Cleveland Clinic Journal of Medicine

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

But some have long suspected too-aggressive treatment would have an adverse effect—the so called “J curve” seen when drug effect is plotted against adverse outcome. The validity of this concept at the extreme is obvious: excessive hypotension or hypoglycemia is not clinically tolerated. So where is the cutoff between benefit and complications, where treatment becomes too aggressive and causes complications that outweigh the benefits?

In this issue of the Journal, Dr. Edward J. Filippone and colleagues discuss the treatment of hypertension with proposed aggressive but seemingly reasonable blood pressure targets. Surprisingly, interventional trials have not jibed with observational data that suggest a beneficial continuous relationship between blood-pressure-lowering within the physiologic range and cardiac outcomes. Potential explanations for this are many. Organs differ in their response to blood-pressure-lowering. The brain, despite considerable autoregulatory circulatory control, benefits from lowered blood pressure with reduced stroke frequency. The heart, uniquely dependent on diastolic flow for perfusion, can be compromised with aggressive lowering of the diastolic pressure, ie, to below 85 mm Hg, although lowering the systolic pressure may be beneficial. Specific drugs may have beneficial or detrimental effects, particularly in combinations needed to control blood pressure in patients with stiff arteries and multiple comorbidities.

In the clinic, attention to the individual’s physiology and clinical response to therapy needs to be paramount in our mind as we determine treatment targets—possibly a source of dissonance, as we are held accountable to external agencies for our practice performance in a depersonalized manner.

Proposed aggressive blood pressure targets remain contentious, but a far greater problem is that we are still not successfully treating hypertension to even a conservative target. In a recent analysis of the National Health and Nutrition Examination Survey database from 2003 to 2006, only about 44% of treated hypertensive patients were appropriately controlled.¹ As a community of physicians, we have a way to go before we hit the J point.

But some have long suspected too-aggressive treatment would have an adverse effect—the so called “J curve” seen when drug effect is plotted against adverse outcome. The validity of this concept at the extreme is obvious: excessive hypotension or hypoglycemia is not clinically tolerated. So where is the cutoff between benefit and complications, where treatment becomes too aggressive and causes complications that outweigh the benefits?

In this issue of the Journal, Dr. Edward J. Filippone and colleagues discuss the treatment of hypertension with proposed aggressive but seemingly reasonable blood pressure targets. Surprisingly, interventional trials have not jibed with observational data that suggest a beneficial continuous relationship between blood-pressure-lowering within the physiologic range and cardiac outcomes. Potential explanations for this are many. Organs differ in their response to blood-pressure-lowering. The brain, despite considerable autoregulatory circulatory control, benefits from lowered blood pressure with reduced stroke frequency. The heart, uniquely dependent on diastolic flow for perfusion, can be compromised with aggressive lowering of the diastolic pressure, ie, to below 85 mm Hg, although lowering the systolic pressure may be beneficial. Specific drugs may have beneficial or detrimental effects, particularly in combinations needed to control blood pressure in patients with stiff arteries and multiple comorbidities.

In the clinic, attention to the individual’s physiology and clinical response to therapy needs to be paramount in our mind as we determine treatment targets—possibly a source of dissonance, as we are held accountable to external agencies for our practice performance in a depersonalized manner.

Proposed aggressive blood pressure targets remain contentious, but a far greater problem is that we are still not successfully treating hypertension to even a conservative target. In a recent analysis of the National Health and Nutrition Examination Survey database from 2003 to 2006, only about 44% of treated hypertensive patients were appropriately controlled.¹ As a community of physicians, we have a way to go before we hit the J point.

But some have long suspected too-aggressive treatment would have an adverse effect—the so called “J curve” seen when drug effect is plotted against adverse outcome. The validity of this concept at the extreme is obvious: excessive hypotension or hypoglycemia is not clinically tolerated. So where is the cutoff between benefit and complications, where treatment becomes too aggressive and causes complications that outweigh the benefits?

In this issue of the Journal, Dr. Edward J. Filippone and colleagues discuss the treatment of hypertension with proposed aggressive but seemingly reasonable blood pressure targets. Surprisingly, interventional trials have not jibed with observational data that suggest a beneficial continuous relationship between blood-pressure-lowering within the physiologic range and cardiac outcomes. Potential explanations for this are many. Organs differ in their response to blood-pressure-lowering. The brain, despite considerable autoregulatory circulatory control, benefits from lowered blood pressure with reduced stroke frequency. The heart, uniquely dependent on diastolic flow for perfusion, can be compromised with aggressive lowering of the diastolic pressure, ie, to below 85 mm Hg, although lowering the systolic pressure may be beneficial. Specific drugs may have beneficial or detrimental effects, particularly in combinations needed to control blood pressure in patients with stiff arteries and multiple comorbidities.

In the clinic, attention to the individual’s physiology and clinical response to therapy needs to be paramount in our mind as we determine treatment targets—possibly a source of dissonance, as we are held accountable to external agencies for our practice performance in a depersonalized manner.

Proposed aggressive blood pressure targets remain contentious, but a far greater problem is that we are still not successfully treating hypertension to even a conservative target. In a recent analysis of the National Health and Nutrition Examination Survey database from 2003 to 2006, only about 44% of treated hypertensive patients were appropriately controlled.¹ As a community of physicians, we have a way to go before we hit the J point.

Medical tourism is on the rise,¹ and since medical tourists are often very important persons (VIPs), hospital-based physicians may be more likely to care for celebrities, royalty, and political leaders. But even in hospitals that do not see medical tourists, physicians will often care for VIP patients such as hospital trustees and board members, prominent physicians, and community leaders.^2–4

However, caring for VIPs raises special issues and challenges. In a situation often referred to as the “VIP syndrome,”^5–9 a patient’s special social or political status—or our perceptions of it—induces changes in behaviors and clinical practice that create a “vicious circle of VIP pressure and staff withdrawal”⁹ that can lead to poor outcomes.

Based on their experience caring for three American presidents, Mariano and McLeod⁷ offered three directives for caring for VIPs:

• Vow to value your medical skills and judgment
• Intend to command the medical aspects of the situation
• Practice medicine the same way for all your patients.⁷

In this paper, we hope to extend the sparse literature on the VIP syndrome by proposing nine principles of caring for VIPs, with recommendations specific to the type of VIP where applicable.

PRINCIPLE 1: DON’T BEND THE RULES

Caring for VIPs creates pressures to change usual clinical wisdom and practices. But it is essential to resist changing time-honored, effective clinical judgment and practices.

To preserve usual clinical practice, clinicians must be constantly vigilant as to whether their judgment is being clouded by the circumstances. As Smith and Shesser noted in 1988, “Since the standard operating procedures […] are designed for the efficient delivery of high-quality care, any deviation from these procedures increases the possibility that care may be compromised.”⁵ In other words, suspending usual practice when caring for a VIP patient can imperil the patient.^2–5,10,11 When caring for VIP physicians, for example, circumventing usual medical and administrative routines and the difficulties that caring for colleagues poses for nurses and physicians have led to poor medical care and outcomes, as well as to hostility.^2–4

A striking example of the potential effects of VIP syndrome is the death of Eleanor Roosevelt from miliary tuberculosis acutissima: she was misdiagnosed with aplastic anemia on the basis of only the results of a bone marrow aspirate study, and she was treated with steroids. The desire to spare this VIP patient the discomfort of a bone marrow biopsy, on which tuberculous granulomata were more likely to have been seen, caused the true diagnosis to be missed and resulted in the administration of a hazardous medication.¹¹ The hard lesson here is that we must resist the pressure to simplify or change customary medical care to avoid causing a VIP patient discomfort or putting the patient through a complex procedure.

We recommend discussing these issues explicitly with the VIP patient and family at the outset so that everyone can appreciate the importance of usual care. An early conversation can communicate the clinician’s experience in the care of such patients and can be reassuring. As Smith and Shesser noted, “Usually, the VIP is relieved if the physician states explicitly, ‘I am going to treat you as I would any other patient.’ ”⁵

PRINCIPLE 2: WORK AS A TEAM, NOT IN ‘SILOS’

Teamwork is essential for good clinical outcomes, ^12–14 especially when the clinical problem is complex, as is often the case when people travel long distances to receive care. All consultants involved in the patient’s care must not only attend to their own clinical issues but also communicate amply with their colleagues.

At the same time, we must recognize that medical practice “is not a committee process; it must be clear at all times which physician is responsible for directing clinical care.”⁵ One physician must be in charge of the overall care. Seeking the input of other physicians must not be allowed to diffuse responsibility. The primary attending physician must speak with the consultants, summarize their views, and then communicate the findings and the plan of care to the patient and family.

Paradoxically, teamwork can be challenged when circumstances lead consultants to defer communicating directly with the family in favor of the primary physician’s doing so. Similarly, consultants must avoid any temptation to simply “do their thing” and not communicate with one another, thereby potentially offering “siloed,” discoordinated care.

We propose designating a primary physician to take charge of the care and the communication. This physician must have the time to talk with each team member about how best to communicate the individual findings to the patient and family. At times, the primary physician may also ask the consultants to communicate directly with the patient and family when needed.

PRINCIPLE 3: COMMUNICATE, COMMUNICATE, COMMUNICATE

As a corollary of principle 2, heightened communication is essential when caring for VIP patients. Communication should include the patient, the family, visiting physicians who accompany the patient, and the physicians providing care. Communicating with the media and with other uninvolved individuals is addressed in principle 4.

The logistic and security challenges of transporting VIP patients through the hospital for tests or therapy demand increased communication. Scheduling a computed tomographic scan may involve arranging an off-hours appointment in the radiology department (to minimize security risks and disruption to other patients’ schedules), assuring the off-hours availability of allied health providers to accompany the patient, alerting hospital security, and discussing the appointment with the patient and the patient’s entourage.

PRINCIPLE 4: CAREFULLY MANAGE COMMUNICATION WITH THE MEDIA

Although the news media and the public may demand medical information about patients who are celebrities, political luminaries, or royalty, the confidentiality of the physician-patient relationship must be protected. The release of health information is at the sole discretion of the patient or a designated surrogate.

The care of President Ronald Reagan after the 1981 assassination attempt is a benchmark of how to release information to the public.¹⁰ A single physician held regularly scheduled press conferences, and these were intentionally held away from the site of the President’s care.

Designating a senior hospital physician to communicate with the media is desirable, and the physician-spokesperson can call on specialists from the patient care team (eg, a critical care physician), when appropriate, to provide further information.

Early implementation of an explicit and structured media communication plan is advisable, especially when the VIP patient is a political or royal figure for whom public clamor for information will be vigorous. A successful communication strategy balances the public’s demand for information with the need to protect the patient’s confidentiality.

PRINCIPLE 5: RESIST ‘CHAIRPERSON’S SYNDROME’

“Chairperson’s syndrome”⁵ is pressure for the VIP patient to be cared for by the department chairperson. The pressure may come from the patient, family, or attendants, who may assume that the chairperson is the best doctor for the clinical circumstance. The pressure may also come from the chairperson, who feels the need to “take command” in a situation with high visibility. Nevertheless, designation of a chairperson to care for a VIP patient is appropriate only when the chairperson is indeed the clinician who has the most expertise in the patient’s clinical issues.

As in principle 1, in academic medical centers, we encourage the participation of trainees in the care of VIP patients because excluding them could disrupt the usual flow of care, and because trainees offer a currency and facility with the nuances of hospital practice and routine that are advantageous to the patient’s care.

PRINCIPLE 6: CARE SHOULD OCCUR WHERE IT IS MOST APPROPRIATE

Decisions about where to place the VIP patient during the medical visit can fall victim to the VIP syndrome if the expectations of the patient or family conflict with usual clinical practice and judgment about the optimal care venue.

For example, caring for the patient in a setting away from the mainstream clinical environment may offer the appeal of privacy or enhanced security but can under some circumstances impede optimal care, including prolonging the response time during emergencies and disrupting the optimal care routine and teamwork of allied health providers.

Critical care services and monitoring are best provided in the intensive care unit, and attempts to relocate the patient away from the intensive care unit should be resisted. We recommend a candid discussion of the importance of keeping the patient in the intensive care unit to ensure optimal care by a seasoned clinical team with short response times if urgencies should arise.

At the same time, a request to transfer a VIP patient to a special setting designed for private care with special amenities (eg, appealing room decor, adjacent sleeping rooms for family members, enhanced security) available in some hospitals^15–16 can be honored as soon as the patient’s condition permits. The benefits of such amenities are often greatly appreciated and can reduce stress and thereby promote recovery. The benefits of enhanced security in sequestered venues may especially drive the decision to move when clinically prudent (see principle 7).

PRINCIPLE 7: PROTECT THE PATIENT’S SECURITY

Providing security is another essential part of caring for VIPs, especially celebrities, political figures, and royalty. Protecting the patient from bodily harm requires special attention to the patient’s location, caregiver access, and other logistic matters.

As indicated in principle 6, the patient’s clinical needs are paramount in determining where the patient receives care. If the patient requires care in a mainstream hospital location such as the intensive care unit, modifications of the unit may be needed to alter access, to accommodate security personnel, and to restrict caregivers’ access to the patient. Modifications include structural changes to windows, special credentials (eg, badges) for essential providers, arranging transports within the hospital for elective procedures during off-hours, and providing around-the-clock security personnel near the patient.

As important as it is to protect VIP patients from bodily harm during the visit, it is equally important to protect them from attacks on confidentiality via unauthorized access to the electronic medical record, and this is perhaps the more difficult challenge, as examples of breaches abound.^10,17–19 Although the duty to protect against these breaches rests with the hospital, the use of “pop-ups” in the electronic medical record can flash a warning that only employees with legitimate clinical reasons should access the record. These warnings should also cite the penalties for unauthorized review of the record, which is supported by the Health Insurance Portability and Accountability Act (HIPAA). Access to celebrities’ health records could be restricted to a few predetermined health care providers.

PRINCIPLE 8: BE CAREFUL ABOUT ACCEPTING OR DECLINING GIFTS

VIP patients often present gifts to physicians, and giving gifts to doctors is a common and long-standing practice.^20,21 Patients offer gifts out of gratitude, affection, desperation, or the desire to garner special treatment or indebtedness. VIP patients from gifting cultures may be especially likely to offer gifts to their providers, and the gifts can be lavish.

The “ethical calculus”²¹ of whether to accept or decline a gift depends on the circumstances and on what motivates the offer, and the physician needs to consider the patient’s reasons for giving the gift.

In general, gifts should be accepted only with caution during the acute episode of care. The acceptance of a gift from a VIP patient or family member may be interpreted by the gift-giver as a sort of unspoken promise, and this misunderstanding may strain the physician-patient relationship, especially if the clinical course deteriorates.

Rather than accept a gift during an episode of acute care, we suggest that the physician graciously decline the gift and offer to accept the gift at the end of the episode of acute care—that is, if the offerer still feels so inclined and remembers. Explaining the reason for deferring the gift can decrease the risk of misunderstandings or of unmet expectations by the gift-giver. Also, deferring the acceptance of a gift allows the caregiver to affirm the commitment to excellent care that is free of gifts, thereby ensuring that the patient will be confident of a similar level of care by providers who have not been offered gifts.

On the other hand, declining a gift may cause more damage than accepting it, particularly if the VIP patient is from a culture in which refusing a gift is impolite.²² A sensible compromise may be to adopt the recommendations of the American Academy of Pediatrics²³—ie, attempt to appreciate appropriate gifts and graciously refuse those that are not.

PRINCIPLE 9: WORKING WITH THE PATIENT’S PERSONAL PHYSICIANS

VIP patients, perhaps especially royalty, may be accompanied by their own physicians and may also wish to bring in consultants from other institutions. Though this outside involvement poses challenges (eg, providing access to medical records, arranging briefings, attending bedside rounds), we believe it should be encouraged when the issue is raised. Furthermore, institutions and caregivers should anticipate these requests and identify potential outside consultants whose names can be volunteered if the issue arises.

Again, if VIP patients wish to involve physicians from outside the institution where they are receiving care, this should not be viewed as an expression of doubt about the care being received. Rather, we prefer to view it as an opportunity to validate current management or to entertain alternative approaches. Most often, when an outside consultant confirms the current medical care, this can have the beneficial effect of increasing confidence and facilitating management.

In a similar way, when VIP patients bring their own physician, whose judgment and care they trust, this represents an opportunity to engage the patient’s trusted physician-advisor in clinical decision-making and thus optimize communication with the patient. Collegial interactions with these physician-colleagues can facilitate communication and decision-making for the patient.