Imaging

Rarely these days do we hear about a new, nongenetic clinical syndrome, and even more rarely does the news make us rapidly change our practice behavior. But the description of nephrogenic systemic fibrosis and its epidemiologic association with gadolinium exposure in patients with chronic renal disease have led to immediate changes in our choice of imaging studies.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

Rarely these days do we hear about a new, nongenetic clinical syndrome, and even more rarely does the news make us rapidly change our practice behavior. But the description of nephrogenic systemic fibrosis and its epidemiologic association with gadolinium exposure in patients with chronic renal disease have led to immediate changes in our choice of imaging studies.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

Rarely these days do we hear about a new, nongenetic clinical syndrome, and even more rarely does the news make us rapidly change our practice behavior. But the description of nephrogenic systemic fibrosis and its epidemiologic association with gadolinium exposure in patients with chronic renal disease have led to immediate changes in our choice of imaging studies.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

 

 

Gadolinium exposure

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

 

 

Gadolinium exposure

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

 

 

Gadolinium exposure

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

Cutaneous changes are the most predominant and impressive manifestations. NSF typically causes dermal hardening with tethering to deep dermal tissues, giving the skin the appearance of textured plaques, papules, or nodules with irregular edges and a brawny wooden texture to palpation (Figure 1). The lesions can be erythematous or brown-pigmented and can be painful and pruritic. NSF typically presents between the ankles and the thighs in a symmetric fashion and progresses proximally and distally to involve the entire lower extremities. Upper extremity involvement occurs frequently, but usually with lower extremity disease.² The trunk is involved less commonly than the legs and arms, and usually late in extensive disease. The face is typically spared (Figure 2).

NSF can cause loss of motion and contractures in multiple joints, leading to almost total loss of function and devastating debility within a short time—days to a few weeks.² These contractures are attributed to periarticular fibrosis of the overlying skin and subcutaneous tissue rather than to erosive joint disease. About 5% of patients develop a fulminant form of NSF³; these patients may become wheelchair-dependent.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

 

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

 

DIFFERENTIAL DIAGNOSIS

Other disorders that can cause thickening and hardening of the skin of the extremities and trunk include systemic sclerosis or scleroderma, scleromyxedema, and eosinophilic fasciitis (Table 1). However, skin thickening, tethering, and hyperpigmentation in a patient with chronic kidney disease or end-stage renal disease after exposure to gadolinium-containing contrast agents suggests NSF.

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

 

 

A cross-sectional study

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

 

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

Cutaneous changes are the most predominant and impressive manifestations. NSF typically causes dermal hardening with tethering to deep dermal tissues, giving the skin the appearance of textured plaques, papules, or nodules with irregular edges and a brawny wooden texture to palpation (Figure 1). The lesions can be erythematous or brown-pigmented and can be painful and pruritic. NSF typically presents between the ankles and the thighs in a symmetric fashion and progresses proximally and distally to involve the entire lower extremities. Upper extremity involvement occurs frequently, but usually with lower extremity disease.² The trunk is involved less commonly than the legs and arms, and usually late in extensive disease. The face is typically spared (Figure 2).

NSF can cause loss of motion and contractures in multiple joints, leading to almost total loss of function and devastating debility within a short time—days to a few weeks.² These contractures are attributed to periarticular fibrosis of the overlying skin and subcutaneous tissue rather than to erosive joint disease. About 5% of patients develop a fulminant form of NSF³; these patients may become wheelchair-dependent.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

 

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

 

DIFFERENTIAL DIAGNOSIS

Other disorders that can cause thickening and hardening of the skin of the extremities and trunk include systemic sclerosis or scleroderma, scleromyxedema, and eosinophilic fasciitis (Table 1). However, skin thickening, tethering, and hyperpigmentation in a patient with chronic kidney disease or end-stage renal disease after exposure to gadolinium-containing contrast agents suggests NSF.

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

 

 

A cross-sectional study

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

 

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

Cutaneous changes are the most predominant and impressive manifestations. NSF typically causes dermal hardening with tethering to deep dermal tissues, giving the skin the appearance of textured plaques, papules, or nodules with irregular edges and a brawny wooden texture to palpation (Figure 1). The lesions can be erythematous or brown-pigmented and can be painful and pruritic. NSF typically presents between the ankles and the thighs in a symmetric fashion and progresses proximally and distally to involve the entire lower extremities. Upper extremity involvement occurs frequently, but usually with lower extremity disease.² The trunk is involved less commonly than the legs and arms, and usually late in extensive disease. The face is typically spared (Figure 2).

NSF can cause loss of motion and contractures in multiple joints, leading to almost total loss of function and devastating debility within a short time—days to a few weeks.² These contractures are attributed to periarticular fibrosis of the overlying skin and subcutaneous tissue rather than to erosive joint disease. About 5% of patients develop a fulminant form of NSF³; these patients may become wheelchair-dependent.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

 

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

 

DIFFERENTIAL DIAGNOSIS

Other disorders that can cause thickening and hardening of the skin of the extremities and trunk include systemic sclerosis or scleroderma, scleromyxedema, and eosinophilic fasciitis (Table 1). However, skin thickening, tethering, and hyperpigmentation in a patient with chronic kidney disease or end-stage renal disease after exposure to gadolinium-containing contrast agents suggests NSF.

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

 

 

A cross-sectional study

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

 

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

Black box restrictions imposed by the Food and Drug Administration on the use of ultrasound contrast agents have caused consternation among cardiologists and radiologists who fear that the agency's decision will have a chilling effect upon the use and further development of these “microbubble” agents.

Efforts at getting the FDA to reconsider the label change, which was issued in October (CARDIOLOGY NEWS, November 2008, p. 20), may have borne fruit in December, when a delegation of four cardiologists met with Dr. Rafel D. Rieves, acting director of the FDA's Division of Medical Imaging and Hematology Products, and his staff in Silver Spring, Md. The cardiologists were Dr. Steven B. Feinstein of the Rush Medical College, Chicago; Dr. Jonathan H. Goldman of the University of California, San Francisco; Dr. Paul A. Grayburn of the Baylor University Medical Center, Dallas; and Dr. Michael L. Main of the Mid-America Heart Institute, Kansas City, Missouri.

The emissaries represented an international group of 160 cardiologists, radiologists, and other medical imaging professionals who had earlier signed a letter to Dr. Rieves asking that the FDA division convene a panel of cardiologists to assess fully the adverse events that have been attributed to the contrast agents and determine the most appropriate corrective actions.

The letter, dated Nov. 10, 2007, said the black box warning ignores the proven efficacy and established safety of perflutren gas microspheres for use as echocardiographic contrast agents, as well as the potential risks of alternative procedures and the likely confounding effect of pseudocomplications that may be pertinent to some of the deaths associated with use of the ultrasound contrast agents.

“Our presentation to the division of medical imaging focused on the critical role that ultrasound contrast agents play in the diagnosis and management of patients with acute coronary syndromes, decompensated heart failure, and respiratory failure,” Dr. Main said in an interview.

“These are patient groups [that] must now undergo more invasive alternative testing when their baseline echocardiographic imaging is inadequate. We were encouraged that the FDA seemed receptive to the basic premise, which was that the risk-benefit ratio of ultrasound contrast is so favorable that the new contraindications will result in more harm than good,” said Dr. Main, medical director of the echocardiography laboratory at the Mid America Heart Institute of St. Luke's Health System.

Dr. Main has received research support from and has a consultant relationship with, POINT Biomedical Corp., Acusphere Inc., and Bristol-Myers Squibb Medical Imaging Inc. Dr. Goldman is a POINT Biomedical shareholder and has a consultant relationship with Bristol-Myers Squibb Medical Imaging. Dr. Grayburn has received grant support from Acusphere, POINT Biomedical, Medtronic Inc., and Guidant Corp.

Two ultrasound contrast agents, Definity (Bristol-Meyers Squibb) and Optison (GE Healthcare), are approved for use to improve suboptimal echocardiograms. Both consist of injectable, perflutren-filled lipid microspheres. Optison is back on the market following a 2-year hiatus attributed to a manufacturing recall.

In issuing the warning, the FDA said it had received reports of serious cardiopulmonary reactions following contrast injection, including 10 deaths following the administration of Definity and 1 death following an Optison injection. Of those 11 deaths, 4 were caused by cardiac arrest and occurred during or within 30 minutes of infusion; the remaining 7 deaths occurred within 12 hours of administration.

In addition, about 190 nonfatal serious reactions were reported in the United States following administration of Definity and Optison.

The boxed warning states that “serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes” after administration of Definity or Optison. Referring to contraindications described on the label, the warning requires that all patients be assessed for the presence of any condition that precludes administration of the contrast agent. In addition, patients are to be monitored during, and for 30 minutes following, contrast administration, including vital sign measurements and electrocardiography in all patients and cutaneous oxygen saturation in patients at risk for hypoxemia. Resuscitation equipment and trained personnel should be readily available.

Additional pressure on the FDA has come from the 12,000-member American Society of Echocardiography (ASE). In late November, ASE President Thomas Ryan wrote a letter to Dr. Andrew C. von Eschenbach, the FDA Commissioner, requesting an opportunity to engage in a dialogue with the agency regarding its decision to issue the black box warning.

“The risk of an adverse event resulting from the administration of a contrast agent must be weighed against the value of a correct diagnosis,” said Dr. Ryan, who noted that he has no conflicts of interest related to the topic. “Because contrast agents improve accuracy and reduce the need for additional downstream testing, we believe their continued use in appropriate cases is justified and consistent with the mission of both the FDA and the ASE,” wrote Dr. Ryan, who is the John G. & Jeanne Bonnet McCoy Chair in Cardiovascular Medicine and the director of the Ohio State University Heart Center in Columbus.

 

A spokesman for the FDA said, “the letter has been received, and the agency is working on a response.” The agency had no further comment on the issue.

“The near-term result of this black box warning, in my opinion, will be a dramatic drop in the use of ultrasound contrast agents, and as a result, the quality of echocardiograms will go down until this scare wears off,” Dr. Peter S. Rahko said in an interview.

“The reaction of the FDA and the rules they imposed seem to be excessive,” said Dr. Rahko of the departments of medicine and public health and director of the adult echocardiography laboratory at the University of Wisconsin, Madison.

But Dr. Rahko does agree with the FDA's expressed concerns that an unknown proportion of patients may suffer allergic reactions to the microsphere contrast agents, which has occurred on a few occasions at Wisconsin.

When the black box warning was issued, the use of contrast-enhanced ultrasound ceased at the University of Wisconsin and other centers. The Wisconsin team developed a two-stage screening protocol for stable and critically ill patients (see box), said Dr. Rahko, who was one of the original investigators in the Definity trials but has no financial conflicts related to the topic.

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Visualization of a left ventricular thrombus is clearer in an echocardiogram with contrast (right) than in a noncontrast image. IMAGES COURTESY DR. PETER S. RAHKO/UNIVERSITY OF WISCONSIN HOSPITAL

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Adjusting to the Black Box Alert

After the FDA issued its warning on ultrasound contrast agents, Dr. Rahko and his colleagues at the University of Wisconsin halted their practice of automatically ordering contrast following a bad-quality echocardiogram.

Previously, “If the patient was appropriate, then the contrast could be administered in the intensive care unit with the assistance of nursing personnel and others taking care of the patient,” Dr. Rahko said.

The hospital now operates with a more costly and time-consuming two-tiered protocol that is tailored to stable and unstable patients undergoing echocardiography.

For an unstable hospitalized patient, the baseline sonogram is read by a cardiologist; if it's of poor quality and a redo with Definity seems appropriate, the cardiologist recommends that the study should be repeated with contrast. “The patient care team now becomes the responsible party ordering the contrast.”

The protocol for stable patients scheduled for echo in the inpatient or outpatient setting shifts responsibility for the final decision to the patient and includes screening for conditions that might contraindicate the use of the microspheres. “Our nurses—in the echo lab or at other sites—screen the patients using oxymetry to make sure that oxygen saturation levels are appropriate and that patients don't have significant hypoxia or lung disease,” Dr. Rahko explained.

Patients who are stable and cleared for a contrast injection are given an information sheet that explains the procedure, why it's being done, and the risks it poses. The patient then decides whether or not to proceed. And “we keep the patient under direct observation for 30 minutes, in case of an allergic reaction,” he said.

Black box restrictions imposed by the Food and Drug Administration on the use of ultrasound contrast agents have caused consternation among cardiologists and radiologists who fear that the agency's decision will have a chilling effect upon the use and further development of these “microbubble” agents.

Efforts at getting the FDA to reconsider the label change, which was issued in October (CARDIOLOGY NEWS, November 2008, p. 20), may have borne fruit in December, when a delegation of four cardiologists met with Dr. Rafel D. Rieves, acting director of the FDA's Division of Medical Imaging and Hematology Products, and his staff in Silver Spring, Md. The cardiologists were Dr. Steven B. Feinstein of the Rush Medical College, Chicago; Dr. Jonathan H. Goldman of the University of California, San Francisco; Dr. Paul A. Grayburn of the Baylor University Medical Center, Dallas; and Dr. Michael L. Main of the Mid-America Heart Institute, Kansas City, Missouri.

The emissaries represented an international group of 160 cardiologists, radiologists, and other medical imaging professionals who had earlier signed a letter to Dr. Rieves asking that the FDA division convene a panel of cardiologists to assess fully the adverse events that have been attributed to the contrast agents and determine the most appropriate corrective actions.

The letter, dated Nov. 10, 2007, said the black box warning ignores the proven efficacy and established safety of perflutren gas microspheres for use as echocardiographic contrast agents, as well as the potential risks of alternative procedures and the likely confounding effect of pseudocomplications that may be pertinent to some of the deaths associated with use of the ultrasound contrast agents.

“Our presentation to the division of medical imaging focused on the critical role that ultrasound contrast agents play in the diagnosis and management of patients with acute coronary syndromes, decompensated heart failure, and respiratory failure,” Dr. Main said in an interview.

“These are patient groups [that] must now undergo more invasive alternative testing when their baseline echocardiographic imaging is inadequate. We were encouraged that the FDA seemed receptive to the basic premise, which was that the risk-benefit ratio of ultrasound contrast is so favorable that the new contraindications will result in more harm than good,” said Dr. Main, medical director of the echocardiography laboratory at the Mid America Heart Institute of St. Luke's Health System.

Dr. Main has received research support from and has a consultant relationship with, POINT Biomedical Corp., Acusphere Inc., and Bristol-Myers Squibb Medical Imaging Inc. Dr. Goldman is a POINT Biomedical shareholder and has a consultant relationship with Bristol-Myers Squibb Medical Imaging. Dr. Grayburn has received grant support from Acusphere, POINT Biomedical, Medtronic Inc., and Guidant Corp.

Two ultrasound contrast agents, Definity (Bristol-Meyers Squibb) and Optison (GE Healthcare), are approved for use to improve suboptimal echocardiograms. Both consist of injectable, perflutren-filled lipid microspheres. Optison is back on the market following a 2-year hiatus attributed to a manufacturing recall.

In issuing the warning, the FDA said it had received reports of serious cardiopulmonary reactions following contrast injection, including 10 deaths following the administration of Definity and 1 death following an Optison injection. Of those 11 deaths, 4 were caused by cardiac arrest and occurred during or within 30 minutes of infusion; the remaining 7 deaths occurred within 12 hours of administration.

In addition, about 190 nonfatal serious reactions were reported in the United States following administration of Definity and Optison.

The boxed warning states that “serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes” after administration of Definity or Optison. Referring to contraindications described on the label, the warning requires that all patients be assessed for the presence of any condition that precludes administration of the contrast agent. In addition, patients are to be monitored during, and for 30 minutes following, contrast administration, including vital sign measurements and electrocardiography in all patients and cutaneous oxygen saturation in patients at risk for hypoxemia. Resuscitation equipment and trained personnel should be readily available.

Additional pressure on the FDA has come from the 12,000-member American Society of Echocardiography (ASE). In late November, ASE President Thomas Ryan wrote a letter to Dr. Andrew C. von Eschenbach, the FDA Commissioner, requesting an opportunity to engage in a dialogue with the agency regarding its decision to issue the black box warning.

“The risk of an adverse event resulting from the administration of a contrast agent must be weighed against the value of a correct diagnosis,” said Dr. Ryan, who noted that he has no conflicts of interest related to the topic. “Because contrast agents improve accuracy and reduce the need for additional downstream testing, we believe their continued use in appropriate cases is justified and consistent with the mission of both the FDA and the ASE,” wrote Dr. Ryan, who is the John G. & Jeanne Bonnet McCoy Chair in Cardiovascular Medicine and the director of the Ohio State University Heart Center in Columbus.

 

A spokesman for the FDA said, “the letter has been received, and the agency is working on a response.” The agency had no further comment on the issue.

“The near-term result of this black box warning, in my opinion, will be a dramatic drop in the use of ultrasound contrast agents, and as a result, the quality of echocardiograms will go down until this scare wears off,” Dr. Peter S. Rahko said in an interview.

“The reaction of the FDA and the rules they imposed seem to be excessive,” said Dr. Rahko of the departments of medicine and public health and director of the adult echocardiography laboratory at the University of Wisconsin, Madison.

But Dr. Rahko does agree with the FDA's expressed concerns that an unknown proportion of patients may suffer allergic reactions to the microsphere contrast agents, which has occurred on a few occasions at Wisconsin.

When the black box warning was issued, the use of contrast-enhanced ultrasound ceased at the University of Wisconsin and other centers. The Wisconsin team developed a two-stage screening protocol for stable and critically ill patients (see box), said Dr. Rahko, who was one of the original investigators in the Definity trials but has no financial conflicts related to the topic.

Document

70107_fx1.sml

Visualization of a left ventricular thrombus is clearer in an echocardiogram with contrast (right) than in a noncontrast image. IMAGES COURTESY DR. PETER S. RAHKO/UNIVERSITY OF WISCONSIN HOSPITAL

Document

70107_fx2.sml

Adjusting to the Black Box Alert

After the FDA issued its warning on ultrasound contrast agents, Dr. Rahko and his colleagues at the University of Wisconsin halted their practice of automatically ordering contrast following a bad-quality echocardiogram.

Previously, “If the patient was appropriate, then the contrast could be administered in the intensive care unit with the assistance of nursing personnel and others taking care of the patient,” Dr. Rahko said.

The hospital now operates with a more costly and time-consuming two-tiered protocol that is tailored to stable and unstable patients undergoing echocardiography.

For an unstable hospitalized patient, the baseline sonogram is read by a cardiologist; if it's of poor quality and a redo with Definity seems appropriate, the cardiologist recommends that the study should be repeated with contrast. “The patient care team now becomes the responsible party ordering the contrast.”

The protocol for stable patients scheduled for echo in the inpatient or outpatient setting shifts responsibility for the final decision to the patient and includes screening for conditions that might contraindicate the use of the microspheres. “Our nurses—in the echo lab or at other sites—screen the patients using oxymetry to make sure that oxygen saturation levels are appropriate and that patients don't have significant hypoxia or lung disease,” Dr. Rahko explained.

Patients who are stable and cleared for a contrast injection are given an information sheet that explains the procedure, why it's being done, and the risks it poses. The patient then decides whether or not to proceed. And “we keep the patient under direct observation for 30 minutes, in case of an allergic reaction,” he said.

Black box restrictions imposed by the Food and Drug Administration on the use of ultrasound contrast agents have caused consternation among cardiologists and radiologists who fear that the agency's decision will have a chilling effect upon the use and further development of these “microbubble” agents.

Efforts at getting the FDA to reconsider the label change, which was issued in October (CARDIOLOGY NEWS, November 2008, p. 20), may have borne fruit in December, when a delegation of four cardiologists met with Dr. Rafel D. Rieves, acting director of the FDA's Division of Medical Imaging and Hematology Products, and his staff in Silver Spring, Md. The cardiologists were Dr. Steven B. Feinstein of the Rush Medical College, Chicago; Dr. Jonathan H. Goldman of the University of California, San Francisco; Dr. Paul A. Grayburn of the Baylor University Medical Center, Dallas; and Dr. Michael L. Main of the Mid-America Heart Institute, Kansas City, Missouri.

The emissaries represented an international group of 160 cardiologists, radiologists, and other medical imaging professionals who had earlier signed a letter to Dr. Rieves asking that the FDA division convene a panel of cardiologists to assess fully the adverse events that have been attributed to the contrast agents and determine the most appropriate corrective actions.

The letter, dated Nov. 10, 2007, said the black box warning ignores the proven efficacy and established safety of perflutren gas microspheres for use as echocardiographic contrast agents, as well as the potential risks of alternative procedures and the likely confounding effect of pseudocomplications that may be pertinent to some of the deaths associated with use of the ultrasound contrast agents.

“Our presentation to the division of medical imaging focused on the critical role that ultrasound contrast agents play in the diagnosis and management of patients with acute coronary syndromes, decompensated heart failure, and respiratory failure,” Dr. Main said in an interview.

“These are patient groups [that] must now undergo more invasive alternative testing when their baseline echocardiographic imaging is inadequate. We were encouraged that the FDA seemed receptive to the basic premise, which was that the risk-benefit ratio of ultrasound contrast is so favorable that the new contraindications will result in more harm than good,” said Dr. Main, medical director of the echocardiography laboratory at the Mid America Heart Institute of St. Luke's Health System.

Dr. Main has received research support from and has a consultant relationship with, POINT Biomedical Corp., Acusphere Inc., and Bristol-Myers Squibb Medical Imaging Inc. Dr. Goldman is a POINT Biomedical shareholder and has a consultant relationship with Bristol-Myers Squibb Medical Imaging. Dr. Grayburn has received grant support from Acusphere, POINT Biomedical, Medtronic Inc., and Guidant Corp.

Two ultrasound contrast agents, Definity (Bristol-Meyers Squibb) and Optison (GE Healthcare), are approved for use to improve suboptimal echocardiograms. Both consist of injectable, perflutren-filled lipid microspheres. Optison is back on the market following a 2-year hiatus attributed to a manufacturing recall.

In issuing the warning, the FDA said it had received reports of serious cardiopulmonary reactions following contrast injection, including 10 deaths following the administration of Definity and 1 death following an Optison injection. Of those 11 deaths, 4 were caused by cardiac arrest and occurred during or within 30 minutes of infusion; the remaining 7 deaths occurred within 12 hours of administration.

In addition, about 190 nonfatal serious reactions were reported in the United States following administration of Definity and Optison.

The boxed warning states that “serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes” after administration of Definity or Optison. Referring to contraindications described on the label, the warning requires that all patients be assessed for the presence of any condition that precludes administration of the contrast agent. In addition, patients are to be monitored during, and for 30 minutes following, contrast administration, including vital sign measurements and electrocardiography in all patients and cutaneous oxygen saturation in patients at risk for hypoxemia. Resuscitation equipment and trained personnel should be readily available.

Additional pressure on the FDA has come from the 12,000-member American Society of Echocardiography (ASE). In late November, ASE President Thomas Ryan wrote a letter to Dr. Andrew C. von Eschenbach, the FDA Commissioner, requesting an opportunity to engage in a dialogue with the agency regarding its decision to issue the black box warning.

“The risk of an adverse event resulting from the administration of a contrast agent must be weighed against the value of a correct diagnosis,” said Dr. Ryan, who noted that he has no conflicts of interest related to the topic. “Because contrast agents improve accuracy and reduce the need for additional downstream testing, we believe their continued use in appropriate cases is justified and consistent with the mission of both the FDA and the ASE,” wrote Dr. Ryan, who is the John G. & Jeanne Bonnet McCoy Chair in Cardiovascular Medicine and the director of the Ohio State University Heart Center in Columbus.

 

A spokesman for the FDA said, “the letter has been received, and the agency is working on a response.” The agency had no further comment on the issue.

“The near-term result of this black box warning, in my opinion, will be a dramatic drop in the use of ultrasound contrast agents, and as a result, the quality of echocardiograms will go down until this scare wears off,” Dr. Peter S. Rahko said in an interview.

“The reaction of the FDA and the rules they imposed seem to be excessive,” said Dr. Rahko of the departments of medicine and public health and director of the adult echocardiography laboratory at the University of Wisconsin, Madison.

But Dr. Rahko does agree with the FDA's expressed concerns that an unknown proportion of patients may suffer allergic reactions to the microsphere contrast agents, which has occurred on a few occasions at Wisconsin.

When the black box warning was issued, the use of contrast-enhanced ultrasound ceased at the University of Wisconsin and other centers. The Wisconsin team developed a two-stage screening protocol for stable and critically ill patients (see box), said Dr. Rahko, who was one of the original investigators in the Definity trials but has no financial conflicts related to the topic.

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Visualization of a left ventricular thrombus is clearer in an echocardiogram with contrast (right) than in a noncontrast image. IMAGES COURTESY DR. PETER S. RAHKO/UNIVERSITY OF WISCONSIN HOSPITAL

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Adjusting to the Black Box Alert

After the FDA issued its warning on ultrasound contrast agents, Dr. Rahko and his colleagues at the University of Wisconsin halted their practice of automatically ordering contrast following a bad-quality echocardiogram.

Previously, “If the patient was appropriate, then the contrast could be administered in the intensive care unit with the assistance of nursing personnel and others taking care of the patient,” Dr. Rahko said.

The hospital now operates with a more costly and time-consuming two-tiered protocol that is tailored to stable and unstable patients undergoing echocardiography.

For an unstable hospitalized patient, the baseline sonogram is read by a cardiologist; if it's of poor quality and a redo with Definity seems appropriate, the cardiologist recommends that the study should be repeated with contrast. “The patient care team now becomes the responsible party ordering the contrast.”

The protocol for stable patients scheduled for echo in the inpatient or outpatient setting shifts responsibility for the final decision to the patient and includes screening for conditions that might contraindicate the use of the microspheres. “Our nurses—in the echo lab or at other sites—screen the patients using oxymetry to make sure that oxygen saturation levels are appropriate and that patients don't have significant hypoxia or lung disease,” Dr. Rahko explained.

Patients who are stable and cleared for a contrast injection are given an information sheet that explains the procedure, why it's being done, and the risks it poses. The patient then decides whether or not to proceed. And “we keep the patient under direct observation for 30 minutes, in case of an allergic reaction,” he said.

SNOWMASS, COLO. — Demonstration of enhanced ventricular interaction upon hemodynamic cardiac catheterization is a novel diagnostic criterion for constrictive pericarditis, with far greater predictive accuracy than that of the classic hemodynamic criteria, Dr. Rick A. Nishimura reported at a conference sponsored by the Society for Cardiovascular Angiography and Interventions.

This concept of enhanced ventricular interaction provides the most reliable means of solving a difficult diagnostic dilemma: how to differentiate constrictive pericarditis from restrictive cardiomyopathy, said Dr. Nishimura, professor of medicine at the Mayo Clinic, Rochester, Minn.

It is a key distinction to make in a timely fashion because constrictive pericarditis is treatable with complete removal of the pericardium via open heart surgery—but the operative risk is severalfold greater, and 5-year survival substantially lower, when pericardiectomy is performed after progression to class III or IV heart failure, he said at the meeting, cosponsored by the American College of Cardiology.

In 70%–75% of cases, diagnosis of constrictive pericarditis can be made on the basis of a clinical examination and two-dimensional and Doppler echocardiography, with no need for invasive hemodynamic studies. But in about one-quarter of cases, constrictive pericarditis can not be differentiated from restrictive cardiomyopathy with noninvasive diagnostic methods, especially in patients who present with right heart failure and a history of cardiac surgery or radiation therapy for breast cancer, Hodgkin's disease, or non-Hodgkin's lymphoma. In this setting, the best way to determine if the heart failure is a result of pericarditis or a noncompliant ventricle is to quantify ventricular interaction during respiration. Enhanced ventricular interaction is unique to constrictive pericarditis, Dr. Nishimura stressed.

Indeed, in his recent series of 100 consecutive patients who underwent hemodynamic catheterization for diagnosis of constrictive pericarditis versus restrictive myocardial disease, of whom 59 were subsequently found to have surgically proven constrictive pericarditis, enhanced ventricular interaction had a 97% sensitivity and 100% positive predictive accuracy for the diagnosis of constrictive pericarditis.

In contrast, the positive predictive accuracy of the conventional hemodynamic criteria, such as early rapid filling, equalization of end-diastolic pressures in all four chambers, or a pulmonary artery systolic pressure less than 55 mm Hg, was 58%–73%.

Enhanced ventricular interaction is an expression of dissociation between intrathoracic and intracardiac pressures resulting in decreased filling of the left ventricle during inspiration in patients with constrictive pericarditis. The rigid, constrictive pericardium also encourages increased filling of the right ventricle during inspiration. It can be identified by measuring the area under the ventricular pressure curves during respiration. This yields the systolic area index—that is, the ratio of the right ventricular to left ventricular systolic pressure-time area during inspiration compared with expiration. A systolic area index greater than 1.1 constitutes enhanced ventricular interaction—and makes the diagnosis of constrictive pericarditis, the cardiologist explained.

Dr. Nishimura urged constrictive pericarditis as a diagnostic consideration in any patient presenting with symptoms of right-sided heart failure and elevated jugular venous pressure with rapid x and y descents in the presence of echocardiographic evidence of normal valvular and left ventricular function. If upon 2-D echo the patient displays the classic septal inspiratory bounce along with Doppler echo findings of restrictive mitral inflow velocity, a normal or increased early diastolic mitral annular tissue velocity, and good hepatic vein flow with inspiration but little flow in expiration, that patient has constrictive pericarditis. Hemodynamic catheterization is not needed, he said.

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Enhanced ventricular interaction is unique to constrictive pericarditis. DR. NISHIMURA

SNOWMASS, COLO. — Demonstration of enhanced ventricular interaction upon hemodynamic cardiac catheterization is a novel diagnostic criterion for constrictive pericarditis, with far greater predictive accuracy than that of the classic hemodynamic criteria, Dr. Rick A. Nishimura reported at a conference sponsored by the Society for Cardiovascular Angiography and Interventions.

This concept of enhanced ventricular interaction provides the most reliable means of solving a difficult diagnostic dilemma: how to differentiate constrictive pericarditis from restrictive cardiomyopathy, said Dr. Nishimura, professor of medicine at the Mayo Clinic, Rochester, Minn.

It is a key distinction to make in a timely fashion because constrictive pericarditis is treatable with complete removal of the pericardium via open heart surgery—but the operative risk is severalfold greater, and 5-year survival substantially lower, when pericardiectomy is performed after progression to class III or IV heart failure, he said at the meeting, cosponsored by the American College of Cardiology.

In 70%–75% of cases, diagnosis of constrictive pericarditis can be made on the basis of a clinical examination and two-dimensional and Doppler echocardiography, with no need for invasive hemodynamic studies. But in about one-quarter of cases, constrictive pericarditis can not be differentiated from restrictive cardiomyopathy with noninvasive diagnostic methods, especially in patients who present with right heart failure and a history of cardiac surgery or radiation therapy for breast cancer, Hodgkin's disease, or non-Hodgkin's lymphoma. In this setting, the best way to determine if the heart failure is a result of pericarditis or a noncompliant ventricle is to quantify ventricular interaction during respiration. Enhanced ventricular interaction is unique to constrictive pericarditis, Dr. Nishimura stressed.

Indeed, in his recent series of 100 consecutive patients who underwent hemodynamic catheterization for diagnosis of constrictive pericarditis versus restrictive myocardial disease, of whom 59 were subsequently found to have surgically proven constrictive pericarditis, enhanced ventricular interaction had a 97% sensitivity and 100% positive predictive accuracy for the diagnosis of constrictive pericarditis.

In contrast, the positive predictive accuracy of the conventional hemodynamic criteria, such as early rapid filling, equalization of end-diastolic pressures in all four chambers, or a pulmonary artery systolic pressure less than 55 mm Hg, was 58%–73%.

Enhanced ventricular interaction is an expression of dissociation between intrathoracic and intracardiac pressures resulting in decreased filling of the left ventricle during inspiration in patients with constrictive pericarditis. The rigid, constrictive pericardium also encourages increased filling of the right ventricle during inspiration. It can be identified by measuring the area under the ventricular pressure curves during respiration. This yields the systolic area index—that is, the ratio of the right ventricular to left ventricular systolic pressure-time area during inspiration compared with expiration. A systolic area index greater than 1.1 constitutes enhanced ventricular interaction—and makes the diagnosis of constrictive pericarditis, the cardiologist explained.

Dr. Nishimura urged constrictive pericarditis as a diagnostic consideration in any patient presenting with symptoms of right-sided heart failure and elevated jugular venous pressure with rapid x and y descents in the presence of echocardiographic evidence of normal valvular and left ventricular function. If upon 2-D echo the patient displays the classic septal inspiratory bounce along with Doppler echo findings of restrictive mitral inflow velocity, a normal or increased early diastolic mitral annular tissue velocity, and good hepatic vein flow with inspiration but little flow in expiration, that patient has constrictive pericarditis. Hemodynamic catheterization is not needed, he said.

Document

70106_fx1.sml

Enhanced ventricular interaction is unique to constrictive pericarditis. DR. NISHIMURA

SNOWMASS, COLO. — Demonstration of enhanced ventricular interaction upon hemodynamic cardiac catheterization is a novel diagnostic criterion for constrictive pericarditis, with far greater predictive accuracy than that of the classic hemodynamic criteria, Dr. Rick A. Nishimura reported at a conference sponsored by the Society for Cardiovascular Angiography and Interventions.

This concept of enhanced ventricular interaction provides the most reliable means of solving a difficult diagnostic dilemma: how to differentiate constrictive pericarditis from restrictive cardiomyopathy, said Dr. Nishimura, professor of medicine at the Mayo Clinic, Rochester, Minn.

It is a key distinction to make in a timely fashion because constrictive pericarditis is treatable with complete removal of the pericardium via open heart surgery—but the operative risk is severalfold greater, and 5-year survival substantially lower, when pericardiectomy is performed after progression to class III or IV heart failure, he said at the meeting, cosponsored by the American College of Cardiology.

In 70%–75% of cases, diagnosis of constrictive pericarditis can be made on the basis of a clinical examination and two-dimensional and Doppler echocardiography, with no need for invasive hemodynamic studies. But in about one-quarter of cases, constrictive pericarditis can not be differentiated from restrictive cardiomyopathy with noninvasive diagnostic methods, especially in patients who present with right heart failure and a history of cardiac surgery or radiation therapy for breast cancer, Hodgkin's disease, or non-Hodgkin's lymphoma. In this setting, the best way to determine if the heart failure is a result of pericarditis or a noncompliant ventricle is to quantify ventricular interaction during respiration. Enhanced ventricular interaction is unique to constrictive pericarditis, Dr. Nishimura stressed.

Indeed, in his recent series of 100 consecutive patients who underwent hemodynamic catheterization for diagnosis of constrictive pericarditis versus restrictive myocardial disease, of whom 59 were subsequently found to have surgically proven constrictive pericarditis, enhanced ventricular interaction had a 97% sensitivity and 100% positive predictive accuracy for the diagnosis of constrictive pericarditis.

In contrast, the positive predictive accuracy of the conventional hemodynamic criteria, such as early rapid filling, equalization of end-diastolic pressures in all four chambers, or a pulmonary artery systolic pressure less than 55 mm Hg, was 58%–73%.

Enhanced ventricular interaction is an expression of dissociation between intrathoracic and intracardiac pressures resulting in decreased filling of the left ventricle during inspiration in patients with constrictive pericarditis. The rigid, constrictive pericardium also encourages increased filling of the right ventricle during inspiration. It can be identified by measuring the area under the ventricular pressure curves during respiration. This yields the systolic area index—that is, the ratio of the right ventricular to left ventricular systolic pressure-time area during inspiration compared with expiration. A systolic area index greater than 1.1 constitutes enhanced ventricular interaction—and makes the diagnosis of constrictive pericarditis, the cardiologist explained.

Dr. Nishimura urged constrictive pericarditis as a diagnostic consideration in any patient presenting with symptoms of right-sided heart failure and elevated jugular venous pressure with rapid x and y descents in the presence of echocardiographic evidence of normal valvular and left ventricular function. If upon 2-D echo the patient displays the classic septal inspiratory bounce along with Doppler echo findings of restrictive mitral inflow velocity, a normal or increased early diastolic mitral annular tissue velocity, and good hepatic vein flow with inspiration but little flow in expiration, that patient has constrictive pericarditis. Hemodynamic catheterization is not needed, he said.

Document

70106_fx1.sml

Enhanced ventricular interaction is unique to constrictive pericarditis. DR. NISHIMURA

Acute aortic syndrome is often a life-threatening emergency, but because the presenting symptoms are nonspecific, it can be difficult to diagnose. Advances in computed tomography (CT)i have made the diagnosis of acute aortic syndromes easier and faster.

See related editorial

This article discusses the role of CT in patients with acute aortic syndrome. We review the imaging features and common indications for treating the various causes of acute aortic syndrome, and we discuss the possibly wider future role of CT for evaluating acute chest pain.

ACUTE AORTIC SYNDROME PRESENTS WITH CHEST PAIN

Acute aortic syndrome is defined as chest pain due to an aortic condition such as acute aortic dissection, intramural hematoma, penetrating atherosclerotic ulcer, or unstable thoracic aneurysm (see below).¹

Risk factors² are listed in Table1. Most patients have a history of hypertension; however, the blood pressure may be low at the time of presentation if the aorta has ruptured.

Of 464 patients included in the International Registry of Acute Aortic Dissection (IRAD),³ 85% had acute symptoms. The pain was more often described as sharp than as the classic tearing pain. More than 70% of patients had hypertension.³ Half of patients younger than 40 years had Marfan syndrome⁴;a young patient with Marfan features who presents with acute chest pain should be strongly suspected of having aortic dissection. A bicuspid aortic valve or a history of aortic surgery should also raise the suspicion of acute aortic dissection.⁴

Acute chest pain is nonspecific

Acute chest pain is a nonspecific symptom: besides esophageal disease, it can be due to pneumonia, pulmonary embolism, pneumothorax, or acute coronary syndrome, and these must be ruled out on the basis of the history, physical findings, cardiac enzyme levels, electrocardiographic findings, and chest radiographic findings (Figure 1).

Furthermore, other possible manifestations of acute aortic syndrome are also nonspecific, eg, unexplained syncope, stroke, acute onset of congestive heart failure, pulse differentials (weaker pulses in one or more extremities), and malperfusion syndromes of the extremities or viscera.

Although aortic disease can sometimes cause acute coronary syndrome, keep in mind that acute coronary syndrome is more than 100 times more common than acute aortic dissection.³

IMAGING STUDIES FOR ACUTE AORTIC SYNDROME

Contrast-enhanced, cardiac-gated multidetector CT is nearly 100% sensitive and specific for evaluating acute aortic syndrome (Table 2).⁵

Transthoracic echocardiography is limited for evaluating acute aortic syndromes. However, transesophageal echocardiography is about 95% sensitive and specific for diagnosing acute aortic dissection, and intramural hematoma, and associated valvular regurgitation if the personnel who perform and interpret the test are highly experienced (although this level of expertise is not always available in the emergency department).⁵

CT has been improved

Several recent advances have contributed to CT’s very high sensitivity and specificity for diagnosing aortic disease.

Multiple detectors. Today’s CT machines have up to 64 rows of detectors, and this enables them to generate multiple simultaneous images with a slice thickness of less than 1 mm. Multidetector CT is also extremely fast: spiral imaging of the thorax can be done in a single breath-hold, which eliminates respiratory motion artifact.

Cardiac synchronization of the image acquisition (cardiac gating) should be performed whenever the heart, coronary vessels, pulmonary veins, or aortic root needs to be evaluated; without cardiac gating, motion of the aortic root wall during the cardiac cycle causes artifacts in more than 90% of CT studies,^5–7 precluding adequate evaluation of these structures (Figure 2). In cardiac gating, CT is synchronized with electrocardiography, “freezing” the action at specific phases of the cardiac cycle, typically during diastole when heart motion is limited. Two types of cardiac synchronization are available: retrospective gating and prospective triggering.

In retrospective gating (“spiral” or “helical” scanning), the x-ray source stays on throughout the cardiac cycle, but only the data from the desired part of the cardiac cycle are used to construct images. With this method, one can refine the images and remove motion abnormalities caused by irregular heartbeats. This acquisition technique is currently the most frequently used.

In prospective triggering (“step and shoot”), the x-ray source is turned on only during diastole or another prespecified part of the cardiac cycle. An advantage is that the patient is exposed to less radiation. A disadvantage is that, afterward, one has very little ability to correct any motion artifacts that occurred due to changes in heart rate or dysrhythmias.

Other improvements that have increased the sensitivity and specificity of CT for evaluating acute aortic syndrome are the ability to generate images in multiple planes (multiplanar reformation) on dedicated computer workstations.

 

INTRAVENOUS CONTRAST IMPROVES IMAGING STUDIES

Intravenous contrast is necessary for CT to achieve its high accuracy for diagnosing aortic disease. However, it should be noted that in a CT study without contrast enhancement, an acute intramural hematoma is easily recognized by the higher Hounsfield-unit value of the blood products in the wall in comparison with the flowing blood in the lumen.

Check renal function

Before doing an intravenous contrast study, the serum creatinine level should be checked as a measure of renal function. Generally, if the serum creatinine concentration is less than 2.0 mg/dL and if the patient is hydrated and does not have diabetes, iodinated intravenous contrast can be given safely. If the patient’s serum creatinine level is between 1.5 and 2.0 mg/dL or if he or she is dehydrated or has diabetes, isosmolar iodinated contrast (iodixanol [Visipaque]) may be used.

An alternative that can be used for some patients with contrast allergy is gadolinium chelate, a paramagnetic compound normally used in magnetic resonance imaging. However, it is less radiopaque and much more expensive than iodinated contrast. It should be noted that the US Food and Drug Administration has recently warned that gadolinium contrast is associated with a systemic fibrosing disorder (nephrogenic systemic fibrosis) in patients with poor renal function (usually but not only in patients on dialysis).⁸ Because of this risk, gadolinium contrast should generally be used only in patients with good renal function who have had a prior serious adverse reaction to iodinated contrast.

Insert a large-gauge intravenous line

Proper intravenous access is needed for contrast injection. To opacify the aorta properly, the contrast must be injected rapidly (3.0 mL/second) using a power injector.

We recommend at least an 18-gauge peripheral intravenous catheter in the forearm or a large-bore central line (an introducer or Hickman catheter). Smaller-gauge intravenous lines (often located in smaller veins such as in the wrist) and most central lines placed without radiographic or surgical assistance (eg, triple-lumen central catheters) cannot safely handle such a rapid rate without infiltration or embolization. Some peripherally inserted central catheters are designed to handle high injection rates and are typically labeled with the injection rate.

USE OF CT IN SPECIFIC ACUTE AORTIC SYNDROMES

Acute aortic dissection

Aortic dissection occurs when a tear in the intimal layer allows blood to enter and accumulate in the medial layer of the aorta, giving rise to a true lumen and a false lumen separated by an intimomedial flap. Dissection is considered to be acute if symptoms have been present for less than 2 weeks.⁹

Aortic dissections are often complex and can spiral around the aorta. The relationship of the intimomedial flap to the coronary arteries, aortic-arch branch vessels, and visceral branch vessels can be described on contrast enhanced, cardiac-gated CT scans. The true lumen is often smaller and more opacified with contrast than the false lumen; intimal calcification often surrounds the true lumen. Slender areas of low attenuation (“cobwebs”) are occasionally seen in the false lumen. The false lumen also has beaked edges where it meets the true lumen, which usually appears rounder.^2,10 The radiologist should state where the dissection begins and ends, determine if target vessel ischemia is evident, and assess for concomitant aneurysmal dilatation of the aorta. Contrast-enhanced, cardiac-gated multidetector CT of the aorta is necessary to properly evaluate the aortic root.

The Stanford system. Two systems exist for classifying the location of aortic dissections: the DeBakey system and the Stanford system (Figure 3). The Stanford system is more clinically useful and uses the following classification:

• 

  Type A dissections involve the ascending aorta and aortic arch, with or without involvement of the descending aorta (Figure 4, Figure 5)

• 

  Type B dissections involve the descending aorta beginning distal to the left subclavian artery (Figure 6).¹¹

Type A acute aortic dissection generally should be surgically repaired immediately to avoid fatal complications such as extension into the pericardium, pleural space, coronary arteries, or aortic valvular ring. It can also cause stroke, visceral ischemia, or circulatory failure.^2,11 Without surgery, 20% of patients with type A acute aortic dissection die within 24 hours, 30% within 48 hours, 40% within 1 week, and 50% within 1 month.² The initial target is the tear in the ascending aorta: typically the aortic root or the ascending aorta or both are replaced and the aortic valve is repaired if indicated (Figure 5). Further aortic repair can often be delayed or may not be needed if the disease does not progress with medical management.

Without surgery, type B acute aortic dissection has a 30-day mortality rate of 10%.² Patients who develop renal failure, ischemic leg symptoms, or visceral ischemic symptoms with acute aortic syndrome should undergo imaging of the chest, abdomen, and pelvis. Type B acute aortic dissection without end-organ ischemia is typically managed with antihypertensive drugs. Except in patients with Marfan syndrome, only a small minority of type B dissections progress to type A dissections.Urgent aortic repair, often with an endovascular stent graft, is needed if imaging shows visceral vessel occlusion or ischemia, acute vessel thrombosis, or progression of aneurysmal dilatation.

 

 

Aortic intramural hematoma

Intramural hematomas are believed to be caused by a spontaneous hemorrhage of the vaso vasorum into the medial layer. They appear as crescent-shaped areas of increased attenuation with eccentric aortic wall-thickening and displacement of intimal calcifications. Hematomas do not enhance after contrast administration, and unlike dissections, they usually do not spiral around the aorta.

Intramural hematomas can also be classified according to the Stanford system. Type A intramural hematomas (Figure 7) have traditionally been urgently treated with surgery because they can progress to dissection, aortic rupture, or pericardial, pleural, or mediastinal hemorrhage. Recent evidence suggests that some patients with a limited type A intramural hematoma may be managed with aggressive medical therapy with frequent serial imaging to monitor progression of disease.^2,12

Type B intramural hematomas are typically managed with medical therapy and often regress with time, although they can progress to dissection or aneurysmal formation.

Unstable thoracic aneurysm

Thoracic aneurysms are considered unstable if they are enlarging rapidly, show signs of imminent rupture, or have already ruptured (typically ,the rupture is contained if the patient survives for imaging).

An aortic aneurysm is defined as a permanent dilation at least 150% of normal size, or larger than 5 cm if in the thoracic aorta or larger than 3 cm if in the abdominal aorta. True aneurysms involve all three layers of the aorta and tend to be fusiform; pseudoaneurysms tend to be saccular and often arise after trauma, surgery, or infection. Dilations are more likely to rupture if they grow at least 1 cm per year or measure 6.0 cm or more (if in the ascending aorta) or 7.2 cm (if in the descending thoracic aorta).¹³

How big the aortic diameter needs to be before invasive treatment—surgery or an endovascular procedure—is indicated depends on the characteristics of the individual patient, and an experienced surgeon should be involved in the decision. Patients are typically treated when a dilation in the ascending aorta reaches 5.5 cm or when one in the descending aorta reaches 6.0 cm; patients with Marfan syndrome should undergo invasive treatment for aneurysms with smaller diameters.^14,15

CT signs of imminent rupture include a high-attenuating crescent in the wall of the aorta, discontinuous calcification in a circumferentially calcified aorta, an aorta that conforms to the neighboring vertebral body (“draped” aorta), and an eccentric nipple shape to the aorta.^16,17

CT signs of rupture include hemothorax (usually in the left hemithorax) and stranding of the periaortic fat (Figure 8).

Penetrating atherosclerotic ulcer

When an atherosclerotic ulcer penetrates the aortic intima and extends into the media, it can lead to dissection, an intramural hematoma, aneurysm, or aortic rupture. Many penetrating aortic ulcers are focal lesions of the descending thoracic aorta. On contrast-enhanced, cardiac-gated CT they appear as contrast-filled irregular outpouchings of the aortic wall (Figure 9).^18,19

Typical patients are elderly, and many have coexisting atherosclerotic atheromata and aneurysmal disease. Some experts contend that most saccular aneurysms are caused by penetrating atherosclerotic ulcers.¹⁹

Surgery to stabilize disease is recommended for a penetrating ulcer that causes acute aortic syndrome, or in patients with hemodynamic instability, aortic rupture, distal embolization, or a rapidly enlarging aorta. For a penetrating ulcer that is found incidentally in a patient without acute aortic syndrome, medical management of risk factors is recommended, with annual follow-up to see if it enlarges.

FUTURE USES OF IMAGING IN PATIENTS WITH ACUTE CHEST PAIN

Multidetector CT systems are undergoing rapid technical advances, including the recently released dual x-ray source multidetector CT scanners and the expected multidetector CTs with 128 to 256 detector rows. These and other developments will improve temporal resolution and decrease radiation exposure. Calcium artifacts—which hinder the evaluation of coronary arteries that contain atherosclerotic calcifications—will be reduced, thereby improving the accuracy of diagnosing acute coronary disease. As clinical knowledge increases based on the experience gained from the new technology, indications for imaging may expand.

CT of the chest performed for aortic disease provides information about other organ systems that may be considered when evaluating the cause of chest pain.²⁰

Evaluating pulmonary artery embolism

Although current contrast-enhanced, cardiac-gated CT of the aorta is not ideal for assessing the pulmonary arteries, it can almost always rule out central pulmonary artery thromboemboli and evaluate the more distal pulmonary arteries in a more limited way.

‘Triple rule-out’ CT

Several institutions now use CT (typically with 64-row scanners) to simultaneously evaluate patients for coronary artery disease, acute aortic syndrome, and pulmonary embolism—or “triple rule-out CT.” The study can be performed with dual intravenous contrast bolus techniques with nongated contrast-enhanced CT of the pulmonary arteries, rapidly followed by cardiac-gated, contrast-enhanced CT of the aorta. The pulmonary arteries can be evaluated on the initial nongated study, and the aorta (including the aortic root) and the coronary arteries are evaluated on the cardiac-gated portion. The timing of the contrast bolus for optimal opacification of the pulmonary arteries and the coronary arteries has yet to be determined.

The usefulness of assessing all three vascular beds with a single study is currently still unclear and the protocol is currently not routinely performed at Cleveland Clinic. Its sensitivity, specificity, and cost-benefit ratio are also unclear and must be determined in prospective clinical trials, which are currently under way.²¹

Acute aortic syndrome is often a life-threatening emergency, but because the presenting symptoms are nonspecific, it can be difficult to diagnose. Advances in computed tomography (CT)i have made the diagnosis of acute aortic syndromes easier and faster.

See related editorial

This article discusses the role of CT in patients with acute aortic syndrome. We review the imaging features and common indications for treating the various causes of acute aortic syndrome, and we discuss the possibly wider future role of CT for evaluating acute chest pain.

ACUTE AORTIC SYNDROME PRESENTS WITH CHEST PAIN

Acute aortic syndrome is defined as chest pain due to an aortic condition such as acute aortic dissection, intramural hematoma, penetrating atherosclerotic ulcer, or unstable thoracic aneurysm (see below).¹

Risk factors² are listed in Table1. Most patients have a history of hypertension; however, the blood pressure may be low at the time of presentation if the aorta has ruptured.

Of 464 patients included in the International Registry of Acute Aortic Dissection (IRAD),³ 85% had acute symptoms. The pain was more often described as sharp than as the classic tearing pain. More than 70% of patients had hypertension.³ Half of patients younger than 40 years had Marfan syndrome⁴;a young patient with Marfan features who presents with acute chest pain should be strongly suspected of having aortic dissection. A bicuspid aortic valve or a history of aortic surgery should also raise the suspicion of acute aortic dissection.⁴

Acute chest pain is nonspecific

Acute chest pain is a nonspecific symptom: besides esophageal disease, it can be due to pneumonia, pulmonary embolism, pneumothorax, or acute coronary syndrome, and these must be ruled out on the basis of the history, physical findings, cardiac enzyme levels, electrocardiographic findings, and chest radiographic findings (Figure 1).

Furthermore, other possible manifestations of acute aortic syndrome are also nonspecific, eg, unexplained syncope, stroke, acute onset of congestive heart failure, pulse differentials (weaker pulses in one or more extremities), and malperfusion syndromes of the extremities or viscera.

Although aortic disease can sometimes cause acute coronary syndrome, keep in mind that acute coronary syndrome is more than 100 times more common than acute aortic dissection.³

IMAGING STUDIES FOR ACUTE AORTIC SYNDROME

Contrast-enhanced, cardiac-gated multidetector CT is nearly 100% sensitive and specific for evaluating acute aortic syndrome (Table 2).⁵

Transthoracic echocardiography is limited for evaluating acute aortic syndromes. However, transesophageal echocardiography is about 95% sensitive and specific for diagnosing acute aortic dissection, and intramural hematoma, and associated valvular regurgitation if the personnel who perform and interpret the test are highly experienced (although this level of expertise is not always available in the emergency department).⁵

CT has been improved

Several recent advances have contributed to CT’s very high sensitivity and specificity for diagnosing aortic disease.

Multiple detectors. Today’s CT machines have up to 64 rows of detectors, and this enables them to generate multiple simultaneous images with a slice thickness of less than 1 mm. Multidetector CT is also extremely fast: spiral imaging of the thorax can be done in a single breath-hold, which eliminates respiratory motion artifact.

Cardiac synchronization of the image acquisition (cardiac gating) should be performed whenever the heart, coronary vessels, pulmonary veins, or aortic root needs to be evaluated; without cardiac gating, motion of the aortic root wall during the cardiac cycle causes artifacts in more than 90% of CT studies,^5–7 precluding adequate evaluation of these structures (Figure 2). In cardiac gating, CT is synchronized with electrocardiography, “freezing” the action at specific phases of the cardiac cycle, typically during diastole when heart motion is limited. Two types of cardiac synchronization are available: retrospective gating and prospective triggering.

In retrospective gating (“spiral” or “helical” scanning), the x-ray source stays on throughout the cardiac cycle, but only the data from the desired part of the cardiac cycle are used to construct images. With this method, one can refine the images and remove motion abnormalities caused by irregular heartbeats. This acquisition technique is currently the most frequently used.

In prospective triggering (“step and shoot”), the x-ray source is turned on only during diastole or another prespecified part of the cardiac cycle. An advantage is that the patient is exposed to less radiation. A disadvantage is that, afterward, one has very little ability to correct any motion artifacts that occurred due to changes in heart rate or dysrhythmias.

Other improvements that have increased the sensitivity and specificity of CT for evaluating acute aortic syndrome are the ability to generate images in multiple planes (multiplanar reformation) on dedicated computer workstations.

 

INTRAVENOUS CONTRAST IMPROVES IMAGING STUDIES

Intravenous contrast is necessary for CT to achieve its high accuracy for diagnosing aortic disease. However, it should be noted that in a CT study without contrast enhancement, an acute intramural hematoma is easily recognized by the higher Hounsfield-unit value of the blood products in the wall in comparison with the flowing blood in the lumen.

Check renal function

Before doing an intravenous contrast study, the serum creatinine level should be checked as a measure of renal function. Generally, if the serum creatinine concentration is less than 2.0 mg/dL and if the patient is hydrated and does not have diabetes, iodinated intravenous contrast can be given safely. If the patient’s serum creatinine level is between 1.5 and 2.0 mg/dL or if he or she is dehydrated or has diabetes, isosmolar iodinated contrast (iodixanol [Visipaque]) may be used.

An alternative that can be used for some patients with contrast allergy is gadolinium chelate, a paramagnetic compound normally used in magnetic resonance imaging. However, it is less radiopaque and much more expensive than iodinated contrast. It should be noted that the US Food and Drug Administration has recently warned that gadolinium contrast is associated with a systemic fibrosing disorder (nephrogenic systemic fibrosis) in patients with poor renal function (usually but not only in patients on dialysis).⁸ Because of this risk, gadolinium contrast should generally be used only in patients with good renal function who have had a prior serious adverse reaction to iodinated contrast.

Insert a large-gauge intravenous line

Proper intravenous access is needed for contrast injection. To opacify the aorta properly, the contrast must be injected rapidly (3.0 mL/second) using a power injector.

We recommend at least an 18-gauge peripheral intravenous catheter in the forearm or a large-bore central line (an introducer or Hickman catheter). Smaller-gauge intravenous lines (often located in smaller veins such as in the wrist) and most central lines placed without radiographic or surgical assistance (eg, triple-lumen central catheters) cannot safely handle such a rapid rate without infiltration or embolization. Some peripherally inserted central catheters are designed to handle high injection rates and are typically labeled with the injection rate.

USE OF CT IN SPECIFIC ACUTE AORTIC SYNDROMES

Acute aortic dissection

Aortic dissection occurs when a tear in the intimal layer allows blood to enter and accumulate in the medial layer of the aorta, giving rise to a true lumen and a false lumen separated by an intimomedial flap. Dissection is considered to be acute if symptoms have been present for less than 2 weeks.⁹

Aortic dissections are often complex and can spiral around the aorta. The relationship of the intimomedial flap to the coronary arteries, aortic-arch branch vessels, and visceral branch vessels can be described on contrast enhanced, cardiac-gated CT scans. The true lumen is often smaller and more opacified with contrast than the false lumen; intimal calcification often surrounds the true lumen. Slender areas of low attenuation (“cobwebs”) are occasionally seen in the false lumen. The false lumen also has beaked edges where it meets the true lumen, which usually appears rounder.^2,10 The radiologist should state where the dissection begins and ends, determine if target vessel ischemia is evident, and assess for concomitant aneurysmal dilatation of the aorta. Contrast-enhanced, cardiac-gated multidetector CT of the aorta is necessary to properly evaluate the aortic root.

The Stanford system. Two systems exist for classifying the location of aortic dissections: the DeBakey system and the Stanford system (Figure 3). The Stanford system is more clinically useful and uses the following classification:

• 

  Type A dissections involve the ascending aorta and aortic arch, with or without involvement of the descending aorta (Figure 4, Figure 5)

• 

  Type B dissections involve the descending aorta beginning distal to the left subclavian artery (Figure 6).¹¹

Type A acute aortic dissection generally should be surgically repaired immediately to avoid fatal complications such as extension into the pericardium, pleural space, coronary arteries, or aortic valvular ring. It can also cause stroke, visceral ischemia, or circulatory failure.^2,11 Without surgery, 20% of patients with type A acute aortic dissection die within 24 hours, 30% within 48 hours, 40% within 1 week, and 50% within 1 month.² The initial target is the tear in the ascending aorta: typically the aortic root or the ascending aorta or both are replaced and the aortic valve is repaired if indicated (Figure 5). Further aortic repair can often be delayed or may not be needed if the disease does not progress with medical management.

Without surgery, type B acute aortic dissection has a 30-day mortality rate of 10%.² Patients who develop renal failure, ischemic leg symptoms, or visceral ischemic symptoms with acute aortic syndrome should undergo imaging of the chest, abdomen, and pelvis. Type B acute aortic dissection without end-organ ischemia is typically managed with antihypertensive drugs. Except in patients with Marfan syndrome, only a small minority of type B dissections progress to type A dissections.Urgent aortic repair, often with an endovascular stent graft, is needed if imaging shows visceral vessel occlusion or ischemia, acute vessel thrombosis, or progression of aneurysmal dilatation.

 

 

Aortic intramural hematoma

Intramural hematomas are believed to be caused by a spontaneous hemorrhage of the vaso vasorum into the medial layer. They appear as crescent-shaped areas of increased attenuation with eccentric aortic wall-thickening and displacement of intimal calcifications. Hematomas do not enhance after contrast administration, and unlike dissections, they usually do not spiral around the aorta.

Intramural hematomas can also be classified according to the Stanford system. Type A intramural hematomas (Figure 7) have traditionally been urgently treated with surgery because they can progress to dissection, aortic rupture, or pericardial, pleural, or mediastinal hemorrhage. Recent evidence suggests that some patients with a limited type A intramural hematoma may be managed with aggressive medical therapy with frequent serial imaging to monitor progression of disease.^2,12

Type B intramural hematomas are typically managed with medical therapy and often regress with time, although they can progress to dissection or aneurysmal formation.

Unstable thoracic aneurysm

Thoracic aneurysms are considered unstable if they are enlarging rapidly, show signs of imminent rupture, or have already ruptured (typically ,the rupture is contained if the patient survives for imaging).

An aortic aneurysm is defined as a permanent dilation at least 150% of normal size, or larger than 5 cm if in the thoracic aorta or larger than 3 cm if in the abdominal aorta. True aneurysms involve all three layers of the aorta and tend to be fusiform; pseudoaneurysms tend to be saccular and often arise after trauma, surgery, or infection. Dilations are more likely to rupture if they grow at least 1 cm per year or measure 6.0 cm or more (if in the ascending aorta) or 7.2 cm (if in the descending thoracic aorta).¹³

How big the aortic diameter needs to be before invasive treatment—surgery or an endovascular procedure—is indicated depends on the characteristics of the individual patient, and an experienced surgeon should be involved in the decision. Patients are typically treated when a dilation in the ascending aorta reaches 5.5 cm or when one in the descending aorta reaches 6.0 cm; patients with Marfan syndrome should undergo invasive treatment for aneurysms with smaller diameters.^14,15

CT signs of imminent rupture include a high-attenuating crescent in the wall of the aorta, discontinuous calcification in a circumferentially calcified aorta, an aorta that conforms to the neighboring vertebral body (“draped” aorta), and an eccentric nipple shape to the aorta.^16,17

CT signs of rupture include hemothorax (usually in the left hemithorax) and stranding of the periaortic fat (Figure 8).

Penetrating atherosclerotic ulcer

When an atherosclerotic ulcer penetrates the aortic intima and extends into the media, it can lead to dissection, an intramural hematoma, aneurysm, or aortic rupture. Many penetrating aortic ulcers are focal lesions of the descending thoracic aorta. On contrast-enhanced, cardiac-gated CT they appear as contrast-filled irregular outpouchings of the aortic wall (Figure 9).^18,19

Typical patients are elderly, and many have coexisting atherosclerotic atheromata and aneurysmal disease. Some experts contend that most saccular aneurysms are caused by penetrating atherosclerotic ulcers.¹⁹

Surgery to stabilize disease is recommended for a penetrating ulcer that causes acute aortic syndrome, or in patients with hemodynamic instability, aortic rupture, distal embolization, or a rapidly enlarging aorta. For a penetrating ulcer that is found incidentally in a patient without acute aortic syndrome, medical management of risk factors is recommended, with annual follow-up to see if it enlarges.

FUTURE USES OF IMAGING IN PATIENTS WITH ACUTE CHEST PAIN

Multidetector CT systems are undergoing rapid technical advances, including the recently released dual x-ray source multidetector CT scanners and the expected multidetector CTs with 128 to 256 detector rows. These and other developments will improve temporal resolution and decrease radiation exposure. Calcium artifacts—which hinder the evaluation of coronary arteries that contain atherosclerotic calcifications—will be reduced, thereby improving the accuracy of diagnosing acute coronary disease. As clinical knowledge increases based on the experience gained from the new technology, indications for imaging may expand.

CT of the chest performed for aortic disease provides information about other organ systems that may be considered when evaluating the cause of chest pain.²⁰

Evaluating pulmonary artery embolism

Although current contrast-enhanced, cardiac-gated CT of the aorta is not ideal for assessing the pulmonary arteries, it can almost always rule out central pulmonary artery thromboemboli and evaluate the more distal pulmonary arteries in a more limited way.

‘Triple rule-out’ CT

Several institutions now use CT (typically with 64-row scanners) to simultaneously evaluate patients for coronary artery disease, acute aortic syndrome, and pulmonary embolism—or “triple rule-out CT.” The study can be performed with dual intravenous contrast bolus techniques with nongated contrast-enhanced CT of the pulmonary arteries, rapidly followed by cardiac-gated, contrast-enhanced CT of the aorta. The pulmonary arteries can be evaluated on the initial nongated study, and the aorta (including the aortic root) and the coronary arteries are evaluated on the cardiac-gated portion. The timing of the contrast bolus for optimal opacification of the pulmonary arteries and the coronary arteries has yet to be determined.

The usefulness of assessing all three vascular beds with a single study is currently still unclear and the protocol is currently not routinely performed at Cleveland Clinic. Its sensitivity, specificity, and cost-benefit ratio are also unclear and must be determined in prospective clinical trials, which are currently under way.²¹

Acute aortic syndrome is often a life-threatening emergency, but because the presenting symptoms are nonspecific, it can be difficult to diagnose. Advances in computed tomography (CT)i have made the diagnosis of acute aortic syndromes easier and faster.

See related editorial

This article discusses the role of CT in patients with acute aortic syndrome. We review the imaging features and common indications for treating the various causes of acute aortic syndrome, and we discuss the possibly wider future role of CT for evaluating acute chest pain.

ACUTE AORTIC SYNDROME PRESENTS WITH CHEST PAIN

Acute aortic syndrome is defined as chest pain due to an aortic condition such as acute aortic dissection, intramural hematoma, penetrating atherosclerotic ulcer, or unstable thoracic aneurysm (see below).¹

Risk factors² are listed in Table1. Most patients have a history of hypertension; however, the blood pressure may be low at the time of presentation if the aorta has ruptured.

Of 464 patients included in the International Registry of Acute Aortic Dissection (IRAD),³ 85% had acute symptoms. The pain was more often described as sharp than as the classic tearing pain. More than 70% of patients had hypertension.³ Half of patients younger than 40 years had Marfan syndrome⁴;a young patient with Marfan features who presents with acute chest pain should be strongly suspected of having aortic dissection. A bicuspid aortic valve or a history of aortic surgery should also raise the suspicion of acute aortic dissection.⁴

Acute chest pain is nonspecific

Acute chest pain is a nonspecific symptom: besides esophageal disease, it can be due to pneumonia, pulmonary embolism, pneumothorax, or acute coronary syndrome, and these must be ruled out on the basis of the history, physical findings, cardiac enzyme levels, electrocardiographic findings, and chest radiographic findings (Figure 1).

Furthermore, other possible manifestations of acute aortic syndrome are also nonspecific, eg, unexplained syncope, stroke, acute onset of congestive heart failure, pulse differentials (weaker pulses in one or more extremities), and malperfusion syndromes of the extremities or viscera.

Although aortic disease can sometimes cause acute coronary syndrome, keep in mind that acute coronary syndrome is more than 100 times more common than acute aortic dissection.³

IMAGING STUDIES FOR ACUTE AORTIC SYNDROME

Contrast-enhanced, cardiac-gated multidetector CT is nearly 100% sensitive and specific for evaluating acute aortic syndrome (Table 2).⁵

Transthoracic echocardiography is limited for evaluating acute aortic syndromes. However, transesophageal echocardiography is about 95% sensitive and specific for diagnosing acute aortic dissection, and intramural hematoma, and associated valvular regurgitation if the personnel who perform and interpret the test are highly experienced (although this level of expertise is not always available in the emergency department).⁵

CT has been improved

Several recent advances have contributed to CT’s very high sensitivity and specificity for diagnosing aortic disease.

Multiple detectors. Today’s CT machines have up to 64 rows of detectors, and this enables them to generate multiple simultaneous images with a slice thickness of less than 1 mm. Multidetector CT is also extremely fast: spiral imaging of the thorax can be done in a single breath-hold, which eliminates respiratory motion artifact.

Cardiac synchronization of the image acquisition (cardiac gating) should be performed whenever the heart, coronary vessels, pulmonary veins, or aortic root needs to be evaluated; without cardiac gating, motion of the aortic root wall during the cardiac cycle causes artifacts in more than 90% of CT studies,^5–7 precluding adequate evaluation of these structures (Figure 2). In cardiac gating, CT is synchronized with electrocardiography, “freezing” the action at specific phases of the cardiac cycle, typically during diastole when heart motion is limited. Two types of cardiac synchronization are available: retrospective gating and prospective triggering.

In retrospective gating (“spiral” or “helical” scanning), the x-ray source stays on throughout the cardiac cycle, but only the data from the desired part of the cardiac cycle are used to construct images. With this method, one can refine the images and remove motion abnormalities caused by irregular heartbeats. This acquisition technique is currently the most frequently used.

In prospective triggering (“step and shoot”), the x-ray source is turned on only during diastole or another prespecified part of the cardiac cycle. An advantage is that the patient is exposed to less radiation. A disadvantage is that, afterward, one has very little ability to correct any motion artifacts that occurred due to changes in heart rate or dysrhythmias.

Other improvements that have increased the sensitivity and specificity of CT for evaluating acute aortic syndrome are the ability to generate images in multiple planes (multiplanar reformation) on dedicated computer workstations.

 

INTRAVENOUS CONTRAST IMPROVES IMAGING STUDIES

Intravenous contrast is necessary for CT to achieve its high accuracy for diagnosing aortic disease. However, it should be noted that in a CT study without contrast enhancement, an acute intramural hematoma is easily recognized by the higher Hounsfield-unit value of the blood products in the wall in comparison with the flowing blood in the lumen.

Check renal function

Before doing an intravenous contrast study, the serum creatinine level should be checked as a measure of renal function. Generally, if the serum creatinine concentration is less than 2.0 mg/dL and if the patient is hydrated and does not have diabetes, iodinated intravenous contrast can be given safely. If the patient’s serum creatinine level is between 1.5 and 2.0 mg/dL or if he or she is dehydrated or has diabetes, isosmolar iodinated contrast (iodixanol [Visipaque]) may be used.

An alternative that can be used for some patients with contrast allergy is gadolinium chelate, a paramagnetic compound normally used in magnetic resonance imaging. However, it is less radiopaque and much more expensive than iodinated contrast. It should be noted that the US Food and Drug Administration has recently warned that gadolinium contrast is associated with a systemic fibrosing disorder (nephrogenic systemic fibrosis) in patients with poor renal function (usually but not only in patients on dialysis).⁸ Because of this risk, gadolinium contrast should generally be used only in patients with good renal function who have had a prior serious adverse reaction to iodinated contrast.

Insert a large-gauge intravenous line

Proper intravenous access is needed for contrast injection. To opacify the aorta properly, the contrast must be injected rapidly (3.0 mL/second) using a power injector.

We recommend at least an 18-gauge peripheral intravenous catheter in the forearm or a large-bore central line (an introducer or Hickman catheter). Smaller-gauge intravenous lines (often located in smaller veins such as in the wrist) and most central lines placed without radiographic or surgical assistance (eg, triple-lumen central catheters) cannot safely handle such a rapid rate without infiltration or embolization. Some peripherally inserted central catheters are designed to handle high injection rates and are typically labeled with the injection rate.

USE OF CT IN SPECIFIC ACUTE AORTIC SYNDROMES

Acute aortic dissection

Aortic dissection occurs when a tear in the intimal layer allows blood to enter and accumulate in the medial layer of the aorta, giving rise to a true lumen and a false lumen separated by an intimomedial flap. Dissection is considered to be acute if symptoms have been present for less than 2 weeks.⁹

Aortic dissections are often complex and can spiral around the aorta. The relationship of the intimomedial flap to the coronary arteries, aortic-arch branch vessels, and visceral branch vessels can be described on contrast enhanced, cardiac-gated CT scans. The true lumen is often smaller and more opacified with contrast than the false lumen; intimal calcification often surrounds the true lumen. Slender areas of low attenuation (“cobwebs”) are occasionally seen in the false lumen. The false lumen also has beaked edges where it meets the true lumen, which usually appears rounder.^2,10 The radiologist should state where the dissection begins and ends, determine if target vessel ischemia is evident, and assess for concomitant aneurysmal dilatation of the aorta. Contrast-enhanced, cardiac-gated multidetector CT of the aorta is necessary to properly evaluate the aortic root.

The Stanford system. Two systems exist for classifying the location of aortic dissections: the DeBakey system and the Stanford system (Figure 3). The Stanford system is more clinically useful and uses the following classification:

• 

  Type A dissections involve the ascending aorta and aortic arch, with or without involvement of the descending aorta (Figure 4, Figure 5)

• 

  Type B dissections involve the descending aorta beginning distal to the left subclavian artery (Figure 6).¹¹

Type A acute aortic dissection generally should be surgically repaired immediately to avoid fatal complications such as extension into the pericardium, pleural space, coronary arteries, or aortic valvular ring. It can also cause stroke, visceral ischemia, or circulatory failure.^2,11 Without surgery, 20% of patients with type A acute aortic dissection die within 24 hours, 30% within 48 hours, 40% within 1 week, and 50% within 1 month.² The initial target is the tear in the ascending aorta: typically the aortic root or the ascending aorta or both are replaced and the aortic valve is repaired if indicated (Figure 5). Further aortic repair can often be delayed or may not be needed if the disease does not progress with medical management.

Without surgery, type B acute aortic dissection has a 30-day mortality rate of 10%.² Patients who develop renal failure, ischemic leg symptoms, or visceral ischemic symptoms with acute aortic syndrome should undergo imaging of the chest, abdomen, and pelvis. Type B acute aortic dissection without end-organ ischemia is typically managed with antihypertensive drugs. Except in patients with Marfan syndrome, only a small minority of type B dissections progress to type A dissections.Urgent aortic repair, often with an endovascular stent graft, is needed if imaging shows visceral vessel occlusion or ischemia, acute vessel thrombosis, or progression of aneurysmal dilatation.

 

 

Aortic intramural hematoma

Intramural hematomas are believed to be caused by a spontaneous hemorrhage of the vaso vasorum into the medial layer. They appear as crescent-shaped areas of increased attenuation with eccentric aortic wall-thickening and displacement of intimal calcifications. Hematomas do not enhance after contrast administration, and unlike dissections, they usually do not spiral around the aorta.

Intramural hematomas can also be classified according to the Stanford system. Type A intramural hematomas (Figure 7) have traditionally been urgently treated with surgery because they can progress to dissection, aortic rupture, or pericardial, pleural, or mediastinal hemorrhage. Recent evidence suggests that some patients with a limited type A intramural hematoma may be managed with aggressive medical therapy with frequent serial imaging to monitor progression of disease.^2,12

Type B intramural hematomas are typically managed with medical therapy and often regress with time, although they can progress to dissection or aneurysmal formation.

Unstable thoracic aneurysm

Thoracic aneurysms are considered unstable if they are enlarging rapidly, show signs of imminent rupture, or have already ruptured (typically ,the rupture is contained if the patient survives for imaging).

An aortic aneurysm is defined as a permanent dilation at least 150% of normal size, or larger than 5 cm if in the thoracic aorta or larger than 3 cm if in the abdominal aorta. True aneurysms involve all three layers of the aorta and tend to be fusiform; pseudoaneurysms tend to be saccular and often arise after trauma, surgery, or infection. Dilations are more likely to rupture if they grow at least 1 cm per year or measure 6.0 cm or more (if in the ascending aorta) or 7.2 cm (if in the descending thoracic aorta).¹³

How big the aortic diameter needs to be before invasive treatment—surgery or an endovascular procedure—is indicated depends on the characteristics of the individual patient, and an experienced surgeon should be involved in the decision. Patients are typically treated when a dilation in the ascending aorta reaches 5.5 cm or when one in the descending aorta reaches 6.0 cm; patients with Marfan syndrome should undergo invasive treatment for aneurysms with smaller diameters.^14,15

CT signs of imminent rupture include a high-attenuating crescent in the wall of the aorta, discontinuous calcification in a circumferentially calcified aorta, an aorta that conforms to the neighboring vertebral body (“draped” aorta), and an eccentric nipple shape to the aorta.^16,17

CT signs of rupture include hemothorax (usually in the left hemithorax) and stranding of the periaortic fat (Figure 8).

Penetrating atherosclerotic ulcer

When an atherosclerotic ulcer penetrates the aortic intima and extends into the media, it can lead to dissection, an intramural hematoma, aneurysm, or aortic rupture. Many penetrating aortic ulcers are focal lesions of the descending thoracic aorta. On contrast-enhanced, cardiac-gated CT they appear as contrast-filled irregular outpouchings of the aortic wall (Figure 9).^18,19

Typical patients are elderly, and many have coexisting atherosclerotic atheromata and aneurysmal disease. Some experts contend that most saccular aneurysms are caused by penetrating atherosclerotic ulcers.¹⁹

Surgery to stabilize disease is recommended for a penetrating ulcer that causes acute aortic syndrome, or in patients with hemodynamic instability, aortic rupture, distal embolization, or a rapidly enlarging aorta. For a penetrating ulcer that is found incidentally in a patient without acute aortic syndrome, medical management of risk factors is recommended, with annual follow-up to see if it enlarges.

FUTURE USES OF IMAGING IN PATIENTS WITH ACUTE CHEST PAIN

Multidetector CT systems are undergoing rapid technical advances, including the recently released dual x-ray source multidetector CT scanners and the expected multidetector CTs with 128 to 256 detector rows. These and other developments will improve temporal resolution and decrease radiation exposure. Calcium artifacts—which hinder the evaluation of coronary arteries that contain atherosclerotic calcifications—will be reduced, thereby improving the accuracy of diagnosing acute coronary disease. As clinical knowledge increases based on the experience gained from the new technology, indications for imaging may expand.

CT of the chest performed for aortic disease provides information about other organ systems that may be considered when evaluating the cause of chest pain.²⁰

Evaluating pulmonary artery embolism

Although current contrast-enhanced, cardiac-gated CT of the aorta is not ideal for assessing the pulmonary arteries, it can almost always rule out central pulmonary artery thromboemboli and evaluate the more distal pulmonary arteries in a more limited way.

‘Triple rule-out’ CT

Several institutions now use CT (typically with 64-row scanners) to simultaneously evaluate patients for coronary artery disease, acute aortic syndrome, and pulmonary embolism—or “triple rule-out CT.” The study can be performed with dual intravenous contrast bolus techniques with nongated contrast-enhanced CT of the pulmonary arteries, rapidly followed by cardiac-gated, contrast-enhanced CT of the aorta. The pulmonary arteries can be evaluated on the initial nongated study, and the aorta (including the aortic root) and the coronary arteries are evaluated on the cardiac-gated portion. The timing of the contrast bolus for optimal opacification of the pulmonary arteries and the coronary arteries has yet to be determined.

The usefulness of assessing all three vascular beds with a single study is currently still unclear and the protocol is currently not routinely performed at Cleveland Clinic. Its sensitivity, specificity, and cost-benefit ratio are also unclear and must be determined in prospective clinical trials, which are currently under way.²¹

CHICAGO — Dual-source computed tomography significantly reduces radiation exposure to patients undergoing heart scans, and eliminates the need for heart-slowing medications, according to a study presented at the annual meeting of the Radiological Society of North America.

Improved temporal resolution with dual-source CT improves diagnostic quality by significantly reducing cardiac motion artifacts, obviating the need for β-blockade, said Dr. U. Joseph Schoepf.

In addition, more effective ECG pulsing techniques and faster scan times available with dual-source CT (DSCT) significantly decrease radiation dose by an average of 10%, compared with conventional 64-slice CT, Dr. Schoepf said in an interview.

“Dual-source CT has built-in features that allow the operator to accurately tailor radiation dose to each patient,” said Dr. Schoepf, associate professor of radiology and medicine at the Medical University of South Carolina (MUSC) in Charleston.

In this study, the first 30 patients who underwent CT angiography with a DSCT scanner (SOMATOM Definition, Siemens Medical Solutions) were compared with the most recent 30 patients to undergo 64-slice CT angiography at MUSC.

“With the DSCT group, we were at the beginning of our learning curve, so by now we're even more facile in using the dual scanner than we were with the study patients,” Dr. Schoepf explained.

A fixed temporal resolution of 83 milliseconds, heart-rate adaptive pitch, and ECG pulsing were used with the DSCT in all cases. Temporal resolution at 64-slice CT was 165 milliseconds at a fixed pitch of 0.2.

With both scanners, the gantry rotation time was 330 milliseconds, collimation was 0.6 millimeters, and the injection protocol was triphasic.

A radiologist and a cardiologist who were blinded to the scanner type evaluated the coronary arteries for motion artifact using the American Heart Association segment model. Patient heart rate, radiation dose, and use of β-blockers were recorded.

“With the previous generation scanner, we still had to use β-blockers to slow heart rate to achieve good images,” Dr. Schoepf said in an interview. “We quickly learned that medications were not necessary with the DS scanner because of the faster shutter speed and better temporal resolution.”

The abandonment of ?-blockade simplifies procedural logistics, he said, explaining that the typical intravenous protocol requires having a nurse available and increases scan time because the drug is administered while the patient occupies the scanner table. “And it's always better to avoid giving drugs when you can,” he added.

The average computed tomography dose index (fundamental radiation dose parameter used in CT) volumes were 61 milligray (mGy) for patients aged 35–72 years and 53 mGy for patients aged 21–89 years, respectively (P < .001).

The average heart rates were 64 beats per minute among the control group and 73 beats per minute among those imaged with the dual scanner. β-Blockers were used in 12 of the 30 patients scanned with 64-slice CT; none were used in the DSCT group.

Cardiac motion artifacts were observed in 24% of coronary segments in 64-slice CT patients, compared with 9% of segments in the DSCT arm. In each group, data sets were completely void of motion artifacts in 3 of 30 and 12 of 30 patients, respectively.

“Overall, the diagnostic quality was better in the DSCT group despite the faster heart rates,” said Dr. Schoepf, who disclosed that he is a consultant to and has received research support from Siemens Medical Solutions and the imaging contrast divisions of Bayer, GE Healthcare, and Bracco Diagnostics. However, no outside funding was used for the current study or the scanners used in it, he said.

“With another step in the evolution of medical imaging, we're closing the gap from invasive to noninvasive diagnostic catheterization and getting to the point of being able to get the same diagnostic information, particularly for excluding coronary artery disease,” Dr. Schoepf said. “But the investment of around &dollar;2.6 million for a dual-source CT probably is only worth it if you want to exploit the particular capabilities of this device, which include the dedicated cardiac, vascular, and dual-energy applications.”

The SOMATOM Definition has been available in the United States since early 2006.

Document

70020_fx1.sml

DSCT (right) of the pulmonary vein shows clearer delineation of all segments, compared with single-source 64-slice CT (left). Photos courtesy Dr. U. Joseph Schoepf

CHICAGO — Dual-source computed tomography significantly reduces radiation exposure to patients undergoing heart scans, and eliminates the need for heart-slowing medications, according to a study presented at the annual meeting of the Radiological Society of North America.

Improved temporal resolution with dual-source CT improves diagnostic quality by significantly reducing cardiac motion artifacts, obviating the need for β-blockade, said Dr. U. Joseph Schoepf.

In addition, more effective ECG pulsing techniques and faster scan times available with dual-source CT (DSCT) significantly decrease radiation dose by an average of 10%, compared with conventional 64-slice CT, Dr. Schoepf said in an interview.

“Dual-source CT has built-in features that allow the operator to accurately tailor radiation dose to each patient,” said Dr. Schoepf, associate professor of radiology and medicine at the Medical University of South Carolina (MUSC) in Charleston.

In this study, the first 30 patients who underwent CT angiography with a DSCT scanner (SOMATOM Definition, Siemens Medical Solutions) were compared with the most recent 30 patients to undergo 64-slice CT angiography at MUSC.

“With the DSCT group, we were at the beginning of our learning curve, so by now we're even more facile in using the dual scanner than we were with the study patients,” Dr. Schoepf explained.

A fixed temporal resolution of 83 milliseconds, heart-rate adaptive pitch, and ECG pulsing were used with the DSCT in all cases. Temporal resolution at 64-slice CT was 165 milliseconds at a fixed pitch of 0.2.

With both scanners, the gantry rotation time was 330 milliseconds, collimation was 0.6 millimeters, and the injection protocol was triphasic.

A radiologist and a cardiologist who were blinded to the scanner type evaluated the coronary arteries for motion artifact using the American Heart Association segment model. Patient heart rate, radiation dose, and use of β-blockers were recorded.

“With the previous generation scanner, we still had to use β-blockers to slow heart rate to achieve good images,” Dr. Schoepf said in an interview. “We quickly learned that medications were not necessary with the DS scanner because of the faster shutter speed and better temporal resolution.”

The abandonment of ?-blockade simplifies procedural logistics, he said, explaining that the typical intravenous protocol requires having a nurse available and increases scan time because the drug is administered while the patient occupies the scanner table. “And it's always better to avoid giving drugs when you can,” he added.

The average computed tomography dose index (fundamental radiation dose parameter used in CT) volumes were 61 milligray (mGy) for patients aged 35–72 years and 53 mGy for patients aged 21–89 years, respectively (P < .001).

The average heart rates were 64 beats per minute among the control group and 73 beats per minute among those imaged with the dual scanner. β-Blockers were used in 12 of the 30 patients scanned with 64-slice CT; none were used in the DSCT group.

Cardiac motion artifacts were observed in 24% of coronary segments in 64-slice CT patients, compared with 9% of segments in the DSCT arm. In each group, data sets were completely void of motion artifacts in 3 of 30 and 12 of 30 patients, respectively.

“Overall, the diagnostic quality was better in the DSCT group despite the faster heart rates,” said Dr. Schoepf, who disclosed that he is a consultant to and has received research support from Siemens Medical Solutions and the imaging contrast divisions of Bayer, GE Healthcare, and Bracco Diagnostics. However, no outside funding was used for the current study or the scanners used in it, he said.

“With another step in the evolution of medical imaging, we're closing the gap from invasive to noninvasive diagnostic catheterization and getting to the point of being able to get the same diagnostic information, particularly for excluding coronary artery disease,” Dr. Schoepf said. “But the investment of around &dollar;2.6 million for a dual-source CT probably is only worth it if you want to exploit the particular capabilities of this device, which include the dedicated cardiac, vascular, and dual-energy applications.”

The SOMATOM Definition has been available in the United States since early 2006.

Document

70020_fx1.sml

DSCT (right) of the pulmonary vein shows clearer delineation of all segments, compared with single-source 64-slice CT (left). Photos courtesy Dr. U. Joseph Schoepf

CHICAGO — Dual-source computed tomography significantly reduces radiation exposure to patients undergoing heart scans, and eliminates the need for heart-slowing medications, according to a study presented at the annual meeting of the Radiological Society of North America.

Improved temporal resolution with dual-source CT improves diagnostic quality by significantly reducing cardiac motion artifacts, obviating the need for β-blockade, said Dr. U. Joseph Schoepf.

In addition, more effective ECG pulsing techniques and faster scan times available with dual-source CT (DSCT) significantly decrease radiation dose by an average of 10%, compared with conventional 64-slice CT, Dr. Schoepf said in an interview.

“Dual-source CT has built-in features that allow the operator to accurately tailor radiation dose to each patient,” said Dr. Schoepf, associate professor of radiology and medicine at the Medical University of South Carolina (MUSC) in Charleston.

In this study, the first 30 patients who underwent CT angiography with a DSCT scanner (SOMATOM Definition, Siemens Medical Solutions) were compared with the most recent 30 patients to undergo 64-slice CT angiography at MUSC.

“With the DSCT group, we were at the beginning of our learning curve, so by now we're even more facile in using the dual scanner than we were with the study patients,” Dr. Schoepf explained.

A fixed temporal resolution of 83 milliseconds, heart-rate adaptive pitch, and ECG pulsing were used with the DSCT in all cases. Temporal resolution at 64-slice CT was 165 milliseconds at a fixed pitch of 0.2.

With both scanners, the gantry rotation time was 330 milliseconds, collimation was 0.6 millimeters, and the injection protocol was triphasic.

A radiologist and a cardiologist who were blinded to the scanner type evaluated the coronary arteries for motion artifact using the American Heart Association segment model. Patient heart rate, radiation dose, and use of β-blockers were recorded.

“With the previous generation scanner, we still had to use β-blockers to slow heart rate to achieve good images,” Dr. Schoepf said in an interview. “We quickly learned that medications were not necessary with the DS scanner because of the faster shutter speed and better temporal resolution.”

The abandonment of ?-blockade simplifies procedural logistics, he said, explaining that the typical intravenous protocol requires having a nurse available and increases scan time because the drug is administered while the patient occupies the scanner table. “And it's always better to avoid giving drugs when you can,” he added.

The average computed tomography dose index (fundamental radiation dose parameter used in CT) volumes were 61 milligray (mGy) for patients aged 35–72 years and 53 mGy for patients aged 21–89 years, respectively (P < .001).

The average heart rates were 64 beats per minute among the control group and 73 beats per minute among those imaged with the dual scanner. β-Blockers were used in 12 of the 30 patients scanned with 64-slice CT; none were used in the DSCT group.

Cardiac motion artifacts were observed in 24% of coronary segments in 64-slice CT patients, compared with 9% of segments in the DSCT arm. In each group, data sets were completely void of motion artifacts in 3 of 30 and 12 of 30 patients, respectively.

“Overall, the diagnostic quality was better in the DSCT group despite the faster heart rates,” said Dr. Schoepf, who disclosed that he is a consultant to and has received research support from Siemens Medical Solutions and the imaging contrast divisions of Bayer, GE Healthcare, and Bracco Diagnostics. However, no outside funding was used for the current study or the scanners used in it, he said.

“With another step in the evolution of medical imaging, we're closing the gap from invasive to noninvasive diagnostic catheterization and getting to the point of being able to get the same diagnostic information, particularly for excluding coronary artery disease,” Dr. Schoepf said. “But the investment of around &dollar;2.6 million for a dual-source CT probably is only worth it if you want to exploit the particular capabilities of this device, which include the dedicated cardiac, vascular, and dual-energy applications.”

The SOMATOM Definition has been available in the United States since early 2006.

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DSCT (right) of the pulmonary vein shows clearer delineation of all segments, compared with single-source 64-slice CT (left). Photos courtesy Dr. U. Joseph Schoepf

CHICAGO — A second multicenter trial has shown that noninvasive CT angiography is highly accurate in assessing coronary artery disease when compared with conventional invasive angiography.

The per-vessel negative predictive value of 64-slice coronary CT angiography (CCTA) was 97% for identifying blockages greater than 50%, and 99% for blockages greater than 70%, when measured in 232 patients with typical or atypical chest pain in the Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography (ACCURACY) trial. Positive predictive values were 51% and 33%, respectively, Dr. James K. Min and his associates reported at the annual meeting of the Radiological Society of North America.

“The ACCURACY results [obtained] in a prospective, multicenter fashion definitively establish the high diagnostic accuracy and high negative predictive value of 64-detector-row CT angiography in chest pain patients with intermediate prevalence of coronary artery disease,” said Dr. Min, director of the cardiac CT laboratory at New York-Presbyterian Hospital.

The findings echo those of the recent Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography (CORE-64) trial, in which CT angiography had a 91% positive predictive value and an 83% negative predictive value for identifying significant coronary artery stenoses. CORE-64 was the first large, multicenter trial of the 64-slice technology for coronary angiography, but was criticized by some attendees at the annual scientific sessions of the American Heart Association where it was presented (CARDIOLOGY NEWS, Dec. 2007, p. 1). Concerns were raised that the radiation dose from repeated CT scans could pose a potential cancer risk. No such concerns were raised at the radiology meeting.

To reduce the amount of radiation given to patients in the ACCURACY trial, investigators used a radiation dose-reduction algorithm called EKG modulation that reduces CT angiography radiation by about 40%, Dr. Min said in an interview. The radiation dose per patient was about 10–15 millisieverts (mSv), which is about twice that of an invasive coronary angiogram and about half that of a noninvasive thallium stress test.

Since the trial began, a new algorithm called perspective axial gating has been commercially released and is reported to reduce exposure by 90%, to about 2–4 mSv. Both algorithms work by activating the CT scanner during select parts of the cardiac cycle only, Dr. Min said. For comparison, New York City residents are exposed to about 3 mSv of radiation annually through background exposure.

Neither study used CT angiography for screening. “I believe very emphatically that the data to date don't support CT angiography as a screening tool at all,” Dr. Min said. “In asymptomatic patients, we don't have any data of what to do with the results, and if treatment benefits them.”

CT angiography is of greatest benefit for patients without known coronary disease who have low or intermediate pretest risk. “If you have a high pretest suspicion that someone has coronary artery disease, then direct progression to invasive coronary angiography or even myocardial perfusion imaging is probably a better alternative,” he said.

The ACCURACY trial was unique in that it included all coronary artery segments in its analysis and all patients irrespective of their baseline coronary calcium score. In the CORE-64 trial, stented segments were excluded, as were patients with a calcium score higher than 600. As a result, the ACCURACY findings of high diagnostic accuracy are even more impressive and representative of actual clinical usage, Dr. Min said.

Between May 2006 and January 2007, ACCURACY investigators performed CCTA prior to conventional quantitative coronary angiography (QCA) on 232 patients who had typical or atypical chest pain and had been referred for evaluation at 16 U.S. centers. The images were obtained on a GE Healthcare LightSpeed VCT CT scanner, and analyzed at 15 different locations throughout the coronary tree. The investigators used equipment made by GE Healthcare, which sponsored the study. Dr. Min is on the speakers' bureau for GE Healthcare.

Three independent radiologists interpreted the CCTA images, and one independent radiologist interpreted the QCA images, Dr. Min said.

The patients' mean age was 57 years (range 31–82 years); 138 were male, 203 were white, and 13 were black, and their average body mass index was 31 kg/m

QCA detected 82 blockages greater than 50% in 55 patients and 31 blockages greater than 70% in 34 patients.

For noninvasive CCTA, per-patient sensitivity was 93% and specificity was 82% for blockages greater than 50%; sensitivity was 91% and specificity was 84% for blockages greater than 70%, Dr. Min said.

CHICAGO — A second multicenter trial has shown that noninvasive CT angiography is highly accurate in assessing coronary artery disease when compared with conventional invasive angiography.

The per-vessel negative predictive value of 64-slice coronary CT angiography (CCTA) was 97% for identifying blockages greater than 50%, and 99% for blockages greater than 70%, when measured in 232 patients with typical or atypical chest pain in the Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography (ACCURACY) trial. Positive predictive values were 51% and 33%, respectively, Dr. James K. Min and his associates reported at the annual meeting of the Radiological Society of North America.

“The ACCURACY results [obtained] in a prospective, multicenter fashion definitively establish the high diagnostic accuracy and high negative predictive value of 64-detector-row CT angiography in chest pain patients with intermediate prevalence of coronary artery disease,” said Dr. Min, director of the cardiac CT laboratory at New York-Presbyterian Hospital.

The findings echo those of the recent Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography (CORE-64) trial, in which CT angiography had a 91% positive predictive value and an 83% negative predictive value for identifying significant coronary artery stenoses. CORE-64 was the first large, multicenter trial of the 64-slice technology for coronary angiography, but was criticized by some attendees at the annual scientific sessions of the American Heart Association where it was presented (CARDIOLOGY NEWS, Dec. 2007, p. 1). Concerns were raised that the radiation dose from repeated CT scans could pose a potential cancer risk. No such concerns were raised at the radiology meeting.

To reduce the amount of radiation given to patients in the ACCURACY trial, investigators used a radiation dose-reduction algorithm called EKG modulation that reduces CT angiography radiation by about 40%, Dr. Min said in an interview. The radiation dose per patient was about 10–15 millisieverts (mSv), which is about twice that of an invasive coronary angiogram and about half that of a noninvasive thallium stress test.

Since the trial began, a new algorithm called perspective axial gating has been commercially released and is reported to reduce exposure by 90%, to about 2–4 mSv. Both algorithms work by activating the CT scanner during select parts of the cardiac cycle only, Dr. Min said. For comparison, New York City residents are exposed to about 3 mSv of radiation annually through background exposure.

Neither study used CT angiography for screening. “I believe very emphatically that the data to date don't support CT angiography as a screening tool at all,” Dr. Min said. “In asymptomatic patients, we don't have any data of what to do with the results, and if treatment benefits them.”

CT angiography is of greatest benefit for patients without known coronary disease who have low or intermediate pretest risk. “If you have a high pretest suspicion that someone has coronary artery disease, then direct progression to invasive coronary angiography or even myocardial perfusion imaging is probably a better alternative,” he said.

The ACCURACY trial was unique in that it included all coronary artery segments in its analysis and all patients irrespective of their baseline coronary calcium score. In the CORE-64 trial, stented segments were excluded, as were patients with a calcium score higher than 600. As a result, the ACCURACY findings of high diagnostic accuracy are even more impressive and representative of actual clinical usage, Dr. Min said.

Between May 2006 and January 2007, ACCURACY investigators performed CCTA prior to conventional quantitative coronary angiography (QCA) on 232 patients who had typical or atypical chest pain and had been referred for evaluation at 16 U.S. centers. The images were obtained on a GE Healthcare LightSpeed VCT CT scanner, and analyzed at 15 different locations throughout the coronary tree. The investigators used equipment made by GE Healthcare, which sponsored the study. Dr. Min is on the speakers' bureau for GE Healthcare.

Three independent radiologists interpreted the CCTA images, and one independent radiologist interpreted the QCA images, Dr. Min said.

The patients' mean age was 57 years (range 31–82 years); 138 were male, 203 were white, and 13 were black, and their average body mass index was 31 kg/m

QCA detected 82 blockages greater than 50% in 55 patients and 31 blockages greater than 70% in 34 patients.

For noninvasive CCTA, per-patient sensitivity was 93% and specificity was 82% for blockages greater than 50%; sensitivity was 91% and specificity was 84% for blockages greater than 70%, Dr. Min said.

CHICAGO — A second multicenter trial has shown that noninvasive CT angiography is highly accurate in assessing coronary artery disease when compared with conventional invasive angiography.

The per-vessel negative predictive value of 64-slice coronary CT angiography (CCTA) was 97% for identifying blockages greater than 50%, and 99% for blockages greater than 70%, when measured in 232 patients with typical or atypical chest pain in the Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography (ACCURACY) trial. Positive predictive values were 51% and 33%, respectively, Dr. James K. Min and his associates reported at the annual meeting of the Radiological Society of North America.

“The ACCURACY results [obtained] in a prospective, multicenter fashion definitively establish the high diagnostic accuracy and high negative predictive value of 64-detector-row CT angiography in chest pain patients with intermediate prevalence of coronary artery disease,” said Dr. Min, director of the cardiac CT laboratory at New York-Presbyterian Hospital.

The findings echo those of the recent Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography (CORE-64) trial, in which CT angiography had a 91% positive predictive value and an 83% negative predictive value for identifying significant coronary artery stenoses. CORE-64 was the first large, multicenter trial of the 64-slice technology for coronary angiography, but was criticized by some attendees at the annual scientific sessions of the American Heart Association where it was presented (CARDIOLOGY NEWS, Dec. 2007, p. 1). Concerns were raised that the radiation dose from repeated CT scans could pose a potential cancer risk. No such concerns were raised at the radiology meeting.

To reduce the amount of radiation given to patients in the ACCURACY trial, investigators used a radiation dose-reduction algorithm called EKG modulation that reduces CT angiography radiation by about 40%, Dr. Min said in an interview. The radiation dose per patient was about 10–15 millisieverts (mSv), which is about twice that of an invasive coronary angiogram and about half that of a noninvasive thallium stress test.

Since the trial began, a new algorithm called perspective axial gating has been commercially released and is reported to reduce exposure by 90%, to about 2–4 mSv. Both algorithms work by activating the CT scanner during select parts of the cardiac cycle only, Dr. Min said. For comparison, New York City residents are exposed to about 3 mSv of radiation annually through background exposure.

Neither study used CT angiography for screening. “I believe very emphatically that the data to date don't support CT angiography as a screening tool at all,” Dr. Min said. “In asymptomatic patients, we don't have any data of what to do with the results, and if treatment benefits them.”

CT angiography is of greatest benefit for patients without known coronary disease who have low or intermediate pretest risk. “If you have a high pretest suspicion that someone has coronary artery disease, then direct progression to invasive coronary angiography or even myocardial perfusion imaging is probably a better alternative,” he said.

The ACCURACY trial was unique in that it included all coronary artery segments in its analysis and all patients irrespective of their baseline coronary calcium score. In the CORE-64 trial, stented segments were excluded, as were patients with a calcium score higher than 600. As a result, the ACCURACY findings of high diagnostic accuracy are even more impressive and representative of actual clinical usage, Dr. Min said.

Between May 2006 and January 2007, ACCURACY investigators performed CCTA prior to conventional quantitative coronary angiography (QCA) on 232 patients who had typical or atypical chest pain and had been referred for evaluation at 16 U.S. centers. The images were obtained on a GE Healthcare LightSpeed VCT CT scanner, and analyzed at 15 different locations throughout the coronary tree. The investigators used equipment made by GE Healthcare, which sponsored the study. Dr. Min is on the speakers' bureau for GE Healthcare.

Three independent radiologists interpreted the CCTA images, and one independent radiologist interpreted the QCA images, Dr. Min said.

The patients' mean age was 57 years (range 31–82 years); 138 were male, 203 were white, and 13 were black, and their average body mass index was 31 kg/m

QCA detected 82 blockages greater than 50% in 55 patients and 31 blockages greater than 70% in 34 patients.

For noninvasive CCTA, per-patient sensitivity was 93% and specificity was 82% for blockages greater than 50%; sensitivity was 91% and specificity was 84% for blockages greater than 70%, Dr. Min said.