing stroke, confusion, and delirium). Cardiac or central nervous system involvement is associated with a high risk of death.

After angiography, clinical manifestations of cholesterol embolization have been reported in 0.06% to 1.4% of patients,^2,3 although the finding of cholesterol emboli is more common in autopsy studies.⁴

Recognizing skin signs is the key

Cutaneous abnormalities are usually the earliest and often the only clinical manifestation of this syndrome. Findings on the lower limbs include blue toes, cutaneous nodules, and livedo reticularis, affecting the feet and legs and sometimes extending upward to the trunk. Other findings include digital infarcts, ulceration, gangrene, purpura, cyanosis, and splinter hemorrhages in the nail bed.

In our patient, microscopic study of skin biopsy specimens showed needle-shaped clefts within the lumen of blood vessels—ie, dissolved cholesterol crystals obstructing small arteries (Figure 2).

Biopsy studies of skin lesions are positive in a high percentage of cases, showing dissolved cholesterol crystals within the lumen of blood vessels, especially in the small to large arteries and arterioles of the deep dermis or subcutaneous fat. Deep biopsies and carefully examination are necessary, as emboli tend to be patchily distributed. Early recognition of cutaneous clinical findings is essential to establish the proper diagnosis and treatment.

The diagnostic triad of this disease includes blue toe syndrome, acute or subacute renal failure, and a temporal relation with an inciting event (particularly angiography). But despite these diagnostic criteria,² the diagnosis is often based on a combination of signs and symptoms specific to end-organ damage and a systemic inflammatory response.³

Histologic confirmation is considered essential to the diagnosis of cholesterol crystal embolism, and as the skin is the most accessible site, skin biopsy provides the best sample for histologic diagnosis.⁵

Postprocedural embolism of a blood clot, vasculitis, and infective endocarditis are the most important differential diagnoses.^6,7

Treatment is supportive, preventive

Treatment is mainly supportive with hemodynamic monitoring, nutritional and metabolic support, mechanical ventilation, and dialysis if necessary. The underlying atherosclerotic disease should be treated aggressively. Prevention of another episode involves modification of traditional risk factors such as serum cholesterol, diabetes, hypertension, and smoking. Additional vascular surgery procedures should be avoided, as they can induce new episodes.

A 64-year-old man with diabetes and hypertension presented with a 2-day history of sudden onset of acute pain and cyanosis on the sole of his right foot 4 days after undergoing cardiac catheterization and coronary angiography.

A few days later, the patient returned with abdominal pain, diarrhea, and acute renal injury with urinary eosinophils (7% of the white blood cells in the urine) and proteinuria.

Q: Which is the most likely diagnosis?

• Infective endocarditis
• Pernio (chilblain)
• Cholesterol crystal embolism
• Cutaneous small-vessel vasculitis

A: Cholesterol crystal embolism is the correct diagnosis.

Infective endocarditis is an infection of the endocardium, but systemic signs may be present, including cutaneous lesions such as Osler nodes (painful papules on the tips of the fingers and toes) and Janeway lesions (painless macules on the palms and soles). Histologic staining of skin biopsy specimens often shows vasculitis, occasionally with a positive Gram stain. Severe renal injury is not common, and the timing of the acute illness and skin lesion fits better with an acute embolic phenomenon.

Pernio is a form of cold injury, localized in peripheral parts of the body and occurring after exposure to cold temperatures in damp conditions. It usually manifests bilaterally as painful erythematous or purple lesions on the acral areas of the hands and feet, nose, ears, and, rarely, the thighs and buttocks. Pernio most commonly affects women between 20 and 40 years of age. It can be idiopathic or associated with a systemic disease such as systemic lupus erythematosus or Sjögren syndrome.

Cutaneous small-vessel vasculitis is a heterogeneous group of disorders with inflammation and damage of the blood vessels; it may be limited to the skin or it may involve multiple systems. Palpable or nonpalpable purpura and ulceration are common clinical findings, and histologic study shows an inflammatory infiltrate of vessel walls, fibrinoid necrosis, thrombosis, and extravasation of red blood cells.

While this patient’s problems are not consistent with small-vessel vasculitis, the single skin lesion, the timing after the catheterization, and the urinary eosinophils are best explained by cholesterol embolization.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol crystal embolism is commonly iatrogenic, a complication of mechanical damage to the arterial walls from vascular surgery or invasive percutaneous procedures. Material dislodged from atheromatous arterial plaques can occlude the small vessels of the feet, producing this syndrome.

The onset of the clinical disease is often delayed for days to weeks after an angiographic procedure.¹ Spontaneous hemorrhage, disruption of plaque, or drug therapy with an anticoagulant or a fibrinolytic can precipitate embolization of cholesterol crystals. The source of the emboli is atheromatous plaque in major blood vessels, particularly the abdominal aorta.

These emboli can affect many organs and systems: eg, the kidneys (causing hypertension and acute renal failure), the muscles (causing myalgias), gastrointestinal organs (causing bleeding, abdominal pain, and bowel infarction), the lungs (causing acute respiratory distress syndrome), the eyes (causing Hollenhorst plaques in retinal arteries), and the central nervous system (causing stroke, confusion, and delirium). Cardiac or central nervous system involvement is associated with a high risk of death.

After angiography, clinical manifestations of cholesterol embolization have been reported in 0.06% to 1.4% of patients,^2,3 although the finding of cholesterol emboli is more common in autopsy studies.⁴

Recognizing skin signs is the key

Cutaneous abnormalities are usually the earliest and often the only clinical manifestation of this syndrome. Findings on the lower limbs include blue toes, cutaneous nodules, and livedo reticularis, affecting the feet and legs and sometimes extending upward to the trunk. Other findings include digital infarcts, ulceration, gangrene, purpura, cyanosis, and splinter hemorrhages in the nail bed.

In our patient, microscopic study of skin biopsy specimens showed needle-shaped clefts within the lumen of blood vessels—ie, dissolved cholesterol crystals obstructing small arteries (Figure 2).

Biopsy studies of skin lesions are positive in a high percentage of cases, showing dissolved cholesterol crystals within the lumen of blood vessels, especially in the small to large arteries and arterioles of the deep dermis or subcutaneous fat. Deep biopsies and carefully examination are necessary, as emboli tend to be patchily distributed. Early recognition of cutaneous clinical findings is essential to establish the proper diagnosis and treatment.

The diagnostic triad of this disease includes blue toe syndrome, acute or subacute renal failure, and a temporal relation with an inciting event (particularly angiography). But despite these diagnostic criteria,² the diagnosis is often based on a combination of signs and symptoms specific to end-organ damage and a systemic inflammatory response.³

Histologic confirmation is considered essential to the diagnosis of cholesterol crystal embolism, and as the skin is the most accessible site, skin biopsy provides the best sample for histologic diagnosis.⁵

Postprocedural embolism of a blood clot, vasculitis, and infective endocarditis are the most important differential diagnoses.^6,7

Treatment is supportive, preventive

Treatment is mainly supportive with hemodynamic monitoring, nutritional and metabolic support, mechanical ventilation, and dialysis if necessary. The underlying atherosclerotic disease should be treated aggressively. Prevention of another episode involves modification of traditional risk factors such as serum cholesterol, diabetes, hypertension, and smoking. Additional vascular surgery procedures should be avoided, as they can induce new episodes.

A 60-year-old man presented with progressive swelling of his face and neck, which had begun 2 weeks earlier. He denied any headache, lightheadedness, blurry vision, syncope, or change in his cognitive or memory function. A review of symptoms was unremarkable.

The patient had hypertension and end-stage renal disease, for which he was receiving hemodialysis via a catheter tunneled into his right internal jugular vein. He had undergone multiple unsuccessful attempts to create an arteriovenous fistula over the previous 2 years.

Doppler ultrasonography revealed chronic thrombosis and reverse flow in the right internal jugular vein and reverse flow in the right subclavian vein. These findings were consistent with central venous thrombosis and superior vena cava (SVC) syndrome.

Diagnosis: SVC syndrome secondary to intravascular thrombosis related to his central venous dialysis catheter.

SVC SYNDROME

The SVC is the major drainage vessel for venous blood from the head, neck, upper extremities, and upper thorax. Obstruction to its flow increases venous pressure, which results in interstitial edema and retrograde collateral flow.¹

More than 80% of cases of SVC syndrome are caused by malignant lung tumors and lymphoma.

Nonmalignant causes include mediastinal fibrosis; vascular diseases (eg, aortic aneurysm, large-vessel vasculitis); infections such as histoplasmosis, tuberculosis, syphilis, and actinomycosis; benign mediastinal tumors such as teratoma, cystic hygroma, thymoma, and dermoid cyst; and thrombosis from central venous catheters, pacemaker leads, and guidewires.^2–6 A recent report suggests that benign causes may now account for up to 40% of cases as a result of a rise in the use of indwelling central venous catheters and cardiac pacemakers during the past 2 decades, resulting in a higher incidence of SVC thrombosis.⁷

An obstructed SVC initiates collateral venous return to the heart from the upper half of the body through different pathways. The most important pathway is the azygos venous system, which includes the azygos vein. Occlusion of the SVC at the level of the azygos vein contributes to the appearance of collateral veins on the chest and abdominal walls, and venous blood flows via these collaterals into the inferior vena cava.^1,8,9

Different presentations

The diagnosis of SVC syndrome is often made on clinical grounds alone, ie, the combination of the clinical presentation and, often, a thoracic malignancy or contributing factors such as a central catheter.¹

With slowly progressive obstruction of the SVC, the most common presenting symptoms include swelling of the face, neck, and both arms. On the other hand, adequate collateral drainage may develop,¹ and patients may have minimal symptoms.

However, a rapid onset of SVC syndrome in the absence of collateral circulation will cause a more dramatic and life-threatening presentation, often with neurologic and respiratory sequelae such as cerebral and laryngeal edema and respiratory embarrassment, which were not present in our patient’s case.^1,10–15 These serious complications are rare and are considered an acute emergency. In these cases, special attention to airway, breathing, and circulation (the “ABCs”) is essential, and endovascular repairs and stenting or open surgical reconstruction and alternate approaches for renal replacement therapy should be considered.^1,12,13,15

CT is diagnostic and provides accurate information about the location of the obstruction and about other critical surrounding structures such as the lungs, mediastinum, and adjacent blood vessels.^1,7,10,11 Our patient’s CT scan confirmed a significant stenosis of the SVC due to thrombosis, with no compression coming from the lungs or mediastinal structures.

Thrombolytic therapy in acute cases

In cases of acute thrombosis (with symptom onset less than 2 days previously), thrombolytic therapy followed by anticoagulation is recommended and may both cause the symptoms to regress within several days and allow the central catheter to be kept in.¹⁶ However, thrombolytic therapy is less effective in chronic thrombosis (with onset of symptoms more than 10 days previously).¹⁶

Vascular or surgical intervention is often needed to treat SVC syndrome related to dialysis access.

Most experts recommend anticoagulation after thrombosis to prevent disease progression and recurrence, although the benefit of either short-term or long-term anticoagulation therapy for this syndrome is unclear.¹⁶

Recommended treatments for cancer-related SVC syndrome include chemotherapy and radiation to shrink the tumor that is causing the obstruction. Tissue diagnosis is often necessary to direct treatment decisions.¹ However, percutaneous angioplasty and the use of intravenous stents are becoming increasingly common and are simple, safe, and effective in rapidly relieving SVC syndrome caused by malignant diseases.¹ A bypass of the SVC may be indicated in some cases.¹ Adjunctive therapies include diuretics, corticosteroids, thrombolytics, anticoagulation, and elevating the head of the patient’s bed.¹

CASE CONTINUED

Our patient was started on heparin intravenously for 7 days and long-term oral anticoagulant therapy with warfarin (Coumadin) to continue as long as the catheter was in place, with a target international normalized ratio between 2 and 2.5. He required no other interventions, and his dialysis catheter remained functioning. He was monitored in the hospital for 2 weeks, during which his symptoms gradually improved, with noticeable resolution of his facial swelling.

He was discharged home to continue on an oral anticoagulant and was then followed to monitor for a reappearance of the symptoms (which would force the removal of the catheter), and to pursue possible percutaneous angioplasty, stenting, or surgical reconstruction of the SVC if needed.

A 60-year-old man presented with progressive swelling of his face and neck, which had begun 2 weeks earlier. He denied any headache, lightheadedness, blurry vision, syncope, or change in his cognitive or memory function. A review of symptoms was unremarkable.

The patient had hypertension and end-stage renal disease, for which he was receiving hemodialysis via a catheter tunneled into his right internal jugular vein. He had undergone multiple unsuccessful attempts to create an arteriovenous fistula over the previous 2 years.

Doppler ultrasonography revealed chronic thrombosis and reverse flow in the right internal jugular vein and reverse flow in the right subclavian vein. These findings were consistent with central venous thrombosis and superior vena cava (SVC) syndrome.

Diagnosis: SVC syndrome secondary to intravascular thrombosis related to his central venous dialysis catheter.

SVC SYNDROME

The SVC is the major drainage vessel for venous blood from the head, neck, upper extremities, and upper thorax. Obstruction to its flow increases venous pressure, which results in interstitial edema and retrograde collateral flow.¹

More than 80% of cases of SVC syndrome are caused by malignant lung tumors and lymphoma.

Nonmalignant causes include mediastinal fibrosis; vascular diseases (eg, aortic aneurysm, large-vessel vasculitis); infections such as histoplasmosis, tuberculosis, syphilis, and actinomycosis; benign mediastinal tumors such as teratoma, cystic hygroma, thymoma, and dermoid cyst; and thrombosis from central venous catheters, pacemaker leads, and guidewires.^2–6 A recent report suggests that benign causes may now account for up to 40% of cases as a result of a rise in the use of indwelling central venous catheters and cardiac pacemakers during the past 2 decades, resulting in a higher incidence of SVC thrombosis.⁷

An obstructed SVC initiates collateral venous return to the heart from the upper half of the body through different pathways. The most important pathway is the azygos venous system, which includes the azygos vein. Occlusion of the SVC at the level of the azygos vein contributes to the appearance of collateral veins on the chest and abdominal walls, and venous blood flows via these collaterals into the inferior vena cava.^1,8,9

Different presentations

The diagnosis of SVC syndrome is often made on clinical grounds alone, ie, the combination of the clinical presentation and, often, a thoracic malignancy or contributing factors such as a central catheter.¹

With slowly progressive obstruction of the SVC, the most common presenting symptoms include swelling of the face, neck, and both arms. On the other hand, adequate collateral drainage may develop,¹ and patients may have minimal symptoms.

However, a rapid onset of SVC syndrome in the absence of collateral circulation will cause a more dramatic and life-threatening presentation, often with neurologic and respiratory sequelae such as cerebral and laryngeal edema and respiratory embarrassment, which were not present in our patient’s case.^1,10–15 These serious complications are rare and are considered an acute emergency. In these cases, special attention to airway, breathing, and circulation (the “ABCs”) is essential, and endovascular repairs and stenting or open surgical reconstruction and alternate approaches for renal replacement therapy should be considered.^1,12,13,15

CT is diagnostic and provides accurate information about the location of the obstruction and about other critical surrounding structures such as the lungs, mediastinum, and adjacent blood vessels.^1,7,10,11 Our patient’s CT scan confirmed a significant stenosis of the SVC due to thrombosis, with no compression coming from the lungs or mediastinal structures.

Thrombolytic therapy in acute cases

In cases of acute thrombosis (with symptom onset less than 2 days previously), thrombolytic therapy followed by anticoagulation is recommended and may both cause the symptoms to regress within several days and allow the central catheter to be kept in.¹⁶ However, thrombolytic therapy is less effective in chronic thrombosis (with onset of symptoms more than 10 days previously).¹⁶

Vascular or surgical intervention is often needed to treat SVC syndrome related to dialysis access.

Most experts recommend anticoagulation after thrombosis to prevent disease progression and recurrence, although the benefit of either short-term or long-term anticoagulation therapy for this syndrome is unclear.¹⁶

Recommended treatments for cancer-related SVC syndrome include chemotherapy and radiation to shrink the tumor that is causing the obstruction. Tissue diagnosis is often necessary to direct treatment decisions.¹ However, percutaneous angioplasty and the use of intravenous stents are becoming increasingly common and are simple, safe, and effective in rapidly relieving SVC syndrome caused by malignant diseases.¹ A bypass of the SVC may be indicated in some cases.¹ Adjunctive therapies include diuretics, corticosteroids, thrombolytics, anticoagulation, and elevating the head of the patient’s bed.¹

CASE CONTINUED

Our patient was started on heparin intravenously for 7 days and long-term oral anticoagulant therapy with warfarin (Coumadin) to continue as long as the catheter was in place, with a target international normalized ratio between 2 and 2.5. He required no other interventions, and his dialysis catheter remained functioning. He was monitored in the hospital for 2 weeks, during which his symptoms gradually improved, with noticeable resolution of his facial swelling.

He was discharged home to continue on an oral anticoagulant and was then followed to monitor for a reappearance of the symptoms (which would force the removal of the catheter), and to pursue possible percutaneous angioplasty, stenting, or surgical reconstruction of the SVC if needed.

A 60-year-old man presented with progressive swelling of his face and neck, which had begun 2 weeks earlier. He denied any headache, lightheadedness, blurry vision, syncope, or change in his cognitive or memory function. A review of symptoms was unremarkable.

The patient had hypertension and end-stage renal disease, for which he was receiving hemodialysis via a catheter tunneled into his right internal jugular vein. He had undergone multiple unsuccessful attempts to create an arteriovenous fistula over the previous 2 years.

Doppler ultrasonography revealed chronic thrombosis and reverse flow in the right internal jugular vein and reverse flow in the right subclavian vein. These findings were consistent with central venous thrombosis and superior vena cava (SVC) syndrome.

Diagnosis: SVC syndrome secondary to intravascular thrombosis related to his central venous dialysis catheter.

SVC SYNDROME

The SVC is the major drainage vessel for venous blood from the head, neck, upper extremities, and upper thorax. Obstruction to its flow increases venous pressure, which results in interstitial edema and retrograde collateral flow.¹

More than 80% of cases of SVC syndrome are caused by malignant lung tumors and lymphoma.

Nonmalignant causes include mediastinal fibrosis; vascular diseases (eg, aortic aneurysm, large-vessel vasculitis); infections such as histoplasmosis, tuberculosis, syphilis, and actinomycosis; benign mediastinal tumors such as teratoma, cystic hygroma, thymoma, and dermoid cyst; and thrombosis from central venous catheters, pacemaker leads, and guidewires.^2–6 A recent report suggests that benign causes may now account for up to 40% of cases as a result of a rise in the use of indwelling central venous catheters and cardiac pacemakers during the past 2 decades, resulting in a higher incidence of SVC thrombosis.⁷

An obstructed SVC initiates collateral venous return to the heart from the upper half of the body through different pathways. The most important pathway is the azygos venous system, which includes the azygos vein. Occlusion of the SVC at the level of the azygos vein contributes to the appearance of collateral veins on the chest and abdominal walls, and venous blood flows via these collaterals into the inferior vena cava.^1,8,9

Different presentations

The diagnosis of SVC syndrome is often made on clinical grounds alone, ie, the combination of the clinical presentation and, often, a thoracic malignancy or contributing factors such as a central catheter.¹

With slowly progressive obstruction of the SVC, the most common presenting symptoms include swelling of the face, neck, and both arms. On the other hand, adequate collateral drainage may develop,¹ and patients may have minimal symptoms.

However, a rapid onset of SVC syndrome in the absence of collateral circulation will cause a more dramatic and life-threatening presentation, often with neurologic and respiratory sequelae such as cerebral and laryngeal edema and respiratory embarrassment, which were not present in our patient’s case.^1,10–15 These serious complications are rare and are considered an acute emergency. In these cases, special attention to airway, breathing, and circulation (the “ABCs”) is essential, and endovascular repairs and stenting or open surgical reconstruction and alternate approaches for renal replacement therapy should be considered.^1,12,13,15

CT is diagnostic and provides accurate information about the location of the obstruction and about other critical surrounding structures such as the lungs, mediastinum, and adjacent blood vessels.^1,7,10,11 Our patient’s CT scan confirmed a significant stenosis of the SVC due to thrombosis, with no compression coming from the lungs or mediastinal structures.

Thrombolytic therapy in acute cases

In cases of acute thrombosis (with symptom onset less than 2 days previously), thrombolytic therapy followed by anticoagulation is recommended and may both cause the symptoms to regress within several days and allow the central catheter to be kept in.¹⁶ However, thrombolytic therapy is less effective in chronic thrombosis (with onset of symptoms more than 10 days previously).¹⁶

Vascular or surgical intervention is often needed to treat SVC syndrome related to dialysis access.

Most experts recommend anticoagulation after thrombosis to prevent disease progression and recurrence, although the benefit of either short-term or long-term anticoagulation therapy for this syndrome is unclear.¹⁶

Recommended treatments for cancer-related SVC syndrome include chemotherapy and radiation to shrink the tumor that is causing the obstruction. Tissue diagnosis is often necessary to direct treatment decisions.¹ However, percutaneous angioplasty and the use of intravenous stents are becoming increasingly common and are simple, safe, and effective in rapidly relieving SVC syndrome caused by malignant diseases.¹ A bypass of the SVC may be indicated in some cases.¹ Adjunctive therapies include diuretics, corticosteroids, thrombolytics, anticoagulation, and elevating the head of the patient’s bed.¹

CASE CONTINUED

Our patient was started on heparin intravenously for 7 days and long-term oral anticoagulant therapy with warfarin (Coumadin) to continue as long as the catheter was in place, with a target international normalized ratio between 2 and 2.5. He required no other interventions, and his dialysis catheter remained functioning. He was monitored in the hospital for 2 weeks, during which his symptoms gradually improved, with noticeable resolution of his facial swelling.

He was discharged home to continue on an oral anticoagulant and was then followed to monitor for a reappearance of the symptoms (which would force the removal of the catheter), and to pursue possible percutaneous angioplasty, stenting, or surgical reconstruction of the SVC if needed.

A 75-year-old man with type 2 diabetes and hypothyroidism underwent bilateral total knee replacement at our hospital.

His functional capacity had been moderately limited by knee pain, but he could easily climb one flight of stairs without symptoms. His medications at that time included levothyroxine (Synthroid) and metformin (Glucophage). He had no known cardiac or pulmonary disease. The preoperative evaluation, including laboratory tests and electrocardiography, was within normal limits.

Spinal anesthesia was used for surgery, and he was given 2 mg of midazolam (Versed) intravenously for sedation. No additional sedation was given. He was given oxygen via nasal cannula at 2 L/min.

All vital signs were stable at the start of the procedure. However, about halfway through, when the thigh tourniquet was released, his oxygen saturation dropped abruptly from 100% to 92%. All other vital signs remained stable, and he was asymptomatic, was oriented to person, time, and place, was conversing freely, and was in no distress. The oxygen flow was increased to 6 L/min, his oxygen saturation improved, and the procedure was then completed as planned.

At the conclusion of the surgery, before the patient was transported to the postanesthesia care unit (PACU) and while his oxygen flow rate was still 6 L/min, his oxygen saturation again dropped to 92%. A simple face mask was placed, and the oxygen flow rate was increased to 10 L/min. His oxygen saturation stayed low, near 90%.

Bleeding during surgery had been nominal. He had received 2 L of lactated Ringer’s solution and 500 mL of hetastarch (Hextend) during surgery. He continued to be asymptomatic in the PACU.

1. What is the most likely cause of oxygen desaturation during bilateral total knee arthroplasty?

• Fat embolism
• Intraoperative pneumonia
• Venous thromboembolism with pulmonary embolism
• Acute myocardial infarction
• Acute pulmonary edema
• Excessive sedation

The differential diagnosis of oxygen desaturation during orthopedic procedures is listed in Table 1.

Fat embolism is the most likely cause, particularly given the greater fatty embolic load that occurs with bilateral total knee arthroplasty than with unilateral total knee arthroplasty.

At what point the maximal showering of fat emboli occurs is not known. Fat may be released into the circulation with pressurization of the medullary canal during surgery or with manipulation of a fracture. The emboli may collect in the leg veins and then be released in a shower when the thigh tourniquet is released. Vasoactive mediators and methylmethacrylate cement released into the circulatory system after tourniquet deflation may also cause vasodilation, hypotension, and increased dead-space ventilation, resulting in hypoxia and a drop in end-tidal CO₂.

Pneumonia during surgery is rare without an apparent aspiration event.

Venous thromboembolism is possible but is more likely later in the postoperative period after major orthopedic surgery.

Acute myocardial infarction could present with hypoxia, particularly in a diabetic patient, who may not experience chest pain. However, intraoperative electrocardiographic changes would likely be seen. If myocardial infarction is suspected, postoperative serial electrocardiograms and measuring troponin and cardiac enzyme levels aid in the diagnosis.

Acute pulmonary edema is possible but not as highly suspected, as the patient had no history of congestive heart failure and received an appropriate amount of fluid for this type of surgery.

Excessive sedation could cause hypoventilation and, thus, oxygen desaturatation. However, this patient’s oxygen desaturatation began more than an hour after the midazolam was given. Midazolam is a short-acting benzodiazepine. It is unlikely that the patient would show signs of hypoventilation and oversedation an hour after the drug was given. Our patient also did not show any signs of excessive sedation, as he was awake and conversing during the surgery.

Fat emboli vs fat embolism syndrome

Fat embolism is the presence of fat drops within the systemic and pulmonary microcirculation, with or without clinical sequelae.¹ Fat embolism syndrome, on the other hand, is defined as injury to and dysfunction of one or more organs as a result of the embolization of fat, usually within 24 hours of injury or orthopedic surgery.²

Fat embolism syndrome is an unpredictable condition with a varied presentation. Fat droplets are thought to embolize via the venous circulation into the pulmonary arteries, occluding small blood vessels in the lung. However, they also get into the arterial circulation and occlude arteries in the brain, kidney, heart, and liver (more on this phenomenon below).

Fat embolism is reported to originate primarily from fractures of the femur, tibia, and pelvis.^2,3 As many as 90% of trauma patients have been shown to have evidence of fat embolism on autopsy.⁴ However, only a small number of patients develop the classic fat embolism syndrome,^2,3,5 Why some develop the syndrome and others do not is still unknown.

Orthopedic procedures associated with fat embolization include knee arthroplasty and hip arthroplasty, particularly if it involves intramedullary manipulation or medullary fixation.⁶ It has also been reported during spinal procedures in which pedicular screws are used.⁷ The syndrome occurs in 0.25% to 30% of patients following multiple fractures and in 0.1% to 12% of patients during or following knee or hip arthroplasty.

One study⁸ showed evidence of fat on transesophageal echocardiography in 88% of patients undergoing medullary reaming of lower-extremity fractures and hip hemiarthroplasty. Blood sampling from the right atrium confirmed that fat was responsible for the echocardiographic abnormalities. The study also showed that the severity of the embolic showering correlated with the severity of hypoxia and the decrease in end-tidal CO₂.⁸

CASE CONTINUED

On arrival at the PACU, our patient’s oxygen saturation was 94% while he was breathing oxygen via a simple face mask at a flow rate of 10 L/min. His heart rate was 60 bpm, blood pressure 110/60 mm Hg, and temperature 37.5°C (96.3°F). Chest sounds were normal on auscultation.

However, 3 hours later, his mental status rapidly deteriorated. He was oriented only to person, and he was drowsy. He had escalating respiratory distress with a rapid respiratory rate and decreasing oxygen saturation. At this point, auscultation of his chest wall revealed bilateral crackles and rales.

He was promptly intubated. Profuse fluid and secretions were noted to be coming from his lungs, filling the endotracheal tube. Arterial blood gas measurement showed a pH of 7.22, Pao₂ 64 mm Hg, and Paco₂ 56 mm Hg on 100% fraction of inspired oxygen, with no increased anion gap.

2. Which consequence of fat embolism is most likely at this time in this patient?

• Coexisting sepsis
• Fat embolism syndrome
• Acute cardioembolic stroke
• Anaphylaxis

Fat embolism syndrome should be highly suspected in this patient. As mentioned, it can affect many different organs. It is the most serious condition resulting from fat embolization after surgery or trauma.

Sepsis was unlikely in our patient, since he presented for his surgery in good health and with no preexisting signs or symptoms of infection. Acute cardioembolic stroke could have caused the neurologic signs, but this would not necessarily explain the coexisting hypoxia. An anaphylactic reaction to drugs or surgical cement would most likely present intraoperatively, shortly after exposure occurred, rather than several hours after surgery.

How common is fat embolism syndrome?

The occurrence rate of fat embolism syndrome has been reported to be 0.25% to 30% after multiple fractures and 0.1% to 12% after knee and hip joint surgery, with a mortality rate of 13% to 36%.^2,9–14 The rate of occurrence after unilateral total knee joint replacement has been reported to be 1.8% to 5%, and 4% to 12% after bilateral total knee replacement.^15–19

The syndrome is relatively more common with traumatic fractures of the lower extremities. However, it has also been reported with liposuction, total parenteral nutrition, bone marrow harvest and transplantation, burns, and acute pancreatitis, to mention a few.¹⁰

The broad range of reported incidence rates can be attributed to the fact that many studies were in patients with multiple trauma, whose concomitant injuries may have made it difficult to clearly define the contribution of fat embolism syndrome to the overall rates of morbidity and mortality. Also, different studies used different criteria to define the syndrome.

How does fat embolism syndrome occur?

Two hypotheses for how this syndrome occurs were proposed nearly a century ago.^20,21

The “mechanical” theory is that fat emboli are formed as a result of trauma and disruption of adipose tissue and other cells in the bone marrow. Increases in intramedullary pressure force the fat emboli through damaged medullary venous channels in the bone and into the circulation of the lower extremities. This embolization of fat causes an initial mechanical pulmonary obstruction. Mechanical obstruction by fat emboli in the pulmonary system leads to increased pulmonary pressures and an increase in right heart outflow pressure. The right heart becomes strained, leading to a decreased right-sided cardiac output. As a result, the left heart filling pressures diminish and hypotension ensues.²⁰

The “biochemical” theory, on the other hand, is that chylomicrons within the vascular system are modified and their stability is compromised as a result of stress. These traumatized chylomicrons then coalesce to form droplets of fat that accumulate in the pulmonary circulation and produce a mechanical obstruction. This would explain why nontraumatic, nonorthopedic insults can produce this syndrome.

Autopsy studies show that there is little correlation between the presence and quantity of intravascular fat and the severity of clinical symptoms, thus implying that the syndrome is caused by more than just mechanical obstruction. The biochemical theory postulates that fat globules within the circulatory system then cause the release of lipase from the pulmonary alveolar cells, which then hydrolyses the fat into free fatty acids. These free fatty acids cause an inflammatory reaction, complementmediated leukocyte aggregation, chemotoxin release, and subsequently endothelial damage. These vasoactive substances damage type 2 pneumocytes and lead to an increased permeability of the pulmonary capillary beds. Acute respiratory distress syndrome (ARDS) may ensue. Disseminated intravascular coagulation may occur as a result of the formation of microthrombi involving lipids, platelets, and fibrin.^21,22

Embolization of fat to the central nervous system can occur as fat globules cross into the systemic circulation via a patent foramen ovale, an atrioventricular shunt, or the pulmonary capillaries. This can then result in cerebral ischemia.²³

Although patent foramen ovale may seem the most direct route for cerebral embolization, the neurologic impairment and signs of cerebral emboli in fat embolism syndrome may occur in the absence of patent foramen ovale.^24,25 The fat globules may actually go through the lung capillaries, being flexible and forced through by increased pulmonary pressure.

But whether the cause of fat embolism syndrome is occlusion by globules, the release of biochemical mediators, or a combination of both is unknown. Both mechanisms are likely responsible. We can only suspect that the degree of fat load and intrinsic metabolic differences between individuals account for the variation in susceptibility.

FAT EMBOLI AFFECT THE LUNGS, SKIN, AND BRAIN

3. Where on the body is the rash associated with fat embolism syndrome usually seen?

• Face
• Near a site of fracture or surgery
• Chest, axilla, conjunctiva
• Distal extremities

Petechiae are part of the classic presenting triad of fat embolism syndrome, which also includes pulmonary and cerebral dysfunction.

Petechiae usually appear on the 2nd to 4th day after injury.²⁶ They are usually found across the chest, the anterior axillary folds, and the neck, as well as on the oral mucosa and the conjunctiva. The rash is caused by occlusion of dermal capillaries by fat, which increases their fragility.¹⁰

Pulmonary changes usually begin with tachypnea, dyspnea, and a drop in oxygen saturation, leading to generalized hypoxia. Respiratory symptoms are present in 100% of cases.² Respiratory symptoms can acutely develop with the sudden manipulation of a fracture, reaming of bone, or release of a limb tourniquet.²⁷

Body systems affected by fat embolism syndrome are summarized in Table 2.

4. How many hours after injury does fat embolism syndrome typically manifest?

• 1 to 2 hours
• 6 to 12 hours
• 12 to 20 hours
• 24 to 48 hours
• 72 to 84 hours

Most patients develop signs and symptoms 24 to 48 hours after injury. Patients presenting earlier than 12 hours usually have a more fulminant course.²⁹

The time between fat embolization and the development of fat embolism syndrome is thought to be related to the time required for the metabolic conversion of fat to free fatty acids.³⁰ We suspect that the early desaturation seen in our patient was the result of a heavy showering of fat intraoperatively. However, this could only be concluded after we had ruled out other causes of acute hypoxia and hypotension.

Fat embolism syndrome is a diagnosis of exclusion and is based on clinical criteria. No specific sign, symptom, or test is pathognomonic. It may often be confused with other conditions such as systemic inflammatory response syndrome or sepsis. However, the triad of respiratory and neurologic symptoms and petechiae coupled with the clinical picture of recent trauma or orthopedic surgery almost assures the diagnosis.

Fat embolism syndrome can range from subclinical to fulminating, with the more fulminating course attributable to a huge load of fat emboli, which leads to acute cor pulmonale.

Regardless of the criteria used, one must have a high index of suspicion for fat embolization syndrome in patients undergoing orthopedic procedures, particularly hip and knee surgery, and in patients with fractures, especially fractures of the femur, tibia, or pelvis and multiple, concomitant fractures.

CASE CONTINUED

Our patient was given furosemide (Lasix) empirically for diuresis and to improve oxygenation. However, his oxygen saturation remained low.

Chest radiography 4 hours after surgery showed bilateral pulmonary infiltrates. Serial electrocardiography showed no acute changes. Levels of cardiac enzymes and troponins were normal. Transthoracic echocardiography showed no left ventricular dysfunction, a normal right ventricle, and no evidence of valvular lesions. Urine and blood fat stains were negative, but the sputum stain was positive for copious extracellular fat. The patient became comatose 5 hours postoperatively. Computed tomography of the brain was normal. He was transferred to the surgical intensive care unit.

The clinical course was marked by hemodynamic instability requiring norepinephrine (Levophed) and vasopressin (Pitressin) for hypotension. Right ventricular filling pressures via central venous pressure monitoring showed no evidence of hypovolemia. The hemoglobin concentration and the hematocrit were stable, with no evidence of acute or ongoing bleeding. Blood, urine, and sputum cultures remained negative. Acute myocardial infarction was ruled out by serial electrocardiography, cardiac enzyme testing, and troponin testing.

Magnetic resonance imaging (MRI) of the brain on postoperative day 2 showed foci of acute ischemia suggestive of embolic phenomena consistent with fat embolism syndrome (Figure  1). Transthoracic echocardiography was repeated but again showed no evidence of a patent foramen ovale. Electroencephalography on postoperative day 4 showed severe, diffuse encephalopathy. There was no petechial skin rash. Other laboratory studies showed progressive thrombocytopenia with a platelet count of 53 × 199/L on postoperative day 3.

TESTS THAT AID THE CLINICAL DIAGNOSIS

Although no single laboratory test is pathognomonic for fat embolism syndrome, several tests may help raise suspicion of it, especially in the setting of fracture or an orthopedic surgical procedure.

Arterial blood gases must be measured. A Pao₂ of less than 60 mm Hg with no other obvious lung pathology in an orthopedic surgery patient is highly suspicious.¹² An alveolar-arterial gradient of greater than 100 mm Hg may further increase suspicion.

Tests for fat. The blood and urine may be examined for fat, although positive findings are not specific for fat embolism syndrome.³³ Fat in the urine indicates the occurrence of massive fat embolism, but this is not always accompanied by the syndrome.³⁴ Gurd and Wilson¹³ found fat globules larger than 8 μm circulating in the serum in all documented cases. They stated that, even though the relationship of large fat globules to the pathogenesis of the clinical picture remains obscure, the demonstration of their presence can be helpful in the diagnosis.¹³

Also, samples obtained with bronchoalveolar lavage may be examined for fat. The macrophages may be stained for fat using the oil red O stain. Again, this is a nonspecific marker, as fat-stained macrophages are seen in trauma patients,³⁵ but the finding has a very high negative predictive value.³⁶ Anemia, thrombocytopenia, hypofibrinogenemia, an elevated lipase level, and a high erythrocyte sedimentation rate may be found in fat embolism syndrome.¹³

Chest radiography may show bilateral infiltrates, as in ARDS, but this is not diagnostic for fat embolism syndrome.

Electrocardiography may show changes in ST and T waves and signs of right heart strain.

Transesophageal echocardiography may show increased right heart and pulmonary artery pressures.

Computed tomography is often negative,^37,38 but T2-weighted MRI is useful in the diagnosis of cerebral fat embolism syndrome, as it can show intracerebral microinfarcts as early as 4 hours after the onset of neurologic symptoms, and these findings correlate well with the clinical severity of brain injury.

Diffusion-weighted MRI may enhance the sensitivity and specificity of the neuroradiologic diagnosis. Diffusion-weighted MRI typically shows multiple nonconfluent areas of high-intensity signals or bright spots on a dark background, known as a “starfield pattern.” This pattern has been suggested to be pathognomonic of acute cerebral microinfarction. The abnormalities presumably reflect foci of cytotoxic edema that develops immediately, unlike vasogenic edema, seen in T2-weighted images, which may take up to several days to develop. Although these images are not necessarily specific for fat emboli, they are useful in helping make the diagnosis. Thus, diffusionweighted MRI should be done if fat embolism syndrome is suspected.^38,39

CASE CONCLUDED

The patient’s course in the intensive care unit was further complicated by gastrointestinal bleeding and renal failure. His neurologic status did not improve. Repeated MRI of the brain showed evolving bilateral watershed infarction throughout the cortices. The neurologic consult service diagnosed the patient as having severe encephalopathy with a very poor prognosis. The decision was made to withdraw care. He was placed under palliative care and died on postoperative day 22.

DRUG TREATMENT OF FAT EMBOLISM SYNDROME

5. Which of the following drugs has been proven to be effective in treating fat embolism syndrome?

• Intravenous ethanol
• Steroids
• Heparin
• Dextran
• Aspirin
• None of the above

None of the above has been proven to be effective in treating this disorder. The management is largely supportive. Thus, prevention, early diagnosis, and symptom management are vital.

Pulmonary and hemodynamic support are the cornerstones of successful treatment. Aggressive respiratory support is often needed. Management of acute lung injury and ARDS focuses on achieving acceptable gas exchange while preventing ventilator-associated lung injury. Intravascular volume must be supported. Inotropes and pulmonary vasodilators may be required to maintain hemodynamics. Exacerbation of central nervous system ischemia from hypotension or hypoxia should be avoided.

If the thrombocytopenia leads to clinical bleeding, platelet transfusions may be warranted.

Supportive care should include prophylaxis of deep venous thrombosis and of gastrointestinal bleeding, and maintenance of nutrition.⁴⁰ Patients who receive supportive care generally have a favorable outcome, with a mortality rate of less than 10%.²⁸

Drug studies have been inconclusive

Drugs suggested in the treatment of fat embolism syndrome include heparin, aspirin, dextran, hypertonic glucose, and alcohol, but the results have been inconclusive.^{3,11,23,40–43}

Heparin stimulates lipase activity, consequently decreasing the concentration of circulating fat globules. However, the increase in levels of free fatty acids may actually worsen the clinical picture. For this reason, and because of anticoagulation concerns and evidence of increased mortality rates, heparin is now contraindicated in the treatment of fat embolism syndrome.^2,41,43

Alcohol. Patients with a higher blood alcohol level at the time of injury have been reported to have a lower incidence of fat embolism syndrome. Alcohol inhibits lipase, suppressing the rise of free fatty acids. In experimental studies, the incidence of fat embolism syndrome was lower when the blood alcohol level was maintained at 20 mg/dL. However, no prospective randomized trial has been done to determine the clinical efficacy of ethanol as a treatment for this condition.^5,42

Dextran has been advocated, owing to its ability to improve small-vessel perfusion, but bleeding risk and acute renal failure associated with this drug have limited its use.⁵

N-acetylcysteine has been shown to attenuate fat-induced lung injury in a study of rats with induced fat embolism syndrome.⁴⁴

Corticosteroid treatment for this condition is controversial. Studies in patients with femoral and tibial fractures show that steroids reduce the incidence of fat embolism syndrome when given prophylactically, and those treated with steroids had a higher Pao₂ than controls. Doses of methylprednisolone in these studies ranged between 9 mg/kg to 90 mg/kg. A drawback of these studies is their small number of patients.^12,32,45,46

A meta-analysis⁴⁷ of randomized trials of corticosteroids to prevent fat embolism syndrome in patients with long-bone fractures identified 104 such studies. Only 7 of the 104 were considered adequate. In 389 patients with long-bone fractures, prophylactic corticosteroids reduced the risk of fat embolism syndrome by 78% (95% confidence interval 43%–92%) and corticosteroids also significantly reduced the risk of hypoxia with no difference in rates of infection or death. However, the overall quality of the trials was poor, and the authors of the meta-analysis concluded that more study is needed before corticosteroids could be formally recommended.⁴⁷

There is no evidence that steroids improve the overall clinical course of already established fat embolism syndrome.^12,32,45 The dosing and optimal timing of administration have also not been established. High doses pose a risk of septic complications, which may be devastating for the posttrauma or postoperative patient.

A 75-year-old man with type 2 diabetes and hypothyroidism underwent bilateral total knee replacement at our hospital.

His functional capacity had been moderately limited by knee pain, but he could easily climb one flight of stairs without symptoms. His medications at that time included levothyroxine (Synthroid) and metformin (Glucophage). He had no known cardiac or pulmonary disease. The preoperative evaluation, including laboratory tests and electrocardiography, was within normal limits.

Spinal anesthesia was used for surgery, and he was given 2 mg of midazolam (Versed) intravenously for sedation. No additional sedation was given. He was given oxygen via nasal cannula at 2 L/min.

All vital signs were stable at the start of the procedure. However, about halfway through, when the thigh tourniquet was released, his oxygen saturation dropped abruptly from 100% to 92%. All other vital signs remained stable, and he was asymptomatic, was oriented to person, time, and place, was conversing freely, and was in no distress. The oxygen flow was increased to 6 L/min, his oxygen saturation improved, and the procedure was then completed as planned.

At the conclusion of the surgery, before the patient was transported to the postanesthesia care unit (PACU) and while his oxygen flow rate was still 6 L/min, his oxygen saturation again dropped to 92%. A simple face mask was placed, and the oxygen flow rate was increased to 10 L/min. His oxygen saturation stayed low, near 90%.

Bleeding during surgery had been nominal. He had received 2 L of lactated Ringer’s solution and 500 mL of hetastarch (Hextend) during surgery. He continued to be asymptomatic in the PACU.

1. What is the most likely cause of oxygen desaturation during bilateral total knee arthroplasty?

• Fat embolism
• Intraoperative pneumonia
• Venous thromboembolism with pulmonary embolism
• Acute myocardial infarction
• Acute pulmonary edema
• Excessive sedation

The differential diagnosis of oxygen desaturation during orthopedic procedures is listed in Table 1.

Fat embolism is the most likely cause, particularly given the greater fatty embolic load that occurs with bilateral total knee arthroplasty than with unilateral total knee arthroplasty.

At what point the maximal showering of fat emboli occurs is not known. Fat may be released into the circulation with pressurization of the medullary canal during surgery or with manipulation of a fracture. The emboli may collect in the leg veins and then be released in a shower when the thigh tourniquet is released. Vasoactive mediators and methylmethacrylate cement released into the circulatory system after tourniquet deflation may also cause vasodilation, hypotension, and increased dead-space ventilation, resulting in hypoxia and a drop in end-tidal CO₂.

Pneumonia during surgery is rare without an apparent aspiration event.

Venous thromboembolism is possible but is more likely later in the postoperative period after major orthopedic surgery.

Acute myocardial infarction could present with hypoxia, particularly in a diabetic patient, who may not experience chest pain. However, intraoperative electrocardiographic changes would likely be seen. If myocardial infarction is suspected, postoperative serial electrocardiograms and measuring troponin and cardiac enzyme levels aid in the diagnosis.

Acute pulmonary edema is possible but not as highly suspected, as the patient had no history of congestive heart failure and received an appropriate amount of fluid for this type of surgery.

Excessive sedation could cause hypoventilation and, thus, oxygen desaturatation. However, this patient’s oxygen desaturatation began more than an hour after the midazolam was given. Midazolam is a short-acting benzodiazepine. It is unlikely that the patient would show signs of hypoventilation and oversedation an hour after the drug was given. Our patient also did not show any signs of excessive sedation, as he was awake and conversing during the surgery.

Fat emboli vs fat embolism syndrome

Fat embolism is the presence of fat drops within the systemic and pulmonary microcirculation, with or without clinical sequelae.¹ Fat embolism syndrome, on the other hand, is defined as injury to and dysfunction of one or more organs as a result of the embolization of fat, usually within 24 hours of injury or orthopedic surgery.²

Fat embolism syndrome is an unpredictable condition with a varied presentation. Fat droplets are thought to embolize via the venous circulation into the pulmonary arteries, occluding small blood vessels in the lung. However, they also get into the arterial circulation and occlude arteries in the brain, kidney, heart, and liver (more on this phenomenon below).

Fat embolism is reported to originate primarily from fractures of the femur, tibia, and pelvis.^2,3 As many as 90% of trauma patients have been shown to have evidence of fat embolism on autopsy.⁴ However, only a small number of patients develop the classic fat embolism syndrome,^2,3,5 Why some develop the syndrome and others do not is still unknown.

Orthopedic procedures associated with fat embolization include knee arthroplasty and hip arthroplasty, particularly if it involves intramedullary manipulation or medullary fixation.⁶ It has also been reported during spinal procedures in which pedicular screws are used.⁷ The syndrome occurs in 0.25% to 30% of patients following multiple fractures and in 0.1% to 12% of patients during or following knee or hip arthroplasty.

One study⁸ showed evidence of fat on transesophageal echocardiography in 88% of patients undergoing medullary reaming of lower-extremity fractures and hip hemiarthroplasty. Blood sampling from the right atrium confirmed that fat was responsible for the echocardiographic abnormalities. The study also showed that the severity of the embolic showering correlated with the severity of hypoxia and the decrease in end-tidal CO₂.⁸

CASE CONTINUED

On arrival at the PACU, our patient’s oxygen saturation was 94% while he was breathing oxygen via a simple face mask at a flow rate of 10 L/min. His heart rate was 60 bpm, blood pressure 110/60 mm Hg, and temperature 37.5°C (96.3°F). Chest sounds were normal on auscultation.

However, 3 hours later, his mental status rapidly deteriorated. He was oriented only to person, and he was drowsy. He had escalating respiratory distress with a rapid respiratory rate and decreasing oxygen saturation. At this point, auscultation of his chest wall revealed bilateral crackles and rales.

He was promptly intubated. Profuse fluid and secretions were noted to be coming from his lungs, filling the endotracheal tube. Arterial blood gas measurement showed a pH of 7.22, Pao₂ 64 mm Hg, and Paco₂ 56 mm Hg on 100% fraction of inspired oxygen, with no increased anion gap.

2. Which consequence of fat embolism is most likely at this time in this patient?

• Coexisting sepsis
• Fat embolism syndrome
• Acute cardioembolic stroke
• Anaphylaxis

Fat embolism syndrome should be highly suspected in this patient. As mentioned, it can affect many different organs. It is the most serious condition resulting from fat embolization after surgery or trauma.

Sepsis was unlikely in our patient, since he presented for his surgery in good health and with no preexisting signs or symptoms of infection. Acute cardioembolic stroke could have caused the neurologic signs, but this would not necessarily explain the coexisting hypoxia. An anaphylactic reaction to drugs or surgical cement would most likely present intraoperatively, shortly after exposure occurred, rather than several hours after surgery.

How common is fat embolism syndrome?

The occurrence rate of fat embolism syndrome has been reported to be 0.25% to 30% after multiple fractures and 0.1% to 12% after knee and hip joint surgery, with a mortality rate of 13% to 36%.^2,9–14 The rate of occurrence after unilateral total knee joint replacement has been reported to be 1.8% to 5%, and 4% to 12% after bilateral total knee replacement.^15–19

The syndrome is relatively more common with traumatic fractures of the lower extremities. However, it has also been reported with liposuction, total parenteral nutrition, bone marrow harvest and transplantation, burns, and acute pancreatitis, to mention a few.¹⁰

The broad range of reported incidence rates can be attributed to the fact that many studies were in patients with multiple trauma, whose concomitant injuries may have made it difficult to clearly define the contribution of fat embolism syndrome to the overall rates of morbidity and mortality. Also, different studies used different criteria to define the syndrome.

How does fat embolism syndrome occur?

Two hypotheses for how this syndrome occurs were proposed nearly a century ago.^20,21

The “mechanical” theory is that fat emboli are formed as a result of trauma and disruption of adipose tissue and other cells in the bone marrow. Increases in intramedullary pressure force the fat emboli through damaged medullary venous channels in the bone and into the circulation of the lower extremities. This embolization of fat causes an initial mechanical pulmonary obstruction. Mechanical obstruction by fat emboli in the pulmonary system leads to increased pulmonary pressures and an increase in right heart outflow pressure. The right heart becomes strained, leading to a decreased right-sided cardiac output. As a result, the left heart filling pressures diminish and hypotension ensues.²⁰

The “biochemical” theory, on the other hand, is that chylomicrons within the vascular system are modified and their stability is compromised as a result of stress. These traumatized chylomicrons then coalesce to form droplets of fat that accumulate in the pulmonary circulation and produce a mechanical obstruction. This would explain why nontraumatic, nonorthopedic insults can produce this syndrome.

Autopsy studies show that there is little correlation between the presence and quantity of intravascular fat and the severity of clinical symptoms, thus implying that the syndrome is caused by more than just mechanical obstruction. The biochemical theory postulates that fat globules within the circulatory system then cause the release of lipase from the pulmonary alveolar cells, which then hydrolyses the fat into free fatty acids. These free fatty acids cause an inflammatory reaction, complementmediated leukocyte aggregation, chemotoxin release, and subsequently endothelial damage. These vasoactive substances damage type 2 pneumocytes and lead to an increased permeability of the pulmonary capillary beds. Acute respiratory distress syndrome (ARDS) may ensue. Disseminated intravascular coagulation may occur as a result of the formation of microthrombi involving lipids, platelets, and fibrin.^21,22

Embolization of fat to the central nervous system can occur as fat globules cross into the systemic circulation via a patent foramen ovale, an atrioventricular shunt, or the pulmonary capillaries. This can then result in cerebral ischemia.²³

Although patent foramen ovale may seem the most direct route for cerebral embolization, the neurologic impairment and signs of cerebral emboli in fat embolism syndrome may occur in the absence of patent foramen ovale.^24,25 The fat globules may actually go through the lung capillaries, being flexible and forced through by increased pulmonary pressure.

But whether the cause of fat embolism syndrome is occlusion by globules, the release of biochemical mediators, or a combination of both is unknown. Both mechanisms are likely responsible. We can only suspect that the degree of fat load and intrinsic metabolic differences between individuals account for the variation in susceptibility.

FAT EMBOLI AFFECT THE LUNGS, SKIN, AND BRAIN

3. Where on the body is the rash associated with fat embolism syndrome usually seen?

• Face
• Near a site of fracture or surgery
• Chest, axilla, conjunctiva
• Distal extremities

Petechiae are part of the classic presenting triad of fat embolism syndrome, which also includes pulmonary and cerebral dysfunction.

Petechiae usually appear on the 2nd to 4th day after injury.²⁶ They are usually found across the chest, the anterior axillary folds, and the neck, as well as on the oral mucosa and the conjunctiva. The rash is caused by occlusion of dermal capillaries by fat, which increases their fragility.¹⁰

Pulmonary changes usually begin with tachypnea, dyspnea, and a drop in oxygen saturation, leading to generalized hypoxia. Respiratory symptoms are present in 100% of cases.² Respiratory symptoms can acutely develop with the sudden manipulation of a fracture, reaming of bone, or release of a limb tourniquet.²⁷

Body systems affected by fat embolism syndrome are summarized in Table 2.

4. How many hours after injury does fat embolism syndrome typically manifest?

• 1 to 2 hours
• 6 to 12 hours
• 12 to 20 hours
• 24 to 48 hours
• 72 to 84 hours

Most patients develop signs and symptoms 24 to 48 hours after injury. Patients presenting earlier than 12 hours usually have a more fulminant course.²⁹

The time between fat embolization and the development of fat embolism syndrome is thought to be related to the time required for the metabolic conversion of fat to free fatty acids.³⁰ We suspect that the early desaturation seen in our patient was the result of a heavy showering of fat intraoperatively. However, this could only be concluded after we had ruled out other causes of acute hypoxia and hypotension.

Fat embolism syndrome is a diagnosis of exclusion and is based on clinical criteria. No specific sign, symptom, or test is pathognomonic. It may often be confused with other conditions such as systemic inflammatory response syndrome or sepsis. However, the triad of respiratory and neurologic symptoms and petechiae coupled with the clinical picture of recent trauma or orthopedic surgery almost assures the diagnosis.

Fat embolism syndrome can range from subclinical to fulminating, with the more fulminating course attributable to a huge load of fat emboli, which leads to acute cor pulmonale.

Regardless of the criteria used, one must have a high index of suspicion for fat embolization syndrome in patients undergoing orthopedic procedures, particularly hip and knee surgery, and in patients with fractures, especially fractures of the femur, tibia, or pelvis and multiple, concomitant fractures.

CASE CONTINUED

Our patient was given furosemide (Lasix) empirically for diuresis and to improve oxygenation. However, his oxygen saturation remained low.

Chest radiography 4 hours after surgery showed bilateral pulmonary infiltrates. Serial electrocardiography showed no acute changes. Levels of cardiac enzymes and troponins were normal. Transthoracic echocardiography showed no left ventricular dysfunction, a normal right ventricle, and no evidence of valvular lesions. Urine and blood fat stains were negative, but the sputum stain was positive for copious extracellular fat. The patient became comatose 5 hours postoperatively. Computed tomography of the brain was normal. He was transferred to the surgical intensive care unit.

The clinical course was marked by hemodynamic instability requiring norepinephrine (Levophed) and vasopressin (Pitressin) for hypotension. Right ventricular filling pressures via central venous pressure monitoring showed no evidence of hypovolemia. The hemoglobin concentration and the hematocrit were stable, with no evidence of acute or ongoing bleeding. Blood, urine, and sputum cultures remained negative. Acute myocardial infarction was ruled out by serial electrocardiography, cardiac enzyme testing, and troponin testing.

Magnetic resonance imaging (MRI) of the brain on postoperative day 2 showed foci of acute ischemia suggestive of embolic phenomena consistent with fat embolism syndrome (Figure  1). Transthoracic echocardiography was repeated but again showed no evidence of a patent foramen ovale. Electroencephalography on postoperative day 4 showed severe, diffuse encephalopathy. There was no petechial skin rash. Other laboratory studies showed progressive thrombocytopenia with a platelet count of 53 × 199/L on postoperative day 3.

TESTS THAT AID THE CLINICAL DIAGNOSIS

Although no single laboratory test is pathognomonic for fat embolism syndrome, several tests may help raise suspicion of it, especially in the setting of fracture or an orthopedic surgical procedure.

Arterial blood gases must be measured. A Pao₂ of less than 60 mm Hg with no other obvious lung pathology in an orthopedic surgery patient is highly suspicious.¹² An alveolar-arterial gradient of greater than 100 mm Hg may further increase suspicion.

Tests for fat. The blood and urine may be examined for fat, although positive findings are not specific for fat embolism syndrome.³³ Fat in the urine indicates the occurrence of massive fat embolism, but this is not always accompanied by the syndrome.³⁴ Gurd and Wilson¹³ found fat globules larger than 8 μm circulating in the serum in all documented cases. They stated that, even though the relationship of large fat globules to the pathogenesis of the clinical picture remains obscure, the demonstration of their presence can be helpful in the diagnosis.¹³

Also, samples obtained with bronchoalveolar lavage may be examined for fat. The macrophages may be stained for fat using the oil red O stain. Again, this is a nonspecific marker, as fat-stained macrophages are seen in trauma patients,³⁵ but the finding has a very high negative predictive value.³⁶ Anemia, thrombocytopenia, hypofibrinogenemia, an elevated lipase level, and a high erythrocyte sedimentation rate may be found in fat embolism syndrome.¹³

Chest radiography may show bilateral infiltrates, as in ARDS, but this is not diagnostic for fat embolism syndrome.

Electrocardiography may show changes in ST and T waves and signs of right heart strain.

Transesophageal echocardiography may show increased right heart and pulmonary artery pressures.

Computed tomography is often negative,^37,38 but T2-weighted MRI is useful in the diagnosis of cerebral fat embolism syndrome, as it can show intracerebral microinfarcts as early as 4 hours after the onset of neurologic symptoms, and these findings correlate well with the clinical severity of brain injury.

Diffusion-weighted MRI may enhance the sensitivity and specificity of the neuroradiologic diagnosis. Diffusion-weighted MRI typically shows multiple nonconfluent areas of high-intensity signals or bright spots on a dark background, known as a “starfield pattern.” This pattern has been suggested to be pathognomonic of acute cerebral microinfarction. The abnormalities presumably reflect foci of cytotoxic edema that develops immediately, unlike vasogenic edema, seen in T2-weighted images, which may take up to several days to develop. Although these images are not necessarily specific for fat emboli, they are useful in helping make the diagnosis. Thus, diffusionweighted MRI should be done if fat embolism syndrome is suspected.^38,39

CASE CONCLUDED

The patient’s course in the intensive care unit was further complicated by gastrointestinal bleeding and renal failure. His neurologic status did not improve. Repeated MRI of the brain showed evolving bilateral watershed infarction throughout the cortices. The neurologic consult service diagnosed the patient as having severe encephalopathy with a very poor prognosis. The decision was made to withdraw care. He was placed under palliative care and died on postoperative day 22.

DRUG TREATMENT OF FAT EMBOLISM SYNDROME

5. Which of the following drugs has been proven to be effective in treating fat embolism syndrome?

• Intravenous ethanol
• Steroids
• Heparin
• Dextran
• Aspirin
• None of the above

None of the above has been proven to be effective in treating this disorder. The management is largely supportive. Thus, prevention, early diagnosis, and symptom management are vital.

Pulmonary and hemodynamic support are the cornerstones of successful treatment. Aggressive respiratory support is often needed. Management of acute lung injury and ARDS focuses on achieving acceptable gas exchange while preventing ventilator-associated lung injury. Intravascular volume must be supported. Inotropes and pulmonary vasodilators may be required to maintain hemodynamics. Exacerbation of central nervous system ischemia from hypotension or hypoxia should be avoided.

If the thrombocytopenia leads to clinical bleeding, platelet transfusions may be warranted.

Supportive care should include prophylaxis of deep venous thrombosis and of gastrointestinal bleeding, and maintenance of nutrition.⁴⁰ Patients who receive supportive care generally have a favorable outcome, with a mortality rate of less than 10%.²⁸

Drug studies have been inconclusive

Drugs suggested in the treatment of fat embolism syndrome include heparin, aspirin, dextran, hypertonic glucose, and alcohol, but the results have been inconclusive.^{3,11,23,40–43}

Heparin stimulates lipase activity, consequently decreasing the concentration of circulating fat globules. However, the increase in levels of free fatty acids may actually worsen the clinical picture. For this reason, and because of anticoagulation concerns and evidence of increased mortality rates, heparin is now contraindicated in the treatment of fat embolism syndrome.^2,41,43

Alcohol. Patients with a higher blood alcohol level at the time of injury have been reported to have a lower incidence of fat embolism syndrome. Alcohol inhibits lipase, suppressing the rise of free fatty acids. In experimental studies, the incidence of fat embolism syndrome was lower when the blood alcohol level was maintained at 20 mg/dL. However, no prospective randomized trial has been done to determine the clinical efficacy of ethanol as a treatment for this condition.^5,42

Dextran has been advocated, owing to its ability to improve small-vessel perfusion, but bleeding risk and acute renal failure associated with this drug have limited its use.⁵

N-acetylcysteine has been shown to attenuate fat-induced lung injury in a study of rats with induced fat embolism syndrome.⁴⁴

Corticosteroid treatment for this condition is controversial. Studies in patients with femoral and tibial fractures show that steroids reduce the incidence of fat embolism syndrome when given prophylactically, and those treated with steroids had a higher Pao₂ than controls. Doses of methylprednisolone in these studies ranged between 9 mg/kg to 90 mg/kg. A drawback of these studies is their small number of patients.^12,32,45,46

A meta-analysis⁴⁷ of randomized trials of corticosteroids to prevent fat embolism syndrome in patients with long-bone fractures identified 104 such studies. Only 7 of the 104 were considered adequate. In 389 patients with long-bone fractures, prophylactic corticosteroids reduced the risk of fat embolism syndrome by 78% (95% confidence interval 43%–92%) and corticosteroids also significantly reduced the risk of hypoxia with no difference in rates of infection or death. However, the overall quality of the trials was poor, and the authors of the meta-analysis concluded that more study is needed before corticosteroids could be formally recommended.⁴⁷

There is no evidence that steroids improve the overall clinical course of already established fat embolism syndrome.^12,32,45 The dosing and optimal timing of administration have also not been established. High doses pose a risk of septic complications, which may be devastating for the posttrauma or postoperative patient.

A 75-year-old man with type 2 diabetes and hypothyroidism underwent bilateral total knee replacement at our hospital.

His functional capacity had been moderately limited by knee pain, but he could easily climb one flight of stairs without symptoms. His medications at that time included levothyroxine (Synthroid) and metformin (Glucophage). He had no known cardiac or pulmonary disease. The preoperative evaluation, including laboratory tests and electrocardiography, was within normal limits.

Spinal anesthesia was used for surgery, and he was given 2 mg of midazolam (Versed) intravenously for sedation. No additional sedation was given. He was given oxygen via nasal cannula at 2 L/min.

All vital signs were stable at the start of the procedure. However, about halfway through, when the thigh tourniquet was released, his oxygen saturation dropped abruptly from 100% to 92%. All other vital signs remained stable, and he was asymptomatic, was oriented to person, time, and place, was conversing freely, and was in no distress. The oxygen flow was increased to 6 L/min, his oxygen saturation improved, and the procedure was then completed as planned.

At the conclusion of the surgery, before the patient was transported to the postanesthesia care unit (PACU) and while his oxygen flow rate was still 6 L/min, his oxygen saturation again dropped to 92%. A simple face mask was placed, and the oxygen flow rate was increased to 10 L/min. His oxygen saturation stayed low, near 90%.

Bleeding during surgery had been nominal. He had received 2 L of lactated Ringer’s solution and 500 mL of hetastarch (Hextend) during surgery. He continued to be asymptomatic in the PACU.

1. What is the most likely cause of oxygen desaturation during bilateral total knee arthroplasty?

• Fat embolism
• Intraoperative pneumonia
• Venous thromboembolism with pulmonary embolism
• Acute myocardial infarction
• Acute pulmonary edema
• Excessive sedation

The differential diagnosis of oxygen desaturation during orthopedic procedures is listed in Table 1.

Fat embolism is the most likely cause, particularly given the greater fatty embolic load that occurs with bilateral total knee arthroplasty than with unilateral total knee arthroplasty.

At what point the maximal showering of fat emboli occurs is not known. Fat may be released into the circulation with pressurization of the medullary canal during surgery or with manipulation of a fracture. The emboli may collect in the leg veins and then be released in a shower when the thigh tourniquet is released. Vasoactive mediators and methylmethacrylate cement released into the circulatory system after tourniquet deflation may also cause vasodilation, hypotension, and increased dead-space ventilation, resulting in hypoxia and a drop in end-tidal CO₂.

Pneumonia during surgery is rare without an apparent aspiration event.

Venous thromboembolism is possible but is more likely later in the postoperative period after major orthopedic surgery.

Acute myocardial infarction could present with hypoxia, particularly in a diabetic patient, who may not experience chest pain. However, intraoperative electrocardiographic changes would likely be seen. If myocardial infarction is suspected, postoperative serial electrocardiograms and measuring troponin and cardiac enzyme levels aid in the diagnosis.

Acute pulmonary edema is possible but not as highly suspected, as the patient had no history of congestive heart failure and received an appropriate amount of fluid for this type of surgery.

Excessive sedation could cause hypoventilation and, thus, oxygen desaturatation. However, this patient’s oxygen desaturatation began more than an hour after the midazolam was given. Midazolam is a short-acting benzodiazepine. It is unlikely that the patient would show signs of hypoventilation and oversedation an hour after the drug was given. Our patient also did not show any signs of excessive sedation, as he was awake and conversing during the surgery.

Fat emboli vs fat embolism syndrome

Fat embolism is the presence of fat drops within the systemic and pulmonary microcirculation, with or without clinical sequelae.¹ Fat embolism syndrome, on the other hand, is defined as injury to and dysfunction of one or more organs as a result of the embolization of fat, usually within 24 hours of injury or orthopedic surgery.²

Fat embolism syndrome is an unpredictable condition with a varied presentation. Fat droplets are thought to embolize via the venous circulation into the pulmonary arteries, occluding small blood vessels in the lung. However, they also get into the arterial circulation and occlude arteries in the brain, kidney, heart, and liver (more on this phenomenon below).

Fat embolism is reported to originate primarily from fractures of the femur, tibia, and pelvis.^2,3 As many as 90% of trauma patients have been shown to have evidence of fat embolism on autopsy.⁴ However, only a small number of patients develop the classic fat embolism syndrome,^2,3,5 Why some develop the syndrome and others do not is still unknown.

Orthopedic procedures associated with fat embolization include knee arthroplasty and hip arthroplasty, particularly if it involves intramedullary manipulation or medullary fixation.⁶ It has also been reported during spinal procedures in which pedicular screws are used.⁷ The syndrome occurs in 0.25% to 30% of patients following multiple fractures and in 0.1% to 12% of patients during or following knee or hip arthroplasty.

One study⁸ showed evidence of fat on transesophageal echocardiography in 88% of patients undergoing medullary reaming of lower-extremity fractures and hip hemiarthroplasty. Blood sampling from the right atrium confirmed that fat was responsible for the echocardiographic abnormalities. The study also showed that the severity of the embolic showering correlated with the severity of hypoxia and the decrease in end-tidal CO₂.⁸

CASE CONTINUED

On arrival at the PACU, our patient’s oxygen saturation was 94% while he was breathing oxygen via a simple face mask at a flow rate of 10 L/min. His heart rate was 60 bpm, blood pressure 110/60 mm Hg, and temperature 37.5°C (96.3°F). Chest sounds were normal on auscultation.

However, 3 hours later, his mental status rapidly deteriorated. He was oriented only to person, and he was drowsy. He had escalating respiratory distress with a rapid respiratory rate and decreasing oxygen saturation. At this point, auscultation of his chest wall revealed bilateral crackles and rales.

He was promptly intubated. Profuse fluid and secretions were noted to be coming from his lungs, filling the endotracheal tube. Arterial blood gas measurement showed a pH of 7.22, Pao₂ 64 mm Hg, and Paco₂ 56 mm Hg on 100% fraction of inspired oxygen, with no increased anion gap.

2. Which consequence of fat embolism is most likely at this time in this patient?

• Coexisting sepsis
• Fat embolism syndrome
• Acute cardioembolic stroke
• Anaphylaxis

Fat embolism syndrome should be highly suspected in this patient. As mentioned, it can affect many different organs. It is the most serious condition resulting from fat embolization after surgery or trauma.

Sepsis was unlikely in our patient, since he presented for his surgery in good health and with no preexisting signs or symptoms of infection. Acute cardioembolic stroke could have caused the neurologic signs, but this would not necessarily explain the coexisting hypoxia. An anaphylactic reaction to drugs or surgical cement would most likely present intraoperatively, shortly after exposure occurred, rather than several hours after surgery.

How common is fat embolism syndrome?

The occurrence rate of fat embolism syndrome has been reported to be 0.25% to 30% after multiple fractures and 0.1% to 12% after knee and hip joint surgery, with a mortality rate of 13% to 36%.^2,9–14 The rate of occurrence after unilateral total knee joint replacement has been reported to be 1.8% to 5%, and 4% to 12% after bilateral total knee replacement.^15–19

The syndrome is relatively more common with traumatic fractures of the lower extremities. However, it has also been reported with liposuction, total parenteral nutrition, bone marrow harvest and transplantation, burns, and acute pancreatitis, to mention a few.¹⁰

The broad range of reported incidence rates can be attributed to the fact that many studies were in patients with multiple trauma, whose concomitant injuries may have made it difficult to clearly define the contribution of fat embolism syndrome to the overall rates of morbidity and mortality. Also, different studies used different criteria to define the syndrome.

How does fat embolism syndrome occur?

Two hypotheses for how this syndrome occurs were proposed nearly a century ago.^20,21

The “mechanical” theory is that fat emboli are formed as a result of trauma and disruption of adipose tissue and other cells in the bone marrow. Increases in intramedullary pressure force the fat emboli through damaged medullary venous channels in the bone and into the circulation of the lower extremities. This embolization of fat causes an initial mechanical pulmonary obstruction. Mechanical obstruction by fat emboli in the pulmonary system leads to increased pulmonary pressures and an increase in right heart outflow pressure. The right heart becomes strained, leading to a decreased right-sided cardiac output. As a result, the left heart filling pressures diminish and hypotension ensues.²⁰

The “biochemical” theory, on the other hand, is that chylomicrons within the vascular system are modified and their stability is compromised as a result of stress. These traumatized chylomicrons then coalesce to form droplets of fat that accumulate in the pulmonary circulation and produce a mechanical obstruction. This would explain why nontraumatic, nonorthopedic insults can produce this syndrome.

Autopsy studies show that there is little correlation between the presence and quantity of intravascular fat and the severity of clinical symptoms, thus implying that the syndrome is caused by more than just mechanical obstruction. The biochemical theory postulates that fat globules within the circulatory system then cause the release of lipase from the pulmonary alveolar cells, which then hydrolyses the fat into free fatty acids. These free fatty acids cause an inflammatory reaction, complementmediated leukocyte aggregation, chemotoxin release, and subsequently endothelial damage. These vasoactive substances damage type 2 pneumocytes and lead to an increased permeability of the pulmonary capillary beds. Acute respiratory distress syndrome (ARDS) may ensue. Disseminated intravascular coagulation may occur as a result of the formation of microthrombi involving lipids, platelets, and fibrin.^21,22

Embolization of fat to the central nervous system can occur as fat globules cross into the systemic circulation via a patent foramen ovale, an atrioventricular shunt, or the pulmonary capillaries. This can then result in cerebral ischemia.²³

Although patent foramen ovale may seem the most direct route for cerebral embolization, the neurologic impairment and signs of cerebral emboli in fat embolism syndrome may occur in the absence of patent foramen ovale.^24,25 The fat globules may actually go through the lung capillaries, being flexible and forced through by increased pulmonary pressure.

But whether the cause of fat embolism syndrome is occlusion by globules, the release of biochemical mediators, or a combination of both is unknown. Both mechanisms are likely responsible. We can only suspect that the degree of fat load and intrinsic metabolic differences between individuals account for the variation in susceptibility.

FAT EMBOLI AFFECT THE LUNGS, SKIN, AND BRAIN

3. Where on the body is the rash associated with fat embolism syndrome usually seen?

• Face
• Near a site of fracture or surgery
• Chest, axilla, conjunctiva
• Distal extremities

Petechiae are part of the classic presenting triad of fat embolism syndrome, which also includes pulmonary and cerebral dysfunction.

Petechiae usually appear on the 2nd to 4th day after injury.²⁶ They are usually found across the chest, the anterior axillary folds, and the neck, as well as on the oral mucosa and the conjunctiva. The rash is caused by occlusion of dermal capillaries by fat, which increases their fragility.¹⁰

Pulmonary changes usually begin with tachypnea, dyspnea, and a drop in oxygen saturation, leading to generalized hypoxia. Respiratory symptoms are present in 100% of cases.² Respiratory symptoms can acutely develop with the sudden manipulation of a fracture, reaming of bone, or release of a limb tourniquet.²⁷

Body systems affected by fat embolism syndrome are summarized in Table 2.

4. How many hours after injury does fat embolism syndrome typically manifest?

• 1 to 2 hours
• 6 to 12 hours
• 12 to 20 hours
• 24 to 48 hours
• 72 to 84 hours

Most patients develop signs and symptoms 24 to 48 hours after injury. Patients presenting earlier than 12 hours usually have a more fulminant course.²⁹

The time between fat embolization and the development of fat embolism syndrome is thought to be related to the time required for the metabolic conversion of fat to free fatty acids.³⁰ We suspect that the early desaturation seen in our patient was the result of a heavy showering of fat intraoperatively. However, this could only be concluded after we had ruled out other causes of acute hypoxia and hypotension.

Fat embolism syndrome is a diagnosis of exclusion and is based on clinical criteria. No specific sign, symptom, or test is pathognomonic. It may often be confused with other conditions such as systemic inflammatory response syndrome or sepsis. However, the triad of respiratory and neurologic symptoms and petechiae coupled with the clinical picture of recent trauma or orthopedic surgery almost assures the diagnosis.

Fat embolism syndrome can range from subclinical to fulminating, with the more fulminating course attributable to a huge load of fat emboli, which leads to acute cor pulmonale.

Regardless of the criteria used, one must have a high index of suspicion for fat embolization syndrome in patients undergoing orthopedic procedures, particularly hip and knee surgery, and in patients with fractures, especially fractures of the femur, tibia, or pelvis and multiple, concomitant fractures.

CASE CONTINUED

Our patient was given furosemide (Lasix) empirically for diuresis and to improve oxygenation. However, his oxygen saturation remained low.

Chest radiography 4 hours after surgery showed bilateral pulmonary infiltrates. Serial electrocardiography showed no acute changes. Levels of cardiac enzymes and troponins were normal. Transthoracic echocardiography showed no left ventricular dysfunction, a normal right ventricle, and no evidence of valvular lesions. Urine and blood fat stains were negative, but the sputum stain was positive for copious extracellular fat. The patient became comatose 5 hours postoperatively. Computed tomography of the brain was normal. He was transferred to the surgical intensive care unit.

The clinical course was marked by hemodynamic instability requiring norepinephrine (Levophed) and vasopressin (Pitressin) for hypotension. Right ventricular filling pressures via central venous pressure monitoring showed no evidence of hypovolemia. The hemoglobin concentration and the hematocrit were stable, with no evidence of acute or ongoing bleeding. Blood, urine, and sputum cultures remained negative. Acute myocardial infarction was ruled out by serial electrocardiography, cardiac enzyme testing, and troponin testing.

Magnetic resonance imaging (MRI) of the brain on postoperative day 2 showed foci of acute ischemia suggestive of embolic phenomena consistent with fat embolism syndrome (Figure  1). Transthoracic echocardiography was repeated but again showed no evidence of a patent foramen ovale. Electroencephalography on postoperative day 4 showed severe, diffuse encephalopathy. There was no petechial skin rash. Other laboratory studies showed progressive thrombocytopenia with a platelet count of 53 × 199/L on postoperative day 3.

TESTS THAT AID THE CLINICAL DIAGNOSIS

Although no single laboratory test is pathognomonic for fat embolism syndrome, several tests may help raise suspicion of it, especially in the setting of fracture or an orthopedic surgical procedure.

Arterial blood gases must be measured. A Pao₂ of less than 60 mm Hg with no other obvious lung pathology in an orthopedic surgery patient is highly suspicious.¹² An alveolar-arterial gradient of greater than 100 mm Hg may further increase suspicion.

Tests for fat. The blood and urine may be examined for fat, although positive findings are not specific for fat embolism syndrome.³³ Fat in the urine indicates the occurrence of massive fat embolism, but this is not always accompanied by the syndrome.³⁴ Gurd and Wilson¹³ found fat globules larger than 8 μm circulating in the serum in all documented cases. They stated that, even though the relationship of large fat globules to the pathogenesis of the clinical picture remains obscure, the demonstration of their presence can be helpful in the diagnosis.¹³

Also, samples obtained with bronchoalveolar lavage may be examined for fat. The macrophages may be stained for fat using the oil red O stain. Again, this is a nonspecific marker, as fat-stained macrophages are seen in trauma patients,³⁵ but the finding has a very high negative predictive value.³⁶ Anemia, thrombocytopenia, hypofibrinogenemia, an elevated lipase level, and a high erythrocyte sedimentation rate may be found in fat embolism syndrome.¹³

Chest radiography may show bilateral infiltrates, as in ARDS, but this is not diagnostic for fat embolism syndrome.

Electrocardiography may show changes in ST and T waves and signs of right heart strain.

Transesophageal echocardiography may show increased right heart and pulmonary artery pressures.

Computed tomography is often negative,^37,38 but T2-weighted MRI is useful in the diagnosis of cerebral fat embolism syndrome, as it can show intracerebral microinfarcts as early as 4 hours after the onset of neurologic symptoms, and these findings correlate well with the clinical severity of brain injury.

Diffusion-weighted MRI may enhance the sensitivity and specificity of the neuroradiologic diagnosis. Diffusion-weighted MRI typically shows multiple nonconfluent areas of high-intensity signals or bright spots on a dark background, known as a “starfield pattern.” This pattern has been suggested to be pathognomonic of acute cerebral microinfarction. The abnormalities presumably reflect foci of cytotoxic edema that develops immediately, unlike vasogenic edema, seen in T2-weighted images, which may take up to several days to develop. Although these images are not necessarily specific for fat emboli, they are useful in helping make the diagnosis. Thus, diffusionweighted MRI should be done if fat embolism syndrome is suspected.^38,39

CASE CONCLUDED

The patient’s course in the intensive care unit was further complicated by gastrointestinal bleeding and renal failure. His neurologic status did not improve. Repeated MRI of the brain showed evolving bilateral watershed infarction throughout the cortices. The neurologic consult service diagnosed the patient as having severe encephalopathy with a very poor prognosis. The decision was made to withdraw care. He was placed under palliative care and died on postoperative day 22.

DRUG TREATMENT OF FAT EMBOLISM SYNDROME

5. Which of the following drugs has been proven to be effective in treating fat embolism syndrome?

• Intravenous ethanol
• Steroids
• Heparin
• Dextran
• Aspirin
• None of the above

None of the above has been proven to be effective in treating this disorder. The management is largely supportive. Thus, prevention, early diagnosis, and symptom management are vital.

Pulmonary and hemodynamic support are the cornerstones of successful treatment. Aggressive respiratory support is often needed. Management of acute lung injury and ARDS focuses on achieving acceptable gas exchange while preventing ventilator-associated lung injury. Intravascular volume must be supported. Inotropes and pulmonary vasodilators may be required to maintain hemodynamics. Exacerbation of central nervous system ischemia from hypotension or hypoxia should be avoided.

If the thrombocytopenia leads to clinical bleeding, platelet transfusions may be warranted.

Supportive care should include prophylaxis of deep venous thrombosis and of gastrointestinal bleeding, and maintenance of nutrition.⁴⁰ Patients who receive supportive care generally have a favorable outcome, with a mortality rate of less than 10%.²⁸

Drug studies have been inconclusive

Drugs suggested in the treatment of fat embolism syndrome include heparin, aspirin, dextran, hypertonic glucose, and alcohol, but the results have been inconclusive.^{3,11,23,40–43}

Heparin stimulates lipase activity, consequently decreasing the concentration of circulating fat globules. However, the increase in levels of free fatty acids may actually worsen the clinical picture. For this reason, and because of anticoagulation concerns and evidence of increased mortality rates, heparin is now contraindicated in the treatment of fat embolism syndrome.^2,41,43

Alcohol. Patients with a higher blood alcohol level at the time of injury have been reported to have a lower incidence of fat embolism syndrome. Alcohol inhibits lipase, suppressing the rise of free fatty acids. In experimental studies, the incidence of fat embolism syndrome was lower when the blood alcohol level was maintained at 20 mg/dL. However, no prospective randomized trial has been done to determine the clinical efficacy of ethanol as a treatment for this condition.^5,42

Dextran has been advocated, owing to its ability to improve small-vessel perfusion, but bleeding risk and acute renal failure associated with this drug have limited its use.⁵

N-acetylcysteine has been shown to attenuate fat-induced lung injury in a study of rats with induced fat embolism syndrome.⁴⁴

Corticosteroid treatment for this condition is controversial. Studies in patients with femoral and tibial fractures show that steroids reduce the incidence of fat embolism syndrome when given prophylactically, and those treated with steroids had a higher Pao₂ than controls. Doses of methylprednisolone in these studies ranged between 9 mg/kg to 90 mg/kg. A drawback of these studies is their small number of patients.^12,32,45,46

A meta-analysis⁴⁷ of randomized trials of corticosteroids to prevent fat embolism syndrome in patients with long-bone fractures identified 104 such studies. Only 7 of the 104 were considered adequate. In 389 patients with long-bone fractures, prophylactic corticosteroids reduced the risk of fat embolism syndrome by 78% (95% confidence interval 43%–92%) and corticosteroids also significantly reduced the risk of hypoxia with no difference in rates of infection or death. However, the overall quality of the trials was poor, and the authors of the meta-analysis concluded that more study is needed before corticosteroids could be formally recommended.⁴⁷

There is no evidence that steroids improve the overall clinical course of already established fat embolism syndrome.^12,32,45 The dosing and optimal timing of administration have also not been established. High doses pose a risk of septic complications, which may be devastating for the posttrauma or postoperative patient.